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Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the in vitro pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical in vivo pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. In vitro inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug-drug interactions upon single-agent use of PF-07817883.

The propensity for aldehyde oxidase (AO) substrates to be implicated in drug-drug interactions (DDIs) is not well understood due to the dearth of potent inhibitors that elicit in vivo inhibition of AO. Although there is only one reported instance of DDI that has been ascribed to the inhibition of AO to date, the supporting evidence for this clinical interaction is rather tenuous, and its veracity has been called into question. Our group recently reported that the epidermal growth factor receptor inhibitor erlotinib engendered potent time-dependent inhibition of AO with inactivation kinetic constants in the same order of magnitude as its free circulating plasma concentrations. At the same time, it was previously reported that the concomitant administration of erlotinib with the investigational drug OSI-930 culminated in a an approximately twofold increase in its systemic exposure. Although the basis underpinning this interaction remains unclear, the structure of OSI-930 contains a quinoline motif that is amenable to oxidation at the electrophilic carbon adjacent to the nitrogen atom by molybdenum-containing hydroxylases like AO. In this study, we conducted metabolite identification that revealed that OSI-930 undergoes AO metabolism to a mono-oxygenated 2-oxo metabolite and assessed its formation kinetics in human liver cytosol. Additionally, reaction phenotyping in human hepatocytes revealed that AO contributes nearly 50% to the overall metabolism of OSI-930. Finally, modeling the interaction between erlotinib and OSI-930 using a mechanistic static model projected an ∼1.85-fold increase in the systemic exposure of OSI-930, which accurately recapitulated clinical observations. SIGNIFICANCE STATEMENT: This study delineates an aldehyde oxidase (AO) metabolic pathway in the investigational drug OSI-930 for the first time and confirmed that it represented a major route of metabolism through reaction phenotyping in human hepatocytes. Our study provided compelling mechanistic and modeling evidence for the first instance of an AO-mediated clinical drug-drug interaction stemming from the in vivo inhibition of the AO-mediated quinoline 2-oxidation pathway in OSI-930 by erlotinib., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Atherosclerosis in more than 1 vs. 1 arterial bed is associated with increased risk for major adverse cardiovascular events (MACE). This study aimed to determine whether the risk of post percutaneous coronary intervention (PCI) MACE associated with polyvascular disease (PVD) differs by sex., Methods: We analyzed 18,721 patients undergoing PCI at a tertiary-care center between 2012 and 2019. Polyvascular disease was defined as history of peripheral artery and/or cerebrovascular disease. The primary endpoint was MACE, a composite of all-cause death, myocardial infarction, or stroke at 1 year. Multivariate Cox regression was used to adjust for differences in baseline risk between patients with PVD vs. coronary artery disease (CAD) alone and interaction testing was used to assess risk modification by sex., Results: Women represented 29.2% (N = 5,467) of the cohort and were more likely to have PVD than men (21.7% vs. 16.1%; P < .001). Among both sexes, patients with PVD were older with higher prevalence of comorbidities and cardiovascular risk factors. Women with PVD had the highest MACE rate (10.0%), followed by men with PVD (7.2%), women with CAD alone (5.0%), and men with CAD alone (3.6%). Adjusted analyses revealed similar relative MACE risk associated with PVD vs. CAD alone in women and men (adjusted hazard ratio [aHR] 1.54, 95% confidence interval [CI] 1.20-1.99; P < .001 and aHR 1.31, 95% CI 1.06-1.62; P = .014, respectively; p-interaction = 0.460)., Conclusion: Women and men derive similar excess risk of MACE from PVD after PCI. The heightened risk associated with PVD needs to be addressed with maximized use of secondary prevention in both sexes., Competing Interests: Conflict of Interest Dr. Spirito received a research grant from the Swiss National Science Foundation. Dr. Dangas has received consulting fees and advisory board fees from AstraZeneca; has received consulting fees from Biosensors; and previously held stock in Medtronic. Dr. Mehran reports institutional research payments from Abbott, Abiomed, Alleviant Medical, Amgen, AM-Pharma, Applied Therapeutics, Arena, AstraZeneca, Biosensors, Biotronik, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi Sankyo, Element Science, Faraday, Humacyte, Idorsia, I-Laser, Janssen, Magenta, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma, Protembis, RenalPro, RM Global, Shockwave, Transverse Medical, Inc., Vivasure, Zoll; personal fees from AstraZeneca, Ionis Pharmaceuticals, J-CalC, Mediasphere, Novartis, Novo Nordisk, Vectura, WebMD; Equity, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sinus tympani is one of the hidden space in the retrotympanic area of middle ear which is commonly invaded by cholesteatoma and known for recidivism. Conventional surgical approaches sometimes fail to access deep sinuses and eradicate the disease. The aim of our study was to measure endoscopic depth of Sinus tympani in Indian Population. Total of 30 patients underwent mastoid exploration and intraoperatively depth of Sinus Tympani was measured using a 0.5 mm calibrated probe with 30 degree rigid Hopkins endoscope. Endoscopic depth in the present study ranges between 2.5 and 5.5 mm. It was higher in right ear in case of females however no significant difference were seen in males and females on left side. It is difficult to clear disease from Sinus Tympani because of its inaccessible location. Sinus Tympani can also show variations in terms of its depth further making difficult to clear disease., Competing Interests: Competing Interests No competing interest., (© Association of Otolaryngologists of India 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Oral anticoagulation (OAC) is the mainstay of treatment for the prevention of strokes in patients with atrial fibrillation (AF). Direct oral anticoagulants (DOACs) account for increasing OAC in patients with AF. However, prescribing DOACs for patients with established AF poses various challenges and general practice pharmacists may have an important role in supporting their management., Aim: To investigate the effectiveness of pharmacist-led interventions in general practice in optimising the use of OAC therapies in AF., Design & Setting: A retrospective observational study in general practices in Bradford., Method: The data were collected retrospectively from 1 November 2018-31 December 2019 using electronic health record data. The data were analysed: 1) to identify patients with AF not on OAC; 2) to describe inappropriate DOAC prescriptions; and 3) to calculate HAS-BLED scores., Results: Overall, 76.3% ( n = 470) of patients with AF received OAC therapy, and of these, 63.4% received DOACs. Pharmacist-led interventions increased DOAC prescribing by 6.0% ( P = 0.03). Inappropriate DOAC use was identified in 24.5% of patients with AF, with underdosed and overdosed identified in 9.7% and 14.8%, respectively. Post-intervention, inappropriate prescribing was reduced to 1.7%. The mean HAS-BLED score decreased from 3.00 to 2.22 ( P <0.01). Successful transition from vitamin K antagonist (VKA) therapy to DOACs was achieved in 25.7% of patients., Conclusion: Pharmacist-led interventions have successfully improved the use of OAC therapies in patients with AF, and effectively managed the bleeding risks and transition from VKA to DOAC therapy, in line with guidelines., (Copyright © 2024, The Authors.)

Background: Peripheral artery disease (PAD) can present as chronic limb threatening ischemia (CLTI) with ischemic pain and tissue loss. Progression of distal disease can lead to a "no option" or end-stage disease without traditional open or endovascular revascularization due to lack of pedal targets. Innovations in endovascular technology allow for the use of percutaneous deep vein arterialization (pDVA) to treat patients with CLTI. Purpose: We describe our experience and technique for treating four patients with end-stage PAD with pDVA. Research Design: Four patients with end-stage PAD were followed during and after pDVA creation. Technical success, complications, wound healing, and freedom from major amputation were analyzed. Data Collection and Analysis: Patient data and outcomes were collected via chart review and at time of follow up appointments in vascular surgery clinic. Results: Technical success was 100%, without post-procedural complications, and patients were continued on antiplatelet and anticoagulation. Three patients (75%) had successful wound healing, with 2 patients healing after transmetatarsal amputation (TMA), and 1 healing a distal foot ulceration that did not require surgery. One patient had worsening ischemic breakdown of a TMA, despite re-intervention on the pDVA, which required a below knee amputation (BKA). Freedom from major amputation was 75% overall, with an average follow-up time of 410 days post-procedure (Range: 113-563 days). Conclusions: Percutaneous deep vein arterialization attempts to provide blood flow to the preserved venous bed in patients with end-stage PAD. Exploration and utilization of this technique continues to expand in the modern vascular era. This case series highlights 4 patients with end-stage PVD who underwent pDVA, with 100% procedural success, and 75% limb salvage rate., 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.

Percutaneous coronary intervention (PCI) has demonstrated its safety and efficacy in treating left main (LM) coronary artery disease (CAD) in select patients. Polyvascular disease (PolyVD) is associated with adverse events in all-comers with CAD. However, there is little data examining the interplay between PolyVD and LM-PCI, which we sought to investigate in a retrospective single-center study. We included patients who underwent unprotected LM-PCI at a tertiary center from 2012 to 2019. The study population was stratified based on the presence or absence of PolyVD (i.e., medical history of cerebrovascular and/or peripheral artery disease in addition to LM-CAD). The primary outcome was major adverse cardiovascular events (MACE) combining all-cause mortality and spontaneous myocardial infarction within 1 year after index PCI. Overall, 869 patients were included, and 23.8% of the population had PolyVD. Subjects with PolyVD were older and had a greater burden of co-morbidities. After 1-year follow-up, PolyVD patients exhibited significantly higher rates of both MACE (22.8% vs 9.4%, p <0.001) and bleeding events compared with those without PolyVD. MACE was primarily driven by an increase in all-cause mortality (18.3% vs 7.1%, p <0.001). Results persisted after adjusting for confounders. In conclusion, in patients who underwent LM-PCI, the presence of PolyVD is linked to an increased risk of MACE and bleeding after 1 year of follow-up, which highlights the vulnerability of this population., Competing Interests: Declaration of competing interest Dr. Dangas received research grants from institutions and support for attending meetings from Daiichi Sankyo. Dr. Mehran reports institutional research payments from: Abbott, Abiomed, Affluent Medical, Alleviant Medical, Amgen, AM-Pharmacia, Arena, AstraZeneca, AtriCure Inc., Biosensors, Biotronik, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CeloNova, CERC, Chiesi, Concept Medical, Cytosorbents, Daiichi Sankyo, Duke, Element Science, Essential Medical, Faraday, Idorsia Pharmaceuticals, Janssen, MedAlliance, Mediasphere, Medtelligence, Medtronic, MJH Healthcare, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma, Population Health Research Institute, Protembis, RecCor Medical Inc., RenalPro, RM Global, Sanofi, Shockwave, Vivasure, Zoll; Personal fees from: Affluent Medical, Cardiovascular Research Foundation (CRF), Cordis, Daiichi Sankyo Brasil, E.R. Squibb & Sons Science/Innovative BioPharma, Europa Group/Boston Scientific, Gaffney Events, Educational Trust, Henry Ford Health Cardiology, Ionis Pharmaceuticals, MedCon International, Novartis, NovoNordisk, PeerView Institute for Medical Education, Terumo Europe N.V., Vectura, VoxMedia, WebMD, IQVIA, Radcliffe, tarsus Cardiology; No Fees from: AMA (Scientific Advisory Board), SCAI (Women in Innovations Committee Member); Faculty CRF; Honorarium: JAMA Cardiology (Associate Editor), ACC (BOT Member, SC Member CTR Program); Equity <1% in: applied Therapeutics, Elixir Medical, Stel, ControlRad (spouse). The remaining authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Individuals suffering from polyvascular atherosclerotic disease (PolyVD) face a higher likelihood of adverse cardiovascular events. Additionally, inflammation, assessed by high-sensitivity C-reactive protein (hsCRP), affects residual risk following percutaneous coronary intervention (PCI). We aimed to explore the interplay between PolyVD and hsCRP in terms of clinical outcomes after PCI., Methods: Patients undergoing PCI for chronic coronary disease at a tertiary center between January 2012 and February 2020 were included for the current analysis. PolyVD was defined by additional history of cerebrovascular and/or peripheral artery disease. HsCRP levels were defined as elevated when the measured baseline concentration was > 3 mg/L. The primary outcome of interest was major adverse cardiovascular events (MACE), a composite of all-cause mortality, spontaneous MI, or target vessel revascularization., Results: Overall, 10,359 participants were included in the current study, with 17.4% affected by PolyVD and 82.6% included in the non-PolyVD subgroup. Patients with PolyVD had higher hsCRP levels than those without. Among the PolyVD group, a larger proportion (33.6%) exhibited elevated hsCRP compared to the non-PolyVD group (24.7%). Patients with both PolyVD and elevated hsCRP levels had significantly higher adverse event rates than all other subgroups at 1-year follow-up. Furthermore, an independent association between elevated hsCRP and MACE was observed within the PolyVD population, while this was not the case for individuals without PolyVD., Conclusion: A residual risk of adverse outcomes after PCI linked to inflammation appears to be present among individuals with PolyVD. This could help define further target populations for anti-inflammatory treatment options., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Brepocitinib is an oral once-daily Janus kinase 1 and Tyrosine kinase 2 selective inhibitor currently in development for the treatment of several autoimmune disorders. Mass balance and metabolic profiles were determined using accelerator mass spectrometry in six healthy male participants following a single oral 60 mg dose of 14 C-brepocitinib (∼300 nCi). The average mass balance recovery was 96.7% ± 6.3%, with the majority of dose (88.0% ± 8.0%) recovered in urine and 8.7% ± 2.1% of the dose recovered in feces. Absorption of brepocitinib was rapid, with maximal plasma concentrations of total radioactivity and brepocitinib achieved within 0.5 hours after dosing. Circulating radioactivity consisted primarily of brepocitinib (47.8%) and metabolite M1 (37.1%) derived from hydroxylation at the C5' position of the pyrazole ring. Fractional contributions to metabolism via cytochrome P450 enzymes were determined to be 0.77 for CYP3A4/5 and 0.14 for CYP1A2 based on phenotyping studies in human liver microsomes. However, additional clinical studies are required to understand the potential contribution of CYP1A1. Approximately 83% of the dose was eliminated as N-methylpyrazolyl oxidative metabolites, with 52.1% of the dose excreted as M1 alone. Notably, M1 was not observed as a circulating metabolite in earlier metabolic profiling of human plasma from a multiple ascending dose study with unlabeled brepocitinib. Mechanistic studies revealed that M1 was highly unstable in human plasma and phosphate buffer, undergoing chemical oxidation leading to loss of the 5-hydroxy-1-methylpyrazole moiety and formation of aminopyrimidine cleavage product M2. Time-dependent inhibition and trapping studies with M1 yielded insights into the mechanism of this unusual and unexpected instability. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of brepocitinib, a JAK1/TYK2 inhibitor for atopic dermatitis, in humans as well as characterization of clearance pathways and pharmacokinetics of brepocitinib and its metabolites., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

A single 300 mg dose of tafenoquine (an 8-aminoquinoline), in combination with a standard 3-day course of chloroquine, is approved in several countries for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged ≥ 16 years. Despite this, questions have arisen on the optimal dose of tafenoquine. Before the availability of tafenoquine, a 3-day course of chloroquine in combination with the 8-aminoquinoline primaquine was the only effective radical cure for vivax malaria. The World Health Organization (WHO)-recommended standard regimen is 14 days of primaquine 0.25 mg/kg/day or 7 days of primaquine 0.5 mg/kg/day in most regions, or 14 days of primaquine 0.5 mg/kg/day in East Asia and Oceania, however the long treatment courses of 7 or 14 days may result in poor adherence and, therefore, low treatment efficacy. A single dose of tafenoquine 300 mg in combination with a 3-day course of chloroquine is an important advancement for the radical cure of vivax malaria in patients without glucose-6-phosphate dehydrogenase (G6PD) deficiency, as the use of a single-dose treatment will improve adherence. Selection of a single 300 mg dose of tafenoquine for the radical cure of P. vivax malaria was based on collective efficacy and safety data from 33 studies involving more than 4000 trial participants who received tafenoquine, including over 800 subjects who received the 300 mg single dose. The safety profile of single-dose tafenoquine 300 mg is similar to that of standard-dosage primaquine 0.25 mg/kg/day for 14 days. Both primaquine and tafenoquine can cause acute haemolytic anaemia in individuals with G6PD deficiency; severe haemolysis can lead to anaemia, kidney damage, and, in some cases, death. Therefore, relapse prevention using an 8-aminoquinoline must be balanced with the need to avoid clinical haemolysis associated with G6PD deficiency. To minimize this risk, the WHO recommends G6PD testing for all individuals before the administration of curative doses of 8-aminoquinolines. In this article, the authors review key efficacy and safety data from the pivotal trials of tafenoquine and argue that the currently approved dose represents a favourable benefit-risk profile., (© 2024. The Author(s).)

Competing Interests: Declaration of competing interest Dr. Spirito reports a relation with Swiss National Science Foundation that includes funding grants. Dr. Mehran reports a relation with Abbott Vascular Inc that includes funding grants; a relation with AstraZeneca that includes funding grants; and a relation with the Society for Cardiovascular Angiography and Interventions that includes funding grants. The remaining authors have no competing interests to declare.

Diabetic ketoacidosis in children is associated with a wide gamut of complications, which can be either disease- or therapy-related. Common complications in children with DKA include cerebral edema, acute kidney injury, hypokalemia, hypoglycemia, etc. As opposed to asymptomatic hypophosphatemia, which is common during the management of DKA, severe symptomatic hypophosphatemia leading to life-threatening complications like rhabdomyolysis, hemolysis, respiratory failure secondary to muscle weakness, and cardiac complications are rare. The authors present a case of a newly diagnosed T1DM patient who, during the course of management, developed severe hypophosphatemia leading to arrhythmias and cardiac dysfunction, which improved with prompt recognition and correction., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Objectives: To study the epidemiology of non-coronavirus disease-2019 (non-COVID-19) respiratory viral infections with respect to their clinical profile, intensive care needs and predictors of outcome once the non-pharmacological interventions (NPI) during the coronavirus disease-2019 (COVID-19) pandemic were relaxed., Methods: Retrospective analysis of children with Severe Acute Respiratory Illness (SARI) who were SARS-CoV-2 negative, admitted to the Pediatric Emergency/Intensive Care Unit (PICU) from July 2021 through October 2021 was conducted., Results: One hundred and thirty nine children with median age of 11 (4-28.5) mo were included. Besides respiratory symptoms in all, diarrhea was reported in 90 (64.7%) children. Nearly half (n = 66; 47%) presented in hypoxemic respiratory failure (SpO 2 <88%). Fifty-two (37.4%) children had co-morbidities, commonest being congenital heart disease in 12 (23.1%). Baseline parameters revealed leukopenia (specifically lymphopenia) 39 (28%), elevated aspartate transaminase [Serum glutamic-oxaloacetic transaminase (SGOT)] in 108 (77.6%), elevated N-acetyl-cysteine-activated creatinine kinase (CK-NAC) 23 (79%) and lactate dehydrogenase (LDH) 15 (88%). Intensive care needs included mechanical ventilation 51 (36.6%), vasoactive support 34 (24.5%), and renal replacement therapy 10 (7.1%). Forty-two (30.2%) children developed multi-organ dysfunction syndrome (MODS). One hundred and three (74.1%) children were discharged, 31 (22.3%) died, and 5 (3.6%) left against medical advice. On multivariate regression analysis, elevated liver enzymes (>5 times normal), hypoxemic respiratory failure at admission, hypotensive shock and MODS predicted mortality., Conclusions: A surge in non-COVID SARI was observed once lockdown measures were relaxed. Nearly 1/3 rd progressed to multi-organ failure and died. Elevated liver enzymes, hypoxemic respiratory failure at admission, hypotensive shock and MODS predicted death., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

The global epidemiological transition of atherosclerotic vascular diseases is witnessing a rapid redistribution of its burden, shifting from high-income to low- and middle-income countries. With a wide clinical spectrum, spanning from intermittent claudication to more complex critical limb threatening ischemia, nonhealing ulcers, gangrene as well as acute limb ischemia, peripheral artery disease is often faced with the challenges of under-diagnosis and under-treatment despite its high prevalence. The management of peripheral arterial disease in patients with multiple comorbidities presents a formidable challenge and remains a pressing global health concern. In this review, we aim to provide an in-depth overview of the pathophysiology of peripheral artery disease and explore evidence-based management strategies encompassing pharmacological, lifestyle, interventional, and surgical approaches. By addressing these challenges, the review contributes to a better understanding of the evolving landscape of peripheral artery disease, offering insights into effective and holistic management strategies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Krittanawong discloses the following relationships – Member of the American College of Cardiology Solution Set Oversight Committee, the American Heart Association Committee of the Council on Genomic and Precision Medicine, and the American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Performance Measures, The Lancet Digital Health (Advisory Board), European Heart Journal Digital Health (Editorial board), Journal of the American Heart Association (Editorial board), JACC: Asia (Section Editor), The Journal of Scientific Innovation in Medicine (Associate Editor), and Frontiers in Cardiovascular Medicine (Associate Editor). Dr. Sharma discloses the following relationships consultant for Cagent and BD. Other authors have no disclosure. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Lower extremity peripheral artery disease (PAD) is common among patients with several risk factors, such as elderly, smoking, hypertension, and diabetes mellitus. Notably, PAD is associated with a higher risk of cardiovascular complications. Non-invasive interventions are beneficial to improve morbidity and mortality among patients with PAD. Traditional risk factors like smoking, diabetes mellitus, hypertension, and dyslipidemia play a significant role in the development of PAD. Still, additional factors such as mental health, glycemic control, diet, exercise, obesity management, lipid-lowering therapy, and antiplatelet therapy have emerged as important considerations. Managing these factors can help improve outcomes and reduce complications in PAD patients. Antiplatelet therapy with aspirin or clopidogrel is recommended in PAD patients, with clopidogrel showing more significant benefits in symptomatic PAD individuals. Managing several risk factors is crucial for improving outcomes and reducing complications in patients with PAD. Further research is also needed to explore the potential benefits of novel therapies. Ultimately, a comprehensive approach to PAD management is essential for improving morbidity and mortality among patients with this condition., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A single 300 mg dose of tafenoquine, in combination with chloroquine, is currently approved in several countries for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged ≥16 years. Recently, however, Watson et al. suggested that the approved dose of tafenoquine is insufficient for radical cure, and that a higher 450 mg dose could reduce P. vivax recurrences substantially (Watson et al., 2022). In this response, we challenge Watson et al.'s assertion based on empirical evidence from dose-ranging and pivotal studies (published) as well as real-world evidence from post-approval studies (ongoing, therefore currently unpublished). We assert that, collectively, these data confirm that the benefit-risk profile of a single 300 mg dose of tafenoquine, co-administered with chloroquine, for the radical cure of P. vivax malaria in patients who are not G6PD-deficient, continues to be favourable where chloroquine is indicated for P. vivax malaria. If real-world evidence of sub-optimal efficacy in certain regions is observed or dose-optimisation with other blood-stage therapies is required, then well-designed clinical studies assessing safety and efficacy will be required before higher doses are approved for clinical use., Competing Interests: RS, CC, LT, KR, IF, SJ, AP, RG, PB Employee of GSK; shareholder in GSK, NG, HS Former employee and shareholder in GSK, (© 2024, Sharma et al.)

Renewed interest in psychedelic substances in the 21 st century has seen the exploration of psychedelic treatments for various psychiatric disorders including substance use disorder (SUD). This review aimed to assess the effectiveness of psychedelic treatments for people with SUD and those falling below diagnostic thresholds (i.e. substance misuse). We systematically searched 11 databases, trial registries, and psychedelic organization websites for empirical studies examining adults undergoing psychedelic treatment for SUD or substance misuse, published in the English language, between 2000 and 2021. Seven studies investigating treatment using psilocybin, ibogaine, and ayahuasca, alone or adjunct with psychotherapy reported across 10 papers were included. Measures of abstinence, substance use, psychological and psychosocial outcomes, craving, and withdrawal reported positive results, however, this data was scarce among studies examining a wide range of addictions including opioid, nicotine, alcohol, cocaine and unspecified substance. The qualitative synthesis from three studies described subjective experience of psychedelic-assisted treatments enhanced self-awareness, insight, and confidence. At present, there is no sufficient research evidence to suggest effectiveness of any of the psychedelics on any specific substance use disorder or substance misuse. Further research using rigorous effectiveness evaluation methods with larger sample sizes and longer-term follow-up is required.

Aims: Brepocitinib is a tyrosine kinase 2/Janus kinase 1 inhibitor being investigated for the treatment of several autoimmune diseases. This study assessed the absorption, distribution, metabolism and excretion of oral brepocitinib, and the absolute oral bioavailability (F) and fraction absorbed (F a ) using a 14 C microtracer approach., Methods: This was a phase 1 open-label, nonrandomized, fixed sequence, two-period, single-dose study of brepocitinib in healthy male participants. Participants received a single oral 60 mg dose of 14 C brepocitinib (~300 nCi) in Period A, then an unlabelled oral 60 mg dose followed by an intravenous (IV) 30 μg dose of 14 C labelled brepocitinib (~300 nCi) in Period B. Mass balance, pharmacokinetic parameters and safety were assessed., Results: Six participants were enrolled. Brepocitinib was absorbed rapidly following oral administration. In Period A, total recovery of the oral dose was 96.7% ± 6.3% (88.0% ± 8.0% in urine, 8.7% ± 2.1% in faeces). In Period B, a small fraction (6.0% of the oral dose) was recovered unchanged in urine. F and F a were 74.6% (90% confidence interval 67.3%, 82.8%) and 106.9%, respectively. Brepocitinib demonstrated an acceptable safety profile and was well tolerated following oral or oral then IV administrations. No deaths, serious adverse events or discontinuations were reported., Conclusion: Intestinal absorption of brepocitinib was essentially complete after oral administration, with F ~75%. Drug-related material recovery was high, with the majority excreted in urine. The major route of elimination of brepocitinib was renal excretion as metabolites, whereas urinary elimination of unchanged brepocitinib was minor. NCT: NCT03770039., (© 2023 Pfizer Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Sensorineural hearing loss is relatively well established in the squamosal chronic otitis media. However, its association with mucosal COM is still debated. The present study aimed at evaluating the prevalence of sensorineural hearing loss in unilateral mucosal COM. The study was conducted at a tertiary care hospital in New Delhi, and 60 patients with unilateral mucosal chronic otitis media were recruited. Pure tone thresholds were ascertained for air and bone conduction in an acoustically treated room and matched against certain patient and disease characteristics. In this study, the combined prevalence of SNHL/Mixed Hearing loss in mucosal COM was found to be 8.3%. A statistically significant association between SNHL/Mixed HL was seen in the 40-50-year age group ( p -0.004). Prevalence with a disease duration of more than 10 years was 33% ( p -0.019). All the patients who presented with SNHL/Mixed HL had an actively discharging ear. 80% of the patients who presented with SNHL/Mixed HL had large perforations. SNHL/Mixed HL prevalence of 28.6% was found in smokers, compared to 5.7% in non-smokers ( p -0.039). The risk of developing SNHL/Mixed HL increased with increasing patients' age, disease duration, and size of the perforation and smokers., Competing Interests: Conflict of interestNone., (© Association of Otolaryngologists of India 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Nitinol interwoven bare metal stents represent an advancement in stent technology; however, nominal deployment remains an area of focus. Intravascular ultrasound (IVUS) has been shown to improve outcomes in both the coronary and peripheral vasculature by providing the operator with greater vessel detail; however, the use of adjunctive IVUS with nitinol bare metal stents has not been widely studied. This studies aims to determine the effect of IVUS when used adjunctively with nitinol interwoven bare metal stents in the management of femoropopliteal lesions., Design: Retrospective study., Methods: This study included a cohort of 200 consecutive patients with peripheral artery disease. All patients were treated with ≥1 Supera bare metal stent, and 91 received adjunctive IVUS imaging prior to stent deployment. Deployment conditions of nominal, compressed, and elongated were measured, and the primary clinical outcomes included target lesion reintervention, amputation, and mortality. This study also showed that 8.3 number needed to treat (NNT) patients must be treated with IVUS to avoid an additional revascularization event., Results: The patients who received IVUS had a significantly greater number of nominally deployed stents (p<0.001). Patients who had IVUS imaging also had significantly lower reintervention rates compared with those who did not receive IVUS imaging (p=0.047)., Conclusion: The IVUS and angiography decreases clinically-driven target lesion reintervention and increases nominal deployment compared with angiography alone in femoropopliteal lesions treated with interwoven bare metal nitinol stents., Clinical Impact: Endovascular surgones may conisder the adjuctive use of IVUS when using the Supera stent for the treatment of infra inguinal superficial femoral artery lesions. The adjunct use of IVUS may lead to improved sizing, vessel prep, deployment, and ultiamtely reduction in CD-TLR.

We recently disclosed SAR studies on systemically acting, amide-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) that addressed metabolic liabilities with the liver-targeted DGAT2 inhibitor PF-06427878. Despite strategic placement of a nitrogen atom in the dialkoxyaromatic ring in PF-06427878 to evade oxidative O -dearylation, metabolic intrinsic clearance remained high due to extensive piperidine ring oxidation as exemplified with compound 1 . Piperidine ring modifications through alternate N -linked heterocyclic ring/spacer combination led to azetidine 2 that demonstrated lower intrinsic clearance. However, 2 underwent a facile cytochrome P450 (CYP)-mediated α-carbon oxidation followed by azetidine ring scission, resulting in the formation of ketone (M2) and aldehyde (M6) as stable metabolites in NADPH-supplemented human liver microsomes. Inclusion of GSH or semicarbazide in microsomal incubations led to the formation of Cys-Gly-thiazolidine (M3), Cys-thiazolidine (M5), and semicarbazone (M7) conjugates, which were derived from reaction of the nucleophilic trapping agents with aldehyde M6. Metabolites M2 and M5 were biosynthesized from NADPH- and l-cysteine-fortified human liver microsomal incubations with 2 , and proposed metabolite structures were verified using one- and two-dimensional NMR spectroscopy. Replacement of the azetidine substituent with a pyridine ring furnished 8 , which mitigated the formation of the electrophilic aldehyde metabolite, and was a more potent DGAT2 inhibitor than 2 . Further structural refinements in 8 , specifically introducing amide bond substituents with greater metabolic stability, led to the discovery of PF-06865571 (ervogastat) that is currently in phase 2 clinical trials for the treatment of nonalcoholic steatohepatitis.

Background: Electronic repeat dispensing (eRD) has been part of the community pharmacy contact since 2005 and a requirement in the General Medical Services contract since 2019. NHS England highlights benefits of eRD as increased efficiency in general practice of 2.7 million hours annually if 80% of all repeat prescriptions are issued as eRD. Despite clear benefits to patients, community pharmacies and general practices, the uptake of eRD remains low and variable across general practices in West Yorkshire, UK., Objectives: To investigate the impact of COVID-19 on eRD in general practice and understand the key enablers to its uptake., Methods: A 19-item questionnaire was developed and piloted during cognitive interviews. A cross-sectional survey was conducted via emails to general practices in West Yorkshire, UK, between July 2020 and November 2020., Results: Sixty-seven complete responses were received (23 pharmacists, 21 practice managers, 11 general practitioners, seven pharmacy technicians, four advanced practitioners, one prescription clerk). 59% of respondents were aware of eRD uptake in their surgery (mean value 4.56% ± 0.229%). Higher uptake of eRD was demonstrated where the general practice integrated eRD into routine workflows during the repeat prescription reauthorisation process (P < 0.001) and where an eRD service lead is nominated (P = 0.04)., Conclusion: Utilising eRD in the respective practices should be considered due to potential efficiency gains and the increase in average eRD utilisation observed in the study participating general practices was from 7.2% average uptake in March 2020 to 10.4% November 2020, as the response to COVID-19. The stated benefits of eRD by NHS England of 2.7 million hours per annum predates the roll out of electronic transmission of prescriptions suggesting further research is needed to quantify the efficiency gains in present NHS general practice environments., (© 2023. The Author(s).)

Introduction  The role of endoscopes in the ear, nose, and throat (ENT) field has been described since the 1980s; It started with endoscopic nasal surgeries, followed by otological and laryngological procedures, and, since then, it has experienced a rapid evolution. Endoscopes help otologists understand how to approach difficult areas of middle ear, as well as the physiology of middle ear cleft. Objectives  Despite the introduction of endoscopes in the field of otology, microscopes are still widely used in clinics and in operation theaters either alone or with endoscopes. The present study, which was conducted amongst otologists in India, is on their experience with and knowledge of the use of the endoscope compared to microscopes. Methods  A Google form-based questionnaire comprising 18 questions was developed and sent online to otologist all over the country. The final dataset included responses from 354 active otologists. Results  Out of 354 participants, only 3% had more than 5 years of experience in endoscopic ear surgery (EES), and 16.1% had never worked with an endoscope. Endoscopes were used in clinics and in operation theaters by 74.9% of the participants. Conclusion  There has been a rise in the acceptance and use of endoscopes among Indian otologists and otology surgeons in last few decades., Competing Interests: Conflict of Interests The authors have no conflict of interests to declare., (Fundação Otorrinolaringologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Two-dimensional (2D) materials have garnered considerable attention as emerging thermoelectric (TE) materials owing to their unique density of states (DOS) near the Fermi level. We investigate the TE performance of Janus β-PdXY (X/Y = S, Se, Te) monolayer materials as a function of carrier concentration and temperature in the mid-range from 300 to 800 K by combining density functional theory (DFT) and semi-classical Boltzmann transport theory. The phonon dispersion spectra and AIMD simulations confirm their thermal and dynamic stability. The transport calculation results reveal the highly anisotropic TE performance of both n and p-type Janus β-PdXY monolayers. Meanwhile, the coexistence of low phonon group velocity and a converged scattering rate leads to a lower lattice thermal conductivity ( K l ) of 0.80 W mK -1 , 0.94 W mK -1 , and 0.77 W mK -1 along the y -direction for these Janus materials, while the high TE power factor is attributed to the high Seebeck coefficient ( S ) and electrical conductivity, which are due to the degenerate top valence bands of these Janus monolayers. The combination of lower K l and a high-power factor at 300 K (800 K) leads to an optimal figure of merit ( ZT ) of 0.68 (2.21), 0.86 (4.09) and 0.68 (3.63) for p-type Janus PdSSe, PdSeTe and PdSTe monolayers, respectively. To evaluate rational electron transport properties, the effects of acoustic phonon scattering ( τ ac ), impurity scattering ( τ imp ), and polarized phonon scattering ( τ polar ) are included in the temperature-dependent electron relaxation time. These findings indicated that the Janus β-PdXY monolayers are promising candidates for TE conversion devices.

Background: Potent P2Y 12 inhibitors such as ticagrelor and prasugrel are superior to clopidogrel in acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI). Whether this benefit extends to a patient population with chronic coronary syndromes (CCS) is unclear., Aims: We sought to compare the safety and efficacy of prasugrel and ticagrelor versus clopidogrel in patients undergoing PCI for CCS., Methods: Consecutive patients undergoing PCI for CCS at a tertiary centre between 2014 and 2019 who were discharged on prasugrel or ticagrelor were compared with those on clopidogrel. The primary endpoint was the composite of death and myocardial infarction (MI), with secondary outcomes including rates of bleeding, stroke, and target vessel revascularisation at 1 year., Results: Overall, 11,508 patients were included in the study (ticagrelor/prasugrel n=2,860 [24.9%], clopidogrel n=8,648 [75.1%]) with an increasing frequency of potent P2Y 12 inhibitor use over the study period (p trend <0.001). Clopidogrel was used more frequently in patients with multimorbid risk factors, whereas anatomical or procedural complexity was associated with ticagrelor/prasugrel use (left main PCI, bifurcation PCI, number of lesions, rotational atherectomy). No difference in the incidence of death or MI was noted across the groups (ticagrelor/prasugrel vs clopidogrel: 2.7% vs 3.1%, adjusted hazard ratio [adjHR] 0.86, 95% confidence interval [CI]: 0.62-1.17; p=0.33) or secondary outcomes including bleeding (adjHR 0.75, 95% CI: 0.46-1.21; p=0.23) on propensity score stratification analysis. Additionally, no difference in the primary outcome was observed across subgroups, including those undergoing complex PCI., Conclusions: Ticagrelor and prasugrel are increasingly used in patients with CCS undergoing PCI with similar 1-year efficacy and safety when compared to clopidogrel. Whether use of these agents can be beneficial in patients undergoing PCI for CCS with a high thrombotic and low bleeding risk warrants further study.

Objectives: To compare the epidemiological, clinical profile, intensive care needs and outcome of children hospitalized with SARS-CoV-2 infection during the first and second waves of the pandemic., Methods: This was a retrospective study of all children between 1 mo and 14 y, admitted to a dedicated COVID-19 hospital (DCH) during the first (1st June to 31st December 2020) and second waves (1st March to 30th June 2021)., Results: Of 217 children, 104 (48%) and 113 (52%) were admitted during the first and second waves respectively. One hundred fifty-two (70%) had incidentally detected SARS-CoV-2 infection, while 65 (30%) had symptomatic COVID-19. Comorbidities were noted in 137 (63%) children. Fifty-nine (27%) and 66 (30%) children required high-dependency unit (HDU) and ICU care respectively. Severity of infection and ICU needs were similar during both waves. High-flow oxygen (n = 5, 2%), noninvasive ventilation [CPAP (n = 34, 16%) and BiPAP (n = 8, 5%)] and invasive ventilation (n = 45, 21%) were respiratory support therapies needed. NIV use was more during the second wave (26% vs. 13%; p = 0.02). The median (IQR) length (days) of DCH stay among survivors was longer during the first wave [8 (6-10) vs. 5.5 (3-8); p = 0.0001]., Conclusions: Disease severity, associated comorbidities, PICU and organ support need and mortality were similar in the first and second waves of the pandemic. Children admitted during the second wave were younger, had higher proportion of NIV use and shorter length of COVID-19 hospital stay., (© 2022. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Purpose: To assess the perception of college-going girls toward corneal donation in Northern India., Methods: An online survey with a pre-structured, pre-validated questionnaire was conducted on 1721 college-going girls in Northern India. The knowledge and attitude scores were regressed, and latent class analysis was carried out., Results: The average of scores for all participants was computed individually for the knowledge questions and the attitude questions, and based on this score, total participants were divided into two groups: Better corneal donation behaviors (BCDB) and poor corneal donation behaviors. The binomial logistic regression model of knowledge domain for predicting BCDB, age of the participant, their awareness about corneal donation, and willingness to discuss eye donation among family members were found significant. Similarly, for the attitude domain, awareness about corneal donation, knowledge about hours within which ideal eye donation needs to be undertaken, and knowledge about eye donation during coronavirus disease 2019 (COVID-19) pandemic were found to be significant. Latent class analysis identified one subset of participants having poorer knowledge and attitude scores and that they were more from a rural background, were having more than first order as birth order, were belonging to SC/ST classes, had illiterate or secondary education of father and mother, and were living in rented houses., Conclusion: The findings of the study significantly contribute to devising a mechanism to improve knowledge and influencing the attitude about eye donation among the youth, especially young women, who can act as counselors and motivators for the masses as well as their own families, in the generations to come., Competing Interests: None

Background: Use of both rotational atherectomy (RA) and intravascular lithotripsy (IVL)-the "RotaTripsy" technique-offers a potentially synergistic calcium-modification strategy that can treat both luminal and abluminal calcification. An upfront RotaTripsy strategy using an undersized burr in large-caliber coronaries also offers the advantage of facilitating IVL catheter passage while being able to undertake the procedure with a 6-Fr system., Methods: Consecutive patients with heavily calcified lesions on angiographic or intravascular imaging and large target-vessel caliber (≥3 mm) who underwent an upfront RA followed by IVL between July 2021 and January 2022 were included in this study. Study aims were to evaluate periprocedural efficacy and safety., Results: Of the 21 patients included, RotaTripsy was used for treatment of de novo lesions in 12 patients (57%) and for in-stent-restenosis in 9 patients (43%). Seven cases of in-stent restenosis (ISR) involved 2 layers of stents. Mean reference vessel diameter was 3.67 ± 0.46 mm and baseline diameter stenosis was 77.4 ± 11.3%. Average RA burr-to-artery ratio was 0.43 ± 0.05 and IVL balloon-to-artery ratio was 0.93 ± 0.06, with IVL balloon crossing the lesion in all cases following RA. Procedural success was attained in 20 of 21 cases; 1 periprocedural complication (a death related to coronary perforation following stent postdilation) was recorded., Conclusions: An upfront RotaTripsy strategy is associated with a high degree of procedural success in de novo lesions and ISR cases by facilitating the use of a smaller burr-to-artery ratio and smaller-bore vascular access. Larger studies are required to further evaluate the potential benefits of an upfront RotaTripsy strategy from a safety and cost-benefit perspective.

Background: In drug development, few molecules from a large pool of early candidates become successful medicines after demonstrating a favourable benefit-risk ratio. Many decisions are made along the way to continue or stop the development of a molecule. The probability of pharmacological success, or PoPS, is a tool for informing early-stage decisions based on benefit and risk data available at the time., Results: The PoPS is the probability that most patients can achieve adequate pharmacology for the intended indication while minimising the number of subjects exposed to safety risk. This probability is usually a function of dose; hence its computation typically requires exposure-response models for pharmacology and safety. The levels of adequate pharmacology and acceptable risk must be specified. The uncertainties in these levels, in the exposure-response relationships, and in relevant translation all need to be identified. Several examples of different indications are used to illustrate how this approach can facilitate molecule progression decisions for preclinical and early clinical development. The examples show that PoPS assessment is an effective mechanism for integrating multi-source data, identifying knowledge gaps, and forcing transparency of assumptions. With its application, translational modelling becomes more meaningful and dose prediction more rigorous. Its successful implementation calls for early planning, sound understanding of the disease-drug system, and cross-discipline collaboration. Furthermore, the PoPS evolves as relevant knowledge grows., Conclusion: The PoPS is a powerful evidence-based framework to formally capture multiple uncertainties into a single probability term for assessing benefit-risk ratio. In GSK, it is now expected for governance review at all early-phase decision gates., (© 2023. The Author(s).)

Necrotizing fasciitis is a rare and fulminant infection of the superficial fascia and subcutaneous cellular tissue. It is commonly polymicrobial, with the combination of aerobic and anaerobic bacteria, which contributes to the rapid progression and severity of the disease. The microbes commonly involved include group A streptococcus, Enterobacteriaceae, anaerobes, and Staphylococcus aureus . Over the past few years, skin and soft tissue infections, including necrotizing fasciitis, due to methicillin-resistant Staphylococcus aureus are increasing.

Sub-Optimal deployment of Self expanding interwoven stents (Supera) has been shown to increase the rate of Clinically Driven Target Lesion Revascularization (CD-TLR). Meanwhile, drug coated balloons (DCB) have been shown to reduce CD-TLR in the femoral-popliteal segment in de- novo and restenotic lesions. However, the clinical effects of vessel preparation with DCB in nominal, compressed, and elongated Supera has not been widely studied. The purpose of this study is to assess the outcomes of clinically driven re-intervention, major amputations, and mortality in relation to the use of DCB as vessel preparation in different deployment conditions (nominal, compressed, elongated) of the Supera stent. Patient chart data was collected at a single center hospital between March 2015 and May 2020. All patients were adults (≥ 18 years old) and were treated with at least one (≥ 1) Supera stent. Deployment status was extrapolated from anonymized angiograms. The primary endpoint of this study was CD-TLR. Secondary endpoints included amputation and mortality rates associated with each deployment condition. A total of 670 limbs were treated and patients were followed for 36 months. Nominal stent deployment was observed in 337 limbs, followed by elongated condition (n = 176), then by compressed conditions (n = 159). CD-TLR was observed most frequently with elongated deployment. Drug coated balloons were used as vessel prep prior to stenting and showed a protective effect regardless of deployment status; O.R = 0.44 (CI 0.30-0.66, p < .05)., (© 2022. The Author(s).)

Typically human absorption, distribution, metabolism, and excretion (ADME) studies are executed using radiolabeled (e.g., carbon-14) material, the synthesis of which is a time-consuming activity. In this study, we were able to assess the metabolism and excretion of unlabeled nirmatrelvir (PF-07321332) within the first-in-human study via a novel application of quantitative fluorine ( 19 F) nuclear magnetic resonance (NMR) spectroscopy in place of a standard radiolabel ADME study. Six healthy participants received a single 300-mg oral dose of nirmatrelvir (in combination with ritonavir), and excreta were collected up to 10 days. Virtually all drug-related material was recovered within 5 days, and mass balance was achieved with 84.9 ± 8.9% (range = 70.7-95.5%) of the administered dose recovered in urine and feces. The excretion of fluorine-containing material in urine and feces was 47.0% and 33.7%, respectively. Unchanged nirmatrelvir represented 82.5% of the normalized drug-related material with a carboxylic acid metabolite M5, derived from hydrolysis of the P2 amide bond, present at 12.1% of dose. Nirmatrelvir was the only drug-related entity observed in plasma. Approximately 4.2% of the dose was excreted as metabolite M8 (measured by liquid chromatography-mass spectrometry), which was 19 F NMR silent due to hydrolysis of the trifluoroacetamide moiety. Hydrolysis of nirmatrelvir to M5 and M8 was shown to occur in cultures of human gut microflora. This successful demonstration of quantitative 19 F NMR spectroscopy to establish the mass-balance, excretion, and metabolic profile of nirmatrelvir offers an advantageous means to execute human ADME studies for fluorine-containing compounds early in drug development., (© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.)

Background: Potent P2Y 12 agents such as ticagrelor and prasugrel are increasingly utilized across the clinical spectrum of patients undergoing percutaneous coronary intervention (PCI). There is a paucity of data supporting their use in a patient population inclusive of both acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients., Objectives: The authors compared the efficacy and safety of ticagrelor and prasugrel in a real-world contemporary PCI cohort., Methods: Consecutive patients undergoing PCI between 2014 and 2019 discharged on either prasugrel or ticagrelor were included from the prospectively collected institutional PCI registry. Primary endpoint was the composite of death and myocardial infarction (MI), with secondary outcomes including rates of bleeding, stroke, and target vessel revascularization at 1 year., Results: Overall, 3,858 patients were included in the study (ticagrelor: n = 2,771; prasugrel: n = 1,087), and a majority (48.4%) underwent PCI in the context of CCS. Patients prescribed ticagrelor were more likely to be female, have a history of cerebrovascular disease, and have ACS presentation, while those receiving prasugrel were more likely to be White with a higher prevalence of prior revascularization. No difference in the risk of death or MI was noted across the groups (ticagrelor vs prasugrel: 3.3% vs 3.1%; HR: 0.88; 95% CI: 0.54-1.43; P = 0.59). Rates of target vessel revascularization were significantly lower in the ticagrelor cohort (9.3% vs 14.0%; adjusted HR: 0.71; 95% CI: 0.55-0.91; P = 0.007) with no differences in stroke or bleeding. The results were consistent in patients with CCS (HR: 0.84; 95% CI: 0.46-1.54) and ACS (HR: 1.18; 95% CI: 0.46-1.54), without evidence of interaction (P = 0.37), and confirmed across multivariable adjustment and propensity score stratification analysis., Conclusions: In this contemporary patient population undergoing PCI, prasugrel and ticagrelor were associated with similar 1-year efficacy and safety., Competing Interests: Funding Support and Author Disclosures Dr Khera has served as a consultant for Abbott, Medtronic, and Boston Scientific; and has received speaker honoraria from Medtronic. Dr Dangas has received personal fees from Biosensors and Philips. Dr Mehran has received institutional research grants from Abbott, Abiomed, Applied Therapeutics, Arena, AstraZeneca, Bayer, Biosensors, Boston Scientific, Bristol Myers Squibb, CardiaWave, CellAegis, CERC, Chiesi, Concept Medical, CSL Behring, Daiichi Sankyo, Insel Gruppe, Medtronic, Novartis Pharmaceuticals, OrbusNeich, Philips, Transverse Medical, and Zoll; has received personal fees from the American College of Cardiology, Boston Scientific, the California Institute for Regenerative Medicine, Cine-Med Research, Janssen, WebMD, and the Society for Cardiovascular Angiography and Interventions; has received consulting fees paid to the institution from Abbott, Abiomed, AM-Pharma, Alleviant Medical, Bayer, Beth Israel Deaconess, CardiaWave, CeloNova, Chiesi, Concept Medical, Daiichi Sankyo, Duke University, Idorsia Pharmaceuticals, Medtronic, Novartis, and Philips; holds equity (<1%) in Applied Therapeutics, Elixir Medical, STEL, and CONTROLRAD (spouse); and has served on the scientific advisory board for the American Medical Association and Biosensors (spouse). Dr S.K. Sharma has received Speakers Bureau fees from Abbott Vascular, Boston Scientific, and Cardiovascular Systems. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

•A patient's age can be a critical factor influencing the outcome following upper brachial plexus injury (BPI) reconstruction.•The favorable factor being younger patients with short denervation period.•In older patients early and more aggressive management for an optimal outcome.•This study supports the various correlation of age with the outcomes of upper brachial plexus reconstruction surgery., 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., (© 2022 The Authors.)

Discovery efforts leading to the identification of ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential development risks of the prototype liver-targeted DGAT2 inhibitor PF-06427878. Key design elements that culminated in the discovery of ervogastat are (1) replacement of the metabolically labile motif with a 3,5-disubstituted pyridine system, which addressed potential safety risks arising from a cytochrome P450-mediated O -dearylation of PF-06427878 to a reactive quinone metabolite precursor, and (2) modifications of the amide group to a 3-THF group, guided by metabolite identification studies coupled with property-based drug design.

For the general public, healthcare facilities are always a safe and secure place for treatment. Generally, healthcare institutions are equipped to deal with exterior interruptions, but circumstances brought on by internal risks are more serious and frequently require an emergency evacuation of the facility. An incident happened at the radiodiagnostic setup of a tertiary care institute in North India. This fire incident created panic among staff and patients. At the place of casualty, there were around 150 persons, including staff, patients, and their attendants. Immediately after the confirmation of the fire incident, the fire department and security department took action in the form of fire control and smoke evacuation. Though six fire handling staff required minor emergency services for asphyxia due to smoke inhalation and were cured by oxygen support only, none of the patients was affected due to timely smoke evacuation. Most often, smoke management techniques implemented are compartmentation, pressurization, dilution, ventilation, buoyancy, and airflow. So, we concluded that the step of timely smoke evacuation and preventing the spread of smoke by various methods help to reduce fatality due to smoke. The training programs and mock drills give stakeholders the needed knowledge, skills, and practice they need to safeguard patients and employees., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Sachdeva et al.)

Maximizing opportunities for climate resilient agriculture is vital for global food security, and ecological sustainability. To explore the improvement potential of mitigation and adaptation strategies in stabilizing wheat production and increasing farm income in sodicity-prone Ghaghar Basin of Haryana, India, participatory research trials on land reclamation (gypsum/pressmud) and crop management (varieties, nutrient management and weed control) practices were undertaken during 2016-2020. Results indicated that combining gypsum and pressmud together accelerated the reclamation process (soil pH: -3.3% and ESP: -22.1%) and improved plant adaptability (RWC: 10%; MI: -15%; Pn: 40%; gS: 36%; NaK&#95;S: -38% and NaK&#95;R: -42%), which in turn increased wheat yield by 20% compared to unamended control. With increasing sodicity stress, salt tolerant wheat variety KRL 210 exhibited better morpho-physiological adaptation, lesser yield reduction (0.8-1.1 t ha -1 ) and attained 4.1% mean yield advantage compared to traditionally cultivated HD 2967. There were genotypic differences for N requirements in sodicity stressed wheat, with 173 kg ha -1 in KRL 210 and 188 kg ha -1 in HD 2967 as the economically optimum dose; further advocating for upward revision of current N recommendations beyond 150 kg N ha -1 . Balanced nutrition through foliage applied K compensated the sodicity hazards with lower proportion of Na + /K + in leaf tissues (13%), and attained higher grain yield (4%) and incremental income (34 US$ ha -1 ) compared to farmers' practice. Sequential use of herbicides provided affordable solution to check Phalaris minor infestation (84% WCE) and enhanced wheat productivity (5.7% higher) with incremental income of 48 US$ ha -1 compared to farmers' sole dependency on post-emergence herbicides. Synergistic integration of gypsum and pressmud-mediated sodic land reclamation, usage of stress tolerant wheat variety, 15% higher N application, foliar K-nutrition and effective P. minor control substantiate appreciable reduction in soil sodicity, improved crop resilience, and ultimately translated into 5% and 26% higher yields over the recommended and local farm practices, respectively. The key insights of this study suggest a range of opportunities wherein inputs of CRISCM could potentially stabilize the wheat production, improve farm economy and reduce environmental risks beyond what is currently being achieved with existing farm practices., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Abrocitinib is an oral once-daily Janus kinase 1 selective inhibitor being developed for the treatment of moderate-to-severe atopic dermatitis. This study examined the disposition of abrocitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite (M) profiles. The results indicated abrocitinib had a systemic clearance of 64.2 L/h, a steady-state volume of distribution of 100 L, extent of absorption >90%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 60%. The half-life of both abrocitinib and total radioactivity was similar, with no indication of metabolite accumulation. Abrocitinib was the main circulating drug species in plasma (∼26%), with 3 major monohydroxylated metabolites (M1, M2, and M4) at >10%. Oxidative metabolism was the primary route of elimination for abrocitinib, with the greatest disposition of radioactivity shown in the urine (∼85%). In vitro phenotyping indicated abrocitinib cytochrome P450 fraction of metabolism assignments of 0.53 for CYP2C19, 0.30 for CYP2C9, 0.11 for CYP3A4, and ∼0.06 for CYP2B6. The principal systemic metabolites M1, M2, and M4 were primarily cleared renally. Abrocitinib, M1, and M2 showed pharmacology with similar Janus kinase 1 selectivity, whereas M4 was inactive. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of abrocitinib, a Janus kinase inhibitor for atopic dermatitis, in humans, as well as characterization of clearance pathways and pharmacokinetics of abrocitinib and its metabolites., (Copyright © 2022 by The Author(s).)

Zimlovisertib (PF-06650833) is a selective, reversible inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) with anti-inflammatory effects. This phase 1, open-label, fixed-sequence, two-period, single-dose study aimed to evaluate the mass balance and excretion rate of zimlovisertib in healthy male participants using a 14 C-microtracer approach. All six participants received 300 mg 14 C-zimlovisertib with lower radioactivity per mass unit orally in Period A, then unlabeled zimlovisertib 300 mg orally and 14 C-zimlovisertib 135 μg intravenously (IV) in Period B. Study objectives included extent and rate of excretion of 14 C-zimlovisertib, pharmacokinetics, and safety and tolerability of oral and IV zimlovisertib. Total radioactivity recovered in urine and feces was 82.4% ± 6.8% (urine 23.1% ± 12.3%, feces 59.3% ± 9.7%) in Period A. Zimlovisertib was absorbed rapidly following oral administration, with the fraction absorbed estimated to be 44%. Absolute oral bioavailability of the 300-mg dose was 17.4% (90% confidence interval 14.1%, 21.5%) using the dose-normalized area under the concentration-time curve from time 0 to infinity. There were no deaths, serious adverse events (AEs), severe AEs, discontinuations or dose reductions due to AEs, and no clinically significant laboratory abnormalities. These results demonstrate that zimlovisertib had low absolute oral bioavailability and low absorption (<50%)., (© 2022 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Competing Interests: There are no conflicts of interest.

Introduction Despite the theoretical advantages of bleeding control, there is increased morbidity in postoperative pain, sleep disturbance, allergy, toxic shock syndrome, and mucosal injury with the nasal packing in septoplasty procedure for deviated nasal septum. Trans-septal suturing after septoplasty has been advocated as an effective alternative to conventional nasal packing. The current study aims to compare the frequency of subjective symptoms, such as postoperative nasal pain, nasal bleeding, postnasal drip, sleep disturbance, dysphagia, headache, and epiphora between the trans-septal suturing technique and nasal packing in septoplasty surgery. Methods We prospectively recruited all adult septoplasty patients for a one-year duration. Trans-septal nasal suturing was done for hemostasis after septoplasty in the case group. Anterior nasal packing after septoplasty was performed in the control group. The postoperative subjective symptoms were evaluated, such as postoperative nasal pain, nasal bleeding, postnasal drip, sleep disturbance, dysphagia, headache, and epiphora. Procedure-related complications were compared between the two groups. Results A total of 50 patients were recruited for the study (25 in each group). The postoperative symptoms evaluation suggested that the number of patients with postoperative pain was significantly higher in the control group on both occasions. Besides pain, a significantly higher number of patients in the control group had symptoms of nasal bleeding, postnasal drip, sleep disturbance, dysphagia, headache, and epiphora. Conclusion Trans-septal suture technique is an effective alternative to nasal packing with a low risk of nasal pain, bleeding, postnasal drip, epiphora, headache, dysphagia, and sleep disturbance. In addition, there is a low risk of complications like nasal bleeding, septal hematoma, septal perforation, and synechiae formation. The only disadvantage of trans-septal suturing compared to PVA-coated nasal packing is the increase in the operative time., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Meena et al.)

Background & Objectives: As severe COVID-19 and mortality are not common in children, there is a scarcity of data regarding the cause of mortality in children infected with SARS-CoV-2. This study was aimed to describe the all-cause mortality and COVID-19 death (disease-specific mortality) in children with SARS-CoV-2 infection admitted to a paediatric COVID facility in a tertiary care centre., Methods: Data with respect to clinical, epidemiological profile and causes of death in non-survivors (0-12 yr old) of SARS-CoV-2 infection admitted to a dedicated tertiary care COVID hospital in north India between April 2020 and June 2021 were retrieved and analyzed retrospectively., Results: A total of 475 SARS-CoV-2-positive children were admitted during the study period, of whom 47 died [18 neonates, 14 post-neonatal infants and 15 children (1-12 yr of age)]. The all-cause mortality and COVID-19 death (disease-specific mortality) were 9.9 per cent (47 of 475) and 1.9 per cent (9 of 475), respectively. Underlying comorbidities were present in 35 (74.5%) children, the most common being prematurity and perinatal complications (n=11, 24%) followed by congenital heart disease (n=6, 13%). The common causes of death included septic shock in 10 (21%), COVID pneumonia/severe acute respiratory distress syndrome in nine (19%), neonatal illnesses in eight (17%), primary central nervous system disease in seven (15%) and congenital heart disease with complication in six (13%) children., Interpretation & Conclusions: Our results showed a high prevalence of underlying comorbidities and a low COVID-19 death (disease-specific mortality). Our findings highlight that mortality due to COVID-19 can be overestimated if COVID-19 death and all-cause mortality in children infected with SARS-CoV-2 are not separated. Standardized recording of cause of death in children with SARS-CoV-2 infection is important.

Introduction Complications during and after dissection of level IIb lymph nodes include spinal accessory nerve (SAN) dysfunction, which results in the limitation of shoulder movements and, thus, hurts the quality of life. The current study aims to know the occurrence of level IIb lymph node positivity in tongue carcinoma. Methods This cross-sectional study was conducted from January 2019 to December 2019 in a tertiary care center in North India. Adult cases with primary ulcer-proliferative growth over the lateral border of the tongue were included in the study. The level IIb lymph node positivity from the postoperative histopathology report was the primary outcome measure of this study. To investigate the potential association of tumor size on level IIb lymph node positivity, we compared the maximum tumor dimensions among the level IIb lymph node-positive and -negative groups. In addition, to analyze the impact of the tumor's invasive nature on level IIb lymph node positivity, we compared the depth of invasion and proportion of cases with muscle involvement among the level IIb lymph node-positive and -negative groups. Lastly, to investigate their concurrent occurrences, we compared the number of level IIb lymph node-positive cases among the level IIa lymph node-positive and -negative groups. Results A total of 39 patients fulfilling the inclusion criteria were included in the study. Only six had positive level-IIb lymph nodes. No significant associations of tumor size, invasion depth, muscle invasion, or involvement of level IIa lymph nodes with the positivity of level IIb lymph nodes were found. However, only three were level IIb lymph node-positive in 28 level IIa lymph node-negative cases. Conclusion Considering the low risk of isolated level IIb lymph node positivity in level IIa lymph node-negative cases, the dissection of level IIb nodes could be omitted during the surgical excision of the tumor. However, radiological investigations detecting metabolic activity should be used in the preoperative period and postoperative follow-up to detect early lymph node involvement and disease recurrence., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Saigal et al.)