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Efficacy and Hypoglycaemia Outcomes With Once-Weekly IcoSema Versus Comparators in Individuals With Type 2 Diabetes by Kidney and Liver Function: A Post Hoc Analysis of the COMBINE 1-3 Trials.

AIMS: This post hoc analysis of COMBINE 1-3 assessed efficacy and hypoglycaemia outcomes with IcoSema (once-weekly combination therapy of basal insulin icodec and semaglutide [a glucagon-like peptide-1 analogue]) versus comparators in adults with type 2 diabetes (T2D) by kidney and liver function subgroups. MATERIALS AND METHODS: Treatment outcomes were analysed by trial according to kidney (estimated glomerular filtration rate &#x2265;&#x2009;90; 60-<&#x2009;90; 30-<&#x2009;60; <&#x2009;30&#x2009;mL/min/1.73&#x2009;m2) and liver (total bilirubin &#x2264;&#x2009;21&#x2009;&#x3bc;mol/L or aspartate aminotransferase [AST] &#x2264;&#x2009;31/&#x2264;&#x2009;37 [female/male] U/L; total bilirubin >&#x2009;21&#x2009;&#x3bc;mol/L or AST >&#x2009;31/>&#x2009;37 [female/male] U/L) function subgroups. RESULTS: In COMBINE 1-3, across kidney and liver function subgroups, there were no statistically significant treatment by subgroup interactions for change in glycated haemoglobin (HbA1c) (baseline to week 52), change in body weight (baseline to week 52) or rates of combined clinically significant or severe hypoglycaemia (not assessed by kidney function for COMBINE 2) (all p&#x2009;>&#x2009;0.05). There were statistically significant treatment by kidney function subgroup interactions for the achievement of HbA1c <&#x2009;7.0% without weight gain and without clinically significant or severe hypoglycaemia in COMBINE 3 (p&#x2009;<&#x2009;0.05) but not COMBINE 1 or 2, and statistically significant treatment by liver function subgroup interactions in COMBINE 1 (p&#x2009;<&#x2009;0.05) but not COMBINE 2 or 3. For COMBINE 1 and 3, there were statistically significant treatment by kidney function subgroup interactions for mean weekly total insulin dose, but not statistically significant treatment by liver function subgroup interactions. CONCLUSIONS: Efficacy and hypoglycaemia outcomes with IcoSema versus comparators were generally consistent among adults with T2D with mild to moderate kidney impairment or impaired liver function. TRIAL REGISTRATION: The COMBINE 1-3 trials were sponsored by Novo Nordisk and are registered with ClinicalTrials.gov (NCT05352815; NCT05259033; NCT05013229).

Humans

Sex Differences in Postoperative Recovery and Mortality After High-Risk Cardiac Surgery: A Propensity Score-Matched Post Hoc Analysis of the SUSTAIN-CSX Trial.

BACKGROUND: Sex-related differences after cardiac surgery remain controversial because women often present with higher baseline risk and complexity than men. We performed a post hoc propensity score-matched analysis of the SUSTAIN-CSX (Sodium Selenite Administration in Cardiac Surgery) trial to evaluate sex differences in mortality, postoperative complications, and recovery after high-risk cardiac surgery. METHODS: Of 1394 trial participants, 1386 had complete data. Women were matched 1:1 to men using nearest-neighbor propensity score matching based on age and European System for Cardiac Operative Risk Evaluation II (EuroSCORE II), with exact matching on surgical category, yielding 327 female-male pairs. Prespecified sensitivity analyses adjusted for frailty, baseline hemoglobin, renal disease, left ventricular ejection fraction, previous myocardial infarction, preoperative medications, and baseline creatinine. RESULTS: In the primary matched analysis, 180-day survival did not differ between women and men (log-rank P=0.086; unadjusted hazard ratio, 1.80 [95% CI, 0.91-3.55]; P=0.091). In descriptive matched comparisons, women had numerically longer intensive care unit stay (median, 3&#x2009;days [quartile 1, quartile 3 (Q1, Q3)=1, 6&#x2009;days] versus 2&#x2009;days [Q1, Q3=1, 5&#x2009;days]) and hospital stay (median, 10&#x2009;days [Q1, Q3=7, 18&#x2009;days] versus 9&#x2009;days [Q1, Q3=6, 16&#x2009;days]; P=0.292), whereas major postoperative complications were similar. In adjusted sensitivity analyses accounting for the matched design and residual imbalance, female sex remained associated with longer intensive care unit stay (adjusted incidence rate ratio [IRR], 1.8 [95% CI, 1.2-2.9]; P=0.009) and hospital stay (adjusted IRR, 1.4 [95% CI, 1.0-1.9]; P=0.031). Mortality sensitivity analyses were model-dependent. CONCLUSIONS: In this propensity score-matched cohort of high-risk cardiac surgery patients, women showed a longer postoperative recovery trajectory in adjusted analyses, whereas mortality findings were sensitive to model specification and should be interpreted cautiously. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02002247.

Aged

Extended Long-Term Effects of Cognitive and Aerobic Training on Cognitive Function in Patients With Stress-Related Exhaustion Disorder: A 4.5-Year Follow-Up of a Randomized Controlled Trial.

Stress-related conditions like clinical burnout and exhaustion disorder (ED) are associated with enduring cognitive problems. We have previously demonstrated that the addition of computerised cognitive training (CCT) and aerobic training (AT) to a multimodal rehabilitation programme (MMR) yielded greater improvements in cognitive function compared to MMR alone in patients with ED. These effects were maintained at the 1-year follow-up for CCT, but not for AT. Building on these findings, the present study examined the extended long-term effects of CCT and AT on cognitive function, psychological health, and work ability, 4.5&#xa0;years after the interventions. Participants were recruited from a stress-rehabilitation clinic and 56 of the initial 132 participants returned for the 4.5-year follow-up. Assessments were conducted before (T1), immediately after (T2), 1-year after (T3) and 4.5-years after (T4) the interventions. Mixed model analyses assessed changes in the intervention groups relative to the control group from T1 to T4, with follow-up comparisons examining within-group stability of outcomes between T3 to T4. The primary outcome was cognitive performance on a global cognitive score. Secondary outcomes included domain-specific cognitive functioning, self-reported cognitive function, psychological health (burnout, depression, anxiety, and fatigue), and work ability. The analysis revealed sustained long-term effects on the global cognitive score, a trained updating task and episodic memory in the CCT group, with stable performance between one- and 4.5-year follow-up. The addition of AT did not yield any extended long-term effects on cognitive performance. Both groups showed extended long-term improvements in self-reported memory problems, although findings were mixed. Extended long-term improvements were observed on burnout for both groups, with additional effects on anxiety and work ability in the AT group. Notably, these effects were not present at the 1-year follow-up and are more plausibly explained by selective attrition rather than a delayed intervention effect. In conclusion, the result indicates that cognitive interventions such as CCT can have lasting positive effects on cognitive function in patients with ED, whereas the long-term psychological effects should be interpreted with caution. TRIAL REGISTRATION: ClinicalTrials.gov: NCT0073772.

Adult

The Association Between NT-Pro BNP, Nephropathy and Endothelial Dysfunction in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) is an established biomarker of heart failure and has been recommended for cardiovascular risk stratification in type 2 diabetes mellitus (T2DM). However, its relationship with diabetic nephropathy and endothelial dysfunction across varying stages of kidney impairment remains unclear. This study examined the associations of NT-Pro BNP, renal impairment, albuminuria and endothelial dysfunction in patients with T2DM without overt heart failure. METHODS: A comparative cross-sectional study was conducted among 192 adults with T2DM. Participants were stratified by KDIGO eGFR groups (&#x2265;&#x2009;90, 60-89, 30-59&#x2009;mL/min/1.73m2). NT-Pro BNP was considered abnormal at a cut-off of &#x2265;&#x2009;125&#x2009;pg/mL. Albuminuria was categorized using the urinary albumin-to-creatinine ratio (uACR). Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD). Logistic regression analysis was performed to identify independent factors of elevated NT-Pro BNP, with p-values <&#x2009;0.05 considered statistically significant. RESULTS: NT-Pro BNP levels were significantly higher in the lower eGFR groups compared with normal eGFR (204.3 vs. 96.8 vs. 62.2&#x2009;pg/mL, p&#x2009;<&#x2009;0001). A weak but significant positive correlation was observed between NT-Pro BNP and uACR (r&#x2009;=&#x2009;0.31, p&#x2009;<&#x2009;0.001). However, no significant association was found between NT-Pro BNP and FMD (p&#x2009;=&#x2009;0.388). Following multivariable adjustments, older age (adjusted OR 1.14, 95% CI: 1.06-1.23, p&#x2009;<&#x2009;0.001), higher systolic blood pressure (adjusted OR 1.05, 95% CI: 1.02-1.08, p&#x2009;=&#x2009;0.010), lower eGFR (adjusted OR 0.97, 95% CI: 0.95-0.99, p&#x2009;=&#x2009;0.003) and beta-blocker use (adjusted OR 4.65, 95% CI: 1.61-13.45, p <&#x2009;0.001) were independently associated with elevated NT-Pro BNP. CONCLUSION: In patients with T2DM without overt heart failure, elevated NT-Pro BNP showed a statistically significant association with lower eGFR and higher albuminuria. Moderate to severe albuminuria becomes an independent factor for elevated NT-Pro BNP after adjustment excluding eGFR. The lack of association with endothelial dysfunction suggests that NT-Pro BNP may reflect different pathophysiological pathways. NT-Pro BNP may serve as a useful biomarker for early cardiovascular risk stratification and identification of individuals at risk of pre-heart failure in diabetic kidney disease.

NT&#x2010;Pro BNP

Characterisation of HIV-1 Gag Cytotoxic T-Lymphocyte Epitopes in the Southern African Region-A Systematic Review.

During early HIV-1 infection, robust Cytotoxic T-lymphocyte (CTL) responses are mostly targeted at immunodominant Gag p24 epitopes to reduce HIV-1 viraemia to a set-point. The aim of this study was to review the current body of knowledge on HIV-1 Gag CTL epitopes in the southern African region where subtype C is prevalent. Peer-reviewed records were obtained from three databases: PubMed Central, Web of Science Core Collection, and Scopus, using the following search terms: HIV subtype C Gag epitopes, and HIV clade C Gag epitopes. The search results were restricted to countries within the southern African region, and only data published in English and between the years 2000-2025 were considered for this review. The search from the three databases produced a total of 2103 peer-reviewed records, and 49 records were included in the review. The majority of studies (58.44%) were conducted in South Africa, followed by Botswana (15.58%), Zambia (10.39%), Malawi (7.79%), Zimbabwe (6.49%) and Angola (1.30%). There were no studies identified from other southern African countries. A total of 60 Gag CTL epitopes were identified, of which 17 (28.33%) were located within the matrix protein (p17), 33 (55.00%) within the capsid protein (p24), and 4 (6.67%) within the Gag polyprotein (p2p7p1p6). The commonly detected immunodominant epitopes were mostly located within the Gag p24 protein; and included TPQDLNTML (TL9, Gag p24 48-56) and TSTLQEQIGW (TW10, Gag p24 108-117) present at 16.00% and 13.3%, respectively. The proportion of HLA-A, B and C allotypes in this systematic review were 18%, 78%, and 4%, respectively. The more common HLA-B allotypes that restrict immunodominant Gag epitopes and facilitate better control of HIV-1 were HLA-B*57, -B*58:01, -B*42:01 and -B*81:01. This systematic review has provided important insights into the description of immunodominant Gag epitopes and HLA-I alleles that contribute to the control of HIV-1 viraemia in the southern African region. It has also exposed that some CTL epitopes identified in the southern African studies are not reported on the Los Alamos HIV database (LANL HIV database). This highlights a need to have this database updated with this information as it is used as a reference for epitopes. This review could provide insights into the design of an epitope-based HIV-1 vaccine that would also be effective in the southern African region.

Humans

Postoperative Curvature Loss in Three-Level Anterior Cervical Discectomy and Fusion With Zero-Profile Device.

PURPOSE: Cervical curvature loss is a frequent complication following 3-level anterior cervical discectomy and fusion (ACDF) using a Zero-Profile device. Consequently, the capacity of this device to maintain cervical sagittal alignment in 3-level ACDF remains highly controversial. This study aimed to identify potential predictors for postoperative curvature loss (PCL) and evaluate its impact on clinical outcomes. METHODS: A total of 113 patients who underwent ACDF for 3-level cervical degenerative disc disease (CDDD) between January 2021 and December 2023 were retrospectively reviewed. Demographic data, radiological parameters, and clinical outcomes were analyzed. Radiographic measures included cervical curvature, T1 slope, C2-7 sagittal vertical axis, and titanium plate and endplate (TPE) distance. Clinical outcomes were assessed using the Visual Analog Scale (VAS), Neck Disability Index (NDI), and Japanese Orthopaedic Association (JOA) scores. Statistical analyses were performed using paired and independent t-tests, as well as Pearson correlation coefficients. RESULTS: The average curvature loss was 6.82&#xb0; from 1&#x2009;week postoperatively to the final follow-up (p&#x2009;<&#x2009;0.001). However, the final curvature (11.65&#xb0;) was maintained, representing a 4.33&#xb0; improvement compared to preoperative values. Significant correlations were observed between PCL and preoperative curvature (r&#x2009;=&#x2009;-0.368, p&#x2009;=&#x2009;0.013), preoperative T1 slope (r&#x2009;=&#x2009;-0.546, p&#x2009;<&#x2009;0.001), &#x2206;T1 slope (r&#x2009;=&#x2009;0.443, p&#x2009;=&#x2009;0.002), and &#x2206;TPE distance (r&#x2009;=&#x2009;0.417, p&#x2009;=&#x2009;0.004). PCL did not correlate with Japanese Orthopaedic Association (JOA) scores or arm VAS scores at the final follow-up. Nevertheless, patients with a PCL&#x2009;&#x2265;&#x2009;6&#xb0; exhibited significantly higher neck VAS (p&#x2009;=&#x2009;0.028) and NDI scores (p&#x2009;=&#x2009;0.041). CONCLUSION: Although contiguous 3-level ACDF with a Zero-Profile device may result in PCL, it preserves an improved cervical lordosis compared to the preoperative baseline. Low preoperative curvature and a low preoperative T1 slope are potentially predictive factors for PCL. Postoperative changes in TPE distance and T1 slope are significantly associated with PCL, suggesting a potential biomechanical link that requires direct validation. Furthermore, PCL may lead to higher neck VAS and NDI scores. Consequently, the Zero-Profile device may require careful consideration in 3-level CDDD patients presenting with low preoperative curvature and a low T1 slope. Importantly, the 6&#xb0; PCL threshold identified is preliminary and requires prospective validation before clinical application.

Humans

Ambrosia beetle invasions are structured by inbreeding, intraspecific hybridisation, and bridgeheads.

When invasive populations establish in regions far from their origin, they may accumulate deleterious mutations that limit population viability and later expansion. Invasions stemming from such bridgehead populations may experience further sequential bottlenecks. However, deleterious mutations can be masked or eliminated when populations outbreed with other lineages. Here, we analyse global invasions of a species complex of persistently inbreeding ambrosia beetles, using genomic data (N=247) from invasive populations in Africa, North America and Australia, and from native populations in Asia. We mostly focus on one species of this complex (Euwallacea fornicatus) which poses a severe threat to tree species worldwide and is rapidly expanding its global range. We uncover a single lineage of this species across California, South Africa, and Western Australia, involving an invasive bridgehead and containing almost no nuclear genetic variation. In South Africa we identify a second lineage that has repeatedly hybridised with the first lineage. Genetic patterns in the native range indicate that such opportunistic outbreeding may be common. Despite lacking nuclear variation, the first lineage contained two CO1 haplotypes that were also observed in every hybrid lineage, pointing to heteroplasmy and possible hybrid origins of this lineage. Native populations had fewer missense mutations than invasive populations, indicating that opportunistic outbreeding may help purge fixed deleterious mutations when local lineage diversity is high. These findings highlight the importance of outbreeding even when inbreeding is common, and they demonstrate the biosecurity threat posed by subsequent gene flow into invasive populations.

Journal Article

Trade-offs in avian parental care: a review of theory and meta-analysis of brood size manipulations.

The selective forces shaping parental care have been studied for over 50&#x2009;years. While theoretical and experimental work has yielded qualitative progress, the large body of empirical work testing predictions about parental investment based on life-history trade-offs has yet to be synthesized. We first provide an overview of the core life-history theory exploring how selection might shape parental care. We then conduct a systematic review and meta-analysis on studies that experimentally manipulated brood size in birds, a widely used experimental approach to manipulate parental investment. We extracted 313 estimates from 62 studies representing 31 species of birds from 19 different families and tested key predictions on trade-offs in parental care derived from theory. Our analysis provides strong support for some predictions about life-history trade-offs in parental care, but weak or equivocal support for others. Specifically, we found that overall, avian parents respond to brood size manipulations as predicted by life-history theory: they increased care in response to brood enlargement, and decreased care in response to brood reductions. Furthermore, for the same relative manipulation size, responses to brood reductions were greater than responses to brood enlargements. This finding is consistent with predictions derived from life-history theory based on some types of non-linear utility curves. However, many predictions derived from theory are not well supported by our comparative analysis. Species' life-history traits such as clutch size (a measure of current reproduction), adult survival, and broods per year (two measures of future reproduction), explained little, if any, among-species variation in response to brood size manipulations. Several factors may explain this. We highlight that brood size manipulations may affect more than just perception of the value of current reproduction, such as altering parents' perception of predation risk. Importantly, these unintended consequences could lead to asymmetric responses like those we observed. Other common experimental approaches - such as hormone manipulations, altering a partner's effort, and food supplementation - often affect multiple traits or fitness components simultaneously, or may involve cues that poorly match the evolved mechanisms guiding parental behaviour. Our review of both theory and experimental approaches suggests that there are multiple opportunities for more precise experiments. We offer several recommendations for effective designs. One is improved understanding of the biology underlying the functions relating to costs and benefits, with careful consideration of not only how the manipulation will affect only one of those, but also the mechanisms that might alter how parents perceive the manipulation. We also emphasize general principles, such as assessing alternative hypotheses and devising multiple independent tests. Armed with these recommendations, we believe there are new opportunities to increase the strength of inference achieved from studies aimed at understanding the trade-offs affecting the evolution of parental care.

Animals

Clinical Efficacy and Learning Curve of Far-Lateral Approach (FLA) in Uni-Portal Non-Coaxial Spinal Endoscopic Surgery (UNSES) in the Treatment of Lumbar Degenerative Diseases: A Prospective Study.

BACKGROUND: Uniportal non-coaxial spinal endoscopic surgery (UNSES) via far-lateral approach (FLA) is an innovative minimally invasive procedure for lumbar degenerative diseases, particularly far-lateral disc herniation and foraminal stenosis. However, complex lateral lumbar anatomy and strict endoscope-instrument coordination create a distinct learning curve that may compromise early surgical efficiency and safety. This study aimed to evaluate the efficacy and safety, quantify the learning curve, and to provide clinical guidance for the standardized promotion and application of this technology. METHODS: A total of 40 consecutive patients with lumbar degenerative diseases who underwent UNSES via FLA by a single surgeon between January 2025 and December 2025 were included. All data were analyzed using SPSS 26.0 statistical software (IBM, USA). Primary outcomes included operation time, blood loss, fluoroscopy frequency, and intraoperative complication rate. Secondary outcomes were VAS, ODI, and modified Macnab criteria at 1, 3, and 6&#x2009;months postoperatively. The learning curve and the inflection point of the learning curve was determined using cumulative sum (CUSUM) analysis. The differences in clinical indicators between early and proficient stage were compared. RESULT: Operation time, blood loss, and fluoroscopy times decreased significantly with case accumulation (p&#x2009;<&#x2009;0.05). CUSUM identified an inflection point at the 16th case, after which operation time stabilized at (55.3&#x2009;&#xb1;&#x2009;8.6) min, much shorter than the early phase (89.5&#x2009;&#xb1;&#x2009;10.3) min (p&#x2009;<&#x2009;0.001). Before the 16th case, the curve was in an upward trend; after the 16th case, the curve tended to be flat, indicating the proficiency stage. Postoperative VAS and ODI improved significantly than those before surgery at each follow-up time (p&#x2009;<&#x2009;0.05). There was no significant difference in postoperative VAS score and ODI between the two groups at each follow-up time point (p&#x2009;>&#x2009;0.05). The total complication rate was 12.5% (5/40), were cured by conservative treatment. The total excellent-good rate was 90.0% (36/40). L5/S1 and Bertolotti's syndrome were independent factors affecting the learning curve. CONCLUSION: UNSES via FLA is a safe and effective minimally invasive technique for treating complex lumbar degenerative diseases. It has a certain learning curve, and the inflection point is about the 16th case. After mastering the key techniques such as anatomical positioning, endoscopic manipulation and hemostasis, the surgeon can gradually reach the proficiency stage, with significantly improved surgical efficiency and clinical efficacy, and controllable complications. This study provides a theoretical basis for the clinical training and technology promotion of UNSES via FLA.

Humans

Sulfonic Ion-Exchange Resins as Versatile Tools for the Oxidative Degradation of Chemical and Biological Hazardous Agents.

Commercial sulfonic styrene-divinylbenzene ion-exchange resins are activated with aqueous H2O2 to generate metal-free decontamination systems that combine strong Br&#xf8;nsted acidity with immobilized oxidizing capability. Among five tested materials, Amberlyst 15 dry showed the best performance in terms of oxidant immobilization capacity and promoting the oxidative degradation of the sulfur mustard simulant (2-chloroethyl)ethyl sulfide, CEES, and the organophosphorus pesticide malathion under very mild conditions. Control experiments with K2CO3-exchanged resin demonstrate that efficient decontamination requires the synergy between surface acidity and peroxide functionality. The activated resins also display rapid biocidal activity, strongly reducing viable Escherichia coli and Staphylococcus aureus and completely suppressing the infectivity of HSV-1 and SARS-CoV-2 within min. These findings identify peroxide-activated sulfonic resins as simple, sustainable, regenerable, and versatile tools for efficient combined hazardous chemical and biological decontamination.

Oxidation-Reduction

Voluntary Knowledge Brokering to Promote Evidence-Based Nursing Practice: A Qualitative Study.

Knowledge brokering is a process of connecting knowledge producers with users to facilitate evidence-based practice through relationship building and information sharing. This descriptive qualitative study aimed to clarify knowledge brokering by nurses in Japanese hospitals. Twelve registered nurses in Japanese hospitals participated. They had over 5&#x2009;years' clinical experience, including experience in conducting research, particularly staff research, and education. Data were collected through semi-structured individual interviews and analyzed using qualitative content analysis. The analysis revealed a central theme: continuous efforts to foster empathy among colleagues and spontaneously promote evidence-based practice: multifaceted brokering activities by clinical nurses. Findings identified 10 categories categorized into four interconnected gears: establishing the foundational ground, assessing clinical needs and staff readiness, tailoring and diffusing evidence, and sustaining and evolving evidence-based practice. Even nurses without formal titles voluntarily bridged the research-practice gap, providing new insights into informal brokering. Brokers communicated considerately, balanced evidence with clinical context, negotiated practical compromises, and fostered staff research competency.

Humans

Psychological interventions to improve maternal mental health and resilience during pregnancy in the COVID-19 pandemic: a systematic review.

BACKGROUND: During the COVID-19 pandemic, pregnant women experienced increased psychological distress, while access to routine mental health care was often disrupted. Psychological interventions may provide an effective strategy to support maternal mental health under these circumstances. OBJECTIVE: This systematic review aimed to provide an overview of psychological interventions for pregnant women during the COVID-19 pandemic and to evaluate their effectiveness in reducing distress and enhancing resilience. METHODS: A systematic search of four databases was conducted up to 3 September 2025. Randomised and non-randomised studies evaluating psychological interventions during pregnancy were included. RESULTS: Sixteen studies met the inclusion criteria. Interventions included cognitive behavioural therapy, mindfulness-based interventions, psychoeducation, and other psychological approaches delivered through individual, group, digital, or hybrid formats. Most studies reported reductions in depression, anxiety, or stress, and some found improvements in resilience-related factors. However, the methodological quality was modest; with heterogeneous outcome measures and limited follow-up. CONCLUSIONS: Overall, psychological interventions adapted for digital or hybrid delivery show promise for improving maternal emotional well-being in times of crises. The findings suggest that accessible and scalable psychological interventions may support maternal mental health during crisis situations when routine care is disrupted. Future research should prioritize larger, methodologically rigorous trials with standardized outcomes, and longer follow-up periods.

Humans

Family-Wise Error Rate Control in Clinical Trials With Overlapping Populations.

We consider clinical trials with multiple, overlapping patient populations that test multiple treatment policies specifically tailored to these populations. Such designs may lead to multiplicity issues, as false statements will affect several populations. For type I error control, often the family-wise error rate (FWER) is controlled, which is the probability to reject at least one true null hypothesis. If the joint distribution of the test statistics is known, the FWER level can be exhausted by determining critical values or adjusted-levels. The adjustment is typically done under the common ANOVA assumptions. However, the performed tests are then only valid under the rather strong assumption of homogeneous null effects, that is, when the null hypothesis applies to all subpopulations and their intersections. We show that under cancelling null effects, when heterogeneous effects cancel out in some or all subpopulations, this procedure does not provide FWER control. We also suggest different alternatives and compare them in terms of FWER control and their power.

Humans

The RrWRKY75-mediated activation of ascorbate synthesis in Rosa roxburghii Tratt contributes to salt stress tolerance.

L-Ascorbic acid (AsA) is a key antioxidant that alleviates oxidative stress in plants. Previous yeast one-hybrid (Y1H) screening identified RrWRKY75 as a transcription factor capable of binding to the promoter of RrGGP2 (GDP-L-galactose pyrophosphatase 2), a key structural gene responsible for massive AsA accumulation in Rosa roxburghii fruit. The function of RrWRKY75 in plant stress responses remains unclear. Here, RrWRKY75 is verified to specifically bind to the RrGGP2 promoter and activate its transcription. This positive regulatory effect on RrGGP2 transcript levels and AsA accumulation is further confirmed through overexpression or silencing of RrWRKY75 in R. roxburghii fruit or callus. Among various abiotic stress conditions, RrWRKY75 expression is significantly induced by salt stress. Upon its overexpression in callus or Arabidopsis thaliana, elevated AsA levels and antioxidant capacity are observed, thereby enhancing salt tolerance. Interestingly, RrWRKY75 also binds to the promoter of RrUNE12, a salt-responsive factor in R. roxburghii, and activates its expression. Moreover, yeast two-hybrid and bimolecular fluorescence complementation (BiFC) assays confirm the physical interaction between RrWRKY75 and RrUNE12, which jointly upregulates RrGGP2 expression and AsA production. Collectively, RrWRKY75 boosts AsA biosynthesis and salt tolerance both by directly trans-activating RrGGP2 and by synergizing with RrUNE12 through transcriptional activation and protein complex formation. These findings provide insights into the regulatory role of RrWRKY75 in abiotic stress tolerance and offer valuable genetic resources for R. roxburghii germplasm improvement.

Rosa

Developmental roles of LSD1/KDM1A-like (LDL) proteins in plants.

LYSINE-SPECIFIC DEMETHYLASE 1-like (LDL) proteins are conserved FAD-dependent amine oxidases that serve as pivotal regulators in plants. While animal systems typically rely on a single LSD1/KDM1A enzyme, the Arabidopsis thaliana genome encodes an expanded family of LDL homologues (FLD, LDL1, LDL2, and LDL3), resulting in substantial subfunctionalization and specialized recruitment mechanisms. This review explores the diverse developmental roles of plant LDLs, ranging from flowering time and circadian clock regulation to heterochromatin maintenance and epigenetic regulation. We discuss the redundant roles of FLD, LDL1, and LDL2 in repressing the floral repressor FLC and their nonredundant specialized function within the CCA1/LHY-TOC1 circadian feedback loop. A central focus of our review is the emerging mechanism of transcription-coupled demethylation, in which LDLs associate with the phosphorylated C-terminal domain of RNA polymerase II to modify chromatin cotranscriptionally within gene bodies. By integrating findings from Arabidopsis thaliana and crops such as tomato and soybean, we illustrate how the diversified LDL-mediated regulatory toolkit facilitates precise, gene-specific regulation. Ultimately, the LDL family represents a cornerstone of the sophisticated epigenetic strategies that regulate plant phenotypic plasticity in response to developmental and environmental cues.

Circadian clock

Positive psychology interventions during pregnancy: A systematic review.

Positive psychology interventions (PPI) have been applied and demonstrated evidence in various population groups. The present systematic review focused on the types and influence of PPI on the physical and psychological health of pregnant women. Studies that matched the selection criteria were identified on EBSCOhost, PsychINFO, Web of Science, PubMed, Scopus and four positive psychology journals. From the 2528 records identified, finally eight studies were included in the review. PPI in this review were delivered utilising various positive psychology components such as hope, gratitude and optimism based on existing theories, for example, the strengths theory, broaden-and-build theory, and hope theory. Most interventions were conducted from 14 gestational weeks onwards and were delivered via virtual platforms or mobile applications. As a result of this systematic review, it was identified that PPIs for maternal well-being were aimed at improving (1) physical health, including labour pain, nausea and vomiting; (2) psychological health, including stress, emotions, anxiety and depression; and (3) subjective health, including life satisfaction, perceived social support and quality of life. Most of the selected studies provided significant evidence towards improvement of well-being outcomes from administering PPI. For future studies, in-depth PPI integrated coping and support approaches should be further evidenced among diverse pregnant populations.

Humans

Dispositional optimism and open-label placebo responses in hair cortisol concentrations and psychological distress-A randomized controlled trial.

Open-label placebo (OLP) treatments show beneficial effects on various health-related outcomes, but studies investigating OLP effects on physiological measures remain scarce. This randomized controlled trial examined the effect of a 4-week OLP intervention on psychological distress and hair cortisol concentrations (HCC) in 202 healthy university students preparing for mandatory oral exams and whether dispositional optimism moderates the OLP effects. Participants were randomly assigned to an OLP or control group. Psychological distress was repeatedly assessed via negative affect, test anxiety, and subjective stress. HCC was measured before and within the intervention. Treatment expectations were additionally examined in interaction with optimism. Results show that OLPs significantly reduced psychological distress and HCC compared to the controls. Optimism moderated the OLP effect on HCC, with less optimistic individuals demonstrating the strongest reduction, independent of expectation. Optimism did not moderate OLP effects in psychological distress. However, the OLP effect on psychological distress depended on the three-way interaction of group, optimism, and expectation. The results suggest that OLPs alleviate the psychophysiological impact of a real-life stressor and indicate that optimism and expectation differently shape psychological and physiological OLP responses. These findings are discussed within the framework of the interactionist perspective.

Humans

Assessing the Frequency of VEXAS-Related Canonical UBA1 Mutations in Myelodysplastic Syndrome Patients.

OBJECTIVES: Somatic mutations in the UBA1 gene cause VEXAS syndrome, which presents with inflammatory and hematological symptoms. Case studies show a strong overlap between VEXAS and myelodysplastic syndrome (MDS). Recognizing VEXAS is important for differential diagnosis in patients with both inflammation and MDS, as accurate identification guides treatment. The study focuses on determining how often canonical UBA1 mutations linked to VEXAS occur in MDS patients. METHODS: Patients diagnosed with MDS were enrolled in the study, and genomic DNA was isolated from bone marrow FFPE samples. Molecular analysis was performed using a specifically designed ARMS-PCR approach. Additionally, protein-protein interaction (PPI) studies combined with bioinformatic analyses were carried out to explore potential links between UBA1 and pyroptosis. RESULTS: Among the 149 MDS patients analyzed, none exhibited high-Variant Allele Frequency (VAF) the canonical UBA1 point mutations linked to VEXAS syndrome. PPI analysis revealed a possible association between UBA1 and the NLRP3 inflammasome component. CONCLUSIONS: Expanding the sample size and using targeted NGS or ddPCR would improve mutation detection sensitivity and could reveal UBA1 canonical and non-canonical variants and more accurately estimate the frequency of VEXAS-related mutations in the MDS population.

Humans