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Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

Genomic studies of diseases can be divided into two types: i) analyses that reveal causal genes by focusing on linkage disequilibrium between observed and causal variants and ii) those that simultaneously assess numerous genetic markers to estimate the polygenic effects of a particular genomic region or entire genome. The field of human genetics has emphasized the discovery of causal genes, but these represent only a fraction of the total genetic variance. Therefore, alternative approaches, such as the polygenic risk score, which estimates the genetic risk for a given trait or disease based on all genetic markers (rather than on known causal variants only), have begun to garner attention. In many respects, these human genetic methods are similar to those originally developed for the estimation of breeding values (i.e., total additive genetic effects) in livestock. However, despite these similarities in methods, the fields of human and animal genetics still differ markedly in terms of research objectives, target populations, and other characteristics. For example, livestock populations have continually been selected and inbred throughout their history; consequently, their effective population size has shrunk and preferred genes (such as those influencing disease resistance and production traits) have accumulated in the modern breeding populations. By examining the characteristics of these two fields, particularly from the perspectives of disease and disease resistance, this review aims to improve understanding of the intrinsic differences between genomic studies using human compared with livestock populations.

Abstract The Alertapnée study followed 555 adults with obstructive sleep apnea treated with CPAP and found that the occurrence of Cheyne-Stokes respiration (CSR) was linked to a 14-fold increase in the risk of significant cardiac events (SCE) after one year. However, the progression and clinical significance of CSR episodes over time remain unclear. This ancillary study aimed to assess CSR progression and clinical outcomes during a second year of follow-up in 66 patients who had experienced at least one CSR episode in the first year. The study focused on the number of nights with CSR, percentage of CSR, SCEs. Results showed that 62 of 66 patients with CSR in the first year also experienced CSR in the second year, with a significant increase in the median number of CSR nights, particularly when CSR was related to cardiovascular conditions (37 vs. 19 nights, p = 0.006). Patients who experienced a SCE in year 2 had significantly more nights with CSR (median 48/90nights; IQR = 35) and a significantly greater mean percentage of CSR (median 13.8%; interquartile range (IQR) = 13.7) as compared with patients free of SCE (median 9.5/90 nights IQR = 27.8 (p = 0.012); 6.1% IQR = 4.5 (p = 0.008), respectively). In conclusion, CSR occurrence and severity depend on the underlying condition. CSR related to cardiovascular aetiology increases over time and is associated with SCEs, whereas CSR linked to non-cardiovascular conditions does not indicate a poor prognosis. Identifying CSR patterns related to cardiovascular aetiologies could enable early detection of SCEs through telemonitoring in CPAP-treated patients.

Background Tafamidis is a kinetic stabilizer that binds to the transthyretin (TTR) gene, inhibiting its dissociation. It is the only disease-modifying treatment for hereditary TTR amyloidosis with peripheral neuropathy (ATTRv-PN) available in the National Therapeutic Form (Formulário Terapêutico Nacional, FTN, in Portuguese) of the Brazilian Unified Health System (Sistema Único de Saúde, SUS, in Portuguese).

The paper aims to analyze the Technical Efficiency of 70 Commercial banks from 19 African countries from 2009-2020. Using the Data Envelopment Analysis (DEA) method of the two main approaches, Variable Return to Scale (VRS) and Constant Return to Scale (CRS) technique on a Panel Data. We find that African banks have a higher efficacy assessment with the VRS than the CRS technique, thus, with a Pure Technical Efficiency (PTE) score than Technical Efficiency (TE) . Our findings show that the majority of the banks are operating at very low levels of efficiency (not technically efficient), and inability to optimize the conversion of bank assets and liabilities into loan production for customers. Furthermore, the banks are operating inefficiently in scale, economic, and allocative manner due to mismatches in scale of production. Considering these findings, the implications of these inefficiencies extend to the overall economic development and financial stability of the region.

BACKGROUNDWeakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adults harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGAs in the general population is unknown, as are the penetrance of nAIGAs in HLA-DRB1*15:02 or 16:02 individuals and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs.METHODSThis study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM.RESULTSWe found that anti-IFN-γ auto-Abs detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype were not neutralizing. Moreover, we did not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02. Additionally, nAIGAs were absent in 1,063 patients with an autoimmune disease. Finally, 7 of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGAs.CONCLUSIONThese findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease.FUNDINGThe Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983 and U19AIN1625568), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), the French National Research Agency (ANR) under the Investments for the Future program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), ANR-GENMSMD (ANR-16-CE17-0005-01), ANR-MAFMACRO (ANR-22-CE92-0008), ANRSECTZ170784, the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AI2D (ANR-22-CE15-0046) projects, the ANR-RHU program (ANR-21-RHUS-08-COVIFERON), the European Unions Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour lenfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea & Bowery Advisory Group, William E. Ford, General Atlantics Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantics Co-President, Managing Director, and Head of business in EMEA, and the General Atlantic Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM) and of Paris Cité University. JR was supported by the INSERM PhD program for doctors of pharmacy (poste daccueil INSERM). JR and TLV were supported by the Bettencourt-Schueller Foundation and the MD-PhD program of the Imagine Institute. MO was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the New York Hideyo Noguchi Memorial Society (HNMS).

Low-velocity orbital penetrating injuries may result in an intracranial retained foreign body that requires surgical removal. We describe the endoscopic transorbital removal of a retained umbrella tip in the frontal lobe, which was secondary to trauma to the orbital roof. This technique facilitated the complete removal of the foreign body without causing additional damage to the surrounding tissue. The patient had a successful postoperative recovery. We also discuss the utility of the transorbital neuroendoscopic procedure in managing these traumatic injuries.

Abstract Background Physiotherapy is effective to reduce pain and improve the quality of life of people living with chronic pain. To offer high-quality physiotherapy services, these services must be patient-centred and respond to patients’ needs. However, few studies seem to target patients’ perceived needs, whereas more studies tend to focus on needs assessed by healthcare experts, which are not always in line with patients’ perceived needs. In addition, people living with chronic pain are often faced with several health inequities and may have varied perceived needs depending on their personal conditions. To offer services that truly meet patients’ needs, it is therefore crucial to understand these needs. This scoping review aims to identify and map the perceived needs of people living with chronic pain towards physiotherapy services. Methods To conduct this review, we followed the six stages framework proposed by Arksey and O’Malley. We searched four databases (Medline, Embase, CINHAL and APA PsycINFO) as well as the grey literature. We included all studies describing the needs, demands, preferences or expectations of adults living with chronic pain towards physiotherapy. We then performed an inductive thematic analysis of the results and discussion sections of these studies to identify the perceived needs. Once those needs were identified, we mapped them into the seven dimensions of the patient-centred healthcare delivery framework. Results Our review included 96 studies. Various perceived needs were identified through the thematic analysis, such as the needs for an empathetic relationship; for a clear, adapted and supervised exercise program; and for personalized treatment. Our mapping into the patient-centred healthcare delivery framework showed that most studies reported needs associated with the dimensions of interpersonal care, individualized healthcare and professional care. Needs associated with the other dimensions of the framework (access; coordination and continuity; services and facilities; data and information) were less frequently mentioned. Conclusions The results of this review have enabled us to identify and better understand multiple needs perceived by people living with chronic pain regarding physiotherapy services. The perceived needs identified through this scoping review were mapped within the seven dimensions of the Patient-centred healthcare delivery framework.

Abstract Background Mineralocorticoid receptor antagonists (MRAs) have been shown to improve outcomes in various populations of heart failure (HF) patients. However, the impact of concomitant diseases, such as diabetes mellitus (DM), on these outcomes remains unclear. This meta-analysis aimed to evaluate the efficacy and safety of MRAs in heart failure patients with and without diabetes mellitus. Methods A systematic search was conducted on PubMed, Scopus, and Google Scholar databases up to April 30, 2024. Data analysis was performed using a random-effects model to account for variability across studies, and statistical analysis was carried out using Review Manager 5.4. Efficacy and safety parameters were evaluated in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Results The meta-analysis included a total of 21,832 subjects from ten studies. The pooled results demonstrated that MRAs, compared to placebo, significantly reduced all-cause mortality in HF patients with and without DM (RR: 0.85; 95%CI 0.75–0.96; p = 0.009). A similar effect was observed in HF patients without DM (RR: 0.83; 95%CI 0.71–0.97; p = 0.02), while no significant effect was detected in the DM subgroup (RR: 0.87; 95%CI 0.69–1.11; p = 0.27). Both treatments had comparable effects on cardiovascular mortality in HF patients with and without DM (RR: 0.88; 95%CI 0.82–0.94; p = 0.0002), in HF patients with DM (RR: 0.90; 95%CI 0.81–1.01; p = 0.08), and in the non-DM subgroup (RR: 0.86; 95%CI 0.79–0.94; p = 0.0009). MRAs significantly reduced the risk of cardiovascular mortality in HF patients with and without DM (RR: 0.82; 95%CI 0.72–0.94; p = 0.005) and in HF patients with DM (RR: 0.79; 95%CI 0.63–0.98; p = 0.03), but no significant effect was observed in the non-DM subgroup (RR: 0.85; 95%CI 0.69–1.05; p = 0.13). Furthermore, compared to placebo, MRAs were associated with an increased risk of hyperkalemia (> 5.5 mEq/L) in HF patients with and without DM (RR: 1.63; 95%CI 1.18–2.24; p = 0.003), particularly in HF patients with DM (RR: 1.44; 95%CI 0.97–2.13; p = 0.07) and in the non-DM subgroup (RR: 1.87; 95%CI 1.34–2.61; p = 0.0002). Conclusion MRAs are effective in reducing all-cause mortality, cardiovascular death, and cardiovascular mortality in heart failure patients. However, the use of MRAs is associated with an increased risk of hyperkalemia, necessitating careful monitoring, particularly in patients with diabetes mellitus.

Malaria remains one of the great killers in tropical regions of the world due to the transmission of the Plasmodium parasite by the bites of the female mosquito Anopheles. The resistance of this species to synthetic insecticides contributes to an increase in the incidence of malaria and therefore necessitates the development of new potent and eco-friendly insecticides. In this study, twelve previously reported limonoids from four Entandrophragma species collected in Cameroon have been computationally evaluated for their Anopheles gambiae AChE inhibitory activity. The docking procedure was carried out through Molecular Operating Environment 2019.01 (MOE), while the UCSF Chimera program was used to model the docking results based on interactions between proteins and ligands, and molecular dynamics trajectories were analyzed using the GROMACS 2021.1 tool. Entandrophragmin and encandollens B and C with docking scores ranging from −6.45 to −7.28 kcal/mol were the most promising hits compared to the reference azadirachtin (−6.22 kcal/mol) and were further evaluated for their mechanism of action. Subsequent evaluation classified encandollen C as the best candidate for the development of new potent eco-friendly insecticides based on its lower average RMSD and RMSF and its compactness over a 150 ns duration with acetylcholinesterase.

ABSTRACT: Most trace minerals (TM) are fed above dairy cow requirements in commercial herds but their fate and effects on dairy cows have not been well documented. In this study, we evaluated the effects of feeding short-term sulfate TM above recommendations on apparent total-tract digestibility of nutrients, rumen fermentation characteristics, serum concentrations, and milk yield and composition, as well as milk, fecal, and urinary TM excretion in midlactation dairy cows. Eight multiparous Holstein cows with an average body weight (± SD) of 684 ± 29 kg at 82 ± 10 DIM in a quadruple 2 × 2 crossover design were fed a basal diet, differing in sulfate TM supplement concentrations, to provide either 0.11, 17, and 63 (control; CON) or 0.95, 114, and 123 (high trace minerals; HTM) mg of dietary Co, Mn, and Zn per kilogram of DM, respectively. Each experimental period had a 21-d adaptation to the diet, followed by a 10-d sample collection period. Feed ingredients and total feces and urine were collected during 4 consecutive d and rumen fluid was collected 0, 1, 2, 4, and 6 h relative to feeding. Milk yield was recorded daily, and milk samples were collected on 4 consecutive milkings. Ingestion of Co, Mn, and Zn was higher for the HTM group compared with the CON group by 216%, 233%, and 93%, respectively. Dry matter intake averaged 25.0 (SE = 0.6) kg/d, and apparent total-tract digestibility of major nutrients was similar between treatments. High trace minerals had no measurable effect on ruminal pH, major volatile fatty acids, and protozoa counts. Isovalerate molar proportion was 9.4% greater for the HTM group compared with the CON group. Neither milk yield (43.5 kg/d; SE = 0.8) nor milk fat and protein concentrations differed between treatments. Milk urea nitrogen concentration was significantly higher for HTM (11.7 mg/dL) compared with CON (9.7 mg/dL; SE = 0.7). Fecal excretion of Co, Mn, and Zn increased by 223%, 198%, and 75%, respectively, for the HTM group compared with the CON group. Urinary excretions of TM were marginal compared with feces, and only urinary Co and Mn were significantly higher for HTM cows than CON cows, as was similarly obtained for serum Co and Mn concentrations. Milk TM yields were not modified by treatments. In summary, short-term dietary sulfate TM supply over the recommendation did not improve cow performance but significantly increased fecal TM excretion, which could affect TM accumulation in soils where manure is applied and could potentially result in leaching into nearby watersheds. Further studies are needed to evaluate the impact of high fecal TM excretion on the environment using the One Health approach. Moreover, the effects of TM oversupply on milk production and cow health should be evaluated by long-term experiments.

Abstract Background Mutations in the TP53 tumor suppressor gene are well-established drivers of colorectal cancer (CRC) development. However, data on the prevalence of TP53 variants and their association with consensus molecular subtype (CMS) classification in patients with CRC from Rwanda are currently lacking. This study addressed this knowledge gap by investigating TP53 mutation status concerning CMS classification in a CRC cohort from Rwanda. Methods Formalin-fixed paraffin-embedded (FFPE) tissue blocks were obtained from 51 patients with CRC at the University Teaching Hospital of Kigali, Rwanda. Exons 4 to 11 and their flanking intron-exon boundaries in the TP53 gene were sequenced using Sanger sequencing to identify potential variants. The recently established immunohistochemistry-based classifier was employed to determine the CMS of each tumor. Results Sequencing analysis of cancerous tissue DNA revealed TP53 pathogenic variants in 23 of 51 (45.1%) patients from Rwanda. These variants were predominantly missense types (18/23, 78.3%). The most frequent were c.455dup (p.P153Afs*28), c.524G > A (p.R175H), and c.733G > A (p.G245S), each identified in three tumors. Trinucleotide sequence context analysis of the 23 mutations (20 of which were single-base substitutions) revealed a predominance of the [C > N] pattern among single-base substitutions (SBSs) (18/20; 90.0%), with C[C > T]G being the most frequent mutation (5/18, 27.8%). Furthermore, pyrimidine bases (C and T) were preferentially found at the 5ʹ flanking position of the mutated cytosine (13/18; 72.2%). Analysis of CMS subtypes revealed the following distribution: CMS1 (microsatellite instability-immune) (6/51, 11.8%), CMS2 (canonical) (28/51, 54.9%), CMS3 (metabolic) (9/51, 17.6%), and CMS4 (mesenchymal) (8/51, 15.7%). Interestingly, the majority of TP53 variants were in the CMS2 subgroup (14/23; 60.1%). Conclusion Our findings indicate a high frequency of TP53 variants in CRC patients from Rwanda. Importantly, these variants are enriched in the CMS2 subtype. This study, representing the second investigation into molecular alterations in patients with CRC from Rwanda and the first to explore TP53 mutations and CMS classification, provides valuable insights into the molecular landscape of CRC in this understudied population.

Abstract The multi-site replication study, Many Labs 2, concluded that sample location and setting did not substantially affect the replicability of findings. Here, we examine theoretical and methodological considerations for a subset of the analyses, namely exploratory tests of heterogeneity in the replicability of studies between “WEIRD and less-WEIRD cultures”. We conducted a review of literature citing the study, a re-examination of the existing cultural variability, a power stimulation for detecting cultural heterogeneity, and re-analyses of the original exploratory tests. Findings indicate little cultural variability and low power to detect cultural heterogeneity effects in the Many Labs 2 data, yet the literature review indicates the study is cited regarding the moderating role of culture. Our reanalysis of the data found that using different operationalizations of culture slightly increased effect sizes but did not substantially alter the conclusions of Many Labs 2. Future studies of cultural heterogeneity can be improved with theoretical consideration of which effects and which cultures are likely to show variation as well as a priori methodological planning for appropriate operationalizations of culture and sufficient power to detect effects.