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While numerous studies have investigated demand management policies as a means of mitigating the impacts of climate change and population growth, little attention has been given to the interaction of spatial population patterns and water institutions that affect water shortages. In this article, we develop a methodology to evaluate how population location under alternative water institutions and climate scenarios impacts water demands, shortages, and derived economic values. We apply this methodology to the South Platte River Basin (SPRB) in Northeastern Colorado under three scenarios with ∼1,800 simulations. Results suggest that while water rights institutions have a negligible impact on total volumetric shortages relative to climate change, they have substantial distributional and economic implications. Results also suggest that continuous population growth in upstream cities yields the lowest water shortages if per capita use decreases with urbanization. However, if we assume that per capita demands do not decrease with population density, an equal distribution of population to upstream and downstream regions yields the lowest water shortage and highest economic value. These findings indicate the need that planning efforts must account for return flows and development patterns throughout a watershed in order to reduce water shortages and promote economic prosperity. Key Points: Water institutions have little effect on basin‐wide water shortages, but clearly determine who experiences shortagesThe location and density of population have significant effects on water shortages and economic valueEven distribution of population between regions in a basin provides lower shortages and higher values assuming constant per capita demand [ABSTRACT FROM AUTHOR]

Background: : Increasing student numbers and logistical challenges in pharmacy education limit patient counselling and clinical placement opportunities. Computer-based simulation (CBS) offers scalable, interactive learning but faces integration barriers. Objective: : To explore global perceptions of CBS implementation in pharmacy education among educators and students. Methods: An online cross-sectional survey was developed based on literature review and expert feedback. The survey was distributed globally through academic pharmacy organisations, social media, and the authors' networks. It included 20 questions targeting pharmacy educators and students. Results: : Responses from 152 educators across 38 countries and 392 students from 46 countries, spanning six WHO regions (AFRO, AMRO, EMRO, EURO, SEARO, and WPRO) were analysed using descriptive and inferential statistics. The majority of educators (90.1%, n = 137) and students (84.2%, n = 330) expressed comfort with using CBS and implementing it in their curriculum. Despite this, CBS was perceived as underutilised by 53.5% (n = 81) of educators and 63.7% (n = 250) of students. Students valued CBS for enhancing communication and problem-solving skills, while educators highlighted its relevance to community pharmacy practice. Both groups supported CBS use in assessments. All educators (100%) identified workload reduction as a key priority, hoped CBS could assist in this area. Educators also reported barriers such as financial constraints (56.6%, n = 86) and insufficient technical support (53.3%, n = 81). On the other hand, students were less optimistic about institutional support, with only a few (7.4%, n = 29) believed institutional leaders would actively support CBS adoption. Regional differences emerged, with SEARO (Southeast Asia) and AFRO (Africa) showing the lowest CBS usage rates. Educators in SEARO, AFRO, and EMRO (Eastern Mediterranean) raised concerns about technical support, while those in SEARO, AFRO, and WPRO (Western Pacific, including Australia, New Zealand, and Singapore) expressed financial concerns. Educators in AFRO and WPRO, however, reported being 100% comfortable with using CBS. Conclusion: : Both students and educators recognised the potential of CBS in pharmacy education, with strong support for its integration. Addressing barriers such as educator workload, financial constraints, and technical support is crucial for broader adoption. Improved resource allocation and targeted training for educators are essential to effectively incorporate CBS into the pharmacy curriculum. [ABSTRACT FROM AUTHOR]

In a study of DNA methylation changes in melatonin-deficient rice mutants, mutant plants showed premature leaf senescence during grain-filling and reduced grain yield. Melatonin deficiency led to transcriptional reprogramming, especially of genes involved in chlorophyll and carbon metabolism, redox regulation, and transcriptional regulation, during dark-induced leaf senescence. Hypomethylation of mCG and mCHG in the melatonin-deficient rice mutants was associated with the expression change of both protein-coding genes and transposable element-related genes. Changes in gene expression and DNA methylation in the melatonin-deficient mutants were compensated by exogenous application of melatonin. A decreased S-adenosyl-L-methionine level may have contributed to the DNA methylation variations in rice mutants of melatonin deficiency under dark conditions. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is a major public health problem. Covid-19 pandemic impacted all areas of daily life, including medical care. In particular, delivering care for patients with cancer or suspected cancer during the crisis was challenging given the competing risks of death from untreated cancer versus serious complications from SARS-CoV-2, and the likely higher lethality of Covid-19 in immunocompromised patients. This study aims to assess the efficacy and immunogenicity of SARS-COV-2 vaccines in breast cancer patients by evaluating antispike antibodies in vaccinated and non-vaccinated patients and also through assessing the infection with Covid-19 after vaccination in vaccinated patients and non-vaccinated patients. The study also aims to assess the safety of SARSCOV-2 vaccine in breast cancer patients (local and systemic toxicity). Methods: Our population consisted of 120 female patients diagnosed with early and locally advanced breast cancer (60 vaccinated and 60 unvaccinated against Covid-19), in the breast cancer unit, clinical oncology department, Ain Shams University Hospitals. All were on oncological systemic therapy (neoadjuvant or adjuvant treatment). The cutoff value of SARS COV-2 antibody is 50 AU/mL (= 50 seropositive, <50 seronegative). Results: Out of 120 patients, anti-SARS COV-2 antibody seropositivity was found to be 48 in non-vaccinated vs.58 in vaccinated patients (80% vs.96.7%), with p-value =0.0046, which was statistically significant. The median titre in both groups was found to be 1434.5 vs.2500, (p=0.0026). In the 120 patients, 26 patients had Covid-19 infection with a significant difference (p= 0.0004), with 21 (35%) non-vaccinated vs.5 (8.3 %) vaccinated. In the sixty vaccinated patients, mild local adverse events were reported such as warmness at site of injection in 17 (28.3%) patients, pain (11, 18.3%), swelling (11, 18.3%), itching (8, 13.3%), and redness (6, 10%) representing the least adverse event. The patients experienced mild systemic adverse events, the highest incidence was fatigue (28, 46.7%), then myalgia/arthralgia (17, 28.3%), headache (2, 3.3%), and fever (16, 26.7%). There was no statistical significance association between antispike Ab titre and age, stage, treatment types, and time since last vaccine. Conclusion: SARSCOV-2 vaccines are effective and safe in localized breast cancer patients on systemic therapy. [ABSTRACT FROM AUTHOR]

Background: End-stage renal disease (ESRD) patients on maintenance hemodialysis (MHD) are highly vulnerable to severe manifestations of coronavirus disease 2019 (COVID-19) as increased risk of thromboembolic disease and worsened neuropsychiatric status. Aim: To assess the long-term thrombotic and neuropsychiatric sequelae of severe acute respiratory syndrome corona virus 2 in post-COVID-19 ESRD patients on MHD. Patients and methods: We followed for 12 months, 35 clinically stable HD patients on MHD who were confirmed or highly suspected for COVID-19 by positive severe acute respiratory syndrome corona virus 2 RT-PCR and/or high probability on high-resolution computed tomography chest imaging. We recorded demographics, HD and COVID-19 related data, thromboembolic history, and psychiatric history. We recorded baseline and follow-up complete blood count with differential counts, D-dimer, prothrombin time, international normalized ratio, and high-resolution computed tomography chest findings. We assessed post-COVID-19 neuropsychiatric sequelae using the Arabic versions of Hamilton's depression rating scale and Taylor's manifest anxiety scale. Results: Total leukocytic count, lymphocytes, and platelets were significantly lower during infection than preinfection, 6 months, and 1-year postinfection (P <0.001, P =0.003, P =0.014, respectively). Six months after infection, d-dimer levels were higher than normal values. The incidence of vascular access thrombosis was 25.7%. The scores of Hamilton's depression rating scale and Taylor's manifest anxiety scale were high [25 (interquartile range; 17–28) and 26 (interquartile range; 19–33)], respectively, and the prevalence of depression and anxiety symptoms were 94.3 and 85.7%, respectively. Conclusions: During infection, ESRD patients showed significantly lower total leukocytic count, lymphocytes, and platelets than preinfection, 6 months, and 1-year postinfection. They had high levels of d-dimer 6 months postinfection and a high risk for vascular access thrombosis. Their psychological wellbeing was markedly impaired by the pandemic resulting in depression and anxiety. [ABSTRACT FROM AUTHOR]

BackgroundMutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers.ObjectiveWe sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC.MethodsWe initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations.ResultsWe identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation.ConclusionsGain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.

BACKGROUND. Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant. METHODS. Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy. RESULTS. With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover). CONCLUSION. Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake. TRIAL REGISTRATION. ClinicalTrials.gov NCT01778556 FUNDING. This research was supported by the intramural research program of the NIDDK., Introduction Leptin is an adipocyte-derived hormone that signals overall body energy sufficiency (1) and acute energy balance (2). Leptin-deficient states, such as starvation or mutations in the leptin gene, lead [...]