Miracle-dz/UniFAR-FTUs huggingface dataset:
Gene expression profiles of multiple brain regions in rats differ between developmental and postpubertal exposure to valproic acid

We have previously reported that the valproic acid (VPA)‐induced disruption pattern of hippocampal adult neurogenesis differs between developmental and 28‐day postpubertal exposure. In the present study, we performed brain region‐specific global gene expression profiling to compare the profiles of VPA‐induced neurotoxicity between developmental and postpubertal exposure. Offspring exposed to VPA at 0, 667, and 2000 parts per million (ppm) via maternal drinking water from gestational day 6 until weaning (postnatal day 21) were examined, along with male rats orally administered VPA at 0, 200, and 900 mg/kg body weight for 28 days starting at 5 weeks old. Four brain regions—the hippocampal dentate gyrus, corpus callosum, cerebral cortex, and cerebellar vermis—were subjected to expression microarray analysis. Profiled data suggested a region‐specific pattern of effects after developmental VPA exposure, and a common pattern of effects among brain regions after postpubertal VPA exposure. Developmental VPA exposure typically led to the altered expression of genes related to nervous system development (Msx1, Xcl1, Foxj1, Prdm16, C3, and Kif11) in the hippocampus, and those related to nervous system development (Neurod1) and gliogenesis (Notch1 and Sox9) in the corpus callosum. Postpubertal VPA exposure led to the altered expression of genes related to neuronal differentiation and projection (Cd47, Cyr61, Dbi, Adamts1, and Btg2) in multiple brain regions. These findings suggested that neurotoxic patterns of VPA might be different between developmental and postpubertal exposure, which was consistent with our previous study. Of note, the hippocampal dentate gyrus might be a sensitive target of developmental neurotoxicants after puberty.
Ripples reflect a spectrum of synchronous spiking activity in human anterior temporal lobe

Direct brain recordings have provided important insights into how high-frequency activity captured through intracranial EEG (iEEG) supports human memory retrieval. The extent to which such activity is comprised of transient fluctuations that reflect the dynamic coordination of underlying neurons, however, remains unclear. Here, we simultaneously record iEEG, local field potential (LFP), and single unit activity in the human temporal cortex. We demonstrate that fast oscillations within the previously identified 80–120 Hz ripple band contribute to broadband high-frequency activity in the human cortex. These ripple oscillations exhibit a spectrum of amplitudes and durations related to the amount of underlying neuronal spiking. Ripples in the macro-scale iEEG are related to the number and synchrony of ripples in the micro-scale LFP, which in turn are related to the synchrony of neuronal spiking. Our data suggest that neural activity in the human temporal lobe is organized into transient bouts of ripple oscillations that reflect underlying bursts of spiking activity.
Efficacy of HIVEC in patients with high-risk non-muscle invasive bladder cancer who are contraindicated to BCG and in patients who fail BCG therapy

Abstract Purpose To evaluate Hyperthermic-Intra-Vesical Chemotherapy (HIVEC) efficacy regarding 1-year disease-free survival (RFS) rate and bladder preservation rate in patients with High-risk Non-Muscle Invasive Bladder Cancer (NMIBC) who fail BCG therapy or are contraindicated to BCG. Methods Between June 2016 and October 2019, patients treated with HIVEC for mostly high-risk NMIBC who failed BCG or BCG-naive if BCG contraindicated have been included in our study. These patients had a theoretical indication for cystectomy but were ineligible for surgery or refused it. Results Fifty-three patients, median age 72 [39–93] years, were included in this study (n = 29 BCG-failure and n = 24 BCG-naive). The median follow-up was 18 months. The bladder preservation rate was 92.4%. The 12 months-RFS rate was 60.5%. The RFS rates for BCG-naive and BCG-failure groups were respectively 70% and 52.2% at 12 months. Three patients progressed to muscle infiltration, all in the BCG-failure group and all in the very high-risk EORTC group. Two of them developed metastatic disease and died from bladder cancer. Conclusion Chemohyperthermia using HIVEC achieved a RFS rate of 60% at 1 year and enabled a bladder preservation rate of 92%. Given the low risk of progression in the BCG-naive group, HIVEC could be a good alternative. Conversely, for patients with very high-risk tumors that fail BCG, cystectomy should remain the standard of care and HIVEC may be discussed cautiously for patients who are not eligible for surgery and well informed of the risk of progression to muscle-invasive disease.
Diabetic ketoacidosis and COVID-19: what have we learned so far?

BACKGROUND AND AIMS In December 2019, a pandemic emerged due to a new coronavirus which imposed various uncertainties and discoveries. It has been reported that diabetes is a risk factor for worst outcomes of COVID-19, and also that SARS-CoV-2 infection was correlated with the occurrence of diabetic ketoacidosis (DKA) in patients. The aim of this work is to discuss this correlation emphasizing the main case reports from 2020 while exploring the management of DKA during the course of COVID-19. METHOD Web of Science, PubMed and Scopus databases were searched using two sets of Medical Subject Heading (MeSH) search terms or Title/Abstract words: Coronavirus Infections (Coronavirus Infections, Middle East Respiratory Syndrome, COVID-19) and Diabetic Ketoacidosis (Diabetic Ketoacidosis, Diabetic Acidosis, Diabetic Ketosis). RESULTS There is a clear correlation between COVID-19 and DKA. The SARS-Cov-2 infection may precipitate both a hyperglycemic state and ketoacidosis occurrence in diabetic and non-diabetic patients, which may lead to fatal outcomes. CONCLUSION DKA in patients with COVID-19 may increase risk and worse outcomes. Hence, the SARS-Cov-2 infection presents a new perspective towards the management of glycemia and acidosis in diabetic and non-diabetic patients, highlighting the need for rapid interventions to minimize the complications from COVID-19 while reducing its spreading.
Expanding the clinico‐molecular spectrum of Angelman syndrome phenotype with the GABRG3 gene: Evidence from methylation and sequencing studies

Angelman syndrome (AS) (OMIM#105830) is an imprinting disorder caused due to alterations in the maternal chr 15q11‐13 region. Majority of cases can be diagnosed by methylation‐specific polymerase chain reaction (MS‐PCR) of SNRPN gene and by UBE3A sequencing, however, about 10% of cases with AS phenotype remain undiagnosed. Differential diagnoses of AS can be detected by chromosomal microarray (CMA) and clinical exome sequencing (CES). In this study, 30 cases with AS features were evaluated by MS‐PCR, CMA, and CES. SNRPN MS‐PCR confirmed AS in eight (26%), CMA and CES diagnosed nine (30%) cases. One case was identified with a novel variant c.1125C > T in GABRG3, located at 15q12 region, which is currently not associated with any syndrome. The GABRG3 gene is also speculated to be imprinted, a MS‐PCR assay was designed to confirm its differential parental methylation status. This assay identified another case with altered GABRG3 methylation. The two cases with GABRG3 alteration—sequence change and methylation indicate that GABRG3 may be associated with a subtype of AS or a new related syndrome. Performing GABRG3 MS‐PCR and sequencing of a larger group of patients with AS phenotype and normal SNPRN and UBE3A status will help in establishing exact genotype—phenotype correlation.
Incidence of Research Gap Years in Orthopaedic Residency Applicants: The New Standard?

Introduction: The purpose of this study was to (1) determine the incidence of a research gap year (RGY) in orthopaedic residency applicants at a single institution over a seven-year span; (2) compare applicant characteristics between applicants who did a RGY with those who did not, and (3) report variables associated with match success for RGY applicants. Methods: Applicants who reported taking a year out from medical school to pursue research on their Electronic Residency Application Service to a single institution from 2014 to 2015 through 2020 to 2021 were reviewed. Results: A strong positive correlation was noted between the percentage of applicants who participated in a RGY and time (Pearson correlation: r = 0.945 [95% confidence interval (CI), 0.6660. 992], P = 0.001). Over the study period, 11% of applicants had done a RGY, most commonly after their third year of medical school (82.7%). Most RGY applicants matched orthopaedics (72.8%) and 19.4% matched at the same institution they did their RGY. Conclusion: The percentage of RGY applicants to the study institution nearly doubled between 2014 to 2015 and 2020 to 2021. RGY applicants had a higher match rate than nationally published match rates. Further study is needed on a national level.
HBV covalently closed circular DNA minichromosomes in distinct epigenetic transcriptional states differ in their vulnerability to damage

HBV covalently closed circular DNA (cccDNA) is a major obstacle for a cure of chronic hepatitis B. Accumulating evidence suggests that epigenetic modifications regulate the transcriptional activity of cccDNA minichromosomes. However, it remains unclear how the epigenetic state of cccDNA affects its stability.
Ecological stoichiometry and fungal community turnover reveal variation among mycorrhizal partners in their responses to warming and drought

Symbiotic fungi mediate important energy and nutrient transfers in terrestrial ecosystems. Environmental change can lead to shifts in communities of symbiotic fungi, but the consequences of these shifts for nutrient dynamics among symbiotic partners are poorly understood. Here, we assessed variation in carbon (C), nitrogen (N) and phosphorus (P) in tissues of arbuscular mycorrhizal (AM) fungi and a host plant (Medicago sativa) in response to experimental warming and drought. We linked compositional shifts in AM fungal communities in roots and soil to variation in hyphal chemistry by using high‐throughput DNA sequencing and joint species distribution modelling. Compared to plants, AM hyphae was 43% lower in (C) and 24% lower in (N) but more than nine times higher in (P), with significantly lower C:N, C:P and N:P ratios. Warming and drought resulted in increases in (P) and reduced C:P and N:P ratios in all tissues, indicating fungal P accumulation was exacerbated by climate‐associated stress. Warming and drought modified the composition of AM fungal communities, and many of the AM fungal genera that were linked to shifts in mycelial chemistry were also negatively impacted by climate variation. Our study offers a unified framework to link climate change, fungal community composition, and community‐level functional traits. Thus, our study provides insight into how environmental change can alter ecosystem functions via the promotion or reduction of fungal taxa with different stoichiometric characteristics and responses.
Assessment of Impact of Patient Recruitment Volume on Risk Profile, Outcomes, and Treatment Effect in a Randomized Trial of Ticagrelor Versus Prasugrel in Acute Coronary Syndromes

BACKGROUND Whether there are differences in the risk profile and treatment effect in patients recruited in a low recruitment center (LRC) versus patients recruited in a high recruitment center (HRC) in a randomized multicenter trial remains unknown. METHODS AND RESULTS This study included 4018 patients with acute coronary syndrome recruited in the ISAR‐REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) trial. The primary end point was a composite of all‐cause death, myocardial infarction, or stroke. Overall, 3011 patients (75%) were recruited in the HRCs (7 centers recruiting 258 to 628 patients; median, 413 patients) and 1007 patients (25%) were recruited in the LRCs (16 centers recruiting 5 to 201 patients; median, 52 patients). Patients recruited in the LRCs had more favorable cardiovascular risk profiles than patients recruited in the HRCs. The primary end point occurred in 72 patients in the LRCs and 249 patients in the HRCs (cumulative incidence, 7.3% and 8.4%; P=0.267). All‐cause mortality was lower among patients recruited in the LRCs (n=29) than among patients recruited in the HRCs (n=134; cumulative incidence 2.9% versus 4.5%; P=0.031). There was no significant interaction between the treatment effect of ticagrelor versus prasugrel and patient recruitment category (LRC versus HRC) regarding the primary efficacy end point (LRC: hazard ratio [HR], 1.42 [95% CI, 0.89–2.28]; HRC: HR, 1.33 [95% CI, 1.04−1.72]; P for interaction=0.800). CONCLUSIONS Patients with acute coronary syndrome recruited in a LRC appear to have more favorable cardiovascular risk profiles and lower 1‐year mortality rates compared with patients recruited in a HRC. The recruitment volume did not interact with the treatment effect of ticagrelor versus prasugrel. REGISTRATION URL: https://www.clinicaltrials. gov; Unique identifier: NCT01944800.
Silencing KLF16 inhibits oral squamous cell carcinoma cell proliferation by arresting the cell cycle and inducing apoptosis

Krüppel‐like factor 16 (KLF16), a member of the Krüppel‐like factor (KLF) family, has been extensively investigated in multiple cancer types. However, the role of KLF16 in oral squamous cell carcinoma (OSCC) remains unknown. Thus, we conducted this study to investigate its related mechanism. KLF16 expression in OSCC cell lines was quantified by western blotting. Then, OECM1 and OC3 cells were divided into Blank, siCtrl, siKLF16#1 and siKLF16#2 groups. Subsequently, cell proliferation was detected using 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide (MTT) assays, cell migration and invasion were detected with wound healing and Transwell assays, and cell cycle distribution and cell apoptosis were detected via flow cytometry. KLF16, p21, CDK4, Cyclin D1 and p‐Rb expression was detected by western blotting. Finally, xenograft models were established in nude mice to observe the in vivo effects of KLF16 on OSCC. KLF16 protein expression was upregulated in OSCC cells. Compared to the cells in the Blank group, the OECM1 and OC3 cells in the siKLF16#1 group and siKLF16#2 group exhibited a sharp decrease in proliferation but a remarkable increase in apoptosis. Moreover, the proportion of cells in the G0/G1 phase notably increased and that in the S phase decreased, with evident decreases in cell invasion and migration. Moreover, KLF16, cyclin‐dependent kinase 4 (CDK4), Cyclin D1 and p‐Rb protein expression was upregulated, but p21 expression was downregulated. The mice in the siKLF16#1 and siKLF16#2 xenograft model groups exhibited slower tumour growth and smaller tumours with evident downregulation of Ki67 expression compared to the mice in the Blank group. KLF16 expression was upregulated in OSCC cells, and interfering with KLF16 led to cell cycle arrest, inhibited OSCC cell growth and promoted cell apoptosis.
Eltrombopag in adult patients with immune thrombocytopenia in the real‐world in France, including off‐label use before 6 months of disease duration: The multicenter, prospective ELEXTRA study

kocytosis and thrombosis in essential thrombocythemia and polycythemia vera: a systematic review and meta-analysis. Blood Adv. 2019; 3(11):1729-1737. 6. Shahneh F, Grill A, Klein M, et al. Specialized regulatory T cells control venous blood clot resolution through SPARC. Blood. 2021;137(11): 1517-1526. 7. Kambas K, Mitroulis I, Apostolidou E, et al. Autophagy mediates the delivery of thrombogenic tissue factor to neutrophil extracellular traps in human sepsis. PLoS One. 2012;7(9):e45427. 8. Gadomska G, Stankowska K, Boinska J, Bartoszewska-Kubiak A, Haus O, Ro s c D. Activation of the tissue factor-dependent extrinsic pathway and its relation to JAK2 V617F mutation status in patients with essential thrombocythemia. Blood Coagul Fibrinolysis. 2016;27(7): 817-821. 9. Maugeri N, Giordano G, Petrilli MP, et al. Inhibition of tissue factor expression by hydroxyurea in polymorphonuclear leukocytes from patients with myeloproliferative disorders: a new effect for an old drug? J Thrombosis Haemostasis. 2006;4(12):2593-2598.
Functional Outcomes After Surgery for Total Colonic, Long-Segment, Versus Rectosigmoid Segment Hirschsprung Disease

ABSTRACT Objectives: Knowledge on long-term outcomes in patients with Hirschsprung disease is progressing. Nevertheless, differences in outcomes according to aganglionic lengths are unclear. We compared long-term bowel function and generic quality of life in Hirschsprung patients with total colonic or long-segment versus rectosigmoid aganglionosis. Methods: In this nationwide, cross-sectional study participants with proven Hirschsprung disease received the Defecation and Fecal Continence questionnaire, and the Child Health Questionnaire Child Form-87, or the WHO Quality of Life-100. We excluded deceased patients, patients who were younger than 8 years, lived abroad, had a permanent enterostomy, or were intellectually impaired. Results: The study population (n = 334) was operated for rectosigmoid (83.9%), long-segment (8.7%), or total colonic aganglionosis (7.5%). Fecal incontinence in general was not significantly different between the three groups, but liquid fecal incontinence was significantly associated with total colonic aganglionosis (odds ratio [OR] = 6.00, 95% confidence interval [CI] 2.07–17.38, P = 0.001). Regarding constipation, patients with total colonic or long-segment aganglionosis were less likely to suffer from constipation than the rectosigmoid group (OR = 0.21, 95% CI, 0.05–0.91, P = 0.038 and OR = 0.11, 95% CI, 0.01–0.83, P = 0.032). Quality of life was comparable between the three groups, except for a lower physical score in children with total colonic aganglionosis (P = 0.016). Conclusions: Over time Hirschsprung patients with total colonic or long-segment aganglionosis do not suffer from worse fecal incontinence in general. A difference in stool consistency may underlie the association between liquid fecal incontinence and total colonic aganglionosis and constipation in patients with rectosigmoid aganglionosis. Despite these differences, generic quality of life is comparable on reaching adulthood.
Surface-water/groundwater boundaries affect seasonal PFAS concentrations and PFAA precursor transformations

Elevated concentrations of per- and polyfluoroalkyl substances (PFAS) in drinking-water supplies are a major concern for human health. It is therefore essential to understand factors that affect PFAS concentrations in surface water and groundwater and the transformation of perfluoroalkyl acid (PFAA) precursors that degrade into terminal compounds. Surface-water/groundwater exchange can occur along the flow path downgradient from PFAS point sources and biogeochemical conditions can change rapidly at these exchange boundaries. Here, we investigate the influence of surface-water/groundwater boundaries on PFAS transport and transformation. To do this, we conducted an extensive field-based analysis of PFAS concentrations in water and sediment from a flow-through lake fed by contaminated groundwater and its downgradient surface-water/groundwater boundary (defined as ≤100 cm below the lake bottom). PFAA precursors comprised 45 ± 4.6% of PFAS (PFAA precursors + 18 targeted PFAA) in the predominantly oxic lake impacted by a former fire-training area and historical wastewater discharges. In shallow porewater downgradient from the lake, this percentage decreased significantly to 25 ± 11%. PFAA precursor concentrations decreased by 85% between the lake and 84–100 cm below the lake bottom. PFAA concentrations increased significantly within the surface-water/groundwater boundary and in downgradient groundwater during the winter months despite lower stable concentrations in the lake water source. These results suggest that natural biogeochemical fluctuations associated with surface-water/groundwater boundaries may lead to PFAA precursor loss and seasonal variations in PFAA concentrations. Results of this work highlight the importance of dynamic biogeochemical conditions along the hydrological flow path from PFAS point sources to potentially affected drinking water supplies.
Racial Disparities in Care Interactions and Clinical Outcomes in Black Versus White Nursing Home Residents With Dementia

Background: With the increase in Black nursing home residents, racial and ethnic disparities in quality of care have been raised. Purpose: The purpose of this study was to evaluate racial disparities in care and outcomes over 12 months. Methods: This was a secondary data analysis using data from the Evidence Integration Triangle for Behavioral and Psychological Symptoms of Dementia study. A total of 553 residents, 24% Black residents and 76% White residents, from 55 nursing homes were included. Results: Differences favoring Black resident were noted in agitation, quality of life, inclusion of person-centered care approaches in care plans, and fewer falls and hospitalizations. Differences in quality-of-care interactions favored White residents. There were no differences in depression, resistiveness to care, function, pain, or transfers to the emergency department. Conclusions: Disparities in clinical outcomes were small and generally favored Black versus White residents except for quality-of-care interactions.
Fish out of water: Genomic insights into persistence of rainbowfish populations in the desert

How populations of aquatic fauna persist in extreme desert environments is an enigma. Individuals often breed and disperse during favorable conditions. Theory predicts that adaptive capacity should be low in small populations, such as in desert fishes. We integrated satellite‐derived surface water data and population genomic diversity from 20,294 single‐nucleotide polymorphisms across 344 individuals to understand metapopulation persistence of the desert rainbowfish (Melanotaenia splendida tatei) in central Australia. Desert rainbowfish showed very small effective population sizes, especially at peripheral populations, and low connectivity between river catchments. Yet, there was no evidence of population‐level inbreeding and a signal of possible adaptive divergence associated with aridity was detected. Candidate genes for local adaptation included functions related to environmental cues and stressful conditions. Eco‐evolutionary modeling showed that positive selection in refugial subpopulations combined with connectivity during flood periods can enable retention of adaptive diversity. Our study suggests that adaptive variation can be maintained in small populations and integrate with neutral metapopulation processes to allow persistence in the desert.