Miracle-dz/UniFAR-FTUs huggingface dataset:
Association between COVID‐19 and myasthenia gravis (MG): A genetic correlation and Mendelian randomization study

Observational studies have suggested an association between coronavirus disease 2019 (COVID‐19) and myasthenia gravis (MG). Here, we aimed to estimate the genetic correlation and causal relationship between COVID‐19 susceptibility, hospitalization, severity, and MG phenotypes using linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR) approach.
Intramacrophage lipid accumulation compromises T cell responses and is associated with impaired drug therapy against visceral leishmaniasis

Under perturbing conditions such as infection with Leishmania, a protozoan parasite living within the phagosomes in mammalian macrophages, cellular and organellar structures, and metabolism are dynamically regulated for neutralizing the pressure of parasitism. However, how modulations of the host cell metabolic pathways support Leishmania infection remains unknown. Herein, we report that lipid accumulation heightens the susceptibility of mice to L. donovani infection and promotes resistance to first‐line anti‐leishmanial drugs. Despite being pro‐inflammatory, the in vitro generated uninfected lipid‐laden macrophages (LLMs) or adipose‐tissue macrophages (ATMs) display lower levels of reactive oxygen and nitrogen species. Upon infection, LLMs secrete higher IL‐10 and lower IL‐12p70 cytokines, inhibiting CD4+ T cell activation and Th1 response suggesting a key modulatory role for intramacrophage lipid accumulation in anti‐leishmanial host defence. We, therefore, examined this causal relationship between lipids and immunomodulation using an in vivo high‐fat diet (HFD) mouse model. HFD increased the susceptibility to L. donovani infection accompanied by a defective CD4+ Th1 and CD8+ T cell response. The white adipose tissue of HFD mice displays increased susceptibility to L. donovani infection with the preferential infection of F4/80+CD11b+CD11c+ macrophages with higher levels of neutral lipids reserve. The HFD increased resistance to a first‐line anti‐leishmanial drug associated with a defective adaptive immune response. These data demonstrate that the accumulation of neutral lipids contributes to susceptibility to visceral leishmaniasis hindering host‐protective immune response and reducing the efficacy of antiparasitic drug therapies.
Diabetes prevention at scale: Narrative review of findings and lessons from the DIPLOMA evaluation of the NHS Diabetes Prevention Programme in England

The NHS Diabetes Prevention Programme (NHS DPP) is a large‐scale, England‐wide behaviour change programme for people at high risk of progressing to type 2 diabetes. We summarise the findings of our six‐year DIPLOMA evaluation of its implementation and impact and highlight insights for future programmes.
Clinical Differences between Posner-Schlossman Syndrome Patients with Intermittent Intraocular Pressure Elevation and Glaucomatous Damage

Introduction: Although there is abundant evidence that Posner-Schlossman syndrome (PSS) can lead to secondary glaucoma, data on the clinical differences between PSS patients with secondary glaucoma and those with intermittent intraocular pressure (IOP) elevation are sparse. Methods: This retrospective observational study included 52 patients (52 eyes) diagnosed with PSS and admitted to Zhongnan Hospital of Wuhan University between January 2019 and February 2022. Demographic characteristics and clinical features were gathered from admission records. Patients were divided into two groups: 27 cases with intermittent IOP elevation (group A) and 25 cases with secondary glaucoma (group B and C). Of the secondary glaucoma cases, 18 were further divided into the topical IOP-lowering medications group (group B) and 7 into the glaucoma surgery group (group C). Clinical characteristics of different groups were compared. Results: Compared to the intermittent IOP elevation group, PSS patients with secondary glaucoma had a longer course of disease, a higher incidence of iris depigmentation, lower best corrected visual acuity, lower endothelial cell density, and higher interferon-γ (IFN-γ) concentration and cytomegalovirus (CMV) deoxyribonucleic acid (DNA) copy number in the aqueous humor (all p < 0.05). Group C presented a higher CMV DNA copy number in the aqueous humor than groups A and B (p < 0.05). Compound trabeculectomy proved effective in group C, with a functional filter bleb and well-controlled IOP without disease progression after 1 year of follow-up. Conclusion: Distinctive characteristics existed between PSS patients with secondary glaucoma and those with intermittent IOP elevation. Compound trabeculectomy appears to be an effective treatment option when IOP cannot be controlled through topical medications.
Bmc Medical Education Effect of a Brief Intervention on Evidence-based Medicine Skills of Pediatric Residents

Background: While Evidence-Based Medicine (EBM) skills are increasingly being taught in medical schools, teaching quality has been insufficient, so that incoming pediatric residents lack adequate EBM skills required for patient care. The objective of this study was to evaluate the effectiveness of a brief teaching module developed to improve EBM skills of pediatric residents.
Hair mercury levels in Amazonian populations : spatial distribution and trends

Background: Mercury is present in the Amazonian aquatic environments from both natural and anthropogenic sources. As a consequence, many riverside populations are exposed to methylmercury, a highly toxic organic form of mercury, because of their intense fish consumption. Many studies have analysed this exposure from different approaches since the early nineties. This review aims to systematize the information in spatial distribution, comparing hair mercury levels by studied population and Amazonian river basin, looking for exposure trends. Methods: The reviewed papers were selected from scientific databases and online libraries. We included studies with a direct measure of hair mercury concentrations in a sample size larger than 10 people, without considering the objectives, approach of the study or mercury speciation. The results are presented in tables and maps by river basin, displaying hair mercury levels and specifying the studied population and health impact, if any. Results: The majority of the studies have been carried out in communities from the central Amazonian regions, particularly on the Tapajós River basin. The results seem quite variable; hair mercury means range from 1.1 to 34.2 μg/g. Most studies did not show any significant difference in hair mercury levels by gender or age. Overall, authors emphasized fish consumption frequency as the main risk factor of exposure. The most studied adverse health effect is by far the neurological performance, especially motricity. However, it is not possible to conclude on the relation between hair mercury levels and health impact in the Amazonian situation because of the relatively small number of studies. Conclusions: Hair mercury levels in the Amazonian regions seem to be very heterogenic, depending on several factors. There is no obvious spatial trend and there are many areas that have never been studied. Taking into account the low mercury levels currently handled as acceptable, the majority of the Amazonian populations can be considered exposed to methylmercury contamination. The situation for many of these traditional communities is very complex because of their high dependence on fish nutrients. It remains difficult to conclude on the Public Health implication of mercury exposure in this context. Published: 21 December 2009 International Journal of Health Geographics 2009, 8:71 doi:10.1186/1476-072X-8-71 Received: 1 September 2009 Accepted: 21 December 2009 This article is available from: http://www.ij-healthgeographics.com/content/8/1/71 © 2009 Barbieri and Gardon; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Interstitial Eosinophilic Aggregates and Kidney Outcome in Patients with CKD

Visual Abstract Background Interstitial eosinophilic aggregates are observed in various kidney diseases, but their clinical implications remain unknown. We assessed the association between interstitial eosinophilic aggregates and kidney outcomes and further analyzed the association between blood eosinophil count, as a surrogate for interstitial eosinophilic aggregates, and the risk of kidney failure in patients with advanced CKD. Methods We analyzed datasets from two retrospective cohort studies: (1) the kidney biopsy cohort including 563 patients who underwent native kidney biopsy at Osaka University Hospital between 2009 and 2021 and (2) the retrospective CKD cohort including 2877 patients with an eGFR of 10–60 ml/min per 1.73 m2 referred to the nephrology outpatient center at Osaka University Hospital between 2005 and 2018. Interstitial eosinophilic aggregates were defined as ≥5 interstitial eosinophils in the high-power field on hematoxylin and eosin staining. This study outcome was initiation of KRT or ≥40% decline in eGFR. Results In the kidney biopsy cohort, interstitial eosinophilic aggregates were found in 17% of patients, most frequently in those with diabetic nephropathy (50%). Interstitial eosinophilic aggregates were associated with a higher rate of the composite kidney outcome after adjustment for clinical and histological variables (hazard ratio, 3.61; 95% confidence interval, 2.47 to 5.29; P < 0.001). LASSO revealed that blood eosinophil count was the strongest predictor of interstitial eosinophilic aggregates. In the retrospective CKD cohort, higher baseline and time-updated blood eosinophil counts were significantly associated with a higher rate of KRT initiation in Cox proportional hazards models and marginal structural models. Conclusions Interstitial eosinophilic aggregates were associated with a higher risk of a composite of KRT initiation or ≥40% decline in eGFR. Podcast This article contains a podcast at https://dts.podtrac. com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_12_08_CJN0000000000000277. mp3
Fluoride induces osteoblast autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway in vivo and in vitro

Fluorosis primarily manifests as bone damage in the form of dental fluorosis and skeletal fluorosis and represents a critical global public health challenge. However, few studies have examined autophagy-related signaling pathways in skeletal fluorosis. This study aimed to investigate the effect of fluoride on autophagy in osteoblasts using comprehensive methods and to explore the role of the PI3K/AKT/mTOR signaling pathway in regulating fluoride-induced autophagy in osteoblasts. Sprague–Dawley (SD) rats were exposed to different concentrations of fluoride (NaF: 5, 50, and 100 mg/L) for six months. Primary osteoblasts were treated with 0.5, 1.0, or 3.0 mM NaF. Hematoxylin and eosin (H&E) staining, transmission electron microscopy (TEM), immunohistochemistry (IHC), immunofluorescence staining, and western blotting were performed to evaluate morphological changes in bone tissues and autophagosomes and to detect the protein expression of autophagy-related markers and PI3K/AKT/mTOR signaling pathway-related molecules both in vivo and in vitro. The bone tissues of fluoride-exposed rats showed osteosclerosis, autophagosomes and autolysosomes. LC3B immunofluorescence staining revealed an increase in autophagosomes in the primary osteoblasts treated with fluoride. The LC3Ⅱ/Ⅰ ratio and levels of autophagy-related markers (Beclin 1 and Atg7) were increased, whereas P62 levels were decreased in bone tissues and primary osteoblasts in the fluoride groups. Simultaneously, p-AKT and p-mTOR levels were reduced in bone tissues and primary osteoblasts in the fluoride groups. Moreover, a PI3K inhibitor (LY294002) further downregulated p-AKT and p-mTOR protein expression but slightly increased the LC3Ⅱ/Ⅰ ratio in primary osteoblasts. These results demonstrate that fluoride induces autophagy in osteoblasts by inhibiting the PI3K/AKT/mTOR signaling pathway, which deepens our understanding of the molecular mechanisms underlying fluoride-induced bone damage and provides a theoretical basis for the prevention and treatment of skeletal fluorosis.
Pyronaridine: a review of its clinical pharmacology in the treatment of malaria

Abstract Pyronaridine-artesunate was recently strongly recommended in the 2022 update of the WHO Guidelines for the Treatment of Malaria, becoming the newest artemisinin-based combination therapy (ACT) for both uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. Pyronaridine-artesunate, available as a tablet and paediatric granule formulations, is being adopted in regions where malaria treatment outcome is challenged by increasing chloroquine resistance. Pyronaridine is an old antimalarial agent that has been used for more than 50 years as a blood schizonticide, which exerts its antimalarial activity by interfering with the synthesis of the haemozoin pigment within the Plasmodium digestive vacuole. Pyronaridine exhibits a high blood-to-plasma distribution ratio due to its tendency to accumulate in blood cells. This feature is believed to play a crucial role in its pharmacokinetic (PK) properties and pharmacological activity. The PK characteristics of pyronaridine include rapid oral absorption, large volumes of distribution and low total body clearance, resulting in a long terminal apparent half-life. Moreover, differences in PK profiles have been observed between healthy volunteers and malaria-infected patients, indicating a potential disease-related impact on PK properties. Despite a long history, there is only limited knowledge of the clinical PK and pharmacodynamics of pyronaridine, particularly in special populations such as children and pregnant women. We here provide a comprehensive overview of the clinical pharmacology of pyronaridine in the treatment of malaria.
Outcomes in elderly patients undergoing hepatic resection compared to liver transplant for hepatocellular carcinoma

Hepatic resection (HR) is an excellent option for patients with hepatocellular carcinoma (HCC). For patients meeting the Milan criteria, a liver transplant (LT) is also a viable option for patients with HCC, especially those with end‐stage liver disease. With increasing rates of LTs amongst the elderly, we sought to determine long‐term outcomes in patients who underwent HR compared to LTs in this patient population.
The role of maternal age on adverse pregnancy outcomes among primiparous women with singleton birth: a retrospective cohort study in urban areas of China

Abstract Background Both young and advanced maternal age pregnancies have strong associations with adverse pregnancy outcomes; however, there is limited understanding of how these associations present in an urban environment in China. This study aimed to analyze the associations between maternal age and pregnancy outcomes among Chinese urban women. Methods We performed a population-based study consisting of 60,209 singleton pregnancies of primiparous women whose newborns were delivered after 20 weeks’ gestation between January 2012 and December 2015 in urban areas of China. Participants were divided into six groups (19 or younger, 20–24, 25–29, 30–34, 35–39, 40 or older). Pregnancy outcomes include gestational diabetes mellitus (GDM), preeclampsia, placental abruption, placenta previa, premature rupture of membrane (PROM), postpartum hemorrhage, preterm birth, low birthweight, small for gestational age (SGA), large for gestational age (LGA), fetal distress, congenital microtia, and fetal death. Logistic regression models were used to assess the role of maternal age on the risk of adverse pregnancy outcomes with women aged 25–29 years as the reference group. Results The risks of GDM, preeclampsia, placenta previa, and postpartum hemorrhage were decreased for women at a young maternal age and increased for women with advanced maternal age. Both young and advanced maternal age increased the risk of preterm birth and low birthweight. Young maternal age was also associated with increased risk of SGA (aOR 1.64, 95% CI 1.46–1.83) and fetal death (aOR 2.08, 95% CI 1.35–3.20). Maternal age over 40 years elevated the odds of placental abruption (aOR 3.44, 95% CI 1.47–8.03), LGA (aOR 1.47, 95% CI 1.09–1.98), fetal death (aOR 2.67, 95% CI 1.16–6.14), and congenital microtia (aOR 13.92, 95% CI 3.91–49.57). There were positive linear associations between maternal age and GDM, preeclampsia, placental abruption, placenta previa, PROM, postpartum hemorrhage, preterm birth, LGA and fetal distress (all P for linear trend < .05), and a negative linear association between maternal age and SGA (P for linear trend < .001). The analysis of the associations between maternal age and adverse fetal outcomes showed U-shape for preterm birth, low birth weight, SGA, fetal death and congenital microtia (all P for quadratic trend < .001). Conclusions Advanced maternal age predisposes women to adverse obstetric outcomes. Young maternal age manifests a bidirectional effect on adverse pregnancy outcomes. The findings may contribute to improving women’s antenatal care and management.
A case series study of compassion‐focused therapy for distressing experiences in psychosis

Abstract Objectives Compassion‐focused therapy (CFT) is an evolution‐informed biopsychosocial approach that seeks to cultivate attachment and care motivational systems and their psychophysiological regulators. These can counteract some of the harmful effects of social threat, inferiority, shame, self‐criticism and depression, which are common in people with psychosis and undermine their well‐being, social trust and ability to feel safe. This study aimed to test the acceptability of a novel manualized individual CFT intervention for psychosis (CFTp). Design A non‐concurrent, multiple‐baseline, case series design, with three phases: baseline, intervention and follow‐up. Methods The 26‐session CFTp intervention was provided for a sample of eight people with distressing psychotic experiences and a psychosis‐related diagnosis. The study aimed to assess acceptability of CFTp and to test clinically reliable improvements while receiving the intervention, compared to a baseline period. Results Seven of eight participants completed the therapy, and clinically reliable improvements were found at both the single‐case and group level of analysis. At the single‐case level, over half the participants showed improvements in depression (5/7), stress (5/7), distress (5/7), anxiety (4/7) and voices (3/5). One participant showed a deterioration in anxiety (1/7) and dissociation (1/7). At the group level (n = 7), there were significant improvements in depression, stress, distress, voices and delusions. The improvements in voices, delusions and distress were sustained at 6‐ to 8‐week follow‐up, but depression and stress dropped slightly to trend‐level improvements. Conclusions CFTp is a feasible and acceptable intervention for psychosis, and further investigation is warranted with a randomized controlled trial.
Healthcare Trajectories and Outcomes in the First Year After Tracheostomy Based on Patient Characteristics*

OBJECTIVES: To define healthcare trajectories after tracheostomy to inform shared decision-making efforts for critically ill patients. DESIGN: Retrospective epidemiologic cohort study. SETTING: California Patient Discharge Database 2018–2019. PATIENTS: Patients who received a tracheostomy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We tracked 1-year outcomes after tracheostomy, including survival and time alive in and out of a healthcare facility (HCF. Patients were stratified based on surgical status (did the patient require a major operating room procedure or not), age (65 yr old or older and less than 65 yr), pre-ICU comorbid states (frailty, chronic organ dysfunction, cancer, and robustness), and the need for dialysis during the tracheostomy admission. We identified 4,274 nonsurgical adults who received a tracheostomy during the study period with 50.9% being 65 years old or older. Among adults 65 years old or older, median survival after tracheostomy was less than 3 months for individuals with frailty, chronic organ dysfunction, cancer, or dialysis. Median survival was 3 months for adults younger than 65 years with cancer or dialysis. Most patients spent the majority of days alive after a tracheostomy in an HCF in the first 3 months. Older adults had very few days alive and out of an HCF in the first 3 months after tracheostomy. Most patients who ultimately died in the first year after tracheostomy spent almost all days alive in an HCF. CONCLUSIONS: Cumulative mortality and median survival after a tracheostomy were very poor across most ages and groups. Older adults and several subgroups of younger adults experienced high rates of prolonged hospitalization with few days alive and out of an HCF. This information may aid some patients, surrogates, and providers in decision-making.
Comprehensive identification of diverse ribosomal RNA modifications by targeted nanopore direct RNA sequencing and JACUSA2

ABSTRACT Ribosomal RNAs are decorated by numerous post-transcriptional modifications whose exact roles in ribosome biogenesis, function, and human pathophysiology remain largely unknown. Here, we report a targeted direct rRNA sequencing approach involving a substrate selection step and demonstrate its suitability to identify differential modification sites in combination with the JACUSA2 software. We compared JACUSA2 to other tools designed for RNA modification detection and show that JACUSA2 outperforms other software with regard to detection of base modifications such as methylation, acetylation and aminocarboxypropylation. To illustrate its widespread usability, we applied our method to a collection of CRISPR-Cas9 engineered colon carcinoma cells lacking specific enzymatic activities responsible for particular rRNA modifications and systematically compared them to isogenic wild-type RNAs. Besides the numerous 2′-O methylated riboses and pseudouridylated residues, our approach was suitable to reliably identify differential base methylation and acetylation events. Importantly, our method does not require any prior knowledge of modification sites or the need to train complex models. We further report for the first time detection of human rRNA modifications by direct RNA-sequencing on Flongle flow cells, the smallest-scale nanopore flow cell available to date. The use of these smaller flow cells reduces RNA input requirements, making our workflow suitable for the analysis of samples with limited availability and clinical work.