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Background: In the CALCIPHYX trial, we investigated hexasodium fytate, an inhibitor of vascular calcification, for the treatment of calcific uraemic arteriolopathy (calciphylaxis), a rare condition characterised by painful, non-healing skin lesions. Methods: In this international, phase 3, randomised, double-blind, placebo-controlled trial, adults with an ulcerated calciphylaxis lesion and pain visual analogue scale (VAS) score ≥50/100 were randomised 1:1 to hexasodium fytate 7 mg/kg or placebo intravenously during maintenance haemodialysis. Primary efficacy outcomes were an 8-item modification of the Bates-Jensen Wound Assessment Tool (BWAT-CUA) and Pain VAS in the intention-to-treat population. ClinicalTrials.gov number: NCT04195906. Findings: Overall, 34/37 patients randomised to hexasodium fytate and 26/34 patients randomised to placebo completed the 12-week randomised treatment period. At Week 12, both groups (hexasodium fytate versus placebo) showed similar improvements in BWAT-CUA (mean [standard deviation (SD)], -5.3 [5.2] versus -6.0 [6.2]; least squares mean difference, 0.3 [96% confidence interval (CI): -2.5, 3.0]; p = 0.88) and Pain VAS (mean [SD], -19.5 [26.9] versus -32.2 [38.5]; least squares mean difference, 11.5 [96% CI: -4.8, 27.8]; p = 0.15). One patient randomised to placebo briefly received hexasodium fytate in error. Serious adverse events through Week 12 included: calciphylaxis-related events leading to hospitalisation (2/38 [5%] versus 11/33 [33%]) and death (1/38 [3%] versus 5/33 [15%]). During the subsequent 12 weeks of open-label hexasodium fytate and 4 weeks of follow-up, there were no additional calciphylaxis-related events leading to hospitalisation. Over the course of the entire trial, deaths were 2/38 [5%] for the hexasodium fytate group and 7/33 [21%] for the placebo group. Interpretation: In patients with calciphylaxis, BWAT-CUA and Pain VAS improved similarly in hexasodium fytate- and placebo-treated patients; over the course of the entire trial, there were fewer deaths and calciphylaxis-related events leading to hospitalisation in the hexasodium fytate group. Funding: Funded by Sanifit, a CSL Vifor company.

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Introduction Bladder cancer is a significant health issue with an increased recurrence and progression rate, requiring invasive follow-up, which shows a poor prognosis. In addition, the prognostic role of mutant fibroblast growth factor receptor 3 (FGFR3) and tumor protein P53 (TP53) is controversial; therefore, we investigated the methylation status and their altered gene expression in low- and high-grade non-muscle-invasive bladder cancer (NMIBC) subjects. Materials and methods This case-control study was conducted between 2020 and 2023, in which n = 115 tumor tissues (NMIBC n = 85) and (controls n = 30) were examined for FGFR3 and FGFR promoter methylation and expression using methylation-specific PCR (MSP) and real-time PCR. The multivariate regression analysis and Kaplan-Meier (KM) plots were used to establish the association of FGFR3 and TP53 with clinicopathological features and survival outcomes of NMIBC patients. Results High-grade NMIBC tumors showed substantial methylation patterns, with TP53 hypomethylated (p = 0.034) and FGFR3 hypermethylated (p = 0.046), as well as significant mRNA expression of Tp53 and FGFR3 (p = 0.001). The multivariate analysis shows FGFR3 and Tp53 were associated with recurrence-free survival with sensitivity (p = 0.045 (78%); 0.034 (70.7%)) and progression-free survival (p = 0.022(61.5%); 0.038 (69.2%)).  Conclusion The findings of this investigation indicate that FGFR3 hypermethylation and TP53 hypomethylation are independent prognostic indicators that aid in the evaluation of disease outcomes in high-grade NMIBC tumors.

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Sleep-disordered breathing (SDB), which includes conditions such as obstructive sleep apnea (OSA) and central sleep apnea (CSA), is an independent risk factor for cerebral small vessel disease (CSVD), stroke, heart failure, arrhythmias, and other cardiovascular disorders. The influence of OSA on brain structure and cognitive function has become an essential focus in the heart-brain axis, given its potential role in developing neurocognitive abnormalities. In this review, we found that OSA plays a significant role in the cardio-neural pathway that leads to the development of cerebral small vessel disease and neurocognitive decline. Although data is still limited on this topic, understanding the critical role of OSA in the heart-brain axis could lead to the utilization of imaging modalities to simultaneously identify early signs of pathology in both organ systems based on the known OSA-driven pathological pathways that result in a disease state in both the cardiovascular and cerebrovascular systems. This narrative review aims to summarize the current link between OSA and neurocognitive disorders, cardio-neural pathophysiology, and the treatment options available for patients with OSA-related neurocognitive disorders.

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Background: The role of induction in low-risk, living-donor kidney transplants being treated with tacrolimus, mycophenolate mofetil, and prednisolone is debatable. Materials and Methods: This was a retrospective study that consisted of patients undergoing living kidney transplantation between February 2010 and June 2021 with a related haplomatch donor, with maintenance immunosuppression of tacrolimus, mycophenolate mofetil, and prednisolone. High-risk transplants, such as second or more transplants, immunologically incompatible transplants, and steroid-free transplants, were excluded. Patients were divided into three groups: no induction, basiliximab induction, and thymoglobulin induction, and the outcomes of all three were compared. Results: A total of 350 transplants were performed. There was a significant difference in the recipient sex distribution (P = 0.0373) and the number of preemptive transplants (P = 0.0272) between the groups. Other parameters were comparable. Biopsy-proven acute rejection (BPAR) was significantly less frequent in the thymoglobulin group than in the no-induction (5.3% vs. 17.5%; P = 0.0051) or basiliximab (5.3% vs. 18.8%; P = 0.0054) group. This persisted even after we performed multivariate regression analysis (thymoglobulin vs. no-induction group, P = 0.0146; thymoglobulin vs. basiliximab group, P = 0.0237). There was no difference in BPAR between the basiliximab and no-induction groups. There were no differences in other outcomes between the groups. Conclusion: In a low-risk haplomatch, related, living-donor kidney transplant on tacrolimus, mycophenolate mofetil, and prednisolone, BPAR was significantly lower with thymoglobulin as opposed to no induction or basiliximab induction with a similar short-term patient and death-censored graft survival and infection rates. Basiliximab did not provide any benefit over no induction.

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Dynamics simulation with frictional contacts is important for a wide range of applications, from cloth simulation to object manipulation. Recent methods using smoothed lagged friction forces have enabled robust and differentiable simulation of elastodynamics with friction. However, the resulting frictional behavior can be inaccurate and may not converge to analytic solutions. Here we evaluate the accuracy of lagged friction models in comparison with implicit frictional contact systems. We show that major inaccuracies near the stick-slip threshold in such systems are caused by lagging of friction forces rather than by smoothing the Coulomb friction curve. Furthermore, we demonstrate how systems involving implicit or lagged friction can be correctly used with higher-order time integration and highlight limitations in earlier attempts. We demonstrate how to exploit forward-mode automatic differentiation to simplify and, in some cases, improve the performance of the inexact Newton method. Finally, we show that other complex phenomena can also be simulated effectively while maintaining smoothness of the entire system. We extend our method to exhibit stick-slip frictional behavior and preserve volume on compressible and nearly-incompressible media using soft constraints.

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Nicotinamide Adenine Dinucleotide Phosphate (NAD(P)H) plays an important role in numerous biologically significant redox reactions. The photochemical restoration of its oxidized form (NAD(P)+) under physiological conditions is intriguing in the context of integrated photo and catalysis. Herein, we report the functionalized graphitic carbon-based solar light active photocatalyst by doping boron and fluorine in the native graphitic carbon nitride (GCN) (nonfunctionalized) for the regeneration of enzymatically visible light active coenzyme and in photo-acetalization reactions. The metal-free functionalized photocatalyst systems such as BFGCN-x leads to higher yield NADH and NADPH regeneration. They are also capable of catalyzing acetal reactions in the absence of any Lewis and Bronsted acids. The current research endeavor provides the advancement and the application of functionalized GCN-based photocatalysts for NADH (61.89%), NADPH (59.84%) regeneration, and photo-acetalization reactions.

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PURPOSE: The objective of this study was to propose a novel preprocessing approach to simultaneously correct for the frequency and phase drifts in MRS data using cross-correlation technique. METHODS: The performance of the proposed method was first investigated at different SNR levels using simulation. Random frequency and phase offsets were added to a previously acquired STEAM human data at 7 T, simulating two different noise levels with and without baseline artifacts. Alongside the proposed spectral cross-correlation (SC) method, three other simultaneous alignment approaches were evaluated. Validation was performed on human brain data at 3 T and mouse brain data at 16.4 T. RESULTS: The results showed that the SC technique effectively corrects for both small and large frequency and phase drifts, even at low SNR levels. Furthermore, the mean square measurement error of the SC algorithm was comparable to the other three methods used, with much faster processing time. The efficacy of the proposed technique was successfully demonstrated in both human brain MRS data and in a noisy MRS dataset acquired from a small volume-of-interest in the mouse brain. CONCLUSION: The study demonstrated the availability of a fast and robust technique that accurately corrects for both small and large frequency and phase shifts in MRS.

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AIMS: The development of cell therapy as a widely-available clinical option for ischemic cardiomyopathy is hindered by the invasive nature of current cell delivery methods. Furthermore, the rapid disappearance of cells after transplantation provides a cogent rationale for using repeated cell doses, which, however, has not been done thus far in clinical trials because it is not feasible with invasive approaches. The goal of this translational study was to test the therapeutic utility of the intravenous route for cell delivery. METHODS AND RESULTS: Pigs with chronic ischemic cardiomyopathy induced by myocardial infarction received one or three intravenous doses of allogeneic bone marrow mesenchymal stromal cells (MSCs) or placebo 35 days apart. Rigor guidelines, including blinding and randomization, were strictly followed. A comprehensive assessment of LV function was conducted with three independent methods (echocardiography, magnetic resonance imaging, and hemodynamic studies). The results demonstrate that three doses of MSCs improved both load-dependent and independent indices of left ventricular (LV) function and reduced myocardial hypertrophy and fibrosis; in contrast, one dose failed to produce most of these benefits. CONCLUSIONS: To our knowledge, this is the first study to show that intravenous infusion of a cell product improves LV function and structure in a large animal model of chronic ischemic cardiomyopathy and that repeated infusions are necessary to produce robust effects. This study, conducted in a clinically-relevant model, supports a new therapeutic strategy based on repeated intravenous infusions of allogeneic MSCs and provides a foundation for a first-in-human trial testing this strategy in patients with chronic ischemic cardiomyopathy.

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BACKGROUND: Sodium valproate (VPA) is an extensively used anti-convulsant, which is an effective drug for treatment of epilepsy in adults and children, as well as for conditions like migraine, bipolar disorder, mania, and trigeminal neuralgia. Sedation, vertigo, ataxia, dose-dependent tremors, headaches, and gastrointestinal side effects are the most often reported adverse effects associated with VPA. A potential life-threatening event reported with VPA is hyperammonemia (HA), which is defined as an increase in serum level of ammonia. Only 587 reported cases of HA were found in the VigiAccess database, representing a mere 0.6% of the 95,000 reported adverse events linked to VPA. Hence, this case series was conducted with emphasis on monitoring of increased serum ammonia levels with or without hepatic enzymes increase for patients who are on VPA. AIMS AND OBJECTIVES: To assess elevated serum ammonia levels following VPA administration, and to ascertain the percentage of individuals with hepatic enzymes increased who took VPA and subsequently had elevated serum ammonia levels. METHODS: This study was conducted at the adverse drug reaction (ADR) monitoring centre (AMC) of the Pharmacovigilance Programme of India (PvPI) and Department of Psychiatry, Christian Medical College and Hospital (CMC&H), Ludhiana. The study comprised of 12 patients who were exclusively on VPA and exhibited symptoms related to elevated serum ammonia. An informed consent form (ICF) was provided to the patient prior to taking their personal details. Laboratory investigations were done to establish the diagnosis and liver function tests (LFTs), chiefly ALT (alanine transferase) and AST (aspartate aminotransferase) were also performed. It is a descriptive study which was for a time period of six months.  Results: This study includes 12 patients who had HA confirmed by laboratory investigation. Out of these 12 patients, two patients (17%) had a corresponding increase in LFT. The average as of the patients was 53.08 years and average serum ammonia levels were 219.15. None of the patients who presented with HA progressed to hyperammonemic encephalopathy (HAE). CONCLUSION:  This case series on valproate-induced HA should be of interest to psychiatrists, physicians, internists, family medicine physicians, hospitalists, and surgeons who will have patients on VPA. Delay in recognition of HA can result in the development of potentially life-threatening complications. Rapid diagnosis and management will help in reducing the number of cases which progress to encephalopathy which is highly fatal.

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OBJECTIVE: Vocal fold scar and sulcus pose significant treatment challenges with no current optimal treatment. Platelet-rich plasma (PRP), an autologous concentration of growth factors, holds promise for regenerating the superficial lamina propria. This study aims to evaluate the potential benefits of serial PRP injections on mucosal wave restoration and vocal function. METHODS: In a prospective clinical trial across two institutions, patients with vocal fold scar underwent four serial PRP injections, one month apart. Blinded independent laryngologists and expert listeners used pretreatment and one-month post-fourth injection videostroboscopy and CAPE-V assessments to evaluate mucosal wave and voice quality changes, respectively. Additionally, patient reported outcome measures (PROMs) were evaluated. RESULTS: In the study, 15 patients received 55 PRP injections without adverse effects. Eight patients (53.3%) had mild, three patients (20%) had moderate, and four patients (26.7%) had severe scar. There was an average reduction of 8.7 points in post-treatment VHI-10 scores (p = 0.007). The raters observed an improvement in post-treatment voice in 73.4% of cases, and CAPE-V scores showed a reduction of 18.8 points on average (p = 0.036). The videostroboscopic VALI ratings showed an improvement in mucosal wave rating from 2.0 to 4.0. On average, the raters perceived the post-PRP exams to be better in 56.7% of cases. CONCLUSIONS: PRP has been validated as a safe autologous option for treatment of vocal fold scar. While results for mucosal wave and voice quality varied, there was a consistent improvement in PROMs. LEVEL OF EVIDENCE: Level 3: Prospective cohort study, with blinded analysis Laryngoscope, 2024.

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Neuroinflammation is a key component underlying multiple neurological disorders, yet non-invasive and cost-effective assessment of in vivo neuroinflammatory processes in the central nervous system remains challenging. Diffusion weighted magnetic resonance spectroscopy (dMRS) has shown promise in addressing these challenges by measuring diffusivity properties of different neurometabolites, which can reflect cell-specific morphologies. Prior work has demonstrated dMRS utility in capturing microglial reactivity in the context of lipopolysaccharide (LPS) challenges and serious neurological disorders, detected as changes of microglial metabolite diffusivity properties. However, the extent to which such dMRS metrics are capable of detecting subtler and more nuanced levels of neuroinflammation in populations without overt neuropathology is unknown. Here we examined the relationship between intrinsic, gut-derived levels of systemic LPS and dMRS-based apparent diffusion coefficients (ADC) of choline, creatine, and N-acetylaspartate (NAA) in two brain regions: the thalamus and the corona radiata. Higher plasma LPS concentrations were significantly associated with increased ADC of choline and NAA in the thalamic region, with no such relationships observed in the corona radiata for any of the metabolites examined. As such, dMRS may have the sensitivity to measure microglial reactivity across populations with highly variable levels of neuroinflammation, and holds promising potential for widespread applications in both research and clinical settings.

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Idiopathic hirsutism (IH) is a common clinical condition with multiple diagnostic and therapeutic uncertainties. There are no clear recommendations for the diagnosis and management of the condition. This practice update was developed to guide the primary care physicians and the specialists in better and more systematic management of IH particularly in the Indian context. Twelve experienced members consisting of eminent endocrinologists, physicians, a dermatologist, a gynaecologist and a psychiatrist were invited by the Integrated Diabetes and Endocrine Academy (IDEA). A literature search was performed using online databases from PubMed, Cochrane Library and Google Scholar. Published articles from peer-reviewed indexed journals, with a preference for meta-analyses and randomized controlled trials, were selected. A meeting took place with all the 12 members individually giving their opinions on predetermined questions of interest. After the initial meeting during IDEACON 2023, two more meetings were held and the practice update was formulated after voting. Practice updates were made on important areas such as the cut-off for modified Ferriman-Gallwey Score for the Indian population, conditions to be excluded before diagnosing IH, when to refer to specialists, investigations in a suspected case of IH and choice of therapies for its management.

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BACKGROUND: Colorectal cancer (CRC) is a disease of the older population in developed countries where the incidence among the young is rising despite the decline in the overall incidence. Contrary to this, in India, which is a low-incidence country for CRCs, the incidence among all age groups including the young is rising. This study aimed at describing the clinico-demographic profile of young CRC cases and the epidemiological trend of the proportion of young cases from 2014 to 2021 in a tertiary cancer center in Eastern India. METHODS: This retrospective observational study was conducted at Department of Radiation Oncology, State Cancer Institute, IGIMS Patna, India a prominent tertiary cancer care center of Bihar. All histopathologically confirmed CRC cases in the 0-39 years age group were considered young and evaluated for the clinical, demographic profile as well as yearly trends in proportion out of total CRC cases. Microsoft Excel (2021) was used for statistical analysis. A P value of 0.05 was considered significant. RESULTS: Young colorectal (less than 40 years) patients constituted a third (n = 344, 33.4%) of total colorectal (n = 1028) cases. The median age among the young CRC cases was 30 years (range: 12 to 39 years). Rectum was the most common subsite noted (n = 255,74.1%) among this group of young patients. The most commonly encountered stage of the disease was III (n = 107, 31.1%) and chemotherapy was the most common treatment offered (n = 153, 44.5%). The proportion of young (0-39 years) CRC cases ranged between 29.4 and 37.4 (mean 33.5 ± 2.77, P value = 0.725) over the calendar years of the study period. CONCLUSION: The proportion of young (<40 years of age) cases out of total CRC cases in our study is higher than that in developed countries. However, the trends of this proportion have been consistent over the study period, i.e., from 2014 to 2021 without any significant change in our hospital-based cancer registry. Rectal cancer affected nearly three out of every four CRC patients in this age group. More advanced disease at presentation emphasizes the need for measures of screening, early diagnosis, and adequate infrastructure for treatment.

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INTRODUCTION: At least 10% of hospital admissions in high-income countries, including Australia, are associated with patient safety incidents, which contribute to patient harm ('adverse events'). When a patient is seriously harmed, an investigation or review is undertaken to reduce the risk of further incidents occurring. Despite 20 years of investigations into adverse events in healthcare, few evaluations provide evidence of their quality and effectiveness in reducing preventable harm.This study aims to develop consistent, informed and robust best practice guidance, at state and national levels, that will improve the response, learning and health system improvements arising from adverse events. METHODS AND ANALYSIS: The setting will be healthcare organisations in Australian public health systems in the states of New South Wales, Queensland, Victoria and the Australian Capital Territory. We will apply a multistage mixed-methods research design with evaluation and in-situ feasibility testing. This will include literature reviews (stage 1), an assessment of the quality of 300 adverse event investigation reports from participating hospitals (stage 2), and a policy/procedure document review from participating hospitals (stage 3) as well as focus groups and interviews on perspectives and experiences of investigations with healthcare staff and consumers (stage 4). After triangulating results from stages 1-4, we will then codesign tools and guidance for the conduct of investigations with staff and consumers (stage 5) and conduct feasibility testing on the guidance (stage 6). Participants will include healthcare safety systems policymakers and staff (n=120-255) who commission, undertake or review investigations and consumers (n=20-32) who have been impacted by adverse events. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Northern Sydney Local Health District Human Research Ethics Committee (2023/ETH02007 and 2023/ETH02341).The research findings will be incorporated into best practice guidance, published in international and national journals and disseminated through conferences.

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Extant research shows that following a cerebrovascular insult to the brain, patients may develop a wide range of cognitive disorders, spanning from mild cognitive impairment (CI) to advanced dementia. Several studies have shown that atherosclerosis in the carotid, coronary, and breast arteries is associated with an increased risk of stroke, CI, and dementia. In this review, we examine the association of subclinical atherosclerotic calcification detected by computed tomography (CT) in these arterial beds and the risk of stroke, CI, and dementia. A major advantage of CT is that it can accurately quantify vascular calcification in different parts of the vasculature during a single examination. However, the strength of the association between CT findings and CI and stroke varies with the location and severity of the arteries involved. Data are still limited on this topic, highlighting the need for additional investigations to further our understanding of the risk of cognitive impairment in patients with subclinical atherosclerosis. It is equally important to test preventive strategies for managing patients in whom vascular calcifications are identified incidentally in randomized controlled trials to study the effects on outcomes, including incidents of stroke and CI.

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Approximately 3% of all diagnosed cases of ascites are of cardiac etiology. Although more commonly associated with heart failure, pulmonary arterial hypertension is a known but rare cause of cardiac ascites, which has not been associated with spontaneous bacterial peritonitis. We present a case of a 75-year-old male with known pulmonary arterial hypertension and new-onset ascites, the fluid analysis of which was consistent with both cardiac ascites and spontaneous bacterial peritonitis. He was successfully managed with antibiotics, loop diuretics, and mineralocorticoid receptor antagonists.

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BACKGROUND: The discriminatory and racist policy of historical redlining in the United States during the 1930s played a role in perpetuating contemporary environmental health disparities. OBJECTIVE: Our objectives were to determine associations between home and school pollutant exposure (fine particulate matter [PM2.5], NO2) and respiratory outcomes (Composite Asthma Severity Index, lung function) among school-aged children with asthma and examine whether associations differed between children who resided and/or attended school in historically redlined compared to non-redlined neighborhoods. METHODS: Children ages 6 to 17 with moderate-to-severe asthma (N = 240) from 9 US cities were included. Combined home and school exposure to PM2.5 and NO2 was calculated based on geospatially assessed monthly averaged outdoor pollutant concentrations. Repeated measures of Composite Asthma Severity Index and lung function were collected. RESULTS: Overall, 37.5% of children resided and/or attended schools in historically redlined neighborhoods. Children in historically redlined neighborhoods had greater exposure to NO2 (median: 15.4 vs 12.1 parts per billion) and closer distance to a highway (median: 0.86 vs 1.23 km), compared to those in non-redlined neighborhoods (P < .01). Overall, PM2.5 was not associated with asthma severity or lung function. However, among children in redlined neighborhoods, higher PM2.5 was associated with worse asthma severity (P < .005). No association was observed between pollutants and lung function or asthma severity among children in non-redlined neighborhoods (P > .005). CONCLUSIONS: Our findings highlight the significance of historical redlining and current environmental health disparities among school-aged children with asthma, specifically, the environmental injustice of PM2.5 exposure and its associations with respiratory health.

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OBJECTIVE: The Risk Analysis Index (RAI) score is a screening tool to assess patient frailty. It has been shown to be predictive of postoperative outcomes and mortality in orthopedic, urologic, and neurosurgical patient populations. We sought to evaluate the predictive ability of RAI score for surgical outcomes in an otolaryngology patient population. STUDY DESIGN: Retrospective study. SETTING: Academic tertiary medical center. METHODS: A retrospective study was conducted of adult patients undergoing otolaryngology surgery at a tertiary medical care center over 21 months. Patients were sent electronic RAI survey questionnaires via direct messaging, which was completed prior to surgery. Endpoint data were analyzed, including demographics, RAI score, and patient outcome data. Univariate analysis, ROC curves, and predictive modeling were utilized. RESULTS: A total of 517 patients responded to the RAI questionnaire, resulting in a 59.6% response rate. Mean RAI score was 21.38 ± 11.83. Higher RAI scores were associated with increased 30-day readmissions (P < .0015), postoperative complications (P < .001), hospital length of stay (P < .001), and discharge with home health (P < .001). Predictive models for RAI score and postoperative outcomes were created, and a cutoff score of RAI = 30 was established to identify frail patients. CONCLUSION: We evaluated if RAI scoring predicted postoperative complications in an otolaryngology patient population. Increased RAI score is significantly associated with poorer surgical outcomes, including increased hospital length of stay, 30-day readmissions, and postoperative complications. We propose a predictive model with suggested RAI cutoff scoring for use in the otolaryngology surgical population.

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HISTORY: A 43-year-old male patient with no known past medical history presented to the emergency department with new-onset bitemporal headache, dizziness, and bilateral lower extremity weakness for 1 day. The patient denied chest pain, shortness of breath, cough, or recent exposure to sick individuals. He was not on any medications and denied alcohol or illicit drug use. Vital signs were unremarkable. Physical examination was notable for a left-sided pronator drift and bilateral dysmetria that was more pronounced on the left. Results of routine laboratory workup, including complete blood count, metabolic panel, and high-sensitivity troponin level, were normal. An electrocardiogram revealed sinus tachycardia with a heart rate of 102 beats per minute, T-wave inversions in the inferior leads, left axis deviation, incomplete right bundle branch block, and frequent premature ventricular contractions. A radiograph of the chest was unremarkable. CT of the head without contrast enhancement demonstrated no acute intracranial abnormities. MRI of the brain without contrast enhancement revealed multiple acute infarcts involving left posterior inferior cerebellar artery distribution, right cerebellar hemisphere, right mesial temporal lobe, and right posterior limb of the internal capsule. CT angiography of the head and neck showed an occlusion of the right posterior cerebral artery near its origin, with a trace of distal flow. Given that these findings were concerning for a cardioembolic etiology of acute ischemic stroke, transesophageal echocardiography was performed. This showed mild left ventricular systolic dysfunction with an ejection fraction of 40%, mild global hypokinesis, and an additional finding also seen at subsequent cardiac CT and MRI that will be disclosed in part 2 of the case. The patient was started on systemic anticoagulation and guideline-directed medical therapy for heart failure with reduced ejection fraction. CT of the chest showed no evidence of lymphadenopathy or abnormalities in the lung parenchyma or interstitium. Coronary CT angiography was performed (Fig 1), followed by cardiac MRI (Fig 2).

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The detection of uranium in drinking water has ignited concerns among the public, regulators, and policymakers, particularly as around 1% of the 55,554 water samples in India have shown uranium levels surpassing the 60 µg/l guideline established by the Atomic Energy Regulatory Board (AERB) based on radiological toxicity. Further, the Bureau of Indian Standard (BIS), has given a limit of 30 µg/l, which is derived from World Health Organization (WHO) guidelines. Besides the chemical and radiological aspects associated with uranium, factors such as technological constraints in water purification, waste management, environmental factors, and socio-economic conditions significantly influence these guideline values, which are often overlooked. This manuscript explores the variations in approaches for establishing guideline values and highlights the uncertainties arising from dependence on various variables such as intake and usage patterns, inter- and intra-species distinctions, and epidemiological data. A critical analysis indicates that adherence to global guidelines may result in some undesirable environmental issues. By considering factors such as population dynamics, socio-economic conditions, and geological influences, we suggest that limit of 60 µg/l for uranium in drinking water is appropriate for India.

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