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Mountains play an outsized role in water resource availability, and the amount and timing of water they provide depend strongly on temperature. To that end, we ask the question: How well are atmospheric models capturing mountain temperatures? We synthesize results showing that high-resolution, regionally relevant climate models produce 2-m air temperature (T2m) measurements colder than what is observed (a 'cold bias'), particularly in snow-covered midlatitude mountain ranges during winter. We find common cold biases in 44 studies across global mountain ranges, including single-model and multimodel ensembles. We explore the factors driving these biases and examine the physical mechanisms, data limitations, and observational uncertainties behind T2m. Our analysis suggests that the biases are genuine and not due to observation sparsity or resolution mismatches. Cold biases occur primarily on mountain peaks and ridges, whereas valleys are often warm biased. Our literature review suggests that increasing model resolution does not clearly mitigate the bias. By analyzing data from the Surface Atmosphere Integrated Field Laboratory (SAIL) field campaign in the Colorado Rocky Mountains, we test various hypotheses related to cold biases and find that local wind circulations, longwave (LW) radiation, and surface-layer parameterizations contribute to the T2m biases in this particular location. We conclude by emphasizing the value of coordinated model evaluation and development efforts in heavily instrumented mountain locations for addressing the root cause(s) of T2m biases and improving predictive understanding of mountain climates. SIGNIFICANCE STATEMENT: Mountain climates are rapidly changing, and along with them are the temperature-sensitive components of the water budget that societies have relied on. Yet atmospheric models, from those that predict the weather to those that predict the future climate, are several degrees too cold on average in these same mountain regions. This cold bias has not been systematically identified in the published literature yet, so we discuss evidence of its pervasiveness across models, its potential causes, and pathways to eliminate it using targeted models and observations. With community support, this bias can be uprooted, thereby enabling model projections that better project the climatic and water resource changes in these vital regions. KEYWORDS: Mountain meteorology; Model evaluation/ performance; Temperature; Climate, 1. Introduction In this study, we compile evidence suggesting that many types of high-resolution atmospheric models (Gutowski et al. 2020) report cold biases in 2-m air temperature ('T2m') measurements across [...]

Human immunodeficiency virus (HIV) is a retrovirus that infects and destroys CD4 T cells. In the United States, HIV infection affects an estimated 1,189,700 individuals 13 years and older. (1) [...]

Background BRCA1 and BRCA2 (BRCA1/2) are the most frequently investigated genes among Caucasian pancreatic cancer patients, whereas limited reports are available among Asians. We aimed to investigate the prevalence of BRCA1/2 germline variants in Pakistani pancreatic cancer patients. Methods One hundred and fifty unselected and prospectively enrolled pancreatic cancer patients were comprehensively screened for BRCA1/2 germline variants using denaturing high-performance liquid chromatography and high-resolution melting analyses, followed by DNA sequencing of the variant fragments. The novel variants were analyzed for their pathogenic effect using in-silico tools. Potentially functional variants were further screened in 200 cancer-free controls. Results Protein truncating variant was detected in BRCA2 only, with a prevalence of 0.7% (1/150). A frameshift BRCA2 variant (p.Asp946Ilefs*14) was identified in a 71-year-old male patient of Pathan ethnicity, with a family history of abdominal cancer. Additionally, we found a novel variant in BRCA2 (p.Glu2650Gln), two previously reported variants in BRCA1 (p.Thr293Ser) and BRCA2 (p.Ile2296Leu) and a recurrent nonsense variant in BRCA2 (p.Lys3326Ter). These variants were classified as variants of uncertain significance (VUS). It is noteworthy that none of these VUS carriers had a family history of pancreatic or other cancers. Conclusions In this first study, BRCA1/2 pathogenic variant is identified with a low frequency in pancreatic cancer patients from Pakistan. Comprehensive multigene panel testing is recommended in the Pakistani pancreatic cancer patients to enhance genetic understanding in this population. Keywords: BRCA1, BRCA2, Germline variants, Pancreatic cancer, Pakistan, Author(s): Noor Muhammad[sup.1,2], Ayesha Azeem[sup.1], Shumaila Arif[sup.1], Humaira Naeemi[sup.1], Iqra Masood[sup.3], Usman Hassan[sup.4], Bushra Ijaz[sup.2], Faisal Hanif[sup.5,6], Aamir Ali Syed[sup.5], Muhammed Aasim Yusuf[sup.7] and Muhammad Usman Rashid[sup.1] Background Pancreatic cancer [...]

The incidence and prevalence of hypothyroidism in pregnancy have increased over the past two decades, leading to the occurrence of neuropsychiatric disorders. However, the underlying mechanisms of thyroid hormone (TH)-regulated gene expression and neuropsychiatric development during the postnatal period remain unknown. Recent achievements have shown that reelin, a large extracellular glycoprotein, plays a crucial role in neuronal migration and localization during the development of neocortex and cerebellar cortex, thereby participating in the development of neuropsychiatric diseases. Reelin- induced neuronal migration requires triiodothyronine (T3) from the deiodination of thyroxine (T4) by fetal brain deiodinases. Previous studies have reported decreased reelin levels and abnormal gene expression, which are the same as the pathological alternations in reelin-induced neuropsychiatric disorders including schizophrenia and autism. Low T3 in the fetal brain due to hypothyroxinemia during pregnancy may be detrimental to neuronal migration, leading to neuropsychiatric disorders. In this review, we focus on the reelin expression between hypothyroidism and neuropsychiatric disorders. Key words: thyroid hormones, reelin, neurological diseases, pregnancy L'incidence et la prevalence de l'hypothyroidie de grossesse ont augmente au cours des vingt dernieres annees, ce qui a mene a la survenue de troubles neuropsychiatriques. Cependant, les modes d'action sous-jacents de l'expression genique regulee par l'hormone thyroidienne (HT) et le developpement neuropsychiatrique au cours de la periode postnatale demeurent inconnus. De recents travaux ont montre que la reeline, une proteine extracellulaire de grande taille, joue un role central dans la migration et la localisation des neurones au cours du developpement du neocortex et du cortex cerebelleux, participant par le fait meme a l'apparition de maladies neuropsychiatriques. La migration neuronale engendree par la reeline exige la presence de triiodothyronine (T3) issue de la deiodination de la thyroxine (T4) par les deiodinases du cerveau foetal. Des etudes anterieures ont rapporte une diminution des taux de reeline et une expression genique anormale, qui sont les memes modifications pathologiques que dans les troubles neuropsychiatriques qu'engendre la reeline, y compris la schizophrenie et l'autisme. Un abaissement de la T3 dans le cerveau foetal an raison de l'hypothyroxinemie pendant la grossesse peut etre nefaste a la migration neuronale et mener a des troubles neuropsychiatriques. Cet article de synthese est axe sur l'expression de la reeline entre l'hypothyroidie et certains troubles neuropsychiatriques. [Traduit par la Redaction] Mots-cles : hormones thyroidiennes, reeline, maladies neurologiques, grossesse, 1. Introduction Recent studies have shown that maternal hypothyroidism is a common endocrine disease, which leads to a high risk of adverse pregnancy outcomes, including pre-eclampsia, premature delivery, postnatal asphyxia, [...]

Purpose Severe community-acquired pneumonia (CAP) requiring intensive care unit admission is associated with significant acute and long-term morbidity and mortality. We hypothesized that downregulation of systemic and pulmonary inflammation with prolonged low-dose methylprednisolone treatment would accelerate pneumonia resolution and improve clinical outcomes. Methods This double-blind, randomized, placebo-controlled clinical trial recruited adult patients within 72-96 h of hospital presentation. Patients were randomized in 1:1 ratio; an intravenous 40 mg loading bolus was followed by 40 mg/day through day 7 and progressive tapering during the 20-day treatment course. Randomization was stratified by site and need for mechanical ventilation (MV) at the time of randomization. Outcomes included a primary endpoint of 60-day all-cause mortality and secondary endpoints of morbidity and mortality up to 1 year of follow-up. Results Between January 2012 and April 2016, 586 patients from 42 Veterans Affairs Medical Centers were randomized, short of the 1420 target sample size because of low recruitment. 584 patients were included in the analysis. There was no significant difference in 60-day mortality between the methylprednisolone and placebo arms (16% vs. 18%; adjusted odds ratio 0.90, 95% CI 0.57-1.40). There were no significant differences in secondary outcomes or complications. Conclusions In patients with severe CAP, prolonged low-dose methylprednisolone treatment did not significantly reduce 60-day mortality. Treatment was not associated with increased complications., Author(s): G. Umberto Meduri [sup.1] [sup.2], Mei-Chiung Shih [sup.3] [sup.4], Lisa Bridges [sup.1] [sup.2], Thomas J. Martin [sup.5] [sup.6] [sup.7], Ali El-Solh [sup.8] [sup.9], Nitin Seam [sup.10], Anne Davis-Karim [sup.11], [...]

Hyponatremia, especially if acute and severe, can be a life-threatening condition. Several conditions can trigger hyponatremia. In this review, we will discuss two conditions that can determine euvolemic hyponatremia: the cerebral/renal salt wasting (CRSW) syndrome and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), including the two subtypes: reset osmostat (RO) and nephrogenic syndrome of inappropriate antidiuresis (NSIAD) and their differential diagnoses. Despite the passage of over 70 years since its first description, to date, the true etiopathogenesis of CRSW syndrome, a rare cause of hypovolemic/euvolemic hyponatremia, is almost unknown. SIADH, including RO and NSIAD, is sometimes difficult to differentiate from CRSW syndrome; in its differential diagnosis, the clinical approach based on the evaluation of the extracellular volume (ECV) was proven insufficient. We therefore suggest a simple diagnostic algorithm based on the assessment of the degree of hyponatremia, urinary osmolality, and the assessment of the fraction of urate excretion (FEUa) in conditions of hyponatremia and after serum sodium correction, to be applied in children over 1 year of life., Author(s): Flaminia Bardanzellu [sup.1] , Maria Antonietta Marcialis [sup.1] , Roberta Frassetto [sup.1] , Alice Melis [sup.1] , Vassilios Fanos [sup.1] Author Affiliations: (1) grid.7763.5, 0000 0004 1755 3242, Neonatal [...]

Multidrug resistance (MDR) is often a major impediment to successful chemotherapy in the treatment of cancer. A common mechanism for MDR is the overexpression of an active ATP-binding cassette (ABC) transporter protein, P-glycoprotein (P-gp/ABCBl, also known as MDR1), multidrug resistance protein 1 (MRP1/ABCC1), or breast cancer resistant protein (BCRP/ABCG2), on the plasma membrane of cancer cells. These transporters can pump many structurally diverse anticancer drugs out of the cancer cells and render these drugs ineffective at a therapeutic dosage, i.e., multidrug resistance. Coadministration of a potent ABC transporter inhibitor with an anticancer drug has been evaluated in several clinical trials to overcome MDR but has led to a disappointing outcome. By taking advantage of the pseudo-dimeric structure of ABC transporters, we demonstrated that some flavonoid dimers, using polyvalent interactions, can be potent inhibitors of ABC transporters. Selective inhibition of the three different transporters with flavonoid dimers can be achieved by placing the two flavonoid moieties at an optimal distance apart specific for each transporter. In addition to being potent and selective inhibitors of the transporters, flavonoid dimers are found to be nontoxic to normal cells at their corresponding effective concentrations. The in vivo efficacy of flavonoid dimers was demonstrated. Further investigation of these flavonoid dimers as clinical candidates to overcome MDR in cancer chemotherapy is warranted Key words: click chemistry, CuAAC reaction, multidrug resistance, P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), breast cancer resistant protein (BCRP), modulators, flavonoids. La multirésistance aux médicaments est souvent un obstacle majeur à la réussite d'une chimiothérapie dans le traitement du cancer. La multirésistance aux médicaments est souvent le résultat de la surexpression d'un transporteur actif ABC (ATP binding cassette) - soit la glycoprotéine P (P gp/ABCBl, également connue sous le nom de MDR1), la protéine de multirésistance aux médicaments 1 (MRP1/ABCC1) ou la protéine de résistance du cancer du sein (BCRP/ABCG2) - sur la membrane plasmique des cellules cancéreuses. Ces transporteurs sont capables de pomper de nombreux agents anticancéreux de structures diverses hors des cellules cancéreuses et les rendre inefficaces aux doses thérapeutiques. On parle alors de multirésistance aux médicaments. La co-administration d'un inhibiteur puissant du transporteur ABC avec un agent anticancéreux a été évaluée dans le cadre de plusieurs essais cliniques afin de contrer la multirésistance aux médicaments, mais les résultats ont été décevants. En tirant parti de la structure pseudo-dimérique des transporteurs ABC, nous avons démontré que certains dimères de flavonoïdes, par des interactions polyvalentes, peuvent agir comme de puissants inhibiteurs des transporteurs ABC. Il est possible d'obtenir une inhibition sélective des trois transporteurs différents par les dimères de flavonoïdes en positionnant les deux groupes flavonoïdes à une distance optimale propre à chacun des transporteurs. Non seulement les dimères de flavonoïdes sont des inhibiteurs puissants et sélectifs des transporteurs, mais ils sont aussi non toxiques pour les cellules normales à leurs concentrations efficaces respectives. Nous avons fait la démonstration de l'efficacité in vivo des dimères de flavonoïdes. Une étude plus approfondie de ces dimères de flavonoïdes comme candidats cliniques pour contrer la multirésistance aux médicaments s'impose dans le contexte de la chimiothérapie contre le cancer. [Traduit par la Rédaction] Mots-clés : chimie clic, réaction CuAAC, multirésistance aux médicaments, glycoprotéine P (P gp), protéine de multirésistance aux médicaments 1 (MRP1), protéine de résistance du cancer du sein (BCRP), modulateurs, flavonoids., 1. Introduction 1.1. ATP-binding cassette transporter proteins ATP-binding cassette (ABC) transporters are a superfamily of proteins in the membrane. They transport a variety of compounds through membranes against concentration gradients, [...]

There is a pervasive and comprehensive history of sexism in the pursuit of scientific truth, extending back beyond the days of 'hysteria' and continuing still. Herein, we discuss a disparity in scientific research on a disorder thought to affect less than 8% of the adult population in the USA with the number of women diagnosed with the disorder estimated to be two to three times higher than that of men. While post-traumatic stress disorder (PTSD) is more likely to be experienced by women, we find that the overwhelming majority of published scientific literature on PTSD involves male combat veterans. For example, since March 2019, according to a widely used medical research search engine, specifically the electronic database PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), over 1,100 articles can be found with the keywords, 'veteran and PTSD' while using the keywords, 'sexual assault and PTSD' yields a little over 100 total articles. While not all victims of sexual assault are female and not all combat veterans are male, the majority sex in each category is such that much of the research on 'veteran' was specifically carried out with male veterans and much of the work on 'sexual abuse' was carried out exclusively with females. This creates a perception that both overinflates the incidence of PTSD experienced by male combat veterans and underemphasizes the experience of PTSD in female victims of sexual assault. Differences in symptoms of PTSD do vary by war and what little research exists on PTSD after sexual assault suggests that it is likely that symptoms as well as associated comorbidities will vary depending on the cause, type, number, and age at first trauma, among other factors. This study focuses on the specific comorbidities of pain, addiction, and immune function in those who experience PTSD following war-based or sexually-based traumas. It is our hope that in reviewing the currently available research, we spotlight the need for research focused on PTSD experienced after sexual assault. Doing so has the potential to lead to better and more tailored treatments for PTSD, thus enriching outcomes for all sufferers of PTSD. Keywords: Sex-differences, PTSD, Bias in research, Introduction Culture, politics, the legal and judicial systems as well as institutionalized 'truths' suffuse our fundamental understanding of biology in a way that usually promotes the status quo to foster [...]

The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy.sup.1,2. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-[alpha] gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes. A robust, cost-effective technique based on whole-exome sequencing data can be used to characterize immune infiltrates, relate the extent of these infiltrates to somatic changes in tumours, and enables prediction of tumour responses to immune checkpoint inhibition therapy., Author(s): Robert Bentham [sup.1] [sup.2] , Kevin Litchfield [sup.2] [sup.3] , Thomas B. K. Watkins [sup.4] , Emilia L. Lim [sup.2] [sup.4] , Rachel Rosenthal [sup.4] , Carlos Martínez-Ruiz [sup.1] [...]

Background Colorectal cancer (CRC) is a highly prevalent disease in developed countries. Inherited Mendelian causes account for approximately 5% of CRC cases, with Lynch syndrome and familial adenomatous polyposis being the most prevalent forms. Scientific efforts are focused on the discovery of new candidate genes associated with CRC and new associations of phenotypes with well-established cancer-related genes. BRCA1-associated ring domain (BARD1) gene deleterious germline variants are associated with a moderate increase in the relative risk of breast cancer, but their association with other neoplasms, such as CRC, remains unclear. Case presentation We present the case of a 49-year-old male diagnosed with rectal adenocarcinoma whose maternal family fulfilled Amsterdam clinical criteria for Lynch syndrome. Genetic test confirmed the presence in heterozygosis of a germline pathogenic deletion of exons 8-11 in BARD1 gene. The predictive genetic study of the family revealed the presence of this pathogenic variant in his deceased cancer affected relatives, confirming co-segregation of the deletion with the disease. Conclusions To the best of our knowledge, this is the first published work in which this BARD1 deletion is detected in a family with familial colorectal cancer type X (FCCTX) syndrome, in which the clinical criteria for Lynch syndrome without alteration of the DNA mismatch repair (MMR) system are fulfilled. Whether this incidental germline finding is the cause of familial colorectal aggregation remains to be elucidated in scientific forums. Patients should be carefully assessed in specific cancer genetic counseling units to account for hypothetical casual findings in other genes, in principle unrelated to the initial clinical suspicion, but with potential impact on their health. Keywords: Colorectal cancer, Hereditary, BARD1, Pathogenic variant, Deletion, Amsterdam clinical criteria, Familial colorectal cancer type X syndrome, Cancer genetic counseling, Author(s): Sergio Carrera[sup.1], Ana Belén Rodríguez-Martínez[sup.2], Intza Garin[sup.3], Esther Sarasola[sup.2], Cristina Martínez[sup.3], Hiart Maortua[sup.3], Almudena Callejo[sup.4], Abigail Ruiz de Lobera[sup.4], Alberto Muéoz[sup.4], Nagore Miéambres[sup.4] and Pablo Jiménez-Labaig[sup.4] Background CRC is [...]

Background Risk assessment for hereditary cancer syndromes is recommended in primary care, but family history is rarely collected in enough detail to facilitate risk assessment and referral - a roadblock that disproportionately impacts individuals with healthcare access barriers. We sought to qualitatively assess a literacy-adapted, electronic patient-facing family history tool developed for use in diverse, underserved patient populations recruited in the Cancer Health Assessments Reaching Many (CHARM) Study. Methods Interview participants were recruited from a subpopulation of CHARM participants who experienced barriers to tool use in terms of spending a longer time to complete the tool, having incomplete attempts, and/or providing inaccurate family history in comparison to a genetic counselor-collected standard. We conducted semi-structured interviews with participants about barriers and facilitators to tool use and overall tool acceptability; interviews were recorded and professionally transcribed. Transcripts were coded based on a codebook developed using inductive techniques, and coded excerpts were reviewed to identify overarching themes related to barriers and facilitators to family history self-assessment and acceptability of the study tool. Results Interviewees endorsed the tool as easy to navigate and understand. However, they described barriers related to family history information, literacy and language, and certain tool functions. Participants offered concrete, easy-to-implement solutions to each barrier. Despite experience barriers to use of the tool, most participants indicated that electronic family history self-assessment was acceptable or preferable in comparison to clinician-collected family history. Conclusions Even for participants who experienced barriers to tool use, family history self-assessment was considered an acceptable alternative to clinician-collected family history. Barriers experienced could be overcome with minor adaptations to the current family history tool. Trial registration This study is a sub-study of the Cancer Health Assessments Reaching Many (CHARM) trial, ClinicalTrials.gov, NCT03426878. Registered 8 February 2018. Keywords: Underserved, Hereditary cancer risk assessment, Digital health, Genetics, Author(s): Kathleen F. Mittendorf[sup.1], Hannah S. Lewis[sup.2], Devan M. Duenas[sup.2], Donna J. Eubanks[sup.3], Marian J. Gilmore[sup.4], Katrina A. B. Goddard[sup.5], Galen Joseph[sup.6], Tia L. Kauffman[sup.3], Stephanie A. Kraft[sup.2,7], Nangel M. [...]

Byline: Shivanshu. Misra, Shankar. Balasubramanian, B. Srikanth, Saravana. Kumar, S. Christinajoice, Deepa. Nandhini, P. Raj Context: The importance of upper gastrointestinal (UGI) contrast study following sleeve gastrectomy (SG) is equivocal. [...]