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Background: Findings from Kronos Early Estrogen Prevention Study (KEEPS)-Cog trial suggested no cognitive benefit or harm after 48 months of menopausal hormone therapy (mHT) initiated within 3 years of final menstrual period. To clarify the long-term effects of mHT initiated in early postmenopause, the observational KEEPS Continuation Study reevaluated cognition, mood, and neuroimaging effects in participants enrolled in the KEEPS-Cog and its parent study the KEEPS approximately 10 years after trial completion. We hypothesized that women randomized to transdermal estradiol (tE2) during early postmenopause would show cognitive benefits, while oral conjugated equine estrogens (oCEE) would show no effect, compared to placebo over the 10 years following randomization in the KEEPS trial., Methods and Findings: The KEEPS-Cog (2005-2008) was an ancillary study to the KEEPS (NCT00154180), in which participants were randomized into 3 groups: oCEE (Premarin, 0.45 mg/d), tE2 (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d for 12 d/mo) or placebo pills and patch for 48 months. KEEPS Continuation (2017-2022), an observational, longitudinal cohort study of KEEPS clinical trial, involved recontacting KEEPS participants approximately 10 years after the completion of the 4-year clinical trial to attend in-person research visits. Seven of the original 9 sites participated in the KEEPS Continuation, resulting in 622 women of original 727 being invited to return for a visit, with 299 enrolling across the 7 sites. KEEPS Continuation participants repeated the original KEEPS-Cog test battery which was analyzed using 4 cognitive factor scores and a global cognitive score. Cognitive data from both KEEPS and KEEPS Continuation were available for 275 participants. Latent growth models (LGMs) assessed whether baseline cognition and cognitive changes during KEEPS predicted cognitive performance at follow-up, and whether mHT randomization modified these relationships, adjusting for covariates. Similar health characteristics were observed at KEEPS randomization for KEEPS Continuation participants and nonparticipants (i.e., women not returning for the KEEPS Continuation). The LGM revealed significant associations between intercepts and slopes for cognitive performance across almost all domains, indicating that cognitive factor scores changed over time. Tests assessing the effects of mHT allocation on cognitive slopes during the KEEPS and across all years of follow-up including the KEEPS Continuation visit were all statistically nonsignificant. The KEEPS Continuation study found no long-term cognitive effects of mHT, with baseline cognition and changes during KEEPS being the strongest predictors of later performance. Cross-sectional comparisons confirmed that participants assigned to mHT in KEEPS (oCEE and tE2 groups) performed similarly on cognitive measures to those randomized to placebo, approximately 10 years after completion of the randomized treatments. These findings suggest that mHT poses no long-term cognitive harm; conversely, it provides no cognitive benefit or protective effects against cognitive decline., Conclusions: In these KEEPS Continuation analyses, there were no long-term cognitive effects of short-term exposure to mHT started in early menopause versus placebo. These data provide reassurance about the long-term neurocognitive safety of mHT for symptom management in healthy, recently postmenopausal women, while also suggesting that mHT does not improve or preserve cognitive function in this population., Competing Interests: K.K. served on the data safety monitoring board for Pfizer Inc. and Takeda Global Research & Development Center, Inc. She received research support from Avid. MM-A received consulting fees from the Biomedical Research Alliance of New York. Radiopharmaceuticals, Eli Lilly. She consults for Biogen., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Health policy debates rely on reliable and timely information on major causes of mortality and their associated attributors, especially to overcome the traditional public health focus restricted to the biomedical cause of death (COD). This study explores relevant social and health system circumstantial barriers to accessing healthcare services among deceased patients with Type 2 Diabetes Mellitus (T2DM) in Saudi Arabia. A total of 302 verbal autopsy (VA) interviews were conducted with relatives or caregivers of the deceased who died between 2018 and 2021, based on T2DM medical records from Alnoor Specialist Hospital in the Western Province, Saudi Arabia. The Bayesian-based InterVA-5 algorithm was employed as a validated source to determine the probable COD and Circumstances Of Mortality Categories (COMCATs) for each case. COMCATs stand for predetermined categories of multiple social and healthcare system circumstances that contribute to an individual's death. The likelihoods of COD and COMCATs derived from InterVA-5 software were computed independently to generate the 'cause-specific mortality fractions' (CSMFs) of the COD and COMCATs. The CSMFs for the seven COMCATs categories were then ranked based on their derived probabilities for the corresponding COMCATs across all major COD categories. The top CODs were circulatory diseases (35.8%), stroke (16.6%), and diabetes mellitus (14.3%). The probabilities of COMCATs indicated that most deaths were attributed to 'inevitable' causes (e.g., terminal illness), followed by 'recognition' (inability to recognize the severity of illness) and 'traditions' (local attitudes deterring patients from seeking medical services on time). Addressing 'recognition' and 'traditions' barriers could reduce mortality rates and improve access to healthcare, helping the Saudi health system accelerate the progress towards the systematic measurement of key universal health coverage indicators. The study emphasizes the need for a robust and standardized VA method within routine medical services to address factors influencing healthcare access towards improved health outcomes., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2024 Alyazidi 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.)

Introduction: Trauma is a major cause of death and disability among young adults in Saudi Arabia, with a road traffic fatality rate three times higher than other high-income countries. The vast expanse of the Riyadh region comprises 21 governorates over 156,078 square miles, most of which is rural. Although delays in access to trauma care pose a significant mortality and economic burden, regions at highest risk of delays have not been previously studied. This paper aims to identify the trauma center distribution, trauma burden, and areas with delayed access to trauma care in the rural governorates of the Riyadh region., Methods: We conducted a retrospective review of 24,268 reports from 17 rural governorates in the Riyadh region from the official data registry of the Red Crescent of Saudi Arabia from January 2021 to March 2023. Higher severity cases were classified under the red criteria (for age 15-64 ys: systolic blood pressure (SBP) < 90 mmHg or heart rate > SBP); for age ≥65 ys: SBP <110 mmHg or heart rate > SBP) based on established trauma activation criteria. We geospatially mapped all level 1-3 trauma centers in the rural governorates of the Riyadh region with an overlay of trauma burden, and identified red criteria cases and those that had delayed access to trauma centers in each of the governorates. Data were mapped using Quantum Geographic Information System, and analysis was performed using R statistics., Results: Rural Riyadh lacks level 1 trauma centers, with level 3 facilities primarily delivering trauma care. Among the reported trauma cases, majority were classified under the red criteria (67.7%, n = 16,433). Al-Kharj emerged as a hotspot for trauma cases, reporting the highest number of cases (21.4%, n = 5202) and red criteria cases (21.4%, n = 3512), followed by Al-Quwayiyah (14.4%, n = 3490) and Al-Majma'ah (9.8%, n = 2369). Blunt trauma predominated (79.4%, n = 19,280), with a substantial portion meeting the red criteria (62.4%, n = 12,032), while penetrating injuries were less common (14.5%, n = 3524). Of the red criteria cases, 38.2% (n = 6048) were delayed, most notably in Al-Kharj (21.8%, n = 1320)., Conclusions: In conclusion, our study reveals significant gaps in trauma care access and burden across rural governorates in the Riyadh region. The absence of level 1 trauma centers, coupled with high proportions of red criteria cases and delays in accessing care, underscores the need for targeted interventions and resource optimization. Addressing these challenges requires standardized trauma systems, improved transfer protocols, and a national trauma registry for comprehensive monitoring of patient outcomes., (Published by Elsevier Inc.)

Aim: The main goal of this study was to synthesize new derivatives of 4-amino-3-chloro benzoate ester, including 1,3,4-oxadiazole derivatives ( N3a-d ), benzohydrazone derivatives ( N4a-c ), and hydrazine-1-carbothioamide derivatives ( N5a-d ) that target epidermal growth factor receptor (EGFR) tyrosine kinase., Materials & Methods: The new derivatives were characterized using various spectroscopic techniques. Docking studies were used to investigate the binding patterns to EGFR, and the anti-proliferative properties were tested in vitro., Results: In silico analysis showed that the hydrazine-1-carbothioamide derivatives ( N5a-d ) had the best matching pattern with EGFR pharmacophoric queries compared to erlotinib, exhibited a favorable safety profile, and showed the best stability among the tested compounds. Compound N5a induced cytotoxicity in the three cancer cell lines tested (A549, HepG2, and HCT-116), by targeting EGFR and activating caspase 3 and caspase 8, therefore, inducing the extrinsic apoptotic pathway., Conclusion: The results of this study show that compound N5a is a promising cytotoxic compound that inhibits the tyrosine kinase activity of EGFR.

The first 8000 days of life, from birth to adulthood, encompasses critical phases that shape a child's health and development. While global health efforts have focused on the first 1000 days, the next 7000 days (ages 2-21) are equally vital, especially concerning the unmet burden of surgical conditions in low- and middle-income countries (LMICs). Approximately 1.7 billion children globally lack access to essential surgical care, with LMICs accounting for 85% of these unmet needs. Common surgical conditions, including congenital anomalies, injuries, infections, and pediatric cancers, often go untreated, contributing to significant mortality and disability. Despite the substantial need, LMICs face severe workforce and infrastructure shortages, with most pediatric surgical conditions requiring specialized skills, equipment, and tailored healthcare systems. Economic analyses have shown that pediatric surgical interventions are cost-effective, with substantial societal benefits. Expanding surgical care for children in LMICs demands investments in workforce training, infrastructure, and health systems integration, complemented by innovative funding and equitable global partnerships. Prioritizing surgical care within national health policies and scaling up children's surgery through initiatives like the Optimal Resources for Children's Surgical Care can improve health outcomes, align with Sustainable Development Goals, and foster equity in global health. Addressing the surgical care gap in LMICs will reduce preventable mortality, enhance quality of life, and drive sustainable growth, emphasizing surgery as an essential component of universal health coverage for children., (© The Author(s) 2024. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: Metabolic risk factors are a significant cause of global burden among adolescents and young adults, but there is a lack of attention to the burden attributable to these metabolic risk factors globally., Aims: This study aims to provide comprehensive estimates of five important metabolic risk factors and the attributable disease burden in people aged 15-39 years from 1990 to 2021, based on the Global Burden of Disease Study (GBD) database., Methods: Global total deaths and disability-adjusted life years (DALYs) were used to describe the burden attributable to five common metabolic risk factors, including high fasting plasma glucose (FPG), high low-density lipoprotein cholesterol (LDL-C), high systolic blood pressure (SBP), high body mass index (BMI), and kidney dysfunction, in adolescents and young adults. The estimated annual percentage changes (EAPC) of DALYs were utilized to depict the trends from 1990 to 2021., Results: From 1990 to 2021, the DALY rates attributable to all metabolic risk factors showed a globally significant upward trend, with EAPC reaching 33.0 % (27.4-38.7). Compared to females, males had a heavier burden and a more significant increase in deaths and DALYs attributable to metabolic risk factors. High BMI and high FPG have become the top two metabolic risk factors in 2021, with summary exposure variables (SEV) rising by 84.2 % and 53.6 %, respectively. Low-middle socio-demographic index (SDI), middle SDI, and high SDI regions experienced upward regional trends in DALY rates, while low SDI regions remained stable. Among 204 countries and territories, 101 (49.5 %) showed a significant increase in DALY rates, as indicated by the EAPC., Conclusions: There is a substantial global burden attributable to metabolic risk factors in adolescents and young adults in 2021, especially high BMI and high FPG. This calls for further investigation and intervention to address this emerging trend., Competing Interests: Conflict of interest Christopher D. Byrne has received grant support from Echosens. Ming-Hua Zheng has received honoraria for lectures from AstraZeneca, Hisky Medical Technologies and Novo Nordisk, consulting fees from Boehringer Ingelheim. Anoop Misra has received honoraria from Novo Nordisk, Astra Zeneca, Janssen, Lupin, Eli Lilly, US Vitamins, and Boehringer Ingelheim. Wah-Kheong Chan is a consultant or advisory board member for Abbott, Roche, Abbvie, Boehringer Ingelheim and Novo Nordisk; and a speaker for Abbott, Novo Nordisk, Echosens, Viatris and Hisky Medical. Alice P.S. Kong has received research grants and/or speaker honoraria from Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli-Lilly, Kyowa Kirin, Merck Serono, Nestle, Novo-Nordisk, Pfizer and Sanofi and Zuellig Pharma. Sander Lefere has received research grant from Inventiva. Mohit Kehar is a consultant for Mirum. Nicholas Beng Hui Ng has received honoraria from Novo Nordisk and Abbott. No other disclosures were reported., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Bile duct injuries (BDIs) are dreaded complications of one of the most common general surgical procedures. The injury impacts the quality of life and may have several long-term complications. In some cases, it can also lead to mortality. This paper aims to review works that have already been published about bile duct injuries and elaborate on the factors leading to it. This includes elaborating on both surgical and non-surgical factors. It also plans to highlight practices and methods to avoid BDIs. Medical research databases were searched using cholecystectomy and bile duct injuries as keywords. Papers including pre-operative or intraoperative factors, that may cause bile duct injuries, were further shortlisted for this study. Understanding and knowledge of anatomy plays a key role in bile duct injuries and is essential before performing the surgery. Factors related to the patients, surgeons, and logistics also play a major role in causing bile duct injuries. Bile duct injuries can be reduced using certain strategies like the B SAFE strategy, R4U line, bail-out methods, imaging techniques along with referrals to Hepatobiliary specialist centers to avoid bile duct injuries., 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, Jindal et al.)

Pakistan is endemic to several bacterial, parasitic and viral infections including tuberculosis, malaria and dengue that account for a high rate of mortality each year. These different types of infections can occur through various routes of transmission and concurrently in individuals, especially in immunocompromised but rarely among immunocompetent. We report a case of a 25 year old immunocompetent female who was admitted with an initial diagnosis of dengue fever and diagnosed as having co-infection of COVID-19 and Brucella leading to secondary hemophagocytic lymphohistiocytosis (HLH). She was managed for all three infections and complications simultaneously., 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 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Immunofluorescence assays are extensively used for the detection of disease-associated biomarkers within patient samples for direct diagnosis. Unfortunately, these 2D microarrays suffer from low repeatability and fail to attain the low limits of detection (LODs) required to accurately discern disease progression for clinical monitoring. While three-dimensional microarrays with increased biorecognition molecule density stand to circumvent these limitations, their viscous component materials are not compatible with current microarray fabrication protocols. Herein, we introduce a platform for 3D microarray bioprinting, wherein a two-step printing approach enables the high-throughput fabrication of immunosorbent hydrogels. The hydrogels are composed entirely of cross-linked proteins decorated with clinically relevant capture antibodies. Compared to two-dimensional microarrays, these proteinaceous microarrays offer 3-fold increases in signal intensity. When tested with clinically relevant biomarkers, ultrasensitive single-plex and multiplex detection of interleukin-6 (LOD 0.3 pg/mL) and tumor necrosis factor receptor 1 (LOD 1 pg/mL) is observed. When challenged with clinical samples, these hydrogel microarrays consistently discern elevated levels of interleukin-6 in blood plasma derived from patients with systemic blood infections. Given their easy-to-implement, high-throughput fabrication, and ultrasensitive detection, these three-dimensional microarrays will enable better clinical monitoring of disease progression, yielding improved patient outcomes.

This report presents the first genomes from positive cases of cholera in Sudan. Genomic analysis of 10 Vibrio cholerae isolates, profiled as serogroup O1, reveals evidence of antimicrobial resistance genes and a 139-kb IncC plasmid with 99.74% identity to the multidrug-resistant plasmid pCNRVC190243 previously reported in Yemen and Lebanon., Competing Interests: The authors declare no conflict of interest.

Background: Infertility has been observed as one of the major issues in humans, one known risk factor is heavy metals., Methods: The main focus of the present research was to assess the toxic effect of hexavalent chromium (Cr (VI)) on sperm and its mitigation by Nigella sativa seed extract (NS) and its conjugated silver nanoparticles (NS + NP). In the present study, we administered 1.5 mg/kg body of Cr (VI) orally in mice for 60 days routinely, to induce toxicity in testes and effect on sperm production and motility in male mice. NS and NS + NP (50 mg/kg body weight) were administered to evaluate protective action against Cr (VI). The sperm were analyzed by computer-assisted semen analysis (CASA) and chromium concentration in testicular tissue was measured via the atomic absorption spectrophotometer., Results: The CASA analysis showed that Cr (VI) was directly linked with a decline in sperm concentration, motility, distance, velocity, straightness, and head beat frequency attributes. However, the administration of Nigella sativa seed extract and its green synthesized silver nanoparticles improved sperm concentration, motility, distance, velocity, straightness, and head beat frequency. The chromium content in the testes of Cr-exposed animals significantly increased, which negatively affected sperm parameters. However, Nigella sativa and Nigella sativa conjugated silver nanoparticles appeared to help in the removal of Cr content from testes hence improving the sperm parameters in exposed mice., Conclusion: The decrease in Cr concentration improved sperm quality and quantity, hence, improve male fertility., Competing Interests: Declaration of Competing interest All the authors reported no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Standard-of-care (SoC) medications for the treatment of obstructive hypertrophic cardiomyopathy (oHCM) are recommended as first-line therapy despite the lack of evidence from controlled clinical trials and well known off-target side effects., Objectives: We describe the impact of SoC therapy downtitration and withdrawal in patients already receiving aficamten in FOREST-HCM (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy; NCT04848506)., Methods: Patients receiving SoC therapy (beta-blocker, nondihydropyridine calcium-channel blocker, and/or disopyramide) were eligible for protocol-guided SoC downtitration and withdrawal at the discretion of the investigator and after achieving a stable dose of aficamten for ≥4 weeks. Successful SoC withdrawal was defined as at least a 50% dose-reduction in ≥1 medication. Adverse events (AEs) were prospectively evaluated 1 to 2 weeks after any SoC withdrawal., Results: Of 145 patients with oHCM who were followed for at least 24 weeks (mean age 60.5 ± 13.2 years; 44.8% female; 42% NYHA functional class III), 136 (93.8%) were receiving ≥1 SoC therapy; of those, 64 (47%) had an attempt at withdrawal, with 59 (92.2%) successful. Thirty-eight (64.4%) patients completely discontinued ≥1 medication, and 27 (45.8%) achieved aficamten monotherapy with 2 later restarting a SoC medication. There were no significant differences in baseline characteristics on day 1 in FOREST-HCM in those with a SoC-withdrawal vs no-withdrawal attempt. In patients who underwent successful SoC therapy withdrawal, NYHA functional class improved by ≥1 class in 79.2% from baseline, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score improved to 83.0 ± 15.8 points, and resting and Valsalva left ventricular outflow tract gradient improved to 14.3 ± 10.9 and 32.9 ± 21.4 mm Hg, respectively. N-terminal pro-B-type natriuretic peptide levels improved to a median of 220.0 pg/mL (Q1-Q3: 102.0-554.0.0 pg/mL) and high-sensitivity troponin I improved to a median of 6.0 ng/L (Q1-Q3:3.5-10.7 ng/L). Downtitration and withdrawal of SoC therapy did not impact these results (all P values for change were >0.05), and these changes were similar in patients who did not undergo SoC therapy withdrawal. There were no serious AEs attributed to SoC withdrawal and treatment emergent AEs were similar between groups., Conclusions: In FOREST-HCM, one-half of the patients with oHCM attempted downtitration and withdrawal of SoC medications while receiving aficamten treatment, with infrequent instances of resumption of SoC. Stopping and dose reduction of SoC medications were well tolerated with no adverse consequences in clinical measures of efficacy (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy [FOREST-HCM]; NCT04848506)., Competing Interests: Funding Support and Author Disclosures The FOREST-HCM trial is funded by Cytokinetics, Incorporated. Dr Masri has received consulting/advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, Eidos, Pfizer, Haya, Lexion, BioMarin, Alexion, and Ionis; and has received research grants from Ionis, Pfizer, Cytokinetics, and Attralus. Dr Choudhury has received advisor fees from Cytokinetics. Dr Barriales-Villa has received consulting/advisor fees from MyoKardia/Bristol Myers Squibb. Dr Elliott has received consulting fees from Bristol Myers Squibb, Pfizer, and Cytokinetics; has received speaker fees from Pfizer; and has received an unrestricted grant from Sarepta. Dr Maron has received consulting/advisor fees from Imbria, Edgewise, and Biomarin; and has received steering committee fees for SEQUIOA-HCM from Cytokinetics, Incorporated. Dr Nassif has received research and grant support from AstraZeneca and Cytokinetics; and has received consulting/advisory fees from Vifor and Cytokinetics. Dr Oreziak has received investigator fees from Cytokinetics and MyoKardia/Bristol Myers Squibb. Dr Owens has received consulting/advisor fees from Bristol Myers Squibb; and has received research grants from Bristol Myers Squibb, Cytokinetics, Novartis, and Actelion Pharmaceuticals. Dr Saberi has received consulting fees from Bristol Myers Squibb and Cytokinetics. Dr Tower-Rader has received research grants from Bristol Myers Squibb and Cytokinetics. Dr Rader has received consulting fees/honoraria from Medtronic, Cytokinetics, Bristol Myers Squibb, and Recor. Dr Garcia-Pavia has received Speakers Bureau fees from Bristol Myers Squibb, Pfizer, BridgeBio, Ionis, AstraZeneca, NovoNordisk, Intellia, and Alnylam; has received consulting fees from Bristol Myers Squibb, Cytokinetics, Rocket Pharma, Lexeo Therapeutics, Pfizer, BridgeBio, Daiichi-Sankyo, Neurimmune, Alnylam, AstraZeneca, Novo Nordisk, Attralus, Intellia, Idoven, General Electric, and Alexion; and has received research/educational support to his institution from Pfizer, BridgeBio, NovoNordisk, AstraZeneca, Intellia, and Alnylam. Dr Olivotto has received Speakers Bureau fees from Bristol Myers Squibb, Amicus, and Genzyme; has received consulting/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, Rocket Pharma, and Lexeo; and has received research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, Chiesi, and Boston Scientific. Dr Wang has received Speakers Bureau fees from Bristol Myers Squibb; has received consulting/advisor fees from Bristol Myers Squibb and Cytokinetics; and has received research grants from Bristol Myers Squibb, Cytokinetics, and Abbott Vascular. Drs Heitner, Jacoby, Kupfer, Malik, Melloni, Meng, and Wei are employees of and hold stock in Cytokinetics Incorporated. Dr Sherrid has received consulting fees/honoraria from Pfizer Inc; and has served as a consultant for Cytokinetics Inc without payment. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Aficamten is a cardiac myosin inhibitor that mitigates left ventricular outflow gradients in obstructive hypertrophic cardiomyopathy (oHCM). The clinical efficacy of aficamten across multiple outcome domains in oHCM has not been fully defined., Objectives: This responder analysis from the SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) trial characterizes the clinical impact of aficamten., Methods: Patients who were symptomatic of oHCM were randomized to aficamten (n = 142) or placebo (n = 140) daily for 24 weeks. Outcomes assessed included the proportion of patients with complete hemodynamic response (rest and Valsalva gradient <30 mm Hg and <50 mm Hg, respectively), relief in limiting symptoms (≥1 improvement in NYHA functional class and/or ≥10-point change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score), enhanced exercise capacity (≥1.5 mL/kg/min change in peak oxygen uptake), and ≥50% reduction in N-terminal pro-B-type natriuretic peptide. Eligibility for septal reduction therapy was also evaluated., Results: At 24 weeks, patients treated with aficamten vs placebo showed significant improvement in limiting symptoms (71% vs 42%), were more likely to have complete hemodynamic response (68% vs 7%), demonstrated enhanced exercise capacity (47% vs 24%), and showed a decrease ≥50% in N-terminal pro-B-type natriuretic peptide (84% vs 8%) (P ≤ 0.002 for all). An improvement in ≥1 of these outcome measures was achieved in 97% of patients treated with aficamten (vs 59% placebo), including 23% on aficamten who achieved all 4 outcomes compared with none in placebo. Among 32 patients receiving aficamten and 29 patients receiving placebo who were eligible for septal reduction therapy, 28 (88%) from the aficamten group were no longer eligible at 24 weeks compared with 15 (52%) from the placebo group (P = 0.002)., Conclusions: Treatment with aficamten was associated with substantial improvements across a broad range of clinically relevant efficacy measures. These results underscore the wide-ranging potential of aficamten for treatment of patients with symptomatic oHCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults with oHCM [SEQUOIA-HCM]; NCT05186818)., Competing Interests: Funding Support and Author Disclosures The SEQUOIA-HCM study was funded by Cytokinetics, Incorporated. Dr Maron has received consultant/advisor fees from Imbria, Edgewise, and BioMarin; and has received steering committee fees for SEQUIOA-HCM from Cytokinetics. Dr Masri has received consultant/advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, and Ionis; and has received research grants from Ionis, Akcea, Pfizer, Ultromics, and the Wheeler Foundation. Dr Nassif has received research and grant support from AstraZeneca and Cytokinetics; and has received consulting/advisory fees from Vifor and Cytokinetics. Dr Barriales-Villa has received consultant/advisor fees from MyoKardia/Bristol Myers Squibb. Dr Arad has received consulting and lecture fees from Bristol Myers Squibb. Dr Cardim has received consultant/advisor fees from Cytokinetics, Bristol Myers Squibb, Pfizer, Menarini, Boehinger Ingelheim, and Bial. Dr Coats has received speaker fees from Alnylam and Roche; and has received advisor fees from Cytokinetics. Dr Düngen has received grants from Novartis, CSL Behring, and Cytokinetics. Dr Garcia-Pavia has received speakers’ bureau fees from Pfizer, AstraZeneca, Novo Nordisk, Ionis, Bridgebio, Bristol Myers Squibb, Intelllia, and Alnylam; has received consulting/advisor fees from Pfizer, Alnylam, MyoKardia/Bristol Myers Squibb, Cytokinetics, Neuroimmune, Intellia, Ionis, Bridgebio, Lexeo, Rocket, Attralus, and AstraZeneca; and has received research/educational grants to his institution from Pfizer, AstraZeneca, Novo Nordisk, BridgeBio, and Alnylam. Dr Hagège has received consulting/advisor fees from Alnylam, Amicus Therapeutics, Bayer, MyoKardia/Bristol Myers Squibb, Pfizer, and Sanofi Genzyme; and has received steering committee fees for SEQUOIA-HCM from Cytokinetics. Dr Januzzi is funded in part by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; has served as a board member for Imbria Pharmaceuticals; has served as a Director at Jana Care; has received grant support from Abbott, Applied Therapeutics, HeartFlow, Innolife, and Roche Diagnostics; has received consulting fees from Abbott, Beckman, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Novartis, Pfizer, Merck, Roche Diagnostics, and Siemens; and has participated in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, CVRx, Intercept, and Takeda. Dr Lee has received research grants through his institution from AstraZeneca, Boehringer Ingelheim, and Roche Diagnostics; has been a member of a Clinical Endpoints Committee for Bayer; and has been a member of the Trial Steering Committee for Cytokinetics. Dr Lewis has received research funding from the National Institutes of Health (R01-HL 151841, R01-HL131029, and R01-HL159514), American Heart Association (15GPSGC-24800006), Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, and SoniVie; has received honoraria for advisory boards from Pfizer, Merck, Boehringer Ingelheim, Novartis, American Regent, Cyclerion, Cytokinetics, and Amgen; and has received royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Michels has received consulting/advisor fees from Bristol Myers Squibb, Cytokinetics, and Pfizer; and has received research grant funding from Bristol Myers Squibb. Dr Olivotto has received speakers’ bureau fees from Bristol Myers Squibb, Amicus, and Sanofi Genzyme; has received consulting/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, Rocket Pharma, and Lexeo; and has received research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, Chiesi, and Boston Scientific. Dr Oreziak has received investigator fees from Cytokinetics and MyoKardia/Bristol Myers Squibb. Dr Owens has received consulting/advisor fees from Cytokinetics, Bristol Myers Squibb/MyoKardia. Dr Spertus is the principal investigator of grants from the NIH, Abbott Vascular, and the American College of Cardiology Foundation; has received consulting fees from Janssen, Novartis, Amgen, Myokardia, AstraZeneca, Bayer, and Merck; has served on the Scientific Advisory Board of United Healthcare and the Board of Directors for Blue Cross Blue Shield of Kansas City; owns the copyright to the KCCQ, SAQ, and PAQ; and has an equity interest in Health Outcomes Sciences. Dr Solomon has received consulting/advisor fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, DiNAQOR, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health; and has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI. Dr Tfelt-Hansen has received consulting fees from Leo Pharma, MicroPort, and Johnson and Johnson. Ms van Sinttruije is a patient advisory committee member and a SEQUOIA-HCM Steering Committee member for Cytokinetics. Dr Watkins has received consulting/advisor fees from Cytokinetics, BioMarin, and BridgeBio. Drs Jacoby, Heitner, Kupfer, Malik, and Meng and Ms Wohltman are employees of Cytokinetics Incorporated and hold stock in Cytokinetics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Little is known about how the epigenomic states change during development and evolution in a 3D genome context. Here we use Drosophila pseudoobscura with complex turnover of sex chromosomes as a model to address this, by collecting massive epigenomic and Hi-C data from five developmental stages and three adult tissues. We reveal that over 60% of the genes and transposable elements (TE) exhibit at least one developmental transition of chromatin state. Transitions on specific but not housekeeping enhancers are associated with specific chromatin loops and topologically associated domain borders (TABs). While evolutionarily young TEs are generally silenced, old TEs more often have been domesticated as interacting TABs or specific enhancers. But on the recently evolved X chromosome, young TEs are instead often active and recruited as TABs, due to acquisition of dosage compensation. Overall we characterize how Drosophila epigenomic landscapes change during development and in response to chromosome evolution, and highlight the important roles of TEs in genome organization and regulation., (© 2024. The Author(s).)

Competing Interests: Declaration of interests None.

Background: This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM)., Methods: Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤ 30 mmHg, left ventricular ejection fraction [LVEF] ≥ 60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] > 300 pg/mL) received aficamten 5-15 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks., Results: We enrolled 41 patients (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥ 1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP levels (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF < 50% (range: 41%-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study., Conclusions: Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers., Trial Registration: ClinicalTrials.gov Identifier: NCT04219826., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Tunnelled central venous dialysis catheters can usually be removed easily. However, their removal can become rarely complicated requiring more invasive techniques. We report a case in which cardiopulmonary bypass and repair of great veins was required for safe removal. A 38-year-old female with end-stage renal failure and a 3-year-old Hickman line inserted into her right internal jugular vein was referred to our cardiac surgical unit following failed attempts of line removal by local vascular surgical team using open vascular surgical techniques. As a result, an MDT decision was made that it was safer to proceed to a cardiothoracic surgical approach rather than other techniques. Investigations showed significant calcification surrounding the line which was adherent to the venous wall. Removal of the retained catheter required median sternotomy and the use of cardiopulmonary bypass as the great veins had to be opened to free the line and allow complete removal. The line was successfully removed with its encircling calcified sheath, and the veins were closed primarily without needing a patch repair. The integrity of the great veins was maintained to meet the on-going need this young patient has for central venous access. The patient made an uneventful recovery. When other measures fail, sternotomy and cardiopulmonary bypass provide a safe option for complete removal of stuck central venous catheters with low risk to the patient., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Despite availability of commercial EEG software for automated epileptiform detection, validation on real-world EEG datasets is lacking. Performance evaluation of two software packages on a large EEG dataset of patients with genetic generalized epilepsy was performed., Methods: Three epileptologists labelled IEDs manually of EEGs from three centres. All Interictal epileptiform discharge (IED) markings predicted by two commercial software (Encevis 1.11 and Persyst 14) were reviewed individually to assess for suspicious missed markings and were integrated into the reference standard if overlooked during manual annotation during a second phase. Sensitivity, precision, specificity, and F1-score were used to assess the performance of the software packages against the adjusted reference standard., Results: One hundred and twenty-five routine scalp EEG recordings from different subjects were included (total recording time, 310.7 hours). The total epileptiform discharge reference count was 5,907 (including spikes and fragments). Encevis demonstrated a mean sensitivity for detection of IEDs of 0.46 (SD 0.32), mean precision of 0.37 (SD 0.31), and mean F1-score of 0.43 (SD 0.23). Using the default medium setting, the sensitivity of Persyst was 0.67 (SD 0.31), with a precision of 0.49 (SD 0.33) and F1-score of 0.51 (SD 0.25). Mean specificity representing non-IED window identification and classification was 0.973 (SD 0.08) for Encevis and 0.968 (SD 0.07) for Persyst., Conclusions: Automated software shows a high degree of specificity for detection of nonepileptiform background. Sensitivity and precision for IED detection is lower, but may be acceptable for initial screening in the clinical and research setting. Clinical caution and continuous expert human oversight are recommended with all EEG recordings before a diagnostic interpretation is provided based on the output of the software., (Copyright © 2023 by the American Clinical Neurophysiology Society.)

Purpose: Olfaction plays a vital role in regulating nutrition, avoiding potentially dangerous situations, and modulating behavior along with interpersonal relationships. Many common disorders can have a negative impact on olfaction; one of these is obesity. Bariatric surgery induces weight loss, and current evidence suggests that it can cause improvement in olfaction. However, more information is needed regarding this topic., Materials and Methods: One hundred eighty-five patients who underwent bariatric surgery and 184 age- and gender-matched control group who did not undergo any surgery have completed a questionnaire including items from the validated Self-Reported Mini Olfactory Questionnaire., Results: Final analysis was based on 369 patients. There was a statistically significant difference between patients before and after surgery (p < 0.05). However, there was a statistically significant difference between people who underwent surgery with < 50% excess body weight loss and the control group but none with those > 50% excess body weight loss. No significant differences were found when comparing people with and without chronic illnesses, head and neck surgery, anti-allergy drug use, and COVID-19. Before surgery, there were statistically significant differences between patients with allergic rhinitis and polyps and those without, but no significant differences were observed after surgery., Conclusion: Patients had significantly improved olfactory scores post-surgery compared to before surgery. Patients who had > 50% excess body weight loss after surgery showed olfactory function as good as the general population represented by the control group. However, those with < 50% excess body weight loss had significantly worse olfactory scores compared to the general population., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The coronavirus disease 2019 (COVID-19) pandemic disrupted essential health care services worldwide, including those related to immunisation. National data from Bangladesh shows that child immunisation may have been adversely affected by the pandemic but regional evidence is limited. We therefore aimed to explore the regional differences in the indirect effects of COVID-19 on child immunisation in Bangladesh., Methods: We extracted data from the District Health Information Software (DHIS2) spanning the period from January 2017 to December 2021. We examined three essential immunisation indicators: Bacille Calmette-Guérin (BCG), pentavalent third dose, and measles vaccinations. We examined both the yearly and monthly trends to explore fluctuations in the number of immunisations to pinpoint specific periods of service utilisation regression. Segmented regression with Poisson distribution was implemented given the count-based outcome. We reported incidence rate ratios (IRRs) with 95% confidence intervals (CIs) in different regions in 2020 and 2021 compared to the reference period (2017-19)., Results: We initially observed a notable decline in vaccine administration in April 2020 compared to the pre-pandemic period of 2017-19 with a drop of approximately 53% for BCG vaccines, 55% for pentavalent third doses, and 51% for measles vaccines followed by May 2020. The second half of 2020 saw an increase in vaccination numbers. There were noticeable regional disparities, with Sylhet (IRR = 0.75; 95% CI = 0.67-0.84 for pentavalent administration, IRR = 0.79; 95% CI = 0.71-0.88 for measles administration) and Chattogram (IRR = 0.77; 95% CI = 0.72-0.83 for BCG administration) experiencing the most significant reductions in 2020. In April 2020, Dhaka also experienced the largest decline of 67% in measles vaccination. In 2021, most divisions experienced a rebound in BCG and pentavalent administration, exceeding 2019 levels, except for Chittagong, where numbers continued to decline, falling below the 2019 figure., Conclusions: Our findings highlight the impact of the COVID-19 pandemic on childhood immunisation across regions in Bangladesh. Sylhet, Chattogram, and Dhaka divisions experienced the most significant reductions in immunisation services during 2020. This underscores the importance of targeted interventions and regional strategies to mitigate the indirect effects of future challenges on essential health care services, particularly childhood immunisation, in Bangladesh., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Consumers are increasingly seeking nutritionally enhanced products, unique flavours and packaging, and ethically sourced ingredients. Significant technological advancements and investments in product innovation by manufacturers are driving the overall market growth for plant-based protein alternatives. In Europe, this growth is largely due to the rising adoption of veganism and the flexitarian trend. During vegetable processing, certain activities generate large amounts of by-products, many of which are discarded by manufacturers. These legumes and their by-products contain substantial amounts of protein. Manufacturers using legumes and their by-products-based proteins in food formulations must comply with European Union (EU) regulations and standards to obtain market approval. For this study, the regulatory framework and novel food dossier application process were sourced from the official EU website (Europa), while relevant standards were obtained from the International Organisation for Standardisation (ISO) and European Committee for Standardisation (CEN)-European Committee for Electrotechnical Standardisation (CENELEC) website. This review provides an overview of protein extraction from legumes and their by-products, followed by an analysis of the legal requirements for processing, production, and commercialisation of these extracted proteins in food formulations. It addresses standardisation and relevant standards in areas such as characterisation and safety. Furthermore, the novel food dossier application process and the EU requirements for legume proteins, if considered novel in the EU, are discussed. This review aims to serve as a guide for manufacturers already using, or considering the use of, legume proteins in food formulations within the EU, providing essential insights for gaining market acceptance and regulatory approval for these ingredients, whether existing or novel. Further research is needed to explore the incorporation of proteins extracted from legume by-products into food formulations., Competing Interests: 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., (© 2024 The Authors.)

Genes of folate-mediated 1 carbon metabolism are found to be highly upregulated in tumor cells and promote cancer cell proliferation. The current study aimed to determine the expression of the MTHFD2 gene in bladder and breast cancers. Furthermore, the determination of potential ligand-based inhibitors against MTHFD2 was performed in comparison with those of chemotherapeutic drugs and natural plant-based compounds. Semiquantitative expression analysis along with structure-based virtual ligand library screening was done to find plausible inhibitors. MTHFD2 expression was significantly increased with tumor stage progression both in low- and high-grade bladder cancer and especially in triple-negative breast cancer. Virtual ligand-based library screening against the three-dimensional MTHFD2 protein structure led to the identification of plausible inhibitors like MCULE-8109969891-0 and MCULE-9715677418-0-1 that displayed lower binding free energy as compared to that of already documented LY345899. Similar scaffold commercial drugs leucal (LEU), epirubicin (EPI), and lometrexol also displayed strong binding to the active site of MTHFD2. EPI and LEU in combinatorial therapy were also tested in vitro on MDA-MB-231 cells. The high doses of LEU in combination with EPI showed a significant reduction in cell viability at 2 and 3 μM concentrations. The interaction of breast cancer serum with high expression of MTHFD2 also showed an increase in binding of epirubicin in the presence of leucovorin. The decrease in the absorbance spectra of epirubicin at 37 and 53 °C displayed the stability induced by LEU on the interaction of EPI with the MTHFD2 binding pocket. Leucovorin tends to stabilize the interaction as the binding affinity is high even at 53 °C. Thus, MTHFD2 might be used as a cancer biomarker since its expression level changes drastically with tumor progression. Further experimental studies are required to establish the potential mode of inhibition of the novel small ligands. Future in vivo trials may validate the effectiveness of the combinatorial therapy., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Antibiotic-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapies. In this study, we observed that prior exposure to broad-spectrum ABX with extended anaerobic coverage like piperacillin-tazobactam and meropenem was associated with worsened anti-CD19 CAR-T therapy survival outcomes in large B-cell lymphoma patients (n=422), compared to other ABX classes. In a discovery subset of these patients (n=67), we found that the use of these ABX was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n=58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery n=40, validation n=28). These findings were recapitulated in an immune-competent CAR-T mouse model, where meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-T cells, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T cell efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy., (Copyright © 2024 American Society of Hematology.)

Introduction: Malignant peripheral nerve sheath tumors (MPNSTs) are rare tumors that develop from peripheral nerve sheath cells and they account for approximately 5% to 10% of all soft-tissue sarcomas. MPNSTs in the head and neck region represent approximately 2% to 6% of all head and neck sarcomas and account for 12% to 19% of all MPNSTs, and the infratemporal fossa is a rare site for MPNSTs. MPNSTs originating from the trigeminal nerve are extremely rare. Case presentation: A 19-year-old female presented with a 6-month history of left-sided facial pain and paresthesia on the same side. On examination, there was left-sided facial paresthesia at the third trigeminal nerve (V3) areas; computed tomography scanning and magnetic resonance imaging showed an infratemporal lesion and surgical resection was done. Histological examination and the immunostaining finding showed high-grade MPNST. Conclusion: MPNSTs in the head and neck region may manifest with nonspecific symptoms. The diagnosis often requires a combination of clinical, pathological, and immunohistochemistry studies. Treatment involves total surgical resection with adjuvant radiotherapy., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: The authors have no conflicts of interest to declare.

Background: Human immunodeficiency virus (HIV), a viral infection impacting CD4 cells, requires an understanding of factors influencing CD4 cell counts to reduce acquired immunodeficiency syndrome(AIDS)-related morbidity and mortality. Despite its importance, no studies have examined predictors of CD4 cell count progression post-transition to adult-oriented HIV care in Ethiopia. This study aimed to identify predictors affecting CD4 cell count trends among adolescents and young adults transitioning to adult-oriented HIV care. Therefore, this study aimed to identify the predictors that affect the trends of CD4 cell count over time among adolescents and young adults who transitioned to adult-oriented HIV care., Methods: A retrospective cohort study was conducted among 206 adolescents and young adults who transitioned to adult-oriented HIV care and had at least two CD4 cell counts in eight selected health facilities in Southern Ethiopia. These facilities were chosen due to their high volume of people living with HIV. A multivariable linear mixed effect model was fitted to identify the predictors of CD4 cell count progression through time. Multi-collinearity between variables was checked using the variance inflation factor. Model comparisons were done using Akaike and Bayesian information criteria. Regression coefficients with 95% confidence intervals (CI) and P-value ≤ 0.05 were used to measure the strength of association and significance level., Results: The average CD4 cell count was raised by 6.7 cells/mm 3 every six months among the study participants. Transitioning at the age of 18 or older (β = 204.71; 95% CI = 81.86347, 327.5574; P < 0.001), being rural residents (β= -119.776; 95% CI = -215.362, -24.189; P < 0.014), having World Health Organization (WHO) stage III & IV HIV (β= -182.161; 95% CI = -318.475, -45.847; P < 0.009), were the predictors for CD4 cell count progression over time., Conclusion: Based on the identified predictors of CD4 cell count progression over time among HIV-positive adolescents and young adults transitioning to adult-oriented HIV care in southern Ethiopia, such as observation time, age at transition, residence, and WHO staging, the study highlights the need for interventions focused on tailored support. Specifically, these interventions should target individuals transitioning with less ART time, those younger than 18, those residing in rural areas, and those with advanced WHO staging, to improve their CD4 cell counts over time., (© 2024. The Author(s).)

(1) Background and Aims: The seasonal factors influencing multiple sclerosis (MS) relapses remain elusive. This study aims to investigate the seasonal variation of MS relapses in Oman and compare it globally. (2) Subject and Methods: This retrospective study was conducted on N = 183 Omani MS patients treated at Sultan Qaboos University Hospital, a tertiary hospital in Muscat, Oman, over sixteen-year period (2007-2022). Demographic and clinical data of all MS patients were juxtaposed with the monthly weather data during this period, using descriptive and inferential statistical techniques. (3) Results: Among the N = 183 MS patients studied, 508 relapses were recorded during the study period. The average number of relapses per patient was 2.8 (range: 1-15). There were significant seasonal variations in MS relapse rate, with the highest prevalence in the winter months of January and February. However, no correlation was found between MS relapses and other climatic parameters (humidity, temperature, and rainfall). (4) Conclusion: The seasonal patterns of MS relapses in Oman differ from other parts of the world, which the local clinicians should take into account while diagnosing and making management decisions. The potential impact of climate change on the anomalous changes in the seasonality of MS relapses warrants further investigation.

Background: Favipiravir is administered orally, even against airborne RNA viruses, in a loading-dose/maintenance dose regimen. We investigated whether-(a) pulmonary delivery of favipiravir would generate high concentrations in the luminal side of the respiratory tract; and (b) avoiding first-pass metabolism by the liver by inhaled drug would generate comparable pharmacokinetics (PK) with doses significantly smaller than the oral maintenance dose., Methods: A dry powder inhalation (DPI) of favipiravir formulated by mixing with Inhalac 400® was prepared and characterized. Inhalations of ~ 120 µg dose strength, with or without a prior oral loading dose were administered to mice. Comparator mice received human-equivalent oral doses (3 mg). Three mice per sampling time point were sacrificed and favipiravir concentrations in the blood plasma, bronchio-alveolar lavage fluid (BALF) and lung tissue homogenate determined by HPLC., Results: One-compartment PK modeling of concentration-time data indicated that the area under the curve (AUC 0-24 h ) generated in the BALF recovered from mice receiving inhalations of ~ 1/25th of the oral dose subsequent to an oral loading dose was 86.72 ± 4.48 µg⋅mL -1 ⋅h. This was consistently higher than the AUC observed in the BALF of orally-dosed mice (56.71 ± 53.89 µg mL -1 ⋅h). In blood serum, the respective values of AUC were 321.55 ± 124.91 and 354.71 ± 99.60 µg⋅mL -1 ⋅h., Conclusion: Pulmonary delivery of significantly smaller doses of favipiravir generates meaningful drug disposition and pharmacokinetics at the site of respiratory viral infections. We provide the rationale for designing a self-administered, non-invasive, low-cost, targeted drug delivery system against airborne RNA virus infection., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background Dietary habits play a significant role in the rising prevalence of oral health disorders, such as dental caries and periodontal diseases, particularly in regions like Pakistan with distinct dietary customs. Objective The primary objective of this research was to investigate the impact of Asian food on the prevalence of oral diseases, with a focus on identifying specific dietary factors that contribute to oral health issues. Methodology A cross-sectional study was carried out in Lahore between February and July 2024. The sample consisted of 384 adults aged 18 and above, selected based on specific inclusion and exclusion criteria. Data were collected through structured questionnaires assessing dietary habits and clinical examinations to diagnose oral diseases. Statistical analyses (SPSS version 26: (IBM Corp., Armonk, NY, USA), including correlation, regression, and Chi-Square, were used to evaluate the relationships between dietary patterns and oral health indicators. Results The study revealed significant correlations between dietary habits and oral disease prevalence. Among the 384 patients, 287 (74.74%) patients reported high sugar consumption, with a mean frequency of 3.26 times per week, correlating strongly with oral diseases (r=0.45, p<0.01). This group exhibited 179 patients (46.60%) with dental caries and 153 patients (39.58%) with periodontal conditions. Additionally, 262 patients (68.32%) with high carbohydrate intake, averaging 4.14 times per week, showed a moderate positive correlation with oral disease prevalence (r=0.32, p<0.05). Conversely, 193 patients (50.26%) who consumed fruits and vegetables with a mean frequency of 2.51 times per week demonstrated a significant negative correlation with oral disease prevalence (r=-0.40, p<0.01), indicating a protective effect. High sugar intake was associated with greater severity of oral diseases, with mean severity scores of 3.12 for dental caries and 3.20 for periodontal conditions. Conclusion The results show that although consuming more fruits and vegetables has a preventive effect, traditional Pakistani dietary practices, particularly excessive sugar and carbohydrate consumption, are associated with an increased incidence of oral illness., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board of Lahore Medical and Dental College issued approval LM&DC: 18674-75/2024. 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, Rafiq et al.)

Background: Adolescence is commonly perceived as a distinct and typically healthy stage of life. However, in regions with a high prevalence of HIV, like Ethiopia, numerous adolescents are contracting the virus. Upon testing and diagnosis, they encounter care-related issues, particularly barriers and facilitators of the healthcare transition from adolescent to adult clinics. Hence, the study aimed to investigate the barriers and facilitators influencing the transition of adolescents living with HIV (ALWHs) in the resource-limited settings of Southern Ethiopia., Methods: The research employed a phenomenological study design with a qualitative methodology. Purposive sampling was used to gather data through in-depth interviews (IDIs) and focus group discussions (FDGs) involving ALWHs and their parents. The data analysis followed Van Manen's principles., Results: Following Van Manen's guidelines, the data analysis revealed a conceptual framework with two major themes: "Barriers" and "Facilitators". The theme barrier was derived from three sub-themes including behavioral barriers, social barriers, and system barriers in the transition. The theme facilitator was derived from four sub-themes including self-acceptance as an adult, a desire to experience new things, a supportive family, and friendly healthcare services. The study identified three levels of factors influencing the transition into adult clinics: individual, family/peer, and healthcare-related factors. The barriers to transition included lack of knowledge, being in a romantic relationship, psychosocial struggles, perceiving us as immature, stigma, negative peer pressure, lack of timely disclosure, absence of transition guidelines, disrespectful treatment, and absence of separate clinics. On the other hand, facilitators such as self-acceptance as an adult, desire for new experiences, family support, informed support and promising outcomes, flexible appointment scheduling, and psycho-social support groups were found to improve the transition process and enhance the overall well-being of adolescents living with HIV., Conclusion: The study highlights the complex transition process for ALWHs into adult healthcare. Barriers such as lack of knowledge, stigma, and disrespectful treatment pose challenges during this critical period. Conversely, facilitators like self-acceptance, family support, and youth-friendly healthcare services can enhance the transition experience and well-being of ALWHs. Collaborative efforts among ALWHs, families, and healthcare providers are crucial for successful transitions and improved health outcomes. Separated clinics catering to the unique needs of ALWHs are recommended to address privacy concerns., (© 2024. The Author(s).)

Over the past few decades, poly(methyl methacrylate) (PMMA) based bone cement has been clinically used extensively in orthopedics for arthroplasty and kyphoplasty, due to its biocompatibility and excellent primary fixation to the host bone. In this focused review, we discuss the use of various fillers and secondary chemical moieties to improve the bioactivity and the physicochemical properties. The viscosity of the PMMA blend formulations and working time are crucial to achieving intimate contact with the osseous tissue, which is highly sensitive to organic or inorganic fillers. Hydroxyapatite as a reinforcement resulted in compromised mechanical properties of the modified cement. The possible mechanisms of the additive- or filler-dependent strengthening or weakening of the PMMA blend are critically reviewed. The addition of layered double hydroxides with surface functionalization appears to be a promising approach to enhance the bonding of filler with the PMMA matrix. Such an approach consequently improves the mechanical properties, owing to enhanced dispersion as well as contributions from crack bridging. Finally, the use of emerging alternatives, such as nanoparticles, and the use of natural biomolecules were highlighted to improve bioactivity and antibacterial properties.

Background: Total body irradiation (TBI) with or without cranial radiation boost (CRB) is an integral component of conditioning prior to allogeneic hematopoietic cell transplantation (allo-HCT) in acute lymphoblastic leukemia (ALL). The benefit of CRB is not yet established., Methods: This is a retrospective single center cohort study. Between January of 2003 and April of 2019, electronic medical records of 166 patients with ALL were retrospectively reviewed. One hundred forty-three patients with ALL and no prior central nervous system (CNS) involvement were included. Patients were divided into two cohorts according to cranial radiation boost (cohort-1: CNS-/CRB+ (110/143, 77%) and cohort-2: CNS-/CRB- (n=33/143; 23%). No patients received post-transplant prophylactic intrathecal chemotherapy., Results: Following alloHCT, 15 patients (10.5%) experienced relapse; 11 relapses (10%) in cohort-1, and 4 (12%) in cohort-2. Four patients (26.6%) experienced systemic medullary relapse with initial central nervous system (CNS) involvement. One patient (6.6%) experienced isolated first central nervous system relapse after allotransplant with no difference between the two cohorts (6.6% vs 0; P-0.59). Age at transplant and phenotypic subtype were predictive of first central nervous system relapse after allotransplant with respective P-values of 0.001 and 0.015.At a median follow-up of 30 months (range: 2.5-128 months), the estimated 3-year overall survival was 61% (95% CI: 53-69), relapse free survival was 60% (95% CI: 52-69) and 3-year central nervous system-relapse-free survival was 99% and 100% in in cohort-1 and cohort-2 respectively, when systemic relapses were censored. There was no statistical significant difference in either survival or relapse free survival between the two cohorts (P > 0.69)., Conclusions: Our results suggest that augmenting total body irradiation with cranial radiation boost in patients with ALL with no prior CNS involvement did not improve relapse risk in central nervous system or survival outcomes., Competing Interests: The authors have no conflicts of interest to declare

Cyanobacteria, being a prominent category of phototrophic organism, exhibit substantial potential as a valuable source of bioactive compounds and phytonutrients, including liposomes, amino derivatives, proteins, and carotenoids. In this investigation, a polyphasic approach was employed to isolate and characterize a newly discovered cyanobacterial strain from a rice field in the Garh Moor district of Jhang. Desertifilum sp. TN-15, a unique and less explored cyanobacterial strain, holds significant promise as a novel candidate for the synthesis of nanoparticles. This noticeable research gap underscores the novelty and untapped potential of Desertifilum sp. TN-15 in the field of nanomedicine. The characterization of the biogenically synthesized ZnO-NPs involved the application of diverse analytical techniques. Ultraviolet-visible spectroscopy revealed a surface plasmon resonance peak at 298 nm. Fourier transform infrared spectral analysis was utilized to confirm the involvement of biomolecules in the biogenic synthesis and stability. Scanning electron microscopy was employed to probe the surface morphology of the biogenic ZnO-NPs unveiling their size of 94.80 nm and star-shaped. Furthermore, X-ray diffraction analysis substantiated the crystalline nature of ZnO-NPs, with a crystalline size measuring 46 nm. To assess the physical stability of ZnO-NPs, zeta potential and dynamic light scattering measurements were conducted, yielding values of + 31.6 mV, and 94.80 nm, respectively, indicative of favorable stability. The antibacterial capabilities of Desertifilum sp. TN-15 are attributed to its abundance of bioactive components, including proteins, liposomes, amino derivatives, and carotenoids. Through the synthesis of zinc oxide nanoparticles (ZnO-NPs) with this strain, we have effectively used these chemicals to generate nanoparticles that exhibit noteworthy antibacterial activity against Staphylococcus aureus (MIC: 30.05 ± 0.003 µg/ml). Additionally, the ZnO-NPs displayed potent antifungal activity and antioxidant properties, as well as significant antihemolytic effects on red blood cells (IC 50 : 4.8 µg/ml). Cytotoxicity assessment using brine shrimps revealed an IC 50 value of 3.1 µg/ml. The multifaceted actions of the biogenically synthesized ZnO-NPs underscore their potential applications in pharmacological and therapeutic fields. This study proposes a novel method for ZnO-NPs production utilizing the recently identified cyanobacterial strain Desertifilum sp. TN-15, highlighting the growing significance of biological systems in the environmentally friendly fabrication of metallic oxide nanomaterials., (© 2024. The Author(s).)

Purpose: Sacituzumab govitecan (SG) is approved for the treatment of metastatic triple-negative breast cancer (mTNBC). We report the real-world clinical effectiveness and toxicity data of SG in patients with mTNBC., Methods: A multi-institution retrospective study of patients with mTNBC treated with SG from January 2021 to May 2023 was conducted. Demographic and clinicopathologic variables were collected. Univariate and multivariate Cox regression models were used for survival analysis., Results: A total of 115 patients were included. The median age at SG initiation was 60 years (range, 31-85). All patients were female; 73 (63.5%) were White and 31 (27.0%) were Black. The median number of previous therapies in the metastatic setting was two (range, 0-8). Sixty-one (56.0%) patients had primary refractory disease. Median relative dose intensity was 92% (range, 33%-100%). Grade 3 or higher adverse events (AEs) were seen in 50.9% of patients, which included neutropenia (35.7%), anemia (27.0%), vomiting (16.5%), fatigue (8.7%), and diarrhea (7.0%). Dose reductions and treatment discontinuation due to AEs were required in 51.3% and 13.2%, respectively. The objective response rate (ORR) was 27.8%. Median overall survival was 9.6 months (95% CI, 7.8 to 12.9) and median progression-free survival (PFS) was 4.8 months (95% CI, 3.6 to 5.9). In patients with human epidermal growth factor receptor 2 (HER2)-low mTNBC who received trastuzumab deruxtecan (T-DXd) after SG, the ORR to T-DXd was 34.8% and median PFS was 7 months (95% CI, 4.6 to 10.1)., Conclusion: In a real-world cohort of heavily pretreated patients with mTNBC, SG retains its clinical activity. In a subgroup with HER2-low disease, T-DXd continues to demonstrate promising clinical activity after SG, supporting the use of sequential antibody-drug conjugates in this population.

Background: Acromegaly is a rare chronic endocrine disorder associated with significant comorbidities. Many patients fail to achieve biochemical control with current medical therapies, including surgery and first-generation somatostatin ligands (fg-SRLs). We aimed to perform a systematic review and single-arm meta-analysis to evaluate the efficacy of the multi-receptor somatostatin ligand pasireotide in patients with active or uncontrolled acromegaly., Methods: We systematically searched PubMed, Embase, and Cochrane databases for studies that assessed the efficacy of pasireotide in patients with acromegaly and reported the outcomes of (1) biochemical control and its composite indicators; (2) normalized IGF-1 level and (3) low GH level. For the statistical analysis, we used R software., Results: We included nine studies with a total of 590 patients: four clinical trials and five observational cohorts. 82.2% of the overall population consisted of inadequately controlled acromegaly patients. After a follow-up of 12 months, the pooled biochemical control rate was 26.50% (95% CI 14.87-42.66). The prevalence of normalized IGF-1 and low GH levels was 36.27% (95% CI 29.15-43.39) and 34.76% (95% CI 24.58-44.95), respectively. Additionally, biochemical response rates were sustained throughout the extension phase of these studies. In a pooled analysis including four studies with extension phase results, the prevalence of biochemical control rate was 29.03% (95% CI 11.49-46.58) with 76 events out of 281 patients. The most commonly reported adverse events were gastrointestinal disturbances in 31.26% (95% CI 7.44-72.01) and hyperglycemia in 29.55% (95% CI 21.80-37.29) of patients. The incidence of new-onset diabetes mellitus significantly increased after pasireotide treatment, with a rate of 23.36% (95% CI 19.58-27.13)., Conclusion: Pasireotide demonstrates biochemical control in patients with active or uncontrolled acromegaly. Although a high rate of hyperglycemic adverse events and diabetes mellitus related to the treatment were observed, most of them were manageable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Microencapsulation has the potential to address the stability issues associated with vitamin A. This study examined the effectiveness of emulsifying a saponin-chitosan polyelectrolyte complex to encapsulate vitamin A. Utilizing response surface methodology (RSM), the effects of the chitosan, saponin, and vitamin A contents on various response variables were measured to optimize the formulation. The optimized emulsion was characterized through fluorescence microscopy, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), storage stability, and release profile. Fluorescence microscopy showed that vitamin A was evenly distributed throughout the optimized emulsion. The polyelectrolyte complex and vitamin A were shown to interact hydrophobically and electrostatically by FTIR analysis. The DSC results verified the effective encapsulation and showed that vitamin A heat stability had been enhanced. Study on storage stability demonstrated that during a 2-month storage period, the encapsulated vitamin A remained stable. Moreover, vitamin A was significantly released from the encapsulated form at pH 1.2, based on release assays. In conclusion, saponin-chitosan polyelectrolyte coating proved to be a potentially useful new material for the stability and applications of vitamin A in a range of formulations., (© 2024 The Author(s). Journal of Food Science published by Wiley Periodicals LLC on behalf of Institute of Food Technologists.)

The emergence of antimicrobial resistance within bacterial communities poses formidable challenges to existing therapeutic strategies aimed at mitigating biofilm-mediated infections. Recent advancements in this domain have spurred the development of targeted antimicrobial agents, designed to selectively eradicate the primary etiological agents while preserving the beneficial microbial diversity of the oral cavity. Targeting glucosyltransferases (GTFs), which play crucial roles in dental biofilm formation, offers a precise strategy to inhibit extracellular polysaccharide synthesis without compromising oral microbiota. This review article delves into the intricate mechanisms underlying dental caries, with a specific focus on the role of GTFs, enzymes produced by S. mutans. It further provides an overview of current research on GTF inhibitors, exploring their mechanisms of action, efficacy, and potential applications in clinical practice. Furthermore, it discusses the challenges and opportunities in the development of novel GTF inhibitors, emphasizing the need for innovative approaches to combat biofilm-mediated oral diseases effectively., 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 Elsevier B.V. All rights reserved.)

Background: Final year nursing students may experience higher levels of stress owing to the increasing complexity and expectations from their clinical practicums. Enhancing psychological readiness may be a potential strategy to enhance nursing students' transition to the clinical area., Objective: To evaluate the effects of a psychological readiness enhancement for transition to professional practice program and a 10-week clinical practicum on students' psychological wellbeing, resilience, practice readiness and confidence., Design: A sequential mixed-methods approach comprising of a single-group evaluation and descriptive qualitative study., Setting: Final year nursing students enrolled in an undergraduate nursing program from one autonomous university in Singapore was recruited., Participants: 148 final year nursing students participated in the single-group evaluation study. A total of 24 participants who completed the psychological readiness program were recruited in the qualitative study., Methods: This study included two phases. Phase I comprised of an evaluation of a blended psychological readiness program and clinical practicum. Data was collected across three waves to assess nursing students' psychological wellbeing, resilience, practice readiness and confidence. In Phase II, a qualitative study using individual semi-structured online interviews was conducted to examine students' experiences of the psychological readiness program and clinical practicum., Results: The psychological readiness program led to significant changes in students' anxiety and patient centeredness scores. The accumulated effects of the psychological readiness and clinical practicum showed significant improvements in students' practice readiness and confidence. Although there were no significant improvements in depression, stress and resilience scores, there were improvements in the trend across three waves. Students attributed these improvements to the psychological readiness program and sharing by the alumni., Conclusions: The findings of this study laid the foundation for the development of psychological readiness programs. However, larger scale studies using randomized controlled trial designs should be used to confirm the effects of these interventions., 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 Elsevier Ltd. All rights reserved.)

Academic global surgery consists of collaborative partnerships that address surgical inequities through research, training, education, advocacy, and diplomacy. It has been characterized by increased scholastic production through global surgery publications, dedicated global surgery sessions within scientific conferences, global surgery-specific research grants, database development to support global surgery research, global surgery research fellowships, and global surgery-based academic promotion paradigms. The increased emphasis on global surgery research has been accompanied by multiple ethical challenges. This article reviews critical ethical dilemmas presented by global surgery research efforts and proposes interventions on the partnership, infrastructural, and policy levels to enhance fidelity within research partnerships., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To determine predictors of successful ictal single photon emission computed tomography (SPECT) injections during Epilepsy Monitoring Unit (EMU) admissions for patients undergoing presurgical evaluation for drug-resistant focal epilepsy., Methods: In this retrospective study, consecutive EMU admissions were analyzed at a single center between 2019 and 2021. All seizures that occurred during the admission were reviewed. "Injectable seizures" occurred during hours when the radiotracer was available. EMU-level data were analyzed to identify factors predictive of an EMU admission with a successful SPECT injection (successful admission). Seizure-level data were analyzed to identify factors predictive of an injectable seizure receiving a SPECT injection during the ictal phase (successful injection). A multivariate generalized linear model was used to identify predictive variables., Results: 125 EMU admissions involving 103 patients (median 37 years, IQR 27.0-45.5) were analyzed. 38.8% of seizures that were eligible for SPECT (n = 134) were successfully injected; this represented 17.4% of all seizures (n = 298) that occurred during admission. Unsuccessful admissions were most commonly due to a lack of seizures during EMU-SPECT (19.3%) or no injectable seizures (62.3%). Successful EMU-SPECT was associated with baseline seizure frequency >1 per week (95% CI 2.1-3.0, P < 0.001) and focal PET hypometabolism (95% CI 2.0-3.7, P < 0.001). On multivariate analysis, the only factor associated with successful injection was patients being able to indicate they were having a seizure to staff (95% CI 1.0-4.4, P = 0.038)., Significance: Completing a successful ictal SPECT study remains challenging. A baseline seizure frequency of >1 per week, a PET hypometabolic focus, and a patient's ability to indicate seizure onset were identified as predictors of success. These findings may assist EMUs in optimizing their SPECT protocols, patient selection, and resource allocation., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

A monster called cancer is still one of the most challenging human problems and one of the leading causes of death in the world. Different types of treatment methods are used for cancer therapy; however, there are challenges such as high cost and harmful side effects in using these methods. Recent years have witnessed a surge in the development of therapeutic peptides for a wide range of diseases, notably cancer. Peptides are preferred over antibiotics, radiation therapy, and chemotherapy in the treatment of cancer due to a number of aspects, including flexibility, easy modification, low immunogenicity, and inexpensive cost of production. The use of therapeutic peptides in cancer treatment is a novel and intriguing strategy. These peptides provide excellent prospects for targeted drug delivery because of their high selectivity, specificity, small dimensions, good biocompatibility, and simplicity of modification. Target specificity and minimal toxicity are benefits of therapeutic peptides. Additionally, peptides can be used to design antigens or adjuvants for vaccine development. Here, types of therapeutic peptides for cancer therapy will be discussed, such as peptide-based cancer vaccines and tumor-targeting peptides (TTP) and cell-penetrating peptides (CPP)., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is present in lean people. However, the magnitude of the prognostic hepatic and cardiovascular risk in these patients compared to non-lean counterparts remains unclear. We aimed to investigate this topic, and to explore whether these risks change based on factors related to NAFLD severity., Methods: PubMed and Embase databases were searched for cohort studies (published through April 2024) that evaluated liver and cardiovascular (CV) outcomes in lean and non-lean individuals with NAFLD and reported unadjusted or adjusted data. We pooled risk ratios (RRs) or hazard ratios (HRs) using a random-effects modeling and performed subgroup and meta-regressions analyses., Results: We identified 22 studies with over 1 million NAFLD patients (13.0% were lean). Lean NAFLD showed a similar risk of liver-related events in unadjusted analysis (RR 1.08, 95% CI 0.79-1.49, I 2  = 31%), but a higher risk in adjusted analysis (HR 1.66, 95% CI 1.17-2.36, I 2  = 83%) compared to non-lean NAFLD. Lean NAFLD had a higher risk of liver-related mortality (RR 2.22, 95% CI 1.57-3.15, I 2  = 0%; HR 2.26, 95% CI 1.14-4.51, I 2  = 0%). For CV outcomes, lean NAFLD had a lower risk of any cardiovascular disease in unadjusted analysis (RR = 0.82, 95% CI 0.70-0.95, I 2  = 88%), but similar risk in adjusted analysis (HR 0.89, 95% CI 0.77-1.02, I 2  = 78%), and similar risk of cardiovascular mortality (RR 1.09, 95% CI 0.71-1.66, I 2  = 85%; HR 1.26, 95% CI 0.89-1.78, I 2  = 46%) compared to non-lean NAFLD., Conclusions: Lean NAFLD patients have worse liver outcomes, but similar CV outcomes compared to non-lean NAFLD patients, highlighting the importance of monitoring both groups closely., (© 2024. Asian Pacific Association for the Study of the Liver.)

The Pharmacogene Variation Consortium (PharmVar) serves as a global repository providing star (*) allele nomenclature for the polymorphic human CYP4F2 gene. CYP4F2 genetic variation impacts the metabolism of vitamin K, which is associated with warfarin dose requirements, and the metabolism of drugs, such as imatinib or fingolimod, and certain endogenous compounds including vitamin E and eicosanoids. This GeneFocus provides a comprehensive overview and summary of CYP4F2 genetic variation including the characterization of 14 novel star alleles, CYP4F2*4 through *17. A description of how haplotype information cataloged by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) is also provided., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Context: Most cancer-associated pain is experienced in low- and middle-income countries (LMICs) due to inequitable access to opioids., Objective: To determine opioid access as estimated by both patients and providers and to understand patient and facility-level factors influencing access among patients with advanced cancer in LMICs in Asia using the Behavioral Model of Health Services Use., Methods: The APPROACH cross-sectional study was conducted in seven LMICs in Asia, involving in-depth surveys with providers and advanced cancer patients. A hierarchical logistic regression model was used to assess predisposing (i.e. individual factors), enabling (i.e. health care system and facility-level resources) and need (i.e. pain severity) factors predicting opioid access., Results: Among patient participants (n=1,933), approximately 40% reported opioid use. Meanwhile 80% of facilities, as reported by providers, indicated at least half of their advanced cancer patients receive oral morphine prescriptions. Predisposing characteristics factored in the least in the model, with patient education positively associated with access (Odds ratio (OR): 1.01; 95% CI=1.00, 1.03). Facility-level enabling resources, factoring the most, included oral morphine prescription duration >14 days (OR: 1.27; 95% CI=1.05, 1.53) and the extent of physician palliative care training (extensive (>160 hours) OR: 3.95; CI=3.19, 4.88; basic (up to 40 hours) OR: 1.03; CI=1.03, 1.04). Patient need as indicated by greater pain severity predicted access (OR: 1.55; CI=1.47, 1.64)., Conclusion: Study findings emphasize the importance of palliative care training-even a minimal amount-in supporting access to opioids for advanced cancer patients. This study also highlights pragmatic site-level policies, such as extended morphine prescription durations, enabling access., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

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.

This narrative review explores the burgeoning field of Artificial Intelligence (AI)-driven Breast Cancer (BC) survival prediction, emphasizing the transformative impact on patient care. From machine learning to deep neural networks, diverse models demonstrate the potential to refine prognosis accuracy and tailor treatment strategies. The literature underscores the need for clinician integration and addresses challenges of model generalizability and ethical considerations. Crucially, AI's promise extends to Low- and Middle-Income Countries (LMICs), presenting an opportunity to bridge healthcare disparities. Collaborative efforts in research, technology transfer, and education are essential to empower healthcare professionals in LMICs. As we navigate this frontier, AI emerges not only as a technological advancement but as a guiding light toward personalized, accessible BC care, marking a significant stride in the global fight against this formidable disease., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Post-bariatric surgery hypoglycemia, also recognized as late dumping syndrome or postprandial hyperinsulinemic hypoglycemia, is a complex condition often driven by multifactorial roots, including postoperative anatomical changes, altered gut hormone responses, metabolic shifts, and other hidden conditions, necessitating a multidisciplinary approach for appropriate evaluation and treatment. We present the case of a 36-year-old female nurse who experienced recurrent hypoglycemia following gastric sleeve surgery. Despite significant weight loss and dietary adjustments, she continued to struggle with unstable blood glucose levels. A comprehensive dysglycemia evaluation revealed the presence of an autoimmune disorder consistent with the criteria for latent autoimmune diabetes in adults (LADA), as defined by "The Immunology of Diabetes Society" (IDS). This new diagnosis added complexity to her clinical management, leading us to reassess her treatment strategy. As a result, her treatment plan was modified to include the initiation of insulin and the introduction of the newly FDA-approved teplizumab, which may help delay the progression of autoimmune diabetes. This case underscores the importance of systematic hypoglycemia evaluations in bariatric surgery patients to optimize clinical outcomes. Managing hypoglycemia in these patients requires a collaborative effort involving endocrinologists, surgeons, and nutritionists to ensure the best outcomes and improve the patient's quality of life., 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: Dr. Mirza works with Lynn Institute of Norman as a principal investigator for ongoing diabetes and Obesity clinical trials., (Copyright © 2024, Ken-Eze et al.)

The Robson Classification System is recognised as a first step for optimising the use of caesarean section and as a strategy for continuous quality improvement in maternal and newborn health. This Viewpoint provides a detailed account of the strategy adopted and lessons learned from a collaborative initiative to institutionalise the Robson Classification into Pakistan's health system. We developed a training package which emphasised capacity building of senior clinicians to act as master trainers. We also developed a mobile application for data collection and analysis. Training workshops took place in 2020 in a selection of public sector, tertiary-level, teaching hospitals from across the country and data was collected on all births in participating hospitals' obstetric units for a full year. Pakistan is poised for scale-up with the Robson Classification embedded in 57% of Pakistan's public, tertiary, teaching hospitals. A core group of master trainers is positioned in every province, and a robust dataset is available. However, integration into any health system cannot be thought of as a finite project. It requires government commitment, training and an ongoing process with built-in data quality assurance and feedback to clinicians., Competing Interests: The current study received technical assistance from the UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), World Health Organization, Geneva, Switzerland. The Robson TGCS implementation over the years has received funding from an anonymous donor, Ministry of Foreign Affairs, Norway; Federal Ministry for Economic Cooperation and Development, Germany and WHO internal funds. TR declares funding from Centre for Global Public Health, Pakistan. LH was hired as a consultant to facilitate training of participants and to write the manuscript. Authors declare no other conflicts of interest., (© 2024 Published by Elsevier Ltd.)