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Single incision access: a novel surgical approach to the extraction of impacted inferior third molars	The recent attention to quality of life and oral health care procedures reflects a renewed 'patient-based' approach to dealing with non-life-threatening conditions. In the current study, we proposed a novel surgical approach to the extraction of impacted inferior third molars (iMs3) through a randomised, blinded, split-mouth controlled clinical trial following the CONSORT guidelines. The novel surgical procedure, hereinafter referred to as single incision access (SIA), will be compared with our previously described flapless surgical approach (FSA). The predictor variable was the novel SIA approach, involving access through a single incision without removal of soft tissue, on the impacted iMs3. The primary endpoint was the acceleration of the iMs3 extraction healing time. The secondary endpoints were the incidences of pain and oedema as well as gum health (pocket probing depth and attached gingiva). The study was carried out on 84 teeth of 42 patients with both iMs3 impacted. The cohort was composed of 42% Caucasian males and 58% Caucasian females, aged 23.8 ± 7.9 (17-49) years. We observed faster recovery/wound-healing on the SIA side (33.6 ± 4.3 days) than at the FSA side (42.1 ± 5.4 days;	[ "To review the literature on the effect of different surgical flaps upon patient morbidity (pain perception, trismus, swelling and osteitis) after impacted third molar extraction. An electronic and complementary search of main databases and grey literature was performed up to January 2019 to retrieve randomized clinical trials. The Cochrane risk of bias assessment tool was used for methodological appraisal. A random-effects meta-analysis was conducted of pain perception and trismus. From the initially 1314 screened studies, only 11 were included in the qualitative synthesis, and 5 in the meta-analysis. There were no statistically significant differences in pain between the envelope and triangular flap designs over time, except on the sixth postoperative day, when the envelope flap proved more painful. Regarding trismus, statistically significant differences were observed on the seventh postoperative day, with greater mouth opening in the envelope flap group than in the triangular flap group. There were no clear differences in swelling and osteitis among the flap designs. Despite its limitations, the present meta-analysis found no clear differences in patient morbidity between the different flap designs.", "Pain, swelling, trismus, and alveolar osteitis often occur after removal of impacted third molar teeth. To minimize these complications a number of mucoperiosteal flap designs have been advocated, but, to date, a pedicle flap design has not been evaluated. In a randomized prospective split mouth study, 52 participants had bilateral symmetrically impacted mandibular third molars removed over two sessions. A buccal envelope or pedicle flap was randomly assigned to the left or right third molar site. Pre-and postoperative pain and swelling were recorded using a standardized visual analogue scale, trismus was measured as the maximum inter-incisal opening distance in millimetres and dry socket was assessed clinically. Greater continuous pain, pain on maximum opening, and oro-facial swelling were recorded with the pedicle flap design. Continuous pain resolved significantly faster with this flap design (p<0.05). Trismus was similar for both flap designs (p>0.05). Five cases of alveolar osteitis occurred with the envelope flap whilst no cases developed with the pedicle flap, but the incidence was too small for statistical analysis. The pedicle flap improved some aspects of postoperative pain experience and reduced the incidence of alveolar osteitis, but further investigation with a larger sample size is required to evaluate its significance.", "The aim of this study was to investigate the effects of two commonly used flap designs (envelope and triangular) used for the removal of mandibular third molars (M3) on postoperative morbidity. 19 patients with bilateral symmetrically impacted mandibular M3 were studied using a split mouth design. Swelling, pain and trismus measures were recorded on days 2, 7 and 14; periodontal indices were recorded on days 7 and 14, one final measure of probing depth on the distal aspect of the mandibular second molar (M2) was taken at the last follow up appointment. Data were analysed using the χ(2) test, the Mann-Whitney U-test and Pearson's correlations. The mean age of the patients was 21.4 ± 2.3 years (± SD). Facial swelling and the reduction in mouth opening were significantly greater in the early postoperative period (P<0.05) with pyramidal flap designs. There was no significant difference in pain scores, plaque accumulation and bleeding on probing indices between the two flap designs (P>0.05). Probing depth was significantly greater with envelope flaps in the early postoperative period (P<0.005). In conclusion, flap design in mandibular M3 surgery has an effect on postoperative recovery." ]
Anti-osteoporosis effects of a mixture of BPX and a tylenol	Osteoporosis is a metabolic skeletal disease characterized by lowered bone mineral density and quality, which lead to an increased risk of fracture. The aim of this study was to evaluate the anti-osteoporosis effects of a mixture (called BPX) of	[ "Osteoporosis diagnosis is based on bone mineral density (BMD) but bone remodeling is also a crucial issue. It can be assessed by bone turnover markers (BTMs). Their interest for the positive and etiological diagnosis of osteoporosis at baseline, and their predictive value for past asymptomatic vertebral fractures, were evaluated by a systematic review of the literature. Medline database was searched to identify all published reports analyzing BTMs and BMD or fractures. We conducted meta-analyses on BTMs levels according to osteoporotic status using random effects models. Moderate and negative correlations were found, mainly in postmenopausal women, between BTMs and BMD, especially with bone alkaline phosphatase (bone ALP), osteocalcin, serum C-terminal and urine N-terminal crosslinking telopeptides of type I collagen (sCTX and uNTX). Bone ALP and sCTX levels are higher in osteoporotic patients compared to controls. High levels of bone ALP in primary hyperparathyroidism and low levels of osteocalcin in endogenous hypercorticism are the most relevant data reported in endocrine diseases associated with osteoporosis. High levels of BTMs, especially osteocalcin, bone ALP or sCTX, may be associated with prevalent vertebral fractures. The diagnosis value of BTMs at baseline in osteoporosis is very low. The interest of BTMs for the etiological diagnostic of secondary osteoporosis has not been demonstrated. Data are lacking to address the interest of BTMs assessment to screen for vertebral fractures in asymptomatic patients with high risk factors of fractures.", "Bone turnover markers (BTMs) reflect the metabolic activity of bone tissue and can be used to monitor osteoporosis therapy. To adequately interpret BTMs, method-specific reference intervals are needed. We aimed to determine reference intervals for serum concentrations of intact amino-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BAP) and carboxy-terminal telopeptide of type I collagen (CTX). We established a healthy reference population of 1107 men as well as 382 pre- and 450 postmenopausal women, who participated in the first follow-up of the Study of Health in Pomerania. Serum PINP, BAP and CTX concentrations were measured on the IDS-iSYS Automated System (Immunodiagnostic Systems, Frankfurt am Main, Germany). The reference interval was defined as the central 95% range. We determined age-specific reference intervals for PINP, BAP, and CTX for men by quantile regression. Reference intervals for women were age-independent. Reference intervals for men for PINP and CTX decreased with age (25-29year-old men: PINP 31.1-95.9ng/mL, CTX 0.12-0.83ng/mL; 75-79year-old men: PINP 15.7-68.1ng/mL, CTX 0.05-0.58ng/mL). The reference interval for men for BAP did not significantly change with age (25-29year-old men: 7.4-27.7ng/mL; 75-79year-old men: 7.6-24.4ng/mL). The reference intervals for 30-54year-old premenopausal women were: PINP 19.3-76.3ng/mL, BAP 6.0-22.7ng/mL, and CTX 0.05-0.67ng/mL. The reference intervals for 50-79year-old postmenopausal women were: PINP 18.2-102.3ng/mL, BAP 8.1-31.6ng/mL, and CTX 0.09-1.05ng/mL. An intensively characterized, large reference population free of bone-related diseases allowed us to determine robust reference intervals for serum concentrations of PINP, BAP and CTX. Our normative data may aid to interpret bone turnover in adult men and pre- and postmenopausal women.", "Serum tartrate-resistant acid phosphatase (TRACP) 5b was investigated for use as a marker for diagnosis of giant cell tumor (GCT) of bone and for detection of its recurrence.Four patients with GCT of bone who were initially referred to our hospital were classified as a primary group. Three patients who had local recurrence following curettage were classified as a local recurrence group. Five with no recurrence were classified as a no-recurrence group. Eighteen patients with primary and metastatic malignant bone tumors were also enrolled in the study as a control group. Serum TRACP 5b was measured before the biopsy in all patients and was measured periodically after the operation in patients with GCT of bone. Student t-tests were used for statistical analyses.TRACP 5b was greater than 1500 Um/dL in all primary group patients. Mean TRACP 5b values decreased gradually with post-operative time, showing lower values until local recurrence. The mean value of TRACP 5b of the local recurrence group (753 ± 68.7 mU/dL) was significantly higher than that of the no-recurrence group (340.6 ± 78.3 mU/dL). The mean value of TRACP 5b of the control group (466.9 ± 130.3 mU/dL) was much lower than that of the primary group and markedly lower than that of the local recurrence group. However, no significant difference was found between the no-recurrence group and the control group.Serum TRACP 5b is a useful and convenient marker for diagnosing GCT of bone and for predicting its recurrence.", "Background: Osteoporosis is a skeletal disease that is associated with a reduction in bone mass and microstructures and deterioration of bone tissue. It is also associated with an increased risk of fracture that is the most important complication of osteoporosis. The knowledge about costs and economic aspects of osteoporosis plays an important role in making policies and planning measures for the prevention and management of this disease; hence, this study systematically investigated the available evidence on the costs associated with osteoporosis worldwide. Methods: In this systematic review, electronic searches were performed on various online databases, including PubMed, Embase, Scopus, web of science, ProQuest, and Cochrane. The timeframe selected for searching articles was from 1980 to 2018. Results: Of a total of 1989 papers, 28 papers were included in the study on the basis of inclusion criteria. Based on the data extracted from the mentioned studies, the mean age of people with osteoporotic fractures was 50 years, with the highest costs associated with hip fractures. Conclusion: Our review indicated that the cost of osteoporosis carries a significant economic burden on countries in the world. The main cost drivers in this study were Fracture-related costs. The direct annual cost of treating osteoporotic fractures of people on average is reported to be between 5000 and 6500 billion USD in Canada, Europe and the USA alone, not taking into account indirect costs such as disability and loss of productivity. Prevention of this disease can significantly reduce the costs incurred by the health system.", "Bone mass density (BMD) is still the gold standard for the diagnosis of osteoporosis, but bone turnover markers (BTMs) can provide helpful information regarding the bone remodeling process. The aim of this study was to determine the correlations between BMD and serum levels of BTMs (tartrate-resistant acid phosphatase-5b [TRAP-5b]), bone-specific alkaline phosphatase (BSAP), estradiol (E2), and magnesium (Mg[2+]) ion concentrations in postmenopausal osteoporotic women as compared to healthy postmenopausal subjects. The study included 132 women with postmenopausal osteoporosis and 81 healthy postmenopausal women without osteoporosis. Dual-energy X-ray absorptiometry scan assessed BMD at different skeleton sites. Serum levels of E2, BSAP, and TRAP-5b were measured by enzyme linked immunosorbent assay. Serum levels of Mg(2+) were determined using the colorimetric spectrometry technique. Serum levels of BTMs were significantly higher in osteoporotic women than in controls. BSAP has a moderate sensitivity (76.5%) and specificity (84.3%) (cutoff point 21.27 U/L). At a cutoff point of 3.45 U/L, TRAP-5b presented a sensitivity of 86.3% and a higher specificity of 90.6%. Osteoporotic patients showed significantly lower concentrations of serum Mg(2+) than the control group. Mg(2+) levels correlated positively with BMD values (r=0.747, P<0.0001). Furthermore, Mg(2+) concentrations correlated positively with E2 levels (r=0.684, P<0.0001). Spine BMD correlated negatively with BSAP levels (r=-0.36, P<0.0001). Our study showed that BMD correlates negatively with BTMs and positively with E2 and Mg(2+) levels. TRAP-5b presents a good specificity in identifying patients with postmenopausal osteoporosis.", "Low bone mineral density (BMD) is a major determinant of fragility fractures (Fx), but its very long-term prediction is poorly documented. We analyzed the risk of Fx beyond 10 years in women. In a longitudinal cohort study (Os des Femmes de Lyon), we studied 867 women aged 40 years and older (mean age 59 ± 10 y) over 20 years. We assessed the risk of the first incident Fx according to the baseline BMD obtained by dual-energy X-ray absorptiometry, clinical risk factors, and the Fracture Risk Assessment Tool (FRAX). During a median (interquartile range) follow-up of 20 years (3), 245 women sustained one or more incident fragility Fx. Women who sustained a first Fx beyond 10 years (Fx 10-20, n = 109) were younger and had lower values of FRAX compared with those in the first 10 years (Fx 0-10, n = 136). After adjustment for age, they still had greater grip strength and BMD. Parental hip Fx was associated with an increased risk of Fx 10-20 but contrasting with Fx 0-10, the risk of Fx 10-20 was not associated with age, previous Fx, and FRAX except in women younger than 70 years. Each SD decrease of BMD at the spine, femoral neck, total hip, and ultradistal radius was associated with an increased risk of Fx 10-20 with adjusted odds ratios [95% confidence interval (CI)] of 1.43 (95% CI 1.12-1.82), 1.39 (95% CI 1.08-1.82), 1.47 (95% CI 1.14-1.89), and 2.00 (95% CI 1.47-2.7). Women with osteoporosis had an increased risk of both Fx 0-10 and Fx 10-20 compared with women with normal BMD, whereas osteopenia was not associated with a higher risk of Fx beyond 10 years. Low BMD in women is significantly associated with an increased risk of Fx over 20 years. Beyond 10 years, the prediction conferred by baseline BMD was better than that from clinical risk factors.", "Monitoring bone turnover of the adult and aging skeleton is essential for optimal treatment of bone metabolic diseases, such as postmenopausal osteoporosis. Diagnosis of osteoporosis is based solely on dual-emission x-ray absorptiometry-based measurements of bone mineral density. However, within the last 20 years, biochemical markers of bone turnover have been implemented to a larger degree, and especially within the field of drug development. Numerous clinical studies have underscored that the markers have promise in terms of predicting patients at high risk of losing bone, future fracture events and importantly also the fracture efficacy of drugs in development. Furthermore, while classical methods often require years to monitor the changes, the bone turnover markers do so within a shorter time span. The aims of this article are to provide an update on the different biochemical markers of bone turnover, and to give an overview of their applications in epidemiological and clinical research especially in women. The main emphasis will be on their utility in clinical trials testing the efficacy of drugs for the treatment of osteoporosis, and their ability to supplement bone mass measurements. Finally, recent evidence suggests that biochemical markers may provide information on bone age that may indirectly relate to bone quality, and this is discussed together with future possibilities for measuring bone quality using bone turnover markers. In summary, a more targeted use of biomarkers could assist in the identification of high-risk patients, the process of drug discovery and monitoring of the efficacy of osteoporosis treatment in clinical settings." ]
Rice blast caused by a biotic stress	Rice is one of the staple foods for the majority of the global population that depends directly or indirectly on it. The yield of this important crop is constantly challenged by various biotic stresses. Rice blast, caused by	[ "Recognition of pathogen-derived molecules by pattern recognition receptors (PRRs) is a common feature of both animal and plant innate immune systems. In plants, PRR signalling is initiated at the cell surface by kinase complexes, resulting in the activation of immune responses that ward off microorganisms. However, the activation and amplitude of innate immune responses must be tightly controlled. In this Review, we summarize our knowledge of the early signalling events that follow PRR activation and describe the mechanisms that fine-tune immune signalling to maintain immune homeostasis. We also illustrate the mechanisms used by pathogens to inhibit innate immune signalling and discuss how the innate ability of plant cells to monitor the integrity of key immune components can lead to autoimmune phenotypes following genetic or pathogen-induced perturbations of these components.", "The aboveground parts of terrestrial plants, collectively called the phyllosphere, have a key role in the global balance of atmospheric carbon dioxide and oxygen. The phyllosphere represents one of the most abundant habitats for microbiota colonization. Whether and how plants control phyllosphere microbiota to ensure plant health is not well understood. Here we show that the Arabidopsis quadruple mutant (min7 fls2 efr cerk1; hereafter, mfec)1, simultaneously defective in pattern-triggered immunity and the MIN7 vesicle-trafficking pathway, or a constitutively activated cell death1 (cad1) mutant, carrying a S205F mutation in a membrane-attack-complex/perforin (MACPF)-domain protein, harbour altered endophytic phyllosphere microbiota and display leaf-tissue damage associated with dysbiosis. The Shannon diversity index and the relative abundance of Firmicutes were markedly reduced, whereas Proteobacteria were enriched in the mfec and cad1S205F mutants, bearing cross-kingdom resemblance to some aspects of the dysbiosis that occurs in human inflammatory bowel disease. Bacterial community transplantation experiments demonstrated a causal role of a properly assembled leaf bacterial community in phyllosphere health. Pattern-triggered immune signalling, MIN7 and CAD1 are found in major land plant lineages and are probably key components of a genetic network through which terrestrial plants control the level and nurture the diversity of endophytic phyllosphere microbiota for survival and health in a microorganism-rich environment.", "Crop breeding aims to balance disease resistance with yield; however, single resistance (R) genes can lead to resistance breakdown, and R gene pyramiding may affect growth fitness. Here we report that the rice Pigm locus contains a cluster of genes encoding nucleotide-binding leucine-rich repeat (NLR) receptors that confer durable resistance to the fungus Magnaporthe oryzae without yield penalty. Among these NLR receptors, PigmR confers broad-spectrum resistance, whereas PigmS competitively attenuates PigmR homodimerization to suppress resistance. PigmS expression, and thus PigmR-mediated resistance, are subjected to tight epigenetic regulation. PigmS increases seed production to counteract the yield cost induced by PigmR Therefore, our study reveals a mechanism balancing high disease resistance and yield through epigenetic regulation of paired antagonistic NLR receptors, providing a tool to develop elite crop varieties.", "Nucleotide-binding site leucine-rich repeat (NLR) receptors perceive pathogen effectors and trigger plant immunity. However, the mechanisms underlying NLR-triggered defense responses remain obscure. The recently discovered Pigm locus in rice encodes a cluster of NLRs, including PigmR, which confers broad-spectrum resistance to blast fungus. Here, we identify PIBP1 (PigmR-INTERACTING and BLAST RESISTANCE PROTEIN 1), an RRM (RNA-recognition motif) protein that specifically interacts with PigmR and other similar NLRs to trigger blast resistance. PigmR-promoted nuclear accumulation of PIBP1 ensures full blast resistance. We find that PIBP1 and a homolog, Os06 g02240, bind DNA and function as unconventional transcription factors at the promoters of the defense genes OsWAK14 and OsPAL1, activating their expression. Knockout of PIBP1 and Os06 g02240 greatly attenuated blast resistance. Collectively, our study discovers previously unappreciated RRM transcription factors that directly interact with NLRs to activate plant defense, establishing a direct link between transcriptional activation of immune responses with NLR-mediated pathogen perception.", "The broad-spectrum rice blast resistance gene Pi9 was cloned using a map-based cloning strategy. Sequencing of a 76-kb bacterial artificial chromosome (BAC) contig spanning the Pi9 locus led to identification of six tandemly arranged resistance-like genes with a nucleotide-binding site (NBS) and leucine-rich repeats (LRRs) (Nbs1-Pi9-Nbs6-Pi9). Analysis of selected Pi9 deletion mutants and transformation of a 45-kb fragment from the BAC contig into the susceptible rice cultivar TP309 narrowed down Pi9 to the candidate genes Nbs2-Pi9 and Nbs3-Pi9. Disease evaluation of the transgenic lines carrying the individual candidate genes confirmed that Nbs2-Pi9 is the Pi9 gene. Sequence comparison analysis revealed that the six paralogs at the Pi9 locus belong to four classes and gene duplication might be one of the major evolutionary forces contributing to the formation of the NBS-LRR gene cluster. Semiquantitative reverse transcriptase (RT)-PCR analysis showed that Pi9 was constitutively expressed in the Pi9-resistant plants and was not induced by blast infection. The cloned Pi9 gene provides a starting point to elucidate the molecular basis of the broad-spectrum disease resistance and the evolutionary mechanisms of blast resistance gene clusters in rice.", "Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is a major constraint to rice production worldwide. In this study, we developed monogenic near-isogenic lines (NILs) NIL , NIL , and NIL carrying genes Pi9, Pizt, and Pi54, respectively, by marker assisted backcross breeding using 07GY31 as the japonica genetic background with good agronomic traits. Polygene pyramid lines (PPLs) PPL combining Pi9 with Pi54, and PPL combining Pizt with Pi54 were then developed using corresponding NILs with genetic background recovery rates of more than 97%. Compared to 07GY31, the above NILs and PPLs exhibited significantly enhanced resistance frequencies (RFs) for both leaf and panicle blasts. RFs of both PPLs for leaf blast were somewhat higher than those of their own parental NILs, respectively, and PPL + exhibited higher RF for panicle blast than NIL and NIL (P < 0.001), hinting an additive effect on the resistance. However, PPL exhibited lower RF for panicle blast than NIL (P < 0.001), failing to realize an additive effect. PPL + showed higher resistant level for panicle blast and better additive effects on the resistance than PPL . It was suggested that major R genes interacted with each other in a way more complex than additive effect in determining panicle blast resistance levels. Genotyping by sequencing analysis and extreme-phenotype genome-wide association study further confirmed the above results. Moreover, data showed that pyramiding multiple resistance genes did not affect the performance of basic agronomic traits. So the way to enhance levels of leaf and panicle blast resistances for rice breeding in this study is effective and may serve as a reference for breeders. Key Message: Resistant levels of rice blast is resulted from different combinations of major R genes, PPL + showed higher resistant level and better additive effects on the panicle blast resistance than PPL .", "The japonica rice cultivar Hokkai 188 shows a high level of partial resistance to leaf blast. For mapping genes conferring the resistance, a set of 190 F2 progeny/F3 families was developed from the cross between the indica rice cultivar Danghang-Shali, with a low level of partial resistance, and Hokkai 188. Partial resistance to leaf blast in the F3 families was assessed in upland nurseries. From a primary microsatellite (SSR) linkage map and QTL analysis using a subset of 126 F2 progeny/F3 families randomly selected from the above set, one major QTL located on chromosome 1 was detected in the vicinity of SSR marker RM1216. This QTL was responsible for 69.4% of the phenotypic variation, and Hokkai 188 contributed the resistance allele. Segregation analysis in the F3 families for partial resistance to leaf blast was in agreement with the existence of a major gene, and the gene was designated as Pi35(t). Another QTL detected on chromosome 8 was minor, explained 13.4% of the phenotypic variation, and an allele of Danghang-Shali increased the level of resistance in this QTL. Additional SSR markers of the targeted Pi35(t) region were further surveyed in the 190 F2 plants, and Pi35(t) was placed in a 3.5-cM interval flanked by markers RM1216 and RM1003." ]
[Myocardial infarction with non-obstructive coronary arteries].	Myocardial infarction with Non Obstructive Coronary Arteries (MINOCA) is defined by patients presenting with signs and symptoms similar to acute myocardial infarction, but are found to have non-obstructive coronary arteries angiography. What was once considered a benign phenomenon, MINOCA has been proven to carry with it significant morbidity and worse mortality when compared to the general population. As the awareness for MINOCA has increased, guidelines have focused on this unique situation. Cardiac magnetic resonance (CMR) has proven to be an essential first step in the diagnosis of patients with suspected MINOCA. CMR has also been shown to be crucial when differentiating between MINOCA like presentations such as myocarditis, takotsubo and other forms of cardiomyopathy. The following review focuses on demographics of patients with MINOCA, their unique clinical presentation as well as the role of CMR in the evaluation of MINOCA.	[ "This study investigated whether T1 mapping by cardiac magnetic resonance (CMR) reflects the clinical evolution of disease in myocarditis and supports its diagnosis independently of the disease stages. Acute viral myocarditis is characterized by a range of intracellular changes due to viral replication and extracellular spill of debris within days of viral infection. Convalescence may be characterized by a chronic low-grade inflammation leading to ventricular remodelling, but also a complete resolution of myocardial changes. Patients with clinical diagnosis of viral myocarditis (N = 165) underwent routine clinical CMR protocol (1.5- and 3.0-T) for assessment of cardiac function and structure, and tissue characterization with T2-weighted imaging and late gadolinium enhancement. T1 mapping was obtained in a mid-ventricular short-axis slice before and >20 min after administration of 0.2 mmol/kg of gadobutrol. Compared with control subjects (n = 40), T1 indexes were increased in patients with myocarditis. Patients with acute symptoms (n = 61) had higher values of T1 indexes compared with patients in clinical convalescence (n = 67). Native T1 is an independent discriminator between health and disease, as well as a discriminator between acute and convalescent stage of the disease. Native T1- was superior to T2-weighted imaging and late gadolinium enhancement with high diagnostic accuracy and positive and negative predictive values. Using pre-defined cutoff values for normal ranges, we demonstrated that acute myocarditis can be independently identified by native T1 of >5 SD above the mean of normal range, whereas convalescence is best defined by either abnormal native T1 (>2 SD) or presence of late gadolinium enhancement. We prospectively tested a new diagnostic algorithm in an independent dataset of patients with clinical diagnosis of myocarditis and achieved similar diagnostic performance. The new diagnostic algorithm using native T1 can reliably discriminate between health and disease and determine the clinical disease stage in patients with a clinical diagnosis of myocarditis.", "Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.", "The diagnosis of acute myocarditis is challenging. Nonspecific clinical presentation and an overlap with the diagnosis of acute myocardial infarction present a diagnostic dilemma. The purpose of this article is to describe the role of cardiac MRI and transthoracic echocardiography (TTE) in the diagnosis of acute myocarditis. Thirty-two sequential patients (all male; average age, 33 years) with clinically suspected myocarditis were included. All patients underwent cardiac MRI with sequences dedicated for the evaluation of myocardial delayed enhancement and TTE for the evaluation of wall motion abnormalities (WMAs). Nine patients were excluded because of diagnosis of acute myocardial infarction (n=2) or inadequate cardiac MRI technique (n=7). Retrospective analysis of the images of the remaining 23 patients was performed. An epicardial pattern of abnormal patchy myocardial delayed enhancement was seen on cardiac MRI in 21 of 23 (91%) patients. WMAs were seen on TTE in eight of 23 (35%) patients. Regional rather than global involvement was seen mainly in the inferolateral segments, with a predominance in the midventricular portion. Cardiac MRI might have a greater impact than TTE in confirming the presence of acute myocarditis and evaluating the extent of myocardial involvement. Cardiac MRI provides noninvasive imaging that may obviate invasive procedures such as coronary catheter angiography or endomyocardial biopsy.", "This study sought to assess the prognostic impact of cardiac magnetic resonance (CMR) and conventional risk factors in patients with myocardial infarction with nonobstructed coronaries (MINOCA). Myocardial infarction with nonobstructed coronary arteries (MINOCA) represents a diagnostic dilemma, and the prognostic markers have not been clarified. A total of 388 consecutive patients with MINOCA undergoing CMR assessment were identified retrospectively from a registry database and prospectively followed for a primary clinical endpoint of all-cause mortality. A 1.5-T CMR was performed using a comprehensive protocol (cines, T2-weighted, and late gadolinium enhancement sequences). Patients were grouped into 4 categories based on their CMR findings: myocardial infarction (MI) (embolic/spontaneous recanalization), myocarditis, cardiomyopathy, and normal CMR. CMR (performed at a median of 37 days from presentation) was able to identify the cause for the troponin rise in 74% of the patients (25% myocarditis, 25% MI, and 25% cardiomyopathy), whereas a normal CMR was identified in 26%. Over a median follow-up of 1,262 days (3.5 years), 5.7% patients died. The cardiomyopathy group had the worst prognosis (mortality 15%; log-rank test: 19.9; p < 0.001), MI had 4% mortality, and 2% in both myocarditis and normal CMR. In a multivariable Cox regression model (including clinical and CMR parameters), CMR diagnosis of cardiomyopathy and ST-segment elevation on presentation electrocardiogram (ECG) remained the only 2 significant predictors of mortality. Using presentation with ECG ST-segment elevation and CMR diagnosis of cardiomyopathy as risk markers, the mortality risk rates were 2%, 11%, and 21% for presence of 0, 1, and 2 factors, respectively (p < 0.0001). In a large cohort of patients with MINOCA, CMR (median 37 days from presentation) identified a final diagnosis in 74% of patients. Cardiomyopathy had the highest mortality, followed by MI. The strongest predictors of mortality were a CMR diagnosis of cardiomyopathy and ST-segment elevation on presentation ECG.", "Cardiovascular magnetic resonance (CMR) has become the primary tool for noninvasive assessment of myocardial inflammation in patients with suspected myocarditis. The International Consensus Group on CMR Diagnosis of Myocarditis was founded in 2006 to achieve consensus among CMR experts and develop recommendations on the current state-of-the-art use of CMR for myocarditis. The recommendations include indications for CMR in patients with suspected myocarditis, CMR protocol standards, terminology for reporting CMR findings, and diagnostic CMR criteria for myocarditis (i.e., \"Lake Louise Criteria\").", "Egger's regression test is often used to help detect publication bias in meta-analyses. However, the performance of this test and the usual funnel plot have been challenged particularly when the summary estimate is the natural log of the odds ratio (lnOR). To compare the performance of Egger's regression test with a regression test based on sample size (a modification of Macaskill's test) with lnOR as the summary estimate. Simulation of meta-analyses under a number of scenarios in the presence and absence of publication bias and between-study heterogeneity. Type I error rates (the proportion of false-positive results) for each regression test and their power to detect publication bias when it is present (the proportion of true-positive results). Type I error rates for Egger's regression test are higher than those for the alternative regression test. The alternative regression test has the appropriate type I error rates regardless of the size of the underlying OR, the number of primary studies in the meta-analysis, and the level of between-study heterogeneity. The alternative regression test has comparable power to Egger's regression test to detect publication bias under conditions of low between-study heterogeneity. Because of appropriate type I error rates and reduction in the correlation between the lnOR and its variance, the alternative regression test can be used in place of Egger's regression test when the summary estimates are lnORs.", "The Lake Louise Criteria (LLC) were established in 2009 and are the recommended cardiac magnetic resonance imaging criterion for diagnosing patients with suspected myocarditis. Subsequently, newer parametric imaging techniques which can quantify T1, T2, and the extracellular volume (ECV) have been developed and may provide additional utility in the diagnosis of myocarditis. However, whether their diagnostic accuracy is superior to LLC remains unclear. In this meta-analysis, we compared the diagnostic performance of native T1, T2, ECV to LLC in diagnosing acute myocarditis. We searched PubMed for published studies of LLC, native T1, ECV, and T2 diagnostic criteria used to diagnose acute myocarditis. Seventeen studies were included, with a total of 867 myocarditis patients and 441 control subjects. Pooled sensitivity, specificity, and diagnostic odds ratio of all diagnostic tests were assessed by bivariate analysis. LLC had a pooled sensitivity of 74%, specificity of 86%, and diagnostic odds ratio of 17.7. Native T1 had a significantly higher sensitivity than LLC (85% versus 74%, P=0.025). Otherwise, there was no significant difference in sensitivity, specificity, and diagnostic odds ratio when comparing LLC to native T1, T2, or ECV. Native T1, T2, and ECV mapping provide comparable diagnostic performance to LLC. Although only native T1 had significantly better sensitivity than LLC, each technique offers distinct advantages for evaluating and characterizing myocarditis when compared with the LLC." ]
Risks of gestational diabetes and pregnancy-induced hypertension in women with polycystic ovary syndrome	To evaluate the risks of developing gestational diabetes (GDM) and pregnancy-induced hypertension (PIH) in women with polycystic ovary syndrome (PCOS) using data from Korea's National Health Insurance Service.	[ "What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference? International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management. Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.", "Polycystic ovary syndrome (PCOS) is of clinical and public health importance as it is very common, affecting up to one in five women of reproductive age. It has significant and diverse clinical implications including reproductive (infertility, hyperandrogenism, hirsutism), metabolic (insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, adverse cardiovascular risk profiles) and psychological features (increased anxiety, depression and worsened quality of life). Polycystic ovary syndrome is a heterogeneous condition and, as such, clinical and research agendas are broad and involve many disciplines. The phenotype varies widely depending on life stage, genotype, ethnicity and environmental factors including lifestyle and bodyweight. Importantly, PCOS has unique interactions with the ever increasing obesity prevalence worldwide as obesity-induced insulin resistance significantly exacerbates all the features of PCOS. Furthermore, it has clinical implications across the lifespan and is relevant to related family members with an increased risk for metabolic conditions reported in first-degree relatives. Therapy should focus on both the short and long-term reproductive, metabolic and psychological features. Given the aetiological role of insulin resistance and the impact of obesity on both hyperinsulinaemia and hyperandrogenism, multidisciplinary lifestyle improvement aimed at normalising insulin resistance, improving androgen status and aiding weight management is recognised as a crucial initial treatment strategy. Modest weight loss of 5% to 10% of initial body weight has been demonstrated to improve many of the features of PCOS. Management should focus on support, education, addressing psychological factors and strongly emphasising healthy lifestyle with targeted medical therapy as required. Monitoring and management of long-term metabolic complications is also an important part of routine clinical care. Comprehensive evidence-based guidelines are needed to aid early diagnosis, appropriate investigation, regular screening and treatment of this common condition. Whilst reproductive features of PCOS are well recognised and are covered here, this review focuses primarily on the less appreciated cardiometabolic and psychological features of PCOS.", "Polycystic ovary syndrome (PCOS) affects 5-20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) - with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder.", "The purpose of this study was to examine which maternal and neonatal complications are associated with polycystic ovary syndrome (PCOS) in pregnant women. The studies that were included compared pregnancy outcomes between women with PCOS and those without diagnosed PCOS. Our primary outcomes included gestational diabetes mellitus, pregnancy-induced hypertension, and preeclampsia. Secondary outcomes included cesarean delivery rates, operative vaginal delivery rates, preterm delivery, small-for-gestational-age (SGA) infants and large-for-gestational-age infants. We found that PCOS in pregnancy was associated with higher rates of gestational diabetes mellitus, pregnancy-induced hypertension, preeclampsia, preterm delivery, cesarean delivery, operative vaginal delivery, SGA, and large-for-gestational age. Only gestational diabetes mellitus, pregnancy-induced hypertension, preeclampsia, preterm delivery, and SGA infants were found to be statistically significant. This metaanalysis confirms the higher association of pregnancy complications and PCOS compared with patients who do not have PCOS. Additionally, there may be a stronger association between PCOS and hypertensive disorders than has been shown previously.", "To study oxidative stress (OS) markers on neonates. The specific aim was to evaluate advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs) serum levels along with the hormonal/metabolic profile and their possible relationship in a cohort of polycystic ovary syndrome PCOS(N) and gestational diabetes GDM(N) neonates and their mothers PCOS(M) and GDM(M). Prospective controlled study. Academic medical center. The study population comprised 151 mother/neonate pairs. Diet and/or insulin administration in GDM(M). Anthropometric, metabolic, hormonal parameters, and OS markers. The AGEs and AOPPs were higher in PCOS(M) and GDM(M) compared with controls (M). The same significant difference was observed in the corresponding groups of neonates. A strong relationship between mothers and neonates regarding AGEs (r = 0.605) and AOPPs levels (r = 0.735) was disclosed. Analogous findings were observed regarding androgens and insulin resistance in mothers and neonates, respectively. The present study demonstrated that in PCOS(N), the OS status was similar to that of GDM(N) and strongly associated with their mothers' oxidative status. These findings may have clinical implications, as exposure of PCOS(N) to high OS levels during pregnancy could affect several health issues of neonates." ]
Non-Squamous Cell Carcinoma-Related Malignant Sinonasal Tract Tumors	Non-squamous cell carcinoma-related malignant sinonasal tract tumors (non-SCC MSTT) are rare and diverse malignancies. In this study, we report our experience in the management of this group of patients. The treatment outcome has been presented, involving both primary treatment and salvage approaches. Data from 61 patients treated radically due to non-SCC MSTT between 2000 and 2016 at the National Cancer Research Institute, Gliwice branch, were analyzed. The group consisted of the following pathological subtypes of MSTT: adenoid cystic carcinoma (ACC), undifferentiated sinonasal carcinoma (USC), sarcoma, olfactory neuroblastoma (ONB), adenocarcinoma, small cell neuroendocrine carcinoma (SNC), mucoepidermic carcinoma (MEC), and acinic cell carcinoma, which were found in nineteen (31%), seventeen (28%), seven (11.5%), seven (11.5%), five (8%), three (5%), two (3%) and one (2%) of patients, respectively. There were 28 (46%) males and 33 (54%) females at the median age of 51 years. Maxilla was the primary tumor localization followed by the nasal cavity and ethmoid sinus in thirty-one (51%), twenty (32.5%), and seven (11.5%) patients, respectively. In 46 (74%) patients, an advanced tumor stage (T3 or T4) was diagnosed. Primary nodal involvement (N) was found in three (5%) cases, and all patients underwent radical treatment. The combined treatment consisted of surgery and radiotherapy (RT) and was given to 52 (85%) patients. The probabilities of overall survival (OS), locoregional control (LRC), metastases-free survival (MFS), and disease-free survival (DFS) were assessed in pathological subtypes and grouped together, along with the ratio and effectiveness of salvage. Locoregional treatment failure was seen in 21 (34%) patients. Salvage treatment was performed in fifteen (71%) patients and was effective in nine (60%) cases. There was a significant difference in OS between patients who underwent salvage and those who did not (median: 40 months vs. 7 months,	[ "Sinonasal malignancies vary in behavior according to histology and anatomical location. Incidence, survival, and optimal treatment for these lesions are thus uncertain in various cases. Our objective was to utilize a national population-based registry to identify the most common sinonasal histopathologies by anatomical site, and subsequently analyze the data by incidence trends, survival rates, patient demographics, and treatment modalities. Retrospective analysis of the United States National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry. The SEER database was examined for patients diagnosed with sinonasal malignancies between 1973 and 2011. Data were stratified according to anatomical site, incidence, survival, histology, staging, and patient demographics. Therapy-based outcomes were analyzed for cases from 1983 to 2011. A total of 13,295 patients were identified, with an incidence of 0.83 per 100,000 people. Males comprised 58.6% of cases. Whites represented 81.5% of cases, while blacks comprised 8.7%. Squamous cell carcinoma was the most common histology (41.9%) across all sites of the sinonasal tract. The most common anatomical site of malignancy was the nasal cavity (45.7%), and least common was the frontal sinus (1.2%). For single sites, 5-year disease-specific survival (DSS) was highest for nasal cavity tumors (67.1%) and lowest for overlapping sinus malignancies (37.6%). The overall 5-year DSS for all sinonasal malignancies was 53.7%. Sinonasal malignancies are rare entities with poor overall prognosis. By anatomical site, prognosis is best for nasal cavity cancers and worst for overlapping lesions. 4.", "The sinuses, nasal cavity, and middle ear represent a rarer location of head and neck malignancy than more common sites such as the larynx and oral cavity. Population-based studies are a useful tool to study the demographic and treatment factors affecting survival in these malignancies. Population-based database search of the Survival, Epidemiology, and End Results (SEER) database from 1973 to 2015 for malignancies involving the nasal cavity, paranasal sinuses, and middle ear. Data were analyzed for demographics, treatment type, stage, primary site and histopathologic type. Kaplan-Meier analysis was used to assess and compare survival. A total of 13,992 cases of sinonasal or middle ear malignancy were identified and analyzed. The majority of patients were between ages 50 and 80 at the time of diagnosis. Overall 5-, 10-, and 20-year survival was 45.7%, 32.2%, and 16.4%, respectively. Lymph node metastasis was reported in 4.4% of patients, while distant metastasis was present in 1.5% of cases. On univariate analysis surgical vs. nonsurgical treatment, sex, race, age at diagnosis, T stage, N stage, M stage, AJCC overall stage, primary site, tumor grade, and histopathologic subtype significantly affected survival. On multivariate analysis age, race, sex, primary site, overall AJCC stage, surgical vs. nonsurgical treatment, and T, N, and M stage remained significant predictors of overall survival. Malignancies of the nasal cavity, paranasal sinuses, and middle ear account for a minority of overall head and neck cancers. The overall 5-, 10-, and 20-year survival for these malignancies is relatively low. Higher T, N, M, and overall stage and higher tumor grade is associated with lower survival. Patients treated with surgery as part of the treatment regimen had higher overall survival. Demographics and primary site also significantly affect survival. Certain histopathologic subtypes were associated with poorer survival.", "Identify prognostic factors after salvage surgery for recurrent sinonasal malignancy (SNM). Case series with chart review. University of Pittsburgh Medical Center. Forty-two patients who underwent curative surgery for locally recurrent SNM ± adjuvant therapy from June 5, 2000, to December 19, 2012. Patients without follow-up were excluded. Chart review with established prognostic indicators for primary malignancies. Statistical analysis included Kaplan-Meier log-rank test, Fisher's exact test, Student's t test, and Cox regression. Forty-two patients met inclusion criteria: 38.5% developed a second recurrence, and 21.4% had metastases following treatment. The average disease-free interval (DFI) was 26.9 months (range, 2-90 months). DFI was significantly affected by ethmoid versus nonethmoid site (P = .049), histology (P = .012), carotid artery involvement (P = .008), perineural extension (P = .006), and clival invasion (P = .015). The overall survival rates at 6 months, 12 months, and 5 years following surgery were 83.3%, 69%, and 47.6%, respectively. Survival was affected by histology (P = .014), stratified grade (P = .042), tumor extension into the orbit (P = .019), carotid artery (P = .001), perineural space (P = .028), and clivus (P = .022). Complications occurred in 28.6% of patients and were associated with histology (P = .04). Length of hospital stay related to treatment was affected by histology (P = .009), grade (P = .013), and postoperative complication (P < .001). The median percentage of time hospitalized was 8%, and 43% of patients who died within 12 months spent >10% of their remaining days in the hospital. High-risk histologic subtype (melanoma, sinonasal undifferentiated carcinoma, adenocarcinoma, neuroendocrine cancer, sarcoma, and squamous cell carcinoma), grade, and orbital and skull base involvement negatively affect survival and/or DFI for patients with local recurrence of SNM. Improved stratification of patients can be used to guide decision making for patients with recurrent SNM and to avoid inappropriate surgery." ]
Role of vascular cell adhesion molecule-1 on hepatic stellate cells in non-alcoholic steatohepatitis	Non-alcoholic fatty liver disease (NAFLD) can progress to non-alcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis. Fibrosis is mediated by hepatic stellate cells (HSC) and their differentiation into activated myofibroblasts; the latter process is also promoted by inflammation. Here we studied the role of the pro-inflammatory adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) in HSCs in NASH. VCAM-1 expression was upregulated in the liver upon NASH induction, and VCAM-1 was found to be present on activated HSCs. We therefore utilized HSC-specific VCAM-1-deficient and appropriate control mice to explore the role of VCAM-1 on HSCs in NASH. However, HSC-specific VCAM-1-deficient mice, as compared to control mice, did not show a difference with regards to steatosis, inflammation and fibrosis in two different models of NASH. Hence, VCAM-1 on HSCs is dispensable for NASH development and progression in mice.	[ "The rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD. Mice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies. Allelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7Δhep livers and human rs641738TT carriers were similar. Mboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.", "There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.", "Although the majority of patients with non-alcoholic fatty liver disease (NAFLD) have only steatosis without progression, a sizeable fraction develop non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis and hepatocellular carcinoma (HCC). Many established diet-induced mouse models for NASH require 24-52 weeks, which makes testing for drug response costly and time consuming. We have sought to establish a murine NASH model with rapid progression of extensive fibrosis and HCC by using a western diet (WD), which is high-fat, high-fructose and high-cholesterol, combined with low weekly dose of intraperitoneal carbon tetrachloride (CCl4), which serves as an accelerator. C57BL/6J mice were fed a normal chow diet ± CCl4 or WD ± CCl4 for 12 and 24 weeks. Addition of CCl4 exacerbated histological features of NASH, fibrosis, and tumor development induced by WD, which resulted in stage 3 fibrosis at 12 weeks and HCC development at 24 weeks. Furthermore, whole liver transcriptomic analysis indicated that dysregulated molecular pathways in WD/CCl4 mice and immunologic features were similar to those of human NASH. Our mouse NASH model exhibits rapid progression of advanced fibrosis and HCC, and mimics histological, immunological and transcriptomic features of human NASH, suggesting that it will be a useful experimental tool for preclinical drug testing. A carefully characterized model has been developed in mice that recapitulates the progressive stages of human fatty liver disease, from simple steatosis, to inflammation, fibrosis and cancer. The functional pathways of gene expression and immune abnormalities in this model closely resemble human disease. The ease and reproducibility of this model make it ideal to study disease pathogenesis and test new treatments.", "Hepatic fibrosis is a dynamic process characterized by the net accumulation of extracellular matrix resulting from chronic liver injury of any aetiology, including viral infection, alcoholic liver disease and NASH. Activation of hepatic stellate cells (HSCs) - transdifferentiation of quiescent, vitamin-A-storing cells into proliferative, fibrogenic myoﬁbroblasts - is now well established as a central driver of fibrosis in experimental and human liver injury. Yet, the continued discovery of novel pathways and mediators, including autophagy, endoplasmic reticulum stress, oxidative stress, retinol and cholesterol metabolism, epigenetics and receptor-mediated signals, reveals the complexity of HSC activation. Extracellular signals from resident and inflammatory cells including macrophages, hepatocytes, liver sinusoidal endothelial cells, natural killer cells, natural killer T cells, platelets and B cells further modulate HSC activation. Finally, pathways of HSC clearance have been greatly clarified, and include apoptosis, senescence and reversion to an inactivated state. Collectively, these findings reinforce the remarkable complexity and plasticity of HSC activation, and underscore the value of clarifying its regulation in hopes of advancing the development of novel diagnostics and therapies for liver disease.", "During liver injury, liver sinusoidal endothelial cells (LSECs) dysfunction and capillarization promote liver fibrosis. We have previously reported that the LSEC vascular cell adhesion molecule 1 (VCAM1) plays a key role in liver inflammation in nonalcoholic steatohepatitis (NASH) and we now aim to uncover its role in LSEC capillarization and liver fibrosis. Wild-type C57BL/6J mice were fed either chow or high fat, fructose and cholesterol diet to induce NASH and treated with either anti-VCAM1 neutralizing antibody or control isotype antibody. Inducible endothelial cell-specific Vcam1 deleted mice (Vcam1 ) and control mice (Vcam1 ) were fed choline-deficient high-fat diet (CD-HFD) to induce NASH or injected with carbon tetrachloride to induce liver fibrosis. LSECs isolated from Vcam1 or Vcam1 and hepatic stellate cells (HSCs) isolated from wild-type mice were cocultured in a 3-D system or a μ-Slide 2 well co-culture system. Immunostaining for Lyve1 (marker of differentiated LSECs) was reduced in Vcam1 mice and restored in Vcam1 mice in both NASH and liver fibrosis models. Co-immunostaining showed increased α-smooth muscle actin in the livers of Vcam1 mice in areas lacking Lyve1. Furthermore, scanning electron microscopy showed reduced LSEC fenestrae in the Vcam1 mice but not Vcam1 mice in both injury models, suggesting that VCAM1 promotes LSEC capillarization during liver injury. HSCs profibrogenic markers were reduced when cocultured with LSECs from CD-HFD fed Vcam1 mice compared to Vcam1 mice. Furthermore, recombinant VCAM1 activated the Yes-associated protein 1 pathway and induced a fibrogenic phenotype in HSCs in vitro, supporting the profibrogenic role of LSEC VCAM1. VCAM1 is not just a scaffold for leukocyte adhesion during liver injury, but also a modulator of LSEC capillarization and liver fibrosis.", "Fibrogenesis is a progressive scarring event resulting from disrupted regular wound healing due to repeated tissue injury and can end in organ failure, like in liver cirrhosis. The protagonists in this process, either liver-resident cells or patrolling leukocytes attracted to the site of tissue damage, interact with each other by soluble factors but also by direct cell-cell contact mediated by cell adhesion molecules. Since cell adhesion molecules also support binding to the extracellular matrix, they represent excellent biosensors, which allow cells to modulate their behavior based on changes in the surrounding microenvironment. In this review, we focus on selectins, cadherins, integrins and members of the immunoglobulin superfamily of adhesion molecules as well as some non-classical cell adhesion molecules in the context of hepatic fibrosis. We describe their liver-specific contributions to leukocyte recruitment, cell differentiation and survival, matrix remodeling or angiogenesis and touch on their suitability as targets in antifibrotic therapies.", "Neutrophils are specialized at killing bacteria and are recruited from the blood in a rapid and robust manner during infection. A cascade of adhesion events direct their attachment to the vascular endothelium and migration into the underlying tissue. A disintegrin and metalloproteinase 17 (ADAM17) functions in the cell membrane of neutrophils and endothelial cells by cleaving its substrates, typically in a cis manner, at an extracellular site proximal to the cell membrane. This process is referred to as ectodomain shedding and it results in the downregulation of various adhesion molecules and receptors, and the release of immune regulating factors. ADAM17 sheddase activity is induced upon cell activation and rapidly modulates intravascular adhesion events in response to diverse environmental stimuli. During sepsis, an excessive systemic inflammatory response against infection, neutrophil migration becomes severely impaired. This involves ADAM17 as indicated by increased levels of its cleaved substrates in the blood of septic patients, and that ADAM17 inactivation improves neutrophil recruitment and bacterial clearance in animal models of sepsis. Excessive ADAM17 sheddase activity during sepsis thus appears to undermine in a direct and indirect manner the necessary balance between intravascular adhesion and de-adhesion events that regulate neutrophil migration into sites of infection. This review provides an overview of ADAM17 function and regulation and its potential contribution to neutrophil dysfunction during sepsis." ]
A novel multifunctional drug delivery system based on mesoporous silica particles	Alendronate (ALN) is the most commonly prescribed oral nitrogen-containing bisphosphonate for osteoporosis therapy. However, its administration is associated with serious side effects. Therefore, the drug delivery systems (DDS) enabling local administration and localized action of that drug are still of great importance. Herein, a novel multifunctional DDS system based on the hydroxyapatite-decorated mesoporous silica particles (MSP-NH	[ "In this paper we review the mathematical models used to determine the kinetics of drug release from drug delivery systems. The quantitative analysis of the values obtained in dissolution/release rates is easier when mathematical formulae are used to describe the process. The mathematical modeling can ultimately help to optimize the design of a therapeutic device to yield information on the efficacy of various release models.", "Biomineral coatings have been extensively used to enhance the osteoconductivity of polymeric scaffolds. Numerous porous scaffolds have previously been coated with a bone-like apatite mineral through incubation in simulated body fluid (SBF). However, characterization of the mineral layer formed on scaffolds, including the amount of mineral within the scaffolds, often requires destructive methods. We have developed a method using micro-computed tomography (μ-CT) scanning to nondestructively quantify the amount of mineral in vitro and in vivo on biodegradable scaffolds made of poly (L-lactic acid) (PLLA) and poly (ε-caprolactone) (PCL). PLLA and PCL scaffolds were fabricated using an indirect solid freeform fabrication (SFF) technique to achieve orthogonally interconnected pore architectures. Biomineral coatings were formed on the fabricated PLLA and PCL scaffolds after incubation in modified SBF (mSBF). Scanning electron microscopy and X-ray diffraction confirmed the formation of an apatite-like mineral. The scaffolds were implanted into mouse ectopic sites for 3 and 10 weeks. The presence of a biomineral coating within the porous scaffolds was confirmed through plastic embedding and μ-CT techniques. Tissue mineral content (TMC) and volume of mineral on the scaffold surfaces detected by μ-CT had a strong correlation with the amount of calcium measured by the orthocresolphthalein complex-one (OCPC) method before and after implantation. There was a strong correlation between OCPC pre- and postimplantation and μ-CT measured TMC (R(2)=0.96 preimplant; R(2)=0.90 postimplant) and mineral volume (R(2)=0.96 preimplant; R(2)=0.89 postimplant). The μ-CT technique showed increases in mineral following implantation, suggesting that μ-CT can be used to nondestructively determine the amount of calcium on coated scaffolds.", "A chitosan-based microsphere delivery system has been fabricated for controlled release of alendronate (AL). The present study aimed to incorporate the chitosan/hydroxyapatite microspheres-loaded with AL (CH/nHA-AL) into poly(L-lactic acid)/nanohydroxyapatite (PLLA/nHA) matrix to prepare a novel microspheres-scaffold hybrid system (CM-ALs) for drug delivery and bone tissue engineering application. The characteristics of CM-ALs scaffolds containing 10% and 20% CH/nHA-AL were evaluated in vitro, including surface morphology and porosity, mechanical properties, drug release, degradation, and osteogenic differentiation. The in vivo bone repair for large segmental radius defects (1.5 cm) in a rabbit model was evaluated by radiography and histology. In vitro study showed more sustained drug release of CM-AL-containing scaffolds than these of CM/nHA-AL and PLLA/nHA/AL scaffolds, and the mechanical and degradation properties of CM-ALs (10%) scaffolds were comparable to that of PLLA/nHA control. The osteogenic differentiation of adipose-derived stem cells (ASCs) was significantly enhanced as indicated by increased alkaline phosphates (ALP) activity and calcium deposition. In vivo study further showed better performance of CM-ALs (10%) scaffolds with complete repair of large-sized bone defects within 8 weeks. A microspheres-scaffold-based release system containing AL-encapsulated chitosan microspheres was successfully fabricated in this study. Our results suggested the promising application of CM-ALs (10%) scaffolds for drug delivery and bone tissue engineering.", "The aim of this study was to investigate the effect of alendronate released from chitosan scaffolds on enhancement of osteoblast functions and inhibition of osteoclast differentiation in vitro. The surface and cell morphologies of chitosan scaffolds and alendronate-loaded chitosan scaffolds were characterized by variable pressure field emission scanning electron microscope (VP-FE-SEM). Alendronate was released in a sustained manner. For evaluating osteoblast functions in MG-63 cells, we investigated cell proliferation, alkaline phosphatase (ALP) activity, and calcium deposition. Furthermore, for evaluating inhibition of osteoclast differentiation in RAW 264.7 cells, we investigated tartrate-resistant acid phosphatase (TRAP) activity, TRAP staining, and gene expressions. The in vitro studies revealed that osteoblasts grown on alendronate-loaded chitosan scaffold showed a significant increment in cell proliferation, ALP activity, and calcium deposition as compared to those grown on chitosan scaffolds. In addition, the in vitro study showed that osteoclast differentiation in RAW 264.7 cells cultured on alendronate-loaded chitosan scaffolds was greatly inhibited as compared to those cultured on chitosan scaffolds by the results of TRAP activity, TRAP staining, and gene expressions. Taken together, alendronate-loaded chitosan scaffolds could achieve the dual functions of improvement in osteoblast functions and inhibition of osteoclast differentiation. Thus, alendronate-eluting chitosan substrates are promising materials for enhancing osteoblast functions and inhibiting osteoclast differentiation in orthopedic and dental fields.", "To better mimic the mineral component and the microstructure of natural bone, novel nano-hydroxyapatite (NHAP)/polymer composite scaffolds with high porosity and well-controlled pore architectures were prepared using thermally induced phase separation (TIPS) techniques. The morphologies, mechanical properties and protein adsorption capacities of the composite scaffolds were investigated. The high porosity (90% and above) was easily achieved and the pore size was adjusted by varying phase separation parameters. The NHAP particles were dispersed in the pore walls of the scaffolds and bound to the polymer very well. NHAP/polymer scaffolds prepared using pure solvent system had a regular anisotropic but open 3D pore structure similar to plain polymer scaffolds while micro-hydroxyapatite (MHAP)/polymer scaffolds had a random irregular pore structure. The introduction of HAP greatly increased the mechanical properties and improved the protein adsorption capacity. In a dioxane/water mixture solvent system, NHAP-incorporated poly(L-lactic acid) (PLLA) scaffolds developed a fibrous morphology which in turn increased the protein adsorption three fold over non fibrous scaffolds. The results suggest that the newly developed NHAP/polymer composite scaffolds may serve as an excellent 3D substrate for cell attachment and migration in bone tissue engineering.", "Recent advancements in drug delivery technologies utilizing a variety of carriers have resulted in a path-breaking revolution in the approach towards diagnosis and therapy alike in the current times. Need for materials with high thermal, chemical and mechanical properties have led to the development of mesoporous silica nanoparticles (MSNs). These ordered porous materials have garnered immense attention as drug carriers owing to their distinctive features over the others. They can be synthesized using a relatively simple process, thus making it cost effective. Moreover, by controlling the parameters during the synthesis; the morphology, pore size and volume and particle size can be transformed accordingly. Over the last few years, a rapid increase in research on MSNs as drug carriers for the treatment of various diseases has been observed indicating its potential benefits in drug delivery. Their widespread application for the loading of small molecules as well as macromolecules such as proteins, siRNA and so forth, has made it a versatile carrier. In the recent times, researchers have sorted to several modifications in the framework of MSNs to explore its potential in drug resistant chemotherapy, antimicrobial therapy. In this review, we have discussed the synthesis of these multitalented nanoparticles and the factors influencing the size and morphology of this wonder carrier. The second part of this review emphasizes on the applications and the advances made in the MSNs to broaden the spectrum of its use especially in the field of biomedicine. We have also touched upon the lacunae in the thorough understanding of its interaction with a biological system which poses a major hurdle in the passage of this carrier to the clinical level. In the final part of this review, we have discussed some of the major patents filed in the field of MSNs for therapeutic purpose.", "α,α-Bisphosphonates (BPs) are well established in the treatment of bone diseases such as osteoporosis and Paget's disease. Their successful application originates from their high affinity to hydroxyapatite. While the initially appreciated features of BPs are already beneficial to many patients, recent developments have further expanded their pleiotropic applications. This review describes the background of the interactions of BPs with bone cells that form the basis of the classical treatment. A better understanding of the mechanism behind their interactions allows for the parallel application of BPs against bone cancer and metastases followed by palliative pain relief. Targeted therapy with bone-seeking BPs coupled with a diagnostic agent in one particle resulted in theranostics which is also described here. For example, in such a system, BP moieties are bound to contrast agents used in magnetic resonance imaging or radionuclides used in positron emission tomography. In addition, another example of the pleiotropic function of BPs which involves targeting the imaging agents to bone tissues accompanied by pain reduction is presented in this work." ]
B-cell CLL/lymphoma 2 and the programmed cell death receptor 1 pathway	Myelodysplastic syndromes (MDSs) belong to a group of clonal bone marrow malignancies. In light of the emergence of new molecules, a significant contribution to the understanding of the pathogenesis of the disease is the study of the B-cell CLL/lymphoma 2 (BCL-2) and the programmed cell death receptor 1 (PD-1) protein and its ligands. BCL-2-family proteins are involved in the regulation of the intrinsic apoptosis pathway. Disruptions in their interactions promote the progression and resistance of MDSs. They have become an important target for specific drugs. Bone marrow cytoarchitecture may prove to be a predictor of response to its use. The challenge is the observed resistance to venetoclax, for which the MCL-1 protein may be largely responsible. Molecules with the potential to break the associated resistance include S63845, S64315, chidamide and arsenic trioxide (ATO). Despite promising in vitro studies, the role of PD-1/PD-L1 pathway inhibitors has not yet been established. Knockdown of the PD-L1 gene in preclinical studies was associated with increased levels of BCL-2 and MCL-1 in lymphocytes T, which could increase their survival and promote tumor apoptosis. A trial (NCT03969446) is currently underway to combine inhibitors from both groups.	[ "Therapy-related myeloid neoplasms (t-MN) are aggressive malignancies in need of effective therapies. The BCL-2 inhibitor venetoclax represents a paradigm shift in the treatment of acute myeloid leukemia. However, the effectiveness of venetoclax has not been studied in a large cohort of t-MN. We retrospectively analyzed 378 t-MN patients, of which 96 (25.4%, 47 therapy-related acute myeloid leukemia, 1 therapy-related chronic myelomonocytic leukemia, 48 therapy-related myelodysplastic syndrome) received venetoclax. Median interval from t-MN to venetoclax initiation was 2.9 (Interquartile range [IQR] 0.7-12) months, and patients received a median of 3 (IQR 1-4) cycles. The composite complete remission (CRc) rate, median progression-free survival (PFS), and overall survival (OS) were 39.1%, 4.9 months, and 7 months, respectively. The upfront use of venetoclax and achieving CRc were associated with improved survival, whereas the presence of Chromosome 7 abnormalities was associated with an inferior survival. Neither the TP53-status nor the percent bone marrow blast predicted the likelihood of CRc or survival. Paired genetic analysis performed at venetoclax initiation and failure did not show the evidence of the selection of the TP53-mutated clone. In a propensity-matched analysis, the use of venetoclax-based regimen as the first-line therapy was associated with a superior survival compared to hypomethylating agent (HMA)-based first-line therapy (9.4 vs. 6.1 months, p = .01). We conclude that the upfront use of venetoclax with HMA improved survival, though PFS and OS remain poor. As the phenotype at diagnosis or the percent blasts did not predict outcomes, venetoclax should be studied in all t-MN phenotypes.", "Myelodysplastic and myeloproliferative disorders are rare in childhood and there is no widely accepted system for their diagnosis and classification. We propose minimal diagnostic criteria and a simple classification scheme which, while based on accepted morphological features and conforming with the recent suggestions of the WHO, allows for the special problems of myelodysplastic diseases in children. The classification recognizes three major diagnostic groups: (1) juvenile myelomonocytic leukemia (JMML), previously named chronic myelomonocytic leukemia (CMML) or juvenile chronic myeloid leukemia (JCML); (2) myeloid leukemia of Down syndrome, a disease with distinct clinical and biological features, encompassing both MDS and AML occurring in Down syndrome; and (3) MDS occurring both de novo and as a complication of previous therapy or pre-existing bone marrow disorder (secondary MDS). The main subtypes of MDS are refractory cytopenia (RC) and refractory anemia with excess of blasts (RAEB). It is suggested retaining the subtype of RAEB-T with 20-30% blasts in the marrow until more data are available. Cytogenetics and serial assessments of the patients are essential adjuncts to morphology both in diagnosis and classification.", "The myelodysplastic syndromes (MDS) constitute a group of heterogeneous clonal haemopoietic stem cell disorders, characterized by ineffective and dysplastic haematopoiesis with varying degrees of peripheral cytopenia. Low-risk MDS is characterized by increased apoptosis in the bone marrow (BM) with autoimmune characteristics whereas the advanced or high-risk stages involve immune evasion and secondary DNA damage, giving cells growth potential to progress into acute myeloid leukaemia (AML). Nevertheless, the causes of MDS remain poorly defined and it is not clear how the disease progresses from an early stage to advanced MDS and AML. Although there are clear indications for a role of the immune system, the exact mechanism by which the immune response contributes to the progression is not yet clear. New insights into the pathophysiology of MDS with regard to the immune system will be instrumental for the development of novel patient-oriented therapies. This review is focused on the role of immune responses in MDS and the implications for the development of novel immune therapies.", "Interferon (IFN)-γ is the major mediator of anti-tumor immune responses; nevertheless, cancer cells use intrigue strategies to alter IFN-γ signaling and avoid elimination. Understanding the immune regulatory mechanisms employed by acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells upon exposure to IFN-γ is critical for development of immunotherapy and checkpoint blockade therapy approaches. This study aims to explore the influence of myeloid maturation on IFN-γ-induced PD-L1 and PD-L2 expression and on pro-leukemogenic transcription factor STAT3 signaling in AML and MDS. Stimulation of myeloid blasts' maturation by all-trans retinoic acid (ATRA) or 1α,25-dihydroxyvitamin D3 (vitamin D) increased the CD11b+ fraction that expressed PD-1 ligands in response to IFN-γ. Intriguingly, STAT3 pathway was potently induced by IFN-γ and strengthened upon prolonged exposure. Nonetheless, STAT3-mediated atypical IFN-γ signaling appeared as a negligible factor for PD-L1 and PD-L2 expression. These negative influences of IFN-γ could be alleviated by a small-molecule inhibitor of STAT3, stattic, which also inhibited the upregulation of PD-L1. In conclusion, induction of myeloid maturation enhances the responsiveness of AML and MDS cells to IFN-γ. However, these malignant myeloid cells can exploit both STAT3 pathway and PD-1 ligands to survive IFN-γ-mediated immunity and maintain secondary immune resistance.", "Little data are available for the expression of immune checkpoint (IC) molecules within myelodysplastic syndrome (MDS). Here, we report increased PD-L1+ CD34+ CD38- and PD-L1+ CD34+ CD38+ stem cell frequencies within MDS patients compared to stem cell recipients in remission. Additionally, we observed exceedingly similar PD1+ and Tim-3+ T-cell frequencies between acute myeloid leukaemia (AML) and MDS samples that were elevated compared to patients in remission. Furthermore, we found highly dynamic Tim-3+ and PD1+ T-cell frequencies within serial samples of relapsing MDS with excess blasts (MDS-EB II) patients, correlating with further disease markers. These findings support the idea of a potential successful implementation of IC inhibitor treatment in suitable MDS patients.", "Intratumoral accumulation of CD4+CD25+Foxp3+ regulatory T (Treg) cells occurs in acute myeloid leukemia (AML), but little is known about the role of tumor cells themselves in this process. Here, we showed that an immune checkpoint PD-L1 expressed by AML cells promoted the conversion and expansion of Treg cells sustaining high expression of Foxp3 and PD-1 as well as a suppressive function. Furthermore, an AML cell line HEL overexpressed PD-L1 promoted the conversion and expansion of Treg cells and CD4+PD-1+Foxp3+ T (PD-1+Treg) cells from the conventional CD4+ T cells. CD4+CD25highPD-1+ T cells secreted more IL-10 production than CD4+CD25highPD-1- T cells. IL-35, another cytokine secreted by Treg cells, promoted the proliferation of HL-60 cells and enhanced chemoresistance to cytarabine. Blockade of PD-1 signaling using anti-PD-L1 antibody dramatically impaired the generation of Treg cells and sharply retarded the progression of a murine AML model injected with C1498 cells. The frequency of intratumoral PD-1+ Treg cells was capable of predicting patient survival in patients with AML. In conclusion, our data suggest that PD-L1 expression by AML cells may directly drive Treg cell expansion as a mechanism of immune evasion and the frequency of PD-1+ Treg cells is a potential prognostic predictor in patients with AML.", "Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML), have a poor prognosis. An earlier Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 868 allogeneic hematopoietic cell transplantations (allo-HCTs) performed between 1990 and 2004 showed a 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%, respectively. Modern supportive care, graft-versus-host disease prophylaxis, and reduced-intensity conditioning (RIC) regimens have led to improved outcomes. Therefore, the CIBMTR analyzed 1531 allo-HCTs performed in adults with t-MDS (n = 759) or t-AML (n = 772) between and 2000 and 2014. The median age was 59 years (range, 18 to 74 years) for the patients with t-MDS and 52 years (range, 18 to 77 years) for those with t-AML. Twenty-four percent of patients with t-MDS and 11% of those with t-AML had undergone a previous autologous (auto-) HCT. A myeloablative conditioning (MAC) regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Nonrelapse mortality at 5 years was 34% (95% confidence interval [CI], 30% to 37%) for patients with t-MDS and 34% (95% CI, 30% to 37%) for those with t-AML. Relapse rates at 5 years in the 2 groups were 46% (95% CI, 43% to 50%) and 43% (95% CI, 40% to 47%). Five-year OS and DFS were 27% (95% CI, 23% to 31%) and 19% (95% CI, 16% to 23%), respectively, for patients with t-MDS and 25% (95% CI, 22% to 28%) and 23% (95% CI, 20% to 26%), respectively, for those with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low-risk t-MDS and those with t-AML undergoing HCT with MAC while in first complete remission, but worse for those with previous auto-HCT, higher-risk cytogenetics or Revised International Prognostic Scoring System score, and a partially matched unrelated donor. Relapse remains the major cause of treatment failure, with little improvement seen over the past 2 decades. These data mandate caution when recommending allo-HCT in these conditions and indicate the need for more effective antineoplastic approaches before and after allo-HCT." ]
Radiogenomic association map linking tumor morphology, shape, texture, and size with gene and miRNA signatures	The heterogeneity of lung tumor nodules is reflected in their phenotypic characteristics in radiological images. The radiogenomics field employs quantitative image features combined with transcriptome expression levels to understand tumor heterogeneity molecularly. Due to the different data acquisition techniques for imaging traits and genomic data, establishing meaningful connections poses a challenge. We analyzed 86 image features describing tumor characteristics (such as shape and texture) with the underlying transcriptome and post-transcriptome profiles of 22 lung cancer patients (median age 67.5 years, from 42 to 80 years) to unravel the molecular mechanisms behind tumor phenotypes. As a result, we were able to construct a radiogenomic association map (RAM) linking tumor morphology, shape, texture, and size with gene and miRNA signatures, as well as biological correlates of GO terms and pathways. These indicated possible dependencies between gene and miRNA expression and the evaluated image phenotypes. In particular, the gene ontology processes "regulation of signaling" and "cellular response to organic substance" were shown to be reflected in CT image phenotypes, exhibiting a distinct radiomic signature. Moreover, the gene regulatory networks involving the TFs	[ "The cell nucleus is a highly organized cellular organelle that contains the genetic material. The study of nuclear architecture has become an important field of cellular biology. Extracting quantitative data from 3D fluorescence imaging helps understand the functions of different nuclear compartments. However, such approaches are limited by the requirement for processing and analyzing large sets of images. Here, we describe Tools for Analysis of Nuclear Genome Organization (TANGO), an image analysis tool dedicated to the study of nuclear architecture. TANGO is a coherent framework allowing biologists to perform the complete analysis process of 3D fluorescence images by combining two environments: ImageJ (http://imagej.nih.gov/ij/) for image processing and quantitative analysis and R (http://cran.r-project.org) for statistical processing of measurement results. It includes an intuitive user interface providing the means to precisely build a segmentation procedure and set-up analyses, without possessing programming skills. TANGO is a versatile tool able to process large sets of images, allowing quantitative study of nuclear organization. TANGO is composed of two programs: (i) an ImageJ plug-in and (ii) a package (rtango) for R. They are both free and open source, available (http://biophysique.mnhn.fr/tango) for Linux, Microsoft Windows and Macintosh OSX. Distribution is under the GPL v.2 licence. [email protected] Supplementary data are available at Bioinformatics online.", "Molecular imaging is being hailed as the next great advance for imaging. This introductory article in the molecular imaging series to be published over the next several months in Radiology sets the stage for the subsequent set of articles by providing relevant definitions and background information and traces the evolution of molecular imaging to its current state of research and clinical practice. It discusses in detail the evolution of molecular imaging and the role that the National Cancer Institute and the National Institutes of Health have had in the funding and development of many of the important molecular imaging research programs that are in existence today. The article also provides basic information about the complex biology of the cell and details of the pathogenesis of cancer and how molecular imaging will be critical for earlier detection and management of cancer in the future. The article lays the foundation for the subsequent articles in the series and describes how and why molecular imaging will be critical and integral for clinical care of patients in the future. The introductory article also discusses the relevance of molecular imaging to clinical radiology practice and why it is critical for the practicing radiologist to understand these evolving techniques, as they will be the future of imaging.", "Lung cancer is the highest cause of mortality among tumor pathologies worldwide. There are no validated techniques for an early detection of pulmonary cancer lesions other than low-dose helical computed tomography scan. Unfortunately, this method has some negative effects. Recent studies have laid the basis for development of exosomes-based techniques to screen/diagnose lung cancers. As the isolation of circulating exosomes is a minimally invasive procedure, this technique opens new possibilities for diagnostic applications. We used a first set of 30 plasma samples from as many patients, including 10 patients affected by lung adenocarcinomas, 10 with lung granulomas, and 10 healthy smokers matched for age and sex as negative controls. Wide-range microRNAs analysis (742 microRNAs) was performed by quantitative real time polymerase chain reaction. Data were compared on the basis of lesion characteristics, using WEKA software for statistics and modeling. Subsequently, selected microRNAs were evaluated on an independent larger group of samples (105 specimens: 50 lung adenocarcinomas, 30 lung granulomas, and 25 healthy smokers). This analysis led to the selection of four microRNAs to perform a screening test (miR-378a, miR-379, miR-139-5p, and miR-200b-5p), useful to divide population into two groups: nodule (lung adenocarcinomas + carcinomas) and non-nodule (healthy former smokers). Six microRNAs (miR-151a-5p, miR-30a-3p, miR-200b-5p, miR-629, miR-100, and miR-154-3p) were selected for a second test on the nodule population to discriminate between lung adenocarcinoma and granuloma. The screening test showed 97.5% sensitivity, 72.0% specificity, and area under the curve receiver operating characteristic of 90.8%. The diagnostic test had 96.0% sensitivity, 60.0% specificity, and area under the curve receiver operating characteristic of 76.0%. Further evaluation is needed to confirm the predictive power of these models on larger cohorts of samples.", "Owing to novel therapy strategies in epidermal growth factor receptor (EGFR)-mutated patients, molecular analysis of the EGFR and KRAS genome has become crucial for routine diagnostics. Till date these data have been derived mostly from clinical trials, and thus collected in pre-selected populations. We therefore screened 'allcomers' with a newly diagnosed non-small cell lung carcinoma (NSCLC) for the frequencies of these mutations. A cohort study. Lung cancer centre in a tertiary care hospital. Within 15 months, a total of 552 cases with NSCLC were eligible for analysis. Frequency of scrutinising exons 18, 19 and 21 for the presence of activating EGFR mutation and secondary codon 12 and 13 for activating KRAS mutations. Of the 552 patients, 27 (4.9%) showed a mutation of EGFR. 19 of these patients (70%) had deletion E746-A750 in codon 19 or deletion L858R in codon 21. Adenocarcinoma (ACA) was the most frequent histology among patients with EGFR mutations (ACA, 22/254 (8.7%) vs non-ACA, 5/298 (1.7%); p<0.001). Regarding only ACA, the percentage of EGFR mutations was higher in women (16/116 (14%) women vs 6/138 (4.3%) men; p=0.008). Tumours with an activating EGFR mutation were more likely to be from non-smokers (18/27; 67%) rather than smoker (9/27; 33%). KRAS mutation was present in 85 (15%) of all cases. In 73 patients (86%), the mutation was found in exon 12 and in 12 cases (14%) in exon 13. Similarly, ACA had a higher frequency of KRAS mutations than non-ACA (67/254 (26%) vs 18/298 (6.0%); p<0.001). We found a lower frequency for EGFR and KRAS mutations in an unselected Caucasian patient cohort as previously published. Taking our results into account, clinical trials may overestimate the mutation frequency for EGFR and KRAS in NSCLC due to important selection biases.", "In the past decade, the characterization of non-small-cell lung cancer (NSCLC) into subtypes based on genotype and histology has resulted in dramatic improvements in disease outcome in select patient subgroups. In particular, molecularly targeted agents that inhibit EGFR or ALK are approved for the treatment of NSCLC harbouring genetic alterations in the genes encoding these proteins. Although acquired resistance usually limits the duration of response to these therapies, a number of new agents have proven effective at tackling specific resistance mechanisms to first-generation inhibitors. Large initiatives are starting to address the role of biomarker-driven targeted therapy in squamous lung cancers, and in the adjuvant setting. Immunotherapy undeniably holds great promise and our understanding of subsets of NSCLC based on patterns of immune response is continuing to evolve. In addition, efforts are underway to identify rare genomic subsets through genomic screening, functional studies, and molecular characterization of exceptional responders. This Review provides an overview of the key developments in the treatment of NSCLC, and discusses potential strategies to further optimize therapy by targeting disease subtypes.", "Early identification of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations is crucial for selecting a therapeutic strategy for patients with non-small-cell lung cancer (NSCLC). We proposed a machine learning-based model for feature selection and prediction of EGFR and KRAS mutations in patients with NSCLC by including the least number of the most semantic radiomics features. We included a cohort of 161 patients from 211 patients with NSCLC from The Cancer Imaging Archive (TCIA) and analyzed 161 low-dose computed tomography (LDCT) images for detecting EGFR and KRAS mutations. A total of 851 radiomics features, which were classified into 9 categories, were obtained through manual segmentation and radiomics feature extraction from LDCT. We evaluated our models using a validation set consisting of 18 patients derived from the same TCIA dataset. The results showed that the genetic algorithm plus XGBoost classifier exhibited the most favorable performance, with an accuracy of 0.836 and 0.86 for detecting EGFR and KRAS mutations, respectively. We demonstrated that a noninvasive machine learning-based model including the least number of the most semantic radiomics signatures could robustly predict EGFR and KRAS mutations in patients with NSCLC.", "Recent diagnostic procedure advances have considerably improved early lung cancer detection. However, the invasive, unpleasant, and inconvenient nature of current diagnostic procedures limits their application. There is a great need for novel noninvasive biomarkers for early lung cancer diagnosis. In the present study, we aimed to determine whether microRNA (miRNA) blood signatures are suitable for early detection of lung cancer. Using quantitative reverse transcriptase PCR analysis, we first selected and identified three aberrant plasma expression miRNAs (miR-21, miR-145, and miR-155) in a training set of 62 patients and 60 healthy smokers to define a panel that had high diagnostic efficiency for lung cancer. Then, we validated the detective ability of this miRNA panel in a testing set of 34 malignant tumor patients, 30 patients with benign pulmonary nodules and 32 healthy smokers. In the training set, miR-21 and miR-155 showed higher plasma expression levels, whereas miR-145 showed a lower expression level in patients with malignant cancer, compared with healthy controls (P ≤ 0.001). The three miRNAs used in combination produced the area under receiver operating characteristic curve at 0.847, which helped distinguish lung cancer from healthy smokers with 69.4% sensitivity and 78.3% specificity. A logistic regression model with the best prediction was constructed on the basis of miR-21, miR-145, and miR-155. Validation of the miRNA panel in the testing set confirmed their diagnostic value, which yields a significant improvement over any single one. Plasma miR-21, miR-145, and miR-155 have strong potential as novel noninvasive biomarkers for early detection of lung cancer.", "The National Institutes of Health have placed significant emphasis on sharing of research data to support secondary research. Investigators have been encouraged to publish their clinical and imaging data as part of fulfilling their grant obligations. Realizing it was not sufficient to merely ask investigators to publish their collection of imaging and clinical data, the National Cancer Institute (NCI) created the open source National Biomedical Image Archive software package as a mechanism for centralized hosting of cancer related imaging. NCI has contracted with Washington University in Saint Louis to create The Cancer Imaging Archive (TCIA)-an open-source, open-access information resource to support research, development, and educational initiatives utilizing advanced medical imaging of cancer. In its first year of operation, TCIA accumulated 23 collections (3.3 million images). Operating and maintaining a high-availability image archive is a complex challenge involving varied archive-specific resources and driven by the needs of both image submitters and image consumers. Quality archives of any type (traditional library, PubMed, refereed journals) require management and customer service. This paper describes the management tasks and user support model for TCIA.", "In the field of glioma, transcriptome subtypes have been considered as an important diagnostic and prognostic biomarker that may help improve the treatment efficacy. However, existing identification methods of transcriptome subtypes are limited due to the relatively long detection period, the unattainability of tumor specimens via biopsy or surgery, and the fleeting nature of intralesional heterogeneity. In search of a superior model over previous ones, this study evaluated the efficiency of eXtreme Gradient Boosting (XGBoost)-based radiomics model to classify transcriptome subtypes in glioblastoma patients. This retrospective study retrieved patients from TCGA-GBM and IvyGAP cohorts with pathologically diagnosed glioblastoma, and separated them into different transcriptome subtypes groups. GBM patients were then segmented into three different regions of MRI: enhancement of the tumor core (ET), non-enhancing portion of the tumor core (NET), and peritumoral edema (ED). We subsequently used handcrafted radiomics features (n = 704) from multimodality MRI and two-level feature selection techniques (Spearman correlation and F-score tests) in order to find the features that could be relevant. After the feature selection approach, we identified 13 radiomics features that were the most meaningful ones that can be used to reach the optimal results. With these features, our XGBoost model reached the predictive accuracies of 70.9%, 73.3%, 88.4%, and 88.4% for classical, mesenchymal, neural, and proneural subtypes, respectively. Our model performance has been improved in comparison with the other models as well as previous works on the same dataset. The use of XGBoost and two-level feature selection analysis (Spearman correlation and F-score) could be expected as a potential combination for classifying transcriptome subtypes with high performance and might raise public attention for further research on radiomics-based GBM models.", "Two major treatment strategies employed in non-small cell lung cancer, NSCLC, are tyrosine kinase inhibitors, TKIs, and immune checkpoint inhibitors, ICIs. The choice of strategy is based on heterogeneous biomarkers that can dynamically change during therapy. Thus, there is a compelling need to identify comprehensive biomarkers that can be used longitudinally to help guide therapy choice. Herein, we report a 18F-FDG-PET/CT-based deep learning model, which demonstrates high accuracy in EGFR mutation status prediction across patient cohorts from different institutions. A deep learning score (EGFR-DLS) was significantly and positively associated with longer progression free survival (PFS) in patients treated with EGFR-TKIs, while EGFR-DLS is significantly and negatively associated with higher durable clinical benefit, reduced hyperprogression, and longer PFS among patients treated with ICIs. Thus, the EGFR-DLS provides a non-invasive method for precise quantification of EGFR mutation status in NSCLC patients, which is promising to identify NSCLC patients sensitive to EGFR-TKI or ICI-treatments." ]
PROTRAIT: A Deep Learning Framework for Single-Cell Chromatin Accessibility Analysis	Recent advances in single-cell sequencing assays for the transposase-accessibility chromatin (scATAC-seq) technique have provided cell-specific chromatin accessibility landscapes of cis-regulatory elements, providing deeper insights into cellular states and dynamics. However, few research efforts have been dedicated to modeling the relationship between regulatory grammars and single-cell chromatin accessibility and incorporating different analysis scenarios of scATAC-seq data into the general framework. To this end, we propose a unified deep learning framework based on the ProdDep Transformer Encoder, dubbed PROTRAIT, for scATAC-seq data analysis. Specifically motivated by the deep language model, PROTRAIT leverages the ProdDep Transformer Encoder to capture the syntax of transcription factor (TF)-DNA binding motifs from scATAC-seq peaks for predicting single-cell chromatin accessibility and learning single-cell embedding. Based on cell embedding, PROTRAIT annotates cell types using the Louvain algorithm. Furthermore, according to the identified likely noises of raw scATAC-seq data, PROTRAIT denoises these values based on predated chromatin accessibility. In addition, PROTRAIT employs differential accessibility analysis to infer TF activity at single-cell and single-nucleotide resolution. Extensive experiments based on the Buenrostro2018 dataset validate the effeteness of PROTRAIT for chromatin accessibility prediction, cell type annotation, and scATAC-seq data denoising, therein outperforming current approaches in terms of different evaluation metrics. Besides, we confirm the consistency between the inferred TF activity and the literature review. We also demonstrate the scalability of PROTRAIT to analyze datasets containing over one million cells.	[ "It is a challenging task to integrate scRNA-seq and scATAC-seq data obtained from different batches. Existing methods tend to use a pre-defined gene activity matrix to convert the scATAC-seq data into scRNA-seq data. The pre-defined gene activity matrix is often of low quality and does not reflect the dataset-specific relationship between the two data modalities. We propose scDART, a deep learning framework that integrates scRNA-seq and scATAC-seq data and learns cross-modalities relationships simultaneously. Specifically, the design of scDART allows it to preserve cell trajectories in continuous cell populations and can be applied to trajectory inference on integrated data.", "The development of high-throughput RNA sequencing (RNA-seq) at the single-cell level has already led to profound new discoveries in biology, ranging from the identification of novel cell types to the study of global patterns of stochastic gene expression. Alongside the technological breakthroughs that have facilitated the large-scale generation of single-cell transcriptomic data, it is important to consider the specific computational and analytical challenges that still have to be overcome. Although some tools for analysing RNA-seq data from bulk cell populations can be readily applied to single-cell RNA-seq data, many new computational strategies are required to fully exploit this data type and to enable a comprehensive yet detailed study of gene expression at the single-cell level.", "Single-cell RNA sequencing technologies suffer from many sources of technical noise, including under-sampling of mRNA molecules, often termed \"dropout,\" which can severely obscure important gene-gene relationships. To address this, we developed MAGIC (Markov affinity-based graph imputation of cells), a method that shares information across similar cells, via data diffusion, to denoise the cell count matrix and fill in missing transcripts. We validate MAGIC on several biological systems and find it effective at recovering gene-gene relationships and additional structures. Applied to the epithilial to mesenchymal transition, MAGIC reveals a phenotypic continuum, with the majority of cells residing in intermediate states that display stem-like signatures, and infers known and previously uncharacterized regulatory interactions, demonstrating that our approach can successfully uncover regulatory relations without perturbations.", "We present cisTopic, a probabilistic framework used to simultaneously discover coaccessible enhancers and stable cell states from sparse single-cell epigenomics data ( http://github.com/aertslab/cistopic ). Using a compendium of single-cell ATAC-seq datasets from differentiating hematopoietic cells, brain and transcription factor perturbations, we demonstrate that topic modeling can be exploited for robust identification of cell types, enhancers and relevant transcription factors. cisTopic provides insight into the mechanisms underlying regulatory heterogeneity in cell populations." ]
The Mediating Effect of Challenges on Demographic Characteristics and Coping Strategies of Healthcare Workers	Healthcare workers (HCWs) including doctors, nurses and allied workers struggled to cope up with the stressful situation as the COVID-19 pandemic unsettled healthcare systems, including India's. Many factors (commonly called as stressors) acted as major sources of stress and resulted in poor mental health of HCWs. Therefore, this study predicted and explained the mediating effect of challenges on demographic characteristics and coping strategies of HCWs. Data from a cross-sectional study was collected from the district hospital of Rajasthan, India, during the period of August 2022-October 2022. HCW's experience level, shift type and distance of greenspaces from their accommodation were significantly correlated with the challenges they faced at work, specifically societal challenges. Thus, HCWs were more inclined to adopt a meaning-focused coping strategy to retain good mental health during the pandemic. Therefore, these findings call for interventions requiring a layered response, comprising strategies and actions that are structural. At the organizational level, these actions may provide supportive workplace environments.	[ "The purpose of this study was to analyze the mediating effect of self-efficacy and coping strategy in the relationship between job stress and the psychological well-being of care workers. The subjects were 112 home-visiting care workers, and data were collected at four home-visiting nursing centers in a metropolitan city and a small and medium-sized city from July to August 2022. The collected data were analyzed by descriptive statistics, t-test, ANOVA, Pearson's correlation co-efficient, multiple linear regression, and Sobel test. The mean score of psychological well-being was 3.33 ± 0.46 out of a possible 5. The subject's psychological well-being was correlated with self-efficacy (r = 0.64, p < 0.001), problem-solving-focused coping (r = 0.58, p < 0.001), social-support-seeking coping (r = 0.34, p < 0.001), job stress (r = -0.31, p = 0.001), avoidance-focused coping (r = -0.37, p < 0.001). Self-efficacy (Z = -4.92, p < 0.001), problem-solving-focused coping (Z = -2.56, p = 0.010), and avoidance-focused coping (Z = -3.07, p = 0.002) had a mediating effect in the relationship between job stress and psychological well-being of the subjects during the COVID-19 pandemic. Based on these results, the psychological well-being nursing intervention program for home-visiting care workers need to include job stress, problem-solving-focused coping, and avoidance-focused coping.", "Although a large body of research supports the theory that exposure to nature results in mental health benefits, research evidence on the effects of having a view of green space from home is still scarce. The aim of the present study is to assess the impact that access to a green space view from home has on anxiety and depression. This is a cross-sectional study extracting data from the \"2018 Green Spaces, Daily Habits and Urban Health Survey\" conducted in Carmona (Spain). The study included variables on sociodemographic and lifestyle, view of green spaces from home, self-perceived health status, and risk of anxiety and depression measured using the Hospital Anxiety and Depression Scale (HADS). Chi-square tests were used to assess variable's associations and a multiple linear regression models used to identify the variables explaining the risk of anxiety and depression, taking into account sociodemographic characteristics, frequency of visits and view of green spaces from home. According to our results, adults who enjoy a view of green spaces from home have a lower risk of anxiety and depression.", "We developed a multidimensional coping inventory to assess the different ways in which people respond to stress. Five scales (of four items each) measure conceptually distinct aspects of problem-focused coping (active coping, planning, suppression of competing activities, restraint coping, seeking of instrumental social support); five scales measure aspects of what might be viewed as emotional-focused coping (seeking of emotional social support, positive reinterpretation, acceptance, denial, turning to religion); and three scales measure coping responses that arguably are less useful (focus on and venting of emotions, behavioral disengagement, mental disengagement). Study 1 reports the development of scale items. Study 2 reports correlations between the various coping scales and several theoretically relevant personality measures in an effort to provide preliminary information about the inventory's convergent and discriminant validity. Study 3 uses the inventory to assess coping responses among a group of undergraduates who were attempting to cope with a specific stressful episode. This study also allowed an initial examination of associations between dispositional and situational coping tendencies.", "Urbanization, resource exploitation, and lifestyle changes have diminished possibilities for human contact with nature in urbanized societies. Concern about the loss has helped motivate research on the health benefits of contact with nature. Reviewing that research here, we focus on nature as represented by aspects of the physical environment relevant to planning, design, and policy measures that serve broad segments of urbanized societies. We discuss difficulties in defining \"nature\" and reasons for the current expansion of the research field, and we assess available reviews. We then consider research on pathways between nature and health involving air quality, physical activity, social cohesion, and stress reduction. Finally, we discuss methodological issues and priorities for future research. The extant research does describe an array of benefits of contact with nature, and evidence regarding some benefits is strong; however, some findings indicate caution is needed in applying beliefs about those benefits, and substantial gaps in knowledge remain." ]
Behavioral, clinical, and vascular variables associated with cognitive impairment in hemodialysis patients	(1) Background: Cognitive impairment (CI) is more prevalent in hemodialysis (HD) patients than in the general population. The purpose of this study was to examine if behavioral, clinical, and vascular variables are linked with CI in individuals with HD. (2) Methods: Initially, 47 individuals with chronic HD volunteered to participate in the trial, but only 27 patients ultimately completed the Montreal Cognitive Assessment (MoCA) and the Computerized Cognitive Assessment Tool (CompBased-CAT). We collected information on smoking, mental activities, physical activity (Rapid Assessment of Physical Activity, RAPA), and comorbidity. The oxygen saturation (rSO2) and pulse wave velocity (PWV; IEM Mobil-O-Graph) of the frontal lobes were measured. (3) Results: Significant associations were discovered between MoCA and rSO2 (r = 0.44, p = 0.02 and r = 0.62,	[ "Patients with chronic kidney disease treated with hemodialysis (HD) have lower cognitive abilities compared to the age-matched healthy population. Recently, physical exercise and cognitive training have been presented as possible interventions to improve cognitive abilities both in the general population and in patients with chronic diseases. To date, there is no general overview of the current knowledge on how these interventions affect cognitive abilities in HD patients and what tests are used to measure these effects. Three electronic databases were searched for randomized controlled studies of physical exercise or cognitive training interventions that examined effects on cognitive abilities/performance in HD patients. Six articles were included. All included studies used physical exercise as an intervention, with one study also including tablet-based cognitive training. Four studies included an intradialytic approach and two included a home-based intervention. Intervention lasted. A significant intervention effect was observed in three studies compared with the control condition. The present review suggests that physical exercise might improve or at least not worsen cognitive performance in HD patients, whereas the effect of cognitive training has not yet been adequately studied. There is a need for more sensitive and specific cognitive tests to adequately measure the effects of interventions in the HD population.", "Cognitive impairment is common in hemodialysis patients and is associated with significant morbidity. Limited information exists about whether cognitive impairment is associated with survival and whether the type of cognitive impairment is important. Longitudinal cohort. Cognitive function was assessed at baseline and yearly using a comprehensive battery of cognitive tests in 292 prevalent hemodialysis patients. Using principal component analysis, individual test results were reduced into 2 domain scores, representing memory and executive function. By definition, each score carried a mean of 0 and SD of 1. Association of each score with all-cause mortality was assessed using Cox proportional hazards models adjusted for demographics and dialysis and cardiovascular (CV) risk factors. Mean age of participants was 63 years, 53% were men, 23% were African American, and 90% had at least a high school education. During a median follow-up of 2.1 (IQR, 1.1-3.7) years, 145 deaths occurred. Each 1-SD better executive function score was associated with a 35% lower hazard of mortality (HR, 0.65; 95% CI, 0.55-0.76). In models adjusting for demographics and dialysis-related factors, this relationship was partially attenuated but remained significant (HR, 0.81; 95% CI, 0.67-0.98), whereas adjustment for CV disease and heart failure resulted in further attenuation (HR, 0.87; 95% CI, 0.72-1.06). Use of time-dependent models showed a similar unadjusted association (HR, 0.62; 95% CI, 0.54-0.72), with the relationship remaining significant after adjustment for demographics and dialysis and CV risk factors (HR, 0.79; 95% CI, 0.66-0.94). Better memory was associated with lower mortality in univariate analysis (HR per 1 SD, 0.82; 95% CI, 0.69-0.96), but not when adjusting for demographics (HR, 1.00; 95% CI, 0.83-1.19). Patients with dementia were excluded from the full battery, perhaps underestimating the strength of the association. Worse executive function and memory are associated with increased risk of mortality. For memory, this association is explained by patient demographics, whereas for executive function, this relationship may be explained in part by CV disease burden.", "Physical activity has been associated with better health status in diverse populations, but the association in patients on maintenance hemodialysis is less established. Patient-reported physical activities and associations with mortality, health-related quality of life, and depression symptoms in patients on maintenance hemodialysis in 12 countries were examined. In total, 5763 patients enrolled in phase 4 of the Dialysis Outcomes and Practice Patterns Study (2009-2011) were classified into five aerobic physical activity categories (never/rarely active to very active) and by muscle strength/flexibility activity using the Rapid Assessment of Physical Activity questionnaire. The Kidney Disease Quality of Life scale was used for health-related quality of life. The Center for Epidemiologic Studies Depression scale was used for depression symptoms. Linear regression was used for associations of physical activity with health-related quality of life and depression symptoms scores. Cox regression was used for association of physical activity with mortality. The median (interquartile range) of follow-up was 1.6 (0.9-2.5) years; 29% of patients were classified as never/rarely active, 20% of patients were classified as very active, and 20.5% of patients reported strength/flexibility activities. Percentages of very active patients were greater in clinics offering exercise programs. Aerobic activity, but not strength/flexibility activity, was associated positively with health-related quality of life and inversely with depression symptoms and mortality (adjusted hazard ratio of death for very active versus never/rarely active, 0.60; 95% confidence interval, 0.47 to 0.77). Similar associations with aerobic activity were observed in strata of age, sex, time on dialysis, and diabetes status. The findings are consistent with the health benefits of aerobic physical activity for patients on maintenance hemodialysis. Greater physical activity was observed in facilities providing exercise programs, suggesting a possible opportunity for improving patient outcomes.", "Hemodialysis (HD) patients are educated and counseled during the HD procedure. There are few studies assessing whether cognitive performance varies with dialysis. Using a randomized cross-over design, 40 patients were assigned to one of two sequences: testing 1 h before dialysis followed 1 month later by testing during the first hour of dialysis (n = 21) versus testing during the first hour of dialysis followed 1 month later by 1 h before dialysis (n = 19). Cognitive tests were administered at each testing period. Mixed regression models evaluated for a dialysis effect (difference between test performance before vs. during dialysis) while adjusting for potential learning (difference between first and second tests). In models accounting for period of testing, there was no difference in test performance between 1 h before versus during the first hour of HD for all administered cognitive tests (p > 0.05). A learning effect was detected between first and second test administration in two tests, specifically, the Word List Learning and the Digit Symbol Substitution Test. We found no difference in cognitive performance depending on the time of testing, suggesting that cognitive tests performed during the first hour of dialysis are a valid assessment of cognitive performance.", "Chronic kidney disease (CKD) patients undergoing hemodialysis (HD) therapy have an increased risk of developing cognitive impairment and dementia, which are known relevant factors in disease prognosis and therapeutic success, but still lack adequate screening in clinical routine. We evaluated the Montreal Cognitive Assessment (MoCA) for suitability in assessing cognitive performance in HD patients in comparison to the commonly used Mini-Mental State Examination (MMSE) and a detailed neuropsychological test battery, used as gold standard. 43 HD patients and 42 healthy controls with an average age of 58 years, were assessed with the MoCA, the MMSE and a detailed neuropsychological test battery, covering the domains of memory, attention, language, visuospatial and executive functions. Composite scores were created for comparison of cognitive domains and test results were analyzed using Spearman's correlation and linear regression. Cognitive dysfunction was defined using z-score values and predictive values were calculated. Sensitivity and specificity of the MoCA were determined using receiver operating characteristic (ROC) analysis. HD patients performed worse in all cognitive domains, especially in memory recall and executive functions. The MoCA correlated well with the detailed test battery and identified patients with cognitive impairment with a sensitivity of 76.7% and specificity of 78.6% for a cut-off value of ≤24 out of 30 points. In the detailed assessment executive functions accounted significantly for performance in the MoCA. The MMSE only discriminated weakly between groups. The MoCA represents a suitable cognitive screening tool for hemodialysis patients, demonstrating good sensitivity and specificity levels, and covering executive functions, which appear to play an important role in cognitive performance of HD patients.", "Older patients with ESKD experience rapid declines in executive function after initiating hemodialysis; these impairments might lead to high rates of dementia and Alzheimer's disease in this population. We estimated incidence, risk factors, and sequelae of diagnosis with dementia and Alzheimer's disease among older patients with ESKD initiating hemodialysis. We studied 356,668 older (age ≥66 years old) patients on hemodialysis (January 1, 2001 to December 31, 2013) from national registry data (US Renal Data System) linked to Medicare. We estimated the risk (cumulative incidence) of diagnosis of dementia and Alzheimer's disease and studied factors associated with these disorders using competing risks models to account for death, change in dialysis modality, and kidney transplant. We estimated the risk of subsequent mortality using Cox proportional hazards models. The 1- and 5-year risks of diagnosed dementia accounting for competing risks were 4.6% and 16% for women, respectively, and 3.7% and 13% for men, respectively. The corresponding Alzheimer's disease diagnosis risks were 0.6% and 2.6% for women, respectively, and 0.4% and 2.0% for men, respectively. The strongest independent risk factors for diagnosis of dementia and Alzheimer's disease were age ≥86 years old (dementia: hazard ratio, 2.11; 95% confidence interval, 2.04 to 2.18; Alzheimer's disease: hazard ratio, 2.11; 95% confidence interval, 1.97 to 2.25), black race (dementia: hazard ratio, 1.70; 95% confidence interval, 1.67 to 1.73; Alzheimer's disease: hazard ratio, 1.78; 95% confidence interval, 1.71 to 1.85), women (dementia: hazard ratio, 1.10; 95% confidence interval, 1.08 to 1.12; Alzheimer's disease: hazard ratio, 1.12; 95% confidence interval, 1.08 to 1.16), and institutionalization (dementia: hazard ratio, 1.36; 95% confidence interval, 1.33 to 1.39; Alzheimer's disease: hazard ratio, 1.10; 95% confidence interval, 1.05 to 1.15). Older patients on hemodialysis with a diagnosis of dementia were at 2.14-fold (95% confidence interval, 2.07 to 2.22) higher risk of subsequent mortality; those with a diagnosis of Alzheimer's disease were at 2.01-fold (95% confidence interval, 1.89 to 2.15) higher mortality risk. Older patients on hemodialysis are at substantial risk of diagnosis with dementia and Alzheimer's disease, and carrying these diagnoses is associated with a twofold higher mortality.", "Physical functioning in patients with end-stage renal disease treated with dialysis is low, whether measured using objective laboratory measures, physical performance testing, or self-reported measures. Peak oxygen uptake (VO2peak), self-reported functioning measures, and physical activity levels are independent predictors of mortality in these patients. Cardiovascular exercise training studies result in improvements in VO2peak, physical performance tests, and self-reported functioning. Resistance exercise training improves muscle strength. Exercise training may have positive benefits on other factors that are important clinical issues in dialysis patients, including cardiovascular risk profile, oxidative stress, and inflammation. Endothelial function, a surrogate marker of atherosclerosis, has been shown to improve with exercise training in dialysis patients. Although there have been numerous recent studies on benefits of exercise, few dialysis clinics or nephrologists provide encouragement or programs as a part of their routine care of their patients. There are many national guidelines that include exercise or increasing physical activity as a part of the treatment of many conditions that are relevant in dialysis patients, including hypertension, hyperlipidemia, and high cardiovascular disease risk. The nephrology community continues to state concern for outcomes; however, a simple, low-tech intervention that has many benefits to their patients (i.e., encouragement, recommendations, and opportunity for increasing physical activity) has not been adopted as part of the standard care. Adoption of routine counseling and encouragement for physical activity has the potential to improve outcomes, improve physical functioning, and optimize quality of life and overall health of dialysis patients." ]
Effect of topical diacerein on imiquimod-induced psoriasis	Psoriasis is an inflammatory skin disease characterized by increased neo-vascularization, keratinocyte hyperproliferation, a pro-inflammatory cytokine milieu and immune cell infiltration. Diacerein is an anti-inflammatory drug, modulating immune cell functions, including expression and production of cytokines, in different inflammatory conditions. Therefore, we hypothesized that topical diacerein has beneficial effects on the course of psoriasis. The current study aimed to evaluate the effect of topical diacerein on imiquimod (IMQ)-induced psoriasis in C57BL/6 mice. Topical diacerein was observed to be safe without any adverse side effects in healthy or psoriatic animals. Our results demonstrated that diacerein significantly alleviated the psoriasiform-like skin inflammation over a 7-day period. Furthermore, diacerein significantly diminished the psoriasis-associated splenomegaly, indicating a systemic effect of the drug. Remarkably, we observed significantly reduced infiltration of CD11c	[ "Psoriasis is a type I-deviated disease characterized by the presence of interferon (IFN)-gamma and multiple IFN-related inflammatory genes in lesions. Because interleukin (IL)-23 is now recognized to play a role in the recruitment of inflammatory cells in a T helper cell (Th)1-mediated disease, we examined psoriasis skin lesions for production of this newly described cytokine. IL-23 is composed of two subunits: a unique p19 subunit and a p40 subunit shared with IL-12. We found a reliable increase in p19 mRNA by quantitative reverse transcription polymerase chain reaction in lesional skin compared with nonlesional skin (22.3-fold increase; P = 0.001). The p40 subunit, shared by IL-12 and IL-23, increased by 11.6-fold compared with nonlesional skin (P = 0.003), but the IL-12 p35 subunit was not increased in lesional skin. IL-23 was expressed mainly by dermal cells and increased p40 immunoreactivity was visualized in large dermal cells in the lesions. Cell isolation experiments from psoriatic tissue showed strong expression of p19 mRNA in cells expressing monocyte (CD14+ CD11c+ CD83-) and mature dendritic cell (DC) markers (CD14- CD11c+ CD83+), whereas in culture, the mRNAs for p40 and p19 were strongly up-regulated in stimulated monocytes and monocyte-derived DCs, persisting in the latter for much longer periods than IL-12. Our data suggest that IL-23 is playing a more dominant role than IL-12 in psoriasis, a Th1 type of human inflammatory disease.", "Psoriasis is a chronic inflammatory skin disease that is thought to be related to oxidative stress. Much progress has been made in understanding the pathophysiology of psoriasis in relation to the immunologic and antioxidant systems. However, this progress has been hindered by the lack of an appropriate animal model for psoriasis. Recently, imiquimod (IQM)-induced psoriasis-like cutaneous inflammation has been reported in mice and humans. We verified the usefulness of an IQM-induced mouse model in relation to the antioxidant system. BALB/C female mice at 8-10 weeks of age were treated with IQM cream in this study. We analyzed clinical and histopathological changes. Increased reactive oxygen species production was measured by glutathione assay. Levels of myeloperoxidase (MPO) and superoxide dismutase-1 (SOD1) were determined by western blotting and immunohistochemical analyses. The activity of SOD was measured by a SOD activity assay kit. Application of IQM-induced skin inflammation similar to psoriasis in clinical and histopathological aspects. Accumulation of immune cells was confirmed. Oxidative stress was increased, the antioxidant enzyme MPO levels were increased, and both SOD levels and activity were decreased. In conclusion, the IQM-induced mouse model showed an aberrant antioxidant system. Levels of MPO and oxidative stress were increased, and the level and activity of SOD were decreased. Since this model seemed to be an appropriate model for psoriasis, it can be used to further study the pathogenic role of redox imbalance in psoriasis.", "In osteoarthritis (OA), the alterations in joint tissues are numerous and involve morphological, biochemical and metabolic changes and an upregulation of the inflammatory pathways. The focus of this article is a brief narrative review of the effects of diacerein, an antirheumatic drug from the anthraquinone chemical class, and its active metabolite, rhein, on the factors that participate in the complex interaction between OA tissues and cells leading to the progression of joint structural changes.", "Psoriasis is associated with atherosclerotic cardiovascular disease (CVD) with significant overlap of inflammatory pathways. A link between vascular inflammation and inflammation in multiple adipose tissue types, spleen, and bone marrow may exist. Therefore, we investigated these associations using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in patients with psoriasis (n = 83) where half had established CVD. Carotid ultrasound imaging was also performed. Inflammation was measured by FDG uptake in the aorta, visceral- (VAT), subcutaneous- (SAT), and pericardial (PAT) adipose tissues, and spleen and bone marrow, respectively. Vascular inflammation was associated with FDG uptakes in all adipose tissues, including VAT (β = 0.26; p < 0.001), SAT (β = 0.28; p < 0.001), PAT (β = 0.24; p < 0.001), spleen (β = 1.35; p = 0.001), and bone marrow (β = 1.14; p < 0.001). Adjustments for age, sex, body mass index, and high sensitivity C-reactive protein did not change the results. These associations were generally preserved in the patients without prior CVD. No associations were observed between vascular inflammation and carotid intima-media thickness or presence of carotid plaques, respectively. The results suggest an inflammatory link between vascular and adipose tissues, spleen, and bone marrow in patients with psoriasis." ]
Acetaminophen and non-steroidal anti-inflammatory drugs in patients with serious acute respiratory syndrome coronavirus 2 infection	Acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) have been widely prescribed to infected patients; however, the safety of them has not been investigated in patients with serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our objective was to evaluate the association between the previous use of acetaminophen or NSAIDs and the clinical outcomes of SARS-CoV-2 infection. A nationwide population-based cohort study was conducted using the Korean Health Insurance Review and Assessment Database through propensity score matching (PSM). A total of 25,739 patients aged 20 years and older who tested for SARS-CoV-2 were included from 1 January 2015 to 15 May 2020. The primary endpoint was a positive result for a SARS-CoV-2 test, and the secondary endpoint was serious clinical outcomes of SARS-CoV-2 infection, such as conventional oxygen therapy, admission to the intensive care unit, need for invasive ventilation care, or death. Of 1058 patients, after propensity score matching, 176 acetaminophen users and 162 NSAIDs users were diagnosed with coronavirus disease 2019. After PSM, 162 paired data sets were generated, and the clinical outcomes of the acetaminophen group were not significantly different from those of the NSAIDs group. This suggests that acetaminophen and NSAIDs can be used safely to control symptoms in patients suspected of having SARS-CoV-2.	[ "Concerns have been expressed that some drugs may increase susceptibility to SARS-CoV-2 infection. In contrast, other drugs have generated interest as potential therapeutic agents. All adults aged ≥18 years who were tested for COVID-19 were included. Exposure was defined as a prescription of study drugs which would have been continued until 7 days prior to test for COVID-19 or later. The outcome measures were the diagnosis of COVID-19 and severe COVID-19. Disease risk score matching and multiple logistic regression was used. Matched claims and testing results were available for 219,961 subjects, of whom 7,341 (3.34%) were diagnosed with COVID-19. Patients were matched to 36,705 controls, and the subset of 878 patients of severe COVID-19 also matched with 1,927 mild-to-moderate patients. Angiotensin receptor blockers were not associated with either the diagnosis of COVID-19 (adjusted OR [aOR], 1.02; 95% confidence interval [CI], 0.90-1.15) or severe disease (aOR, 1.11; 95% CI, 0.87-1.42). The use of hydroxychloroquine was not associated with a lower risk for COVID-19 (aOR, 0.94; 95% CI, 0.53-1.66) or severe disease (aOR, 3.51; 95% CI, 0.76-16.22). In this national claims data-based case-control study, no commonly prescribed medications were associated with risk of COVID-19 infection or COVID-19 severity.", "Due to the fact that coronavirus disease 2019 (COVID-19) is still prevalent, and current reports show that some parts of the world have seen increase in incidence, it is relevant that health professionals and scientists know about recent or novel trends, especially drug treatments. Additionally, the safety profiles of these drug treatments need to be documented and shared with the public. Some studies have demonstrated the clinical benefits of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids in COVID-19 treatment. On the contrary, others have also reported that NSAIDs and corticosteroids may worsen symptoms associated with COVID-19. While some researchers have suggested that corticosteroids may be helpful if used in the early stages of COVID-19, there are still some conflicting findings regarding the use of corticosteroids in certain viral infections. Our review suggests that methylprednisolone, dexamethasone, and ibuprofen have therapeutic potential in reducing mortality due to COVID-19 among hospitalized patients. This review also highlights the fact that the use of NSAIDs is not associated with adverse outcomes of COVID-19. In reality, evidence suggests that NSAIDs do not increase the risk of COVID-19 infections. Also, the literature reviewed suggests that corticosteroid treatment in COVID-19 was linked with a decrease in all-cause mortality and disease progression, without increase in adverse events when compared to no corticosteroid treatment.", "There is limited information describing the presenting characteristics and outcomes of US patients requiring hospitalization for coronavirus disease 2019 (COVID-19). To describe the clinical characteristics and outcomes of patients with COVID-19 hospitalized in a US health care system. Case series of patients with COVID-19 admitted to 12 hospitals in New York City, Long Island, and Westchester County, New York, within the Northwell Health system. The study included all sequentially hospitalized patients between March 1, 2020, and April 4, 2020, inclusive of these dates. Confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by positive result on polymerase chain reaction testing of a nasopharyngeal sample among patients requiring admission. Clinical outcomes during hospitalization, such as invasive mechanical ventilation, kidney replacement therapy, and death. Demographics, baseline comorbidities, presenting vital signs, and test results were also collected. A total of 5700 patients were included (median age, 63 years [interquartile range {IQR}, 52-75; range, 0-107 years]; 39.7% female). The most common comorbidities were hypertension (3026; 56.6%), obesity (1737; 41.7%), and diabetes (1808; 33.8%). At triage, 30.7% of patients were febrile, 17.3% had a respiratory rate greater than 24 breaths/min, and 27.8% received supplemental oxygen. The rate of respiratory virus co-infection was 2.1%. Outcomes were assessed for 2634 patients who were discharged or had died at the study end point. During hospitalization, 373 patients (14.2%) (median age, 68 years [IQR, 56-78]; 33.5% female) were treated in the intensive care unit care, 320 (12.2%) received invasive mechanical ventilation, 81 (3.2%) were treated with kidney replacement therapy, and 553 (21%) died. As of April 4, 2020, for patients requiring mechanical ventilation (n = 1151, 20.2%), 38 (3.3%) were discharged alive, 282 (24.5%) died, and 831 (72.2%) remained in hospital. The median postdischarge follow-up time was 4.4 days (IQR, 2.2-9.3). A total of 45 patients (2.2%) were readmitted during the study period. The median time to readmission was 3 days (IQR, 1.0-4.5) for readmitted patients. Among the 3066 patients who remained hospitalized at the final study follow-up date (median age, 65 years [IQR, 54-75]), the median follow-up at time of censoring was 4.5 days (IQR, 2.4-8.1). This case series provides characteristics and early outcomes of sequentially hospitalized patients with confirmed COVID-19 in the New York City area.", "The role of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in the setting of the coronavirus disease 2019 (COVID-19) pandemic is hotly debated. There have been recommendations to discontinue these medications, which are essential in the treatment of several chronic disease conditions, while, in the absence of clinical evidence, professional societies have advocated their continued use. To study the association between use of ACEIs/ARBs with the likelihood of testing positive for COVID-19 and to study outcome data in subsets of patients taking ACEIs/ARBs who tested positive with severity of clinical outcomes of COVID-19 (eg, hospitalization, intensive care unit admission, and requirement for mechanical ventilation). Retrospective cohort study with overlap propensity score weighting was conducted at the Cleveland Clinic Health System in Ohio and Florida. All patients tested for COVID-19 between March 8 and April 12, 2020, were included. History of taking ACEIs or ARBs at the time of COVID-19 testing. Results of COVID-19 testing in the entire cohort, number of patients requiring hospitalizations, intensive care unit admissions, and mechanical ventilation among those who tested positive. A total of 18 472 patients tested for COVID-19. The mean (SD) age was 49 (21) years, 7384 (40%) were male, and 12 725 (69%) were white. Of 18 472 patients who underwent COVID-19 testing, 2285 (12.4%) were taking either ACEIs or ARBs. A positive COVID-19 test result was observed in 1735 of 18 472 patients (9.4%). Among patients who tested positive, 421 (24.3%) were admitted to the hospital, 161 (9.3%) were admitted to an intensive care unit, and 111 (6.4%) required mechanical ventilation. Overlap propensity score weighting showed no significant association of ACEI and/or ARB use with COVID-19 test positivity (overlap propensity score-weighted odds ratio, 0.97; 95% CI, 0.81-1.15). This study found no association between ACEI or ARB use and COVID-19 test positivity. These clinical data support current professional society guidelines to not discontinue ACEIs or ARBs in the setting of the COVID-19 pandemic. However, further study in larger numbers of hospitalized patients receiving ACEI and ARB therapy is needed to determine the association with clinical measures of COVID-19 severity.", "Angiotensin-converting enzyme 2 (ACE2) has emerged as a novel regulator of cardiac function and arterial pressure by converting angiotensin II (Ang II) into the vasodilator and antitrophic heptapeptide, angiotensin-(1-7) [Ang-(1-7)]. As the only known human homolog of ACE, the demonstration that ACE2 is insensitive to blockade by ACE inhibitors prompted us to define the effect of ACE inhibition on the ACE2 gene. Blood pressure, cardiac rate, and plasma and cardiac tissue levels of Ang II and Ang-(1-7), together with cardiac ACE2, neprilysin, Ang II type 1 receptor (AT1), and mas receptor mRNAs, were measured in Lewis rats 12 days after continuous administration of vehicle, lisinopril, losartan, or both drugs combined in their drinking water. Equivalent decreases in blood pressure were obtained in rats given lisinopril or losartan alone or in combination. ACE inhibitor therapy caused a 1.8-fold increase in plasma Ang-(1-7), decreased plasma Ang II, and increased cardiac ACE2 mRNA but not cardiac ACE2 activity. Losartan increased plasma levels of both Ang II and Ang-(1-7), as well as cardiac ACE2 mRNA and cardiac ACE2 activity. Combination therapy duplicated the effects found in rats medicated with lisinopril, except that cardiac ACE2 mRNA fell to values found in vehicle-treated rats. Losartan treatment but not lisinopril increased cardiac tissue levels of Ang II and Ang-(1-7), whereas none of the treatments had an effect on cardiac neprilysin mRNA. Selective blockade of either Ang II synthesis or activity induced increases in cardiac ACE2 gene expression and cardiac ACE2 activity, whereas the combination of losartan and lisinopril was associated with elevated cardiac ACE2 activity but not cardiac ACE2 mRNA. Although the predominant effect of ACE inhibition may result from the combined effect of reduced Ang II formation and Ang-(1-7) metabolism, the antihypertensive action of AT1 antagonists may in part be due to increased Ang II metabolism by ACE2.", "The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces a range of mild to severe pathologies, including microcephaly. To understand the pathophysiology of ZIKV infection, we used models of the developing brain that faithfully recapitulate the tissue architecture in early to midgestation. We identify the brain cell populations that are most susceptible to ZIKV infection in primary human tissue, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by reducing viral proliferation. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, oligodendrocyte precursor cells, and microglia, whereas neurons were less susceptible to infection. These findings suggest mechanisms for microcephaly and other pathologic features of infants with congenital ZIKV infection that are not explained by neural stem cell infection alone, such as calcifications in the cortical plate. Furthermore, we find that blocking the glia-enriched putative viral entry receptor AXL reduced ZIKV infection of astrocytes in vitro, and genetic knockdown of AXL in a glial cell line nearly abolished infection. Finally, we evaluate 2,177 compounds, focusing on drugs safe in pregnancy. We show that the macrolide antibiotic azithromycin reduced viral proliferation and virus-induced cytopathic effects in glial cell lines and human astrocytes. Our characterization of infection in the developing human brain clarifies the pathogenesis of congenital ZIKV infection and provides the basis for investigating possible therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic." ]
Peer Relationship Profiles among Early Adolescents from Low-Income Families	Using research data gathered from multiple sources, the current study explored positive aspects of peer relationship profiles (indexed by peer-nominated acceptance and self-reported friendships) in a person-centered approach among early adolescents from low-income families. Moreover, this study investigated the unique and combined associations of adolescents' attachment to mothers and parent-rated conscientiousness with emerging peer relationship profiles. A total of 295 early adolescents (42.7% girls;	[ "The present study concerns an overlooked trait indicator of childhood peer status: Being fun. The study is designed to identify the degree to which being fun is uniquely associated with the peer status variables of likeability and popularity. Two studies of children in grades 4 to 6 (ages 9 to 12) are reported. The first involved 306 girls and 305 boys attending school in northern Colombia. The second involved 363 girls and 299 boys attending school in southern Florida. Students completed similar peer nomination inventories, once in the first study and twice (8 weeks apart) in the second. In both studies, being fun was positively correlated with likeability and popularity. In the second study, being fun predicted subsequent changes in likeability and popularity, after controlling for factors known to be related to each. Initial likeability and popularity also predicted subsequent changes in perceptions of being fun. Anecdotal evidence suggests that children are intensely focused on having fun. The findings indicate that this focus extends beyond the immediate rewards that fun experiences provide; some portion of peer status is uniquely derived from the perception that one is fun to be around.", "Two studies examine the convergence between measures of friendship and measures of liking in the assessment of friendship and peer acceptance. In the first study, 551 (301 boys and 250 girls) Canadian primary school children (ages 8 to 11) nominated friends and liked-most classmates. In the second study, 282 (127 boys and 155 girls) U.S. primary school children (ages 9 to 11) nominated friends and rated classmates on a sociometric preference scale. The results revealed considerable convergence in the assessment of friendship. Most 1st, 2nd, and 3rd ranked friends were also nominated and rated as liked-peers, suggesting that when measures of liking are used to identify friends, few top-ranked friendships are overlooked. There was less convergence in assessments of peer acceptance. Peer acceptance scores derived from friend nominations were more strongly correlated with peer acceptance scores derived from liking nominations than with those derived from sociometric preference ratings. We conclude that liking nominations accurately capture friendships, particularly best friendships. Friend nominations may be a suitable substitute for assessments of liking, but they are a poor substitute for assessments of sociometric preference.", "The potential role that children's classroom peer relations play in their school adjustment was investigated during the first 2 months of kindergarten and the remainder of the school year. Measures of 125 children's classroom peer relationships were obtained on 3 occasions: at school entrance, after 2 months of school, and at the end of the school year. Measures of school adjustment, including children's school perceptions, anxiety, avoidance, and performance, were obtained during the second and third assessment occasions. After controlling mental age, sex, and preschool experience, measures of children's classroom peer relationships were used to forecast later school adjustment. Results indicated that children with a larger number of classroom friends during school entrance developed more favorable school perceptions by the second month, and those who maintained these relationships liked school better as the year progressed. Making new friends in the classroom was associated with gains in school performance, and early peer rejection forecasted less favorable school perceptions, higher levels of school avoidance, and lower performance levels over the school year.", "A systematic meta-analysis was conducted of the association between preference and popularity across childhood and adolescence. The role of development, sex, and region of the world were examined. The analysis was conducted on 135 samples including 136,014 participants. The samples were divided by age (upper grades primary school, k = 41; lower grades secondary school, k = 72; upper grades secondary school, k = 22) and region (North America, k = 54; Europe, k = 66; China, k = 10). Across all samples, a moderate positive association between preference and popularity was found (r = 0.45). The association was significantly weaker in the upper grades of secondary school (r = 0.37) than in the lower grades of secondary school (r = 0.47) or the upper grades of primary school (r = 0.47). The association was weaker for girls (r = 0.26) than for boys (r = 0.38) in the upper grades of secondary school. The association was weaker in European samples (r = 0.41) than in those from North America (r = 0.50) and China (r = 0.57). The results confirmed that preference and popularity are related but distinct dimensions of adolescent peer status. The association differed significantly by age, sex, and region of the world. Further research should examine additional factors that explain the variability in the association between preference and popularity.", "Conscientiousness, the propensity to be organized, responsible, self-controlled, industrious, and rule-following, is related to numerous important outcomes including many forms of psychopathology. Given the increasing awareness of the importance of conscientiousness, it is becoming common to want to understand how to foster it. In this paper we first describe and update a recent model that was put forward as a theoretically informed intervention to change conscientiousness. We then consider recent life span theories focused on conscientiousness that might inform how best to use existing interventions as well as identify potential moderators of the effectiveness of intervention. Finally, we integrate these perspectives into a framework for how to foster conscientiousness that we label the Sociogenomic Trait Intervention Model (STIM). (PsycINFO Database Record", "This research examined how conscientiousness contributes to adolescents' positive peer relationships and vulnerability to poorer ones. Given its temperamental origins in effortful control, conscientiousness was expected to be particularly important. A total of 256 fifth to eighth graders completed personality, peer-relationship, and victimization measures. Peers, parents, and teachers also completed assessments. Adolescents higher on conscientiousness experienced less victimization, better quality friendships, and higher peer acceptance even after controlling for the other Big Five dimensions. Externalizing and/or attention problems mediated the link between conscientiousness and peer relations. Conscientiousness moderated the relation between internalizing problems and poor interpersonal functioning. Results suggest that self-control processes associated with conscientiousness are important in developing and maintaining relationships in adolescence." ]
The extent of practice variation in emergency medicine in The Netherlands.	Structural insights in the use of protocols and the extent of practice variation in EDs are lacking. The objective is to determine the extent of practice variation in EDs in The Netherlands, based on specified common practices. We performed a comparative study on Dutch EDs that employed emergency physicians to determine practice variation. Data on practices were collected via a questionnaire. Fifty-two EDs across The Netherlands were included. Thrombosis prophylaxis was prescribed for below-knee plaster immobilization in 27% of EDs. Vitamin C was prescribed in 50% of EDs after a wrist fracture. Splitting of applied casts to the upper or lower limb was performed in one-third of the EDs. Analysis of the cervical spine after trauma was performed by the NEXUS criteria (69%), the Canadian C-spine Rule (17%) or otherwise. The imaging modality for cervical spine trauma in adults was a CT scan (98%). The cast used for scaphoid fractures was divided between the short arm cast (46%) and the navicular cast (54%). Locoregional anaesthesia for femoral fractures was applied in 54% of the EDs. EDs in The Netherlands showed considerable practice variation in treatments among the subjects studied. Further research is warranted to gain a full understanding of the variation in practice in EDs and the potential to improve quality and efficiency.	[ "Feedback is essential to learning and practice improvement, yet challenging both to provide and receive. The purpose of this paper was to explore reflective processes which physicians described as they considered their assessment feedback and the perceived utility of that reflective process. This is a qualitative study using principles of grounded theory. We conducted interviews with 28 family physicians participating in a multi-source feedback program and receiving scores across the spectrum from high to low. Feedback, especially negative feedback, evoked reflective responses. Reflection seemed to be the process through which feedback was or was not assimilated and appeared integral to decisions to accept and use the feedback. Facilitated reflection upon feedback was viewed as a positive influence for assimilation and acceptance. Receiving feedback inconsistent with self-perceptions stimulated physicians' reflective processes. The process of reflection appeared instrumental to feedback acceptance and use, suggesting that reflection may be an important educational focus in the formative assessment and feedback process.", "Implantable cardioverter defibrillator (ICD) therapy is used for primary prevention of death among people with heart failure, and new evidence in 2005 on its effectiveness changed practice guidelines in the United States. The objective of this study is to examine how the connectedness of physicians and hospitals, measured using network analysis, relates to guideline-consistent ICD implantation. We constructed physician and hospital networks for cardiovascular disease. Physicians were linked if they shared cardiovascular disease patients; these links were aggregated by hospital affiliation to construct a hospital network. Medicare beneficiaries who underwent ICD therapy for primary prevention from 2007 to 2011. The clinical outcome of interest was guideline-consistent ICD implantation, calculated using the National Cardiovascular Data Registry. The exposure variables of interest were the network measures of the ICD surgeon, the referring hospital, and the hospital where the ICD surgery occurred. We focused on patients who were referred between hospitals for ICD implantation because they were more likely influenced by the hospital network (n=28,179). Patients were less likely to meet guidelines if their referring hospital had more connections to other hospitals (OR, 0.49; 95% confidence interval, 0.25-0.96) and more likely to meet guidelines if their ICD surgery hospital had more connections (OR, 1.61; 95% confidence interval, 0.98-2.64). The ICD surgeon's network measures were not associated with guideline-consistent implantation. Associations between the hospital network measures and guideline adherence suggests new approaches to better disseminate clinical guidelines across health systems.", "In the past decades, extensive research has been performed on the phenomenon of unwarranted clinical variation in clinical practice. Many studies have been performed on signaling, describing and visualizing clinical variation. We argue that it is time for next steps in practice variation research. In addition to describing and signaling variation patterns, we argue that a better understanding of causes of variation should be gained. Moreover, target points for improving and decreasing clinical variation should be created. Key elements in this new focus should be research on the complex interaction of networks, reflective medicine, patient beliefs and objective criteria for treatment choices. By combining these different concepts, alternative research objectives and new targets for improving and reducing unwarranted variation may be defined. In this perspective, we reflect on these concepts and propose target points for future research.", "From previous work, we know that medical practice varies widely, and that unwarranted variation signals low value for patients and society. We also know that public reporting helps to create awareness of the need for quality improvement. Despite the availability of rich data, most Western countries have no routine surveillance of the geographic distribution of utilization, costs, and outcomes of healthcare, including trends in variation over time. This paper highlights the role of transparent public reporting as a necessary first step to spark change and reduce unwarranted variation. Two recent examples of public reporting are presented to illustrate possible ways to reduce unwarranted variation and improve care. We conclude by introducing the Value Improvement Cycle, which underscores that reporting is only a necessary first step, and suggests a path toward developing a multi-stakeholder approach to change.", "Whether one examines the average length of hospital stay at the level of geographic areas, at the level of hospitals, or at the level of doctors, length-of-stay figures are known to vary widely. Even for hospital admissions for comparable surgical procedures among comparable groups of patients, significant length-of-stay variations have been reported. As is the case for variations in the occurrence of common surgical procedures, the overall conclusion is that large variations in duration of hospital stay associated with these common surgical procedures are the rule rather than the exception. The objective of the study is to examine whether variations in hospital medical practice, indicated by the duration of hospital stay in this study, can be reduced to differences in practice style between individual doctors within the same institutional setting or to differences in practice style between groups of doctors within the same institutional setting. The latter is assumed to be the combined effect of restrictions on the (hospital) supply side and the predilection of doctors to conform to the practice of immediate colleagues. It was found out that the variation in length of hospital stay, adjusted for patient case-mix, within hospitals is much smaller than the length-of-stay variation between different hospitals. The within hospital variation between (partnership of) doctors is in most of the cases statistically insignificant. Doctors working in more than one hospital on average choose a length of stay close to the average length of stay prevailing in the different hospitals.", "Plaster casts are often split to accommodate swelling following injury. This is not influenced by the axis of the split. The aim of this study was to compare the mechanical properties of plasters split along different axes. Full plasters were applied to mannequin forearms, and then split along dorsal, volar, radial or ulnar sides. Following this the plasters were loaded in a dorsal direction. We found that of all the axes tested, the dorsal split was the best for maintaining fracture reduction (p = 0.001)." ]
How do I get a list of all the fruits of a tree?	The fruits of	[ "The aim of the present study was to investigate and compare the anti-platelet action of extracts from three different plants: bark of Yucca schidigera, seeds of grape and berries of Aronia melanocarpa (chokeberry). Anti-platelet action of tested extracts was compared with action of well characterized antioxidative and anti-platelet commercial monomeric polyphenol-resveratrol. The effects of extracts on platelet adhesion to collagen, collagen-induced platelet aggregation and on the production of O2-* in resting platelets and platelets stimulated by a strong platelet agonist-thrombin were studied. The in vitro experiments have shown that all three tested extracts (5-50 microg/ml) rich in polyphenols reduce platelet adhesion, aggregation and generation of O2-* in blood platelets. Comparative studies indicate that all three plant extracts were found to be more reactive in reduction of platelet processes than the solution of pure resveratrol. The tested extracts due to their anti-platelet effects may play an important role as components of human diet in prevention of cardiovascular or inflammatory diseases, where blood platelets are involved.", "Reactive oxygen species (ROS) are produced by living organisms as a result of normal cellular metabolism and environmental factors, such as air pollutants or cigarette smoke. ROS are highly reactive molecules and can damage cell structures such as carbohydrates, nucleic acids, lipids, and proteins and alter their functions. The shift in the balance between oxidants and antioxidants in favor of oxidants is termed \"oxidative stress.\" Regulation of reducing and oxidizing (redox) state is critical for cell viability, activation, proliferation, and organ function. Aerobic organisms have integrated antioxidant systems, which include enzymatic and nonenzymatic antioxidants that are usually effective in blocking harmful effects of ROS. However, in pathological conditions, the antioxidant systems can be overwhelmed. Oxidative stress contributes to many pathological conditions and diseases, including cancer, neurological disorders, atherosclerosis, hypertension, ischemia/perfusion, diabetes, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma. In this review, we summarize the cellular oxidant and antioxidant systems and discuss the cellular effects and mechanisms of the oxidative stress.", "Most reactive oxygen species (ROS) can oxidize methionine (Met) residues of proteins to methionine sulfoxide (MetO). However, unlike the ROS-dependent oxidation of other amino acid residues of proteins (except cysteine residues), the oxidation of Met residues is readily reversed by the action of methionine sulfoxide reductase (Msr) that catalyzes the thioredoxin-dependent reduction of MetO residues of proteins back to Met. We summarize here results of studies showing that the cyclic interconversion of Met and MetO residues of proteins is involved in several different biological processes: (a) It is the basis of an important antioxidant mechanism for the scavenging of ROS. (b) It is likely involved in the regulation of enzyme activities. (c) It is involved in cell signaling. (d) It can target proteins for proteolytic degradation. Furthermore, a loss in the ability to catalyze the reduction of protein MetO to Met residues leads to a decrease in the maximum life span, whereas overexpression of this activity leads to an increase in the life span of animals. In addition, a decrease in Msr activities in brain tissues is associated with the development of Alzheimer's disease.", "We previously reported that dimethylarsinic acid (DMAA), a major metabolite of inorganic arsenics, induced DNA single-strand breaks (ssb) both in vivo and in cultured alveolar type II (L-132) cells in vitro, possibly via the production of dimethylarsenic peroxyl radicals. Here, the interaction of superoxide anion radicals (O2-) in the induction of ssb in L-132 cells was investigated using paraquat, an O2(-)-producing agent. A significant enhancement of ssb formation was observed in the DMAA-exposed cells when coexposed to paraquat. This enhancement occurred even when post-exposed to DMAA after washing, suggesting that the DMAA exposure caused some modification of DNA such as DNA-adducts, which was recognized by active oxygens to form ssb. An experiment with UV-irradiation, which was likely to induce ssb at the modified region, supported the possibility of DNA modification by DMAA exposure. An ESR study indicated that O2- produced by paraquat in DMAA-exposed cells was more consumed than in non-exposed cells, assumingly through the reaction with the dimethylarsenic-modified region of DNA. The species of active oxygens were estimated by using diethyldithiocarbamate, aminotriazole, diethylmaleate, hydrogen peroxide (H2O2), gamma-irradiation and ethanol. O2- but neither H2O2 nor hydroxyl radicals was very likely to contribute to the ssb-enhancing action of paraquat." ]
Gut microbiota in chronic kidney disease	A bidirectional kidney-gut axis was described in patients with chronic kidney disease (CKD). On the one hand, gut dysbiosis could promote CKD progression, but on the other hand, studies reported specific gut microbiota alterations linked to CKD. Therefore, we aimed to systematically review the literature on gut microbiota composition in CKD patients, including those with advanced CKD stages and end-stage kidney disease (ESKD), possibilities to shift gut microbiota, and its impact on clinical outcomes.	[ "The human gut microbiota has been identified as a possible novel risk factor for cardiovascular disease. The intestinal microbiome plays a role in the pathogenesis of atherosclerosis and heart failure. Even though studies in rodents suggested that gut microbes may affect the risk of heart disease, this link has not been shown in humans. In the present study, we review several potential mechanisms by which the gut microbiome and bacterial translocation are associated with the development of cardiac disorders making them potential targets for novel therapeutic measures for these conditions. Modulation of the gut microbiota as a mechanism for altering the pathogenesis of disorders is an area of growing interest. Alteration in the gut microbiota is being explored as a method of reducing risk factors associated with cardiac diseases.", "To investigate alteration of intestinal microflora in uremia patients with or without blood purification treatments. The present study included a total of 109 adult patients who were administered in our hospital during 2014 August to 2015 December, 85 cases had already received hemodialysis treatment and 24 cases had not received any renal transplantation treatments. Serum levels of hemoglobin, albumin, creatinine, hypersensitive C reactive protein, and cystatin C, as well as blood urea nitrogen and estimated glomerular filtration rate were determined. 16S rRNA sequencing was conducted to determine the levels of Bifidobacterium, Lactobacillus acidophilus, Escherichia coli, and Enterococcus faecalis. The hemoglobin level in the hemodialysis group was significantly higher than that of the non-hemodialysis patients. The levels of Bifidobacterium and Lactobacillus acidophilus were significantly lower while the levels of Escherichia coli and Enterococcus faecalis were significantly higher in both of the patient groups compared with the healthy control. In all treatment groups, levels of Bifidobacterium and Lactobacillus acidophilus were significantly higher and levels of Escherichia coli and Enterococcus faecalis were significantly lower compared with the non-blood purification treatment group. The intestinal microflora might be influenced by uremia and might also be affected by blood purification treatments.", "The interplay of the gut microbes with gut-producing nephrotoxins and the renal progression remains unclear in large human cohort. Significant compositional and functional differences in the intestinal microbiota (by 16S rRNA gene sequencing) were noted among 30 controls and 92 (31 mild, 30 moderate and 31 advanced) patients at different chronic kidney disease (CKD) stages (discovery cohort). A core CKD-associated microbiota consisted of 7 genera (Escherichia_Shigella, Dialister, Lachnospiraceae_ND3007_group, Pseudobutyrivibrio, Roseburia, Paraprevotella and Ruminiclostridium) and 2 species (Collinsella stercoris and Bacteroides eggerthii) were identified to be highly correlated with the stages of CKD. Paraprevotella, Pseudobutyrivibrio and Collinsella stercoris were superior in discriminating CKD from the controls than the use of urine protein/creatinine ratio, even at early-stage of disease. The performance was further confirmed in a validation cohort comprising 22 controls and 76 peritoneal dialysis patients. Bacterial genera highly correlated with indoxyl sulfate and p-cresyl sulfate levels were identified. Prediction of the functional capabilities of microbial communities showed that microbial genes related to the metabolism of aromatic amino acids (phenylalanine, tyrosine, and tryptophan) were differentially enriched among the control and different CKD stages. Collectively, our results provide solid human evidence of the impact of gut-metabolite-kidney axis on the severity of chronic kidney disease and highlight a usefulness of specific gut microorganisms as possible disease differentiate marker of this global health burden.", "Gut dysbiosis is associated with chronic kidney disease (CKD), and serum free immunoglobulin light chains (FLCs) are biomarkers for CKD. This study aims to assess the CKD gut microbiome and to determine its impact on serum FLC levels. To control for confounders, 100 patients and sex- and age-matched healthy controls (HCs) were recruited. The gut microbiome was assessed by sequencing 16S rRNA gene V3-V4 hypervariable regions. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was applied to infer functional metabolic pathways. When observing group differences in the microbiome and predicted metabolic pathways, demographic confounders were adjusted using binary logistic regression; when examining impacts of the gut microbiome and metabolic pathways on serum FLCs, factors influencing FLC levels were adjusted using multiple regression. Principal coordinate analysis revealed a significantly different bacterial community between the CKD and HC groups (P < 0.05). After adjusting for confounders, lower Chao 1, observed species and Shannon indices based on binary logistic regression predicted CKD prevalence. Actinobacteria, Alistipes, Bifidobacterium and Bifidobacterium longum enrichment, upregulation of metabolic pathways of bacterial toxin, chloroalkane and chloroalkene degradation, and Staphylococcus aureus infection also predicted CKD prevalence (P < 0.05). Furthermore, depletion of Actinobacteria and Bifidobacterium and reduced chloroalkane and chloroalkene degradation predicted high levels of FLC λ (P < 0.05). Gut dysbiosis in CKD patients was confirmed by controlling for confounders in the present study. Additionally, the association between gut dysbiosis and FLC λ levels demonstrates the existence of crosstalk between the microbiome and immune response in CKD.", "The gut microbiota can affect human metabolism, immunity, and other biologic pathways through the complex gut-kidney axis (GKA), and in turn participate in the occurrence and development of kidney disease. In this study, 39 patients with stage 4-5 chronic kidney disease (CKD) and 40 healthy individuals were recruited and 16S rDNA sequencing was performed to analyze the V3-V4 conserved regions of their microbiota. A total of 795 operational taxonomic units (OTUs) shared between groups or specific to each group were obtained, among which 255 OTUs with significant differences between the two groups were identified (P<0.05). Adonis differential analysis showed that the diversity of gut microbiota was highly correlated with CKD stages 4-5. Additionally, 61 genera with differences in the two groups were identified (P<0.05) and 111 species with significant differences in the phyla, classes, orders, families, and genera between the two groups were identified (P<0.05). The differential bacterial genera with the greatest contribution were, in descending order: c_Bacteroidia, o_Bacteroidales, p_Bacteroidetes, c_Clostridia, o_Clostridiales, etc. Those with the greatest contribution in stages 4-5 CKD were, in descending order: p_Proteobacteria, f_Enterobacteriaceae, o_Enterobacteriales, c_Gammaproteobacteria, c_Bacilli, etc. The results suggest that the diversity of the microbiota may affect the occurrence, development, and outcome of the terminal stages of CKD.", "Recent studies have shown that gut microbiota is associated with immunomodulation in transplant recipients, but the composition and function of gut microbiota in renal transplant recipients have not been understood. We analyzed the composition and function of gut microbiota in the fecal samples from 16 renal transplant (RT) recipients by deep sequencing of the 16S rRNA V3 variable region. The gut microbiota of RT recipients was compared to that of 84 patients with chronic kidney disease (CKD) and 53 healthy subjects. The overall microbial structure of RT recipients was similar to that of CKD. The abundance of Firmicutes, Lachnospiraceae, Ruminococcaceae and Faecalibacterium was decreased and that of Bacteroidetes, Proteobacteria, Clostridiales, and Enterobacteriaceae was increased significantly in RT recipients and CKD patients compared with the healthy control subjects. Functional comparison revealed significantly enhanced carbohydrate metabolism and decreased metabolism of cofactors, vitamins, cell motility and genetic information processing in RT recipients and CKD patients. RT recipients and CKD patients also showed slight differences in that the abundance of Proteobacteria and Enterobacteriaceae and the pathways involving transport system members and carbohydrate metabolism were much greater in the former. We found that several beneficial genera in the Lachnospiraceae and Veillonellaceae were negatively correlated with such clinical markers as serum creatinine and blood urea nitrogen. Our results suggested that alterations in the composition and function of gut microbiota are significantly correlated with the clinical conditions of in RT recipients, and future prospective studies of these correlations may provide evidence for predicting the clinical outcomes of RT recipients.", "Disrupted circadian rhythms and alterations of the gut microbiome composition were proposed to affect host health. Therefore, the aim of this research was to identify whether these events are connected and if circadian rhythm disruption by abnormal light-dark (LD) cycles affects microbial community gene expression and host vulnerability to intestinal dysfunction. Mice were subjected to either a 4-week period of constant 24-h light or of normal 12-h LD cycles. Stool samples were collected at the beginning and after the circadian rhythm disruption. A metatranscriptomic analysis revealed an increase in Ruminococcus torques, a bacterial species known to decrease gut barrier integrity, and a decrease in Lactobacillus johnsonii, a bacterium that helps maintain the intestinal epithelial cell layer, after circadian rhythm disruption. In addition, genes involved in pathways promoting host beneficial immune responses were downregulated, while genes involved in the synthesis and transportation of the endotoxin lipopolysaccharide were upregulated in mice with disrupted circadian cycles. Importantly, these mice were also more prone to dysfunction of the intestinal barrier. These results further elucidate the impact of light-cycle disruption on the gut microbiome and its connection with increased incidence of disease in response to circadian rhythm disturbances." ]
Experiences of NBGQ youth with microaggressions	This study explores the experiences of NBGQ youth with microaggressions. It investigates the types of microaggressions they face and their subsequent needs and coping mechanisms and the impacts on their lives. Semi-structured interviews with ten NBGQ youth in Belgium were conducted and analyzed using a thematic approach. The results showed that experiences of microaggressions were centered around denial. The most common ways to cope were finding acceptance from (queer) friends and therapists, engaging in a conversation with the aggressor, and rationalizing and empathizing with the aggressor, leading to self-blame and normalization of the experiences. Microaggressions were experienced as exhausting, which influenced the extent to which the NBGQ individuals wanted to explain themselves to others. Furthermore, the study shows an interaction between microaggressions and gender expression, in which gender expression is seen as a motive for microaggressions and microaggressions have an impact on the gender expression of NBGQ youth.	[ "It is vital that the treatment offered at transgender health services can be evaluated to ensure a high quality of care. However, the tools currently used to evaluate treatment at transgender health services are limited by mainly focusing on mental health or because they have been developed for binary transgender people only. This study therefore aimed to develop and validate a tool that addresses these limitations. The Gender Congruence and Life Satisfaction Scale (GCLS) was developed through reviewing the literature, conducting interviews with transgender people, and holding discussions with experts working in transgender healthcare. An initial pool of items was developed and feedback on these was obtained. The tool was then validated. For the validation of the tool, a total of 789 participants (451 transgender [171 transgender females, 147 transgender males, 133 people identifying as non-binary], and 338 cisgender [254 females, 84 males]) were recruited from the United Kingdom to test the factor structure and validity of the GCLS. Exploratory factor analysis retained 38 items which formed seven subscales (psychological functioning; genitalia; social gender role recognition; physical and emotional intimacy; chest; other secondary sex characteristics; and life satisfaction). These seven subscales were found to have good internal consistency and convergent validity. The GCLS was also found to be capable of discriminating between groups (e.g., people who have and have not undergone gender affirming medical interventions). Transgender and cisgender subscale norms are provided for the GCLS. The GCLS is a suitable tool to use with the transgender population to measure health-related outcomes for both clinical and research purposes.", "Although literature documents the experiences of socially assigned gender nonconformity (SAGNC) by minority sexual orientation (i.e., lesbian, gay, and bisexual [LGB]), examination of the role of gender expression on school violence outcomes in the presence of sexual orientation and gender identity is not well understood. This study describes SAGNC among a representative sample of adolescents, accounting for sexual orientation and gender identity (e.g., transgender). A secondary data analysis was conducted using Youth Risk Behavior Survey data from Los Angeles Unified School District high schools in 2013 (N = 1,496). The prevalence of school violence by self-reported SAGNC and gender identity was obtained. Associations between SAGNC and school violence were examined using multivariate logistic regression adjusted for mischievous response bias. Two hundred ninety-one (19.5%) adolescents reported SAGNC. Having missed school due to a safety concern and being bullied in the past year were more common among socially assigned gender nonconforming adolescents than those who conformed to gender expression expectations. Socially assigned gender nonconforming adolescents, regardless of sexual orientation or gender identity, are at greater risk of missed school due to safety concerns, and bullying, as compared with those who conform to norms of gender expression. Future research should measure SAGNC, sexual orientation, gender identity, and expression with larger representative samples of school populations across contexts (urban and rural), and inclusive of structural factors (e.g., school climate) to guide the development of prevention efforts.", "In recent years, puberty suppression by means of gonadotropin-releasing hormone analogs has become accepted in clinical management of adolescents who have gender dysphoria (GD). The current study is the first longer-term longitudinal evaluation of the effectiveness of this approach. A total of 55 young transgender adults (22 transwomen and 33 transmen) who had received puberty suppression during adolescence were assessed 3 times: before the start of puberty suppression (mean age, 13.6 years), when cross-sex hormones were introduced (mean age, 16.7 years), and at least 1 year after gender reassignment surgery (mean age, 20.7 years). Psychological functioning (GD, body image, global functioning, depression, anxiety, emotional and behavioral problems) and objective (social and educational/professional functioning) and subjective (quality of life, satisfaction with life and happiness) well-being were investigated. After gender reassignment, in young adulthood, the GD was alleviated and psychological functioning had steadily improved. Well-being was similar to or better than same-age young adults from the general population. Improvements in psychological functioning were positively correlated with postsurgical subjective well-being. A clinical protocol of a multidisciplinary team with mental health professionals, physicians, and surgeons, including puberty suppression, followed by cross-sex hormones and gender reassignment surgery, provides gender dysphoric youth who seek gender reassignment from early puberty on, the opportunity to develop into well-functioning young adults.", "Background: The social challenges that non-binary people experience, due in part to social intolerance and the lack of validation of non-binary gender identities, may affect the mental health and quality of life of this population. However, studies that have distinguished between non-binary and binary transgender identities are lacking. Aim: To compare the mental health and quality of life of a community sample of non-binary transgender adults with controls (binary transgender people and cisgender people) matched on sex assigned at birth. Method: A total of 526 participants were included. Ninety-seven were classified as non-binary and were compared with two control groups: 91 people classified as binary and 338 cisgender people. Only transgender people not on gender affirming hormone treatment or who had not undergone gender affirming surgery were included. Participants were invited to complete an online survey that included mental health and quality of life measures. Results: Non-binary people reported significantly better mental health than binary transgender people, but worse than cisgender people. Overall, there were no significant differences in quality of life between non-binary and binary transgender participants assigned male at birth and transgender females, but non-binary assigned males at birth had better scores on the psychological and social domains of quality of life than transgender males. Quality of life was better across all domains in cisgender people than transgender groups. Conclusion: There is an inequality with regard to mental health and quality of life between non-binary (and binary) transgender people and the cisgender population that needs to be addressed. The better mental health scores in non-binary people may reflect lower levels of body dissatisfaction among the non-binary population. Mental health problems and poor quality of life are likely to have social causes and hence legislative measures and broader government-led inclusive directives should be put in place to recognize and to validate non-binary identifying people." ]

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