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Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database
Abstract Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. Here, we identify explanations for the presumed lack of disease manifestation in 701 of 734 variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders are rare, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.
Effect of semen dilution rate and dimethyl acetamide levels on post-thaw motility and fertility parameters of rooster sperm
This study evaluated the impact of pre-freezing semen dilution rate and dimethyl acetamide (DMA) concentration on the post-thaw motility and fertility of cryopreserved rooster sperm. Rooster ejaculates were diluted with a standard EK extender to achieve low (LSC; 1 × 10⁹ sperm/mL) and high (HSC; 2 × 10⁹ sperm/mL) sperm concentrations. Each dilution group was further treated with three DMA concentrations (3%, 6%, or 9%) before cryopreservation. Post-thaw sperm motility traits were obtained by computer-assisted sperm analysis (CASA), and fertility features were evaluated through artificial insemination in hens. The current results showed that HSC significantly improved total motility (TM), curvilinear velocity (VCL), amplitude of lateral head displacement (ALH), and beat cross frequency (BCF), but reduced linearity (LIN) and straightness (STR) compared to LSC. DMA concentration had a quadratic effect on motility, with 6% yielding the highest progressive motility (PM), straight line velocity (VSL), and BCF. Fertility outcomes revealed that HSC resulted in higher fertilization rates, while neither DMA concentrations nor their interaction with dilution rates exerted significant effects on fertility traits. VCL, ALH, and BCF showed positive correlations with pipping-chicks rates, whereas STR, LIN, and WOB displayed negative correlations. These findings underscore the critical interplay between dilution rate and cryoprotectant concentration and provide practical guidance for developing more reliable cryopreservation protocols that can be applied under field conditions to enhance fertility management in poultry production.
Biomimetic strong and tough MXene fibers with synergy between micropores and dual interfaces
Association of health behaviors with healthcare workers’ physical and psychological well-being: Learning from the COVID-19 pandemic
Background During the COVID-19 pandemic healthcare workers reported using a variety of positive or negative health behaviors as a strategy to cope with the increased stress at work and home. This study examined the extent of healthcare workers’ engagement in various health behaviors and the association of these behaviors with changes in self-reported physical and psychological well-being during the pandemic. Methods A survey was developed and administered to healthcare workers in a large healthcare system in Southeast Michigan between November 2, 2020, and January 21, 2021, during Michigan’s second COVID-19 surge. Results During the study period 368 healthcare workers completed the survey. The majority of participants were female (83.2%) and aged between 25−34 years (29.3%). Most participants reported a drop in their psychological well-being and physical health during the pandemic. Overall, 14.8% to 47.7% of participants rated their engagement in a positive health behavior as “often” or “very often”. Engagement in most positive health behaviors was associated with higher self-rating of physical health and psychological well-being. The estimated decrease in psychological well-being scores for participants who often/very often engaged in pleasurable activities was 0.91 points less (p = 0.003, 95% CI [−1.50, −0.32]) than for those who rarely/never engaged in such activity. Exercise , healthy eating , getting enough sleep , engaging in pleasurable activities , focusing on gratitude and positive things , and getting social support appeared to positively influence the degree to which participant’s physical health declined. After controlling for age, gender and other potential confounders, each additional positive health behavior was associated with a 0.22-point decrease in the rate of decline in overall physical health (p = 0.000, 95% CI −0.35, −0.10). Discussion Healthcare workers who regularly engaged in positive health behaviors during the pandemic reported better psychological and physically well-being than those who did not before and during COVID-19. Engaging in pleasurable activities was the only health behavior in our study that demonstrated a potential protective effect against the decline in psychological well-being during the pandemic. Several other positive health behaviors were associated with a lower rate of decline of physical health during the pandemic. Health systems should consider implementing strategies to increase opportunities for pleasurable activities for healthcare workers, both in the workplace and at home, especially during times of increased stress.
A Rho GTPase-effector ensemble governs cell migration behavior
Abstract How can a cell navigate its environment without any external cues? Since such cues are not always present in the environment, cells rely on internal machinery to explore their surroundings. Although Rho GTPases are known for orchestrating cell motility, the intrinsic Rho GTPase-effector mechanisms governing spontaneous migration remain incompletely understood. Here we show an imaging-based method that profiles protein-protein interactions (PPIs) through phase-separated condensates. By applying this method to hundreds of interaction profiles between Rho small GTPases and their effector proteins, we uncovered two intrinsic mechanisms governing cell migration. Formin-like protein (FMNL) determines the front of the cell by restricting Cdc42 activity, establishing front-rear polarity. In contrast, Rac1-ROCK-interaction-mediated arc stress fiber formation at the front inherently enables spontaneous directional changes and enhances cellular responses to external cues. Our findings elucidate the intricate roles of the Rho GTPase-effector ensemble that governs cell migration behavior, revealing an intrinsic program for efficient motility strategies.
Satellite clinics to bring pediatric cancer care closer to patients in Ethiopia: Perceived relevance, opportunities and anticipated challenges
Background Ethiopia faces significant gaps in paediatric cancer care, with limited treatment centers and a shortage of trained professionals, leading to delayed diagnoses, high treatment abandonment, and mortality. Establishing Paediatric Cancer Satellite Clinics (PCSCs) in underserved regions offers a potential solution. Objective This study explores the needs, relevance, and feasibility of the Paediatric Cancer Satellite Clinic (PCSC) model in Ethiopia, identifying resources, opportunities, and barriers to guide its development and implementation. Methods This formative study was conducted from August to October 2023 in eight hospitals across Ethiopia, selected for establishing PCSCs. Data were collected through 19 focus group discussions (FGDs) with hospital and health system leaderships and purposively selected health professionals including physician, nurses, pharmacists and other categories. Data were analyzed using ATLAS.ti, with themes developed through iterative coding and categorization. Results Participants consistently identified pediatric cancer as a significant community health issue, worsened by limited diagnostic and treatment facilities, leading to under diagnosis. The study revealed a strong unmet need for pediatric cancer care, with widespread support for establishing PCSCs to improve access. Participants expressed confidence in the feasibility and effectiveness of PCSCs, citing enablers such as existing adult oncology programs, patient demand, adequate staff, leadership interest, stakeholder support, and alignment with government plans. Opportunities included leadership backing, resource availability, partnerships with private labs, and community-based health insurance. However, challenges like inconsistent lab services and medical supplies, staff demotivation due to lack of risk allowances, role confusion, inadequate personal protective equipment (PPE), poor infection control, and insufficient psychosocial support were identified as potential barriers. Conclusions This study underscored the urgent need for pediatric cancer care and strong support for PCSCs as a feasible and appropriate solution. Although challenges like supply chain disruptions, staff demotivation, unclear role delineation, diagnostic limitations, safety concerns, and gaps in psychosocial support-, the strong commitment of healthcare providers offer a solid foundation for success. To ensure the long-term effectiveness and sustainability of PCSCs, these obstacles must be addressed through targeted improvements in diagnostics, enhanced staff support, strengthened safety protocols, and integrated psychosocial care.
ClairS-TO: a deep-learning method for long-read tumor-only somatic small variant calling
The impact of structure adjustment of energy consumption on the structural upgrading of the construction industry
Using spatial Durbin model on panel data from 30 provinces in China from 2008 to 2022, this article explores the technical effect, price effect, and spatial effect of energy consumption structure on the structure of the construction industry. It is found that structure adjustment of energy consumption (SAEC) has a significant promoting effect on structural upgrading of the construction industry (SUC), exhibiting a negative spillover effect in space. Technology spillovers and research and development (R&D) are also the main channels through which SAEC affects SUC, while the channel effect of energy price effect is not significant. Further research has found that reducing the proportion of coal, oil, and natural gas consumption can promote SUC, with natural gas having the strongest effect. At the regional level, SAEC has a stronger promoting effect on SUC in the central and western regions, but its spatial negative spillover effect is more pronounced in the eastern region; On the temporal level, the promotion effect of SAEC on SUC was stronger from 2008 to 2014, while its spatial negative spillover effect was more pronounced from 2015 to 2022. In addition, with the increase in energy prices and human capital levels, it can further stimulate the promoting effect of SAEC on SUC.
Structural order differentiation unlocks the energy storage performance of commensurate antiferroelectric ceramics
Abstract Commensurate modulated antiferroelectric ceramics exhibit limited application prospects, a quasi transient antiferroelectric-ferroelectric phase transition has locked their energy storage performance. Highly homogeneous oxygen octahedra set produce only one type of antiferrodistortion-ferrodistortion transition, followed by a rapid triggering of the antiferroelectric-ferroelectric phase transition. Here, we propose a strategy of structural order differentiation engineering to disrupt the homogeneity of oxygen octahedra by initiator/enhancer co-substitution, and we have successfully unlocked the energy storage performance of commensurate modulated antiferroelectric ceramics. By constructing oxygen octahedra sets with highly differentiated rotational distortions, an energy storage density of 23.11 J/cm 3 , an energy storage efficiency of 85.55%, and a discharge energy density of up to 16.45 J/cm 3 are simultaneously achieved, which is superior to other antiferroelectric ceramics and dielectric ceramics. By limiting the doping window, the commensurate modulation characteristics of polarization order can be maintained, which ensures the maximum polarization. A highly differentiated octahedra rotational distortion yields a multi-stage antiferrodistortion-ferrodistortion transition and a coexistence of polymorphic ferroelectric phases, significantly prolonging the polarization process. The proposed structural order differentiation shows guiding significance for the development of antiferroelectric, and the obtained energy storage performance promotes the practical applications of antiferroelectric ceramic capacitors.
The impact of 6-week flywheel eccentric training on sprint speed and change-of-direction of female basketball players
Given the demands of basketball for rapid sprinting and directional changes, and the growing interest in flywheel eccentric training (FET) to enhance these abilities, this study examines a six-week FET regimen compared to barbell squat training (BST)—the control condition—on sprint and change-of-direction performance in female collegiate basketball players.Nineteen female collegiate basketball players were randomized to flywheel eccentric training (n = 9) or barbell squat training (n = 10) groups. Both groups trained twice weekly over six weeks, following a standardized warm-up protocol. The FET group performed 4× (2 + 8) maximal concentric–eccentric repetitions on a flywheel device (inertia = 0.075 kg·m²), and the BST group completed 4 × 8 back-squat repetitions at 80% of their pre-test one-repetition maximum (1RM); all sets were separated by 3-minute rest intervals. A 2 × 2 factorial analysis of variance (ANOVA) was conducted to assess pre– to post-intervention changes in sprint speed (20-m sprint) and change-of-direction ability (505 agility test and lane agility test).The results of the analysis of variance indicated that in the FET group, the main effect of time and the interaction effect were significant for the 20m sprint and 505 agility tests (p < 0.05), while the group main effect was not significant (p > 0.05). However, no significant effects were observed for the lane agility test (p > 0.05). In the BST group, there were no significant effects regarding the main effect of time, the group main effect, or the interaction effect in any of the tests (p > 0.05). In collegiate female basketball players, six weeks of moderate-inertia (0.075 kg·m²) flywheel eccentric training elicited superior improvements in linear sprint speed and rapid direction changes ability compared to an equivalent barbell squat regimen.
Dual-band high-dissymmetry circularly polarized luminescence from cholesteric liquid crystals overlaid a gold cluster film
Trends, district-level variations, and socioeconomic disparities in cesarean section delivery in Bangladesh
Background Cesarean section (CS) delivery rates have risen dramatically worldwide, with most countries exceeding the World Health Organization’s (WHO) recommended rate of 10–15%. However, disparities exist, with evidence suggesting that socioeconomic disadvantage and geographic location significantly influence CS rates. Despite this, comprehensive estimates, particularly in Bangladesh, remain limited. This study aims to examine trends, district-level variations, and socioeconomic disparities in CS rates in Bangladesh. Methods Data from seven rounds of the Bangladesh Demographic and Health Surveys, conducted between 1999/2000 and 2022, were analyzed. The outcome variable was CS delivery, categorized by mode of delivery and place of delivery. Explanatory variables included districts, wealth quintiles, and socio-demographic characteristics. Descriptive statistics were used to illustrate trends and variations in CS delivery over time in Bangladesh. Multilevel mixed-effects binary logistic regressions were employed to identify the factors associated with CS delivery. Results Between 1999/2000 and 2022, hospital births in Bangladesh increased by 55%, largely driven by a significant rise in CS deliveries, from 32% to 69%. Around 85% of the total CS deliveries occurred in the private healthcare facilities in 2022, a marked increase from 41.5% in 1999/2000. In contrast, CS delivery rates in government healthcare facilities fell from 53% to 13.6% during the same period. Mothers in border and hilly districts, as well as those in the poorest wealth quintile, reported lower rates of CS delivery compared to their counterparts. Conclusion The uneven distribution of CS delivery across districts and socioeconomic groups highlights the need for a more tailored approach to childbirth. While government efforts to reduce unnecessary CS use have been insufficient, this study suggests that a one-size-fits-all strategy may exacerbate disparities. Instead, the focus should shift from increasing access to ensuring justified and appropriate use of CS, with public healthcare facilities playing a crucial role in providing safe alternatives.
Gut bacterial dysbiosis in pediatric severe malaria associates with post-discharge mortality
Antidiabetic drug utilization pattern, affordability and cost analysis in Iran from 2009 to 2021: A need to revise guideline
Diabetes Mellitus is a chronic disease that has a notable prevalence and continues to rise. It has a significant economic burden and consumes lots of financial resources of the health sector, while about half of the diabetic patients have uncontrolled diabetes. Therefore, surveilling the utilization pattern and affordability of antidiabetic drugs is vital for appropriate policymaking. It was a retrospective descriptive study that evaluated the utilization of antidiabetic medications.. The Anatomical Therapeutic Classification (ATC) was applied to categorize medicine. The Anatomical Therapeutic Classification/Defined Daily Dose (ATC/DDD) methodology was used to calculate the number of consumed Defined Daily Doses (DDDs) and the number of DDDs per 1000 inhabitants per day (DID). The Drug Utilization 90% (DU-90) method was also used to determine the most used antidiabetic drugs and compare them with the WHO essential medicine list. The affordability of antidiabetic medicine was measured by comparing the one-month consumption price with the minimum daily wage. The utilization of antidiabetic drugs increased from 22.5 DID to 63.9 DID during the study period with a 9.05 Compound Annual Growth Rate (CAGR). The overall expenditure has increased by about 18 times. Expenditure analysis showed that the cost per DDD has increased significantly over the years. The DU-90 list completely matches the WHO essential medicine list. All human insulin products were affordable, while almost all insulin analogues were unaffordable until the last year of the study period. Most novel non-insulin antidiabetic products such as empagloflozin, sitagliptin and extended-release metformin were unaffordable during the study period. The utilization of antidiabetic drugs has increased substantially. The expenditure on antidiabetic drugs has grown more rapidly than the utilization of these drugs. The number of unaffordable medicines increased during the study due to the introduction of some novel antidiabetic drugs. Therefore, it is important to revise the diabetes guidelines to promote rational drug use.
Neutrophil elastase-activatable ratiometric photoacoustic nanoprobes for imaging atherosclerotic plaque vulnerability
Understanding the social dimensions of kidney care pathways: A scoping review protocol
Objective This scoping review aims to map the social dimensions of kidney care pathways. Introduction End-stage kidney disease places significant demands on patients, caregivers, healthcare professionals, and the broader healthcare system. Kidney replacement therapy and conservative kidney management are the common management pathways for end stage kidney disease, but its delivery entails substantial time, financial, and social costs. Research has documented some social aspects of kidney care pathways, but findings are fragmented across disciplines and have not been synthesised coherently. A scoping review is therefore needed to map the existing evidence, identify key domains of social impact, and highlight gaps to inform future research and policy. Method Eligible studies will include primary research that reports on the social dimensions of managing end-stage kidney disease (ESKD) in adults. Studies from all settings, involving relevant stakeholder groups including patients with end stage kidney disease, informal caregivers, healthcare staff, and Industrial and supply chain workers engaged in different roles associated with kidney replacement therapy and/or conservative kidney management, will be included. The review will follow JBI methodology. Peer-reviewed and grey literature will be identified through searches of electronic databases (MEDLINE, CINAHL, PsycInfo, SocINDEX, EconLit, Web of Science) and grey literature sources (including Google Scholar and organisational reports). Reference lists of relevant reviews and identified articles will also be screened to identify any other relevant articles. Two reviewers will independently screen records and extract data using a predefined form. Results will be synthesised narratively and presented in thematic and tabular formats. Discussion This scoping review aims to generate evidence on the social impact of kidney replacement therapy and conservative management across multiple stakeholder groups. The review will provide a structured overview of how social outcomes are conceptualised, measured, and reported across the kidney care continuum. Review registration Open Science Framework osf.io/63wpk.
Molecular genetic portrait of virulence and ciprofloxacin resistance genes in clinical Pseudomonas aeruginosa Isolates from Khartoum, Sudan
Background Pseudomonas aeruginosa remains a major cause of hospital- and community-acquired infections, with increasing ciprofloxacin resistance driven by mutations in quinolone resistance–determining regions (QRDRs) and plasmid-mediated mechanisms. This study aimed to determine the prevalence of key virulence genes (oprI, toxA, lasB, nan1) and ciprofloxacin resistance determinants (gyrA, parC, qnrA, qnrB, qnrS ) in clinical isolates from Khartoum State, Sudan, and to explore associations with demographic and clinical variables. Methods This cross-sectional study, which was conducted from January to April 2023, included eighty-six clinical isolates of P.aeruginosa that were collected from various hospitals in Khartoum State. The isolates were reidentified via standard microbiological techniques, and DNA was extracted via the boiling method. Multiplex polymerase chain reaction was utilized to detect the presence of virulence and ciprofloxacin resistance genes. Data analysis was performed via IBM SPSS software (version 20). Results All the isolates carried one or more virulence genes, with oprI being the most prevalent (88.4%), followed by lasB (80.2%), toxA (57%), and nan1 (6.98%). Among the isolates, 30 (34.9%) were resistant to ciprofloxacin, whereas 56 (65.1%) were susceptible. All resistant isolates carried at least one of the resistance genes studied. The parC gene was the most prevalent (40.7%), followed by gyrA (20.9%) and qnrS (19.8%). qnrA and qnrB each had a prevalence of 17.4%. This investigation revealed the coexistence of the gyrA and parC genes in seven isolates (23.3%), and we also reported that the qnrA , qnrB, and qnrS genes coexisted in 11 (36.7%) of the ciprofloxacin resistant P. aeruginosa isolates. A significant association was detected between ciprofloxacin resistance and the presence of the gyrA , qnrS , qnrA , and qnrB genes (p < 0.001) but not the parC gene (p = 0.6). There was no significant association between ciprofloxacin resistance genes and virulence genes (p > 0.05). Conclusions The prudent use of ciprofloxacin is vital in managing P.aeruginosa infections amid rising resistance. Detection of gyrA and parC in susceptible isolates signals potential for future resistance through future mutations, highlighting the need for ongoing monitoring. The coexistence of resistance and virulence genes highlights the pathogen’s combined threat. These findings reinforce the public health importance of continuous molecular surveillance and genetic profiling, not only to guide effective treatment but also to inform targeted infection control strategies and antimicrobial stewardship programs.
Variability of the lymphocyte-to-monocyte ratio in patients with chronic kidney disease on hemodialysis
Introduction Chronic kidney disease (CKD) is a global public health issue characterized by a state of persistent inflammation that leads to immune system dysregulation. The lymphocyte-to-monocyte ratio (LMR) has emerged as an inflammatory biomarker of interest for monitoring the progression of this condition. Objective To determine the clinical-epidemiological, biochemical, and hematological characteristics associated with differences in the LMR in patients with chronic kidney disease undergoing hemodialysis. Materials and Methods A retrospective cohort study was conducted by reviewing the medical records of 120 CKD patients on hemodialysis treated at a private nephrology center in Lima, Peru. Patients were divided into two groups based on the median LMR value: high LMR (< 3.06) and low LMR (≥ 3.06). Logistic regression was used to analyze risk factors associated with LMR variation, complemented by longitudinal regression analysis (up to three years follow-up). Results The median age of the patients was 58 years at the time of analysis. Chronic glomerulonephritis, arterial hypertension, and type 2 diabetes mellitus (T2DM) were the most frequently reported causes of end-stage CKD. A total of 54.2% of patients had been on hemodialysis for more than seven years. Risk factors associated with decreased LMR, and thus with increased inflammation, were: older age (OR = 1.03, p < 0.001), more than three years on hemodialysis (OR = 2.17, p = 0.002), more than seven years on hemodialysis (OR = 2.38, p < 0.001), and presence of T2DM (OR = 2.2, p = 0.006). In addition, a direct positive contribution was found with hematocrit levels (Beta = 0.25, p < 0.001) and the presence of an arteriovenous fistula (Beta = 0.17, p = 0.038). Conclusions A reduced LMR is a useful inflammatory biomarker for monitoring CKD severity. Increased age, prolonged duration of hemodialysis (more than three years), presence of T2DM, and elevated ferritin levels are associated with lower LMR values. In contrast, higher hematocrit levels and the presence of an arteriovenous fistula are directly associated with higher LMR values.
Reference intervals for hematology and biochemistry in juvenile Eastern spot-billed ducks (Anas zonorhyncha) and validation of an automated hematology analyzer for avian blood analysis
The Eastern spot-billed duck ( Anas zonorhyncha ) is a common migratory waterfowl widely distributed throughout East Asia. However, the lack of species-specific reference intervals, defined as the normal range of values derived from a healthy population for clinical interpretation, hampers accurate health assessment and clinical diagnostics in this species. This is further complicated by hematologic characteristics of avian blood, such as nucleated red blood cells and thrombocytes, which pose challenges to conventional automated measurement systems optimized for mammals. This study aimed to establish hematological and biochemical reference intervals for juvenile Eastern spot-billed ducks and to evaluate the accuracy of an automated hematology analyzer (XN-1000V, Sysmex, Japan), which newly supports avian blood analysis, compared to traditional manual counting methods. Blood samples were collected from 55 clinically healthy juvenile ducks. The established reference intervals were largely consistent with those reported in related Anas species, though Eastern spot-billed ducks exhibited a heterophil-predominant leukogram. No significant differences were observed between sexes. Comparison between manual and automated methods revealed statistically significant differences in most hematological parameters; however, most of these differences were not clinically relevant, except for thrombocyte counts. Moderate correlations were found for key parameters, including WBC, RBC, hemoglobin, PCV, and MCV, suggesting potential clinical applicability of the automated analyzer with some limitations. This study provides the first species-specific hematologic and biochemical reference intervals for juvenile Eastern spot-billed ducks under semi-captive conditions, offering valuable baseline data for clinical assessments in this subset of the population. Additionally, it highlights the need for further optimization of XN-1000V analyzers for reliable and precise application in avian diagnostics.