Miracle-dz/UniFAR-FTUs huggingface dataset:
High density of cytotoxic T-lymphocytes is linked to tumoral PD-L1 expression regardless of the mismatch repair status in colorectal cancer

Abstract Background Immune checkpoint-inhibitors targeting the PD-1/PD-L1 system are FDA approved in microsatellite instable (MSI) or mismatch repair deficient (dMMR) colorectal cancer (CRC). PD-L1 expression is tightly linked to features connected to immune checkpoint inhibitor response, but studies on large subsets of cancers analyzing the correlation between different status of MSI/dMMR, tumor infiltrating lymphocytes and PD-L1 expression are still lacking. Methods More than 1800 CRC were analyzed for PD-L1 by immunohistochemistry in a tissue microarray format. Data were compared to MMR, the number of intratumoral CD8+ cytotoxic T-cells, and adverse clinico-pathological parameters. Different cutoff levels for defining PD-L1 positivity in tumor cells (1%, 5%, 10%, and 50%) yielded comparable results. Results At a cutoff level of 5%, PD-L1 positivity was seen in 5.1% of tumors. PD-L1 was more often positive in dMMR (18.6%) than in MMR proficient (pMMR) cancers (4.1%; p < 0.0001). The number of intratumoral CD8+ lymphocytes was strikingly higher in PD-L1 positive (939.5 ± 118.2) than in PD-L1 negative cancers (310.5 ± 24.8). A higher number of intratumoral CD8+ lymphocytes was found in dMMR CRC (PD-L1 positive: 1999.7 ± 322.0; PD-L1 negative: 398.6 ± 128.0; p < 0.0001) compared to pMMR CRC (PD-L1 positive: 793.2 ± 124.8; PD-L1 negative: 297.2 ± 24.2; p < 0.0001). In dMMR and pMMR CRC, PD-L1 expression in tumor cells was unrelated to tumor stage, lymph node status or lymphatic/venous invasion. PD-L1 positivity in tumor associated immune cells was seen in 47.5% of cases and was significantly linked to high numbers of tumor infiltrating CD8+, low tumor stage, and absence of lymph node metastasis and lymphatic/venous invasion (p < 0.0001 each). Conclusion The data support the previously suggested fact that PD-L1 expression in tumor cells is driven by extensive cytotoxic T-cell infiltration in highly immunogenic dMMR and pMMR CRC. Frequent and intense PD-L1 expression in tumor cells of dMMR CRC may contribute to the high response rates of dMMR CRC to immune checkpoint-inhibitors.
Annual precipitation explains variability in dryland vegetation greenness globally but not locally

Dryland vegetation productivity is strongly modulated by water availability. As precipitation patterns and variability are altered by climate change, there is a pressing need to better understand vegetation responses to precipitation variability in these ecologically fragile regions. Here we present a global analysis of dryland sensitivity to annual precipitation variations using long‐term records of normalized difference vegetation index (NDVI). We show that while precipitation explains 66% of spatial gradients in NDVI across dryland regions, precipitation only accounts for <26% of temporal NDVI variability over most (>75%) dryland regions. We observed this weaker temporal relative to spatial relationship between NDVI and precipitation across all global drylands. We confirmed this result using three alternative water availability metrics that account for water loss to evaporation, and growing season and precipitation timing. This suggests that predicting vegetation responses to future rainfall using space‐for‐time substitution will strongly overestimate precipitation control on interannual variability in aboveground growth. We explore multiple mechanisms to explain the discrepancy between spatial and temporal responses and find contributions from multiple factors including local‐scale vegetation characteristics, climate and soil properties. Earth system models (ESMs) from the latest Coupled Model Intercomparison Project overestimate the observed vegetation sensitivity to precipitation variability up to threefold, particularly during dry years. Given projections of increasing meteorological drought, ESMs are likely to overestimate the impacts of future drought on dryland vegetation with observations suggesting that dryland vegetation is more resistant to annual precipitation variations than ESMs project.
Lipoprotein Particle Profiles Compared With Standard Lipids in the Association With Subclinical Aortic Valve Calcification in Apparently Healthy Japanese Men.

BACKGROUND Risk factors for atherosclerotic disease including dyslipidemia have been shown to be associated with aortic valve calcification (AVC). Nuclear magnetic resonance (NMR)-measured lipoprotein particles, low-density and high-density lipoprotein particles (LDL-p, HDL-p) in particular, have emerged as novel markers of atherosclerotic disease; however, whether NMR-measured particles are associated with AVC remains to be determined. This study aimed to examine the association between NMR-based lipoprotein particle measurements and standard lipids with AVC. The primary variables of interest were LDL-p (nmol/L), HDL-p (μmol/L), LDL-cholesterol, and HDL-cholesterol (both in mg/dL). Methods and Results:A community-based random sample of Japanese men aged 40-79 years examined in 2006-2008, in Shiga, Japan was studied. Presence of AVC was defined as an Agatston score >0. Lipoprotein particles were measured using NMR spectroscopy. In the main analysis, multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for the prevalence of AVC across the higher quartiles of lipids in reference to the lowest ones were obtained. Of 874 participants analyzed, 153 men had AVC. Multivariable-adjusted ORs of prevalent AVC for the highest vs. the lowest quartile were significantly elevated for LDL-p (OR, 2.20; 95% CI: 1.23-3.93) and LDL-cholesterol (OR, 2.16; 95% CI: 1.23-3.78). In contrast, neither HDL-p nor HDL-cholesterol was associated with AVC. CONCLUSIONS The association of prevalent AVC with NMR-based LDL-p was comparable to that with LDL-cholesterol.
Connexin 43 contributes to phenotypic robustness of the mouse skull

We compared skull shape and variation among genetically modified mice that exhibit different levels of connexin43 (Cx43) channel function, to determine whether Cx43 contributes to craniofacial phenotypic robustness. Specifically, we used two heterozygous mutant mouse models (G60S/+ and I130T/+) that, when compared to their wildtype counterparts, have an ~80% and ~50% reduction in Cx43 function, respectively.
Maternal and fetal outcome of burn during pregnancy: 3rd report from Kermanshah, Iran.

OBJECTIVE Burn injuries in the course of pregnancy can lead to significant complications and mortality for both mother and fetus. Mortality and morbidity depend on the severity of burn. The current article is the third report authored on burn during pregnancy from Kermanshah, Iran. METHOD The present descriptive analytic study seeks to review the entire number of files belonging to the pregnant women with burn injury admitted in the Burn Ward of Imam Khomeini Hospital in Kermanshah during the period 2012-2020. Demographic data and fetal and maternal complications and outcome were extracted. Chi-square test was applied to analyze quantitative parameters statistically, and probit regression analysis was performed to calculate the Lethal Area 50% (LA50%) index. RESULTS Thirty-seven patients with mean age of 32 ± 6.07 years and mean gestational age of 19.5 ± 10.47 years were enrolled. Fifteen (40.5%) patients had undergone less than 25% total burn surface area (TBSA), 5 (13.5%) 25%-50%, and 17 (45.9%) more than 50%. Maternal mortality was 16 (43.2%). Fetal complications included premature labor in 4, abortion in 14, and intrauterine fetal death in 7 cases. LA50% was calculated as 54%. CONCLUSION Burn during pregnancy has a high rate of maternal and fetal mortality. These complications are highly related to severity of burn and TBSA. Preventive measures can play an important role in decreasing complications.
A Comparison of Two Five-Factor Model Operationalizations of the Triarchic Model of Psychopathy in a Clinical Sample

Structural models of personality traits, particularly the five-factor model (FFM), continue to inform ongoing debates regarding what personality attributes and trait domains are central to psychopathy. A growing body of literature has linked the constructs of the triarchic model of psychopathy (boldness, meanness, disinhibition) to the FFM. Recently, researchers developed both item and regression-based measures of the triarchic model of psychopathy using the NEO Personality Inventory–Revised—a popular measure of the FFM. The current study examines the correlates of these two FFM-derived operationalizations of the triarchic model using data from the Collaborative Longitudinal Personality Disorders Study. The two approaches had strong convergent validity coefficients and similar patterns of criterion-related validity coefficients. Meanness related to greater personality pathology characterized by exploitation of others and poor attachment, whereas disinhibition related to indicators of greater negative affect and poor behavioral constraint. Boldness related to reduced negative affect and greater narcissistic personality traits. Although the item and regression-based approaches showed similar patterns of associations with criterion-variables, the item-based approach has some practical and psychometric advantages over the regression-based approach given strong correlations between the meanness and disinhibition scores from the regression approach.
An open-label pilot study of pregabalin pharmacotherapy for alcohol use disorder

ABSTRACT Background: There is a need for alcohol use disorder (AUD) pharmacotherapy that can be administered to actively drinking outpatients. Pregabalin, a gabapentoid anticonvulsant, has preliminary evidence supporting effects on alcohol withdrawal and AUD. Objectives: To evaluate the safety, tolerability, and optimal dosing of pregabalin for treating AUD. Methods: In an open-label, 8-week, outpatient trial of eighteen adults (nine women) with AUD, participants were titrated to 600 mg/day (or the maximum tolerated dose) over 3 weeks and then maintained for 5 weeks. Results: The majority (11/14, 78.6%) of participants with at least one-week of medication exposure achieved a maximum dose of 600 mg/day. Mean retention was 6.8 weeks (SD = 2.6). Eighty percent (12/15) of participants with post-enrollment data reported any adverse effects during the trial; and for those reporting adverse effects the most common were drowsiness (33.3%, 4/12), and fogginess (25%, 3/12), dizziness (25%, 3/12), and insomnia (25%, 3/12). Two participants discontinued study medication due to adverse effects and one had a dose reduction. Mean Heavy Drinking Days (HDD)/week decreased significantly by 3.43 days (SD = 2.47; median (IQR) = 4.00 (1.00 to 5.50)); Wilcoxon signed rank test statistic ((S) = 49.5, p = . 0006). Mean proportion of HDD significantly decreased on average by 48.7% (SD = 35.1%; median (IQR) = 57.1% (14.3% to 78.6%)). The proportion of abstinent days increased significantly on average by 36.1% (SD = 35.0%; median (IQR) = 17.9% (14.3% to 75.0%); S = 49.5, p = . 0005). Conclusions: Pregabalin treatment of AUD appears to be safe and well tolerated in doses up to 600 mg per day. Trial Registration: clinicaltrials.gov identifier: NCT03256253
Household slow sand filter efficiency with schmutzdecke evaluation by microsensors

ABSTRACT Slow sand filtration is a common technology providing potable water in rural households across Latin America, Asia and Africa. Two PVC household slow sand filters (HSSF) were operated in continuous (C-HSSF) and intermittent (I-HSSF) flow modes for eight consecutive months. A non-woven blanket was installed on the fine sand top to facilitate cleaning with scheduled maintenance undertaken every 30 days. The efficiency of each HSSF was evaluated via physico-chemical indicators (reduction of turbidity and colour) with biological performance assessed via total coliform and E. coli enumeration post treatment. There were no statistically significant differences between the continuous flow and intermittent flow models for physical–chemical and total coliform reduction parameters. However, when evaluating E. coli, C-HSSF performed better (p = 0.02). The non-woven blanket was subjected to weekly analysis using a Clark-type amperometric microsensor (diameter < 20 µm), which measured dissolved oxygen (DO) concentration in the adherent biofilm. DO microprofiles illustrated a variation in biofilm growth, which were associated with a progressive increase in the HSSF efficiency. The maximum DO depletion value measured during several months of operation showed no significant difference between I-HSSF and C-HSSF (p = 0.98). The microsensor measurements provided unprecedented results in real time. These results can help to understand the efficiency of the filter in relation to the biofilm growth, the dissolved oxygen depletion and turbidity removal. GRAPHICAL ABSTRACT
IL-23 inhibition for the treatment of psoriatic arthritis

ABSTRACT Introduction Psoriatic arthritis (PsA) is a complex, polygenic immune-mediated disease with varying clinical presentations involving the skin, nails, entheses, and axial/peripheral skeleton. Areas covered Pathophysiology of PsA with special focus on IL-23/IL-17 axis. Novel classes of targeted therapies for PsA. Pharmacologic properties, efficacy and safety of guselkumab, the only FDA approved agent from IL-23p19 inhibitor class. Data regarding other IL-23 inhibitors (Ustekinumab – an IL-12/IL-23p40 inhibitor, Risankizumab and Tildrakizumab – both IL23p19 inhibitors), in the treatment of PsA. Expert opinion There are seven classes of FDA-approved therapies for the treatment of PsA. IL-23p19 inhibitors are the newest class of medications that has shown efficacy and reasonable safety profile in the treatment of PsA in phase 2 and phase 3 studies; Guselkumab is the only FDA-approved biologic for PsA within this class . While no head-to-head studies of IL-23p19 inhibitors and other PsA targeted therapies are available, the efficacy of these agents on musculoskeletal system appears to be comparable to TNF-inhibitors (TNFi), and the efficacy on the skin appears to be comparable, or modestly superior to the IL-17 inhibitors (IL-17i). With a superior safety profile compared to TNFi and IL-17i, IL-23p19 inhibitors have the potential to become a first-line biologic in the treatment of PsA.
Exenatide, dapagliflozin or phentermine/topiramate differentially affect metabolic profiles in polycystic ovary syndrome.

CONTEXT Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors reduce weight and improve insulin sensitivity via different mechanisms. OBJECTIVE The efficacy of once-weekly exenatide (EQW) and dapagliflozin (DAPA) alone and co-administered (EQW/DAPA), DAPA/extended release metformin (DAPA/MET), and phentermine topiramate extended release (PHEN/TPM) on metabolic parameters, body composition, and sex hormones were examined in obese women with PCOS. RESEARCH DESIGN AND METHODS Non-diabetic women (n=119; 18-45y) with BMI>30 <45 and PCOS (NIH criteria) were randomized in a single-blind fashion to EQW (2 mg weekly); DAPA (10 mg daily), EQW/DAPA (2 mg weekly/10 mg daily), DAPA (10 mg)/MET (2000mg XR daily) or PHEN (7.5 mg)/TPM (46mg ER daily) treatment for 24 weeks. Study visits at baseline and 24 weeks included weight, blood pressure (BP), waist (WC) measures and body composition evaluated by dual-energy X-ray absorptiometry (DXA). Oral glucose tolerance tests (OGTT) were done to assess glycemia, mean blood glucose (MBG), and compute insulin sensitivity (SI) and secretion (IS) measures. Sex steroids, free androgen index (FAI) and lipid profiles were measured in the fasting sample. RESULTS EQW/DAPA and PHEN/TPM resulted in the most loss of weight, total body fat by DXA, and WC. Despite equivalent reductions in BMI and WC with PHEN/TPM, only EQW/DAPA and EQW resulted in significant improvements in MBG, SI and IS. Reductions in fasting glucose, testosterone, FAI and BP were seen with all drugs. CONCLUSION Dual therapy with EQW/DAPA was superior to either alone, DAPA/MET and PHEN/TPM in terms of clinical and metabolic benefits in this patient population.
A Literature Review: Pet Bereavement and Coping Mechanisms

ABSTRACT The loss of a companion animal results in millions of pet owners grieving annually. To date, little information has been synthesized on the grief response and coping mechanisms of bereaved pet owners. The aim of this review was to examine the relationship between pet loss and owner grief response. Major themes included: factors that influence the grief response, the disenfranchised nature surrounding pet loss, ambiguous pet loss and coping mechanisms used. Across the 48 studies included in this review, bereaved pet owners frequently reported feelings of embarrassment and loneliness following the loss of their pet. Types of coping mechanisms used by bereaved pet owners were identified and included: isolation, social support, continuing bonds, memorialization, religion, and relationships with other animals. Overall, this review was able to identify a consensus among the literature that bereaved pet owners are likely to experience disenfranchisement surrounding their loss. Based on the present findings, suggestions for future research include a focus on the effectiveness of coping mechanisms used by bereaved pet owners.
Measuring Recovery With Ecological Momentary Assessment in a Randomized Trial of Exercise After Sport-Related Concussion

Objective: Investigate the reliability of concussion symptoms captured through ecological momentary assessment (EMA) and compare time with recovery based on 3 definitions of symptomatic recovery and the date of clinical clearance to begin the return-to-play (RTP) process. Design: We used a mobile app with EMA to monitor concussion symptoms as part of a multicenter randomized controlled trial. Setting: Three sports medicine practices. Participants: Patients between 13 and 18 years old with sport-related concussion were prompted to complete the Post-Concussion Symptom Inventory daily over 4 weeks. Interventions: None. Main Outcome Measures: We compared the elapsed days to reaching the 4 outcomes using scatterplots and Kaplan–Meier curves. Results: Among 118 participants, symptoms reported into the app had excellent agreement with symptoms reported at a clinical visit on the same day (intraclass correlation coefficient = 0.97). Most (>50%) participants reached “specific symptom return to preinjury levels,” “overall symptom return to preinjury levels,” and “current symptom resolution” based on EMA symptom reports between several days and 1 week before achieving “clinical clearance to RTP” determined at a clinical visit, which had 100% sensitivity, but between 56.3% and 78.1% specificity, relative to the app-measured symptom outcomes. Conclusions: Time until symptom recovery varies based on the chosen definition of symptomatic recovery but is a more precise correlate with clinical clearance to begin the RTP process when defining symptom recovery as a return to a preinjury baseline level of symptomatology. Real-time symptom monitoring may be beneficial clinically, allowing providers to assess patients' recovery status and make more timely and remote treatment recommendations.
Plasma Protein Profile of Incident Myocardial Infarction, Ischemic Stroke, and Heart Failure in 2 Cohorts

Background The aim is to study common etiological pathways for 3 major cardiovascular diseases (CVD), as reflected in multiple proteins. Methods and Results Eighty‐four proteins were measured using the proximity extension technique in 870 participants in the PIVUS (Prospective Investigation of Uppsala Seniors Study) cohort on 3 occasions (age 70, 75, and 80 years). The sample was followed for incident myocardial infarction, ischemic stroke or heart failure. The same proteins were measured in an independent validation sample, the ULSAM (Uppsala Longitudinal Study of Adult Men) cohort in 595 participants at age 77. During a follow‐up of up to 15 years in PIVUS and 9 years in ULSAM, 222 and 167 individuals experienced a CVD. Examining associations with the 3 outcomes separately in a meta‐analysis of the 2 cohorts, 6 proteins were related to incident myocardial infarction, 25 to heart failure, and 8 proteins to ischemic stroke following adjustment for traditional risk factors. Growth differentiation factor 15 and tumor necrosis factor‐related apoptosis‐inducing ligand receptor 2 were related to all 3 CVDs. Including estimated glomerular filtration rate in the models attenuated some of these relationships. Fifteen proteins were related to a composite of all 3 CVDs using a discovery/validation approach when adjusting for traditional risk factors. A selection of 7 proteins by lasso in PIVUS improved discrimination of incident CVD by 7.3% compared with traditional risk factors in ULSAM. Conclusions We discovered and validated associations of multiple proteins with incident CVD. Only a few proteins were associated with all 3 diseases: myocardial infarction, ischemic stroke, and heart failure.
Comparison of Symptom Control in Pediatric Gastroparesis Using Endoscopic Pyloric Botulinum Toxin Injection and Dilatation

ABSTRACT Objectives: The objective of this study was to assess the tolerance and efficacy of endoscopic intrapyloric botulinum toxin injection compared with pyloric dilatation in children with gastroparesis. Methods: This was a retrospective descriptive multicentre study that included pediatric patients treated between 2010 and 2018 at 4 tertiary hospitals. Results: Data were collected for 24 patients. The median age at diagnosis was 2.5 years (range 0.5–4.7). A total of 46 endoscopic procedures were performed. The endoscopic procedure was multiple in 63% of patients. Among the interventions, 76% were successful and 15% were unsuccessful. The recurrence rate was 57% and the median time to recurrence was 3.7 months (0.1–73). The efficacy did not differ significantly between the 2 methods at the first intervention and as a second-line treatment. The recurrence rate also did not differ significantly between the 2 methods. No complications were reported. The median follow-up was 19.8 months (1.7–61.7). Conclusions: In this retrospective multicentre study, endoscopic management of gastroparesis by balloon dilatation or botulinum toxin was safe in children and seemed to be partially efficient within the first months. Symptoms recurred frequently and required repetition of the interventions.