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Stem cell treatment shows promise in treating conditions such as neurodegenerative disorders and spinal injuries, but its effectiveness is hampered by cell death and apoptosis. Improving the differentiation of MSCs into neural cells could enhance their therapeutic potential. The role of miR-22-3p in human dental pulp stem cells (HDPSCs), a superior alternative to treat neurodegenerative disorders, and its molecular mechanisms during neural differentiation remain elusive. Therefore, we investigated the miR-22-3p transfections during HDPSC differentiation into neural progenitor-like cells (NPCs) and elucidated the molecular processes through transcriptomic analysis. HDPSCs were differentiated into NPCs after transfection with a miR-22-3p mimic and inhibitor; the differentiation process was assessed by cell viability and expression of Nestin protein. mRNA sequencing on days 1, 3, and 7 of the differentiation process identified several differentially expressed genes (DEGs). Cytoscape and functional enrichment analysis pinpointed central hub genes among the DEGs and uniquely expressed genes. miR-22-3p mimic hindered HDPSC differentiation by reducing proliferation and increasing apoptosis. It downregulated genes linked to extracellular matrix, synaptic and vesicle functions, lipid metabolism, JAK-STAT, and cell cycle pathways across all days while activating proteasome and digestion pathways. In contrast, miR-22-3p inhibition boosts NPC proliferation and elevates Nestin neural marker protein expression. Altogether, miR-22-3p disrupts synapse functioning and lipid metabolism pathways, resulting in apoptosis and death. Conversely, inhibiting miR-22-3p enhances neural differentiation and proliferation of HDPSCs, suggesting its potential application in generating a greater quantity of NPCs and neurons., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Previous results from the KEYNOTE-716 trial demonstrated significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) with adjuvant pembrolizumab versus placebo in patients with resected stage IIB or IIC melanoma. We present a post hoc analysis of efficacy according to primary tumor location., Methods: KEYNOTE-716 (NCT03553836) is a randomized, multicenter, double-blind, phase III study. Patients aged ≥ 12 years with newly diagnosed, resected stage IIB or IIC melanoma (sentinel node-negative) were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. This post hoc analysis evaluated RFS and DMFS by primary tumor location of the head/neck, trunk, or extremities., Results: Overall, 976 patients were assigned to pembrolizumab (n = 487) or placebo (n = 489). Median follow-up was 39.4 months (range 26.0-51.4). The hazard ratios {HRs (95% confidence interval [CI])} for RFS were 0.60 (0.38-0.93) for the head/neck subgroup, 0.57 (0.38-0.84) for the trunk subgroup, and 0.69 (0.47-1.02) for the extremities subgroup. The HRs (95% CI) for DMFS were 0.65 (0.37-1.14) for the head/neck subgroup, 0.59 (0.38-0.92) for the trunk subgroup, and 0.53 (0.31-0.90) for the extremities subgroup., Conclusion: RFS and DMFS consistently favored adjuvant pembrolizumab over placebo in most subgroups analyzed in this post hoc analysis from the KEYNOTE-716 trial. These results support the benefit of adjuvant pembrolizumab on RFS and DMFS in patients with resected high-risk stage II melanoma, irrespective of primary tumor location., Competing Interests: Disclosure: Charles H. Yoon has no conflicts of interest to declare. Merrick I. Ross has received consulting fees from, support for travel from, and participated on advisory boards for Merck & Co., Inc., Rahway, NJ, USA. Brian R. Gastman conducted an investigator-initiated trial unrelated to this work and has received honorarium from and participated in an advisory board meeting for Merck & Co., Inc., Rahway, NJ, USA. Jason J. Luke has received grants or contracts from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck & Co., Inc., Rahway, NJ, USA, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; consulting fees from 7 Hills, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, Stipe, Tempest, AbbVie, Alnylam, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck & Co., Inc., Rahway, NJ, USA, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Ribon, Roivant, Servier, STINGthera, Synlogic, and Synthekine; has the following patents (both provisional): Serial #15/612,657 (Cancer Immunotherapy) and PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof); participated on a data monitoring committee or advisory board for AbbVie, Immutep, Evaxion; had a leadership role in the Society for Immunotherapy of Cancer; and has stock ownership in Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, Stipe, and Tempest. Paolo A. Ascierto has received grants from or contracts with Bristol Myers Squibb, Roche-Genentech, Pfizer/Array, and Sanofi; has received consulting fees from Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, and Erasca; has received honoraria from Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, and Pfizer; has received support for attending meetings from Pfizer, Bio-AI Health, and RepImmune; and has participated on a data safety monitoring board or advisory board for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, and Erasca. Georgina V. Long is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, GI Innovation, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Immunocore, Innovent Biologics USA, IOBiotech, Iovance Biotherapeutics, MSD, Novartis, PHMR Ltd, Pierre Fabre, Regeneron, Scancell, SkylineDX B.V. Piotr Rutkowski has received consulting fees from Bristol Myers Squibb, Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pierre Fabre, Philogen, Pfizer, Genesis, and Madison Pharma; has received honoraria from Bristol Myers Squibb, Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, Pierre Fabre, Sanofi, AstraZeneca, Pfizer, Novartis, Pierre Fabre, Merck & Co., Inc., Rahway, NJ, USA, and BMS; has received support for attending meetings and/or for travel from Orphan Europe and Pierre Fabre; and has received research funding (Inst) from Novartis, Pfizer, Roche, and Bristol Myers Squibb. Muhammad Khattak has received honoraria from and participated on an advisory board meeting for Merck & Co., Inc., Rahway, NJ, USA. Michele Del Vecchio has received consulting fees from Bristol Myers Squibb, Immunocore, Merck & Co., Inc., Rahway, NJ, USA, Novartis, and Pierre Fabre, and has received honoraria from Bristol Myers Squibb, Pierre Fabre, Merck & Co., Inc., Rahway, NJ, USA, Immunocore, and Novartis. Lius de la Cruz Merino has received consulting fees from BMS, Merck & Co., Inc., Rahway, NJ, USA, Roche, AstraZeneca, and Gilead; has received honoraria from AstraZeneca, Merck & Co., Inc., Rahway, NJ, USA, and BMS; and has received support for attending meetings and/or for travel from Gilead. Jacek Mackiewicz has received honoraria from Bristol Myers Squibb, Merck & Co., Inc., Rahway, NJ, USA, Pierre Fabre, and Novartis; has participated on advisory boards for Bristol Myers Squibb, and Merck & Co., Inc., Rahway, NJ, USA; and has received travel grants from Bristol Myers Squibb, Merck & Co., Inc., Rahway, NJ, USA, Pierre Fabre, and Novartis. Vanna Chiarion-Sileni has received honoraria from Immunocore, support for attending meetings and/or travel from Pierre Fabre and Sanofi, and has participated on a data monitoring committee for Pierre Fabre and Merck Sharp & Dohme. Dirk Schadendorf has received grants or contract (Inst) from BMS, Amgen, and Merck & Co., Inc., Rahway, NJ, USA; has received consulting fees from Anaveaon, Agenus, BMS, Novartis, Merck & Co., Inc., Rahway, NJ, USA, Merck-Serono, Sanofi, Regenereon, Pierre Fabre, Pfizer, 4SC, InFlarX, Seagen, Replimune, Sunpharma, Philogen, Neracare, BioAlta, Daiichi Sanyo, AstraZeneca, Immatics, PamGene, BioNTech, CureVac, Ersaca, Formycon, NoviGenix, Haystack, IOBioTech, Immunocore, Nektar, and OncoSec; has received honoraria from BMS, Novartis, Merck & Co., Inc., Rahway, NJ, USA, Merck-Serono, Sanofi, Pierre Fabre, Pfizer, and Sun Pharma; has participated on advisory boards for BioAlta, 4SC, InFlarX, Daiichi Sanyo, AstraZeneca, and Immunocore; and has a leadership role in Dermatologic Cooperative Group (DeCOG), EuMelaREg, NVKH, and Hiege-Stiftung. Matteo S. Carlino has received consulting fees from Amgen, Bristol Myers Squibb, Eisai, Ideaya, Merck & Co., Inc., Rahway, NJ, USA, Nektar, Novartis, Oncosec, Pierre Fabre, Qbiotics, Regeneron, Roche, and Sanofi; and honoraria from BMS and Merck & Co., Inc., Rahway, NJ, USA. Yujie Zhao, Mizuho Fukunaga-Kalabis, and Clemens Krepler are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock in Merck & Co., Inc., Rahway, NJ, USA. Alexander M.M. Eggermont has received support for the present manuscript from Merck & Co., Inc., Rahway, NJ, USA; has received consulting fees from Agenus, Boehringer Ingelheim, BioInvent, BioNTech, Brenus, CatalYm, Eurobio, Galecto, GenOway, ImCheck, IO Biotech, Ipsen, IQVIA, ISA Pharmeuticals, Merck & Co., Inc., Rahway, NJ, USA, Pfizer, Pierre Fabre, Scancell, Scorpion, TigaTx, and Trained Immunity Discovery; has received honoraria from Merck & Co., Inc., Rahway, NJ, USA, and BMS; has participated on advisory boards for Agenus, Boehringer Ingelheim, BioInvent, BioNTech, Brenus, CatalYm, Eurobio, Galecto, GenOway, ImCheck, IO Biotech, Ipsen, IQVIA, ISA Pharmeuticals, Merck & Co., Inc., Rahway, NJ, USA, Pfizer, Pierre Fabre, Scancell, Scorpion, TigaTx, and Trained Immunity Discovery; and has stock ownership in IO Biotech, Sairopa B.V., and SkylineDX B.V. Jeffrey E. Gershenwald has received royalties from UpToDate, consulting fees and advisory board participation fees from Merck & Co., Inc., Rahway, NJ, USA, and is Vice Chair of the American Joint Committee on Cancer. Vernon K. Sondak has received grants or contracts from Neogene Therapeutics, SkylineDx, and Turnstone Biologics; and has received consulting fees from Bristol Myers Squibb, Genesis Drug Discovery & Development, Iovance, Merck & Co., Inc., Rahway, NJ, USA, Mural Oncology, Novartis, and Sun Pharmaceuticals., (© 2025. Merck & Co., Inc., Rahway, NJ, USA and its Affiliates & The Authors.)

The purpose of this review is to report clinical outcomes of patients undergoing hip arthroscopy for femoroacetabular impingement (FAI) with initial access to the peripheral compartment (PC) of the hip. A search following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed in the PubMed, Embase, and Scopus databases. Studies in which clinical outcomes were reported for patients who underwent hip arthroscopy for FAI with initial access to the PC were included. Data on study characteristics, patient demographics, radiographic outcomes, patient-reported outcomes (PROs), complications, and secondary surgery were extracted. Five studies with 881 patients and 976 hips (55.2% male, age range 32.1 to 48.4 years, follow-up range 3.0 to 74.4 months) were included. In two studies reporting radiographic measurements, the range of preoperative and postoperative alpha angle was 55.5° to 68.7° and 45.5° to 48.3°, respectively. The range of preoperative and postoperative lateral center-edge angles was 33.8° to 39.2° and 30.5° to 32.9°, respectively. Four studies reported one or more PRO measures with all demonstrating significant preoperative to postoperative improvement. The postoperative Non-Arthritic Hip Score (NAHS) and Visual Analog Score (VAS) pain scales ranged from 78.0 to 83.2 and 1.4 to 2.8, respectively. Complication rates ranged from 0.3% to 23.3%, with the rate of paresthesia specifically ranging from 0% to 8.1%. The rate of secondary surgery ranged from 0% to 6.3%. The rate of revision hip arthroscopy and conversion to total hip arthroplasty, specifically, ranged from 0% to 3.1% and 0% to 3.7%, respectively. This systematic review demonstrates that hip arthroscopy for FAI with initial access to the PC shows significant improvements in PROs with low rates of complications and secondary surgery., 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 © 2025, Baig et al.)

Neoadjuvant immunotherapies have shown antitumor activity in melanoma. Substudy 02C of the global, rolling-arm, phase 1/2, adaptive-design KEYMAKER-U02 trial is evaluating neoadjuvant pembrolizumab (anti-PD-1) alone or in combination, followed by adjuvant pembrolizumab, for stage IIIB-D melanoma. Here we report results from the first three arms: pembrolizumab plus vibostolimab (anti-TIGIT), pembrolizumab plus gebasaxturev (coxsackievirus A21) and pembrolizumab monotherapy. Pathologic complete responses occurred in 10 of 26 patients (38%) with pembrolizumab plus vibostolimab, 7 of 25 (28%) with pembrolizumab plus gebasaxturev and 6 of 15 (40%) with pembrolizumab monotherapy. Major pathologic responses occurred in 13 (50%), 10 (40%) and 7 (47%) patients, respectively. Safety was manageable. Treatment-related adverse events occurred in 24 of 26 patients (92%) with pembrolizumab plus vibostolimab, 21 of 25 (84%) with pembrolizumab plus gebasaxturev and 12 of 15 (80%) with pembrolizumab monotherapy; grade 3 or 4 treatment-related adverse events occurred in 2 (8%), 7 (28%) and 1 (7%) patient in each arm, respectively. No deaths due to adverse events occurred. Exploratory objective responses per RECIST v1.1 were observed in 13 (50%), 8 (32%) and 4 (27%) patients, in each arm, respectively. In a post hoc analysis, scores for tumor mutational burden and an 18-gene T cell-inflamed gene expression profile were generally higher in patients with major pathologic response. Longer follow-up will provide insight into the incremental benefit of combining neoadjuvant pembrolizumab with other therapies in stage IIIB-D melanoma. ClinicalTrials.gov registration: NCT04303169 ., Competing Interests: Competing interests: The authors declare the following competing interests: R.D. reports consulting fees and payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma, Takeda, Sanofi, Caralym, Second-Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME. C.R. reports consulting fees from BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Sun Pharma and AstraZeneca and participation on a Data Safety Monitoring Board or Advisory Board for BMS, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Sun Pharma and AstraZeneca. R.A.S. reports consulting fees from SkylineDx BV, F. Hoffman-La Roche Ltd, MetaOptima Technology Inc., Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc, Bristol Myers Squibb, Myriad Genetics, GlaxoSmithKline and IO Biotech ApS. J.M.T. reports grants or contracts to their institution from BMS; consulting fees from Merck & Co, BMS, AstraZeneca, Regeneron, Roche, Elephas, Lunaphore and Akoya Biosciences; a patent planned for machine learning for irPRC; and a Task Force role with the Society for Immunotherapy of Cancer. A.M.M. reports consulting fees from BMS, MSD, Novartis, Pierre Fabre, Roche and Qbiotics. M.T.T. reports support for the present paper to their institution from Merck and payment or honoraria and support for attending the Clinical Care Options, AACR 2023 companion course. A.H. has no conflicts of interest to declare. J.-J.G. reports consulting fees from Novartis and BMS, and participation on a Data Safety Monitoring Board or Advisory Board for Novartis, BMS, MSD, Philogen, Pierre Fabre, Sanofi, Roche and Amgen. D.C.P. has no conflicts of interest to declare. C.L. reports participating on an Advisory Board for MSD, BMS, Pierre Fabre, Novartis, Regenron and Seacraft; and travel expenses from BMS. M.A.K. reports consulting fees from MSD Australia, BMS Australia and Moderna; payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from MSD Australia and Moderna; and support for attending meetings and/or travel from Moderna and Pierre Fabre. J.C. has no conflicts of interest to declare. G.B.-S. reports payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from BMS, MSD, Merck, Novartis, Medison and Sanofi, and a role as the chairman of the Israeli Society of Clinical Oncology & Radiation Therapy. I.M. reports payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from BMS and Immunocore, and stock or stock options in Immunocore, Delcath and In8 Bio Iovance Ideaya. R.S.-F. reports medical writing support for the present paper; grants or contracts to their institution from MSD; payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from MSD, BMS, Novartis, Sanofi, Roche, AstraZeneca, Medison and Neopharm; and participation on an advisory board for MSD, Novartis and Clovis Oncology. N.M. reports grants or contracts from BMS, Novartis, Merck, MSD and Pierre Fabre; payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from BMS; payment for expert testimony from BMS, Pierre Fabre, MSD and Novartis; and support for attending meetings and/or travel from Pierre Fabre, Janssen, BMS and AbbVie. A.L.W. is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns stock in Merck & Co., Inc., Rahway, NJ, USA, and Organon. Y.R., M.F.-K. and C.K. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock in Merck & Co., Inc., Rahway, NJ, USA. G.V.L. reports consulting fees from and participation on a Data Safety Monitoring Board or Advisory Board for Agenus Inc, Amgen Inc, Array BioPharma, AstraZeneca, Bayer Health Care, BioNTech, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IO Biotech, Immunocore Ireland Limited, Innovent Biologics USA Inc, Merck Sharp & Dohme (Australia) Pty Limited, Novartis Pharma AG, PHMR Ltd, Pierre Fabre, Qbiotics Group Limited, Regeneron Pharmaceuticals, Scancell Limited and SkylineDX B.V.; and payment or honoraria for lectures, presentations, speakers’ bureaus, paper writing or educational events from Bristol Myers Squibb and Pierre Fabre., (© 2025. The Author(s).)

Background: Immunotherapy has emerged as a standard treatment for deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC). Pembrolizumab became widely available as a first-line (1L) option in Australia following the Pharmaceutical Benefits Scheme (PBS) listing in August 2021. The uptake of new treatment options can be lengthy., Methods: The Treatment of Recurrent and Advanced Colorectal Cancer mCRC registry data at participating Australian sites was analysed from January 2015 (when MMR testing became routine). 1L treatment of dMMR cancers was compared with pre- and post-PBS funding., Results: Out of 2819 patients, 2344 (83%) had known MMR status. Of these, 162 (7%) were dMMR, which was associated with older age (median age 69 vs 63 years, P = 0.001), a right-side primary (68% vs 31%, P < 0.001) and a BRAF V600E mutation (49% vs 11%, P < 0.001). Prior to August 2021, 85 out of 117 (73%) patients with dMMR received 1L treatment: 63 out of 85 (74%) chemotherapy and 20 out of 85 (24%) immunotherapy. Following approval, 39 out of 45 (87%) received 1L treatment and 39 out of 39 (100%) pembrolizumab. Of the patients 75 years and older, a significantly higher proportion of patients were treated with any 1L therapy post-PBS listing (89% vs 60%, P = 0.036)., Conclusion: Previously reported associations of dMMR were observed. The higher-than-expected proportion of patients with dMMR is likely driven by the inclusion of older patients in this real-world study. Many patients were able to access immunotherapy prior to PBS listing, potentially through trials or access programs. Early uptake of pembrolizumab following PBS listing has been high, and this effective and well-tolerated option has increased the proportion of elderly patients receiving active therapy., (© 2024 Royal Australasian College of Physicians.)

Medical and dental professionals should continue to adhere to preventive measures after COVID-19 vaccination due to their increased risk of exposure to the virus, particularly as new variants emerge that may heighten their risk perception and susceptibility. Therefore, this study aimed to explore the effects of COVID-19 vaccination on complacency to adherence to COVID-19 preventive behavioral measures and mental health among medical and dental professionals. In this cross-sectional study 410 medical and dental professionals were recruited from different medical and dental hospitals in Islamabad, Pakistan. The data was collected using a valid and reliable questionnaire comprising of three sections (socio-demographic, information of preventive behaviors performance against COVID-19 after vaccination, mental health status). A chi-square test and ordinal logistic regression were used for analysis. Post COVID-19 vaccination there was decrease in the frequency of use of hand washing, sanitizers (70.2%), and social distancing (60.5%), however greeting with a handshake (58.8%) and use of public transport (45.9%) seen upward trend among participants. Only face mask usage post-vaccination was statistically significant ( p  < .05) in association with age, marital status, and years of working Experience. The greatest decrease in the usage of masks after COVID-19 vaccination was seen in age group of 10-30 (41.7%) and working experience group of 0-5 years (39.7%). All the preventive behaviors are statistically significant ( p  < .05) associated with the mental status of the participants except online shopping and use of public transport. These results indicate the presence of vaccination-induced complacency in adherence to COVID-19 preventive behavioral measures among healthcare professionals.

Introduction Sleep disorders are prevalent among psychiatric patients, and pharmacological treatments such as melatonin, trazodone, and doxepin are commonly prescribed. This study aimed to assess the efficacy and acceptability of these three medications in improving sleep quality and reducing daytime drowsiness in psychiatric patients. Methodology A total of 175 psychiatric patients with sleep disturbances participated in this cohort study at the Abbas Institute of Medical Sciences, Muzaffarabad, Pakistan.Participants were initially randomized, with assignments subsequently reviewed and confirmed by physicians based on clinical considerations, into one of three therapy groups: doxepin, trazodone, or melatonin. They were monitored over the course of six months, from February to July 2024. The Pittsburgh Sleep Quality Index (PSQI) was used to measure sleep quality, the Epworth Drowsiness Scale (ESS) was used to measure daytime drowsiness, and the Clinical Global Impression-Improvement (CGI-I) scale was used to determine clinical improvement. Pre- and post-treatment data were analyzed in IBM SPSS Statistics for Windows, Version 26.0 (Released 2019; IBM Corp., Armonk, New York, United States) using statistical techniques such as paired t-tests, ANOVA, and chi-square tests. Results Trazodone, doxepin, and melatonin were evaluated for their effectiveness and tolerability in improving sleep quality and reducing daytime drowsiness among 175 psychiatric patients (n=58 for melatonin, n=59 for trazodone, n=58 for doxepin). Trazodone showed the greatest improvement in sleep quality, with significant reductions in PSQI scores at six months (mean decrease = 7.0, SD = 1.9) and the highest CGI-I improvement rates (n=59, 76%, p = 0.02), but it was associated with frequent adverse effects, including morning grogginess (n=59, 15%, p = 0.03) and orthostatic hypotension (n=59, 10%, p = 0.02). Doxepin significantly enhanced sleep continuity (PSQI reduction = 6.8, SD = 2.1) and had a better tolerability profile than trazodone but was linked to dry mouth (n=58, 13%, p = 0.04). Melatonin, while slightly less effective in improving sleep quality (PSQI reduction = 6.1, SD = 2.0), had the fewest adverse effects, including the lowest rates of morning grogginess (n=58, 5%, p = 0.03) and dizziness (n=58, 10%, p = 0.41), and significantly reduced daytime drowsiness (ESS decrease = 3.9, SD = 1.7, p = 0.04). These findings highlight trazodone and doxepin as the most effective treatments, while melatonin offers better tolerability for patients concerned about adverse effects. Conclusion In psychiatric patients, trazodone was the most successful medication for enhancing sleep quality; however, other groups cannot use it due to its adverse effects. For patients who were more likely to have side effects, melatonin was a safer option, but doxepin offered a good balance between effectiveness and tolerability., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Abbas Institute of Medical Sciences, Muzaffarabad issued approval 7828/AIMS/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, Mamoon et al.)

Introduction Depression is a prevalent and debilitating condition that often requires long-term medication management. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used but have limitations in efficacy and tolerability for some individuals. New antidepressant drugs targeting multiple pathways have shown potential in recent research. This study aimed to evaluate the efficacy, quality of life (QoL) improvements, and adverse effect profiles of SSRIs, SNRIs, and novel agents in patients with depression. Methodology This prospective cohort study was conducted at inpatient and outpatient psychiatric units of Abbas Institute of Medical Sciences, over six months, from March to August 2024, enrolling 300 patients diagnosed with depression. Participants were evenly divided into three treatment groups: SSRIs, SNRIs, and novel agents. Depression severity was assessed using the Hamilton Depression Rating Scale (HAM-D), and QoL was measured using standardized QoL scores. Statistical analyses, including paired t-tests, Analysis of Variance (ANOVA), and chi-square tests, were performed for comparison. Results All groups showed notable declines in Hamilton Depression Rating Scale (HAM-D) scores; the group with the new agents showed the largest mean HAM-D reduction: (17.2, p < 0.001). All groups' QoL rose; the mean rise in QoL ratings among the novel agents' group (19.7, p < 0.01) was the highest. Compared to SSRIs (84%) and SNRIs (82%), the novel agent group likewise had the lowest incidence of side effects, which raised the adherence rate (91%). Conclusion Novel antidepressants showed better efficacy and tolerability than SSRIs and SNRIs, therefore enhancing QoL and adherence. These findings imply that for those who do not react well to conventional treatments, novel medicines could be a good substitute. Confirming these conclusions will require more long-term, multi-center research., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Abbas Institute of Medical Sciences issued approval 8572/AIMS/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, Nawaz et al.)

Introduction: The degree of improvement in serum creatinine (SCr) has previously been suggested as a sensitive indicator of treatment response in patients with hepatorenal syndrome-acute kidney injury (HRS-AKI), while HRS reversal remains the primary endpoint in clinical trials., Methods: A total of ≥ 30% SCr improvement was analyzed as an exploratory prespecified endpoint in the CONFIRM trial. In this post hoc analysis, intent-to-treat population data from three Phase 3 studies (OT-0401, REVERSE, and CONFIRM) conducted in North America in patients with HRS-AKI were pooled to assess the incidence of > 30% improvement in SCr and its association with clinical outcomes., Results: Significantly more patients treated with terlipressin achieved > 30% improvement in SCr compared with those who received a placebo (42.9% vs. 23.4%; p  < 0.001). Compared with patients who did not achieve > 30% improvement in SCr, those who achieved this threshold had a lower incidence of renal replacement therapy (RRT) (55.2% vs. 14%, respectively; p  < 0.001) and greater overall survival at Day 90 (41.6% vs. 71.1%, respectively; p  < 0.001); a greater proportion achieved durability of HRS reversal (1% [95% confidence interval, 95% CI: 0] vs. 68.9% [95% CI: 0.6, 0.8]) and more patients were alive without RRT (22.7% vs. 61.6%, respectively; p  < 0.001) or transplant (11.6% vs. 43.0%, respectively; p  < 0.0001). Additionally, the overall survival and RRT-free survival in the group that achieved > 30% improvement in SCr without HRS reversal were comparable to the overall group that achieved HRS reversal., Conclusion: A total of > 30% improvement in SCr levels even without HRS reversal may serve as a clinically meaningful endpoint to define renal recovery in patients with HRS-AKI., Competing Interests: M.A.M. reports participation in a Mallinckrodt Pharmaceuticals advisory board. M.K. has received grant funding not related to this project from CareDx Inc. and is an equity holder in R and R Medical LLC. K.J. is employed by Mallinckrodt Pharmaceuticals. The other authors declare no conflicts of interest., (© 2024 The Author(s). JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: The investigation of prevalence trends of metabolic cardiovascular risk factors is important for appropriate planning of future health programs aiming to prevent cardiovascular morbidity and mortality. In a previous study, we demonstrated an increase in the prevalence of type 2 diabetes (T2D) between 2000 and 2010 in Northeast Germany. The purpose of this study is to investigate prevalence trends of T2D treatment, dyslipidemia and hepatic steatosis in Northeast Germany., Methods: The baseline examinations of the first Study of Health in Pomerania (SHIP) project were carried out from 1997 to 2001 (SHIP-START-0, 4308 subjects). A second, independent random sample of the same region was enrolled between 2008 and 2012 (SHIP-TREND-0, 4420 subjects). All data were standardized with post-stratification weighting derived from the adult population of the German federal state of Mecklenburg-West Pomerania., Results: The prevalence of metformin intake increased from 2.1% to 4.1% and insulin use from 2.0% to 2.8%. While the prevalence of statin intake increased from 6.8% to 12.2%, the prevalence of dyslipidemia decreased slightly from 49.0% in SHIP-START-0 to 45.5% in SHIP-TREND-0. The prevalence of hepatic steatosis increased from 29.7% to 37.3%. This increase was most prominently observed in women and younger age groups., Conclusions: T2D, dyslipidemia and hepatic steatosis are common and increasing health problems among adults in Northeast Germany. Reassuring healthy diet and controlling obesity may result in prevention of above-mentioned health problems., (© The Author(s) 2024. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In phase 1-2 trials in patients with resectable, macroscopic stage III melanoma, neoadjuvant immunotherapy was more efficacious than adjuvant immunotherapy., Methods: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or nonresponse received adjuvant treatment. The primary end point was event-free survival., Results: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% in patients in the neoadjuvant group who had a major pathological response, 76.1% among those with a partial response, and 57.0% among those with a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of patients in the neoadjuvant group and in 14.7% in the adjuvant group., Conclusions: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.)., (Copyright © 2024 Massachusetts Medical Society.)

Introduction: The use of electronic cigarettes (ECs) has surged globally, particularly among young individuals. This study aimed to assess the perceptions of vaping-related oral health risks, clinical oral health status, and self-perceived dental and periodontal conditions among young adult users of ECs in Pakistan., Methods: A cross-sectional study was conducted from June 2023 to March 2024, recruiting 142 young users of ECs. Intraoral examinations assessed Decayed, Missing, and Filled Teeth (DMFT) index, Oral Hygiene Index Simplified (OHI-S), Gingival Bleeding Index (GBI), Plaque Index (PI), and dental stain. Data on sociodemographic characteristics, oral health behaviors, vaping habits, and perceptions of impact of vaping on oral health were gathered through a self-administered questionnaire. Associations between EC use and various oral health variables were analyzed using the chi-squared and Fisher's exact tests., Results: Mean DMFT was 5.66 (SD=2.20). Poor oral hygiene (29.6%) and severe dental staining were prevalent. Most participants (76.1%) brushed once daily, while only 34.5% attended regular dental check-ups. Gingival bleeding and plaque accumulation were observed in 47.2% and 35.3% of participants. Around 66% reported daily EC use, with 80.3% initiating vaping before the age of 18 years. Most common reason for vaping was perception that ECs are safer than traditional smoking (31.7%). Participants' perceptions of vaping-related oral health risks were relatively low, with 45% associating vaping with tooth decay, 48% with gum disease, and 58.5% with tooth staining. Tooth brushing frequency, vaping frequency (per day), and time since vaping started, were significantly associated with oral clinical indicators (p<0.05). The education level was the only variable significantly associated with vaping-related risk perception (p<0.05)., Conclusions: The study reveals that oral health awareness among young vapers is low, with many starting EC use at a young age and exhibiting poor oral health behaviors. Misconceptions about the safety of ECs compared to conventional cigarettes may contribute to increased vaping., Competing Interests: The authors have completed and submitted the ICMJE Form for disclosure of Potential Conflicts of Interest and none was reported., (© 2024 Khattak O. et al.)

Background Monkeypox (Mpox) is a virulent disease caused by orthopoxvirus. Mpox is emerging as a major global health threat. Currently, more than 100 countries are facing outbreaks. Pakistan, too, is witnessing the spread of this virus, with 11 confirmed cases and one death since its first detection in April 2023. Mpox infection can be diagnosed using polymerase chain reaction (PCR) and treated with antiviral agents. The smallpox vaccine is also proven to be effective against Mpox. Methodology This cross-sectional survey aimed to evaluate the knowledge, attitude, and behaviors (KAB) of the Pakistani population toward the Mpox pandemic and determine the factors affecting it. Data were collected through Google Forms using a validated questionnaire to assess the population's KAB. In total, 1,511 individuals were included in the final analysis. Results Study participants had good knowledge of the disease, poor attitude toward Mpox risk and severity, and poor behavior with low adherence to recommended protocols. Overall, 58% (n = 888) of the participants were male, and most of the respondents were aged between 18 and 30 years (n = 743, 49.2%). Most participants were married (n = 983, 65.1%), from urban areas (n = 837, 55.4%), and living in shared households (n = 876, 58%). Age showed a significant relationship with knowledge level and behavior, but not with attitude. The 18-30-year age group demonstrated higher knowledge levels (p = 0.007), regardless of gender. Shared households were significantly associated with a higher incidence of good knowledge (p < 0.05) compared to independent households (p = 0.038). Additionally, higher income was linked to better attitudes and behaviors. KAB outcomes also varied significantly based on marital status, individual education level, and parents' education levels. Conclusions Population dynamics such as cultural norms, religious beliefs, misperceptions about the disease associated with sexual behavior, health literacy, education level, rural and urban division of the population, gender role, migrant and refugee population, poverty, cost-seeking healthcare, and distrust in the government and healthcare system should be considered when constructing a public health policy because the behavior of the population is important for the implementation of preventive measures., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Ethical Review Board, Abbas Institute of Medical Sciences issued approval AIMS/1018/2022. 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, Hafeez et al.)

Background: As a major maternal health concern, the prevalence of human immunodeficiency virus (HIV) among pregnant women was previously investigated in European, African, and Latin American regions other than the North American region. This study analyzed the prevalence of HIV among pregnant women in the North American region including 3 major countries: the USA, Canada, and Mexico., Methods: Relevant studies were screened from 3 online databases: Google Scholar, PubMed, and ScienceDirect using specific search keywords. Ultimately, 10 studies of the North American region were included with a total of 339,831 pregnant women residing in the USA, Canada, and Mexico., Results: The overall pooled prevalence was 0.6% (95% confidence interval [CI]: 0.4-0.8) with a high degree of heterogeneity (I2 = 97%). Pooled prevalence rates of HIV among pregnant women in Canada, Mexico, and the USA were 0.3% (95% CI: 0.1-0.5), 0.5% (95% CI: 0.2-0.8), and 2.3% (95% CI: 0.0-5.7), respectively with high degrees of heterogeneity., Conclusion: The overall prevalence rate of HIV among pregnant women in the USA, Canada, and Mexico was minimal as compared with the countries of Eastern Europe, sub-Saharan Africa, or Latin America. Awareness, adequate testing and healthcare facilities, better socioeconomic, and geopolitical conditions might be crucial to lowering the prevalence of HIV among pregnant women., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction Parasitic infection is an overlooked cause of diarrhea in adults. It can cause persistent or chronic diarrhea that contributes to a significant burden on the overall morbidity of the population. Stool sampling would aid in the diagnosis of parasitic infection in adults presenting with diarrhea. Methods A cross-sectional study was conducted from January to June 2024 at Medical Teaching Institution (MTI)-Hayatabad Medical Complex, Peshawar, Pakistan. A total of 500 stool samples were collected using non-probability consecutive sampling. All the patients presenting with complaints of persistent or chronic diarrhea to the medical outpatient department or admitted to the medical units were included in the study. Patients with bloody diarrhea and those less than 13 years of age were excluded from the study. Verbal and written informed consent was obtained from all the patients included in the study. The stool samples of all the patients were collected, reported, and verified by the microbiology department. Results Out of 500 stool samples of the patients with persistent or chronic diarrhea, 174 (34.8%) were found to be infected with cysts or trophozoites of parasites. Gender distribution of parasitic infections showed that 89 out of 245 females (36.3%) and 85 out of 255 males (33.3%) were affected. The comparison between genders yielded a p-value of 0.482. All the patients showed mono parasitism. The most common isolate was Giardia lamblia in 90 (51.72%) cases, followed by H-Nana in 49 (28.17%) isolates, Entamoeba histolytica in 16 (9.20%), Ascaris lumbricoides in 14 (8.04%), Trichuris trichura in two (1.15%), Taenia saginata in two (1.15%), and Cryptosporidium in one (0.6%) infected patient.  Conclusion Parasitic intestinal infections, particularly Giardia and H-Nana, are prevalent yet overlooked causes of persistent and chronic diarrhea in adults. These findings underscore the importance of routine stool examination as a cost-effective diagnostic tool, potentially improving patient outcomes and reducing unnecessary medical interventions.​​​​​​​​​., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Institutional Research and Ethical Board of Hayatabad Medical Complex issued approval 2019 (dated 13-12-2023). 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, Iftikhar et al.)

Background: Recent studies have associated total neoadjuvant therapy (TNT) with better treatment adherence, decreased toxicity, improved complete clinical response and anal sphincter preservation rates in patients with locally advanced rectal cancer (LARC). However, real-world experience with TNT in the management of LARC remains limited., Aim: This study aimed to evaluate the efficacy and safety outcomes of TNT for LARC in Western Australia., Methods: Patients with LARC (cT2-4 and/or cN1-2) who underwent induction chemotherapy followed by neoadjuvant chemoradiotherapy or neoadjuvant chemoradiotherapy followed by consolidation chemotherapy, followed by surgery were recruited from two hospitals in Western Australia. Efficacy outcomes assessed included clinical response (complete, partial, no response), and pathologic complete response (pCR) rate, R0 resection rate, and R1 resection rate were evaluated. Those patients who achieved clinical complete response following TNT were given the option of active surveillance. The safety and tolerability of TNT were assessed., Results: 32 patients with LARC were treated with TNT. In total, 17 patients (53%) received chemoradiotherapy followed by consolidation chemotherapy and 15 patients (47%) received induction chemotherapy followed by chemoradiotherapy. Nine (28%) of the patients with LARC treated with TNT had a complete clinical response, twenty-one (66%) patients had a partial clinical response, and two (6%) patients had no response to TNT. Of the 32 patients, 27 (84%) underwent surgery. There was a 100% R0 resection rate. The pCR rate was 15%. pCR, clinical response, and the R0 resection rate were similar between the two TNT regimens. TNT was well tolerated, with the majority of patients (88%) completing the chemotherapy course with grade 1 and 2 adverse effects., Conclusions: In conclusion, TNT emerges as a promising approach for the management of LARC. However, further research is warranted to refine the optimal TNT protocols, determine its long-term outcomes, and identify patient populations who would benefit the most from this innovative therapeutic strategy.

Introduction: Renal colic is a prevalent acute urological emergency caused by urinary stones and commonly manifests as severe loin pain. This audit assesses the management of acute renal colic at a National Health Service (NHS) Trust in the West Midlands, England, comparing practices against the National Institute for Clinical Excellence (NICE) and the British Association of Urological Surgeons (BAUS) guidelines., Method: This retrospective audit reviewed 417 patients with suspected renal colic over a month. Data collected included patients' demographics, time to complete CT scan, laboratory investigations requested and management modalities. Patients assessed were either admitted through the Emergency Department, Surgical Assessment Unit, or previously admitted for other conditions on the wards. The audit benchmarked against NICE and BAUS guidelines, focusing on diagnostic timeliness and management, including essential blood investigations. Data analysis performed using SPSS (IBM Corp., Armonk, NY, USA) included descriptive statistics and Chi-square tests, with significance set at p < 0.05., Results: A total of 417 patients met the inclusion criteria. The average age of patients was 47.4 years with slightly higher male population (51.1%). The diagnostic rate for renal or ureteric stones using computed tomography of the kidneys, ureters, and bladder (CT-KUB) was 41.2%. The positive detection rate was significantly higher in males (54%) compared to females (27.5%) while females have more alternate diagnosis than males (13.7% vs 6.1%). The average completion time of CT-KUB was nine hours with 7.7% of patients having their CT-KUB beyond the 24-hour benchmark. Most patients (48%) were managed conservatively with analgesia, 32% received tamsulosin as medical expulsive therapy and others had interventions like ureteric stent insertion (9.3%), nephrostomy (6.4%) or primary ureteroscopy (4.1%)., Conclusion: The audit of renal colic management at our centre revealed a 41.2% diagnostic rate for renal or ureteric stones via CT-KUB, with a significantly higher rate in males than females. Diagnostic delays were minimal, with only 7.7% of scans exceeding 24 hours. Conservative management was common, however non-steroidal anti-inflammatory drugs (NSAIDs) were underutilized despite guideline recommendations. There was a notable gender disparity in diagnostic and alternate findings rates. The results showed the need for adherence to pain management protocols and highlight the effectiveness of existing renal colic protocol, while also pointing to potential areas for improvement in treatment uniformity and guideline adherence., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. 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, Abdulrasheed et al.)

Introduction: Laparoscopic sleeve gastrectomy (LSG) is a widely performed bariatric surgery that involves the removal of a portion of the stomach. Routinely, the resected gastric tissue is sent for histopathological examination to screen for malignancies or other significant pathological findings. However, the necessity of this routine practice remains uncertain. This study aims to evaluate the histopathological outcomes of LSG specimens over a five-year period at our institution., Methods: We conducted a retrospective analysis of 203 patients who underwent LSG between January 2017 and December 2022 at Heartlands Hospital, University Hospitals Birmingham. Data collected included patient demographics, body mass index (BMI), use of preoperative oesophagogastroduodenoscopy (OGD), and histopathological findings. Patients with incomplete records or those who underwent Roux-en-Y gastric bypass were excluded from the study., Results: Data were extracted for 310 patients, of whom 107 were excluded. The majority of the 203 patients analyzed were female (83%), with a mean age of 45.7 years and a mean BMI of 45.4 ± 7.3. Preoperative OGD was performed in only 0.5% of cases. Histopathological examination revealed that 81.3% (n=165) of patients had normal gastric mucosa, while 14.3% (n=29) had chronic gastritis. Clinically significant findings were rare, with only 1% (n=2) of patients showing gastrointestinal stromal tumors (GISTs) or focal intestinal metaplasia. None of the patients required additional treatment or follow-up based on these histopathological findings., Conclusion: Most LSG specimens in our study showed normal or non-significant histopathological findings, raising questions about the routine use of histopathological examination in LSG procedures. It remains unclear whether histopathology is necessary following sleeve gastrectomy. While no patients in our cohort required further treatment or surveillance, there are reports in the literature where surveillance or further treatment was necessary, though the incidence remains low. Given the low incidence of clinically significant pathology, further studies with larger sample sizes and multi-center data are needed to establish clear guidelines on this issue., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. 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, Khattak et al.)

Objective: This study aimed to assess the quality of primary transurethral resection of bladder tumor (TURBT) procedures performed at Aga Khan University Hospital (AKUH) over nine years, focusing on proper documentation, completeness of tumor resection, quality of histopathology reports, complication rates, and adherence to European Association of Urology (EAU) guidelines., Materials and Methods: A retrospective analysis of patients aged 25-75 who underwent primary TURBT at AKUH between 2010 and 2019 was done. Patients with incomplete records, concomitant procedures, or those who underwent emergency TURBT were excluded. Data was collected on patient demographics, clinical presentation, intraoperative details, and histopathology reports. Statistical analysis was performed using SPSS Version 27.0., Results: 300 patients were initially identified, with 265 meeting the inclusion criteria. The mean age was 61.5 years, with 83% being male. Complete tumor resection was achieved in 35% (n=92) of cases, while deep biopsy was taken in 85% (n=226). Detrusor muscle (DM), a marker of resection quality, was noted in 75% (n=200) of histopathology reports. However, documentation quality varied, with 54% (n=143) of cases lacking clear information on resection completeness. The administration of a single instillation of a chemotherapeutic agent (SICA) was recorded in 79% (n=210) of patients, and the 30-day postoperative complication rate was monitored., Conclusion: The study highlights areas for improvement in the quality of TURBT procedures at AKUH, particularly in the documentation of resection completeness and adherence to established guidelines. Ensuring thorough resection and proper documentation is critical to optimizing patient outcomes and future management plans., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. 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, Khattak et al.)

Burn patients are generally prone to infection, which causes the patient's condition to be even worse. However, there is no study regarding the difference between the mortality rate of infected and non-infected patients. Therefore, the aim was to identify and compare the global mortality rate between infected and non-infected patients who were admitted to plastic surgery units. We searched PubMed, ScienceDirect, and Google Scholar and finally included five articles for this meta-analysis. We determined the odds ratio (OR) value by forest plot and assessed the study bias by a funnel plot. We also analyzed the quality and heterogeneity. The OR was determined as 0.43 (95%CI: 0.07-2.60), indicating a higher mortality rate in infected burn patients as compared to non-infected patients. The funnel plot showed no significant study bias. The quality of the studies was assessed high as well, and the heterogeneity was determined significant (I 2 >75%). The sensitivity analysis with the fixed effect model reconfirmed our main outcome. However, as a study limitation, we could not specifically determine the impact of strain-specific infection on the mortality rate and could not find more relevant research regarding this issue. We conclude that the overall non-infected burn patient mortality rate is lower as compared to the infected burn patients; however, non-infected patients can be prone to death if the burn degree is higher, the respiratory organ is injured, or the treatment is poor or delayed., 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, Saleem et al.)

Objective: This study aimed to investigate perineal wound healing rates following abdominoperineal resection (APR) or extralevator abdominoperineal excision (ELAPE) for rectal cancer, with a focus on identifying associated risk factors and outcomes., Methodology: A retrospective analysis was conducted on patients undergoing APR or ELAPE for rectal cancer in a tertiary centre between 2013 and 2020. Data on demographics, comorbidities, surgical techniques, and perineal wound outcomes were collected and analyzed using Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 27.0, Armonk, NY). Statistical significance was set at p<0.05., Results: A total of 87 patients were included, with a mean age of 64 years and the majority being male (66.7%). Neoadjuvant radiotherapy was administered in 87.4% of cases. Perineal wound complications were documented in 52 cases (59.8%), with major complications observed in 11 cases (12.6%). Healing within six months was achieved in 48 patients (55.2%), while 39 patients (44.8%) developed chronic perineal wounds. Logistic regression analysis revealed omentoplasty as a significant predictor of perineal wound healing rate showing a significant negative association (p=0.0289)., Conclusion: Perineal wound healing rates following APR or ELAPE varied. While most patients achieved complete healing, chronic perineal wounds presented challenges. Omentoplasty was associated with lower odds of healing, suggesting the need for further investigation into its role. These findings underscore the importance of patient counselling and multidisciplinary management strategies to optimize outcomes in rectal cancer surgery., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. 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, Khattak et al.)

Background: The Model for End-Stage Liver Disease (MELD) score, introduced in 2002 by the United Network for Organ Sharing (UNOS), is a vital tool for predicting mortality for liver transplant candidates. Comprising serum creatinine, serum bilirubin, and international normalized ratio (INR), the MELD score includes kidney, liver, and coagulation pathway function, providing a comprehensive prognostic tool. Recent studies suggest broader prognostic implications, extending beyond organ allocation. Despite its benefits, around 15-20% of patients may not experience accurate survival predictions., Methods: This retrospective single-center study, covering January 2016 to September 2023 with 87 patients, explores the correlation between pre-transplant MELD scores and 30 to 60-day post-transplant survival., Results: Our analysis reveals no significant impact of MELD scores on survival during this period, challenging existing literature (p=0.068). The study underscores the need for nuanced risk assessment beyond MELD scores, considering diverse clinical scenarios and patient-specific variables., Conclusions: Our findings contribute to refining predictive models and advocate for larger-scale investigations, emphasizing a holistic approach to optimize liver transplantation outcomes.

Background: Pain is a traumatic experience for most patients on hemodialysis. In this trial, we compared prilocaine/lidocaine cream with piroxicam gel for pain reduction during arteriovenous fistula needling., Methods: This randomized double-blind crossover clinical trial was done at dialysis unit of a tertiary care hospital from June to August 2022. Adult patients, aged 18-75 years, on maintenance hemodialysis through an arteriovenous fistula were selected randomly. Pain severity during needling of fistula was assessed during initial two hemodialysis sessions without application of any drug. Patients were then randomized into two groups receiving 5% prilocaine/lidocaine cream or 0.5% piroxicam gel 1 h before the next two hemodialysis sessions. After a 7-day washout period, patients crossed over to other groups for another two hemodialysis sessions. Pain was assessed on all these occasions. Primary outcome was reduction in pain with each intervention., Results: There were 32 patients aged 46.44 ± 11.58 years. Pain intensity was 6.69 ± 0.58, 3.13 ± 1.28, and 4.55 ± 1.95 without any medication, prilocaine/lidocaine cream and piroxicam gel respectively. There was greater pain reduction with prilocaine/lidocaine cream than piroxicam gel (3.56 ± 1.35 vs 2.14 ± 1.78; p  = 0.001). Local redness with prilocaine/lidocaine cream was reported by one (3.13%) patient, whereas no side effects were seen with piroxicam gel ( p  = 1.000)., Conclusion: Prilocaine/lidocaine cream provides better pain relief than piroxicam gel during arteriovenous fistula needling., 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.

Background and Aim: As the spleen plays a significant role in immunity, the aim was to investigate the associations of different body composition markers derived from various sources with spleen volume in a general population sample., Materials and Methods: Cross-sectional data of 1095 individuals (570 women; 52%) aged between 30 and 90 years were collected in the Study of Health in Pomerania (SHIP-START-2). We measured spleen volume by magnetic resonance imaging (MRI).Body composition markers were derived from classic anthropometry, bioelectrical impedance analysis, including absolute fat mass (FM) and fat-free mass (FFM), as well as from MRI, including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver fat content. Sex-stratified-adjusted linear regression models were used to analyze the associations of body composition markers with spleen volumes., Results: We observed positive associations of body mass index, body weight, waist circumference, hip circumference, waist-to-height ratio, absolute FM, absolute FFM, and VAT and SAT with spleen volume in men and women. An 8.12 kg higher absolute FFM was associated with a 38.4 mL (95% confidence interval [CI]: 26.7-50.1) higher spleen volume in men and a 5.21 kg higher absolute FFM with a 42.6 mL (95% CI: 26.2-59.0) higher spleen volume in women., Conclusion: Our findings indicate that obesity-related body composition markers and FFM are associated with a higher spleen volume. Particularly, higher absolute FFM showed a strong association with a larger spleen volume in both men and women. Further studies are warranted to understand the clinical significance of body composition markers on large spleen volume., Competing Interests: The authors report no conflicts of interest., (© 2024 The Author(s). Published by Upsala Medical Society.)

This study reviews the challenges and management strategies for complex renal stones in Africa. Historically viewed as infection or struvite stones, recent studies highlight diverse compositions of staghorn stones. These complex stones pose significant risks, including recurrent urinary tract infections and renal impairment. In the past, conservative management of staghorn stones was associated with high morbidity; thus, surgical intervention was necessary for complete eradication. While percutaneous nephrolithotomy (PCNL) remains the standard, it carries notable risks, leading to a shift towards minimally invasive techniques. This study reviews challenges and management practices for complex renal stones and staghorn calculi in African countries, evaluating stone-free rates and associated complications. A scoping review of the literature, following the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, was performed. A systematic search was conducted in PubMed, African Journal Online (AJOL) and Google Scholar, yielding 1,101 articles, but only 11 articles satisfied the inclusion criteria. The study included 1,513 patients with 1,582 renal units, predominantly male (67.2%) with an average age of 40.7 years. Percutaneous nephrolithotomy (PCNL) was the primary treatment for the majority (71.3%), followed by open surgery (21.9%), laparoscopic surgery (4.1%), and retrograde intrarenal surgery (RIRS) (2.7%). The stone clearance rates for PCNL, open surgery, laparoscopic pyelolithotomy, and RIRS were 82.8%, 83.7%, 100%, and 92.8%, respectively. Stone sizes ranged between 22 and 80 mm, with 66% being staghorn stones. Complication rates were highest for open surgery (30.8%) and lowest for RIRS (4.7%). Despite PCNL being the global standard, African studies still indicate a high reliance on open surgery, likely due to healthcare infrastructure, resource availability and socioeconomic factors. Enhancing access to urological care and addressing healthcare disparities are imperative for improving staghorn stone management in Africa., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Abdulrasheed et al.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Pembrolizumab adjuvant therapy was shown to significantly improve recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB or IIC melanoma in earlier analyses of the randomized, double-blind, phase III KEYNOTE-716 study (ClinicalTrials.gov identifier: NCT03553836). We report results of the protocol-specified final analysis of DMFS for KEYNOTE-716. Overall, 976 patients were randomly allocated to pembrolizumab (n = 487) or placebo (n = 489). As of January 4, 2023, median follow-up was 39.4 months (range, 26.0-51.4 months). The median DMFS was not reached in either treatment group, and the estimated 36-month DMFS was 84.4% for pembrolizumab and 74.7% for placebo (hazard ratio [HR], 0.59 [95% CI, 0.44 to 0.79]). The median RFS was not reached in either treatment group, and the estimated 36-month RFS was 76.2% for pembrolizumab and 63.4% for placebo (HR, 0.62 [95% CI, 0.49 to 0.79]). DMFS and RFS results were consistent across most prespecified subgroups, including stage IIB and stage IIC melanoma. The safety profile of pembrolizumab was manageable and consistent with previous reports. These results continue to support the use of pembrolizumab adjuvant therapy in patients with resected stage IIB or IIC melanoma.

Objectives: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials., Study Design: Retrospective observational study; review of patient records in fifteen Australian institutions., Setting, Participants: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 - 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme., Main Outcome Measures: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression-free survival., Results: A total of 286 people with advanced CSCC received ICI therapy during May 2017 - May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3-97.5 years) and 232 were men (81%); median follow-up time was 12.2 months (interquartile range, 5.5-20.5 months). Eighty-eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve-month overall survival was 78% (95% confidence interval [CI], 72-83%); progression-free survival was 65% (95% CI, 58-70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0-4.3) and progression-free survival (aHR, 2.4; 95% CI, 1.8-3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1-3.0; progression-free: aHR, 1.8; 95% CI, 1.2-2.7). Fifty-five people (19%) reported immune-related adverse events of grade 2 or higher; there were no treatment-related deaths., Conclusion: In our retrospective study, the effectiveness and toxicity of ICI therapy were similar to those determined in clinical trials. Our findings suggest that ICIs could be effective and well tolerated by people with advanced CSCC who are ineligible for clinical trials., (© 2024 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

The study aimed to determine if deranged liver function tests (LFTs) can predict severe dengue or mortality. It included 135 dengue patients, with a mean age of 30.9 ± 12.09 years. Among the patients, 82 (60.7%) were under 30 years of age. Nearly half of the patients (64, 47. 4%) had some degree of liver damage indicated by deranged LFTs, 27 (42.1%) had elevated alanine transaminase (ALT), 7 (10.9%) had increased bilirubin, and 30 (46.9%) had high values of alkaline phosphatase (ALP). However, only elevated ALP levels were positively correlated with mortality (Pearson's R = 0.282, p = <0.05). The mean bilirubin was 11.711 ± 8.602 umol/l, and the mean values of ALT and ALP were 107 ± 240 and 113.571 ± 59.91 IU/L, respectively, which were higher than the normal. The study findings suggested that hepatic derangement is a common occurrence in dengue patients, and increased ALP levels could be an indicator of a higher risk of mortality. These findings can help improve patient care by identifying the potential risk factors for mortality. Key Words: Dengue, Liver function tests, Alanine transaminase, Alkaline phosphatase.

Objective: To evaluate the impact of haemodialysis on plasma carnitine levels., Methods: The cross-sectional study was conducted from April 20, 2020 to May 10, 2022, at the dialysis unit of the nephrology ward of Jinnah Postgraduate Medical Centre, Karachi, and the Pakistan Navy Ship Shifa Hospital, Karachi, in collaboration with the Department of Biochemistry, University of Karachi, and comprised patients of either gender aged >18 years. They were divided into chronic kidney disease group A and end-stage renal disease group B. Control group C included subjects from the general population. Free carnitine and total carnitine values were detected using enzyme-linked immunosorbent assay. Acyl carnitine was estimated by applying the standard formula, and the ratio between acyl carnitine and free carnitine was calculated for accurate assessment of the carnitine status. Data was analysed using SPSS 23., Results: Of the 203 subjects, 143(70.44%) were cases and 60(29.55%) were controls. Among the cases, 120(84%) were recruited from Jinnah Postgraduate Medical Centre and 23(16%) from Pakistan Navy Ship Shifa Hospital. There were 60(29.55%) patients in group A, 83(40.88%) in group B and 60(29.55%) in group C. The mean age in group A was 47.90 5.±65 years, it was 44.10 ±8.92 years in group B and 40.90 ± 6.73 years in group C. There was a significant difference related to free carnitine, total carnitine, acyl carnitine values and the ratio between acyl carnitine and free carnitine values in groups A and B compared to control group C (p<0.05)., Conclusion: Patients on maintenance haemodialysis developed were found to have developed carnitine deficiency.

Background: Epilepsy is a common neurological disease but around 30% of patients fail to respond to antiepileptic drug (AED) treatment. Genetic variation of the ATP-binding cassette subfamily B, member 1 (ABCB1) gene, a drug efflux transporter may infer treatment resistance by decreasing gastrointestinal absorption and preventing AED entry into the brain. This study examined the impact of ABCB1 genetic variants on carbamazepine responsiveness., Materials and Methods: Genomic DNA was extracted from whole blood of 104 epileptic patients. Genotyping of 3 ABCB1 variants (c.C3435T, c.G2677T/A and c.C1236T) was undertaken using validated TaqMan allelic discrimination assays. Plasma carbamazepine levels were measured at 3 and 6 months following the initial dose using high-performance liquid chromatography (HPLC) alongside clinical outcomes evaluation., Results: Nonresponse to carbamazepine (CBZ) was associated significantly with the ABCB1 variants c.C3435T, c.G2677T/A, c.C1236T and TTT, TTC haplotypes (P < 0.05). There was no significant association between variants and plasma CBZ level (P > 0.05)., Conclusions: Our results showed that variant alleles of the ABCB1 gene and TTT, TTC haplotypes were significantly associated with CBZ resistance without affecting the plasma level of carbamazepine. The findings of this study may help to predict patient's response to treatment ultimately it will improve the personalized and evidence based treatment choice of patients with epilepsy., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The i-DREAMS project established a 'Safety Tolerance Zone (STZ)' to maintain operators within safe boundaries through real-time and post-trip interventions, based on the crucial role of the human element in driving behavior. This paper aims to model the inter-relationship among driving task complexity, operator and vehicle coping capacity, and crash risk. Towards that aim, data from 80 drivers, who participated in a naturalistic driving experiment carried out in three countries (i.e., Belgium, Germany, and Portugal), resulting in a dataset of approximately 19,000 trips were collected and analyzed. The exploratory analysis included the development of Generalized Linear Models (GLMs) and the choice of the most appropriate variables associated with the latent variables "task complexity" and "coping capacity" that are to be estimated from the various indicators. In addition, Structural Equation Models (SEMs) were used to explore how the model variables were interrelated, allowing for both direct and indirect relationships to be modeled. Comparisons on the performance of such models, as well as a discussion on behaviors and driving patterns across different countries and transport modes, were also provided. The findings revealed a positive relationship between task complexity and coping capacity, indicating that as the difficulty of the driving task increased, the driver's coping capacity increased accordingly, (i.e., higher ability to manage and adapt to the challenges posed by more complex tasks). The integrated treatment of task complexity, coping capacity, and risk can improve the behavior and safety of all travelers, through the unobtrusive and seamless monitoring of behavior. Thus, authorities should utilize a data system oriented towards collecting key driving insights on population level to plan mobility and safety interventions, develop incentives for road users, optimize enforcement, and enhance community building for safe traveling.

Background: Approximately 50% of uveal melanoma (UM) patients will develop metastatic disease depending on the genetic features of the primary tumour. Patients need 3-12 monthly scans, depending on their prognosis, which is costly and often non-specific. Circulating tumour DNA (ctDNA) quantification could serve as a test to detect and monitor patients for early signs of metastasis and therapeutic response., Methods: We assessed ctDNA as a biomarker in three distinct UM cohorts using droplet-digital PCR: (A) a retrospective analysis of primary UM patients to predict metastases; (B) a prospective analysis of UM patients after resolution of their primary tumour for early detection of metastases; and (C) monitoring treatment response in metastatic UM patients., Results: Cohort A: ctDNA levels were not associated with the development of metastases. Cohort B: ctDNA was detected in 17/25 (68%) with radiological diagnosis of metastases. ctDNA was the strongest predictor of overall survival in a multivariate analysis (HR = 15.8, 95% CI 1.7-151.2, p = 0.017). Cohort C: ctDNA monitoring of patients undergoing immunotherapy revealed a reduction in the levels of ctDNA in patients with combination immunotherapy., Conclusions: Our proof-of-concept study shows the biomarker feasibility potential of ctDNA monitoring in for the clinical management of uveal melanoma patients., (© 2023. The Author(s).)

Oral cancer is a fatal disease and ranks seventh among the most common cancers throughout the whole globe. Oral cancer is a type of cancer that usually affects the head and neck. The current gold standard for diagnosis is histopathological investigation, however, the conventional approach is time-consuming and requires professional interpretation. Therefore, early diagnosis of Oral Squamous Cell Carcinoma (OSCC) is crucial for successful therapy, reducing the risk of mortality and morbidity, while improving the patient's chances of survival. Thus, we employed several artificial intelligence techniques to aid clinicians or physicians, thereby significantly reducing the workload of pathologists. This study aimed to develop hybrid methodologies based on fused features to generate better results for early diagnosis of OSCC. This study employed three different strategies, each using five distinct models. The first strategy is transfer learning using the Xception, Inceptionv3, InceptionResNetV2, NASNetLarge, and DenseNet201 models. The second strategy involves using a pre-trained art of CNN for feature extraction coupled with a Support Vector Machine (SVM) for classification. In particular, features were extracted using various pre-trained models, namely Xception, Inceptionv3, InceptionResNetV2, NASNetLarge, and DenseNet201, and were subsequently applied to the SVM algorithm to evaluate the classification accuracy. The final strategy employs a cutting-edge hybrid feature fusion technique, utilizing an art-of-CNN model to extract the deep features of the aforementioned models. These deep features underwent dimensionality reduction through principal component analysis (PCA). Subsequently, low-dimensionality features are combined with shape, color, and texture features extracted using a gray-level co-occurrence matrix (GLCM), Histogram of Oriented Gradient (HOG), and Local Binary Pattern (LBP) methods. Hybrid feature fusion was incorporated into the SVM to enhance the classification performance. The proposed system achieved promising results for rapid diagnosis of OSCC using histological images. The accuracy, precision, sensitivity, specificity, F-1 score, and area under the curve (AUC) of the support vector machine (SVM) algorithm based on the hybrid feature fusion of DenseNet201 with GLCM, HOG, and LBP features were 97.00%, 96.77%, 90.90%, 98.92%, 93.74%, and 96.80%, respectively.

We report the proteomic profile of Epidermal Mucus (EM) from Labeo rohita and identified the differentially abundant proteins (DAPs) against Aeromonas hydrophila infection through label-free liquid chromatography-mass spectrometry (LC-MS/MS). Using discovery-based proteomics, a total of 2039 proteins were quantified in nontreated group and 1,328 proteins in the treated group, of which 114 were identified as DAPs in both the groups. Of the 114 DAPs, 68 proteins were upregulated and 46 proteins were downregulated in the treated group compared to nontreated group. Functional annotations of these DAPs shows their association with metabolism, cellular process, molecular process, cytoskeletal, stress, and particularly immune system. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Fisher's exact test between the two groups shows that most of the proteins were immune-related, which were significantly associated with the proteasome, phagosome, and Salmonella infection pathways. Overall, this study shows a basic and primary way for further functional research of the involvement of vitellogenin 2, alpha-2-macroglobulin-like protein, toll-like receptors (TLR-13), calpain, keratin-like proteins, and heat shock proteins against bacterial infection. Nonetheless, this first-ever comprehensive report of a proteomic sketch of EM from L. rohita after A. hydrophila infection provides systematic protein information to broadly understand the biological role of fish EM against bacterial infection., 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., (© 2023 The Author(s).)

Introduction and Objectives: Clinical data for older patients with advanced liver disease are limited. This post hoc analysis evaluated the efficacy and safety of terlipressin in patients aged ≥65 years with hepatorenal syndrome using data from 3 Phase III, randomized, placebo-controlled studies (OT-0401, REVERSE, CONFIRM)., Patients and Methods: The pooled population of patients aged ≥65 years (terlipressin, n = 54; placebo, n = 36) was evaluated for hepatorenal syndrome reversal-defined as a serum creatinine level ≤1.5 mg/dL (≤132.6 μmol/L) while receiving terlipressin or placebo, without renal replacement therapy, liver transplantation, or death-and the incidence of renal replacement therapy (RRT). Safety analyses included an assessment of adverse events., Results: Hepatorenal syndrome reversal was almost 2-times higher in terlipressin-treated patients compared with patients who received placebo (31.5% vs 16.7%; P = 0.143). Among surviving patients, the need for RRT was significantly reduced in the terlipressin group, with an almost 3-times lower incidence of RRT versus the placebo group (Day 90: 25.0% vs 70.6%; P = 0.005). Among 23 liver-transplant-listed patients, significantly fewer patients in the terlipressin versus placebo group needed RRT by Days 30 and 60 (P = 0.027 each). Fewer patients in the terlipressin group needed RRT post-transplant (P = 0.011). More terlipressin-treated patients who were listed for and received a liver transplant were alive and RRT-free by Day 90. No new safety signals were revealed in the older subpopulation compared with previously published data., Conclusions: Terlipressin therapy may lead to clinical improvements in highly vulnerable patients aged ≥65 years with hepatorenal syndrome., Clinical Trial Numbers: OT-0401, NCT00089570; REVERSE, NCT01143246; CONFIRM, NCT02770716., Competing Interests: Declaration of interests Muhammad Mujtaba: None; Ann Kathleen Gamilla-Crudo: is a speaker for Natera, Inc and receives support from the University of Texas Medical Branch for meeting attendance and/or travel; Shehzad Merwat: has a speaker agreement with AbbVie that is unrelated to the current work and no other financial disclosures; Syed Hussain: None; Michael Kueht: has received funding from CareDx, Inc. for an Investigator Initiated Trial and has received honoraria from CareDx, Inc. and Veloxis Pharmaceuticals, Inc.; Aftab Karim: None; Muhammad W. Khattak: None; Peggy Rooney: is an employee of Mallinckrodt Pharmaceuticals, has received support from Mallinckrodt Pharmaceuticals for meeting attendance and travel, and has participated in Advisory Boards as a representative of Mallinckrodt Pharmaceuticals; Khurram Jamil: is an employee of Mallinckrodt Pharmaceuticals, has received support from Mallinckrodt Pharmaceuticals for meeting attendance and travel, and has participated in Advisory Boards as a representative of Mallinckrodt Pharmaceuticals., (Copyright © 2023. Published by Elsevier España, S.L.U.)

Purpose: To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma., Methods: Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype., Results: In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup., Conclusion: Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients.

ABSTRACT       Objective: To compare the clinical parameters of 4th and 5th COVID waves in Karachi, Pakistan., Study Design: Descriptive study. Place and Duration of the Study: PNS Shifa Hospital, Karachi, from July 2021 to February 2022., Methodology: All patients with COVID-19 in PNS Shifa Hospital were included in the study. The patients were divided into two groups, those who had COVID-19 during the 4th wave, and others who had it during the 5th wave. The patients' demographic details, comorbidities, vaccination status, initial presentation, the severity of disease, clinical progress, and final disposal from the hospital were noted. A comparison of severity, length of hospital stays, and mortality was made between the groups., Results: There were 747 patients admitted during the Delta variant-dominated 4th wave of COVID-19, and 490 patients during the 5th wave, dominated by the Omicron variant. A vast majority of fifth-wave patients had the mild disease (87.35% vs. 49.39%), with significantly lower critical patients (2.04% vs. 7.09%). Vaccination was effective against both the Delta and the Omicron variant of the SARS-CoV-2 virus. The mean length of stay in the hospital for patients was significantly lesser (p < 0.001) during the 5th wave as compared to the 4th wave (6.43 ± 3.37 vs. 9.56 ± 5.45 days). The mortality rate was 7.09% among patients admitted in the 4th wave and 2.04% in the 5th wave. This difference was statistically significant (p < 0.001)., Conclusion: The severity of disease, length of hospital stays, and mortality were higher in the Delta variant-dominated 4th wave of COVID-19 as compared to the Omicron variant-dominated 5th wave in Pakistan. The vaccination was effective against both the Delta and the Omicron variant of COVID 19, as the mortality rate among the vaccinated patients during the two waves was not significantly different., Key Words: COVID 19, Vaccination, Disease outcome, Mortality.

Purpose: To determine the feasibility, safety and preliminary efficacy of a telehealth supervised exercise programme in patients with advanced melanoma receiving checkpoint inhibitor therapy., Methods: A 8-week non-randomised feasibility pilot trial utilising a telehealth delivered multimodal exercise programme undertaken thrice weekly with assessments at baseline and post-intervention. The study was considered feasible if there were no severe or life-threatening adverse events as a result of exercise, and three or more of the following criteria were met: the recruitment rate was >50%, completion rate was >80%, median programme attendance was >75%, median exercise compliance >75%, and average tolerance was >70%. Preliminary efficacy was assessed for objective measures of physical function (2-min step test, repeated chair stand test, 30-s push-up test, and a modified static balance test) and quality of life (QoL), fatigue and other patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30., Results: Eleven patients (32-80 years) were included in the study (6 female, 5 male). The recruitment rate was 48%, completion rate 91%, programme attendance 88%, median exercise compliance 82.1% and 84.9% for resistance and aerobic exercise, respectively, and tolerance 88%, with no severe or life-threatening adverse events as a result of exercise. In terms of preliminary efficacy, physical function significantly improved while QoL was maintained following the intervention., Conclusion: An 8-week telehealth exercise intervention is feasible and safe for patients with advanced melanoma and appears to improve physical function while preserving QoL during checkpoint inhibitor therapy., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Speech enhancement (SE) reduces background noise signals in target speech and is applied at the front end in various real-world applications, including robust ASRs and real-time processing in mobile phone communications. SE systems are commonly integrated into mobile phones to increase quality and intelligibility. As a result, a low-latency system is required to operate in real-world applications. On the other hand, these systems need efficient optimization. This research focuses on the single-microphone SE operating in real-time systems with better optimization. We propose a causal data-driven model that uses attention encoder-decoder long short-term memory (LSTM) to estimate the time-frequency mask from a noisy speech in order to make a clean speech for real-time applications that need low-latency causal processing. The encoder-decoder LSTM and a causal attention mechanism are used in the proposed model. Furthermore, a dynamical-weighted (DW) loss function is proposed to improve model learning by varying the weight loss values. Experiments demonstrated that the proposed model consistently improves voice quality, intelligibility, and noise suppression. In the causal processing mode, the LSTM-based estimated suppression time-frequency mask outperforms the baseline model for unseen noise types. The proposed SE improved the STOI by 2.64% (baseline LSTM-IRM), 6.6% (LSTM-KF), 4.18% (DeepXi-KF), and 3.58% (DeepResGRU-KF). In addition, we examine word error rates (WERs) using Google's Automatic Speech Recognition (ASR). The ASR results show that error rates decreased from 46.33% (noisy signals) to 13.11% (proposed) 15.73% (LSTM), and 14.97% (LSTM-KF)., Competing Interests: Enter: The authors have declared that no competing interests exist., (Copyright: © 2023 Peracha 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.)

In this work, an effective approach based on a nonlinear output frequency response function (NOFRF) and improved convolution neural network is proposed for analog circuit fault diagnosis. First, the NOFRF spectra, rather than the output of the system, are adopted as the fault information of the analog circuit. Furthermore, to further improve the accuracy and efficiency of analog circuit fault diagnosis, the batch normalization layer and the convolutional block attention module (CBAM) are introduced into the convolution neural network (CNN) to propose a CBAM-CNN, which can automatically extract the fault features from NOFRF spectra, to realize the accurate diagnosis of the analog circuit. The fault diagnosis experiments are carried out on the simulated circuit of Sallen-Key. The results demonstrate that the proposed method can not only improve the accuracy of analog circuit fault diagnosis, but also has strong anti-noise ability., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Background: Both hormonal and genetic data reveal that the stress hormone cortisol and its regulating genes may affect the level of testosterone in humans. It is uncertain whether type 2 diabetes mellitus would manifest similarly. Furthermore, a genetic strategy to screen out the stress system genes that may contribute to testosterone decline in humans is less understood., Objectives: In this study, we aimed to elucidate the link between stress and testosterone levels, both hormonally and genetically., Method: This study comprised 37 individuals with type 2 diabetes mellitus and 50 healthy individuals. For the analysis of hormones and the targeted genes, we used the RIA system and bioinformatics expertise., Results: The patients had significantly elevated cortisol and lower testosterone readings, according to data from hormonal analyses. The bioinformatics approach reveals that SHBG was intracellularly suppressed by 2 defined stress system genes: FKB5 and CYP17. TCF4/TCF8, ATRX, and AR in skeletal muscle were inversely related to stress system genes. Furthermore, all testosterone regulated genes were positively linked with SHBG in the current study. A strong relationship between GNAS and PKA with CYP17 and FKBP5 reveals that the Gαs-cAMP/PKA signaling pathway may be one of the regulatory pathways through which the suppression of testosterone system genes happens. In conclusion, this study demonstrated that beyond stress, the key stress system genes might affect cortisol levels, which in turn affect testosterone figures via the Gαs-cAMP/PKA signaling pathway., 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) 2023.)

Objective: The rationale of study was to find the magnitude of amblyopia with reference to type of squint among the strabismus patients visiting Hayatabad Medical Complex Peshawar, Pakistan. Materials and Methods: After ethical approval, a cross sectional study was carried out in the Department of Ophthalmology, Hayatabad Medical Complex, Peshawar, Pakistan, from April 2022 to October 2022, the total number of patients included being 237. Results: Amblyopia was observed in 113 out of 160 (70.6%) cases of uniocular squint, while in alternating squint it was found to be 11 out of 77 (14.2%). Amblyopia in patients with esotropia was seen in 73.2% (107 out of 146), while 59.3% (54 out of 91) exotropia had associated amblyopia. Conclusion: Strabismus amblyopia leads to developmental arrest of vision in early critical years of life. Permanent visual loss can be avoided with comprehensive screening and detailed examination of strabismic patient., (#x00A9; The Authors.Romanian Society of Ophthalmology.)

Purpose: Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136)., Methods: Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review., Results: A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti-PD-1 plus anti-CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count)., Conclusion: Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.

Background: Gut microbiome (GM) composition and diversity have recently been studied as a biomarker of response to immune checkpoint blockade therapy (ICB) and of ICB-related colitis., Aim: To conduct a systematic review on the role of GM composition and diversity in predicting response and colitis in patients with melanoma treated with ICB., Methods: The review protocol was registered in PROSPERO: CRD42021228018. From a total of 300 studies, nine studies met inclusion criteria. Two studies were phase I clinical trials, while the remainder were prospective observational studies. All but one study has moderate risk of bias. In addition, we conducted a relevant search by Reference Citation Analysis ( RCA ) (https://www.referencecitationanalysis.com)., Results: Fecal samples enriched in Firmicutes phylum were associated with good response to ICB, whereas the Bacteroidales family was associated with poor response to ICB. Samples with greater GM diversity were associated with more favorable response to ICB [hazard ratio (HR) = 3.57, 95% confidence interval = 1.02-12.52, P < 0.05]. Fecal samples with a higher abundance in Firmicutes were more susceptible to ICB-related colitis ( P < 0.01) whereas samples enriched in Bacteroidetes were more resistant to ICB-related colitis ( P < 0.05). Overall, there was limited concordance in the organisms in the GM identified to be associated with response to ICB, and studies evaluating GM diversity showed conflicting results., Conclusion: This highlights the need for further prospective studies to confirm whether the GM could be used as a biomarker and potential intervention to modulate ICB response in melanoma patients., Competing Interests: Conflict-of-interest statement: Khattak MA reports receiving travel support from Merck Sharp and Dohme (MSD), Bristol-Myers Squibb and Merck Serono. Gray E reports receiving travel sponsorship from MSD. Oey O, Liu Y, Sunjaya AF, and Simadibrata DM report no competing interests., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

The present study reports the fish fauna of Gomal Zam Dam at three different sites from October 2018 to July 2019. The total sampled fish belong to 18 species, 15 genera, 5 families, and 4 orders. Fourteen species belong to family Cyprinidae, which was the most abundant, while one species belong to each family Mastacembelidae, Channidae, Siluridae, and Sisoridae. The prominent species were Labeo dyochielus (18.6%), Barilius vagra (16.5%), and Barilius pakistanicus (13.8%), while the rare species were Tor zhobensis , Wallago attu , Hyphophthalmicthys molitrix , Ctenophyrngodon idella , and Bagarius bagarius each one forming (0.1%). Species were rich in spring with ideal temperature, followed by summer, whereas species abundance was high in summer with high temperature and minimum abundance was recorded in autumn. In conclusion, the Gomal Zam Dam is a favorable reservoir for the fish particularly for family Cyprinidae. This present study will provide useful information about the diversity of fish fauna of Gomal Zam Dam that could be used in systematic fisheries management and conservation of the country., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Aziz Ur Rehman et al.)

Background: Patients with stage IIB or IIC melanoma who undergo surgery alone are at a substantial risk for disease recurrence. Adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo in stage IIB or IIC melanoma in the first interim analysis of the KEYNOTE-716 trial. Here, we report results from the secondary endpoint of distant metastasis-free survival (prespecified third interim analysis), and recurrence-free survival with longer follow-up., Methods: KEYNOTE-716 is a multicentre, double-blind, placebo-controlled, crossover or rechallenge, randomised, phase 3 trial done at 160 academic medical centres and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly-diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in paediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomisation was done using an interactive response technology system and stratified by T category and paediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment., Findings: Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1-31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]-NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47-0·88, p=0·0029) versus placebo. Median recurrence-free survival was 37·2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0·64, 95% CI 0·50-0·84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs 17 [4%] of 486 patients in the placebo group), diarrhoea (eight [2%] vs one [&lt;1%]), rash (seven [1%] vs two [&lt;1%]), autoimmune hepatitis (seven [1%] vs two [&lt;1%]), and increased lipase (six [1%] vs eight [2%]). Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) patients in the placebo group. No treatment-related deaths were reported., Interpretation: Adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, with significant improvement in distant-metastasis free survival versus placebo and continued reduction in the risk of recurrence with an adverse event profile consistent with previous studies of pembrolizumab. The overall benefit-risk of pembrolizumab continues to be positive in the adjuvant setting., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co., Competing Interests: Declaration of interests GVL reports research funding to their institution from Merck Sharp & Dohme (MSD), a subsidiary of Merck & Co; fees for consulting or advisory roles for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim International, Bristol Myers Squibb, Evaxion Biotech, Hexal (Sandoz Company), Highlight Therapeutics, MSD (Australia), Novartis, Oncosec Medical Australia, Pierre Fabre, Provectus, Qbiotics, and Regeneron Pharmaceuticals; and honoraria for speaker's bureau from Bristol-Myers Squibb (BMS) and Pierre Fabre. JJL reports research funding to the institution for clinical studies from MSD, AbbVie, Agios, Array, Astellas, AstraZeneca, BMS, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; membership on data safety monitoring board for AbbVie and Immutep; membership on scientific advisory boards for 7 Hills, Bright Peak, Fstar, Inzen, RefleXion, and Xilioo; stocks for Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, NeoTx, Onc.AI, Pyxis, and Tempest; compensation for consultancy with AbbVie, Alnylam, Bayer, BMS, CheckMate, Codiak, Crown, Cstone, Day One, Eisai, EMD Serono, Flame, Genentech, Gilead, HotSpot, Kadmon, KSQ, Janssen, Ikena, Immunocore, Incyte, Macrogenics, Merck, Mersana, Nektar, Novartis, Pfizer, Regeneron, Ribon, Rublus, Silicon, Synlogic, Synthekine, TRex, Werewold, and Xencor; and patents (provisional) for cancer immunotherapy (PCT/US18/36052; microbiome biomarkers for Anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic and therapeutic uses thereof). MAK, J-JG, FdG, and CHY report research funding to their institution for clinical studies from MSD. LdlCM reports research funding to their institution for clinical studies from Celgene, MSD, and Roche; reimbursement for travel expenses from Roche; and consultant or advisory roles for BMS, MSD, Novartis, and Roche. MDV reports research funding to their institution for clinical studies from MSD and honoraria as a consultant or advisor for Novartis, BMS, MSD, and Pierre Fabre. PR reports research funding to their institution from MSD and Pfizer; honoraria for lectures and advisory board participation for MSD, BMS, Novartis, Pierre Fabre, Sanofi, Merck, Philogen, and Blueprint Medicines. FS reports research funding to their institution for clinical studies from MSD; and fees for consulting and honoraria for speakers bureaus from MSD, Novartis, Pierre Fabre, Philogen, Sun Pharma, Merck, and BMS. JM reports research funding to their institution for clinical studies from MSD; honoraria from BMS, MSD, Roche, Novartis, and Pierre Fabre; and consultant or advisory roles for BMS and MSD. VC-S reports research funding to their institution for clinical studies from MSD; reimbursement for travel and accommodation for medical congress from Novartis and Pierre Fabre; and honoraria for advisory board participation for Novartis, Pierre Fabre, BMS, and Merck-Serono. JMK reports research funding to their institution from MSD, Amgen, BMS, Checkmate Pharmaceuticals, Immunocore, Iovance Biotherapies, Novartis Pharmaceuticals, Castle Biosciences, and Merck; fees from Amgen, Ankyra Therapeutics, Axios Research Instil Bio, BMS, Checkmate Pharmaceuticals, DermTech, Elsevier, Harbour BioMed, Immunocore, Iovance Biotherapies, Istari Oncology, Millenium Pharmaceuticals or Takeda Pharmaceuticals, Natera, Novartis Pharmaceutical, OncoCyte Corporation, OncoSec Medical, Pfizer, Scopus BioPharma, and Merck. CR reports research funding to their institution for clinical studies from MSD and fees as a consultant or advisor for Amgen, AstraZeneca, BMS, MSD, Novartis, Pfizer, Pierre Fabre, Roche, and Sanofi. DS reports research finding to their institution for clinical studies from BMS, MSD, Novartis, Amgen, and Array; patient fees to their institution from BMS, MSD, Novartis, Merck–EMD, Philogen, Pfizer, Array, InflarX, OncoSec, Replimune, Neracare, Nektar, Sun Pharma, Sandoz, and UltimoVacs; reimbursement for travel from BMS, Merck, Novartis, Merck-EMD, Pfizer, Pierre Fabre, InflarX, NeraCare, and Nektar; and non-financial support from BMS, MSD, Novartis, Merck-EMD, Pierre-Fabre, InFlarX, Neracare, Nektar, Sun Pharma, and Sandoz. MSC reports research funding to their institution for clinical studies for MSD and honoraria for consulting from BMS, Eisia, IDEAYA Biosciences, Merck Serono, MSD, Novartis, Oncosec, Pierre Fabre, Qbiotics, Roche, and Sanofi. PM reports research funding to their institution for clinical studies from MSD, Amgen, Johnson & Johnson, Merck Serono, Novartis, Pfizer, Sanofi, and Sun Pharma; honoraria from Amgen, BMS, Merck, MSD, Novartis, Pierre Fabre, Genentech (Roche Group), and Sanofi; consulting or advisory roles for Amgen, BMS, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi; fees for speakers bureau from Amgen, BMS, MSD, Novartis, Roche, and Sanofi; and reimbursement for travel, accommodations, and expenses from Amgen, BMS, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma. RD reports research funding to their institution for clinical studies from MSD and consulting or advisory roles with MSD, Novartis, Roche, BMS, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX, Pfizer, and touchIME. JEG reports research funding to their institution for clinical studies from Merck; royalties for content contribution to UpToDate; consulting or advisory roles for Merck, Regeneron, Syndax, and Bristol-Myers Squibb; fees for speakers bureau for Banner MD Anderson Phoenix; reimbursement for travel to meetings from American Joint Committee on Cancer (AJCC), American College of Surgeons, Melanoma Research Alliance, and Bridges Melanoma meeting; and leadership roles for AJCC and Melanoma Research Alliance. XLW, MF-K, and CK are employees of and own stock in MSD. AMME reports research funding to their institution for clinical studies from MSD; fees for advisory board membership for Merck, Agenus, Biocad, BioInvent, BioNTech, BMS, CatalYm, Ellipses, Galecto, GSK, IO Biotech, ISA Pharmaceuticals, Merck, MSD, Nektar, Novartis, Pfizer, Sellas, SkylineDX, TigaTx, and TxDiscovery; fees for independent data monitoring committee for Biocad, GSK, Pfizer, and Novartis;fees for speakers bureau from Biocad, BMS, and Merck; and equity in IO Biotech and SkylineDX. PAA reports research funding to their institution for clinical studies by MSD, BMS, Genentech (Roche Group), Sanofi, and Pfizer or Array BioPharma; fees as a consultant or advisor from BMS, Genentech (Roche Group), MSD, Novartis, Merck Serono, Pierre Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Nektar, Italfarmaco, Pfizer or Array BioPharma, Lunaphore, Medicenna, Bio-Al Health, and ValoTx; and participation on data safety monitoring boards or advisory boards for BMS, Genentech (Roche Group), MSD, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, and ITeos., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) versus placebo in resected stage IIB and IIC melanoma in the phase 3 KEYNOTE-716 study. Health-related quality of life (HRQoL) results are reported., Methods: Patients were randomly assigned 1:1 to pembrolizumab 200 mg (2 mg/kg, patients ≥12 to <18 years) Q3W or placebo for ≤17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. Change from baseline in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) was a prespecified exploratory end point. Change in EORTC QLQ-C30 functioning, symptom, and single-item scales, and EQ-5D-5L visual analog scale (VAS) were also summarized. Primary analyses were performed at week 48 to ensure adequate completion/compliance. The HRQoL population comprised patients who received ≥1 dose of treatment and completed ≥1 assessment., Results: The HRQoL population included 969 patients (pembrolizumab, n = 483; placebo, n = 486). Compliance at week 48 was ≥80% for both instruments. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores were stable from baseline to week 48 in both arms, with no clinically meaningful decline observed. Scores did not differ significantly between pembrolizumab and placebo. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores remained stable through week 96 in both arms., Conclusions: HRQoL was stable with adjuvant pembrolizumab, with no clinically meaningful decline observed. Change from baseline in HRQoL was similar between arms. These results, in conjunction with the improved RFS and manageable safety previously reported, support the use of adjuvant pembrolizumab for high-risk stage II melanoma., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MK has no conflicts of interest to declare. JJL reports advisory/consultancy roles with AbbVie, Immutep, Evaxion, 7 Hills, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, STipe, Tempest, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Day One, Duke St, EMD Serono, Endeavor, Flame, Genentech, Gilead, Glenmark, HotSpot, Kadmon, Janssen, Ikena, Immunocore, Incyte, IO Biotech, Macrogenics, Merck, Nektar, Novartis, Partner, Pfizer, Regeneron, Roivant, Servier, STINGthera, Synlogic, and Synthekine; stock ownership in Actym, AlphamabOncology, Arch Oncology, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, STipe, and Tempest; research grants/funding to their institution from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, and Xencor; travel, accommodation, and/or expenses from Castle; and the following provisional patents: Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). GVL is consultant advisor for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. PAA reports grants or contracts from Bristol Myers Squibb, Roche-Genentech, Pfizer/Array, and Sanofi; consulting fees from Bristol Myers Squibb, Roche-Genentech, MSD, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Italfarmaco, Nektar, Pfizer/Array, Lunaphore, and Medicenna.Bio-Al Health; and participation on a data safety monitoring board or advisory board for Bristol Myers Squibb, Roche-Genentech, MSD, Novartis, AstraZeneca, Immunocore, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, and iTeos. PR reports advisory/consultancy roles with MSD, BMS, Merck, Sanofi, Pierre Fabre, Blueprint Medicines, and Philogen; speaker bureau for BMS, MSD, Novartis, Pierre Fabre, Merck, and Sanofi; research grant/funding to their institution from Pfizer; and officer/board of director roles with ASCO, ESMO, and the Polish Oncological Society. DS reports advisory/consultancy roles with 4SC, Amgen, Array Biopharma, AstraZeneca, BMS, Daiichi Sankyo, Haystack, Immunocore, InFlarX, Innovent, Labcorp, Merck Serono, MSD, Nektar, Neracare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, and Sun Pharma; speaker bureau for BMS, Merck/MSD, Merck Serono, Novartis, Roche, Sanofi, and Sun Pharma; research grant/funding to their institution from Amgen, Array/Pfizer, BMS, MSD, Novartis, and Roche; travel, accommodation, and/or expenses from BMS, Merck Serono, MSD, Novartis, and Sanofi; officer/board of director role with WTZ; and the following nonremunerated activities: EORTC-MG, member of board of directors; coordinating PI for 4SC, BMS, MSD, Nektar, Novartis, and Pierre Fabre; local PI for Philogen, Roche, and Sanofi. CR worked in a consulting/advisory role for BMS, Roche, Amgen, Novartis, Pierre Fabre, MSD, Sanofi, Biothera, CureVac, and Merck. MAP worked in a consulting/advisory role for BMS, Merck, Eisai, Novartis, Incyte, NewLink Genetics, Aduro, and Pfizer; received research/grant support from BMS, Merck, Novartis, Array BioPharma, RGenix, Infinity, and AstraZeneca. JJG reports advisory/consultancy roles with BMS, MSD, Novartis, Roche, Philogen, Pierre Fabre, Sanofi, Amgen, Merck, and Pfizer; and travel, accommodations, and/or expenses from BMS and Pierre Fabre. LDLCM reports advisory/consultancy roles with Roche, BMS, and MSD-Merck; research grant/funding to their institution from Roche, Celgene, and MSD; and travel, accommodation, and/or expenses from Gilead. MDV reports honoraria and advisory/consultancy roles with Bristol Myers Squibb, Novartis, MSD, and Pierre Fabre. FS reports honoraria from BMS, Novartis, MSD, Pierre Fabre, Sanofi, Sun Pharma, Merck; and advisory/consultancy roles with Novartis, MSD, Pierre Fabre, Sun Pharma, and Philogen. JM reports honoraria from MSD, Bristol Myers Squibb, Pierre Fabre, Roche, Novartis; advisory/consultancy roles with MSD and Bristol Myers Squibb; and travel, accommodations, and/or expenses from MSD, Bristol Myers Squibb, Pierre Fabre, Roche, and Novartis. VCS reports travel, accommodation, and/or expenses from Pierre-Fabre and Novartis; and nonremunerated activities for BMS, Pierre-Fabre, and Merck-Serono. MSC reports honoraria from Bristol Myers Squibb, MSD, and Novartis; and advisory/consultancy roles with Amgen, Bristol Myers Squibb, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre Fabre, Qbiotics, Regeneron, and Roche. PM reports honoraria and advisory/consultancy roles with Pierre Fabre, GSK, MSD, Merck Germany, Roche, BMS, Novartis, Sanofi, and Immunocore; research grant/funding from BMS, Novartis, and MSD; and travel, accommodation, and/or expenses from Pierre Fabre, MSD, Merck Germany, and Roche. FDG reports advisory/consultancy roles with BMS and Novartis; and research grant/funding to their institution from Novartis. MR reports advisory/consultancy roles with MSD; and travel, accommodation, and/or expenses from MSD. ZE reports advisory/consultancy roles with Pfizer, Novartis, Genentech, Regeneron, OncoSec, Natera, and Eisai; and research grant/funding to their institution from Pfizer and Novartis. KC is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ USA. RJ, MFK, and CK are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ USA, and are stockholders of Merck & Co., Inc., Rahway, NJ USA. AE reports honoraria from Agenus, Biocad, BioInvent, BioNTech, Brenus, CatalYm, Clover, Ellipses, Galecto, GSK, IO Biotech, IQVIA, Merck/MSD, Nektar, Pfizer, Pierre Fabre, Sairopa, Sellas, SkylineDx, TigaTx, and TTxDiscovery; advisory/consultancy roles with Agenus, Biocad, BioInvent, BioNTech, Brenus, CatalYm, Clover, Ellipses, Galecto, GSK, IO Biotech, IQVIA, Merck/MSD, Nektar, Pfizer, Pierre Fabre, Sairopa, Sellas, SkylineDx, TigaTx, and TTxDiscovery; speaker bureau for Biocad, BMS, and Merck/MSD; a leadership role with the European Academy of Cancer Sciences; stock ownership in IO Biotech and SkylineDx; and nonremunerated activities for the European Academy of Cancer Sciences (EACS) and the Fondation Cancer (FOCA). JMK reports advisory/consultancy roles with Applied Clinical Intelligence LLC, Amgen Inc., Ankyra Therapeutics, Axio Research/Instil Bio, Becker Pharmaceutical Consulting, Bristol Myers Squibb, Checkmate Pharmaceuticals, DermTech, Fenix Group International, Harbour BioMed, Immunocore LLC, Intellisphere LLC/Cancer Network, Iovance Biotherapeutics, IQVIA, Istari Oncology, Merck, Millennium Pharmaceuticals/Takeda Pharmaceutical, Natera Inc, Novartis Pharmaceuticals, OncoCyte Corporation, OncoSec Medical Inc., Pfizer, Replimune, Scopus BioPharma, and SR One Capital Management; and research grant/funding to their institution from Amgen Inc., Bristol Myers Squibb, Castle Biosciences Inc, Checkmate Pharmaceuticals, Harbour BioMed, Immvira Pharma Co., Immunocore LLC, Iovance Biotherapeutics, Merck, Novartis Pharmaceuticals, Schering-Plough, Takeda, and Verastem Inc., (Copyright © 2022 The Author(s), Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc.,. Published by Elsevier Ltd.. All rights reserved.)

Flavonoids are a group of naturally occurring polyphenolic secondary metabolites which have been reported to demonstrate a wide range of pharmacological properties, most importantly, antidiabetic and anti-inflammatory effects. The relationship between hyperglycaemia and inflammation and vascular complications in diabetes is now well established. Flavonoids possessing antidiabetic properties may alleviate inflammation by reducing hyperglycaemia through different mechanisms of action. It has been suggested that the flavonoids' biochemical properties are structure-dependent; however, they are yet to be thoroughly grasped. Hence, the main aim of this review is to understand the antidiabetic and anti-inflammatory properties of various structurally diverse flavonoids and to identify key positions responsible for the effects, their correlation, and the effect of different substitutions on both antidiabetic and anti-inflammatory properties. The general requirement of flavonoids for exerting both anti-inflammatory and antidiabetic effects is found to be the presence of a C2-C3 double bond (C-ring) and hydroxyl groups at the C3', C4', C5, and C7 positions of both rings A and B of a flavonoid skeleton. Furthermore, it has been demonstrated that substitution at the C3 position of a C-ring decreases the anti-inflammatory action of flavonoids while enhancing their antidiabetic activity. Correlation is discussed at length to support flavonoids possessing essential pharmacophores to demonstrate equipotent effects. The consideration of these structural features may play an important role in synthesizing better flavonoid-based drugs possessing dual antidiabetic and anti-inflammatory effects. A meta-analysis further established the role of flavonoids as antidiabetic and anti-inflammatory agents.

A novel three-mode step impedance resonator (TSIR) is developed to design a miniaturized multi-pole microstrip planar ultra-wideband (UWB) filter with independently controlled notched bands at different frequencies is presented in this work. The basic UWB filter consists of four L-shaped λ/4 short-circuited stubs operating in the range of i.e. 2.7 to 12.1 GHz with fractional bandwidth (FBW) 127%, and the TSIR is constructed using two T-shaped λ/2 open ended step impedance resonator (SIR) and one λ/4 short-circuited uniform impedance resonator (UIR) is coupled to the basic UWB design in order to achieve the stopbands performance at 5.1 GHz, 6 GHz, and 8 GHz, to supress the unwanted bands of WLAN, Wi-Fi 6E, and X-band satellite communication system, respectively. Commercial full-wave electromagnetic (EM) software HFSS-13 was used to design an ultra-compact structure having size 0.07 λg×0.02 λg on Rogers RT/Duroid 5880 substrate to justify good agreement between simulated and measured S-parameters., Competing Interests: The authors have declared that no competing interests exist.