To describe the safety profile of once-weekly insulin icodec (icodec), focusing on aspects beyond hypoglycemia, in a pooled population from the ONWARDS phase 3a trials. ONWARDS 1-6 investigated the efficacy and safety of icodec versus once-daily basal insulin comparators in insulin-naive and insulin-experienced adults with type 2 diabetes (T2D), and insulin-experienced adults with type 1 diabetes (T1D). Adverse event (AE) data from all trial periods were pooled. Hypersensitivity, injection-site reactions, and medication errors, as well as microvascular and macrovascular (including time to first major adverse cardiovascular event [MACE]) complications, were among the safety areas evaluated. Total treatment exposure was 2118.70 and 2127.76 patient-years of exposure (PYE) in the icodec (n=2170) and comparator groups (n=2170), respectively. Adjusted rates (events/100 PYE) were similar for icodec and comparators for all AEs (248.49 vs 242.53), serious AEs (14.51 vs 14.03), and severe AEs (7.92 vs 7.50), respectively. Adjusted rates of hypersensitivity were 5.88 and 6.74 events/100 PYE in the icodec and comparator groups, respectively. Most injection-site reactions were mild; adjusted rates: 5.86 and 3.66 events/100 PYE, respectively. Medication error rates were 2.47 and 2.53 events/100 PYE, respectively. Time to first MACE was similar between groups (hazard ratio [95% confidence interval (CI)]: 0.93 [0.56-1.56]). Adjusted rates for other AEs were broadly similar between groups. Based on a detailed evaluation of safety focus areas across the ONWARDS 1-6 trials, the safety profile of once-weekly icodec was generally similar to that of once-daily basal insulin comparators in individuals with T2D or T1D.
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.
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.
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.
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)].
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.
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 .
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.
Background/Objectives: Endoscopic retrograde cholangiopancreatography (ERCP) in patients with surgically altered anatomy (SAA) presents significant technical challenges due to altered bowel reconstructions. Endoscopic peroral cholangioscopy (POC) offers a less invasive alternative to percutaneous or transmural techniques, but robust evidence validating its performance in SAA is lacking. This systematic review and meta-analysis (SRMA) aims to evaluate the feasibility and safety of endoscopic POC as a primary strategy in SAA. Methods: A systematic search was performed on PubMed and Embase up to December 2025 for studies reporting cholangioscopic outcomes in SAA patients utilizing an endoscopic approach. The primary outcome was the cholangioscopic access rate (AR). Secondary outcomes included endoscopic success rate (SR), technical SR, and adverse events. Pooled rates were calculated using Generalized Linear Mixed Models (GLMM). Results: Eight studies comprising 469 patients were included. The pooled endoscopic SR was 86.7% (95% CI, 74.4-93.6%) but showed high heterogeneity (I2 = 79.9%), largely driven by the variation in anatomical reconstructions. Subgroup analysis revealed higher endoscopic SR in short-limb anatomies (86.5%) compared to long-limb configurations (76.2%). Conversely, once biliary cannulation was achieved, the procedure was highly reliable: the pooled cholangioscopic AR was 95.9% (95% CI, 78.7-99.3%), with no significant difference across anatomical subgroups. The pooled adverse event rate was 3.1% (95% CI, 1.3-6.8%), predominantly characterized by mild complications. Conclusions: Endoscopic POC is a feasible and safe technique for managing biliary disease in SAA. The procedure's overall success appears to be strictly dependent on the ability to navigate the altered anatomy (endoscopic phase), whereas the cholangioscopic phase itself proves highly effective and reproducible once biliary access is secured.
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 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: 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.
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.
Adult attention-deficit/hyperactivity disorder (ADHD) is likely underdiagnosed and is under-treated. Adults with ADHD are at increased risk of experiencing significant impairments in their interpersonal relationships, economic opportunities, and safety. Primary care clinicians can efficiently screen for ADHD in adults and may utilize validated instruments to aid in making the diagnosis. Primary care clinicians should also feel empowered to treat ADHD once diagnosed. Long-acting stimulants are first-line. Monitoring for side effects of medications is important as adverse effects are more common among adults and can lead to cessation of treatment.
ObjectivesTo examine whether the Social Vulnerability Index (SVI) moderated changes in physical function during supervised and unsupervised phases of an exercise intervention in older adults with HIV.MethodsThis exploratory analysis used data from the High Intensity Exercise Study to Attenuate Limitations and Train Habits in Older Adults with HIV. Participants completed 16 weeks of supervised high- or moderate-intensity exercise, followed by 12 weeks of unsupervised support (personalized coaching or educational text messages). Linear mixed-effects models assessed SVI moderation effects on 400-meter walk time (400-MWT) and Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF).ResultsAmong 117 participants, SVI did not moderate 400-MWT in either phase or PROMIS-PF during supervised exercise; however, higher SVI was associated with declines in self-reported physical function during the unsupervised phase (P = .03), robust to adjustment and sensitivity analyses.ConclusionsFindings suggest supervised exercise benefits participants across vulnerability levels, but sustained support may be needed to prevent disparities.Parent Trial InformationThe High-Intensity Exercise Study to Attenuate Limitations and Train Habits in Older Adults with HIV trial, ClinicalTrials.gov: NCT04550676. How Social and Economic Challenges Shape Exercise ResultsWe studied whether living in a more socially and economically disadvantaged community affected how older adults with HIV responded to an exercise program. Participants took part in 16 weeks of supervised exercise, followed by 12 weeks where they exercised on their own with either coaching support or educational text messages. We looked at two outcomes: how fast participants could walk 400 meters and how they rated their own physical function. Community disadvantage did not affect improvements in walking speed during either phase of the program. It also did not affect self-reported physical function while exercise was supervised.However, once the supervised program ended, people living in more disadvantaged communities were more likely to report declines in their physical function.These findings suggest that supervised exercise programs benefit older adults with HIV regardless of where they live, but ongoing support may be especially important for those facing greater social and economic challenges.
This article reviews the evolving landscape and high prevalence of hyperaldosteronism and hypercortisolism, two previously under-recognized disorders for which cardiologists should have a high index of suspicion when managing patients with resistant hypertension. Resistant hypertension is estimated to occur in approximately 10-20% of people with hypertension, or 10 million people in the United States, and is associated with substantially increased cardiovascular morbidity and mortality. Hyperaldosteronism, previously considered a rare disease, has been shown to be a relatively common cause of hypertension and is a multisystem disease associated with a significantly higher risk of multiple comorbid conditions, including resistant hypertension. Likewise, endogenous hypercortisolism, once considered a rare disease, is now known to have a higher prevalence than previously estimated and is associated with a wide spectrum of clinical and biochemical presentations, including resistant hypertension, that result from prolonged exposure to excess cortisol activity. However, despite the prevalence and negative clinical consequences of hyperaldosteronism and hypercortisolism, screening rates remain low. Cardiologists are well positioned to provide timely screening for both hyperaldosteronism and hypercortisolism. To optimize clinical outcomes, patients with these endocrine causes of resistant hypertension require aldosterone-directed and/or cortisol-directed therapy in addition to therapy for hypertension.
Dietary transition is reshaping cropland demand and intensifying the challenge of matching food demand with land supply in rapidly urbanizing regions. This study examines how different dietary structure scenarios generate differentiated cropland demand, how these demands match with land supply under alternative development pathways, and how the land system responds when diet-driven demand is incorporated into land-use simulation. Using Jiangsu Province, China, as a case study, we developed a coupled diet-land simulation framework. On the demand side, five dietary structure scenarios-current, balanced, U.S., Japanese, and Greek-were constructed based on seven food categories, and their cropland demand in 2035 and 2050 was estimated using the cropland footprint approach and LSTM forecasting. On the supply side, the GeoSOS-FLUS model was used to simulate future land-use patterns under four development scenarios: natural development, cultivated land protection, ecological protection, and economic development. The cropland demand associated with each dietary scenario was then introduced into the land-use simulation process as an external demand constraint to identify land-system feedbacks and scenario differences. The results show that cropland demand differs markedly across dietary scenarios, forming a clear gradient from moderate-demand to high-demand diets. These differences are driven primarily by changes in the composition of key food categories, especially grains, livestock and poultry meat, plant oils, and fruits, rather than by proportional increases across all foods. In terms of supply-demand matching, the cultivated land protection scenario provides the strongest support for high-demand diets, whereas the natural development, ecological protection, and economic development scenarios are more compatible with moderate-demand dietary pathways. Once diet-driven demand is incorporated into land-use simulation, the land system shows clear sensitivity and strong scenario dependence. High-demand dietary scenarios intensify cropland compensation pressure and trigger structural reallocation among cultivated land and flexible land types. Under natural development, the response is mainly reflected in cropland expansion and grassland compression; under cultivated land protection and ecological protection, it is expressed more through substitutions among grassland, water bodies, and unused land; under economic development, the most prominent feedback is the competitive reallocation among cultivated land, construction land, and water bodies, with high dietary demand even constraining construction land expansion. Overall, the robustness of cropland supply-demand matching depends not only on the scale of dietary demand but also on how different dietary pathways interact with development-oriented land-use structures.
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.
This study evaluated the neuroprotective effects of pomegranate peel polyphenols (PPEP) and their nanoparticles in a rodent model of DOX-induced neurotoxicity. Polysorbate 80- coated PPEP poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP) were synthesized by the double emulsification solvent evaporation technique. Successful encapsulation of PPEP was confirmed by Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), and Differential Scanning Calorimetry (DSC) analyses. Neurotoxicity was induced in male Wistar rats by administering DOX (2.5 mg/kg bw) once every five days i.p. Treatment with PPEP and its nanoparticles (10 mg/kg bw equivalent polyphenols p.o) was performed for 60 days. At the end of the treatment, the Morris water maze test was performed to assess cognitive function, and rat brains were removed for further histopathological, biochemical, and molecular analyses. To understand the pathophysiology of DOX-induced neurodegeneration, oxidative stress, inflammatory, and apoptosis markers were assessed by ELISA and Western blotting. Treatment with an encapsulated pomegranate peel polyphenolic extract reduced oxidative stress as evidenced by increased catalase and superoxide dismutase levels and decreased malondialdehyde levels. Mechanistically, it alleviated inflammation by downregulating the expression of pro-inflammatory markers NF-kB (p65) and TNF-α; restored acetylcholine levels, and reduced apoptosis markers (caspase 3 and cytochrome c). Furthermore, histopathological findings supported the attenuation of DOX-induced pathologies in the hippocampus and cortex regions of the brain. Enhanced bioavailability and efficacy of polyphenols were observed for the encapsulated extract. Our results demonstrate the neuroprotective potential of free and encapsulated PPEP in DOX-induced neurotoxicity and highlight the effective valorization of pomegranate peel waste for health applications.