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Sirolimus is currently used off-label for paediatric patients with vascular anomalies. However, the optimal dosage regimen for paediatric patients remains controversial. This study aimed to determine the optimal dosing regimen of sirolimus in these patients using a population pharmacokinetic (PK) model. Prospective study data (seven subjects) were used as the structural model without covariates, while the retrospective study data (21 subjects) were used as the structural model with size and maturation functions for evaluation. The model was assessed using general model-building criteria, and a bootstrap stepwise covariate modelling method was used to identify relevant covariates. Simulations were performed for various scenarios to determine the optimal dosing regimen for maintaining sirolimus trough concentrations within a specific range. NONMEM software (Version 7.5) with the first-order conditional estimation method with interaction was used. The final sirolimus model was developed using a two-compartment model, which was implemented by a maturation function using postmenstrual age (PMA), allometrically scaled body weight to account for size differences, and haemoglobin as a covariate on clearance. Simulations were conducted to propose an optimal dosing regimen. A once-daily dose of 0.01-0.1 mg/kg over 1 month maintained the trough concentration within the range of 5-15 ng/mL, taking into account patient-specific weight and the influence of haemoglobin constrained on PMA. The optimal dose varied by group, within the range of 0.06-0.09 mg/kg. We developed a robust and reliable PK model of sirolimus for paediatric patients with vascular anomalies. Paediatric optimal dosing regimens should be based on individual growth patients.
During deepwater oil and gas production and shut-in operations, the high-pressure and low-temperature environment readily induces hydrate formation of CO2-rich associated gas in oil-water systems, thereby posing serious flow assurance risks. This study systematically investigated the nucleation, growth, and morphological evolution of hydrates in oil-water systems under different gas-phase states using fully visualized high-pressure apparatus, along with the effects of temperature, pressure, CO2 concentration, and inhibitors on hydrate formation behavior. The results showed that gas phase transition significantly altered the hydrate induction time, gas consumption, and growth time. However, once the gas was liquefied, mass transfer became hindered, and the growth process exhibited pronounced dynamic fluctuations. Phase transitions caused by variations in CO2 concentration also exerted a significant influence on hydrate growth, among which the terminal subcooling had the most pronounced effect on the integrated growth index. Compared with monoethylene glycol (MEG), methanol lowered the peak value during the rapid hydrate formation stage, markedly reduced the hydrate growth rate, and led to a prolonged period during which the pressure remained above its initial value. These findings revealed the hydrate formation characteristics in oil-water systems and mechanism of thermodynamic inhibitors, providing a theoretical basis for ensuring flow safety in CO2-rich oil and gas wellbores and pipelines.
Background and Clinical Significance: Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant disorder caused by pathogenic variants in the SERPINA1 gene, resulting in reduced circulating alpha-1 antitrypsin (AAT) or production of dysfunctional protein. AAT is the principal inhibitor of neutrophil elastase, and its deficiency leads to unchecked proteolytic activity, progressive destruction of lung parenchyma, and increased susceptibility to infections. Severe deficiency, particularly in individuals homozygous for the Z allele (PI*ZZ), predisposes to early-onset panacinar emphysema, chronic airflow obstruction, and liver disease. Despite its clinical relevance, AATD remains markedly underdiagnosed and is frequently misclassified as smoking-related chronic obstructive pulmonary disease (COPD), delaying access to disease-modifying therapy, genetic counselling, and preventive strategies. Early recognition is therefore essential to improve outcomes. Case Presentation: We report the case of a 68-year-old ex-smoker with a long-standing diagnosis of "COPD" who presented with acute-on-chronic type 2 respiratory failure and community-acquired pneumonia. Spirometry revealed severe airflow obstruction, and high-resolution computed tomography demonstrated extensive basilar panlobular emphysema, raising suspicion for AATD. Serum AAT concentration was critically low at 26.8 mg·dL-1, and isoelectric focusing confirmed a PI*ZZ phenotype. Next-generation sequencing identified homozygosity for the SERPINA1 c.1096G>A (Z) variant, with no additional pathogenic alleles. Cascade family screening revealed multiple heterozygous PI*MZ relatives. Before augmentation therapy could be initiated, the patient developed severe Legionella pneumophila pneumonia with secondary bacterial superinfection, progressing to refractory septic shock and death. Conclusions: This case illustrates how AATD can masquerade as smoking-related COPD for years, leading to missed opportunities for timely intervention. It underscores the importance of testing all adults with COPD or refractory asthma at least once, regardless of age or smoking history. Early diagnosis enables initiation of augmentation therapy, targeted vaccination, lifestyle modification, and genetic counselling, ultimately improving prognosis and reducing preventable morbidity and mortality.
Background/Objectives: Oral iron supplementation is widely used to treat iron deficiency but frequently causes gastro-intestinal side effects that limit treatment adherence. Unabsorbed luminal iron has been proposed to influence intestinal microbial communities, yet the effects of different oral iron doses on the human gut microbiome remain insufficiently characterized. Methods: In this randomized open-label study, 30 healthy premenopausal women with iron deficiency without anaemia received either low-dose oral iron supplementation (6 mg twice daily) administered under fasting conditions or standard-dose iron supplementation (100 mg once daily) taken with a meal for four weeks. Stool samples were collected before and after treatment and analyzed using 16S rRNA sequencing to evaluate microbiome composition. Results: Baseline characteristics, including age, body mass index, hemoglobin concentration and serum ferritin, were comparable between groups. After four weeks of treatment, distinct alterations in gut microbiome composition were observed between the low-dose and standard-dose groups. The genera Colidextribacter and GCA-900066575 decreased in the low-dose group but increased in the standard-dose group, whereas Oscillospira showed the opposite pattern. Gastrointestinal adverse events were reported by 87% of participants receiving standard-dose iron supplementation compared with 7% receiving low-dose iron supplementation (p < 0.0001). Conclusions: Oral iron supplementation induces dose-dependent changes in the intestinal microbiome and higher doses are associated with substantially increased gastrointestinal intolerance. These findings suggest that lower iron doses may reduce microbiome disruption and improve treatment tolerability.
Blood biomarkers can characterize the atrial substrate and help elucidate mechanisms of atrial fibrillation (AF) development. Understanding whether sedentary behavior affects AF-related biomarkers may inform prevention strategies. We studied 252 participants in PREDIMED-Plus, a multicenter randomized trial in Spain for the primary prevention of cardiovascular disease. Participants wore wrist accelerometers for one week at baseline and at least once during follow-up (years 3 or 5). Blood samples were collected at each time point to measure selected biomarkers: propeptide of procollagen type I, high-sensitivity (hs) troponin T (hsTnT), hs C-reactive protein, 3-nitrotyrosine, and N-terminal propeptide of B-type natriuretic peptide (NT-proBNP). Using isotemporal substitution, we estimated the effect of replacing 30 min/day of sedentary time (< 1.5 METs in waking time) with low-intensity physical activity (LPA, 1.5-3 METs), moderate-to-vigorous PA (MVPA, > 3 METs), or time in bed (bedtime to wake-up) on log-transformed biomarker levels, cross-sectionally and longitudinally, via linear regression and mixed models. At baseline, participants (mean age 65 ± 4.9 years, BMI 32.2 ± 3.3 kg/m², 40% women) showed no significant cross-sectional associations between substituting sedentary time and biomarker levels. After 5 years, replacing baseline 30-min of sedentary time per day with LPA or MVPA was associated with lower hs-TnT concentrations compared to baseline (-4%, 95% CI -8%, -1%; and - 2%, 95% CI -7%, 4%). Substitutions showed nonsignificant reductions in NT-proBNP but no consistent associations with other biomarkers. Among overweight/obese individuals, replacing sedentary time with PA was associated with favorable 5-year changes of hs-TnT, but not other AF-related biomarkers. The trial was registered on July 24, 2014, at ISRCTN (ISRCTN89898870) [www.isrctn.com/ISRCTN89898870 (accessed on December 10, 2025)].
Combination therapy with the PARP inhibitor niraparib and the androgen-receptor inhibitor abiraterone acetate plus prednisone (AAP) has recently shown improvement in radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations, particularly BRCA1/2, in the phase III MAGNITUDE trial. Evidence outside clinical trials remains limited. We retrospectively reviewed the clinical courses of five consecutive patients with HRR-mutated mCRPC treated with niraparib (200 mg once daily) plus abiraterone acetate (1000 mg once daily) and prednisone (5 mg twice daily) at our institution. Baseline characteristics, PSA kinetics (including time to PSA 50% decline), radiological responses, progression-free survival (PFS; defined as a composite clinical, radiological, and biochemical endpoint), overall survival (OS), and safety outcomes were assessed. All patients underwent radiological evaluation every three months, including contrast-enhanced CT of the chest and abdomen and bone scintigraphy. Tumor response was assessed according to RECIST 1.1 criteria for measurable disease. All patients harbored pathogenic HRR gene alterations: somatic and/or germline BRCA1/2 (three BRCA2, two BRCA1), and one patient with concurrent PALB2. Median age at therapy initiation was 70 years (range 60-80). Three patients (Patients 1, 4, 5) achieved significant and sustained PSA declines (≥50%) and prolonged disease control, including elderly and frail individuals. Two patients (Patients 2, 3) exhibited early progression with limited clinical benefit, consistent with aggressive disease course. Median PFS varied widely across the cohort, reflecting heterogeneity of clinical phenotypes. Treatment was generally manageable; dose interruptions or reductions were required in selected cases, with no new safety signals observed. Niraparib-abiraterone demonstrated anti-tumor activity in a subset of HRR-mutated mCRPC patients, including elderly and frail individuals. However, the very small sample size, retrospective design, and absence of standardized rPFS assessment limit generalizability. These findings are primarily hypothesis-generating but align with prospective trial results and underscore the heterogeneity of HRR-mutated mCRPC, highlighting the need for individualized therapeutic strategies.
Islamic bioethics is a recent, albeit growing, academic discipline. Despite commendable contributions, the field remains critically limited. Most notably, its methodology of strict application of Islamic law to ethical analyses and recommendations often lacks sufficient moral analysis, intellectual engagement, or social context. The practice's emphasis on religio-legal rulings- without an investigation of their underpinning moral values- has resulted in a field of inquiry devoid of robust normative foundations and dependent upon ineffective and unsubstantiated claims. This paper calls for a revival of Islamic philosophical discourse to enrich Islamic bioethical practice. Although once popularized by Medieval Muslim philosophers like Ibn Sina (Avicenna) and Ibn Rushd (Averroes), philosophical discourse has fallen out of favor in the Muslim world, largely due to a perceived tension with religion. This work highlights the rich tradition of philosophical discourse in the Medieval Muslim world, disproving claims of an inherent conflict between philosophy and Islam. Following an Islamic philosophical framework, three goals for Islamic bioethics are established. First, theoretical rigor aimed at continually re-assessing and re-understanding concepts integral to the practice of bioethics such as personhood, dignity, futility, autonomy, and justice. Second, a shift from essentialist understandings of the Quran- and other sources of Islamic law- to more contextual examinations in the formulation of ethical opinions. Third, an active and interdisciplinary collaboration between Muslim scholars in the determination of Islamic rulings on medical matters. Only when these goals are met is the practice of Islamic bioethics capable of meeting the needs of Muslim patients and clinicians.
Background: Endoscopic submucosal dissection (ESD) is widely used for the treatment of gastric neoplasia; however, the large artificial ulcer created during the procedure requires several weeks to heal. Although proton pump inhibitors (PPIs) are routinely administered after ESD, evidence comparing individual PPIs for artificial ulcer healing in real-world practice remains limited. This study compared the effectiveness of oral ilaprazole and oral esomeprazole as maintenance therapy after gastric ESD. Methods: This retrospective single-center study included patients who underwent gastric ESD between January 2020 and December 2024. All patients received intravenous PPI therapy for two days after ESD and were subsequently prescribed either oral ilaprazole 20 mg once daily or esomeprazole 40 mg once daily for 8 weeks. The primary outcome was complete artificial ulcer healing at 8 weeks. The secondary outcome was post-discharge delayed bleeding. Results: A total of 229 patients were analyzed (147 in the esomeprazole group and 82 in the ilaprazole group). The overall 8-week ulcer healing rate was 94.3%, with no significant difference between the ilaprazole and esomeprazole groups (97.5% vs. 92.5%, p = 0.114). In multivariate analysis, artificial ulcer size ≥ 30 mm was the only independent predictor of incomplete ulcer healing (odds ratio 20.850, 95% confidence interval 1.884-230.712, p = 0.013). Post-discharge delayed bleeding occurred in 8 patients (3.4%), all in the esomeprazole group (p = 0.032). No treatment-related adverse events were observed. Conclusions: Ilaprazole demonstrated ulcer-healing efficacy comparable to esomeprazole after gastric ESD. Artificial ulcer size ≥ 30 mm was the principal determinant of delayed healing, whereas the treatment group was not independently associated with healing outcomes. Ilaprazole may be considered a reasonable maintenance PPI option in routine post-ESD management.
Incretins have improved the management of obesity and its related complications, but maintaining these health benefits requires ongoing administration, which can be challenging. Orforglipron, a once-daily oral nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated weight loss efficacy, improvements in cardiometabolic risk factors, and safety generally similar to injectable GLP-1 receptor agonists. Here this double-blind, placebo-controlled trial randomized participants previously treated with tirzepatide (cohort 1: N = 205) or semaglutide (cohort 2: N = 171) during the SURMOUNT-5 study to orforglipron once daily or placebo. Cohort 1 participants who achieved body weight plateau maintained a model-based estimate (MBE) of 74.7% (s.e.m. 4.05) of body weight reduction with orforglipron compared with an MBE of 49.2% (s.e.m. 3.92) with placebo, resulting in an estimated treatment difference of MBE 25.5% (95% confidence interval 14.5 to 36.5); P < 0.001; treatment-regimen estimand) at week 52. Cohort 2 participants who achieved body weight plateau maintained an MBE of 79.3% (s.e.m. 4.42) of body weight reduction with orforglipron compared with an MBE of 37.6% (s.e.m. 7.46) with placebo, resulting in an estimated treatment difference of MBE 41.7 (95% confidence interval 24.4 to 59.0); P < 0.001; treatment-regimen estimand) at week 52. All key secondary endpoints were met. The most common adverse events were gastrointestinal effects, which were mostly mild to moderate in severity. These data demonstrate orforglipron's potential as a globally scalable option for minimizing weight changes after injectable therapy. Trial limitations include the absence of a comparator arm involving continued use of injectable obesity-management medications and the trial's 1-year duration. ClinicalTrials.gov registration: NCT06584916 .
Visceral leishmaniasis (VL) is a neglected tropical disease caused by kinetoplastid parasites. If left untreated, VL has a case fatality >90%, making treatment essential for patient survival. Existing therapies have several limitations that impact treatment outcomes, including toxicity, requirement for parenteral administration, long treatment duration, and development of parasite resistance, driving the need for newer therapies. This Phase 1 first-time-in-human study evaluated the tolerability, safety, and pharmacokinetics (PK) of GSK3494245, a novel highly selective Leishmania kinetoplastid proteasome inhibitor. This was a randomized, double-blind, placebo-controlled, single ascending dose study evaluating the oral administration of GSK3494245 in healthy participants aged 18 to ≤55 years (NCT04504435). The study was conducted at a single center in the United Kingdom between October 2020 and January 2024. GSK3494245 had an acceptable safety profile following administration of single doses of up to 240 mg in healthy male participants. All adverse events (AEs) were considered resolved or recovered, with most AEs being of mild or moderate severity. One serious AE of mild tachycardia was reported. The increase in exposure was slightly more than dose-proportional and approximately proportional under fasted and fed conditions, respectively. The median time to reach the maximum plasma concentration (Cmax) ranged from 0.50 to 1.79 hours, and the geometric mean of the elimination half-life ranged from 1.04 to 2.27 hours. Two participants met the Cmax stopping criterion. GSK3494245 showed an acceptable safety profile over the dose range studied. However, based on its observed PK profile, GSK3494245 is unlikely to achieve the effective dose while ensuring safe exposure within the once- or twice-daily monotherapy target product profile recommended by the Drugs for Neglected Diseases initiative. NCT Number (www.clinicaltrials.gov): NCT04504435 EudraCT, CTIS: 2019-004492-39.
The development of self-powered environmental and chemical sensing systems capable of reliable operation under irregular mechanical inputs is essential for realizing practical and autonomous electronics. Here, we present a mechanically-triggered, self-powered triboelectric sensor platform that overcomes this limitation through arbitrary-to-constant mechanical input conversion. The platform employs a magnetic latching mechanism that stores elastic potential energy in a cantilever coupled with a flexible sagged film and releases it once an external displacement exceeds a predefined threshold. Once released, the cantilever exhibits a high-frequency free vibration at its natural frequency of approximately 52.6 Hz and a consistent amplitude of 8.2 mm initially, independent of the input amplitude range of 25-35 mm and frequency range of 0.1-1 Hz. This process produces stable electrical outputs through the triboelectric energy conversion mechanism with less than 9.6% deviation across the tested input conditions. To demonstrate the versatility of this platform, we fabricated two types of active sensors, a humidity sensor based on charge dissipation in a hydrolyzed electrospun polyethylene terephthalate layer and an ammonia sensor utilizing impedance modulation of a polyaniline layer. Both devices exhibited highly stable, mechanical input-independent performance, confirming the platform's adaptability to different sensing mechanisms and materials. This mechanically triggered architecture provides a robust structural solution to an often overlooked source of signal ambiguity in self-powered sensors, offering the potential for reliable, portable, and human-interactive sensing applications.
Background/Objectives: The COVID-19 pandemic intensified concerns regarding the resilience and financing architecture of mental health services, yet it remains unclear whether crisis-induced adjustments fundamentally altered hospital case-mix complexity or merely exposed pre-existing structural configurations. This study examines the relationship between financing regimes and case-mix complexity in psychiatric hospitals in Romania, a Central and Eastern European health system characterized by mixed financing arrangements and pronounced interregional heterogeneity. Methods: Using administrative data comprising 752 hospital section-year observations (2019-2024), we identify structural financing-organization regimes through a two-step clustering procedure (hierarchical Ward method followed by K-means refinement) based on revenue composition, expenditure allocation, workforce structure, and operational pressure indicators. Results: Three distinct regimes emerge, reflecting persistent institutional configurations rather than temporary crisis-induced groupings. Chi-square tests confirm that regime membership is statistically independent of pandemic timing. A multivariate regression model controlling for financing composition and expenditure structure shows that structural variables (particularly the share of contract-based revenues and the allocation of expenditures) exert systematic and economically meaningful effects on the case-mix index (CMI). Pandemic and post-pandemic indicators do not retain robust explanatory power once structural determinants are accounted for. Regional robustness analyses further demonstrate that financing architecture consistently outweighs temporal shock effects in explaining territorial variation in clinical complexity. Conclusions: The findings suggest that psychiatric hospital case-mix dynamics are structurally embedded within differentiated financing regimes whose influence persists beyond crisis periods. By integrating regime identification with outcome modeling in a Central and Eastern European context, this study contributes to the international literature on health system resilience and highlights the primacy of institutional financing architecture over episodic shock effects in shaping hospital complexity.
Over the past several centuries, the Baltic Proper harbour porpoise (Phocoena phocoena) has undergone significant population declines, resulting in its current IUCN classification as critically endangered. While conservation efforts are extensive and multinational, the population's abundance has only been estimated once (SAMBAH Project, 2011-2013). Ad hoc historical sources and the sub-fossil archaeological record, dating to 7000 years BP, suggest that the population once had a wider distribution in the Baltic Sea. However, the historical abundance and distribution of the Baltic Proper harbour porpoise population remain largely unknown, especially before the mid-20th century. This study examines archival Swedish newspaper records from the late 1700s to the early 1900s to assess the presence and distribution of porpoises. Digitized articles were searched for by keyword in the National Library of Sweden Newspaper Archive. This dataset was combined with HELCOM/ASCOBANS historic data. The records show that harbour porpoises historically occurred regularly along the entire Swedish coast, including the northernmost parts of the Gulf of Bothnia, where the species is virtually absent today, suggesting a notable range retraction. While harbour porpoises appeared less frequently in the Baltic Sea than along the west coast of Sweden, the number of Baltic records indicates that porpoises occurred more frequently than today. The peak occurrence of porpoises during spring and summer suggests that the Gulf of Bothnia historically constituted an important foraging habitat for animals migrating from the southern Baltic. By integrating historical records with modern conservation data, this study provides critical insights into the long-term effects of human activity on the Baltic Proper harbour porpoise. Understanding past ranges and approximate population size is vital for guiding more effective conservation strategies.
The pathogenesis of IgA nephropathy is mediated by B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Telitacicept is a fusion protein that targets and neutralizes both BAFF and APRIL and, as such, might be effective in IgA nephropathy. We now report a prespecified interim analysis of a phase 3, multicenter, double-blind, randomized, placebo-controlled trial, which enrolled adults with biopsy-proven IgA nephropathy and persistent proteinuria (protein level, ≥1.0 g per day), despite appropriate supportive care. Patients were randomly assigned in a 1:1 ratio to receive subcutaneous once-weekly telitacicept (240 mg) or matching placebo. The primary end point was the geometric mean ratio of the 24-hour urinary protein-to-creatinine ratio at 39 weeks relative to baseline. Safety was also evaluated. A total of 318 patients were assigned to receive telitacicept or placebo (159 in each group). At week 39, the percentage change in the 24-hour urinary protein-to-creatinine ratio was -58.9% with telitacicept and -8.8% with placebo, which corresponded to a relative difference (based on the ratio of geometric mean reductions between the two groups) of -55.0% (95% confidence interval [CI], -61.3 to -47.6; P<0.001) in favor of active medication. The percentage change in the estimated glomerular filtration rate relative to baseline was -1.0% (95% CI, -3.2 to 1.2) with telitacicept and -7.7% (95% CI, -9.9 to -5.4) with placebo. Adverse events were more common with telitacicept than with placebo (in 89.3% vs. 78.6% of patients), although serious adverse events were less common (in 2.5% vs. 8.2%). No unexpected safety findings were reported with telitacicept. In patients with IgA nephropathy at high risk for progression, 39 weeks of treatment with telitacicept led to a greater reduction in the 24-hour urinary protein-to-creatinine ratio than placebo. (Funded by RemeGen; TELIGAN ClinicalTrials.gov number, NCT05799287.).
Muscle atrophy occurs during physiological (i.e., fasting) and pathological conditions (i.e., cancer) and anticipates death. Since not all patients will undergo muscle wasting, it would be highly useful to identify them soon to intervene early. We aim to generate a reporter system to follow only pathological, but not physiological, muscle wasting through in vivo imaging. Comparing the upstream non-coding regions of a subset of atrophy-related genes or atrogenes, using the MuRF1 promoter as a backbone, we cloned various promoters upstream of Firefly Luciferase. The best hits selected in vitro were further compared in in vivo imaging if able to sense early atrophy induced by MCG101 sarcoma or sciatic nerve resection through plasmid electroporation or AAV9 injections. The best promoter was used to generate the reporter mouse MyoRep, expressing the cassette in all skeletal and cardiac muscles using the loxP system. Luciferase assays showed that only the newly generated promoters of MuRF1, one containing glucocorticoid-responsive elements or GRE (TWIST) (p ≤ 0.01, 1.7 FC) and a GRE-less promoter (GREDEL) (p ≤ 0.0001, 1.6 FC), discriminated the supernatants from cachectic tumoural cells (C26) from non-cachectic ones (4T1). Comparing both reporters electroporated in leg muscles, we found that GREDEL, but not TWIST, anticipated atrophy by 6 days in MCG101 carriers (p ≤ 0.05) and by 8 days upon denervation (p ≤ 0.05), recapitulating MuRF1 inductions. TWIST, but not GREDEL, drove an undesirable bioluminescent signal in vitro to dexamethasone (p ≤ 0.001, 1.5 FC) and in vivo upon fasting (p = 0.0553, 3 FC). GREDEL-carrying AAV9 injected in the legs of ApcMin/+ mice unraveled sex-different cachexia and anticipated body emaciation by 1 week (p ≤ 0.001, 3.7 FC). GREDEL was then used to generate the MyoRep mouse. Dorsal view of bioluminescent signal of MCG101-carrying MyoRep mice increased already 6 days from tumour injection (p ≤ 0.01, 1.7 FC) when tumour is still unpalpable. Denervated MyoRep mice emitted a signal already 1 day after surgery (p ≤ 0.05, 1.4 FC), anticipating atrophy. Male ApcMin/+ mice display less musclin in their muscles (p ≤ 0.05, 0.4 FC) and plasma (p ≤ 0.01, 0.6 FC). Such mice, when expressing MyoRep in their muscle legs, were given the anti-catabolic myokine musclin. The emitted signal was decreased by 30% 3 weeks after musclin-AAV9 administration (p ≤ 0.05), supporting MyoRep useful to test anti-atrophic drugs. Since MyoRep detects only pathological atrophy anticipating wasting, it represents an unprecedented tool to predict it early in diseases with local or systemic atrophy. It could also be useful to identify early biomarkers of atrophy and new drugs at once.
The degradation of organic matter (OM) by microorganisms in thawing permafrost produces greenhouse gases. Terrestrial OM is transported into fjords through hydrological runoff, but it is unclear whether the microbial mechanisms of OM degradation on land persist after soils enter marine environments, which differ greatly in conditions and microbial communities. This question is particularly relevant for low-OM soils, which dominate Arctic landscapes and are more exposed to oxidants. Here, we compared OM-degrading capacity in permafrost-affected active layer soils and adjacent fjord sediments from Kongsfjorden, Svalbard, focusing on carbohydrate-active enzymes (CAZymes), which target some of the most abundant types of organic matter in soils. Using multi-omics approaches-metagenomics, metagenome-assembled genomes (MAGs), metabolomics, metatranscriptomics, and metaproteomics-we examined CAZyme presence, distribution, and activity. Despite environmental differences, both soils and sediments harbored diverse glycoside hydrolases and polysaccharide lyases, most of which showed evidence of activity. Verrucomicrobia expressed the highest number of CAZyme transcripts, indicating that they dominated active carbohydrate degradation in fjord sediments, while Acidobacteria and Actinobacteria were more active in soils. Notably, CAZymes in fjord sediments targeted primarily soil-derived OM, and the proportions of enzymes degrading terrestrial OM, marine OM, and microbial necromass-remnants of dead microbial cells were similar across both environments. These results suggest that microbial communities in both soils and fjord sediments are equipped to degrade carbohydrates, and that burial of terrestrial-derived OM in fjord sediments may not protect it from microbial breakdown under Arctic warming.IMPORTANCEPermafrost thaw may be a critical climate feedback because microbial degradation of organic matter (OM) can release greenhouse gases. While fjords serve as major carbon burial sites, our results show that burial of terrestrial-derived OM in these sediments does not ensure protection from microbial degradation. Microbial communities in both active layer soils and fjord sediments harbor a broad arsenal of carbohydrate-active enzymes, with evidence of activity across diverse taxa. This functional continuity indicates that once terrestrial material is washed into fjords, it remains vulnerable to microbial breakdown despite different environmental conditions. Understanding these cross-system continuities in microbial function is essential for predicting the fate of OM in a rapidly warming Arctic and highlights the importance of including fjord sediments in global carbon cycle models.
Over recent decades, Emotion-Focused Therapy, aging, and forgiveness have garnered significant attention in the field of psychology. However, there is a lack of studies on Emotion-Focused Therapy and forgiveness specifically tailored for older adults. This article presents a protocol designed to assess the feasibility and acceptability of a randomized controlled trial of Emotion-Focused Therapy aimed at resolving emotional injuries in individuals aged 65 and older, within the context of interpersonal offenses. Feasibility will be evaluated through recruitment and retention rates, as well as adherence to the intervention protocol. Acceptability will be assessed based on perceived treatment credibility, participants' expectations regarding outcomes, levels of engagement, and overall satisfaction with the intervention. The study is structured as a two-arm, parallel-group randomized trial with a waiting list control. We propose recruiting a sample of 70 participants, randomly assigned to either an immediate intervention group, which will receive Emotion-Focused Therapy over twelve weekly sessions, or a control group that will receive the same therapy after a twelve-week waiting period. Data will be collected in the beginning, middle, and at the end of therapy, and in two planned follow-ups (three and six months after therapy). Once this protocol is implemented, if the therapy proves to be feasible, acceptable, and shows promising results, the findings will inform a large-scale randomized clinical trial to advance the understanding of this treatment for individuals aged 65 + .
Primary atopic disorders (PADs), a subset of inborn errors of immunity, are a growing group of more than 50 monogenic diseases characterized by severe, early-onset allergic inflammation, often coexisting with immune deficiency or dysregulation. Once considered clinical curiosities, PADs have emerged as powerful human models for understanding immune homeostasis. Advances in next-generation sequencing have accelerated gene discovery, revealing that allergic disease can arise from disruption of interconnected regulatory systems rather than immune hyperactivity alone. Here, we synthesize insights from genetically defined PADs to illustrate how defects across epithelial barrier function, immune signaling, cytoskeletal organization, antigen receptor pathways, lymphocyte repertoire, and regulatory networks converge on impaired tolerance and persistent type 2 inflammation. Beyond mechanistic insights, PADs provide a framework for precision therapy enabling targeted use of cytokine inhibitors, JAK inhibitors, biologics, hematopoietic stem cell transplantation, and emerging gene therapies. These insights bridge rare and common disease, informing the pathophysiology and treatment of polygenic atopy.
Early stopping has been widely used to regularize models and can reduce the amount of computation by halting the training process when the performance of the model on a validation set stops improving. However, conventional early stopping applies the same stopping criterion to all instances without considering their individual learning status, which can leads to both potential overfitting and redundant computational costs on instances that are already well learned. To further improve efficiency, we propose Instance-dependent Early Stopping (IES), which adapts the early stopping mechanism from the entire training set to the instance level, based on the core principle that once the model has mastered an instance, the training on it should stop. IES considers an instance mastered if the second-order differences of its loss value remain within a small range around zero. This provides a uniform stopping criterion that is applicable across all instances, unlike a simple loss value threshold which is affected by sample difficulty. We show that excluding mastered instances from backpropagation can increase gradient norms, thereby accelerating the decrease in the training loss and speeding up the training process. To address the remaining overhead in forward propagation, we introduce an enhanced variant, IES+, designed for aggressive training acceleration. The foundational IES accelerates training, reducing the number of instances receiving backpropagation by 10%-50% while maintaining or even improving performance. For scenarios where speed is the top priority, IES+ further optimizes the forward pass to achieve state-of-the-art reductions in wall-clock time. Furthermore, we extend our evaluation to validate the effectiveness of IES for the supervised fine-tuning of large language models, where it achieves notable computational savings while preserving or improving performance.