Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of EPAT: An assessment tool for pediatric hematology/oncology training programs

In the absence of a standardized tool to assess the quality of pediatric hematology/oncology training programs, the Education Program Assessment Tool (EPAT) was conceptualized as a user‐friendly and adaptable tool to evaluate and identify areas of opportunity, pinpoint needed modifications, and monitor progress for training programs around the world.
Early Postoperative Complications and Associated Variables After High Tibial Osteotomy and Distal Femoral Osteotomy: A 15-Year Experience From a Single Academic Institution

Background: High tibial osteotomy (HTO) and distal femoral osteotomy (DFO) are well-recognized treatments to address varus and valgus malalignment, respectively, in the setting of symptomatic unicompartmental arthritis of the tibiofemoral joint. The existing literature is limited in its ability to characterize complications after HTO or DFO procedures. Purpose: The objective of this study was to determine the rate of early (≤90 days) postoperative complications and associated variables from the 15-year experience of a single academic institution. Study Design: Case series; Level of evidence, 4. Methods: Patients treated at a single academic institution between 2008 and 2022 who underwent HTO or DFO procedures were identified. All patients with minimum 90-day follow-up were considered for inclusion in the study. Exclusion criteria were inadequate follow-up, unavailable medical records, age <14 years, and revision osteotomy. Patient demographic characteristics, surgical history, and concomitant procedures were identified, and risk factor analysis was performed to identify variables associated with early postoperative complications. All intraoperative complications were recorded. Results: A total of 243 knees in 232 patients met eligibility and were included in the final analysis. Three intraoperative complications (1.2%) involving fracture extension of the osteotomy occurred. There were 127 early postoperative complications (121 surgical, 6 medical) in 102 knees (68 with HTO and 34 with DFO). Medical complications included pulmonary embolus in 3 patients (1.2%), urinary tract infection in 2 patients (0.8%), and postoperative ileus requiring prolonged hospitalization in 1 patient (0.4%). The most common complications were stiffness requiring a non–standard of care intervention (17.7%), superficial wound infection or wound dehiscence (13.2%), and hemarthrosis or effusion requiring aspiration (6.6%). The rate of deep infection requiring irrigation and debridement was 4.1%. Variables associated with early postoperative complications included smoking (odds ratio [OR], 3.05; 95% CI, 1.34-6.94; P = .008), concomitant chondroplasty and/or loose body removal (OR, 2.55; 95% CI, 1.50-4.33; P = .001), and concomitant ligament reconstruction (OR, 3.97; 95% CI, 1.37-11.53; P = .011). Conclusion: These 15-year data revealed a low rate of intraoperative complications (1.2%) and a relatively high rate of early (≤90 days) postoperative complications (42.0%) after an HTO or DFO procedure. Surgeons should be aware of the increased postoperative complications associated with smoking, concomitant chondroplasty, and concomitant ligament reconstruction and should use this information to counsel patients regarding appropriate expectations in the postoperative period.
Endoplasmic stress sensor Ire1 is involved in cytosolic/nuclear protein quality control in Pichia pastoris cells independent of HAC1

In eukaryotic species, dysfunction of the endoplasmic reticulum (ER), namely, ER stress, provokes a cytoprotective transcription program called the unfolded protein response (UPR). The UPR is triggered by transmembrane ER-stress sensors, including Ire1, which acts as an endoribonuclease to splice and mature the mRNA encoding the transcription factor Hac1 in many fungal species. Through analyses of the methylotrophic yeast Pichia pastoris (syn. Komagataella phaffii), we revealed a previously unknown function of Ire1. In P. pastoris cells, the IRE1 knockout mutation (ire1Δ) and HAC1 knockout mutation (hac1Δ) caused only partially overlapping gene expression changes. Protein aggregation and the heat shock response (HSR) were induced in ire1Δ cells but not in hac1Δ cells even under non-stress conditions. Moreover, Ire1 was further activated upon high-temperature culturing and conferred heat stress resistance to P. pastoris cells. Our findings cumulatively demonstrate an intriguing case in which the UPR machinery controls cytosolic protein folding status and the HSR, which is known to be activated upon the accumulation of unfolded proteins in the cytosol and/or nuclei.
Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis

Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of the tissue-specific metabolic response to sepsis. The current study sought to fill this gap. We analyzed skeletal muscle transcriptomics of critically ill patients, versus elective surgical controls, which revealed reduced expression of genes involved in mitochondrial metabolism and electron transport, with increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. We then performed untargeted metabolomics and 13C isotope tracing to analyze systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model. We found an increased number of correlations between the metabolomes of liver, kidney, and spleen, with loss of correlations between the heart and quadriceps and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for muscles during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine’s contribution to TCA cycle anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine’s contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming to support liver energetic demands and antioxidant synthesis, rather than global mitochondrial dysfunction, as a metabolic consequence of sepsis.
Pitfalls of predicting age‐related traits by polygenic risk scores

Polygenic risk scores (PRS) are a method increasingly used to capture the combined effect of genome‐wide significant variants and those which individually do not show genome‐wide significant association but are likely to contribute to the risk of developing diseases. However, their practical use incurs complications and inconsistencies that so far limit their clinical applicability. The aims of the present review are to discuss the PRS for age‐related diseases and to highlight pitfalls and limitations of PRS prediction accuracy due to ageing and mortality effects. We argue that the PRS is widely used but the individual's PRS values differ substantially depending on the number of genetic variants included, the discovery GWAS and the method employed to generate them. Moreover, for neurodegenerative disorders, although an individual's genetics do not change with age, the actual score depends on the age of the sample used in the discovery GWAS and is likely to reflect the individual's disease risk at this particular age. Improvement of PRS prediction accuracy for neurodegenerative disorders will come from two sides, both the precision of clinical diagnoses, and a careful attention to the age distribution in the underlying samples and validation of the prediction in longitudinal studies.
Mean first passage times for piecewise deterministic Markov processes and the effects of critical points

In this paper, we use probabilistic methods to determine the mean first passage time (MFPT) for a two-state piecewise deterministic Markov process (PDMP), also known as a dichotomous noise process, to escape from a finite interval. In particular, we consider the case where the set of functions generating the piecewise deterministic dynamics have one or more critical points. In order to solve this type of problem, we partition the domain into a set of subintervals that contain no critical points and impose conditions at the critical points separating these regions. Our analysis exploits the fact that a PDMP satisfies the strong Markov property. We prove that in the absence of common critical points, the MFPT is finite. Through specific examples, we also explore how the MFPT depends on the number of critical points and prove that the MFPT can be infinite if there are common critical points.
Noyaux temporellement élastiques régularisés et ACP non-linéaire

In the context of time series data mining, recent studies exploit kernels constructed from elastic distances such as Dynamic Time Warping within kernel based methods. Yet matrix, related to Gram matrices, constructed from these kernels do not always have the required definiteness property which can make them unsuitable for such use. Emerging approaches dedicated to the regularization of time elastic kernels can be used in place of classical ones such as direct spectral approaches. We present in this paper a recent regularization method ($K_ {DTW}$) for the DTW kernel and propose an experimental study exploiting a kernel principal component analysis for evaluating the ability of some kernels (elastic v.s. non elastic, definite v.s. not definite) to provide good classifications of the analyzed data, while providing an important reduction of dimensionality. This study shows the effectiveness of the regularization technique for time elastic kernels that is behind $K_ {DTW}$
Emergence of linezolid-resistant Enterococcus faecium in a tertiary hospital in Copenhagen

Linezolid is used as first-line treatment of infections caused by vancomycin-resistant Enterococcus faecium . However, resistance to linezolid is increasingly detected. The aim of the present study was to elucidate the causes and mechanisms for the increase in linezolid-resistant E. faecium at Copenhagen University Hospital – Rigshospitalet. We therefore combined patient information on linezolid treatment with whole-genome sequencing data for vancomycin- or linezolid-resistant E. faecium isolates that had been systematically collected since 2014 (n=458). Whole-genome sequencing was performed for multilocus sequence typing (MLST), identification of linezolid resistance-conferring genes/mutations and determination of phylogenetically closely related strains. The collection of E. faecium isolates belonged to prevalent vancomycin-resistant MLST types. Among these, we identified clusters of closely related linezolid-resistant strains compatible with nosocomial transmission. We also identified linezolid-resistant enterococcus isolates not genetically closely related to other isolates compatible with de novo generation of linezolid resistance. Patients with the latter isolates were significantly more frequently exposed to linezolid treatment than patients with related linezolid-resistant enterococcus isolates. We also identified six patients who initially carried a vancomycin-resistant, linezolid-sensitive enterococcus, but from whom vancomycin-resistant, linezolid-resistant enterococci (LVRE) closely related to their initial isolate were recovered after linezolid treatment. Our data illustrate that linezolid resistance may develop in the individual patient subsequent to linezolid exposure and can be transmitted between patients in a hospital setting.
Promise and peril: how health system reforms impacted public health in three Canadian provinces

Several Canadian provinces and territories have reformed their health systems by centralizing power, resources, and responsibilities. Our study explored motivating factors and perceived impacts of centralization reforms on public health systems and essential operations. A multiple case study design was used to examine three Canadian provinces that have undergone, or are in the process of undergoing, health system reform. Semi-structured interviews were conducted with 58 participants within public health at strategic and operational levels, from Alberta, Ontario, and Québec. Data were analyzed using a thematic analytical approach to iteratively conceptualize and refine themes. Three major themes were developed to describe the context and impacts of health system centralization reforms on public health: (1) promising “value for money” and consolidating authority; (2) impacting intersectoral and community-level collaboration; and (3) deprioritizing public health operations and contributing to workforce precarity. Centralization highlighted concerns about the prioritization of healthcare sectors. Some core public health functions were reported to operate more efficiently, with less duplication of services, and improvements in program consistency and quality, particularly in Alberta. Reforms were also reported to have diverted funding and human resources away from core essential functions, and diminished the public health workforce. Our study highlighted that stakeholder priorities and a limited understanding about public health systems influenced how reforms were implemented. Our findings support calls for modernized and inclusive governance, stable public health funding, and investment in the public health workforce, which may help inform future reforms.
The use of antibiotic prophylaxis in patients undergoing urologic procedures in an academic hospital Surabaya: A retrospective study.

INTRODUCTION Prophylactic antibiotics in urological procedures are essential to prevent postoperative infections. A different approach in selecting antibiotic prophylaxis according to the type of procedure is needed. METHODOLOGY A retrospective study was carried out at an academic hospital in Surabaya, Indonesia, by collecting medical records of patients who underwent urologic procedures within 2019- 2020, including microbiological data. RESULT One hundred seventy-nine urological procedures were assessed. Antibiotic prophylaxis was administered in the clean-contaminated and clean procedures (93.2% and 6.8%, respectively). Ceftriaxone was commonly used (69.3%), single-dose, one day before the surgery. Gram-negative bacteria were widely found in the urinary culture of patients (75.2%). E. coli, K. pneumoniae, and P. aeruginosa were dominating with low susceptibility to cephalosporins. ESBL-producing bacteria were E. coli (64%) and K. pneumoniae (89%). CONCLUSIONS The 3rd generation cephalosporins (ceftriaxone) are mostly used in urological procedures despite the low susceptibility against this antibiotic in cultured E coli, P. aeruginosa, and K. pneumonia. The aminoglycosides have relatively good activity and have been suggested in several guidelines for urologic procedures, such as prostate and urinary tract stone procedures. It is crucial to consider the incision site, type of procedure, and bacterial profile in the hospital to propose antibiotic prophylaxis guidelines.
Conformational response to ligand binding of TMPRSS2, a protease involved in SARS‐CoV‐2 infection: Insights through computational modeling

Thanks to the considerable research which has been undertaken in the last few years to improve our understanding of the biology and mechanism of action of SARS‐CoV‐2, we know how the virus uses its surface spike protein to infect host cells. The transmembrane prosthesis, serine 2 (TMPRSS2) protein, located on the surface of human cells, recognizes the cleavage site in the spike protein, leading to the release of the fusion peptide and entry of the virus into the host cells. Because of its role, TMPRSS2 has been proposed as a drug target to prevent infection by the virus. In this study, we aim to increase our understanding of TMPRSS2 using long scale microsecond atomistic molecular dynamics simulations, focusing on the conformational changes over time. The comparison between simulations conducted on the protein in the native (apo) and inhibited form (holo), has shown that in the holo form the inhibitor stabilizes the catalytic site and induces rearrangements in the extracellular domain of the protein. In turn, it leads to the formation of a new cavity in the vicinity of the ligand binding pocket that is stable in the microsecond time scale. Given the low specificity of known protease inhibitors, these findings suggest a new potential drug target site that can be used to improve TMPRSS2 specific recognition by newly designed inhibitors.
Comprehensive Evaluation System for Post-Metabolic Activity of Potential Thyroid-Disrupting Chemicals

Endocrine-disrupting chemicals (EDCs) are compounds that disturb hormonal homeostasis by binding to receptors. EDCs are metabolized through hepatic enzymes, causing altered transcriptional activities of hormone receptors, and thus necessitating the exploration of the potential endocrine-disrupting activities of EDC-derived metabolites. Accordingly, we have developed an integrative workflow for evaluating the post-metabolic activity of potential hazardous compounds. The system facilitates the identification of metabolites that exert hormonal disruption through the integrative application of an MS/MS similarity network and predictive biotransformation based on known hepatic enzymatic reactions. As proof-of-concept, the transcriptional activities of 13 chemicals were evaluated by applying the in vitro metabolic module (S9 fraction). Identified among the tested chemicals were three thyroid hormone receptor (THR) agonistic compounds that showed increased transcriptional activities after phase I+II reactions (T3, 309.1 ± 17.3%; DITPA, 30.7 ± 1.8%; GC-1, 160.6 ± 8.6% to the corresponding parents). The metabolic profiles of these three compounds showed common biotransformation patterns, particularly in the phase II reactions (glucuronide conjugation, sulfation, GSH conjugation, and amino acid conjugation). Data-dependent exploration based on molecular network analysis of T3 profiles revealed that lipids and lipid-like molecules were the most enriched biotransformants. The subsequent subnetwork analysis proposed 14 additional features, including T4 in addition to 9 metabolized compounds that were annotated by prediction system based on possible hepatic enzymatic reaction. The other 10 THR agonistic negative compounds showed unique biotransformation patterns according to structural commonality, which corresponded to previous in vivo studies. Our evaluation system demonstrated highly predictive and accurate performance in determining the potential thyroid-disrupting activity of EDC-derived metabolites and for proposing novel biotransformants.
The Hyper-Kamiokande detector: R&D studies of a new generation of photosensors

Hyper-Kamiokande is a large water Cherenkov detector which, just like the successful Super-Kamiokande, requires large aperture, high sensitivity photosensors able to detect the weak Cherenkov light generated by neutrino interactions or proton decay. The capability of a water Cherenkov detector largely relies on the performance of its photosensors. Currently the photosensors used in Super-Kamiokande, characterised by the 50 cm diameter photocathode, are the world's largest photomultiplier tubes. The ambitious physics program of Hyper-Kamiokande will be possible only by using a new generation of photosensors whose performances are considerably improved with respect to those currently available. In this paper the current status of development of Hyper-Kamiokande photodetectors will be reviewed.
Development of novel salicylic acid–donepezil–rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer’s disease

Abstract Alzheimer’s disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The multi-target-directed ligands (MTDLs) strategy has been recognised as the most promising approach due to the complexity of the pathogenesis of AD. Herein, novel salicylic acid–donepezil–rivastigmine hybrids were designed and synthesised. The bioactivity results exhibited that 5a was a reversible and selective eqBChE inhibitor (IC50 = 0.53 μM), and the docking provided the possible mechanism. Compound 5a also displayed potential anti-inflammatory effects and significant neuroprotective effect. Moreover, 5a exhibited favourable stabilities in artificial gastrointestinal solution and plasma. Finally, 5a demonstrated potential cognitive improvement in scopolamine-induced cognitive dysfunction. Hence, 5a was a potential multifunctional lead compound against AD. Graphical Abstract
Association of Performance on Olfactory and Cognitive Screening Tests With Conversion to Dementia in a Biracial Cohort of Older Adults

Background and Objectives Odor identification deficits are associated with transition to dementia, whereas intact odor identification and global cognition test performance may identify lack of transition. The purpose of this study was to examine intact odor identification and global cognition as prognostic indicators of lack of transition to dementia in a biracial (Black and White) cohort. Methods In a community-dwelling sample of older adults from the Health, Aging, and Body Composition study, odor identification was measured using the Brief Smell Identification Test (BSIT), and global cognition was measured using the Teng Modified Mini-Mental State Examination (3MS). Survival analyses for dementia transition over 4 and 8 years of follow-up used Cox proportional hazards models. Results A total of 2,240 participants had an average age of 75.5 years (SD 2.8). Approximately 52.7% were female individuals. Approximately 36.7% were Black and 63.3% were White individuals. Impaired odor identification (hazard ratio [HR] 2.29, 95% CI 1.79–2.94, p < 0.001) and global cognition (HR 3.31, 95% CI 2.26–4.84, p < 0.001) were each independently associated with transition to dementia (n = 281). Odor identification remained robustly associated with transition to dementia for Black (HR 2.02, 95% CI 1.36–3.00, p < 0.001, n = 821) and White participants (HR 2.45, 95% CI 1.77–3.38, p < 0.001, n = 1,419), whereas global cognition was associated with transition among Black participants only (HR 5.06, 95% CI 3.18–8.07, p < 0.001). ApoE genotype was consistently associated with transition among White participants only (HR 1.75, 95% CI 1.20–2.54, p < 0.01). Among participants with intact performance on both odor identification (BSIT ≥9/12 correct) and global cognition (3MS ≥ 78/100 correct), 8.8% transitioned to dementia over 8 years. Intact performance on both measures had high positive predictive value for identifying individuals who did not transition to dementia over 4 years (0.98 for ages 70–75 years with only 2.3% transitioning, 0.94 for ages 76–82 years with only 5.8% transitioning). Discussion Odor identification testing paired with a global cognitive screening test identified individuals at low risk of transition to dementia in a biracial community cohort with a pronounced effect in the eighth decade of life. Identification of such individuals can reduce the need for extensive investigation to establish a diagnosis. Odor identification deficits showed utility in both Black and White participants, unlike the race-dependent utility of a global cognitive test and ApoE genotype.