Randomised trials have suggested the benefit of potassium-competitive acid blockers (P-CABs) is superior to proton pump inhibitors (PPIs) for ulcer recurrence in high-risk aspirin users. However, real-world comparative effectiveness across diverse antithrombotic regimens remains poorly defined. We evaluated P-CABs versus PPIs for preventing upper gastrointestinal (GI) bleeding in patients with acute atherothrombotic disease and using antithrombotic therapy. This retrospective cohort study utilised hospital-based Common Data Model data (2018-2024). Patients with acute cardiovascular or cerebrovascular disease receiving antithrombotic therapy who initiated a PPI or P-CAB were included. Drug exposure was modelled as a time-varying variable to mitigate immortal-time bias. The primary outcome was upper GI bleeding, analysed via time-dependent Cox regression adjusted for age, sex, comorbidities, and concomitant medications. Among 2255 patients (PPI: 1726; P-CAB: 529) in which 53 upper GI bleeding events occurred during a median follow-up of 637 days. P-CAB use was associated with a significantly lower risk of upper GI bleeding than PPIs (incidence rate 5.7 vs. 25.8 per 1000 person-year; adjusted hazard ratio [HR] 0.22, 95% CI 0.06-0.75, p = 0.016). P-CABs showed a profound reduction in moderate-to-severe upper GI bleeding (HR 0.11, 95% CI 0.02-0.60; p = 0.011). Notably, no bleeding events occurred in P-CAB users with high antithrombotic burden (≥ 2 agents). In patients receiving antithrombotic therapy, P-CABs are associated with a significantly lower risk of clinically significant GI bleeding compared to PPIs. These findings support P-CABs as a potent acid-suppressive strategy for gastroprotection in high-risk populations.
Oral antibiotics usually given for 24 h prior to surgery have been shown to result in lower anastomotic leak rates, as a result of luminal decontamination. Delivering antibiotics into the lumen of the intestine at the time of surgery may be a simpler way to achieve this outcome. An audit was undertaken of the first 50 consecutive patients undergoing luminal peri-anastomotic antibiotic washout performed by a single surgeon at two surgical institutions. The luminal washout initially involved metronidazole (500 mg) and gentamicin (240 mg) followed by the addition of ampicillin (1000 mg) for latter patients. The combined solution was delivered to the lumen of both sides of the colorectal anastomosis using either a soaked Raytec surgical gauze or syringe, or both. Follow up was performed for 30 days to assess for anastomotic leak, complications, clostridium difficile colitis and acute kidney injury, and at 90 days for mortality. The 30 and 90 day mortality was zero. There were no anastomotic leaks and no cases of clostridium difficile colitis. Complications occurred in six patients, with three readmissions within 30 days. There were no cases of acute kidney injury. Peri-anastomotic luminal washout with antibiotics is feasible and safe. It does not appear to have deleterious effects and should be compared to peri-operative oral antibiotics in larger clinical trials.
Peer bullying in physical education (PE) poses a significant threat to student psychosocial development. This study examines pre-service PE teachers' perceptions, empathy levels, and intervention tendencies towards physical, verbal, and relational bullying situations. Using a vignette-based mixed-methods design, data were collected between April and June 2025 from 105 final-year teacher candidates (N = 105; 67.6% male). Participants were recruited via convenience sampling from six state universities across Türkiye: Dicle, Bartın, Tokat Gaziosmanpaşa, Çanakkale Onsekiz Mart, İnönü, and Akdeniz. All candidates had completed or were enrolled in the 12-week teaching internship. Quantitative data were analysed using ANOVA and t-tests, while qualitative data underwent thematic analysis following Braun and Clarke's framework. Quantitative results indicated that candidates attributed high seriousness, felt strong empathy, and showed a high likelihood of intervention across all bullying types, with no significant differences regarding gender or prior training. However, qualitative findings revealed three primary themes: Behavioural Control, Emotional Support, and Inclusive/Relational Strategies. These themes highlighted that sensitivity often failed to translate into pedagogical action, as most candidates relied on superficial, authority-based warnings. The findings suggest that high emotional awareness does not guarantee pedagogical competence in conflict resolution. Anti-bullying training should be integrated into teacher education through applied case analyses and scenario-based pedagogical studies to bridge the gap between intention and practice.
BACKGROUND Procedural sedation and analgesia (PSA) can relieve pain and anxiety during invasive procedures. Carbon dioxide (CO₂) monitoring or integrated pulmonary index (IPI) can reduce respiratory depression in adults with PSA, but the effect of the combination of these 2 methods on intraoperative hypoxemia in pediatric urologic surgery is unclear. This study was conducted to determine whether capnography combined with IPI could lessen intraoperative hypoxemia during pediatric urinary procedures with PSA. MATERIAL AND METHODS We conducted a randomized controlled trial (ChiCTR 2300073943). Children referred for urinary procedures with PSA were randomly assigned to either a control group with standard monitoring or an intervention group with standard monitoring combined with capnography and IPI monitoring. The primary outcome was intraoperative hypoxemia. Secondary outcomes were severe intraoperative hypoxemia, airway management, and perioperative complications. RESULTS A total of 133 patients completed the analysis (67 in the intervention group and 66 in the control group). Compared with the control group, the incidence of intraoperative oxygen saturation decline was significantly lower in the intervention group (34.33% vs 56.06%, odds ratio=0.410, 95% confidence interval: 0.203-0.825, P=0.012). Simultaneously, the incidence of severe oxygen desaturation (SpO₂ <90%) was also significantly reduced in the intervention group (19.40% vs 36.40%, odds ratio=0.421, 95% confidence interval: 0.192-0.925, P=0.034). Regarding airway management interventions, the intervention group exhibited a higher frequency of jaw thrust maneuvers (1.84±1.31 vs 1.17±1.12 times, P=0.004) and a significantly reduced need for invasive positive-pressure ventilation (1.64±1.31 vs 2.39±1.48, P=0.002). No differences in other airway management techniques or perioperative complications were observed between the 2 groups. CONCLUSIONS The addition of capnography and IPI monitoring to standard monitoring reduces the risk of intraoperative hypoxemia in pediatric urologic surgery and reduces the need for aggressive ventilation through early intervention.
Gut barrier integrity prevents microbial translocation and systemic infection. Chronic alcohol disrupts this barrier, but its role in infection susceptibility among immune-compromised hosts remains unclear. We investigated how chronic alcohol promotes gut barrier dysfunction, endotoxemia, and dysbiosis, predisposing to bacterial translocation and sepsis. Twenty-four-week-old female FcγRIIb-/- and wild-type mice received oral gavage of 35% ethanol (4.2 g/kg/day) or water for 10 weeks. Gut barrier integrity was assessed by serum endotoxin, FITC-dextran permeability, ileal claudin-1, and intestinal IgG/neutrophil infiltration. Systemic inflammation was evaluated by serum TNF-α, IL-1β, and IL-6; gut microbiota by 16S rRNA sequencing. Bone marrow-derived macrophages and hepatocytes from both genotypes were stimulated with LPS or ethanol to assess inflammatory responses, mitochondrial damage, and cGAS-STING activation. Chronic alcohol induced gut barrier dysfunction in both groups, with more severe effects in FcγRIIb-/- mice, which showed marked increases in serum endotoxin and FITC-dextran permeability, reduced claudin-1, and enhanced intestinal IgG deposition with neutrophil accumulation. Serum TNF-α, IL-1β, and IL-6 were significantly elevated, reflecting a sepsis-like profile. Alcohol induced dysbiosis with an increased Firmicutes-to-Bacteroidota ratio, elevated Lachnospiraceae, and reduced Alistipes, Bacteroides, and Odoribacter. In vitro, LPS elicited stronger inflammation than ethanol in both cell types, with FcγRIIb-/- cells producing greater cytokine levels. Both stimuli caused comparable mitochondrial damage and cGAS-STING activation. Alcohol-induced gut barrier dysfunction, endotoxemia, and dysbiosis predispose to bacterial translocation and early sepsis, particularly in hosts with impaired inhibitory Fcγ receptor signaling, supporting gut barrier preservation as a strategy for preventing alcohol-associated infections and sepsis.
Alcohol is one of the most widely consumed substances worldwide. It is hypothesized that people who use alcohol have poor emotional regulation strategies, something shared by people who commit suicide. Therefore, the aim of this work is to study the mediational effect of coping strategies and distress tolerance in the relationship between excessive alcohol use and suicidal risk. A sample of 1014 participants (33.82% male, 66.17% female; M = 33.0, SD = 15.15) were assessed using a custom sociodemographic questionnaire, the Alcohol Use Disorders Identification Test (AUDIT), the Coping with Stress Questionnaire (CSQ), Distress Tolerance Stress (DTS), and Suicide Risk (RS). Two mediation models were performed in which AUDIT scores were used as the independent variable, RS score as the dependent and sex as a covariate. In the first model the mediating variable was the CSQ scores and in the second the DTS scores. The relationship was mediated positively by Negative Auto-Focused, Appraisal and Absorption, and negatively by Social Support Seeking and Tolerance. Emotional regulation is a transdiagnostic strategy that can reduce not only alcohol consumption, but also suicidal risk. Given these results, there is a pressing need to develop preventive programs centered on adaptive emotion regulation strategies. Emotional regulation plays a key role in the relationship between excessive alcohol use and suicidal risk. El alcohol es una de las sustancias más consumidas en todo el mundo. Se hipotetiza que las personas que consumen alcohol tienen pobres estrategias de regulación emocional, algo que comparten las personas que se suicidan. Por ello, el objetivo de este trabajo es estudiar el efecto mediacional de las estrategias de afrontamiento y la tolerancia a la angustia en la relación entre el consumo excesivo de alcohol y el riesgo suicida. En una muestra de 1014 participantes (33,82% hombres, 66,17% mujeres; M = 33,0, DE = 15,15) se aplicó un cuestionario sociodemográfico personalizado, el Test de Identificación de Trastornos por Consumo de Alcohol (AUDIT), el Cuestionario de Afrontamiento del Estrés (CSQ), la escala de Tolerancia al Distrés (DTS) y el de Riesgo Suicida (RS). Se realizaron dos modelos de mediación en los que se utilizaron las puntuaciones del AUDIT como variable independiente, la puntuación del RS como dependiente y el sexo como covariable. En el primer modelo la variable mediadora fueron las puntuaciones CSQ y en el segundo las puntuaciones DTS. La relación fue mediada positivamente por Autoenfoque Negativo, Valoración y Absorción, y negativamente por Búsqueda de Apoyo Social y Tolerancia. La regulación emocional es una estrategia transdiagnóstica que puede reducir no sólo el consumo de alcohol, sino también el riesgo suicida. Dados estos resultados, existe una necesidad imperiosa de desarrollar programas preventivos centrados en estrategias adaptativas de regulación emocional. La regulación emocional juega un papel clave en la relación entre el consumo excesivo de alcohol y el riesgo suicida.
PurposeTo examine the relationship between fall-related mortality, disability-adjusted life years (DALY), healthcare expenditures, and research funding and determine whether fall prevention funding is proportional to fall-related public health impact.DesignCross-sectional.SettingUnited States.SampleNot applicable.MeasuresMortality rates (2018-2022) for leading causes of death were obtained from CDC WONDER. Disability-adjusted life-year (DALY) rates (2021) were obtained from the World Health Organization. Healthcare expenditures (2016) were obtained from the Institute for Health Metrics and Evaluation. Research funding data (2018-2022) were obtained from NIH ExPORTER and linked to causes of death using MeSH term searches.AnalysisLinear regression models were used with log-transformed research funding as the dependent variable and log-transformed mortality rates, DALY rates, and healthcare expenditures as predictors.ResultsFall mortality rate was 13.1 deaths per 100 000 individuals, fall-related DALY rate was 713.2 per 100 000, and fall-related healthcare expenditures were $106.6 billion. Falls ranked 12th in mortality, 8th in DALY, and 5th in healthcare costs but 20th in research funding, receiving $489 million over 5 years. Falls received significantly less funding than expected based on mortality rates (predicted $1.95 billion), DALY rates (predicted $3.27 billion) and healthcare expenditures (predicted $5.63 billion).ConclusionAlthough falls have a significant impact on older adults' health and mortality, fall research funding is disproportionately low. To reduce mortality and mitigate rising healthcare costs associated with falls, federal investment in fall prevention research should be a higher priority.
In this study, latent profile analysis (LPA) was used to identify naturally occurring patterns or profiles of maladaptive and adaptive perfectionism, impulsivity, and disordered eating (DE) in early adolescence (111 boys, 138 girls; M age = 13.6 years). Profile membership at age 13 was used to examine disordered eating patterns assessed at ages 11 and 12, providing insights into how symptoms had developed prior to profile formation. Using LPA, we identified five profiles: (1) high functioning (2), maladaptively impulsive (3), anxious-avoidant (4), maladaptively perfectionistic, and (5) maladaptively impulsive-perfectionistic. The maladaptively perfectionistic profile showed the highest levels of dieting, preoccupation with food, and body concerns as well as perceived sociocultural pressure to be thin, followed by the maladaptively impulsive-perfectionistic profile. Analyses of earlier DE patterns indicated that the anxious-avoidant profile consistently showed the lowest BMI and highest perceived pressure to eat, both at age 13 and at earlier assessment points, suggesting possible feeding-related difficulties. The findings confirm that maladaptive and adaptive perfectionism, impulsivity, and BMI are jointly associated with the development of DE in early adolescence, demonstrating that considering these traits together yields greater explanatory value than focusing on any single factor alone. While identifying general risk factors is essential, differentiating personality-based profiles of vulnerable adolescents may be particularly valuable for targeted early prevention. This study examined how perfectionism and impulsivity are linked to disordered eating in early adolescence. We studied 249 boys and girls aged 13 to 14 and also looked at their eating patterns from ages 11 to 12. We identified naturally occurring groups of adolescents based on their levels of perfectionism, impulsivity, and disordered eating, and found five distinct profiles that differed in their eating-related attitudes and behaviors. Among the profiles found, adolescents with high perfectionism showed the strongest signs of restrictive eating, preoccupation with food, and concerns about their body. Another group had low body weight and reported feeling pressure from others to eat, suggesting feeding-related challenges. Some of these differences were already evident at ages 11–12, suggesting that these patterns were present across early adolescence. These findings highlight that young people can experience disordered eating in different ways. Recognising such patterns may help identify those at greater risk and improve early prevention and support.
In Mexico, tobacco use represents one of the leading threats to public health, being associated with thousands of preventable deaths and diseases. Social factors, such as peer pressure, play a significant role in the initiation of tobacco use among young people, who seek acceptance and identity. Although intervention studies exist, few address peer pressure comprehensively and from a theoretical framework. Therefore, a psychoeducational intervention is proposed for university students, with the aim of assessing its acceptability and feasibility, as well as exploring changes in self-esteem, emotional dependence, and social skills. Its contribution lies in providing preliminary evidence for future large-scale clinical trials. The study was designed as a prospective, single-arm pilot. Nursing students from a faculty in Veracruz will participate, with a recruitment target of 30 students aged 18 years or older. The group intervention consists of four 50-min sessions, in addition to pre- and post-test evaluations, addressing peer pressure, self-esteem, social skills, and emotional dependence. Tobacco use among young people is a multifactorial problem in which peer pressure constitutes a central factor. The proposed psychoeducational intervention seeks to strengthen resistance, promote self-esteem, enhance social skills, and address emotional dependence. Its implementation entails practical challenges, including student participation, retention, logistical organization, and resource availability. This study will allow for the evaluation of the intervention's acceptability and feasibility, generating preliminary evidence for future trials. The findings will contribute to the design of evidence-based preventive strategies relevant to the university setting and adolescent public health. UMIN000059102.
Lipid abnormalities-particularly low-density lipoprotein cholesterol (LDL-c) and lipoprotein(a) [Lp(a)]-have been implicated in aortic stenosis (AS), yet translation into clinically actionable risk assessment remains underdeveloped, especially regarding sex-specific evaluation. This study aims to quantify sex-specific associations between a comprehensive lipid profile and the risks of AS and aortic regurgitation (AR), and to identify the most informative markers and marker combinations for improved risk assessment. In 365,771 UK Biobank participants (mean age 56.1±8.07 years; 55.74% female) free of baseline cardiovascular disease. Routine lipid traits underwent hierarchical clustering and were related to incident AS and AR using sex-stratified Cox models. Discordance analyses and time-dependent concordance index were employed to compare risk assessment performance of different markers. Hierarchical clustering revealed three clusters in both sexes-an apolipoprotein B (apoB)-containing cluster and an apolipoprotein A containing cluster-while Lp(a) occupied an independent branch. During a median follow-up of 13.8 years, there were 3118 incident AS and 1239 AR cases. Total cholesterol, apoB, LDL-c, non-high-density lipoprotein cholesterol in apoB-containing cluster and Lp(a) were each independently associated with higher AS risk in both sexes (all P < 0.01), with Lp(a) conferred additional sex-specific effect (P for interaction = 0.004). Discordance analyses showed that apoB outperformed LDL-c in association with AS. Addition of Lp(a) to ApoB or LDL-c improved AS risk prediction over either marker alone-especially in men. No lipid trait was associated with AR. ApoB may substitute for LDL-c as the primary particle-burden marker, whereas Lp(a) should be incorporated as an independent sex-specific risk enhancer in AS risk assessment. These results support sex-specific, multi-biomarker assessment to optimize AS risk stratification and future preventive strategies. In 365,771 UK Biobank participants followed for a median of 13.8 years, apoB and Lp(a) improved identification of incident aortic stenosis risk compared with LDL-C alone. Incorporating Lp(a) into models with apoB or LDL-c improves AS risk discrimination, especially in men. ApoB outperforms LDL-c for AS risk assessment in both men and women.Elevated Lp(a) significantly increases AS risk, with a stronger effect in men.
Immunoglobulin replacement therapy is an essential approach for treating patients with inborn errors of immunity that impair humoral response. The main goal of immunoglobulin replacement treatment is to provide antibodies passively, preventing severe or recurrent infections, as well as medium/long-term complications. Currently, there are different administration routes: intravenous, conventional subcutaneous, and facilitated subcutaneous with recombinant hyaluronidase. Therefore, the choice of the administration route should be individualized, with the active participation of the patient and guidance from healthcare professionals regarding the advantages and limitations of each option. This guideline aims to clarify the available immunoglobulin treatment modalities, provide practical guidance for their selection, and thereby promote better treatment adherence and effectiveness, leading to improved clinical stability for patients. A terapêutica substitutiva com imunoglobulina é parte essencial do tratamento dos erros inatos da imunidade que comprometem a resposta humoral. O seu principal objetivo é fornecer anticorpos de forma passiva, prevenindo infeções graves ou recorrentes, bem como as suas complicações a médio e longo prazo. Atualmente, existem diferentes vias de administração: endovenosa, subcutânea convencional, e subcutânea facilitada com hialuronidase recombinante. A escolha da via de administração deve ser feita de forma individualizada, com participação ativa do doente e orientação pelos profissionais de saúde quanto às vantagens e limitações de cada alternativa. Este protocolo pretende esclarecer sobre as modalidades disponíveis de tratamento com imunoglobulina, propor orientações práticas para a sua escolha e, com isso, favorecer uma maior adesão e eficácia terapêutica, promovendo maior estabilidade clínica dos doentes.
Brushing with fluoride-containing toothpaste without rinsing significantly increases salivary fluoride concentration. To compare the effects of rinsing versus non-rinsing after toothbrushing with 1500 ppm fluoride (ppmF) toothpaste on salivary fluoride concentration up to 90 min and fluoride intake in 6-year-old children. A crossover clinical trial was conducted in 18 healthy 6-year-old children. Children brushed their teeth with 1500 ppmF toothpaste (0.6 g) with rinsing (WR) or without rinsing (WOR) in a three-day washout period. Unstimulated saliva was collected at baseline and at 1, 5, 15, 30, 60, and 90 min after toothbrushing. Salivary fluoride concentration was measured using an ion-specific electrode. Fluoride intake was also determined. The geometric mean salivary fluoride concentration was significantly higher in WOR than in WR over time (p = 0.023). Pairwise comparisons at specific time points showed a significant difference at 1-min post-brushing (p < 0.001). Fluoride intake was significantly greater in WOR than in WR (0.216 ± 0.046 vs. 0.176 ± 0.056 mgF; p = 0.012). Toothbrushing with 1500 ppmF toothpaste without rinsing produced higher fluoride intake and total fluoride exposure (AUC) due to a large initial peak; however, salivary fluoride concentrations were comparable between rinsing methods from 5 min onward and remained caries-preventive for up to 90 min.
Australia's healthcare system, a crucial economic pillar, faces significant workforce shortages, impacting its ability to meet increasing demand. These shortages, particularly acute for physiotherapists, are exacerbated by an aging population, rising chronic disease incidence, and the COVID-19 pandemic. The Australian Government's 2024 Skills Priority List confirms this national shortage, highlighting the urgent need for strategies to improve workforce planning, expand roles, and enhance retention. Therefore, it is vital to gain a deeper understanding of why Australian physiotherapists leave clinical practice and what would encourage them to remain. This study aimed to explore physiotherapists' perspectives on factors associated with the retention and attrition of physiotherapists in Australia and to identify potential strategies to encourage physiotherapists to stay in practice. This study used a mixed-data collection approach, qualitatively analyzing open-ended cross-sectional survey responses from Australian registered physiotherapists and 21 semi-structured interviews with physiotherapists who volunteered to provide further insights. Study analysis identified four themes: (1) Anchors of physiotherapists retention, (2) Barriers to workforce entry: Navigating identity and system constraints, 3) Drivers of physiotherapists' attrition and (4) Retention strategies: Addressing systemic constraints and individual needs to sustain clinical engagement. These themes demonstrate the complex, bidirectional relationships between factors influencing physiotherapist workforce retention, highlighting a profession sustained by purpose but challenged by systemic issues. Overall, a collegial work environment, the ability to work close to family and being embedded in the local community, and career advancement motivate physiotherapists to stay in the profession. Conversely, poor financial sustainability, limited career progression pathways, and poor workplace conditions and burnout contribute to attrition. Strategies to support retention include improved remuneration, more opportunities for career progression and a focus on preventing burnout.
Ketamine triggers cellular pyroptosis through an NOD-like receptor protein 3 (NLRP3)/caspase-1 pathway, leading to neurotoxicity and cognitive deficits. Dopamine receptor D1 (DRD1) activation, however, suppresses NLRP3 inflammasome activation, thereby curbing inflammation. We hypothesized that ketamine induces pyroptosis through the NLRP3/caspase-1 pathway, resulting in neurotoxicity and cognitive dysfunction, and that DRD1 activation could counteract these effects. To investigate the relationship between DRD1 and ketamine-induced pyroptosis and behavioral changes in mice, we conducted both in vivo and in vitro experiments. Our findings reveal that ketamine induces dose-dependent pyroptosis in HT22 cells, which is alleviated by NLRP3 and caspase-1 antagonists. Furthermore, a DRD1 agonist effectively reduces ketamine-induced pyroptosis in these cells. In vivo, DRD1 activation decreases ketamine-induced NLRP3/caspase-1-dependent neuronal pyroptosis and ameliorates cognitive impairment in mice by inhibiting NLRP3. Conversely, a DRD1 antagonist enhances NLRP3/caspase-1-mediated pyroptosis, replicating the behavioral deficits seen with ketamine exposure. Moreover, DRD1-specific knockdown in neuronal cells prevents ketamine-induced cognitive dysfunction and reduces pyroptosis. Dopamine receptor D1 activation mitigates ketamine-induced cognitive dysfunction in mice by inhibiting NLRP3/caspase-1-dependent pyroptosis. These findings offer new insights into the psychobehavioral disorders and cytotoxicity associated with ketamine.
Repression of DNA damage repair by PARP inhibitors (PARPi) has shown great efficacy in cancer treatment. However, therapy resistance remains a significant clinical challenge. Here, we demonstrate that the N6-methyladenosine (m6A) modification of long interspersed nucleotide element-1 (LINE1, or L1) facilitates DNA damage repair in cancer cells, whereas removal of L1 m6A modifications enhances the sensitivity of both BRCA-wild-type and BRCA-mutant cells to PARPi. Specifically, following olaparib treatment, METTL3 accumulates on chromatin at non-damage sites, which results in increased chromatin accessibility. Knockdown of METTL3 or removal of m6A on L1 RNAs increases H3K9me3 levels, leading to reduced chromatin accessibility. This, in turn, inhibits DNA end resection at damage sites and prevents PARP1 dissociation, ultimately impairing homologous recombination repair and enhancing tumor sensitivity to PARPi. Our findings unveil a novel regulatory mechanism of L1 m6A that governs the DNA damage repair response, providing a potential strategy of targeting METTL3 in combination with PARPi for cancer therapy.
It has been 40 years since Francis Crick [1] noted the problem molecular turnover poses for maintaining memories and offered a general solution. The solution requires that the critical molecules must be replaced without altering the overall structure of the complex. It is timely then that Todd Sacktor's group [2] has identified critical intermolecular interactions that satisfy Crick's requirement. Sacktor's early work identified the continuously active kinase, protein kinase Mzeta (PKMzeta) as a critical molecule for maintaining localized postsynaptic AMPA receptors that support long-term potentiation (LTP) and memory. More recent work revealed that PKMzeta forms heterodimers with the scaffolding protein KIBRA (KIbra BRAin) and preventing dimerization erased both LTP and memory. Even so, dimers degrade too fast to support long-lasting memories. Based on biophysical modeling, Sacktor's group with Harel Shouval reasoned that if KIBRA-PKMzeta heterodimers interact to form oligomers (such as hexamers), they can survive molecular turnover because as a dimer degrades it can be replaced by another. AlphaFold 3 predicted a site where the small molecule inhibitor, zeta-stat, would bind and disrupt oligomer formation. If so, then infusing zeta-stat into the hippocampus should erase long-term memory. This predicted outcome was observed. Thus, Crick's solution has been achieved. Oligomers formed from KIBRA-PKMzeta dimers allow degraded individual molecules to be replaced one at a time while maintaining their overall structure. This permits a continuous presence of PKMzeta where it interacts with AMPA receptors (through GluA2 subunits) and other molecules to ensure long-term memories endure.
ObjectiveThis systematic review summarizes factors associated with immunological non-response (INR) among people with HIV on antiretroviral therapy (ART) in Southeast Asia.MethodsWe conducted a systematic search of PubMed, ScienceDirect, DOAJ, and Lens.org for studies published between 2010 and 2025. Observational studies examining immunological outcomes following ART initiation and related factors were included. Study quality was assessed using the Newcastle-Ottawa Scale, and results were synthesized using a harvest plot.ResultTen eligible studies were included in the synthesis, comprising a total of 6,988 participants with substantial heterogeneity observed across studies. Factors associated with INR included age, sex, baseline CD4 cell count, HIV RNA levels, and co-infections. Among these factors, baseline CD4 cell count at the initiation of ART emerged as the most consistently associated determinant; lower baseline CD4 levels were linked to a higher risk of INR even with virological suppression.ConclusionThis review highlights baseline immunological status at ART initiation as a key predictor of immunological non-response in Southeast Asia. These findings underscore the critical importance of early HIV diagnosis and timely initiation of ART to prevent advanced immune damage and optimize immunological recovery.
Childhood trauma exerts lasting negative effects on mental health, with hard-of-hearing adolescents particularly vulnerable compared to their hearing peers. Yet we still know little about the relationship between childhood trauma, non-suicidal self-injury (NSSI) and depressive symptoms in this population, especially at symptoms level. In this study, a total of 2,008 Chinese students (hearing = 1,386; hard-of-hearing = 622) completed self-report questionnaires assessing childhood trauma, depressive symptoms and NSSI. Mediation analysis tested the indirect effect of depressive symptoms. Network analysis identified central and bridge symptoms, and directed acyclic graphs (DAGs) were used to explore potential directional pathways between symptoms. Depressive symptoms mediated the trauma-NSSI association, with a stronger effect among hard-of-hearing adolescents; For hearing adolescents, emotional abuse- and neglect-related items were central symptoms in trauma-depressive-NSSI network, whereas only an emotional neglect-related item was central for hard-of-hearing adolescents; DAGs further supported a pathway from trauma to depression to NSSI, pinpointing key symptoms driving this progression. Overall, this study underscores that trauma-depression-NSSI pathways vary across population at both construct and symptom levels, highlighting the importance of early identification and interventions targeting depressive symptoms to help prevent and relieve NSSI risk in trauma-exposed adolescents.
Although many studies have examined temperature-related non-accidental mortality, the impact of heat waves on the mortality burden of chronic kidney disease (CKD) remains poorly understood. This study aimed to assess the CKD mortality burden associated with heat waves in China under global warming. Mortality data on CKD from 2,790 counties/districts in China from 2004 to 2022 were collected from the Chinese Center for Disease Control and Prevention; meteorological data for the same period were obtained from the fifth-generation European Reanalysis Land dataset. A time-stratified case-crossover design combined with a distributed lag nonlinear model was used to examine the association between heat waves and CKD mortality. Future CKD mortality burdens attributable to heat waves under climate change and future population scenarios were projected. In total, 236,260 CKD deaths were included in this study. Compared to that during non-heat wave days, CKD mortality increased by 3.48% (95% confidence interval [ CI]: 1.67% to 5.33%) during heat waves, and the mortality risk escalated by 2.48% (95% confidence interval [ CI]: 0.12% to 4.91%) for each 1 °C increment during heat wave days. Stratified analyses revealed that CKD mortality risks were greater for women (Excess Risk [ER] = 5.52%, 95% CI: 2.71% to 8.40%), individuals aged 65 years and older (ER = 4.60%, 95% CI: 2.30% to 6.96%), and people in mesic/cold regions (ER = 6.20%, 95% CI: 1.13% to 11.53%). The projections showed that the attributable fraction(AF) of CKD mortality due to heat waves would rise from 0.64% (95% CI: 0.52% to 0.78%) in the 2020s to 2.44% (95% CI: 1.97% to 2.95%) in the 2090s under the SSP5-8.5 scenario, with the highest burden in southeastern China, including Hainan (3.31%, 95% CI: 1.66% to 5.02%), Yunnan (3.05%, 95% CI: 1.46% to 4.75%), and Guangdong Province (2.84%, 95% CI: 1.24% to 4.41%). This nationwide study demonstrated that exposure to heat waves significantly increased the mortality risk of CKD, and that women, older individuals, and people in mesic/cold regions are more susceptible to heat waves. Global warming will significantly increase the future CKD mortality burden attributed to heat waves, particularly in southeastern China. Our findings emphasize the need to address CKD in the context of ongoing climate change.
Rock outcrops are geological formations that harbor a highly specialized biota adapted to harsh environmental conditions that differ from their surrounding landscapes. They are globally distributed, especially in old, highly weathered landscapes, and can function as habitat islands containing high levels of endemism and distinct evolutionary lineages. Despite their ecoevolutionary importance, rock outcrops remain largely overlooked in global conservation policy, ecosystem typologies, and biodiversity monitoring frameworks. Extractive activities directly remove the geological substrate that underpins these habitats, and climate change intensifies drought, heatwaves, and hydrological instability. Rising global demand for energy-transition metals required for decarbonization is expected to further accelerate these pressures, particularly in biodiverse regions of the Global South where governance is weaker. Given that rock outcrop ecosystems are ecologically and evolutionarily significant, we devised a policy-relevant conservation roadmap structured around prevention, mitigation, restoration, and governance issues. Priority actions include recognizing rock outcrops as unique ecosystems in global classifications and ecosystem typologies, integrating them into biodiversity monitoring frameworks, and improving the identification of key biodiversity areas and the International Union for Conservation of Nature (IUCN) Red List of Ecosystems assessments. We call for stronger environmental impact assessments, cumulative-impact evaluations for mining and quarrying projects, and the designation of mining and quarrying exclusion sites of high irreplaceability. Coordinated international policy, improved ecological data, and meaningful engagement with local and Indigenous communities are essential to safeguard these ancient ecosystems before further, irreversible losses occur. Advertencia de los científicos sobre la destrucción global de los ecosistemas de afloramientos rocosos Resumen Los afloramientos rocosos son formaciones geológicas que albergan una biota altamente especializada, adaptada a condiciones ambientales adversas que difieren de los paisajes circundantes. Se distribuyen por todo el mundo, especialmente en paisajes antiguos y muy erosionados, y pueden actuar como islas de hábitat con altos niveles de endemismo y linajes evolutivos distintivos. A pesar de su importancia ecoevolutiva, los afloramientos rocosos siguen siendo en gran medida ignorados en las políticas de conservación mundiales, las tipologías de ecosistemas y los marcos de seguimiento de la biodiversidad. Las actividades extractivas eliminan directamente el sustrato geológico que sustenta estos hábitats, y el cambio climático intensifica la sequía, las olas de calor y la inestabilidad hidrológica. Se prevé que el aumento de la demanda mundial de metales para la transición energética, necesarios para la descarbonización, acelere aún más estas presiones, especialmente en las regiones con gran biodiversidad del Sur Global, donde la gobernanza es más débil. Los ecosistemas de afloramientos rocosos revisten gran importancia desde el punto de vista ecológico y evolutivo. Por ello, hemos elaborado un protocolo para la conservación, relevante desde el punto de vista normativo, estructurada en torno a cuestiones de prevención, mitigación, restauración y gobernanza. Entre las medidas prioritarias se incluyen el reconocimiento de los afloramientos rocosos como ecosistemas únicos en las clasificaciones y tipologías de ecosistemas a nivel mundial, su integración en los marcos de seguimiento de la biodiversidad, y la mejora de la identificación de las áreas clave para la biodiversidad y de las evaluaciones de la Lista Roja de Ecosistemas de la Unión Internacional para la Conservación de la Naturaleza (UICN). Pedimos evaluaciones de impacto ambiental más rigurosas, evaluaciones del impacto acumulativo de los proyectos de minería y explotación de canteras, y la designación de zonas de exclusión para la minería y la explotación de canteras que sean irremplazables. Una política internacional coordinada, la mejora de los datos ecológicos y una participación significativa de las comunidades locales e indígenas son esenciales para salvaguardar estos ecosistemas ancestrales antes de que se produzcan más pérdidas irreversibles.