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To examine how integrated nursing curricula protect vulnerable knowledge domains once those domains are distributed across a program and to propose a conceptual framework for understanding and responding to this challenge. Integrated curriculum design is widely valued in nursing education for its capacity to reduce fragmentation and support learning across complex practice contexts. However, integration alone does not protect essential knowledge domains from dilution, containment, or invisibility over time. Discussion paper. The paper undertakes a critical analysis of curriculum scholarship relevant to integrated nursing education, vulnerable knowledge domains and whole-of-program coherence. It develops a conceptual argument supported by an illustrative example from a recently redeveloped undergraduate nursing program. The paper introduces epistemic erosion as a concept for understanding the gradual weakening of knowledge domains whose visibility, developmental progression, assessability and stewardship are not explicitly protected within integrated curricula. It argues that domains such as mental health, cultural safety, trauma-informed care, disability, health promotion and end-of-life care may be especially vulnerable when responsibility for their ongoing integrity becomes diffuse or when formal inclusion creates a false sense of security. In response, the paper proposes structural safeguarding as a curriculum design principle and curriculum stewardship as the ongoing work required to sustain such protection beyond initial design and accreditation. Integrated nursing curricula require not only thoughtful design, but durable forms of stewardship and governance capable of resisting epistemic erosion over time.

Exposure to high altitude induces hypobaric hypoxia and consequent ventilatory and metabolic adaptations, including increased anaerobic glycolysis and lactate production. Acetazolamide, a carbonic anhydrase inhibitor widely used for altitude sickness prophylaxis, enhances ventilatory drive through renal bicarbonate excretion and mild metabolic acidosis. We aimed to evaluate its effects on blood lactate accumulation and on complementary ventilatory and oxygenation parameters during progressive high-altitude ascent. We performed a randomized, placebo-controlled pilot field trial during the Everest Base Camp trek in the Nepal Himalaya. Twelve healthy adults were randomized 1:1 to acetazolamide 250mg once daily or placebo. Physiological variables were recorded at rest at four specific altitudes: 2550m, 3853m, 4325m, and 5160m. The main outcome was blood lactate concentration; the secondary outcomes were peripheral oxygen saturation (SpO2), partial pressure of carbon dioxide (pCO2), partial pressure of oxygen (pO2), and heart rate. Between-group comparisons were done using the bootstrap resampling method and an exploratory linear mixed model. Lactate concentrations increased with altitude in both groups but remained consistently lower in the acetazolamide group, with a mean between-group difference of -0.75mmol/L (95% CI -1.03 to -0.50). Participants receiving acetazolamide also demonstrated lower pCO₂ (-0.27 kPa, 95% CI -0.52 to -0.02) and directionally higher SpO₂ (+1.6%, 95% CI -0.10 to 3.15). Altitude was the dominant determinant of physiological changes across all parameters. In this pilot study, acetazolamide was correlated with reduced lactate accumulation, decreased pCO2, and increased oxygenation during high-altitude ascent. These results are consistent with increased ventilatory compensation and reduced reliance on anaerobic metabolism. They suggest that larger and adequately powered studies should be conducted.

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.

Visceral leishmaniasis (VL) is a neglected tropical disease caused by kinetoplastid parasites. If left untreated, VL has a case fatality >90%, making treatment essential for patient survival. Existing therapies have several limitations that impact treatment outcomes, including toxicity, requirement for parenteral administration, long treatment duration, and development of parasite resistance, driving the need for newer therapies. This Phase 1 first-time-in-human study evaluated the tolerability, safety, and pharmacokinetics (PK) of GSK3494245, a novel highly selective Leishmania kinetoplastid proteasome inhibitor. This was a randomized, double-blind, placebo-controlled, single ascending dose study evaluating the oral administration of GSK3494245 in healthy participants aged 18 to ≤55 years (NCT04504435). The study was conducted at a single center in the United Kingdom between October 2020 and January 2024. GSK3494245 had an acceptable safety profile following administration of single doses of up to 240 mg in healthy male participants. All adverse events (AEs) were considered resolved or recovered, with most AEs being of mild or moderate severity. One serious AE of mild tachycardia was reported. The increase in exposure was slightly more than dose-proportional and approximately proportional under fasted and fed conditions, respectively. The median time to reach the maximum plasma concentration (Cmax) ranged from 0.50 to 1.79 hours, and the geometric mean of the elimination half-life ranged from 1.04 to 2.27 hours. Two participants met the Cmax stopping criterion. GSK3494245 showed an acceptable safety profile over the dose range studied. However, based on its observed PK profile, GSK3494245 is unlikely to achieve the effective dose while ensuring safe exposure within the once- or twice-daily monotherapy target product profile recommended by the Drugs for Neglected Diseases initiative. NCT Number (www.clinicaltrials.gov): NCT04504435 EudraCT, CTIS: 2019-004492-39.

Mitochondria divide and fuse, and the balance between these processes maintains mitochondrial morphology and function. Although the core fusion and division machinery is well established, how cells sense mitochondrial morphology and actively adjust it remains unclear. In this Opinion article, we propose a new conceptual framework, termed 'Mitochondrial Safeguard (MitoSafe)', in which cells monitor mitochondrial size and rebalance division and fusion through four branches: activation of fusion or inhibition of division in small mitochondria and activation of division or inhibition of fusion in enlarged mitochondria. Recent findings show that fusion is suppressed once mitochondria exceed a healthy size threshold. Dysregulation of this branch of MitoSafe, involving Parkin, PINK1, SLC25A3, SOD1, and cytochrome-c oxidase, causes mitochondrial enlargement, mitochondrial DNA release, and stimulator of interferon genes (STING)-mediated inflammation.

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 and Clinical Significance: Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant disorder caused by pathogenic variants in the SERPINA1 gene, resulting in reduced circulating alpha-1 antitrypsin (AAT) or production of dysfunctional protein. AAT is the principal inhibitor of neutrophil elastase, and its deficiency leads to unchecked proteolytic activity, progressive destruction of lung parenchyma, and increased susceptibility to infections. Severe deficiency, particularly in individuals homozygous for the Z allele (PI*ZZ), predisposes to early-onset panacinar emphysema, chronic airflow obstruction, and liver disease. Despite its clinical relevance, AATD remains markedly underdiagnosed and is frequently misclassified as smoking-related chronic obstructive pulmonary disease (COPD), delaying access to disease-modifying therapy, genetic counselling, and preventive strategies. Early recognition is therefore essential to improve outcomes. Case Presentation: We report the case of a 68-year-old ex-smoker with a long-standing diagnosis of "COPD" who presented with acute-on-chronic type 2 respiratory failure and community-acquired pneumonia. Spirometry revealed severe airflow obstruction, and high-resolution computed tomography demonstrated extensive basilar panlobular emphysema, raising suspicion for AATD. Serum AAT concentration was critically low at 26.8 mg·dL-1, and isoelectric focusing confirmed a PI*ZZ phenotype. Next-generation sequencing identified homozygosity for the SERPINA1 c.1096G>A (Z) variant, with no additional pathogenic alleles. Cascade family screening revealed multiple heterozygous PI*MZ relatives. Before augmentation therapy could be initiated, the patient developed severe Legionella pneumophila pneumonia with secondary bacterial superinfection, progressing to refractory septic shock and death. Conclusions: This case illustrates how AATD can masquerade as smoking-related COPD for years, leading to missed opportunities for timely intervention. It underscores the importance of testing all adults with COPD or refractory asthma at least once, regardless of age or smoking history. Early diagnosis enables initiation of augmentation therapy, targeted vaccination, lifestyle modification, and genetic counselling, ultimately improving prognosis and reducing preventable morbidity and mortality.

Background/Objectives: 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: 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.

Alcohol use disorders are a group of behavioural, cognitive, and physical symptoms caused by repeated alcohol use. The impacts of alcohol consumption are particularly concerning in developing countries, where the burden of sickness and social repercussions linked to alcohol use are significantly greater than the global average. Alcohol consumption can affect the outcome of the disease and worsen its course through a number of mechanisms. Clinically, early intervention via creative screening, brief intervention, and referral strategies can successfully manage the hazardous drinking of diabetes mellitus in primary care settings. In Ethiopia, no research has been conducted on the prevalence of alcohol consumption among diabetes mellitus or the factors that are linked to alcohol consumption. To assess the prevalence and associated factors of alcohol consumption among diabetes mellitus patients who had follow up at selected Hospitals in the East Gojam Zone, Amhara Region, Northwest Ethiopia, in 2022. An institution-based cross-sectional study design was conducted at hospitals located in the East Gojam Zone. A total of 616 participants were selected via a systematic random sampling technique and interviewed via a structured questionnaire. The first participant was selected via the lottery method for each hospital, and other participants were selected every other interval. Alcohol consumption was assessed via the alcohol use disorder identification test (AUDIT). The data were coded and entered into Epi data version 4.4.2.1 and exported to SPSS version 25 for analysis. To indicate the strength of the association, odds ratios and 95% confidence intervals were used. A total of 616 participants were interviewed, for a response rate of 96.86. Once medication was started, 228 (37%) of the study participants consumed alcohol. Male sex (AOR&#x2009;=&#x2009;3.26, 95% CI: 2.07-5.13), living in rural areas (AOR&#x2009;=&#x2009;3.84, 95% CI: 1.85-8.00), poor social support (AOR&#x2009;=&#x2009;1.76, 95% CI: 1.02-3.08) and moderate stress (AOR&#x2009;=&#x2009;3.57, 95% CI: 1.12-11.31) were found to be significantly associated with alcohol consumption (p&#x2009;<&#x2009;0.05). The prevalence of alcohol consumption among diabetes mellitus was high in this study area. Being male, living in rural areas, having poor social support and having moderate stress were found to be significantly associated with alcohol consumption (p&#x2009;<&#x2009;0.05).

During night shifts, surgeons experience prolonged periods without sleep, which might impact their laparoscopic performance. Therefore, this study aimed to elucidate the effects of sleep deprivation on tissue handling and motion parameters during laparoscopic surgery. A total of 55 medical students and 20 surgeons participated in this single-center, prospective, randomized crossover trial. All students underwent standardized laparoscopic training until they reached proficiency. Afterward, all participants performed three different laparoscopic tasks twice, once sleep-deprived in the middle of the night and once well rested. Endpoints were tissue handling, defined by force exertion, instrument motion, task time, and error rate. Sleep-deprived students and surgeons demonstrated a significantly lower mean force exertion but only in one task, respectively. Sleep-deprived students showed a significant slower speed of the non-dominant hand in all tasks. Surgeons were significantly slower with their dominant hand in all tasks and produced a significant shorter path length and smaller motion volume. In two of the tasks, the task completion time of sleep-deprived surgeons was significantly higher compared to the control. There was no difference regarding the occurrence of errors in both cohorts. In subgroup analysis comparing tired vs. less tired participants, both very tired students and surgeons showed a tendency, in part significant, toward higher force exertion. Prolonged periods of sleep deprivation appear to have an overall effect on laparoscopic skills regarding instrument motion. There is also an alteration of tissue-handling skills in terms of force exertion among very tired students and surgeons.

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.

Oncogenic viruses cause high-risk cancers in humans and are responsible for nearly 20% of all cancer cases worldwide. Currently, very limited data exist in the realm of wastewater-based viral epidemiology (WBE) for cancer-causing viruses, with existing studies using targeted approaches (i.e., PCR-based approaches) that lack genomic resolution. In this study, we used a hybrid-capture approach to detect, filter, and sequence all known oncogenic virus signals from wastewater samples collected over 3 years (May 2022-May 2025) in 16 Texas cities, covering nearly 25% of the state's population. Once sequenced, we used custom computational tools designed for wastewater metagenomics to assign reads into their respective virus of origin, estimate viral abundances over time, and measure genomic read coverage. Our data indicate that we successfully detected oncogenic viruses, including six known oncogenic viruses, and three suspected oncogenic viruses, across all sampling locations within Texas. We observed a gradual increase in the viral abundance of oncogenic viruses over 3 years, with distinct peaks and dips over the summer and winter months. The prevalence of high-risk viruses such as human papillomavirus (HPV) and Epstein-Barr virus (EBV) rose, with sharp increases in viral abundance observed post-2024. We also obtained nearly 100% genome coverage with viral reads captured using this hybrid-capture technique for nearly all oncogenic viruses, with resolution down to the species and type taxonomic levels in some cases, such as that of HPV. Our study showcases the utility of hybrid-capture techniques to detect and track multiple oncogenic viruses simultaneously.IMPORTANCECancer-causing viruses are of major clinical significance, responsible for nearly 20% of all recorded cancer incidences in humans worldwide. There is a need for improved detection, tracking, and control of oncogenic viruses across the globe. To our knowledge, this work is the first comprehensive WBE approach used to detect all known oncogenic viruses concurrently, demonstrating the feasibility of monitoring the presence and levels of cancer-causing viruses and enabling the possibility of public health interventions in the future. Using this method, we obtain broad genomic coverage at strong depth and specificity, coupled with consistent real-time tracking dynamics of multiple oncogenic viruses. Furthermore, we showcase the ability to identify genomic regions on viral reference genomes from which sequenced reads originate. This information can be an invaluable tool toward understanding the viral prevalence dynamics in general populations, their relationship to cancer incidences in humans, and their mechanisms of viral evolution, including mutations.

Given the increasing challenge of multidrug-resistant infections, there is a significant push to explore alternative treatments beyond conventional antibiotics. Historically, heavy metals have served as antimicrobial agents, and the current review focuses on elucidating their mechanisms of action and effectiveness against multidrug-resistant pathogens. Among these, gallium has emerged as a particularly promising antimicrobial agent with the potential to address the growing threat of antibiotic resistance. Using a "Trojan horse" strategy, gallium leverages its chemical similarity to iron to deceive pathogens. Because their ionic properties are nearly identical, pathogens readily import gallium through their native iron uptake systems. Once inside, the gallium is unable to perform iron's necessary functions and instead acts as a poison, disrupting the microbe's metabolism and ultimately causing its death. However, the question remains whether pathogens might adapt genetically, potentially leading to more harmful strains resistant to gallium's effects. Given the significant threat posed by multidrug-resistant pathogens, such as Escherichia coli, Staphylococcus aureus, and Candida tropicalis, this review explores new approaches to combating antimicrobial resistance. This hybrid review uses experimental evolution to identify the adaptive mechanisms that allow bacteria and Candida to overcome gallium's therapeutic "Trojan horse" effect. Studying gallium resistance is important for medical applications, as it provides critical insights into combating drug-resistant pathogens.

This case study illustrates the vulnerability of individuals with intellectual developmental disorders and autism spectrum disorders to crisis situations and severe, life-threatening complications that can arise from the loss of primary caregivers and changes in their environment. With time and a tightly knit network of dedicated caregivers and a multidisciplinary professional team, the patient was accompanied through the serious illness, successfully treated, and ultimately discharged to a new home in order to participate in life once again. Die vorliegende Fallstudie illustriert die Vulnerabilit&#xe4;t von Personen mit St&#xf6;rungen der Intelligenzentwicklung und Autismus-Spektrum-St&#xf6;rungen f&#xfc;r krisenhafte Zust&#xe4;nde und schwerwiegende vital bedrohlichen Komplikationen, die durch den Ausfall prim&#xe4;rer Bezugspersonen und Umgebungsver&#xe4;nderungen ausgel&#xf6;st werden k&#xf6;nnen. Mit viel Zeit und einem engmaschigen Netzwerk aus engagierten Bezugspersonen und einem multidisziplin&#xe4;rem Fachteam konnte der Patient durch die schwere Erkrankung begleitet, erfolgreich behandelt und schlie&#xdf;lich in ein neues Zuhause entlassen werden, um wieder am Leben teilzuhaben.

The pathogenesis of IgA nephropathy is mediated by B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Telitacicept is a fusion protein that targets and neutralizes both BAFF and APRIL and, as such, might be effective in IgA nephropathy. We now report a prespecified interim analysis of a phase 3, multicenter, double-blind, randomized, placebo-controlled trial, which enrolled adults with biopsy-proven IgA nephropathy and persistent proteinuria (protein level, &#x2265;1.0 g per day), despite appropriate supportive care. Patients were randomly assigned in a 1:1 ratio to receive subcutaneous once-weekly telitacicept (240 mg) or matching placebo. The primary end point was the geometric mean ratio of the 24-hour urinary protein-to-creatinine ratio at 39 weeks relative to baseline. Safety was also evaluated. A total of 318 patients were assigned to receive telitacicept or placebo (159 in each group). At week 39, the percentage change in the 24-hour urinary protein-to-creatinine ratio was -58.9% with telitacicept and -8.8% with placebo, which corresponded to a relative difference (based on the ratio of geometric mean reductions between the two groups) of -55.0% (95% confidence interval [CI], -61.3 to -47.6; P<0.001) in favor of active medication. The percentage change in the estimated glomerular filtration rate relative to baseline was -1.0% (95% CI, -3.2 to 1.2) with telitacicept and -7.7% (95% CI, -9.9 to -5.4) with placebo. Adverse events were more common with telitacicept than with placebo (in 89.3% vs. 78.6% of patients), although serious adverse events were less common (in 2.5% vs. 8.2%). No unexpected safety findings were reported with telitacicept. In patients with IgA nephropathy at high risk for progression, 39 weeks of treatment with telitacicept led to a greater reduction in the 24-hour urinary protein-to-creatinine ratio than placebo. (Funded by RemeGen; TELIGAN ClinicalTrials.gov number, NCT05799287.).

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.