Miracle-dz/UniFAR-FTUs huggingface dataset:
Divergent confidence intervals among pre-specified analyses in the HiSTORIC stepped wedge trial: An exploratory post-hoc investigation

Background The high-sensitivity cardiac troponin on presentation to rule out myocardial infarction (HiSTORIC) study was a stepped-wedge cluster randomised trial with long before-and-after periods, involving seven hospitals across Scotland. Results were divergent for the binary safety endpoint (type 1 or type 4b myocardial infarction or cardiac death) across certain pre-specified analyses, which warranted further investigation. In particular, the calendar-matched analysis produced an odds ratio in the opposite direction to the primary logistic mixed-effects model analysis. Methods Several post-hoc statistical models were fitted to each of the co-primary outcomes of length of hospital stay and safety events, which included adjusting for exposure time, incorporating splines, and fitting a random time effect. We improved control of patient characteristics over time by adjusting for multiple additional covariates using different methods: direct inclusion, regression adjustment for propensity score, and weighting. A data augmentation approach was also conducted aiming to reduce the effect of sparse data bias. Finally, the raw data was examined. Results The new statistical models confirmed the results of the pre-specified trial analysis. In particular, the observed divergence between the calendar-matched and other analyses remained, even after performing the covariate adjustment methods, and after using data augmentation. Divergence was particularly acute for the safety endpoint, which had an event rate of 0.36% overall. Examining the raw data was particularly helpful to assess the sensitivity of the results to small changes in event rates and identify patterns in the data. Conclusions Our experience reveals the importance of conducting multiple pre-specified sensitivity analyses and examining the raw data, particularly for stepped wedge trials with low event rates or with a small number of sites. Before-and-after analytical approaches that adjust for differences in patient populations but avoid direct modelling of the time trend should be considered in future stepped wedge trials with similar designs.
Predictive evaluation of SIRI, SII, PNI, and GPS in cholecystostomy application in patients with acute cholecystitis

ABSTRACT BACKGROUND: The aims of this study were to investigate the clinical significance of systemic inflammatory response index (SIRI), systemic inflammation index (SII), prognostic nutritional index (PNI), and Glasgow prognostic score (GPS) in deciding whether to perform cholecystostomy when determining if cholecystostomy is the right choice for acute cholecystitis (AC) patients. METHODS: Between January 2018 and December 2020, 126 consecutive patients with AC with and without cholecystostomy were retrospectively recruited from the Trakya University in Edirne, Turkey. Group I included AC patients with cholecystostomy and Group II included AC patients without cholecystostomy. The neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR) were calculated. The PNI and SII were calculated RESULTS: There is significant difference between the two groups by the comparison of SIRI, SII, PNI, and GPS values (p<0.001). In Group I, SIRI, SII, and GPS values are higher than the Group II and PNI value in Group I is lower than the Group II. Furthermore, the NLR and PLR ratios in Group I are significantly higher than Group II, and the LMR ratio in Group I is significantly lower than Group II. CONCLUSION: According to our study, we can say that NLR, PLR, SII, SIRI, and GPS are positive predictors and LMR and PNI are negative predictors for the severity of AC. Therefore, when we decide to treat AC medically, we may prefer the application of cholecystostomy tube at the beginning of hospitalization by the help of evaluating NLR, PLR, LMR, SIRI, SII, GPS, and PNI values.
Prevalence of burnout in medical students: A systematic review and meta-analysis

Background: Medical students are at a significant risk of experiencing psychological issues, such as burnout. Over the past few years, more studies have been conducted on this topic, producing different results. Aims: The purpose of this review was to determine the global pooled prevalence rate and risk factors associated with burnout and its components among undergraduate (pre-intern) medical students. Method: From inception until 30 November 2021, nine electronic databases were used for an electronic search. Using random-effects meta-analysis, we pooled the estimates using the DerSimonian-Laird method. The prevalence of burnout in medical students was the primary outcome of interest. Data were analyzed globally, by country, by research measure. Age and sex were examined as confounders using meta-regression analysis. Results: A random-effects meta-analysis of 42 studies involving 26,824 evaluating the prevalence of burnout in medical students showed an overall prevalence rate 37.23% [32.66%; 42.05%], Q = 2,267.15(41), p < . 0001, τ2 = . 42, τ = . 65, I2 = 98.2%; H = 7.5. Prevalence of emotional exhaustion, depersonalization, and personal accomplishment were 38.08% [30.67%; 46.10%], 35.07% [26.74%; 44.41%], and 37.23% [32.66%; 42.05%], respectively. Variations were observed between countries and research measures. Age (older) and sex (female) were both significant predictors of burnout. Conclusion: The prevalence of burnout in medical students was estimated to be 37.23%. It is urgent that future studies serve as a basis for the development of prevention and treatment programs to prevent and treat burnout in students.
Periodontitis and COVID-19: Biological Mechanisms and Meta-analyses of Epidemiological Evidence

Since the beginning of 2020, the entire global health care system has been severely challenged by the outbreak of coronavirus 2019 disease (COVID-19). Robust evidence has demonstrated a more severe course of COVID-19 in the presence of several comorbidities, such as cardiovascular diseases, diabetes mellitus, and obesity. Here, we critically appraise the recent research discoveries linking periodontitis to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and to severe COVID-19, with a special focus on the associated biological mechanisms and the available epidemiological evidence. SARS-CoV-2 main receptors and coreceptors (ACE2, TMPRSS2, furin, CD147) are overexpressed in periodontal tissues of periodontitis patients, with inflammation, periodontal pathogens, and damage-induced pyroptosis triggering a positive feedback loop. However, meta-analyses of epidemiological studies only indicated a nonstatistically significant tendency for an increased risk of SARS-CoV-2 infection in subjects with periodontitis (odds ratio [OR] = 1.69; 95% CI, 0.91–3.13, P = 0.09). Furthermore, periodontitis may worsen clinical COVID-19 courses through multiple direct and indirect pathways, including damage to lower airways due to aspiration of periodontal pathogens, exacerbation of the cytokine storm via the low-grade chronic systemic inflammation, and SARS-CoV-2 dissemination through the ulcerated gingival epithelium with consequent induced pulmonary vessels vasculopathy. Indeed, meta-analyses of epidemiological studies indicated that periodontitis subjects are more likely to experience a more severe course of COVID-19. Specifically, periodontitis was associated with a 4-fold increased odds of hospitalization (OR = 4.72; 95% CI, 1.11–20.03, P = 0.04), 6-fold of requiring assisted ventilation (OR = 6.24; 95% CI, 2.78–14.02, P = 0.00), and more than 7-fold of death due to COVID-19 complications (OR = 7.51; 95% CI, 2.16–26.10, P = 0.00). The breakthrough analyzed here emphasizes the relevance of the mouth-systemic connection as a target to mitigate the current COVID-19 emergency and the future predicted coronavirus pandemics.
Sympatric Recombination in Zoonotic Cryptosporidium Leads to Emergence of Populations with Modified Host Preference

Abstract Genetic recombination plays a critical role in the emergence of pathogens with phenotypes such as drug resistance, virulence, and host adaptation. Here, we tested the hypothesis that recombination between sympatric ancestral populations leads to the emergence of divergent variants of the zoonotic parasite Cryptosporidium parvum with modified host ranges. Comparative genomic analyses of 101 isolates have identified seven subpopulations isolated by distance. They appear to be descendants of two ancestral populations, IIa in northwestern Europe and IId from southwestern Asia. Sympatric recombination in areas with both ancestral subtypes and subsequent selective sweeps have led to the emergence of new subpopulations with mosaic genomes and modified host preference. Subtelomeric genes could be involved in the adaptive selection of subpopulations, while copy number variations of genes encoding invasion-associated proteins are potentially associated with modified host ranges. These observations reveal ancestral origins of zoonotic C. parvum and suggest that pathogen import through modern animal farming might promote the emergence of divergent subpopulations of C. parvum with modified host preference.
Staphylococcus aureus-induced immunosuppression mediated by IL-10 and IL-27 facilitates nasal colonisation

Staphylococcus aureus persistently colonises the anterior nares of a significant proportion of the healthy population, however the local immune response elicited during S. aureus nasal colonisation remains ill-defined. Local activation of IL-17/IL-22 producing T cells are critical for controlling bacterial clearance from the nasal cavity. However, recurrent and long-term colonisation is commonplace indicating efficient clearance does not invariably occur. Here we identify a central role for the regulatory cytokine IL-10 in facilitating bacterial persistence during S. aureus nasal colonisation in a murine model. IL-10 is produced rapidly within the nasal cavity following S. aureus colonisation, primarily by myeloid cells. Colonised IL-10-/- mice demonstrate enhanced IL-17+ and IL-22+ T cell responses and more rapidly clear bacteria from the nasal tissues as compared with wild-type mice. S. aureus also induces the regulatory cytokine IL-27 within the nasal tissue, which acts upstream of IL-10 promoting its production. IL-27 blockade reduces IL-10 production within the nasal cavity and improves bacterial clearance. TLR2 signalling was confirmed to be central to controlling the IL-10 response. Our findings conclude that during nasal colonisation S. aureus creates an immunosuppressive microenvironment through the local induction of IL-27 and IL-10, to dampen protective T cell responses and facilitate its persistence.
Upstream open reading frames control PLK4 translation and centriole duplication in primordial germ cells

In this study, Phan et al. show that PLK4 abundance is translationally controlled through conserved upstream open reading frames (uORFs) in the 5′ UTR of the mRNA and that Plk4 uORFs suppress Plk4 translation and prevent excess protein synthesis. Their data uncover a specific requirement for uORF-dependent control of PLK4 translation in counterbalancing the increased Plk4 transcription in PGCs.
Pharmacotherapy alleviates pathological changes in human direct reprogrammed neuronal cell model of myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat disorder affecting multiple organs. However, most of the research is focused on studying and treating its muscular symptoms. On the other hand, despite the significant impact of the neurological symptoms on patients’ quality of life, no drug therapy was studied due to insufficient reproducibility in DM1 brain-specific animal models. To establish DM1 neuronal model, human skin fibroblasts were directly converted into neurons by using lentivirus expressing small hairpin RNA (shRNA) against poly-pyrimidine tract binding protein (PTBP). We found faster degeneration in DM1 human induced neurons (DM1 hiNeurons) compared to control human induced neurons (ctrl hiNeurons), represented by lower viability from 10 days post viral-infection (DPI) and abnormal axonal growth at 15 DPI. Nuclear RNA foci were present in most of DM1 hiNeurons at 10 DPI. Furthermore, DM1 hiNeurons modelled aberrant splicing of MBNL1 and 2, MAPT, CSNK1D and MPRIP at 10 DPI. We tested two drugs that were shown to be effective for DM1 in non-neuronal model and found that treatment of DM1 hiNeurons with 100 nM or 200 nM actinomycin D (ACT) for 24 h resulted in more than 50% reduction in the number of RNA foci per nucleus in a dose dependent manner, with 16.5% reduction in the number of nuclei containing RNA foci at 200 nM and treatment with erythromycin at 35 μM or 65 μM for 48 h rescued mis-splicing of MBNL1 exon 5 and MBNL 2 exons 5 and 8 up to 17.5%, 10% and 8.5%, respectively. Moreover, erythromycin rescued the aberrant splicing of MAPT exon 2, CSNK1D exon 9 and MPRIP exon 9 to a maximum of 46.4%, 30.7% and 19.9%, respectively. These results prove that our model is a promising tool for detailed pathogenetic examination and novel drug screening for the nervous system.
PrEP user profiles, dynamics of PrEP use and follow‐up: a cohort analysis at a Belgian HIV centre (2017–2020)

The number of individuals initiating antiretroviral pre‐exposure prophylaxis (PrEP) is increasing, but we do not fully understand who is coming forward for PrEP, how they use it and how they are followed‐up. The objective of this study was to examine PrEP user profiles, dynamics in PrEP use and follow‐up over time.
Seropositivity Rates of Strongyloides stercoralis Antibody in the Southeastern Region of Republic of Korea: A Single-Center Retrospective Study

Strongyloides stercoralis infection is not endemic in the Republic of Korea (Korea) with a positivity rate of <1% in stool examination. However, there is a risk of hyperinfection in immunosuppressed individuals. It is necessary to determine the seropositivity of S. stercoralis antibodies in Korea. This study investigated the seropositivity of S. stercoralis antibodies in the southeastern area of Korea. From January 2019 to June 2021, serum samples were collected from participants who visited the study center in the southeastern region of Korea for routine health check-ups. We determined serum levels of specific anti-Strongyloides IgG antibodies in 834 samples by enzyme-linked immunosorbent assay. We observed that 92 samples (11.0%) tested showed a positive response. The age of the participants was 51±10.7 years, and 43.4% of them were men. The antibody positivity rate based on the location of the participants’ residence were 12.3% (Gyoungsangnam-do), 10.2% (Busan), and 10.1% (Ulsan), respectively. Total eosinophil count was associated with positive test results (154.8±152.0 per mm3 versus 202.1±178.9 per mm3, P=0.006). Logistic regression analysis revealed that blood eosinophil count, age above 50 years, and residence in Sacheon were factors associated with the positive status of S. stercoralis antibody. Our finding suggests that it is necessary to test for S. stercoralis in actual clinical settings in Korea.
Distal femoral arthroplasty for native knee fractures : results from the Australian Orthopaedic Association National Joint Replacement Registry.

AIMS The aim of this study was to investigate the rate of revision for distal femoral arthroplasty (DFA) performed as a primary procedure for native knee fractures using data from the Australian Orthopaedic Association National Joint Arthroplasty Registry (AOANJRR). METHODS Data from the AOANJRR were obtained for DFA performed as primary procedures for native knee fractures from 1 September 1999 to 31 December 2020. Pathological fractures and revision for failed internal fixation were excluded. The five prostheses identified were the Global Modular Arthroplasty System, the Modular Arthroplasty System, the Modular Universal Tumour And Revision System, the Orthopaedic Salvage System, and the Segmental System. Patient demographic data (age, sex, and American Society of Anesthesiologists grade) were obtained, where available. Kaplan-Meier estimates of survival were used to determine the rate of revision, and the reasons for revision and mortality data were examined. RESULTS The AOANJRR identified 153 primary DFAs performed for native knee fractures in 151 patients during the study period, with 63.3% of these (n = 97) performed within the last five years. The median follow-up was 2.1 years (interquartile range 0.8 to 4.4). The patient population was 84.8% female (n = 128), with a mean age of 76.1 years (SD 11.9). The cumulative percent revision rate at three years was 10%. The most common reason for revision was loosening, followed by infection. Patient survival at one year was 87.5%, decreasing to 72.8% at three years postoperatively. CONCLUSION The use of DFA to treat native knee fractures is increasing, with 63.3% of cases performed within the last five years. While long-term data are not available, the results of this study suggest that DFA may be a reasonable option for elderly patients with native knee fractures where fixation is not feasible, or for whom prolonged non-weightbearing may be detrimental. Cite this article: Bone Joint J 2022;104-B(7):894-901.
Lysine‐specific demethylase 1 aggravated oxidative stress and ferroptosis induced by renal ischemia and reperfusion injury through activation of TLR4/NOX4 pathway in mice

Acute kidney injury (AKI) is mainly caused by renal ischaemia reperfusion injury (IRI). Lots of evidence suggests that ferroptosis and oxidative stress play the vital role in renal IRI. However, the specific mechanism of renal IRI has not been fully elucidated. lysine‐specific demethylase 1 (LSD1) has been shown to regulate the pathogenesis of kidney disease. In this study, we firstly found that LSD1 was positively related to renal IRI. TCP, a classical LSD1 inhibitor, could alleviate tissue damage induced by renal IRI. Inhibition of LSD1 with either TCP or LSD1 knockdown could alleviate ferroptosis and oxidative stress caused by IRI both in vivo and in vitro. Furthermore, the results showed that suppression of LSD1 decreased the expression of TLR4/NOX4 pathway in HK‐2 cells subjected to H/R. With the si‐RNA against TLR4 or NOX4, it showed that the silence of TLR4/NOX4 reduced oxidative stress and ferroptosis in vitro. Moreover, to demonstrate the crucial role of TLR4/NOX4, TLR4 reduction, mediated by inhibition of LSD1, was compensated through delivering the adenovirus carrying TLR4 in vitro. The results showed that the compensation of TLR4 blunted the alleviation of oxidative stress and ferroptosis, induced by LSD1 inhibition. Further study showed that LSD1 activates TLR4/NOX4 pathway by reducing the enrichment of H3K9me2 in the TLR4 promoter region. In conclusion, our results demonstrated that LSD1 inhibition blocked ferroptosis and oxidative stress caused by renal IRI through the TLR4/NOX4 pathway, indicating that LSD1 could be a potential therapeutic target for renal IRI.
Multiple-Line Identiﬁcation of Socio-Ecological Stressors A ﬀ ecting Aquatic Ecosystems in Semi-Arid Countries: Implications for Sustainable Management of Fisheries in Sub-Saharan Africa

: Water resources are among the fundamental resources that are the most threatened worldwide by various pressures. This study applied the Driver–Pressure–State–Impact–Response (DPSIR) framework as an innovative tool to better understand the dynamic interlinkages between the di ﬀ erent sources of multiple stressors on aquatic ecosystems in Burkina Faso. The triangulation of evidences from interviews, literature reviews, and strategic simulations shows that several human impacts as well as climate change and its e ﬀ ects (such as the decrease of the water level, and the increase of the surface water temperature) are detrimental to ﬁsh productivity, abundance, and average size. Furthermore, the ongoing demographic and nutritional transition is driving cumulative pressures on water and ﬁsh resources. In this context, the development of aquaculture could o ﬀ er alternative livelihoods and help ﬁsh stocks in natural ecosystems to recover, thereby reducing ﬁshermen’s vulnerability and easing overﬁshing pressures. Further, the empowerment of the actors and their participation to reinforce ﬁsheries regulation are required to escape the current “regeneration trap” and to achieve a sustainable management of aquatic ecosystems in Burkina Faso.
INNOVATIVE METHODOLOGY Quantifying ceramide kinetics in vivo using stable isotope tracers and LC-MS/MS

Quantifying ceramide kinetics in vivo using stable isotope tracers and LC-MS/MS. Am J Physiol Endocrinol 315: E416–E424, studies have implicated dyslipidemia as a key factor in mediating insulin resistance. Ceramides have received special attention since their levels are inversely associated with normal insulin signaling and positively associated with factors that are involved in cardiometabolic disease. Despite the growing literature surrounding ceramide biology, there are limited data regarding the activity of ceramide synthesis and turnover in vivo. Herein, we demonstrate the ability to measure ceramide kinetics by coupling the administration of [ 2 H]water with LC-MS/MS analyses. As a “proof-of-concept” we determined the effect of a diet-induced alteration on ceramide ﬂux; studies also examined the effect of myriocin (a known inhibitor of serine palmitoyltransferase, the ﬁrst step in sphingosine biosynthesis). Our data suggest that one can estimate ceramide synthesis and draw conclusions regarding the source of fatty acids; we discuss caveats in regards to method development in this area. The fractional synthesis rates of the [ 13 C]ceramides were estimated by assuming that the respective [ 13 C]dihydroceramides reﬂect the precursor labeling (46, 59). Note that those calculations used samples which were collected over the initial 5.5 h following the bolus injection of [U- 13 C]serine; the sample collected at 25.5 h showed very little 13 C labeling and was not used in any calculations.