This post hoc analysis assessed the benefit-risk profile of aripiprazole once-monthly 400 mg (AOM 400) as a long-term maintenance treatment in patients diagnosed with bipolar I disorder (BP-I), using the evidence-based metrics of number needed to treat (NNT), number needed to harm (NNH), and the likelihood to be helped or harmed (LHH). Data were derived from a double-blind, randomized withdrawal study that evaluated the efficacy and safety/tolerability of AOM 400 versus placebo over 52 weeks (NCT01567527). The main efficacy outcome was the proportion of patients free from recurrence of any mood episode, while the main safety/tolerability outcome was the incidence of patient discontinuation due to treatment-emergent adverse events (TEAEs). Overall, 73.5% of 132 patients randomized to AOM 400 and 48.9% of 133 patients randomized to placebo were free from recurrence of any mood episode at Week 52 (NNT = 5 [95% CI: 3,8]). NNT (95% CI) values were 5 (4, 9), 4 (3, 7), and-116 (not significant) for patients free from recurrence of a manic mood episode, mixed mood episode, and depressive mood episode, respectively. Discontinuation due to TEAEs was lower with AOM 400 (17.4%) versus placebo (25.6%), resulting in a negative NNH. Using an imputed NNH versus placebo of 1000, LHH was 200 for patients free from recurrence of any mood episode relative to discontinuation due to any TEAE at 52 weeks. Data suggest a favorable benefit-risk profile for AOM 400 versus placebo as a long-term maintenance treatment for BP-I.
Recent studies suggest that copy number variants (CNVs) may contribute to the missing heritability of complex diseases such as Alzheimer's disease (AD) and related dementias (ADRD). We performed a CNV analysis using genotyping data (Axiom 815 K Spanish biobank array) from the GR@ACE/DEGESCO dementia dataset (n = 20,067) of the Spanish population. Applying PennCNV and extensive quality control, 8275 controls and 7818 dementia cases were selected for gene-level case/control associations. We identified 43,833 CNVs with deletions (47%) and duplications (53%). No genome-wide significant associations were found, but nominal associations were observed in PKP3-SIGIRR and FBRSL1 loci. CNVs in 2970 genes were exclusive to dementia cases and enriched in vascular-related pathways. Notable findings included 14q11.2 duplication and VPS13B deletions in ADRD cases, the latter confirmed by optical genome mapping. Our findings suggest potential novel genes associated with ADRD in the Spanish population. However, the limited resolution of array-based technologies in detecting CNVs warrants further investigation.
Objective: To investigate the role of BCL-2-interacting mediator of cell death (BIM), a pro-apoptotic molecule, in retinal ganglion cell (RGC) injury after optic nerve crush (ONC), and to analyze its association with changes in the expression of inflammation-related genes. Methods: This was an experimental study. The study was conducted from January 2025 to December 2025. Healthy male mice aged 6-8 weeks were randomly divided into four groups: control, ONC, AAV2-scramble, and AAV2-shBim, with 6 mice in each group. The control group received no intervention, the ONC group underwent ONC only, the AAV2-scramble group received intravitreal injection of AAV2-mediated scrambled negative control sequence after ONC, and the AAV2-shBim group received intravitreal injection of AAV2-mediated short hairpin RNA targeting the BIM gene after ONC. Immunohistochemical staining was used to detect the protein expression of Bim, complement component 3 (C3), and lipocalin 2 (Lcn2). Hematoxylin-eosin (HE) staining was used to observe retinal structural changes. Retinal flat-mount immunofluorescence staining was used to assess RGC survival. Optical coherence tomography (OCT) was used to measure ganglion cell complex (GCC) thickness. Flash visual evoked potential (F-VEP) and flash electroretinography (F-ERG) were used to evaluate visual electrophysiological function. RNA sequencing was performed to analyze retinal transcriptomic changes after BIM knockdown. Quantitative real-time PCR (qPCR) was used to validate inflammation-related differentially expressed genes. Independent-sample t-test and one-way analysis of variance were used for statistical analysis. Results: The proportions of Bim-positive RGCs in the peripheral and central retina were 0.56±0.06 and 0.63±0.06 in the ONC group, respectively, both of which were higher than those in the control group (0.00±0.00) (t=21.60, 24.61; both P<0.001). The numbers of RNA-binding protein with multiple splicing(RBPMS)-positive RGCs in the peripheral and central retina were 74.2±4.4 and 118.5±8.0 in the ONC group, respectively, both of which were lower than those in the control group (222.7±6.0 and 325.0±6.5, respectively) (t=48.94, 48.88; both P<0.001). Significant differences were observed among the four groups in ganglion cell complex thickness, the number of TUJ1-positive RGCs, F-VEP N2-P2 amplitude, and F-ERG b-wave amplitude (F=57.42, 1 216.78, 467.88, 423.76; all P<0.001). In the AAV2-shBim group, ganglion cell complex thickness, the number of TUJ1-positive RGCs, F-VEP N2-P2 amplitude, and F-ERG b-wave amplitude were 54.64±2.61 μm, 242.8±13.1, 11.13±0.80 μV, and 318.00±25.14 μV, respectively, all of which were higher than those in the ONC group [(44.29±1.95) μm, 140.0±5.3, (3.43±0.48) μV, and (190.68±25.50) μV, respectively] (all P<0.001). RNA sequencing showed that the expression levels of the inflammation-related genes C3, CCL12, LCN2, S100A9, CCL6, and ANGPTL4 were lower in the AAV2-shBim group than in the ONC group (t=10.21, 12.02, 8.98, 12.19, 7.33, 9.41; all P<0.001), and the quantitative polymerase chain reaction results were consistent with the RNA sequencing results. The C3-positive cell rates in the central and peripheral retina were 0.11±0.04 and 0.08±0.02 in the AAV2-shBim group, respectively, both of which were lower than those in the ONC group (0.64±0.06 and 0.57±0.05, respectively) (t=18.63, 21.04; both P<0.001). The Lcn2-positive cell rates in the central and peripheral retina were 0.08±0.03 and 0.09±0.02 in the AAV2-shBim group, respectively, both of which were lower than those in the ONC group (0.55±0.06 and 0.48±0.07, respectively) (t=17.19, 12.38; both P<0.001). Conclusions: BIM expression is upregulated after ONC. AAV2-mediated BIM knockdown alleviates RGC loss, retinal structural damage, and visual electrophysiological dysfunction, accompanied by downregulation of inflammation-related gene expression. 目的： 探讨促凋亡分子BCL-2相互作用细胞死亡介导因子（BIM）在视神经钳夹（ONC）后视网膜神经节细胞（RGC）损伤中的作用，并分析其与炎性反应相关基因表达变化的关联。 方法： 实验研究。于2025年1月至12月实施。选用6~8周龄健康雄性小鼠，随机分为4个组：对照组、ONC组、AAV2-scramble组和AAV2-shBim组，每组6只小鼠。对照组不进行任何干预，ONC组仅进行ONC，AAV2-scramble组在ONC基础上玻璃体腔注射AAV2介导的乱序阴性对照序列，AAV2-shBim组在ONC基础上玻璃体腔注射AAV2介导靶向BIM基因的短发夹RNA。采用免疫组织化学染色检测Bim、补体成分3（C3）和脂质运载蛋白2（Lcn2）蛋白表达；苏木精-伊红（HE）染色观察视网膜结构变化；视网膜铺片免疫荧光染色检测RGC存活情况；相干光层析成像术（OCT）检测神经节细胞复合层（GCC）厚度；闪光视觉诱发电位（F-VEP）和闪光视网膜电图（F-ERG）检测视觉电生理功能；RNA测序分析BIM敲低后视网膜转录组变化；实时荧光定量PCR（qPCR）验证炎性反应相关差异表达基因。采用独立样本t检验和单因素方差分析进行统计分析。 结果： ONC组周边和中央视网膜Bim阳性RGC比例分别为0.56±0.06和0.63±0.06，均高于对照组的0.00±0.00（t=21.60、24.61，均P<0.001）；ONC组周边和中央视网膜兔抗RNA结合蛋白多重剪接因子阳性RGC数量分别为（74.2±4.4）和（118.5±8.0）个，均低于对照组的（222.7±6.0）和（325.0±6.5）个（t=48.94、48.88，均P<0.001）。4个组GCC厚度、βⅢ-微管蛋白（TUJ1）阳性RGC数量、F-VEP N2~P2振幅和F-ERG b波振幅比较，差异均有统计学意义（F=57.42、1 216.78、467.88、423.76，均P<0.001）；AAV2-shBim组GCC厚度、TUJ1阳性RGC数量、F-VEP N2~P2振幅和F-ERG b波振幅分别为（54.64±2.61）μm、（242.8±13.1）个、（11.13±0.80）μV和（318.00±25.14）μV，均高于ONC组的（44.29±1.95）μm、（140.0±5.3）个、（3.43±0.48）μV和（190.68±25.50）μV（均P<0.001）。RNA测序结果显示，AAV2-shBim组炎性反应相关基因补体成分3基因（C3）、趋化因子C-C基序配体12基因（CCL12）、脂质运载蛋白2基因（LCN2）、S100钙结合蛋白A9基因（S100A9）、趋化因子C-C基序配体6基因（CCL6）和血管生成素样蛋白4基因（ANGPTL4）归一化表达水平均低于ONC组（t=10.21、12.02、8.98、12.19、7.33、9.41，均P<0.001），qPCR验证结果与RNA测序结果一致。AAV2-shBim组中央和周边视网膜C3阳性细胞率分别为0.11±0.04和0.08±0.02，均低于ONC组的0.64±0.06和0.57±0.05（t=18.63、21.04，均P<0.001）；AAV2-shBim组中央和周边视网膜Lcn2阳性细胞率分别为0.08±0.03和0.09±0.02，均低于ONC组的0.55±0.06和0.48±0.07（t=17.19、12.38，均P<0.001）。 结论： 在小鼠ONC模型中，BIM表达显著上调，BIM敲低可减轻RGC损伤，并伴随炎性相关基因表达下调。.
Globally, the infertility prevalence (both genders) has shown a gradual upward trend, with a 0.5%-0.7% annual rise in infertility rates between 1990 - 2021. An increasing proportion of women in Romania experiencing infertility are resorting to in vitro fertilization (IVF) to achieve pregnancy. Our study included 47 women who completed an IVF cycle at the 1st Obstetrics and Gynecology Clinic (Cluj-Napoca), between April - October 2019, and July - December 2022. All participants completed a questionnaire. We collected data from the participant medical records on antral follicle count, levels of hormones, response to ovarian stimulation, number of retrieved oocytes, thickness of the endometrial mucosa, and IVF endpoints (fertilized oocytes, number and quality of embryos, pregnancy, live births). Urine, blood, ovarian follicular fluid, and endometrial flushing fluid specimens were collected at the time of oocyte retrieval, for metal and genetic analysis. Lead (Pb), arsenic (As) and cadmium (Cd) levels were measured in biological samples collected from our study participants using the Inductively Coupled Plasma Mass Spectrometry (ICP-MS) technique. In approximately 19% of the analyzed samples, the total urinary As exceeded the reference value of 15 µg/L. Also, in 15% of the samples, urinary Cd exceeded the reference value of 2 µg/L, while the blood Pb levels were below 10 µg/dl. Our study results indicated no significant differences as regards the IVF outcomes in relation with low-level As, Cd and Pb exposure, whereas higher tobacco smoke exposure, assessed via urinary cotinine, was linked to a lower fertilized oocytes and blastocysts number.
Child abuse is associated with lifetime risks for psychiatric disorders. This study evaluated 30-month effects of Safer Kids, a parenting program designed for rapid implementation following suspected child abuse. In an open-label, randomized controlled trial, families reported for child abuse to 26 Swedish child welfare agencies were randomized to Safer Kids or intervention as usual (IAU). Primary outcomes were official child abuse reports (time to first new report and total number of reports) and caregiver abuse risk (the Brief Child Abuse Potential Inventory [BCAP]). The secondary outcome was child mental health (the Strengths and Difficulties Questionnaire [SDQ]). The trial was pre-registered at Clinicaltrials.gov (NCT04163367). The trial included 112 families (194 parents). The cumulative number of new child abuse reports was lower for Safer Kids compared to IAU (IRR = 1.79, 95% CI=1.06, 3.02, p = 0.028), although there was no difference in time to first new report (HR = 0.74, 95% CI=0.31, 1.76, p = 0.50). At 30 months, SDQ showed a consistent effect favoring Safer Kids across analytical approaches (non-imputed data: d = 0.60, 95% CI=0.11, 1.09, p = .001). For BCAP, an effect was observed in non-imputed analyses (d = 0.41, 95% CI=0.08, 0.89, p = .044), but was not supported in sensitivity analyses. Safer Kids did not reduce the time to the first new abuse report but was associated with somewhat fewer total reports and better child mental health at 30 months, suggesting preventive effects in families with suspected abuse. A Randomized Controlled Study of Safer Kids: A Manualized Intervention to Prevent Child Abuse; https://clinicaltrials.gov/study/NCT04163367 DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way.
Total born number (TBN) and number born alive (NBA) are primary selection targets for improving reproduction performance in pigs; however, genetic progress is constrained by the low heritability of single-parity records. To better capture the genetic potential underlying litter size, we evaluated maximum (maxTBN and maxNBA) and mean (meanTBN and meanNBA) litter size traits derived from multiple parities as alternative selection criteria. Using data from a Dongliao Black (DL) pig population, heritability estimates for maxTBN (h2 = 0.19), meanTBN (h2 = 0.16), maxNBA (h2 = 0.24) and meanNBA (h2 = 0.17) were substantially higher than those for single-parity TBN (h2 = 0.06) and NBA (h2 = 0.07). Genome-wide association analyses (GWAS) based on estimated breeding values of maximum and mean traits identified 158 significant single-nucleotide polymorphisms, implicating several candidate genes, including BPI, KCNC2, ELMO1, CHD6, OPCML, and MND1. Validation in an independent Large White population with high litter size (TBN > 16) showed that favorable alleles at representative loci were close to fixation, supporting their effects on reproduction performance. Furthermore, genomic prediction models based on maxTBN and maxNBA exhibited higher cross-validation variance than those using conventional litter size traits, reflecting greater prediction instability. Collectively, these results demonstrate that mean litter size traits constitute robust phenotypes for genetic evaluation of sow fertility, while maximum traits may serve as supplementary indicators for identifying elite individuals, and provide functionally relevant markers that can be exploited to inform balanced selection strategies for reproduction in pig breeding programs.
To evaluate knowledge, attitudes and practices towards routine vaccination in the Lebanese population in the post-COVID-19 period, and to examine differences between COVID-19 vaccinated and non-vaccinated individuals. The study also aimed to identify sociodemographic and behavioural factors associated with vaccination status, and to explore changes in vaccination practices before and after the pandemic. Unmatched case-control study. Community-based survey conducted across all regions of Lebanon between July and October 2023. A total of 730 adults were included, comprising 277 COVID-19-positive individuals who were not vaccinated against COVID-19 (cases) and 453 COVID-19-positive individuals who had received at least one dose of a COVID-19 vaccine (controls). Participants were randomly selected from the national COVID-19 surveillance database. Adults aged ≥18 years were eligible; individuals who tested negative for COVID-19 or were unable to provide consent were excluded. Primary outcomes were vaccination knowledge and attitudes, measured using the Zingg knowledge scale and the 7C vaccination attitude scale. Secondary outcomes included self-reported adherence to routine and influenza vaccination before and after COVID-19. Factors associated with non-vaccination were examined using multivariable regression models. Vaccinated participants were older and more likely to be employed, have higher education, work in healthcare and report financial coverage for vaccines. They had higher knowledge scores, more positive attitudes towards vaccination and increased adherence to routine and influenza vaccination after COVID-19, while adherence declined among non-vaccinated participants. In multivariable analysis, older age (OR 0.98, 95% CI 0.96 to 0.99), higher education (OR 0.68, 95% CI 0.60 to 0.78), number of children (OR 0.88, 95% CI 0.78 to 1.00) and more positive vaccination attitudes (OR 0.97, 95% CI 0.94 to 1.00) were independently associated with lower odds of non-vaccination. Older age, higher education, greater number of children and more positive attitudes were associated with lower odds of non-vaccination. Vaccinated participants also had higher knowledge scores, more positive attitudes and better adherence to routine and influenza vaccination practices than non-vaccinated participants.
The global increase in multidrug-resistant tuberculosis strains poses a major threat; consequently, there is an urgent need to identify and develop novel drugs. We have previously presented a simple fibroblast assay (SFA) screening method that enables the simultaneous assessment of antibacterial activity and cytotoxicity toward host cells. This method was developed based on our finding that live (but not dead) Mycobacterium tuberculosis bacilli exhibit cytotoxic activity against human lung fibroblasts, and that this cytotoxicity, which is proportional to the number of viable bacterial cells, is inhibited by known antimycobacterial drugs. While conventional methods to measure M. tuberculosis growth require 2-4 weeks to detect antibacterial activity; the SFA method enables detection within 2-3 days and can detect compounds that are active within host cells. Here, we applied high-throughput screening, based on assessment of cytotoxicity, to identify candidate antimycobacterial agents. In parallel, by comparing the direct antibacterial activity of compounds in liquid medium (using the broth dilution test) with that observed via SFA, we developed a new SFA-based screening system to select compounds with low cytotoxicity that are active outside or inside the host cells. Using this dual system, we screened 742 compounds from the Ōmura Natural Compound Library (Kitasato University, Japan), with 62 hits. Of these, 19 were excluded owing to their toxicity, and six exhibited antibacterial activity only via SFA screening. Four promising antimycobacterial candidates with no cytotoxicity at the 10 μg/mL threshold-aridicin A, lankamycin, streptovaricin, and lariatin A-were identified. This novel system supports the rapid identification of low-cytotoxicity antimycobacterial compounds that are active inside or outside the host cells. This screening system, comprising the simple fibroblast assay (SFA) and broth dilution test (BDT), effectively identifies low-cytotoxicity compounds that exhibit antimycobacterial activity inside or outside the host cells.
Under the new Ambient Air Quality Directive, monitoring of ultrafine particles as particle number (PN) and black carbon (BC) is required due to their health impacts, making their improved representation in air quality models particularly relevant. This study investigates the influence of spatial resolution and anthropogenic emission inventories on the simulation of PN, BC, and regulated pollutants (NO2, O3, PM10, PM2.5) at urban background sites in Europe, with particular focus on Barcelona (Spain). Simulations were performed with the WRF/CHIMERE/SSH-aerosol system over three nested domains at 15, 5, and 1 km horizontal resolution. Over Spain, at 5 and 1 km resolutions, the European-scale EMEP inventory (10 km spatial resolution) and the Spanish high-resolution bottom-up emission inventory HERMESv3 BU (1 km spatial resolution) were evaluated. The choice of emission inventory exerts a control on model performance, particularly for NO2, BC and PN. At 5 km resolution, HERMESv3 reduces the systematic underestimation of pollutant concentrations compared to EMEP. While increasing resolution from 15 km to 5 km improves urban gradients, further refinement to 1 km does not substantially improve statistical performance at the urban background station of Barcelona; however, it enhances the representation of spatial heterogeneities and sharpens intra-urban gradients, especially for NO2, BC, and PN. The modelling framework and methodology implemented enable the simulation of emerging pollutants, such as BC and PN, with a statistical performance comparable to that achieved for regulated pollutants.
Age-related hearing loss (ARHL), or presbycusis, is a very common sensory disorder resulting from cumulative exposure to environmental factors, biological aging and a significant genetic component. Although most cases of ARHL result from the combined influence of numerous low-effect variants, the increasing number of monogenic forms has shown the importance of rare, highly penetrant mutations in ARHL. Advances in whole-exome and whole-genome sequencing have strengthened the evidence for monogenic contributions, identifying deleterious variants consistent with dominant, recessive, or mitochondrial inheritance patterns. These monogenic cases provide valuable insights into the molecular mechanisms underlying cochlear aging and the vulnerability of sensory cells. To date, several genes have been clearly identified as responsible for familial or sporadic late-onset hearing loss, including KCNQ4, GRHL2, ILDR1, EYA4, MYO6, MYO7A, TECTA, WFS1, CDH23, and TMC1. Mutations in these genes affect diverse biological pathways such as potassium recycling, epithelial integrity, transcriptional regulation, mechanotransduction, extracellular matrix stability, and hair cell maintenance-functions that are fundamental to the long-term preservation of hearing. It is important to note that there is a growing overlap between the genes involved in Mendelian deafness and the susceptibility loci identified in ARHL, suggesting the existence of common molecular mechanisms between early-onset hereditary deafness and some forms of progressive ARHL. Furthermore, new data highlight the role of epigenetic regulation, mitochondrial dysfunction, cochlear synaptopathy, and non-coding RNAs in hearing loss. Despite major advances, several challenges remain, including phenotypic heterogeneity, limited representation of non-European populations, and a lack of consistency in the reproducibility of results across studies. Distinguishing between subtypes of ARHL characterized by audiometry-including sensory, neural and synaptopathic, metabolic forms, will likely be essential for improving genetic analyses and precision medicine approaches. Moreover, although polygenic risk scores (PRS) represent a promising strategy for risk prediction, their clinical applicability remains limited. Overall, the integration of monogenic, polygenic, environmental, and epigenetic data will be essential for understanding the complex genetic architecture of ARHL and for developing future personalized therapeutic interventions.
In-stent restenosis (ISR) remains a significant complication after percutaneous coronary intervention. Identifying patients at high risk for ISR from visually patent post-procedural angiograms is challenging. We developed and validated deep learning models using routine post-procedural digital subtraction angiography (DSA) to predict future ISR risk, emphasizing the role of mask-guided spatial attention. We retrospectively enrolled 237 patients with 1-year angiographic follow-up across three centers. Immediate post-procedural DSA frames were used as inputs, with 1-year outcomes as ground truth. Deep learning architectures were trained using full-image and mask-guided strategies. On the independent external test set, the mask-guided DenseNet-121 achieved the highest predictive performance (AUC: 0.885, AUPRC: 0.912). Crucially, models trained on full images exhibited severe shortcut learning, erroneously focusing on task-irrelevant background noise. The mask-guided strategy successfully corrected this, demonstrating excellent calibration and robust clinical net benefit. Grad-CAM visualization confirmed precise attention on stented vessel regions associated with future restenosis. In conclusion, mask-guided deep learning analysis of post-procedural DSA provides an accurate, interpretable, and automated prognostic tool. By overcoming shortcut learning, this approach effectively stratifies future ISR risk, holding potential to guide personalized post-procedural surveillance and optimize secondary prevention.Trial registration: This study was registered with the Chinese Clinical Trial Registry (ChiCTR) under the registration number ChiCTR2500115474 on December 26, 2025.
In order to achieve outstanding fault diagnosis classification performance, most deep learning-based intelligent fault diagnosis methods require a large number of labeled samples for training. However, collecting sufficient labeled fault samples in practice is challenging because the process is time-consuming and labor-intensive, resulting in an imbalanced dataset. Aiming at the problem of degraded fault diagnosis performance due to severely skewed data distribution in industrial scenarios, this paper proposes an anti-bias fault diagnosis network, ATUB-Net, to achieve high-precision classification under unbalanced data through a multilevel feature reconstruction and attention mechanism. By designing the anti-imbalance mode, separating the normal and faulty sample feature streams with multi-branch feature cuts, enhancing the extraction ability of local high-frequency mutation signals by combining 3 × 3 group convolution, and dynamically reinforcing the key fault regions and suppressing the noise interference through the compression while fusion unit integration channel and spatial attention mechanism. Experiments show that in two different extreme imbalance datasets, the accuracy and G-Means metrics of ATUB-Net significantly outperform those of other mainstream models, and the Grad-CAM visualization shows that its thermal distribution accurately focuses on the faulty time-frequency mutation region, and the T-SNE feature clustering boundary is clear.
This study examined whether children and adolescents meet the guideline of 60 min of daily moderate-to-vigorous physical activity by analyzing the proportion of active days on school and non-school days. Cross-sectional study. Data from three Finnish school-aged physical activity studies (n = 3,221; ages 7-15 years) were analyzed. Participants wore hip accelerometers for seven consecutive days and completed questionnaires. Moderate-to-vigorous physical activity was derived from accelerometer data using mean amplitude deviation in 6-second epochs, further processed with 1-10-minute exponential moving averages. A day met guidelines if it included at least 60 minutes of moderate-to-vigorous physical activity, based on data from the accelerometer, questionnaire or both. Overall, the mean number of days meeting the recommendation was 5.3 (standard deviation 2.1) days per week according to the questionnaire, and 6.3 (1.2) days with 6-second epochs, 5.3 (1.8) days with the 1-minute exponential moving average, and 4.2 (2.1) days with the 10-minute exponential moving average according to the accelerometer. From 1st to 9th grades, boys' proportion of active days decreased from 96% to 64% on school days and from 92% to 40% on non-school days using the 1-minute exponential moving average. Similarly, girls' proportion of active days dropped from 95% to 53% on school days and from 81% to 30% on non-school days. The proportion of active days approach captures day-to-day variation in physical activity. The closest agreement between questionnaire and accelerometer estimates was observed when using a 1-minute exponential moving average.
Understanding how different hosts respond to a shared pathogen is essential for predicting host-pathogen dynamics and coexistence. In this study, we conducted a series of complementary bioassays to examine how two congeneric species of Tribolium beetles differed in their functional traits when exposed to the entomopathogenic fungus Beauveria bassiana in the absence of competition. The mean fungal concentration required to kill 25% of the beetles and the time to sporulation onset were significantly greater for T. castaneum than T. confusum (9.24% and 23% greater, respectively). There was no difference in infection probability between the two species from the lowest to highest fungal concentrations, but the mean proportion of individuals infected increased by 87% for T. castaneum and 54% for T. confusum. Moreover, the relationship between beetle density and number of individuals killed (i.e., pathogen functional response) fit a Holling type II curve for both species. The two key parameters in the Holling model, attack rate and handling time, did not differ significantly between beetle species. Surprisingly, adult beetles that were exposed to the same range of pathogen concentrations for 24 h did not exhibit a significant reduction in reproductive output (adult offspring produced), likely due to the short timeframe of the study. Together, our results suggest that T. confusum is less resistant to B. bassiana infection compared to T. castaneum. Our findings underscore important interspecific differences in host functional traits and we discuss how variation in host responses to pathogens may influence competitive interactions, coexistence outcomes, and biological control efficiencies.
Dependencies among microorganisms often appear mutualistic, as microbes grow faster together than alone. However, the Black Queen hypothesis (BQH) posits that these dependencies are underpinned by benefits from 'cheating' when others supply necessary common goods (CGs). The BQH often describes the evolution of a pair of ecotypes, a cooperator producing a CG and a cheater free-riding upon it. With multiple goods, their production can be centralized, with one ecotype producing everything and others cheating. We previously proposed an alternative BQH endpoint describing a community of 'mutual cheating', with production distributed over multiple interdependent ecotypes. Here, we present an individual-based eco-evolutionary model that predicts BQH dynamics resulting in various endpoints, including both distributed and centralizedproduction, and novel intermediate ecosystems involving apparent functional redundancy. These endpoints critically depend on the interaction range, the number of beneficiaries a producer can locally support. The intermediate ecosystems involve stable coexistence among ecotypes partially distributing production, with this coexistence punctuated by rare evolutionary transitions resulting in further distribution. These punctuated dynamics arise from cheaters stalling the division of labour by occupying the limited space within the producers' interaction ranges. Overall, our findings unveil complex evolutionary dynamics beyond the simple cheater-cooperator narrative, broadening the predictions of BQH.
Asthma is a prevalent chronic respiratory disease characterised by airway inflammation, reversible airflow obstruction and airway hyper-responsiveness. Most patients with severe asthma (SA) remain uncontrolled despite the availability of multiple therapies, representing a significant global health burden.Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays a central role in asthma initiation via both allergic and non-allergic mechanisms as well as in the persistence of airway inflammation in patients with asthma, acting upstream in the inflammatory cascade.Tezepelumab, a monoclonal antibody that targets TSLP, has shown clinical efficacy and safety in pivotal trials in patients with T2 and non-T2 asthma. Tezepelumab was approved for use in Europe in October 2022, and the marketing authorisation was issued in Spain in October 2023. The T-ROSS II study is a retrospective, observational, single-arm, multicentre study planned to include 400 patients aged ≥12 years treated in SA units. T-ROSS II will represent the largest published series of patients with SA who initiated tezepelumab after its market authorisation.Eligible patients must have at least 12 months of medical history prior to treatment initiation and a minimum of 3 months of follow-up data recorded in the electronic health records.The co-primary outcomes are to describe baseline patient demographics and clinical characteristics and evaluate changes in the annualised asthma exacerbation rate before and after the initiation of tezepelumab. These findings will complement clinical trial data and inform physicians and healthcare decision-makers about the real-world effectiveness and utilization of tezepelumab in patients with SA. This study is expected to provide valuable insights into the clinical outcomes and treatment patterns of this population. The final protocol of the study has been approved by the ethics committee/Institutional Review Board (EC/IRB) of the University Hospital 12 de Octubre (Madrid, Spain) (EC/IRB number: 25/226). The results will be disseminated through scientific publications, including manuscripts submitted to peer-reviewed journals and presentations at national and international congresses. NCT07013760.
The Riemann Hypothesis (RH), one of the most profound unsolved problems in mathematics, concerns the nontrivial zeros of the Riemann zeta function. Linking these zeros to physical phenomena offers new perspectives on their origin and verification. Here we establish a direct correspondence between these zeros and dynamical quantum phase transitions in two complementary engineered quantum many-body systems, characterized by the average accumulated phase factor and the Loschmidt amplitude, respectively. This precise correspondence recasts the RH as the occurrence of phase transitions at a unique temperature and identifies it as a previously unknown transition mechanism. We demonstrate this correspondence in a proof-of-principle experiment on a quantum processor. Moreover, we propose a quantum computational framework that implements both systems with polynomial resources, suggesting quantum advantage in probing the hypothesis. Our work bridges nonequilibrium quantum dynamics and number theory, positioning quantum computing as a powerful platform for exploring mathematical conjectures, phase transitions and beyond.
Proximal junctional kyphosis (PJK) remains a major complication after surgery for adult spinal deformity (ASD). While postoperative alignment is a recognized modifiable risk factor, objective methods for selecting the upper instrumented vertebra (UIV), a key modifiable factor, are lacking. We aimed to determine whether preoperative sagittal alignment, specifically cervicothoracic alignment, predicts the risk of PJK, and whether this risk can be mitigated by UIV selection, focusing on factors available at the time of surgical planning. From a multicentre, prospective ASD registry, we identified patients who had undergone fusion to the sacrum or pelvis and had an upper (T1-T5) or lower thoracic (T9-L1) UIV, with a two-year or more radiological follow-up, excluding those with a previous fusion over more than four levels. The primary outcome was PJK within two years. Multivariable logistic regression modelled the risk of PJK by UIV region, preoperative C2-T9 pelvic angle (PA), age, sex, and pelvic incidence, testing for interaction between UIV region and C2-T9 PA. Adjusted absolute risk reduction (ARR) and number needed to be exposed (NNEB) were calculated. Multivariable linear regression estimated two-year patient-reported outcome measures, adjusting for baseline scores, age, UIV, and PJK. A total of 627 patients across 20 centres were included (median age 66 years (IQR 59 to 70); 483 (77%) female). The UIV was lower thoracic in 380 (61%) and upper thoracic in 247 (39%) patients. PJK occurred in 149 (39%) lower thoracic and 38 (15%) upper thoracic UIV patients. There was a significant interaction (p = 0.028) between preoperative C2-T9 PA and UIV region. At a preoperative C2-T9 PA of 14° (cohort median), an upper thoracic UIV had an adjusted ARR of 36% and NNEB was 2.8. Females had an adjusted odds ratio of 1.62 (95% CI 1.03 to 2.59; p = 0.042) for PJK. Worse preoperative sagittal malalignment, measured by C2-T9 PA, was associated with a higher risk of PJK and depended on UIV region. An upper thoracic UIV in patients with high preoperative C2-T9 PA may reduce PJK.
Substitution boxes (S-boxes) are a type of nonlinear component which provides confusion and robustness to cryptanalysis in modern symmetric ciphers. Due to the requirements of lightweight encryption (LWE) systems to achieve a high degree of security while minimizing computational overhead, we propose chaos-driven constructions of highly nonlinear S-boxes using permutations of the logistic map to create bijective and statistically randomized substitution patterns. We have extensively evaluated the cryptographic strength of our proposed S-box using standard metrics, including Nonlinearity (NL), Strict Avalanche Criteria (SAC), Bit Independence Criteria (BIC), Balancedness, Differential Approximation Probability (DAP), and Linear Approximation Probability (LAP). Our proposed S-box has demonstrated competitive performance with existing S-boxes by achieving average nonlinearity values of 112.75 and SAC/BIC values very close to ideal thresholds. To demonstrate practical applicability, we have integrated the proposed S-box into an image encryption scheme, where statistical analyses confirm near ideal entropy and negligible pixel correlation, demonstrating strong resistance to both statistical and differential attacks. Additionally, our proposed scheme has achieved comparable levels of security within a smaller number of rounds than traditional methods, thus enhancing both computational efficiency and throughput, making it suitable for real-time and resource-constrained multimedia security applications.
Individuals with autism experience many barriers to receiving high-quality healthcare. With 1 in 31 children now being diagnosed with autism, a number that has only been increasing over the last decade, it is imperative to address these barriers. One of the most prevalent barriers is communication. Social communication challenges are a defining characteristic of autism, but there exists a wide spectrum of communication abilities that can be difficult for healthcare providers to understand. This tutorial introduces the differences in informational processing experienced by those with autism with practical guidance on how healthcare providers can individualize their approach to communication when providing patient-centered care. The three levels of autism support are used as a framework, with suggestions specific to each level to help healthcare providers better understand the differences seen in autism and how they can more readily address the needs of each patient.