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Background: Little is known about the real-world use of systemic glucocorticoids to treat patients hospitalized with community-acquired pneumonia (CAP) outside of the intensive care unit (ICU)., Methods: This retrospective cohort study included 11,588 hospitalizations for CAP without chronic pulmonary disease at seven hospitals in Ontario, Canada. We report physician-level variation in the use of glucocorticoids and trends over time. We investigated the association between glucocorticoid prescriptions and clinical outcomes, using propensity score overlap weighting to account for confounding by indication., Results: Glucocorticoids were prescribed in 1283 (11.1%) patients, increasing over time from 10.0% in 2010 to 11.9% in 2020 (p = .008). Physician glucocorticoid prescribing ranged from 2.9% to 34.6% (median 10.0%, inter quartile range [IQR]: 6.7%-14.6%). Patients receiving glucocorticoids tended to be younger (median age 73 vs. 79), have higher Charlson comorbidity scores (score of 2 or more: 42.4% vs. 31.0%), more cancer (26.6% vs. 13.2%), more renal disease (11.5% vs. 6.6%), and less dementia (7.8% vs. 14.8%). Patients treated with glucocorticoids had higher rates of in-hospital mortality (weighted Risk Difference = 1.72, 95% confidence interval [95% CI]: 0.16-3.3, p = .033). Glucocorticoid use was not associated with ICU admission, hospital length-of-stay, or 30-day readmission., Conclusion: Glucocorticoids were prescribed in 11.1% of patients hospitalized with CAP outside of ICU and one in four physicians prescribed glucocorticoids in more than 14% of patients. Glucocorticoid use was associated with greater in-hospital mortality, although these findings are limited by large selection effects. Clinicians should exercise caution in prescribing glucocorticoids for nonsevere CAP, and definitive trials are needed in this population., (© 2024 The Author(s). Journal of Hospital Medicine published by Wiley Periodicals LLC on behalf of Society of Hospital Medicine.)

Objectives: Bupropion toxicity can lead to adverse cardiovascular events (ACVE), but delayed onset of toxicity makes risk stratification difficult. This study aimed to validate previously defined predictors of ACVE and identify novel predictors among patients presenting to the emergency department (ED) after bupropion overdose., Methods: This secondary analysis of prospective data from the Toxicology Investigators Consortium Core Registry analyzed adult acute or acute-on-chronic bupropion exposures from 2015 to 2018. The primary outcome was ACVE (any of the following: myocardial injury, shock, ventricular dysrhythmia, or cardiac arrest). Potential predictors of ACVE included previously derived predictors in the overall drug overdose population (prior cardiac disease, initial serum bicarbonate < 20 mEq/L, and initial QTc ≥ 500 ms), exposure circumstances, and initial serum lactate value. Candidate predictors were evaluated using univariate analysis and multivariable regression modeling. Receiver operator characteristic curves were used to derive optimal cutoff points for novel predictors, and prognostic test characteristics were calculated., Results: Of 355 patients analyzed, ACVE occurred in 34 (9.6%) patients. Initial serum bicarbonate < 20 mEq/L (adjusted odds ratio [aOR] 4.42, 95% confidence interval [CI] 1.94-10.0) and initial QTc ≥ 500 ms (aOR 2.52, 95% CI 1.01-6.09) independently predicted ACVE. Exposure circumstances did not predict ACVE. Initial serum lactate > 5.2 mmol/L independently predicted ACVE (aOR 12.2, 95% CI 2.50-75.2) and was 90.7% specific with 80.3% negative predictive value., Conclusions: Metabolic acidosis and QTc prolongation were validated as predictors of ACVE in ED patients with bupropion overdose. Serum lactate elevation was strongly predictive of ACVE in this study and warrants further investigation., (© 2024 Society for Academic Emergency Medicine.)

Introduction: Opioid overdose deaths in the U.S. have risen dramatically in the past decade, largely due to the surge in illicitly manufactured fentanyl. Injection drug use is a known risk factor for HIV, further complicating the long-term consequences of opioid use. The baseline prevalence of HIV among adults in the US is 0.46 %. The primary purpose of this study was to determine the prevalence and risk factors of HIV among patients presenting to the emergency departments (ED) with an acute opioid overdose., Methods: This study is a prospective observational cohort study from the ToxIC Fentalog Study group. Patients age 18 years of age or older are included if they present to one of 10 participating U.S. hospitals in 9 states between September 2020 and May 2023 with a suspected opioid overdose and had waste serum available after routine laboratory testing. Clinical data is collected from the medical record and patient serum is sent for comprehensive toxicologic analysis via liquid chromatography quadrupole time-of-flight mass spectroscopy to detect the presence of over 1200 substances including illicit opioids, novel synthetic opioids, medications, and adulterants. Logistic multivariable regression was performed to examine the association between demographic, behavioral, and serum toxicology data with risk factors and HIV status., Results: Among the total cohort (n=1690), 1062 cases had known HIV status (62.8 % of total sample). Among patients with a known HIV status, 60 (5.6 % [95 % CI: 4.2 %, 7.0 %]) were HIV positive. Patients with HIV reported stimulant use more frequently (13.3 %) than those without HIV (6.8 %; p=0.003). After controlling for confounding, bipolar psychiatric history was a significant independent predictor of HIV positivity (aOR: 1.08; 95 % CI: 1.02, 1.13) in this population., Conclusions: In this large multicenter cohort, the prevalence of HIV for ED patients with illicit opioid overdose was 9 times higher than that expected by the general population. Bipolar disorder appears to be a novel risk factor for HIV positivity in this patient population., Competing Interests: Declaration of Competing Interest There are no financial, litigational, or other conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. C max and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median T max for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (T 1/2 ) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 C max but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

This work introduces a novel 1-pot, 0-waste, 0-VOC methodology for synthesizing polymeric surfactants using acrylated epoxidized soybean oil and acrylated glycerol as primary monomers. These macromolecular surfactants are synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, allowing for tunable hydrophilic-lipophilic balance (HLB) and ionic properties. We characterize the copolymers' chemical composition and surface-active properties, and evaluate their effectiveness in forming and stabilizing emulsions of semiepoxidized soybean oil and poly(acrylated epoxidized high oleic soybean oil). Comprehensive analyses, including gel permeation chromatography, nuclear magnetic resonance spectroscopy, dynamic light scattering, particle size distribution, zeta potential, and critical micelle concentration, provide detailed insights into the copolymers and the emulsions they form. The results demonstrate that the RAFT-polymerized surfactants offer long-lasting stability and effectively disperse both common oil-in-water emulsions and highly viscous and hydrophobic polymer latexes. These surfactants outperform traditional small molecule surfactants by reducing particle size and preventing phase separation, even over extended storage periods. Stable polymer-water interfaces are achieved through HLB control, tailored by monomer composition, and the final product requires no additional purification since polymerization occurs in liquid surfactants. While small molecules contribute to rapid micelle formation, the polymeric components enhance long-term stability through steric repulsion and slower dynamics. This method enables even the emulsification of polymers with submicron particle size, which ordinarily requires emulsion polymerization. Integrating biobased polymeric surfactants with advanced polymer processing techniques opens new possibilities for transforming highly hydrophobic polymers into latexes, facilitating downstream applications. This innovation enhances the environmental sustainability of surfactant production and broadens the potential for polymer emulsification technologies. Additionally, the integrated solution-processing approach demonstrated here can be applied to other emerging polymers, where judiciously selected nonvolatile solvents facilitate the polymerization and play a role in the final application.

Background: In parturients, post-spinal hypotension is common due to loss of sympathetic tone. Compression of the inferior vena cava by the gravid uterus further aggravates it. Various pharmacologic and non-pharmacologic techniques are used to reduce the severity of hypotension. Ondansetron, a selective 5-hydroxytryptamine receptor antagonist, nullifies the Bezold Jarisch reflex response to spinal anaesthesia and glycopyrrolate, an anti-cholinergic, has been used to prevent post-spinal hypotension. We estimated the efficacy of intravenous (IV) glycopyrrolate plus IV ondansetron versus intramuscular (IM) glycopyrrolate plus IV ondansetron to reduce post-spinal hypotension in caesarean section. We compared hypotension episodes and the total ephedrine dose required to treat hypotension among the groups., Methods: Ninety parturients undergoing elective and emergency caesarean section under spinal anaesthesia were randomly assigned into three groups of 30 each. Group A received prophylactic IV glycopyrrolate 0.2mg plus IV ondansetron 4mg, Group B received IM glycopyrrolate 0.2mg plus IV ondansetron 4mg and Control Group C received 10ml of normal saline plus IV ondansetron 4mg. The total ephedrine dose required to treat hypotension (primary objective), incidence of hypotension and maternal heart rate variations were analysed., Results:  Group B required significantly less vasopressor as compared to Group C (6.4286mg±1.6036 vs 8.7mg±3.6288, p=0.0420). There is no statistically significant difference between Group A and Group C for vasopressor requirement (7.8750mg±2.8723 vs 8.7mg±3.6288, p=0.5425). Maternal heart rate in Group A was higher at the eighth minute compared to Group B and Group C (100.2±21.3 vs 95.3±14.4 vs 86.2±19.0, p=0.015). Incidence of hypotension was same in all the groups (46.7% vs 46.7% vs 51.1%, p=0.491) and complications among groups were comparable., Conclusion:  Prophylactic use of IM glycopyrrolate plus IV ondansetron decreases total vasopressor required to treat hypotension but does not decrease the incidence of hypotension. Prophylactic use of IV glycopyrrolate increases maternal heart rate., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Dr. D Y Patil Medical College, Hospital and Research Centre, Dr. D Y Patil Vidyapeeth (Deemed to be University) issued approval IESC/PGS/2022/159. The study is approved for research with CTRI registration No. CTRI/2023/05/053038. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Baheti et al.)

Lysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based multi-omic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes and lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between lipids and proteins identified autophagy defects, notably the accumulation of ferritinophagy substrates and receptors, especially in NPC1 -/- and NPC2 -/- mutants, where lysosomes accumulate cholesterol. Autophagic and endocytic cargo delivery failures correlated with elevated lyso-phosphatidylcholine species and multi-lamellar structures visualized by cryo-electron tomography. Loss of mitochondrial cristae, MICOS-complex components, and OXPHOS components rich in iron-sulfur cluster proteins in NPC2 -/- cells was largely alleviated when iron was provided through the transferrin system. This study reveals how lysosomal dysfunction affects mitochondrial homeostasis and underscores nMOST as a valuable discovery tool for identifying molecular phenotypes across LSDs., Competing Interests: DECLARATION OF INTERESTS J.W.H. is a consultant and founder of Caraway Therapeutics (a wholly owned subsidiary of Merck & Co, Inc) and is a member of the scientific advisory board for Lyterian Therapeutics. B.A.S. is a co-founding scientific advisory board member of Interline Therapeutics and on the scientific advisory boards of Biotheryx and Proxygen. J.M.P. holds a position on the advisory board of Thermo Fisher Scientific. J.J.C. is a consultant for Thermo Fischer Scientific. Other authors declare no competing interests. S.P.G. is on the advisory board for Thermo Fisher Scientific, Cedilla Therapeutics, Casma Therapeutics, Cell Signaling Technology, and Frontier Medicines.

In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [ 14 C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half-life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug-related exposure (DRE), while a direct N-glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of the recovered dose in excreta, while metabolites resulting from phase 1 oxidative pathways accounted for more than 30% of the excreted dose. Overall, a single oral dose of 200 mg [ 14 C]atuliflapon suspension was well tolerated in healthy male subjects. The human metabolism and disposition data obtained will support future development and submissions of atuliflapon as a potential candidate drug for the treatment of cardiovascular, cardiorenal, and respiratory indications., (© 2024 AstraZeneca. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

The steroid hormone progesterone (P4) regulates multiple aspects of reproductive and metabolic physiology. Classical P4 signaling operates through nuclear receptors that regulate transcription. In addition, P4 signals through membrane P4 receptors (mPRs) in a rapid nongenomic modality. Despite the established physiological importance of P4 nongenomic signaling, the details of its signal transduction cascade remain elusive. Here, using Xenopus oocyte maturation as a well-established physiological readout of nongenomic P4 signaling, we identify the lipid hydrolase ABHD2 (α/β hydrolase domain-containing protein 2) as an essential mPRβ co-receptor to trigger meiosis. We show using functional assays coupled to unbiased and targeted cell-based lipidomics that ABHD2 possesses a phospholipase A2 (PLA2) activity that requires mPRβ. This PLA2 activity bifurcates P4 signaling by inducing clathrin-dependent endocytosis of mPRβ, resulting in the production of lipid messengers that are G-protein coupled receptors agonists. Therefore, P4 drives meiosis by inducing an ABHD2 PLA2 activity that requires both mPRβ and ABHD2 as obligate co-receptors.

Androgen receptor (AR) is a ligand-responsive transcription factor that drives terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to activate malignant phenotypes, the molecular mechanisms of which remain unknown. Here, we show that tumor-specific AR enhancers are critically reliant on H3K36 dimethyltransferase activity of NSD2. NSD2 expression is abnormally induced in prostate cancer, where its inactivation impairs AR transactivation potential by disrupting over 65% of its cistrome. NSD2-dependent AR sites distinctively harbor the chimeric FOXA1:AR half-motif, which exclusively comprise tumor-specific AR enhancer circuitries defined from patient specimens. NSD2 inactivation also engenders increased dependency on the NSD1 paralog, and a dual NSD1/2 PROTAC degrader is preferentially cytotoxic in AR-dependent prostate cancer models. Altogether, we characterize NSD2 as an essential AR neo-enhanceosome subunit that enables its oncogenic activity, and position NSD1/2 as viable co-targets in advanced prostate cancer., (© 2024. The Author(s).)

Object detection and classification in autonomous vehicles are crucial for ensuring safe and efficient navigation through complex environments. This paper addresses the need for robust detection and classification algorithms tailored specifically for Indian roads, which present unique challenges such as diverse traffic patterns, erratic driving behaviors, and varied weather conditions. Despite significant progress in object detection and classification for autonomous vehicles, existing methods often struggle to generalize effectively to the conditions encountered on Indian roads. This paper proposes a novel approach utilizing the YOLOv8 deep learning model, designed to be lightweight, scalable, and efficient for real-time implementation using onboard cameras. Experimental evaluations were conducted using real-life scenarios encompassing diverse weather and traffic conditions. Videos captured in various environments were utilized to assess the model's performance, with particular emphasis on its accuracy and precision across 35 distinct object classes. The experiments demonstrate a precision of 0.65 for the detection of multiple classes, indicating the model's efficacy in handling a wide range of objects. Moreover, real-time testing revealed an average accuracy exceeding 70% across all scenarios, with a peak accuracy of 95% achieved in optimal conditions. The parameters considered in the evaluation process encompassed not only traditional metrics but also factors pertinent to Indian road conditions, such as low lighting, occlusions, and unpredictable traffic patterns. The proposed method exhibits superiority over existing approaches by offering a balanced trade-off between model complexity and performance. By leveraging the YOLOv8 architecture, this solution achieved high accuracy while minimizing computational resources, making it well suited for deployment in autonomous vehicles operating on Indian roads.

Purpose: This systematic review and meta-analysis aimed to synthesize the evidence and examine the effect of telerehabilitation interventions compared to face-to-face rehabilitation interventions on physical functioning, mental health, and pain reduction among employed individuals, 18 years old and older., Methods: Following the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive search syntax was created and inputted into Ovid Medline, APA PsycINFO, Ovid Embase, CINAHL, and Scopus. Critical appraisal of the included studies was conducted by two researchers to assess the risk of bias. A meta-analysis was completed for the randomized controlled trials and GRADE was used to determine the certainty of the evidence., Results: A total of 16 out of 4319 articles were included in this review. This systematic review and meta-analysis found no significant differences between telerehabilitation interventions for physical functioning, mental health, and pain reduction outcomes compared to traditional rehabilitation interventions., Conclusion: The study findings indicate that telerehabilitation is less effective than in-person care for occupational therapy and physical therapy services. Future research may look at addressing the limitations of the current study to produce more conclusive results, such as exploring the length of the intervention, knowledge and confidence of intervention application, and follow-ups., Systematic Review Registration: This systematic review has been registered with PROSPERO under registration number CRD42022297849 on April 8th, 2022., (© 2024. The Author(s).)

Learning efficient and interpretable policies has been a challenging task in reinforcement learning (RL), particularly in the visual RL setting with complex scenes. While neural networks have achieved competitive performance, the resulting policies are often over-parameterized black boxes that are difficult to interpret and deploy efficiently. More recent SRL frameworks have shown that high-level domain-specific programming logic can be designed to handle both policy learning and symbolic planning. However, these approaches rely on coded primitives with little feature learning, and when applied to high-dimensional visual scenes, they can suffer from scalability issues and perform poorly when images have complex object interactions. To address these challenges, we propose Differentiable Symbolic Expression Search (DiffSES), a novel symbolic learning approach that discovers discrete symbolic policies using partially differentiable optimization. By using object-level abstractions instead of raw pixel-level inputs, DiffSES is able to leverage the simplicity and scalability advantages of symbolic expressions, while also incorporating the strengths of neural networks for feature learning and optimization. Our experiments demonstrate that DiffSES is able to generate symbolic policies that are simpler and more and scalable than state-of-the-art SRL methods, with a reduced amount of symbolic prior knowledge. Our codes are available at: https://github.com/VITA-Group/DiffSES.

Heart disease is a leading cause of mortality, with calcific aortic valve disease (CAVD) being the most prevalent subset. Being able to predict this disease in its early stages is important for monitoring patients before they need aortic valve replacement surgery. Thus, this study explored hydrodynamic, mechanical, and hemodynamic differences in healthy and very mildly calcified porcine small intestinal submucosa (PSIS) bioscaffold valves to determine any notable parameters between groups that could, possibly, be used for disease tracking purposes. Three valve groups were tested: raw PSIS as a control and two calcified groups that were seeded with human valvular interstitial and endothelial cells (VICs/VECs) and cultivated in calcifying media. These two calcified groups were cultured in either static or bioreactor-induced oscillatory flow conditions. Hydrodynamic assessments showed metrics were below thresholds associated for even mild calcification. Young's modulus, however, was significantly higher in calcified valves when compared to raw PSIS, indicating the morphological changes to the tissue structure. Fluid-structure interaction (FSI) simulations agreed well with hydrodynamic results and, most notably, showed a significant increase in time-averaged wall shear stress (TAWSS) between raw and calcified groups. We conclude that tracking hemodynamics may be a viable biomarker for early-stage CAVD tracking.

Background Acute coronary syndrome (ACS) is a result of the interplay between genetic and environmental risk factors. A unique cytokine macrophage migration inhibitory factor (MIF), expressed by inflammatory cells, acts via a cluster of differentiation 74 (CD74) and a cluster of differentiation 44 (CD44) receptors, leading to the recruitment of mononuclear neutrophils and lymphocytes. This cascade results in exaggerated inflammation and atherosclerosis. MIF's distinctive characteristics and functions make it an essential target for achieving therapeutic atherosclerosis regression, setting it apart from other cytokines. Hence, this study aims to detect the MIF gene polymorphism in ACS patients and to assess the incidence of in-hospital major adverse cardiac events (MACE). Methodology This study was conducted in a tertiary care hospital. A total of 90 patients who had ACS were enrolled, of which 83 were included, and seven patients were excluded based on exclusion criteria (four cases of old myocardial infarction, two cases of valvular heart disease, and one case of dilated cardiomyopathy). After detailed clinical examination, laboratory evaluation, and genetic test, patients were divided into two groups based on MIF gene mutation. Five patients who had positive MIF gene mutation were termed as group A (n=5), and 78 patients with negative MIF gene mutation were termed as group B (n=78). The statistical analysis for the collected data was done using IBM SPSS Statistics for Windows, Version 20 (Released 2011; IBM Corp., Armonk, New York, USA). Results Out of the 83 patients in this study, the male gender was predominant; there were three male patients in group A (n=3; 60%) and 48 male patients in group B (n=48; 61.5%). The most common age group was between 60 and 69 years; two of five patients (n=2; 40%) in group A and 30 out of 78 patients (n=30; 38.4%) in group B belonged to this age group. The common symptom was chest pain present in five patients in group A (n=5; 100%) and 76 patients (n=76; 97.5%) in group B. A common risk factor in group A patients was tobacco chewing, seen in three patients (n=3; 60%), and group B smoking was the most common risk factor seen in 30 patients (n=30; 38.5%). The most common ECG finding in group A was ST-elevation myocardial infarction (STEMI), seen in three patients (n=3; 60%), and in group B, the commonest ECG finding was non-ST-elevation myocardial infarction (NSTEMI) seen in 23 patients (n=23; 29.5%). The most common MACE was heart failure seen in two patients in group A (n=2; 40%) and in 50 patients in group B (n=50; 64.1%), followed by arrhythmias seen in one patient in group A (n=1; 20%), and eight patients in group B (n=8; 10.3%). Conclusion This study demonstrated a significant positive association between MIF gene polymorphism and the occurrence of cardiovascular events like myocardial infarction, with a statistically significant p-value (p=0.001). This study showed the presence of the disease in young age groups and individuals without conventional risk factors, underscoring the importance of genetic studies. Genetic risk factors independently contribute to the pathophysiology of coronary artery disease; hence, understanding the mechanisms of these genes and incorporating genetic testing into standard clinical practice can help future research to develop therapeutic agents that can specifically target these genes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee BLDE (Deemed to Be University) issued approval BLDE(DU)/IEC/748/2022-23. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, M J et al.)

Background Ischemic stroke, characterized by the obstruction of blood flow to the brain, is a major cause of morbidity and mortality worldwide. The severity of ischemic stroke is commonly assessed using the National Institutes of Health Stroke Scale (NIHSS), which helps predict patient outcomes. Recent research suggests a potential link between low vitamin D levels and an increased risk of cerebrovascular events, including ischemic stroke. However, the specific relationship between vitamin D deficiency and stroke severity remains underexplored. Objectives The study aimed to investigate the correlation between serum vitamin D levels and NIHSS scores in patients with ischemic stroke to determine whether vitamin D deficiency is associated with the severity of neurological deficits in these patients. Materials and methods This prospective observational study was conducted at Saveetha Medical College, Chennai, and involved 86 patients presenting with acute ischemic stroke. Inclusion criteria were age ≥18 years, a confirmed diagnosis of acute ischemic stroke by neuroimaging, and presentation within 24 hours of symptom onset. Exclusion criteria included hemorrhagic stroke, conditions affecting vitamin D metabolism, and current vitamin D supplementation. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured using chemiluminescence immunoassay (CLIA), and NIHSS scores were assessed within 24 hours of admission. Statistical analyses included Pearson's correlation and multivariate linear regression to adjust for confounding variables. Results The study found that lower serum 25(OH)D levels were correlated with higher severity of stroke symptoms, as indicated by a significant negative correlation between 25(OH)D levels and NIHSS scores at admission (Pearson correlation coefficient r = -0.4081, p < 0.001). Multivariate regression analysis confirmed this association (β = -0.3994, p < 0.001) after adjusting for age, sex, and comorbidities, with p < 0.05 considered statistically significant. In addition, age (β = 0.1123, p = 0.009) and comorbid conditions (β = 0.9565, p = 0.008) were significantly associated with higher NIHSS scores. Conclusion The study demonstrates a significant negative correlation between serum 25-hydroxyvitamin D levels and ischemic stroke severity, suggesting that higher vitamin D levels may be associated with less severe strokes. Further research is needed to explore the mechanistic pathways and therapeutic potential of vitamin D in stroke management. Emphasizing the importance of maintaining adequate vitamin D levels could be crucial for potentially reducing stroke severity and improving patient outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Saveetha Medical College and Hospital Institutional Ethics Committe issued approval 022/03/2023/IEC/SMCH. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Simon et al.)

Background/Objectives : Chronic limb-threatening ischaemia (CLTI) is a significant life and limb-threatening condition. Two recent seminal trials, BEST-CLI and BASIL-2, have provided seemingly conflicting results concerning the optimal treatment modality for patients with CLTI. We sought to investigate the outcomes of patient undergoing infrainguinal bypass at two centres in Aotearoa New Zealand. Methods : A cross-sectional retrospective review of all patients who underwent infrainguinal bypass grafting for CLTI at Auckland City Hospital and Waikato Hospital between January 2020 and December 2021 was performed. The primary outcome was a composite of death, above-ankle amputation, and major limb reintervention. The secondary outcome was minor limb reintervention. Kaplan-Meier survival analysis was performed to determine time to the primary and secondary endpoints. Demographic factors were examined using the log-rank test to examine the effect on the outcome. Results: One hundred and nineteen patients who underwent infrainguinal bypass for CLTI in the study period were identified. Of these, 93 patients had a bypass with ipsilateral or contralateral GSV. The median follow-up time was 1.85 years. The most common indication for surgery was tissue loss (69%, n = 63), with the most common distal bypass target being the below-knee popliteal artery (45%, n = 41). The primary composite outcome occurred in 42.8% of the cohort ( n = 39). Death was the most common component of the primary outcome (26%, n = 24). Male sex (HR 0.48, 95% CI 0.26-0.88, p = 0.018) and statin use (HR 0.49, 95% CI 0.24-0.98, p = 0.044) were independent predictors of protection from the composite outcome on multivariate analysis. Dialysis dependence (HR 3.32, 95% CI 1.23-8.99, p = 0.018) was an independent predictor for patients meeting the composite outcome. Conclusions : This study's results are consistent with the published outcomes of BEST-CLI. The patient cohorts examined, anatomical disease patterns, and conduit use may explain some of the differences observed between this study, BEST-CLI and BASIL-2. Further work is required to define the specific patient populations who will benefit most from an open surgical or endovascular first approach to the management of CLTI.

Introduction ST-segment elevation myocardial infarction (STEMI) is an acute presentation of myocardial infarction (MI). It is caused by the complete occlusion of coronary arteries by a thrombus secondary to atherosclerotic plaque formation within these vessels. The Thrombolysis in Myocardial Infarction (TIMI) risk score is a seven-item scale used to categorize patients based on risk and to predict mortality in acute MI patients. The neutrophil-to-lymphocyte ratio (NLR) is an independent assessor of prognosis in cardiovascular diseases; it holds a pivotal role in inflammation and atherosclerotic plaque formation. Methodology A hospital-based cross-sectional study was undertaken among 76 patients who had acute MI, out of which 50 patients who had STEMI were included and 26 patients were excluded (13 patients had non-ST-segment elevation myocardial infarction (NSTEMI), four patients had unstable angina, nine patients had arrhythmias). After detailed clinical and laboratory evaluation, NLR was calculated for all 50 patients, and they were distributed into low NLR, intermediate NLR and high NLR groups based on the ratio. Patients then underwent coronary angiography, and their TIMI-STEMI score was calculated and compared with their NLR score. Using SPSS software (IBM Corp., Armonk, NY, USA), the collected data was statistically analyzed. Results Fifty patients with acute coronary syndrome (ACS) based on their NLR were distributed into three categories: Category A with low NLR of <1.7 (n=2), Category B with intermediate NLR of 1.7-3 (n=10), and Category C with high NLR of >3 (n=38). In this study, there were more male patients (two in Category A, six in Category B, 28 in Category C), mean age group was 55 +/- 10 (one in Category A, five in Category B, 32 in Category C), the most common presentation was chest pain (two in Category A, nine in Category B, 37 in Category C), the most common risk factor was smoking (two in Category A, six in Category B, 15 in Category C), the angiographic TIMI-STEMI score was calculated and two, six, and two patients in Category A, Category B, Category C respectively had a low score of <4, four and 36 patients in Category B and C respectively had a high score of >4, and there was a significant correlation between high NLR and high TIMI-STEMI score (P = 0.001). Conclusion This study infers that a simple bedside parameter like the NLR, which is easily available and affordable, can predict the outcome in STEMI patients and stands on par with conventional angiographic scores., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee BLDE (Deemed to be University) issued approval BLDE (DU)/IEC/1095/2023-24. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Badiger et al.)

Background Acute ST-elevation myocardial infarction (STEMI) is the most common cause of mortality across the world. The electrocardiogram (ECG) Tpeak-Tend/QT interval appears to be a measure of the left ventricle's transmural dispersion of repolarization (TDR). Prolongation of this time could indicate adverse cardiac events like heart failure, arrhythmias, etc. Heart failure is a clinical syndrome that includes signs and symptoms such as peripheral edema and high jugular vein pressure. N-terminal pro B-type natriuretic peptide (NT-proBNP) is an effective predictor of left ventricular function and also helps in predicting the disease prognosis. Elevated levels of NT-proBNP are seen in many cases of left ventricular dysfunction. This study aims to evaluate the predictive utility of the Tpeak-Tend/QT interval ratio in predicting major adverse cardiac events (MACEs), such as heart failure, by examining the Tend/QT interval ratio values with NT-proBNP in STEMI. Methodology This cross-sectional study was conducted at a tertiary hospital between April 2024 and June 2024. It included STEMI patients, excluding those with non-STEMI (NSTEMI), valvular heart diseases, bundle branch block, or pacemakers. The patients with a Tpeak-Tend/QT ratio < 0.3 were included in group A, and the Tpeak-Tend/QT ratio > 0.3 in group B. They were monitored for MACE-like heart failure during hospitalization and were compared with a study of the Tpeak-Tend/QT interval ratio in predicting heart failure in STEMI and its correlation with NT-proBNP levels. Results In this study, out of 45 patients, male predominance was observed, with 35 (78%) being men and 10 (22%) being women. In group A, the most common age group was 60-70 years, with 16 (51%) patients; in Group B, it was 50-60 years, with six (42.8%) patients. Out of 31 patients in group A, 25 were male, and six were female. In group B, out of 14 patients, 10 were male, and four were female. In this study, out of the 45 patients included, 12 (85%) among 14 patients who had MACEs like heart failure had a Tpeak-Tend/QT interval ratio of more than 0.3, and their measured NT-proBNP levels were also more than 900 pg/mL, thus showing a statistically significant association between Tpeak-Tend/QT interval ratio and NT-proBNP. Conclusion The present study showed an increased Tpeak-Tend/QT interval ratio and NT-proBNP in patients who developed heart failure in STEMI. As ECG is a readily available and affordable tool, the Tpeak-Tend/QT interval ratio can be used along with conventional markers like NT-proBNP to predict MACE in patients with STEMI., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional ethics committee BLDE (Deemed to be University) Vijayapura issued approval BLDE (DU)/IEC/1093/2023-24. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Badiger et al.)

Background: Dental caries remains a significant oral health concern, particularly in young children. With an increasing interest in preventive strategies, pediatric and preventive dentistry research is now more focused on developing newer materials and techniques to coat the primary teeth to prevent the onset of new carious lesions. While traditional preventive measures such as fluoride application and sealants have been effective in reducing caries incidence, there is still a need for innovative approaches., Aim: To evaluate the effectiveness of surface prereacted glass ionomer (S-PRG) light-cured varnish in inhibiting demineralization of primary teeth enamel., Materials and Methods: In this study, primary teeth samples were randomly divided into two groups: the control group received no coating, while the test group received an S-PRG filler coat. The samples were allowed to demineralize, and various analyses, including Fourier transform infrared (FTIR) spectroscopy, scanning electron microscope (SEM), energy-dispersive X-ray analysis (EDX), and Vickers microhardness analysis, were conducted. Additionally, biofilms of Streptococcus mutans and Enterococcus faecalis were developed on solid surfaces such as microtiter plates, glass, and dentures, and the quantity of bacterial biofilm was measured using crystal violet assay and fluorescence microscopy., Results: The study results showed that the primary teeth samples in both groups had a significantly greater calcium content than the controls. The S-PRG group demonstrated a significant reduction in the development of biofilms of S. mutans and E. faecalis, as well as bacterial attachment to glass and denture surfaces compared to the control group, as indicated by crystal violet assay and fluorescence microscopy., Conclusion: The findings of this study suggest that S-PRG filler-containing coating materials have the potential to prevent demineralization and inhibit S. mutans and E. faecalis biofilm formation on primary tooth enamel., Clinical Significance: These results are promising and may have implications for the prevention of dental caries in young children., How to Cite This Article: Fernandes RM, Kumar S, Suvarna R, et al. Surface Prereacted Glass Ionomer Varnish as a Multifaceted Anticaries Agent: Investigating its Inhibitory Effects on Demineralization and Biofilm Formation on Primary Tooth Enamel. Int J Clin Pediatr Dent 2024;17(9):1049-1056., Competing Interests: Source of support: R P Shastry was supported by ICMR-DHR, Government of India, New Delhi (ICMR/5/13/84/2020/NCD-III dated 16/03/2021) in acquiring biofilms of Streptococcus mutans and Enterococcus faecalis. Conflict of interest: NoneConflict of interest: None, (Copyright © 2024; The Author(s).)

Background and Aims: Gastric varices (GVs) are reported in up to 20% of patients with portal hypertension, and bleeding is often more severe and challenging than esophageal variceal bleeding. Data are limited on prophylaxis of GV bleeding or management in the acute setting, and different techniques are used. This study evaluated outcomes after EUS-guided placement of coils in combination with thrombin to manage GVs., Methods: We retrospectively reviewed all patients treated with combination EUS-guided therapy with coils and thrombin between October 2015 and February 2020., Results: Twenty patients underwent 33 procedures for GV therapy; 16 of 20 (80%) had type 1 isolated GVs and 4 patients had type 2 gastroesophageal varices. The median follow-up was 842 days (interquartile range [IQR], 483-961). Seventeen patients (85%) had underlying cirrhosis, the most common etiologies being alcohol-related liver disease and nonalcoholic steatohepatitis. The median Child-Pugh score was 6 (IQR, 5-7). In 11 patients (55%), the indication was secondary prophylaxis to prevent recurrent bleeding; in 2 of 20 patients (10%), the bleeding was acute. Technical success was achieved in 19 patients (95%). During follow-up, the obliteration of flow within the varices was achieved in 17 patients (85%). The 6-week survival rate was 100%, and 2 adverse events, recurrent bleeding at day 5 and at day 37, were reported; both recurrent bleeding events were successfully managed endoscopically., Conclusions: EUS-guided GV obliteration combining coil placement with thrombin, in our experience, was technically safe with good medium-term efficacy. A multicenter randomized controlled trial comparing different treatment strategies is desirable to understand options better., Competing Interests: Disclosure The following author disclosed financial relationships: D. Tripathi: Speaker and consultant for Gore Medical. All other authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Modern medicine is well-versed in aseptic and infection control practices, such as hand hygiene, proper use of disinfectants, and personal protective equipment. The early 1800s lacked any concept of effective antisepsis because they predominantly believed in the miasma theory (now abandoned), which believed that disease was caused by bad air coming out of rotting organic matter. In the era of "miasma theory," Ignaz Semmelweis dared to pave the way for germ theory disease. Vienna General Hospital supported his work, but his hypothesis remained unpublished and unheard by the rest of the world. In 1861, his major publication, "The etiology, concept, and prophylaxis of childbed fever," sparked strong opposition and rejection of his theories. His mental condition deteriorated due to the strong rejection and criticism from his peers, leading to the development of amnesia, anxiety, and severe depression. He was unfortunately admitted to an Austrian asylum, where he was confined and beaten. Eventually, the man who conquered puerperal fever succumbed to septicemia due to an infected wound from the beating., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Dash et al.)

The hypothalamic-pituitary-adrenal (HPA) axis plays a pivotal role in the body's response to stress, orchestrating the release of glucocorticoids. In chronic scenarios, these glucocorticoids contribute to various neurological disorders, including Alzheimer's disease (AD) and depression. This abstract explores the potential mechanisms through which HPA axis dysregulation links stress-induced pathways to the pathogenesis of AD and subsequent depression. Chronic stress triggers prolonged HPA axis activation, resulting in elevated cortisol levels, which can lead to hippocampal atrophy, synaptic dysfunction, and neuroinflammation, recognized as key pathological features of AD. These alterations impair cognitive function and may exacerbate amyloid-beta plaque formation and tau hyperphosphorylation, hallmarks of AD. Concurrently, persistent cortisol elevation affects the prefrontal cortex and limbic structures, contributing to depressive symptoms. The interplay between chronic stress, HPA axis dysregulation, and neuroinflammation is crucial in understanding the comorbidity of AD and depression. Unveiling these mechanisms provides insights into potential therapeutic targets aimed at modulating the HPA axis and reducing stress-induced neurodegeneration, offering a dual benefit in managing both AD and depression. Further research is essential to elucidate the precise molecular pathways and develop effective interventions to mitigate the impact of chronic stress on brain health., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, P et al.)

Tropical co-infections, characterized by overlapping clinical manifestations and the potential for diagnostic confusion, pose significant challenges in the management of febrile illnesses in endemic regions. This case report presents a 33-year-old male with a five-day history of fever, gastrointestinal symptoms, and dry cough, ultimately diagnosed with co-infections of dengue, leptospirosis, and Salmonella paratyphi A . This case underscores the challenges posed by the overlapping clinical features of endemic tropical diseases, emphasizing the necessity for comprehensive diagnostic strategies and tailored treatment protocols in managing febrile illnesses in endemic regions. Clinicians must also consider serological cross-reactivity when interpreting diagnostic tests, as it can complicate the identification of co-infections and impact treatment decisions, necessitating vigilance and an integrated approach in clinical practice., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Simon et al.)

Background: United States drug overdose deaths are being driven by the increasing prevalence of fentanyl, but whether patients are knowingly using fentanyl is unclear. We examined the analytical confirmation of fentanyl in emergency department (ED) patients with documented heroin overdose., Hypothesis: We hypothesized that the proportion of fentanyl and fentanyl analogs would be higher than that of confirmed heroin., Methods: This is a subgroup analysis from a prospective multicenter consecutive cohort of ED patients age 18+ with opioid overdose presenting to 10 US sites within the Toxicology Investigators Consortium from 2020 to 2021. Toxicology analysis was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. De-identified toxicology results were paired with the clinical database. The primary outcome was the proportion of patients with fentanyl analytes detected in their serum., Results: Of 1006 patients screened, 406 were eligible, and of 168 patients who reported that they had taken heroin or had a documented heroin overdose, 88% ( n  = 147) were in fact found to have fentanyl and/or a fentanyl analog present on serum analysis ( p  < 0.0001). In contrast, only 46 of the 168 patients with reported or documented heroin overdose (27%) were found to have heroin biomarkers present., Conclusion: The prevalence of confirmed fentanyl in ED patients with suspected heroin overdose was extremely high, while the prevalence of heroin was very low. There was a high degree of mismatch between the opioids believed to be the overdose agent versus the actual opioids identified on serum toxicology. Clinicians in the United States should presume that fentanyl is involved in all illicit opioid overdoses and should counsel patients on harm reduction measures., Competing Interests: The authors declare no commercial conflicts of interest., (© 2024 The Author(s). Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Diabetic striatopathy (DS) is an acute hyperkinetic movement disorder arising from non-ketotic hyperglycemia. This condition predominantly affects females and is more common in the elderly, highlighting the interplay between diabetes, striatal pathology, and neurological movement disorders. DS is characterized by involuntary movements, such as hemichorea or hemiballism, and distinctive neuroimaging findings that can be mistaken for more common cerebrovascular events. In this case report, we describe a 67-year-old female with a history of poorly controlled type 2 diabetes mellitus who presented with the sudden onset of involuntary movements affecting her left upper and lower limbs. Clinical examination and laboratory investigations revealed hyperglycemia without ketosis. Neuroimaging via computed tomography (CT) of the brain identified a hyper density in the right lentiform nucleus, consistent with DS. The patient was treated with vesicular monoamine transporter 2 (VMAT) inhibitors, oral hypoglycemic agents, and insulin, resulting in marked symptom improvement over 10 days. This case underscores the importance of recognizing DS as a differential diagnosis in patients with hyperkinetic movement disorders and hyperglycemia. Proper diagnosis and management, including stringent glycemic control, are crucial for symptom resolution., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nilofar et al.)

This case report describes the successful management of a 23-year-old male with traumatic aortic aneurysm and dissection, concomitant with bilateral lower limb fractures, highlighting the complexities and challenges of managing such a patient. The patient presented with extensive trauma, including chest pain, cough, and hoarseness of voice, and was diagnosed with a large fusiform aneurysm and dissection of the aorta. A multidisciplinary approach was adopted, and the patient underwent open reduction and internal fixation (ORIF) under combined spinal-epidural anesthesia. Meticulous hemodynamic control and vigilant monitoring ensured a stable intraoperative course. The aortic aneurysm was managed conservatively, and the patient was closely monitored for complications. This case report emphasizes the importance of interdisciplinary synergy, meticulous planning, and vigilant monitoring in managing high-risk patients and demonstrates the successful implementation of evidence-based practices in mitigating potential risks. The patient's successful outcome highlights the impact of collaboration between anesthesiologists, orthopedic surgeons, cardiovascular surgeons, and intensivists in managing complex and daunting injuries., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bagle et al.)

An open-label, single-center, phase I study was conducted to determine the absolute bioavailability and absorption, distribution, metabolism, and excretion of capivasertib-a potent, selective AKT serine/threonine kinase inhibitor-in healthy males. In part 1, six participants received a single oral dose of capivasertib (400 mg; tablets) followed by a [ 14 C]-radiolabeled intravenous microdose of capivasertib (100 μ g). After a 14-day washout, five of the participants proceeded to part 2 and received a single oral dose of [ 14 C]capivasertib (400 mg; solution). In part 1, median time of maximum observed concentration for capivasertib was 1.7 hours, geometric mean terminal elimination half-life was 12.9 hours, and absolute bioavailability was estimated at 28.6% (90% confidence interval, 23.9 to 34.2). In part 2, a high proportion of the administered radioactivity was recovered over the 168-hour sampling period [mean recovery: 95.1% (feces, 50.4%; urine, 44.7%)]. Unchanged capivasertib in urine accounted for 7.4% of the total dose and 21.1% of the systemically available drug. Geometric mean renal clearance was 8.3 L/h, suggesting active tubular secretion. Twelve metabolites were identified in plasma. M11 (AZ14102143)-the glucuronide conjugate of capivasertib, inactive as an AKT serine/threonine kinase inhibitor-was the most abundant, accounting for a mean 78.4% of the plasma drug-related area under the curve. Of 22 metabolites identified in excreta, M11 was the most abundant (mean 28.2% of administered dose), indicating direct glucuronidation as one of the major routes of metabolism. No new safety concerns were identified. SIGNIFICANCE STATEMENT: This study provides characterization of the pharmacokinetics of capivasertib-a potent, selective AKT serine/threonine kinase (AKT) inhibitor-including absolute bioavailability, mass balance, and metabolic fate in humans; the findings are being used to inform further clinical development. Absolute bioavailability was estimated at 28.6%, and mean recovery of the administered dose in excreta over 168 hours was 95.1%. M11 (AZ14102143)-the glucuronide conjugate, inactive as an AKT inhibitor-was the most abundant identified metabolite in plasma and excreta., (Copyright © 2024 by The Author(s).)

Ethylene dimerization is an efficient industrial chemical process to produce 1-butene, with demanding selectivity and activity requirements on new catalytic systems. Herein, a series of monodentate phosphinoamine-nickel complexes immobilized on UiO-66 are described for ethylene dimerization. These catalysts display extensive molecular tunability of the ligand similar to organometallic catalysis, while maintaining the high stability attributed to the metal-organic framework (MOF) scaffold. The highly flexible postsynthetic modification method enables this study to prepare MOFs functionalized with five different substituted phosphines and 3 N-containing ligands and identify the optimal catalyst UiO-66-L5-NiCl 2 with isopropyl substituted nickel mono-phosphinoamine complex. This catalyst shows a remarkable activity and selectivity with a TOF of 29 000 (mol ethyl /mol Ni /h) and 99% selectivity for 1-butene under ethylene pressure of 15 bar. The catalyst is also applicable for continuous production in the packed column micro-reactor with a TON of 72 000 (mol ethyl /mol Ni ). The mechanistic insight for the ethylene oligomerization has been examined by density functional theory (DFT) calculations. The calculated energy profiles for homogeneous complexes and truncated MOF models reveal varying rate-determining step as β-hydrogen elimination and migratory insertion, respectively. The activation barrier of UiO-66-L5-NiCl 2 is lower than other systems, possibly due to the restriction effect caused by clusters and ligands. A comprehensive analysis of the structural parameters of catalysts shows that the cone angle as steric descriptor and butene desorption energy as thermodynamic descriptor can be applied to estimate the reactivity turnover frequency (TOF) with the optimum for UiO-66-L5-NiCl 2 . This work represents the systematic optimization of ligand effect through combination of experimental and theoretical data and presents a proof-of-concept for ethylene dimerization catalyst through simple heterogenization of organometallic catalyst on MOF., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. All authors report support from the National Institute on Drug Abuse of the National Institutes of Health. No other potential conflicts of interest were disclosed.

Hurst disease, or Weston-Hurst syndrome, or acute hemorrhagic encephalomyelitis (AHEM), is an infrequent condition that usually gets provoked after a viral infection (respiratory tract infection) or, as reported in many case reports, post-vaccination. Hurst disease is a difficult-to-diagnose condition because it mimics common presentations such as stroke, decreased or loss of consciousness, brain abscess, and seizures, making clinical diagnosis challenging. Radiological imaging, such as magnetic resonance imaging (MRI) of the brain with diffusion-weighted imaging, now serves as the primary modality to identify such conditions, despite its lack of specificity. The treating doctor needs to do an in-depth analysis of the patient's history, as this carries a very high mortality rate. We hereby discuss a case that presented with seizures and deteriorating Glasgow Coma Scale (GCS) score, on imaging revealed posterior circulation acute hemorrhagic leukoencephalitis (AHLE)/AHEM, therein treated with steroids, plasmapheresis resulted in a good outcome implicating, early detection and timely management can reduce the mortality due to this condition., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Singh et al.)

Progressive multifocal leukoencephalopathy (PML) is considered an often fatal, demon-leading disease primarily associated with immunosuppression. Immunocompromised individuals predominantly exhibit this manifestation, while immunocompatible patients rarely encounter it. We present a unique case of PML in an immunocompetent individual who initially presented with stroke-like symptoms, received management, and was subsequently discharged. He returned to our hospital a few days later with similar complaints, prompting further investigations that revealed PML, a condition often overlooked, especially in individuals with an intact immune system. Although he received successful treatment with mefloquine and other anti-malarial medications and followed up on an outpatient basis, his subsequent outcome was unfavourable. As a result, this case emphasises the importance of having PML as a significant differential and therapeutic option., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Arumugam et al.)

Current convolutional neural networks (CNNs) are not designed for large scientific images with rich multi-scale features, such as in satellite and microscopy domain. A new phase of development of CNNs especially designed for large images is awaited. However, application-independent high-quality and challenging datasets needed for such development are still missing. We present the 'UltraMNIST dataset' and associated benchmarks for this new research problem of 'training CNNs for large images'. The dataset is simple, representative of wide-ranging challenges in scientific data, and easily customizable for different levels of complexity, smallest and largest features, and sizes of images. Two variants of the problem are discussed: standard version that facilitates the development of novel CNN methods for effective use of the best available GPU resources and the budget-aware version to promote the development of methods that work under constrained GPU memory. Several baselines are presented and the effect of reduced resolution is studied. The presented benchmark dataset and baselines will hopefully trigger the development of new CNN methods for large scientific images., (© 2024. The Author(s).)

The Toxicology Investigators Consortium (ToxIC) was launched as a prospective multi-center registry of cases who receive medical toxicology consultations. Now, with over 100,000 cases, the Core Registry continues to address many medical toxicology research questions and has served as the foundation for multiple sub-registries, including the North American Snakebite Registry and the Medications for Opioid Use Disorder sub-registry. ToxIC also has evolved a portfolio of non-registry-based projects utilizing medical toxicology physician site principal investigators who enroll patients through emergency departments, irrespective of whether they received a medical toxicology consultation. These studies include the FDA-ACMT COVID-19 ToxIC Pharmacovigilance Project, which identifies adverse drug reactions related to the treatment of COVID-19, the Fentalog Study a toxico-surveillance study of suspected opioid overdose cases, the Drug Overdose Toxico-Surveillance Reporting Program which enrolls either suspected stimulant or opioid overdose cases, and the just being launched Real-World Examination of Naloxone for Drug Overdose Reversal project. Given ToxIC's experience in multi-center studies and its well-developed infrastructure, it is well-positioned to provide a nimble response on the part of the medical toxicology community to addressing evolving toxicological threats, drug and chemical toxicosurveillance, and other important medical toxicology priorities., (© 2024. American College of Medical Toxicology.)

Background: The current approach to treatment of multiple sclerosis (MS) involves use of disease-modifying therapies to slow progression of the disease, as well as the symptomatic management of fixed neurological deficits. Although pharmacists are uniquely positioned to support MS care teams with all aspects of medication management, their presence is rare among MS ambulatory care teams in Canada., Objectives: To document the pharmacist's contributions and to evaluate the impact of the pharmacist's role following creation of a clinical pharmacist position in a Canadian MS clinic within a large, urban, university-affiliated, tertiary care centre., Methods: This study was conducted in 2 parts: a prospective, descriptive case study of the clinical pharmacist's role and a retrospective assessment of medication-related patient calls before and after implementation of the pharmacist position., Results: The pharmacist performed a variety of clinical activities, with the greatest proportions of time spent on patient care (63.3%), drug access research (15.7%), and development and review of internal documents (9.0%). Patient care primarily involved conducting patient assessments, making medication recommendations, and assisting patients with medication-related issues. The proportion of medication-related issues resolved remained similar at 92.9% before and 95.7% after implementation of the clinical pharmacist ( p = 0.48). The median time to resolve medication-related issues was reduced from 4.1 to 2.9 days ( p = 0.016) with pharmacist involvement., Conclusions: Pharmacists can support MS care teams through a variety of medication-related clinical activities aligned with their scope and expertise. The presence of a pharmacist on the MS care team significantly reduced turnaround times for resolving medication-related issues, improving the efficiency and timeliness of care., Competing Interests: Competing interests: Gabrielle Busque received a scholarship from the Consortium of Multiple Sclerosis Centers (CMSC) for travel to the organization’s 2023 annual meeting, where this project was presented as a poster. In uncompensated roles not related to the study reported here, Sharon Lail was a member of the Viiv Digital Advisory Board (2022–2023) and was Secretary of the Canadian HIV/AIDS Pharmacists Network (CHAP) in 2023/24. No other competing interests were declared., (2024 Canadian Society of Hospital Pharmacists. All content in the Canadian Journal of Hospital Pharmacy is copyrighted by the Canadian Society of Hospital Pharmacy. In submitting their manuscripts, the authors transfer, assign, and otherwise convey all copyright ownership to CSHP.)

Importance: This pilot study evaluates a remote strategy-based intervention for individuals with multiple sclerosis who experience everyday memory impairments. The intervention can potentially inform cognitive rehabilitation for this population., Objective: To investigate the feasibility and efficacy of an intervention (TELE-Self-GEN) to determine whether it can alleviate everyday memory impairments of individuals with multiple sclerosis., Design: Pretest-posttest., Setting: Community., Participants: Ten adults with multiple sclerosis., Intervention: Six synchronous treatment sessions were delivered online via Zoom. The treatment protocol embedded a memory strategy (self-generated learning) within a metacognitive framework, including self-awareness and self-management strategies. The treatment emphasizes when and how self-generation should be used., Outcome: Measurements assessed feasibility and participants' satisfaction with the intervention and its delivery method, as well as memory, everyday memory, and functional performance., Results: Participants expressed high satisfaction with the virtual treatment, highlighting its convenience as a key factor. Treatment resulted in improvements in memory performance, perceived memory ability in daily life, and functional performance., Conclusions and Relevance: Results provide initial proof of concept in the utilization of a remotely delivered, strategy-based treatment approach to improve memory performance and functional abilities. The pilot data support a larger randomized clinical trial of the TELE-self-GEN. Plain-Language Summary: The results of this pilot study highlight the promising potential of TELE-self-GEN for people with multiple sclerosis (MS), who face memory challenges every day. This remotely delivered, strategy-based occupational therapy treatment approach, TELE-self-GEN, has the potential to significantly improve functional memory. The study participants reported improvements in their memory performance, perceived memory ability in daily life, and functional performance. These encouraging results serve as a foundation for more extensive clinical trials using TELE-self-GEN for people with MS., (Copyright © 2024 by the American Occupational Therapy Association, Inc.)

Background: Gene therapy is an emerging treatment for sickle cell disease that works by replacing a defective gene with a healthy gene, allowing the body to produce normal red blood cells. This form of treatment has shown promising results in clinical trials, and is a promising alternative to traditional treatments. Gene therapy involves introducing a healthy gene into the body to replace a defective gene. The new gene can be delivered using a viral vector, which is a modified virus that carries the gene. The vector, carrying the healthy gene, is injected into the bloodstream. The healthy gene then enters the patient's cells and begins to produce normal hemoglobin, the protein in red blood cells that carries oxygen throughout the body., Methodology: We conducted an all-language literature search on Medline, Cochrane, Embase, and Google Scholar until December 2022. The following search strings and Medical Subject Heading (MeSH) terms were used: "Sickle Cell," "Gene Therapy" and "Stem Cell Transplantation". We explored the literature on Sickle Cell Disease for its epidemiology, etiopathogenesis, the role of various treatment modalities and the risk-benefit ratio of gene therapy over conventional stem cell transplant., Results: Gene therapy can reduce or eliminate painful episodes, prevent organ damage, and raise the quality of life for those living with the disease. Additionally, gene therapy may reduce the need for blood transfusions and other traditional treatments. Gene therapy has the potential to improve the lives of those living with sickle cell disease, as well as reduce the burden of the disease on society., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Plasma exchanges (PEX) and immunosuppression are the cornerstone of management of anti-factor H (FH) antibody-associated atypical hemolytic uremic syndrome (aHUS), particularly if access to eculizumab is limited. The duration of therapy with PEX for anti-FH aHUS is empirical., Methods: We compared the efficacy of abbreviated PEX protocol (10-12 sessions) in a prospective cohort of patients diagnosed with anti-FH aHUS (2020-2022), to standard PEX protocol (20-22 sessions) in a historical cohort (2016-2019; n = 65). Efficacy was defined as 70% decline in anti-FH titers or fall to ≤ 1300 AU/ml at 4 weeks. Patients in both cohorts received similar immunosuppression with oral prednisolone, IV cyclophosphamide (5 doses) and mycophenolate mofetil. Outcomes included efficacy, rates of hematological remission and adverse kidney outcomes at 1, 3 and 6 months., Results: Of 23 patients, 8.2 ± 2.1 years old enrolled prospectively, two were excluded for significant protocol deviation. PEX was abbreviated in 18/21 (86%) patients to 11.5 ± 3.3 sessions. Abbreviation failed for lack of hematological remission by day 14 (n = 2) and persistent neurological manifestations (n = 1). All patients in whom PEX was abbreviated achieved > 70% reduction in anti-FH titers at day 28. The percentage fall in anti-FH titers was similar for the abbreviated vs. standard PEX protocols at 1, 3 and 6 months. At last follow-up, at median 50 months and 25 months for standard and abbreviated cohorts, the estimated GFR was similar at 104.8 ± 29.1 vs. 93.7 ± 53.4, respectively (P = 0.42)., Conclusion: Abbreviation of the duration of PEX is feasible and efficacious in reducing anti-FH titers. Short-term outcomes were comparable in patients managed by abbreviated and standard PEX protocols., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Importance: Unlike medications, procedural interventions are rarely trialed against placebo prior to becoming accepted in clinical practice. When placebo-controlled trials are eventually conducted, procedural interventions may be less effective than previously believed., Objective: To investigate the importance of including a placebo arm in trials of surgical and interventional procedures by comparing effect sizes from trials of the same procedure that do and do not include a placebo arm., Data Sources: Searches of MEDLINE and Embase identified all placebo-controlled trials for procedural interventions in any specialty of medicine and surgery from inception to March 31, 2019. A secondary search identified randomized clinical trials assessing the same intervention, condition, and end point but without a placebo arm for paired comparison., Study Selection: Placebo-controlled trials of anatomically site-specific procedures requiring skin incision or endoscopic techniques were eligible for inclusion; these were then matched to trials without placebo control that fell within prespecified limits of heterogeneity., Data Extraction and Synthesis: Random-effects meta-regression, with placebo and blinding as a fixed effect and intervention and end point grouping as random effects, was used to calculate the impact of placebo control for each end point. Data were analyzed from March 2019 to March 2020., Main Outcomes and Measures: End points were examined in prespecified subgroups: patient-reported or health care professional-assessed outcomes, quality of life, pain, blood pressure, exercise-related outcomes, recurrent bleeding, and all-cause mortality., Results: Ninety-seven end points were matched from 72 blinded, placebo-controlled trials (hereafter, blinded) and 55 unblinded trials without placebo control (hereafter, unblinded), including 111 500 individual patient end points. Unblinded trials had larger standardized effect sizes than blinded trials for exercise-related outcomes (standardized mean difference [SMD], 0.59; 95% CI, 0.29 to 0.89; P < .001) and quality-of-life (SMD, 0.32; 95% CI, 0.11 to 0.53; P = .003) and health care professional-assessed end points (SMD, 0.40; 95% CI, 0.18 to 0.61; P < .001). The placebo effect accounted for 88.1%, 55.2%, and 61.3% of the observed unblinded effect size for these end points, respectively. There was no significant difference between unblinded and blinded trials for patient-reported end points (SMD, 0.31; 95% CI, -0.02 to 0.64; P = .07), blood pressure (SMD, 0.26; 95% CI, -0.10 to 0.62; P = .15), all-cause mortality (odds ratio [OR], 0.23; 95% CI, -0.26 to 0.72; P = .36), pain (SMD, 0.03; 95% CI, -0.52 to 0.57; P = .91), or recurrent bleeding events (OR, -0.12; 95% CI, -1.11 to 0.88; P = .88)., Conclusions and Relevance: The magnitude of the placebo effect found in this systematic review and meta-regression was dependent on the end point. Placebo control in trials of procedural interventions had the greatest impact on exercise-related, quality-of-life, and health care professional-assessed end points. Randomized clinical trials of procedural interventions may consider placebo control accordingly.

Objective: The menstrual cycle often presents barriers to participation in daily life activities, including physical activity (PA), which is a cornerstone of health and well-being. The purpose of this systematic review was to explore and summarize the impact of symptoms, experiences, and perceptions of the menstrual cycle on recreational PA (RPA), including sports, exercise and active recreation, in the general population., Methods: Six databases were searched for studies that investigated the impact of the menstrual cycle on PA among individuals who were cyclically menstruating, healthy, and not involved in professional sports training., Results: The search yielded 3025 studies that were screened for relevance and eligibility, resulting in 25 eligible studies, which were found to be of moderate-to-high quality following a quality and risk-of-bias assessment. Thematic synthesis of qualitative and quantitative data from the selected studies, constituting 16,557 adults and 3715 adolescents, identified the impact of menstrual symptoms on the physical and psychological capability to participate in RPA, social opportunity barriers to RPA (e.g., social pressure due to the sociocultural taboo against menstruation), as well reflective (knowledge) and automatic (habit) motivation on RPA behaviours., Conclusion: The variability in menstrual symptoms and corresponding experiences suggested the need for an individualized approach to RPA promotion. Furthermore, this review highlighted the need to address the sociocultural taboo against menstruation, as well as improve the provision of knowledge and resources related to the menstrual cycle and RPA, in order to promote and facilitate RPA for cyclically menstruating individuals throughout the menstrual cycle., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Current scores for predicting sepsis outcomes are limited by generalizability, complexity, and electronic medical record (EMR) integration. Here, we validate a simple EMR-based score for sepsis outcomes in a large multi-centre cohort., Design: A simple electronic medical record-based predictor of illness severity in sepsis (SEPSIS) score was developed (4 additive lab-based predictors) using a population-based retrospective cohort study., Setting: Internal medicine services across four academic teaching hospitals in Toronto, Canada from April 2010-March 2015 (primary cohort) and 2015-2019 (secondary cohort)., Patients: We identified patients admitted with sepsis based upon receipt of antibiotics and positive cultures., Measurements and Main Results: The primary outcome was in-hospital mortality and secondary outcomes were ICU admission at 72 hours, and hospital length of stay (LOS). We calculated the area under the receiver operating curve (AUROC) for the SEPSIS score, qSOFA, and NEWS2. We then evaluated the SEPSIS score in a secondary cohort (2015-2019) of hospitalized patients receiving antibiotics. Our primary cohort included 1,890 patients with a median age of 72 years (IQR: 56-83). 9% died during hospitalization, 18.6% were admitted to ICU, and mean LOS was 12.7 days (SD: 21.5). In the primary and secondary (2015-2019, 4811 patients) cohorts, the AUROCs of the SEPSIS score for predicting in-hospital mortality were 0.63 and 0.64 respectively, which were similar to NEWS2 (0.62 and 0.67) and qSOFA (0.62 and 0.68). AUROCs for predicting ICU admission at 72 hours, and length of stay > 14 days, were similar between scores, in the primary and secondary cohorts. All scores had comparable calibration for predicting mortality., Conclusions: An EMR-based SEPSIS score shows a similar ability to predict important clinical outcomes compared with other validated scores (qSOFA and NEWS2). Because of the SEPSIS score's simplicity, it may prove a useful tool for clinical and research applications., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Cressman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The success of prime editing depends on the prime editing guide RNA (pegRNA) design and target locus. Here, we developed machine learning models that reliably predict prime editing efficiency. PRIDICT2.0 assesses the performance of pegRNAs for all edit types up to 15 bp in length in mismatch repair-deficient and mismatch repair-proficient cell lines and in vivo in primary cells. With ePRIDICT, we further developed a model that quantifies how local chromatin environments impact prime editing rates., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Case: A 37-year-old man American Society of Anesthesiologists grade 1 patient with lumbar canal stenosis at the L4-L5 level underwent endoscopic decompression. Toward the end of the procedure, the patient developed sudden-onset bradycardia, followed by ventricular arrhythmia and acute pulmonary edema. The patient was successfully managed with resuscitation and supportive management and recovered uneventfully thereafter. A diagnosis of perioperative stress cardiomyopathy was subsequently made after evaluation of the patient., Conclusion: The possibility of takotsubo cardiomyopathy should be considered in cases of acute perioperative cardiac decompensation and pulmonary edema in patients undergoing spinal surgery., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C358)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

von Hippel-Lindau (VHL) syndrome (OMIM #193300) is an autosomal dominant disorder with incomplete penetrance occurring due to a mutation in the VHL gene present on chromosome 3. We present the case of a 21-year-old male with a history of retinoblastoma presenting with intermittent headaches for one month. He was a known hypertensive and his blood pressure on presentation was 180/100 mmHg. A secondary cause for his hypertension was sought. Multiple cysts in his pancreas, both his kidneys, and a mass in the right suprarenal fossa were detected on an abdominal ultrasonogram and a subsequent computed tomography scan of the abdomen. VHL and a pheochromocytoma were suspected, and a positron emission tomography-computed tomography scan was done which collaborated with the above findings. The presence of multiple cystic lesions in the pancreas and kidneys, especially in an individual with a family history of VHL syndrome, should alert the physician to the possibility of VHL syndrome. The need for evaluation of causes for hypertension, especially in young individuals with resistant hypertension, is also highlighted., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bose et al.)

Despite linkage to chromosome 16q in 1996, the mutation causing spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, remained unknown. Here, using long-read single-strand whole-genome sequencing (LR-GS), we identified a heterozygous GGC-repeat expansion in a large Utah pedigree encoding polyglycine (polyG) in zinc finger homeobox protein 3 (ZFHX3), also known as AT-binding transcription factor 1 (ATBF1). We queried 6,495 genome sequencing datasets and identified the repeat expansion in seven additional pedigrees. Ultrarare DNA variants near the repeat expansion indicate a common distant founder event in Sweden. Intranuclear ZFHX3-p62-ubiquitin aggregates were abundant in SCA4 basis pontis neurons. In fibroblasts and induced pluripotent stem cells, the GGC expansion led to increased ZFHX3 protein levels and abnormal autophagy, which were normalized with small interfering RNA-mediated ZFHX3 knockdown in both cell types. Improving autophagy points to a therapeutic avenue for this novel polyG disease. The coding GGC-repeat expansion in an extremely G+C-rich region was not detectable by short-read whole-exome sequencing, which demonstrates the power of LR-GS for variant discovery., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

We conducted a pre-post intervention study to determine knowledge, attitude, and practice toward dietary salt intake before, immediately, and 1-month after nurse-led one-on-one counseling. We purposively selected three public health facilities in Agra, India, and enrolled all eligible hypertensive patients aged 18-60 under treatment for ≥6 months. Of the 153 patients at the 1-month follow-up, counseling improved knowledge (4% vs. 42%, p < .001), a greater prioritization of a low salt diet (34% vs. 52%, p < .001), and practice of adding less salt to the dough (48% to 41%, p < .001). The counseling intervention improved knowledge, attitude, and practice toward dietary salt intake., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Axial spondyloarthritis (SpA) is a chronic inflammatory condition predominantly affecting the sacroiliac joints and spine, typically presenting before the age of 45 years with inflammatory back pain. However, diagnostic challenges arise when atypical features and negative autoimmune markers obscure the clinical picture. We present a case of a male in his 40s with no significant medical history, presenting with a three-month history of inflammatory back pain. Despite negative human leukocyte antigen B27 (HLA-B27) status, clinical examination, including positive findings on the FABER (flexion, abduction, and external rotation) test and exaggerated muscle tenderness, raised suspicion of axial SpA. An MRI of the pelvis confirmed bilateral symmetrical sacroiliitis, supporting the diagnosis. Unexpectedly, further investigations revealed a very low vitamin D level, normal calcium levels, and elevated parathyroid hormone (PTH), suggesting secondary hyperparathyroidism. A subsequent PET scan disclosed increased uptake posterior to the right lobe of the thyroid, prompting consideration of secondary hyperparathyroidism due to severe vitamin D deficiency. Treatment with vitamin D supplementation and nonsteroidal anti-inflammatory drugs yielded remarkable improvement in symptoms, with normal repeat blood investigations post-treatment. This case underscores the importance of a comprehensive diagnostic approach in patients with inflammatory back pain, especially when classical markers such as HLA-B27 are negative. It highlights the potential interplay between axial SpA and secondary hyperparathyroidism, emphasizing the need for vigilance and interdisciplinary collaboration in clinical practice., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bose et al.)

Introduction Acute coronary syndromes (ACS), encompassing non-ST elevation myocardial infarction (NSTEMI) and unstable angina (UA), present significant challenges in risk assessment and management, particularly in resource-constrained environments like India. The burden of cardiovascular diseases in such regions necessitates cost-effective and readily accessible tools for risk stratification. Previous research has emphasized the role of inflammatory markers in coronary artery disease (CAD), prompting investigations into simple and affordable biomarkers for risk assessment. Platelet lymphocyte ratio (PLR) and neutrophil lymphocyte ratio (NLR) have emerged as potential biomarkers for thrombotic activity in cardiac illnesses, offering simplicity, accessibility, and cost-effectiveness in risk assessment making them particularly valuable in resource-poor settings like India, where advanced diagnostic tools may be limited. Objective This study aims to evaluate the effectiveness of PLR and NLR as predictors of high-risk HEART (history, ECG, age, risk factors, and troponin) scores in patients with NSTEMI and UA. Methods A prospective cross-sectional study was conducted at the Saveetha Medical College and Hospitals in Chennai, India, from March 2021 to September 2022. The study included 288 adults diagnosed with NSTEMI or UA, aged 18 years and above. The inclusion criteria comprised patients with confirmed diagnoses of NSTEMI or UA based on clinical symptoms, electrocardiographic findings, and cardiac biomarker elevation. The exclusion criteria encompassed patients with active infections, acute traumatic injuries, end-stage renal disease, malignant neoplasms, and ST-elevation myocardial infarction (STEMI). In addition to the HEART score, PLR, and NLR were computed to assess the prognosis of patients admitted to the Saveetha Medical College and Hospitals. Results The statistical analysis revealed significant correlations between PLR, NLR, and HEART score risk categories. The Pearson's correlation coefficient indicated strong associations between PLR/NLR values and HEART score risk groups, suggesting their potential as predictive markers for adverse clinical outcomes. Additionally, analysis of variance (ANOVA) demonstrated significant differences in PLR/NLR values across different HEART score risk categories, further highlighting their relevance in risk stratification. The effect sizes for these correlations were moderate to large, indicating clinically meaningful associations between PLR/NLR and cardiovascular risk. Conclusion In cases of NSTEMI and UA, PLR and NLR show potential as simple and inexpensive indicators of high-risk patients. By leveraging these inexpensive biomarkers, healthcare providers can enhance risk assessment and prognostication in patients presenting with ACS, facilitating timely interventions and tailored management strategies., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Saveetha Medical College and Hospital Institutional Ethics committee issued approval SMC/IEC/2021/03/001. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Simon et al.)

The European as low as reasonably achievable(ALARA) network regularly organises workshops on topical issues in radiation protection (RP). The topic of the 20th workshop was: 'ALARA for interventional radiology (IR) and nuclear medicine (NM)'. The objective was to examine the challenges faced when applying the optimisation principle (ALARA) in IR and NM and to consider how ALARA could be better implemented for patient and staff exposures. This memorandum provides a synthesis of the workshop sessions, and recommendations coming from the working groups discussion. Parallels are drawn with the recommendations arising from the 13th EAN workshop on 'ALARA and the medical sector (2011)' to consider how the optimisation challenges in IR and NM have evolved over the past decade. Current levels of exposure are presented along with operational practice and the challenges and opportunities for improvement, both in monitoring and practice. Whilst RP challenges remain, the application of ALARA appears more established in IR compared with experiences reported in 2011. The application of ALARA to emerging technologies in the NM setting is in need of further development to ensure that RP is considered at all stages in the development process of new radiopharmaceuticals. Besides the obvious technical and operational aspects, the importance of education and training, human factors and broadly the RP 'culture' were deemed fundamental to the success of the application of ALARA and where further emphasis is needed. All concerned parties, medical physics experts (MPEs), radiation protection experts, clinical staff, manufacturers and regulators have a role to play in the application of ALARA and this is discussed in the memorandum. Many of the recommendations from the 13th EAN workshop remain applicable today and overlap with the recommendations arising from the 20th workshop. This should prompt attention given that the use of IR and the development of novel radiopharmaceuticals for NM is only anticipated to increase with time., (© 2024 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)