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Objectives: To identify early indicators for invasive mechanical ventilation utilization among COVID-19 patients., Methods: This retrospective study evaluated COVID-19 patients who were admitted to hospital from 20 September 2020, to 8 August 2021. Multivariable logistic regression and machine learning (ML) methods were employed to assess variable significance., Results: Among 1,613 confirmed COVID-19 patients, 365 patients (22.6%) received invasive mechanical ventilation (IMV). Factors associated with IMV included older age >65 years (OR,1.46; 95%CI, 1.13-1.89), current smoking status (OR, 1.71; 95%CI, 1.22-2.41), critical disease at admission (OR, 1.97; 95%CI, 1.28-3.03), and chronic kidney disease (OR, 2.07; 95%CI, 1.37-3.13). Laboratory abnormalities that were associated with increased risk for IMV included high leukocyte count (OR, 2.19; 95%CI, 1.68-2.87), low albumin (OR, 1.76; 95%CI, 1.33-2.34) and high AST (OR, 1.71; 95%CI, 1.31-2.22)., Conclusion: Our study suggests that there are several factors associated with the increased need for IMV among COVID-19 patients. These findings will help in early identification of patients at high risk for IMV and reallocation of hospital resources toward patients who need them the most to improve their outcomes.

Objectives: We aimed to perform a systematic review and meta-analysis of randomized controlled trials to summarize the overall association between the choice of fluid (lactated Ringer's [LR] or normal saline [NS]) and clinical outcomes in patients with acute pancreatitis., Methods: A systematic literature search was performed in electronic databases to identify eligible randomized controlled trials. Meta-analyses with the random-effects and IVhet models were used to estimate the pooled odds ratio (OR) for outcomes of interest with the administration of LR relative to NS, at 95% confidence intervals (CIs)., Results: There was a significant reduction in the odds of intensive care unit admission and development of local complications, respectively, with the administration of LR among hospitalized patients with acute pancreatitis relative to administration of NS (pooled ORs, 0.33 [95% CI, 0.13-0.81] and 0.43 [95% CI, 0.21-0.89], respectively)., Conclusions: Our findings are able to assist clinicians in the navigation of the proper choice of fluid in patients with acute pancreatitis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Universal Health Coverage (UHC), initiative from the World Health Organization (WHO), is a means to provide the human right to health by providing essential health services to everyone, enabling disease prevention, treatment, rehabilitation, and palliative care. In line with the WHO recommendations, the UHC was first introduced in Pakistan in Khyber Pakhtunkhwa (KP) province under the name 'Sehat Sahulat Programme' (SSP), literally 'Health Facility Program' in 2015. The provincial Government in Punjab approved a similar initiative in Punjab, the largest province (by population) of the country, and the program was later rolled out in Islamabad Capital Territory (ICT), Azad and Jammu Kashmir (AJK), Gilgit Baltistan (GB), Sindh, and Baluchistan provinces leaping into the nation-wide coverage. This article provides a current overview of the UHC initiative in Pakistan, analyses its progress in appraising key milestones, and makes recommendations to achieve a robust universal health coverage across Pakistan.

Objectives: To develop, validate and evaluate a computerized clinical decision support system (MedReview) that aids medication reviewers with pharmacological decision-making., Methods: This study included three phases; the development phase included computerizing a consolidated medication review algorithm (MedReview), followed by validation and evaluation of MedReview and responding to a web-based survey designed using patient scenarios. Participants had to be 'fully registered' with the Malaysian Pharmacy Board and work full-time at a community pharmacy., Results: MedReview was developed as a web app. It was validated among 100 community pharmacists from May-July 2021 using the Technology Acceptance Model (TAM). There was acceptable content validity and fair inter-rater agreement, and good convergent and discriminant validity. Exploratory factor analysis resulted in five domains to determine the attitude of pharmacists about using MedReview: perceived ease of use, perceived usefulness, intention to use, trust, and personal initiatives and characteristics; the total variance explained by five factors was 76.36%. The survey questionnaire had a high overall reliability value of 0.96. Evaluation of MedReview was based on mean scores of survey items. Of all items included in the survey, the highest mean score (out of 7) was achieved for 'I could use MedReview if it is meaningful/relevant to my daily tasks' (5.78 ± 1.10), followed by 'I could use MedReview if I feel confident that the data returned by MedReview is reliable' (5.77 ± 1.21), and 'I could use MedReview if it protects the privacy of its users' (5.73 ± 1.20)., Conclusion: Community pharmacists generally had a positive attitude towards MedReview. They found that MedReview is trustworthy and they had the intention to use it when conducting medication reviews. The adaptation of the TAM in the survey instrument was reliable and internally valid., Competing Interests: The authors have declared that no competing interests exist.

Background: Periodic surveillance of antibiotic consumption in the form of point prevalence studies is a quick and robust methodology to evaluate prescribing trends in hospitals. The current study was undertaken to document antibiotic consumption among neonates and children from hospitals in Pakistan., Methods: This large multicenter study using the World Health Organization standardized methodology and AWaRe (Access, Watch, and Reserve) classification examined antibiotic consumption for suspected bacterial infection among neonates and children admitted hospitals in Punjab, Pakistan., Results: A total of 708 beds of children wards of the 16 health facilities were examined. Almost all (97%) hospitalized children were prescribed antibiotics on the day of the assessment with 2.6 antibiotics per patient. The three most common indications were respiratory tract infections (31.58%), sepsis (26.52%), and prophylaxis for medical problems (10.30%). The three most frequently prescribed antibiotics were ceftriaxone (24.2%), amikacin (23.2%), and ampicillin (16.7%). Almost half of the antibiotics were prescribed from the 'Access' (49.5%) and 'Watch' (45.5%) categories under the AWaRe classification. However, no antimicrobial was prescribed from the 'Reserved' category., Conclusions: Our findings indicate that empirical antimicrobials use among hospitalized children is highly prevalent in Pakistan. The utilization of 'Watch' category of antimicrobials is frequent, stressing immediate action.

Background and Aim: Recent studies have highlighted the high worldwide prevalence of irritable bowel syndrome (IBS) and disparities in its management between ethnic groups. For instance, gut-directed hypnotherapy (GDH), one of the most effective evidence-based treatments for IBS, is not recommended in Asian countries partly due to lack of population-specific outcome data. In this context, we evaluated the outcomes of GDH in an Asian population., Methods: Consecutive British Asian patients with refractory IBS who received 12-sessions of GDH using the Manchester protocol were included. Patients were treated by a team including a therapist able to speak several Asian languages. All patients prospectively completed the following questionnaires before and after GDH: IBS symptom severity score (IBS-SSS), hospital anxiety and depression scale (HADS), non-colonic symptom score, and the quality-of-life (QOL) score. The primary outcome measure was response to GDH defined by ≥50-point reduction in IBS-SSS. Pre- and post-treatment data were compared statistically., Results: Forty-four Asian patients with IBS (age 49 ± 13 years; 29 [66%] female; baseline IBS-SSS: 332.8 ± 94.6) completed GDH. Overall, 37 of 44 (84%) achieved a ≥50-point reduction in IBS-SSS and 25 of 44 (57%) achieved ≥30% reduction in abdominal pain scores. Following GDH, there were also significant mean improvements in IBS-SSS (-132.1, P  < 0.0001), non-colonic symptom score ( P  < 0.0001), QOL score ( P  < 0.0001), HADS-anxiety ( P  < 0.0001), and HADS-depression ( P  < 0.0001), compared with baseline., Conclusion: Regardless of the ethnicity of the therapist, GDH was highly effective with similar response rates to outcomes in other IBS populations, supporting the development of GDH in Asian countries., (© 2022 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Objective: Gabapentinoids are the first-line drugs for neuropathic pain. These drugs are the substrate of organic cation transporter (OCTN1) for renal excretion and absorption across the intestinal epithelium. Gabapentinoids exhibit wide interindividual variability in daily dosage and therapeutic efficacy which makes titration regimens prolonged for optimal efficacy. The present study aimed to investigate the possible influence of the single nucleotide polymorphism (SNP) of OCTN1 on therapeutic efficacy and safety of gabapentinoids in neuropathic pain patients of the Pakistani population., Methods: Four hundred and twenty-six patients were enrolled in the study. All participants were genotyped for OCTN1 rs1050152 and rs3792876 by PCR-RFLP method and followed up for eight weeks. The therapeutic outcomes of gabapentinoids, reduction in pain score, inadequate or complete lack of response, adverse events (AEs) in responders and discontinuation of treatment on account of AEs were recorded for all patients., Results: There was no significant association of genotypes and alleles of both SNPs on the clinical response of gabapentinoids (P ˃ 0.05). Similarly, significant differences were not found in the reduction of pain scores and AEs among different genotypes in the responders. The present study has reported the association of OCTN1 rs1050152 and rs3792876 polymorphisms with clinical outcomes of gabapentinoids for the first time in the real-world clinical setting., Conclusion: Our results suggest a lack of influence of OCTN1 genetic variants in the determination of clinical response to gabapentinoids in patients with neuropathic pain in the Pakistani population. These findings signify the role of renal functions in predicting the interindividual variability to therapeutic responsiveness of gabapentinoids., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Since the onset of the pandemic, prescribing antimicrobials has become a common practice to treat patients infected with COVID-19., Areas Covered: A systematic literature search was performed in the electronic databases MEDLINE, CINAHL, WHO COVID-19 database, including EMBASE, Scopus, WHO-COVID, LILACS, and Google Scholar to identify original articles published up to 31 July 2021. A random-effects model was used to estimate the pooled prevalence or proportion of antimicrobial consumption among COVID-19 patients., Expert Opinion: We identified 43 original articles, 33 studies from high-income countries, six from upper-middle-income countries, and four from lower-middle-income countries. Most of the studies presented data from hospital or secondary health-care settings (n = 34). Included studies measured antimicrobial consumption as Daily Defined Doses (DDD) or day of therapy (DOT) or percentage. A total of 19 studies measured antimicrobial consumption as DDDs or DOT. Meta-analysis revealed an overall high antimicrobial consumption of 68% (95% CI: 60% to 75%). The subgroup analysis found a lower consumption in high-income countries (58%, 95% CI: 48% to 67%), compared with lower and middle-income countries (89%, 95% CI: 82% to 94%). High antimicrobial consumption found in COVID-19 patients demands implementation of appropriate antimicrobial stewardship interventions.

We aimed to perform meta-analyses to summarize the overall effectiveness of the mRNA-1273 vaccine against COVID-19 caused by the Delta variant from real-world studies. A systematic literature search with no language restriction was performed in electronic databases to identify eligible observational studies that reported the effectiveness of the mRNA-1273 vaccine to prevent reverse transcription-polymerase chain reaction (RT-PCR) confirmed COVID-19 caused by Delta variant of SARS-CoV-2 (B.1.617.2). A random-effects meta-analysis model was used to estimate the pooled odds ratio (OR) at a 95% confidence interval (CI), and the vaccine effectiveness was indicated as (pooled OR - 1)/OR. Five studies were included for this systematic review and meta-analysis. The meta-analysis revealed that the administration of mRNA-1273 vaccine protected against RT-PCR confirmed COVID-19 caused by Delta variant ≥21 days post first dose, with pooled vaccine effectiveness of 66% (95% CI: 65%-67%), as well as ≥14 days after the second dose, with pooled vaccine effectiveness of 91% (95% CI: 84%-95%). In conclusion, the mRNA-1273 vaccine offers a substantial protection rate against RT-PCR confirmed COVID-19 caused by the Delta variant upon full vaccination, although with slightly reduced effectiveness relative to other strains of SARS-CoV-2., (© 2022 Wiley Periodicals LLC.)

High-grade Acromioclavicular (AC) injuries are complete dislocations, involving ruptures of the AC and coracoclavicular ligaments. They occur following trauma after a fall, direct-blow to an adducted arm, or indirectly by falling onto an abducted, outstretched extremity. Given this traumatic etiology, additional intra-articular pathologies can arise and may go unnoticed because of the painful and prominent AC joint (ACJ). Previous studies have evaluated patients with high-grade ACJ injuries with diagnostic arthroscopy at the time of an ACJ reconstruction. They found associated injuries to the labrum/biceps, rotator cuff, and articular cartilage. The arthroscopic-assisted ACJ reconstruction (AA-ACJR) technique has made it possible to identify the associated injuries and treat them concurrently. The previous studies have performed this reconstruction in the beach chair position (BCP) and have addressed the concomitant pathology in the same position. As opposed to the BCP, the lateral decubitus position (LDP) allows for easier application of traction to the arm and, thus, improves visualization of the glenoid, especially the inferior and posteroinferior portions. It is imperative to gain appropriate access to the inferior glenoid for anchor placement to address this component of traumatic instability. We present the technique for addressing high-grade ACJ injuries with AA-ACJR in the BCP preceded by labral repair in the LDP.

Blood vessel formation is dependent on metabolic adaption in endothelial cells. Glucose and fatty acids are essential substrates for ATP and biomass production; however, the metabolism of other substrates remains poorly understood. Ketone bodies are important nutrients for cardiomyocytes during starvation or consumption of carbohydrate-restrictive diets. This raises the question whether cardiac endothelial cells would not only transport ketone bodies but also consume some of these to achieve their metabolic needs. Here, we report that cardiac endothelial cells are able to oxidize ketone bodies and that this enhances cell proliferation, migration, and vessel sprouting. Mechanistically, this requires succinyl-CoA:3-oxoacid-CoA transferase, a key enzyme of ketone body oxidation. Targeted metabolite profiling revealed that carbon from ketone bodies got incorporated into tricarboxylic acid cycle intermediates as well as other metabolites fueling biomass production. Elevation of ketone body levels by a high-fat, low-carbohydrate ketogenic diet transiently increased endothelial cell proliferation in mouse hearts. Notably, in a mouse model of heart hypertrophy, ketogenic diet prevented blood vessel rarefication. This suggests a potential beneficial role of dietary intervention in heart diseases., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Medication reviews are effective in improving the quality of medication use among older people. However, they are conducted to various standards resulting in a wide range of outcomes which limit generalisability of findings arising from research studies. There also appear to be funding and time constraints, lack of data storage for quality improvement purposes, and non-standardised reporting of outcomes, especially clinically relevant outcomes. Furthermore, the coronavirus disease-19 (COVID-19) pandemic has restricted many face-to-face activities, including medication reviews. This article introduces a technology-enabled approach to medication reviews that may overcome some limitations with current medication review processes, and also make it possible to conduct medication reviews during the COVID-19 pandemic by providing an alternate platform. The possible advantages of this technology-enabled approach, legislative considerations and possible implementation in practice are discussed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: There has been an increase in prescribing and costs of oral hypoglycaemic agents in England and other countries. This study aims to investigate the trends in prescriptions, costs, and adverse events of metformin and metformin-based single pill drug combinations from 2015 to 2020 and explore why changes in use or cost are occurring., Methods: Prescriptions and costs data from Prescription Cost Analysis database and Interactive Drug Analysis Profiles presenting all suspected ADRs reported for each drug were examined. Pharmacy level prices were also obtained. Linear regression analysis was used to investigate the trends in prescribing and costs., Results: Prescribing and costs of metformin-based single pill drug combinations (as a percent mean change per year) saw an increase of 8.78% (95% Cl: 7.45%, 10.11%, p = 0.001) and 5.17% (95% Cl: 2.13%, 8.22%, p = 0.009) on average each year, respectively. Metformin was the most prescribed monotherapy drug between 2015 and 2020. The cost of prescribing metformin (as a proportion of total oral hypoglycaemic agents) has been reduced from 30% in 2015 to 17% in 2020. Metformin-dipeptidyl peptidase-4 inhibitor (e.g., metformin-sitagliptin) combination was the most popular metformin-based single pill drug combination. The number of adverse drug reactions per million items dispensed shows that metformin has the lowest adverse drug reactions per million items compared to other oral hypoglycaemic drugs., Conclusions: Overall, an increase in prescription items can be seen for metformin-based single pill drug combinations along with an increase in their costs in primary care in England between 2015 and 2020. There was a declining trend for the number of ADRs reported per million prescription items dispensed for metformin-containing single pill combinations, even though their prescription rate increased., (Copyright © 2022 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Background: Several randomized trials have evaluated the effects of sofosbuvir-based direct-acting antivirals on the clinical outcomes in patients with COVID-19., Methods: A systematic literature search with no language restrictions was performed on electronic databases and preprint repositories to identify eligible randomized trials published up to 8 July 2021. A random-effects model was used to estimate the pooled odds ratio (OR) for outcomes of interest with the use of sofosbuvir combined with direct-acting antiviral agents relative to the nonuse of sofosbuvir-based direct-acting antiviral agents at 95% confidence intervals (CI)., Results: The meta-analysis of 11 trials (n = 2,161) revealed statistically significant reduction in the odds of mortality (pooled odds ratio = 0.59; 95% confidence interval 0.36 to 0.99) but no statistically significant difference in the odds of development of composite endpoint of severe illness (pooled odds ratio = 0.79; 95% confidence interval 0.43 to 1.44) with the administration of sofosbuvir-based direct-acting antiviral agents among patients with COVID-19, relative to non-administration of sofosbuvir-based direct-acting antiviral agents.Subgroup analysis with seven trials involving sofosbuvir-daclatasvir revealed no significant mortality benefit (pooled odds ratio = 0.77; 95% confidence interval 0.48 to 1.22)., Conclusion: Sofosbuvir-based direct-acting antiviral agents have no protective effects against the development of severe illness in patients with COVID-19 with the current dosing regimen. Whether sofosbuvir-based direct-acting antiviral agents could offer mortality benefits would require further investigations.

Background: Mental health is a public health issue for European young people, with great heterogeneity in resource allocation. Representative population-based studies are needed. The Global Burden of Disease (GBD) Study 2019 provides internationally comparable information on trends in the health status of populations and changes in the leading causes of disease burden over time., Methods: Prevalence, incidence, Years Lived with Disability (YLDs) and Years of Life Lost (YLLs) from mental disorders (MDs), substance use disorders (SUDs) and self-harm were estimated for young people aged 10-24 years in 31 European countries. Rates per 100,000 population, percentage changes in 1990-2019, 95% Uncertainty Intervals (UIs), and correlations with Sociodemographic Index (SDI), were estimated., Findings: In 2019, rates per 100,000 population were 16,983 (95% UI 12,823 - 21,630) for MDs, 3,891 (3,020 - 4,905) for SUDs, and 89·1 (63·8 - 123·1) for self-harm. In terms of disability, anxiety contributed to 647·3 (432-912·3) YLDs, while in terms of premature death, self-harm contributed to 319·6 (248·9-412·8) YLLs, per 100,000 population. Over the 30 years studied, YLDs increased in eating disorders (14·9%;9·4-20·1) and drug use disorders (16·9%;8·9-26·3), and decreased in idiopathic developmental intellectual disability (-29·1%;23·8-38·5). YLLs decreased in self-harm (-27·9%;38·3-18·7). Variations were found by sex, age-group and country. The burden of SUDs and self-harm was higher in countries with lower SDI, MDs were associated with SUDs., Interpretation: Mental health conditions represent an important burden among young people living in Europe. National policies should strengthen mental health, with a specific focus on young people., Funding: The Bill and Melinda Gates Foundation., Competing Interests: T W Bärnighausen reports Research grants from the European Union (Horizon 2020 and EIT Health), German Research Foundation (DFG), US National Institutes of Health, German Ministry of Education and Research, Alexander von Humboldt Foundation, Else-Kröner-Fresenius-Foundation, Wellcome Trust, Bill & Melinda Gates Foundation, KfW, UNAIDS, and WHO; consulting fees from KfW on the OSCAR initiative in Vietnam; participation on a Data Safety Monitoring Board or Advisory Board with NIH-funded study “Healthy Options” as Chair, Data Safety and Monitoring Board (DSMB) for the German National Committee on the “Future of Public Health Research and Education”, Chair of the scientific advisory board to the EDCTP Evaluation, Member of the UNAIDS Evaluation Expert Advisory Committee, National Institutes of Health Study Section Member on Population and Public Health Approaches to HIV/AIDS (PPAH), US National Academies of Sciences, Engineering, and Medicine's Committee for the “Evaluation of Human Resources for Health in the Republic of Rwanda under the President's Emergency Plan for AIDS Relief (PEPFAR)”, University of Pennsylvania Population Aging Research Center (PARC) External Advisory Board Member; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid as Co-chair of the Global Health Hub Germany, initiated by the German Ministry of Health); all outside the submitted work. J S Chandan reports grants or contracts from the National Institute of Health Research and has been awarded funds from the NIHR and the Youth Endowment Fund, outside the submitted work. J J Jozwiak reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing or educational events from Teva, Amgen, Synexus, Boehringer Ingelheim, ALAB Laboratories, and Zentiva, all as personal fees and outside the submitted work. S V Katikireddi reports support for the present manuscript form Medical Research Council and the Scottish Government Chief Scientist Office as funding to their institution. J H Kauppila reports grants or contracts from The Finnish Cancer Foundation, and Sigrid Juselius Foundation as payments made to their institution, outside the submitted work. M Kivimäki reports grants or contracts form Wellcome Trust, UK (221854/Z/20/Z), and the Medical Research Council, UK (MR/R024227/1, MR/S011676/1) as the PI of research funding for their university, outside the submitted work. G Logroscino reports honoraria for lectures from Amplifon, outside the submitted work. J A Louriero reports support for the present manuscript from Fundação para a Ciência e Técnologia (FCT) under the Scientific Employment Stimulus [CEECINST/00049/2018]. A-F A Mentis reports grants or contracts from ‘MilkSafe: A novel pipeline to enrich formula milk using omics technologies’, a research co-financed by the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH - CREATE - INNOVATE (project code: T2EDK-02222), as well as from ELIDEK (Hellenic Foundation for Research and Innovation, MIMS-860); stock or stock options in a family winery; all outside the submitted work. M J Postma reports stock or stock options from Health-Ecore and PAG, outside the submitted work. N Steel reports grants from Public Health England to their institution, outside the submitted work. R M Viner reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Canadian Academy of Child & Adolescent Psychiatry for lecture on mental health aspects of COVID-19 pandemic; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, as the President of Royal College of Paediatrics & Child Health, 2018-2021; all outside the submitted work., (© 2022 The Author(s).)

Objective: The virtual airway skills trainer (VAST) is a virtual reality simulator for training in cricothyroidotomy (CCT). The goal of the study is to test the effectiveness of training and transfer of skills of the VAST-CCT., Methods: Two groups, control (no training) and simulation (2 weeks of proficiency-based training), participated in this study. Subjects in the control condition did not receive any training on the task whereas those in the simulation received a proficiency-based training on the task during a period of 2 weeks. Two weeks post-training, both groups performed CCT on the TraumaMan to demonstrate the transfer of skills., Results: A total of (n=20) subjects participated in the study. The simulation group performed better than the control group at both the post-test (p<0.001) and retention test (p<0.001) on the simulator. The cumulative sum analysis showed that all subjects in the simulation group reached proficiency with acceptable failure rate within the 2 weeks of training. On the transfer test, the simulation group performed better on skin cut (p<0.001), intubation (p<0.001) and total score (p<0.001) than the control group., Conclusions: The VAST-CCT is effective in training and skills transfer for the CCT procedure., Level of Evidence: Not applicable. Simulator validation study., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: In Pakistan, a wide range of repurposed drugs are recommended to manage hospitalized patients with COVID-19. Therefore, the current study was conducted to evaluate the pattern of utilization of repurposed drugs and other potential therapeutic options among hospitalized patients with COVID-19 in Pakistan., Methods: This retrospective, multicenter, descriptive study enrolled consecutive hospitalized patients with COVID-19 who were admitted between March 1, 2021, and April 30, 2021, from three District Headquarter Hospitals in the Punjab province of Pakistan. We described patient and clinical characteristics and medications, stratified by COVID-19 severity during hospitalization: mild, moderate, and severe. In addition, an analytical study of drug utilization was conducted., Findings: A total of 444 hospitalized patients with COVID-19 were included. Remdesvir, corticosteroids, antibiotics, and antithrombotics were administered to 45.0%, 93.9%, 84.9%, and 60.1% of patients, respectively. Specifically, dexamethasone was the most commonly used corticosteroid among the included patients ( n  = 405; 91.2%), irrespective of their clinical severity. Only 60.1% of patients hospitalized with COVID-19 in our cohort received antithrombotic therapy, and the prevalence of use was especially low (27.8%) in patients with mild illness. Of 444 patientsscreened, 399 (89.9%) patients had been discharged, and 45 patients (10.1%) died., Implications: We provided an important glimpse into the utilization patterns of several medications of interest for the treatment of COVID-19 in Pakistan, which had not been entirely evidence-based, especially concerning systemic corticosteroids and antibiotics., 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., (© 2021 The Authors.)

Purpose: The advent of clinically adapted machine learning algorithms can solve numerous problems ranging from disease diagnosis and prognosis to therapy recommendations. This systematic review examines the performance of machine learning (ML) algorithms and evaluates the progress made to date towards their implementation in clinical practice., Methods: Systematic searching of databases (PubMed, MEDLINE, Scopus, Google Scholar, Cochrane Library and WHO Covid-19 database) to identify original articles published between January 2011 and October 2021. Studies reporting ML techniques in clinical practice involving humans and ML algorithms with a performance metric were considered., Results: Of 873 unique articles identified, 36 studies were eligible for inclusion. The XGBoost (extreme gradient boosting) algorithm showed the highest potential for clinical applications (n = 7 studies); this was followed jointly by random forest algorithm, logistic regression, and the support vector machine, respectively (n = 5 studies). Prediction of outcomes (n = 33), in particular Inflammatory diseases (n = 7) received the most attention followed by cancer and neuropsychiatric disorders (n = 5 for each) and Covid-19 (n = 4). Thirty-three out of the thirty-six included studies passed more than 50% of the selected quality assessment criteria in the TRIPOD checklist. In contrast, none of the studies could achieve an ideal overall bias rating of 'low' based on the PROBAST checklist. In contrast, only three studies showed evidence of the deployment of ML algorithm(s) in clinical practice., Conclusions: ML is potentially a reliable tool for clinical decision support. Although advocated widely in clinical practice, work is still in progress to validate clinically adapted ML algorithms. Improving quality standards, transparency, and interpretability of ML models will further lower the barriers to acceptability., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Numerous studies have shown that hypnotherapy (HT) is effective in irritable bowel syndrome (IBS) using traditional symptom severity end points. However, there is now interest in capturing the patient's perception of their illness and treatment because what patients expect from their treatment may differ from that of their healthcare provider., Objective: To record patient perceptions and expectations of hypnotherapy as well as their symptom response., Methods: 150 consecutive IBS patients (116 females, 34 males, aged 16-81 years) receiving hypnotherapy completed questionnaires recording IBS symptom severity, quality of life, noncolonic symptoms, anxiety and depression levels before and after treatment. Their expectations and perceptions of HT were also recorded, including a free text reflection., Results: 121 patients (81%) responded to treatment consistent with our previous experience. Symptom severity scores, noncolonic symptoms, quality of life, anxiety and depression significantly all improved after HT ( p  < 0.001). Expectancy of an improvement with hypnotherapy was greater in those who did not respond to treatment (63%) than those who did (57%, p  < 0.001). Scepticism and apprehension were common before treatment and replaced with enthusiasm afterwards. Free text responses after treatment were overwhelmingly positive. Patients also reported a variety of other benefits and even 20 of 29 symptom nonresponders (70%) still considered treatment worthwhile., Conclusion: Although initially perceived negatively, hypnotherapy improved symptoms and resulted in a wide range of additional benefits. Expectation did not necessarily influence outcome. Recording IBS symptoms alone does not fully capture the patient's experience of treatment and needs to be considered in future research., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s), 2022.)

Understanding the development mechanism of drought events, characterization of future drought metrics, and its impact on crop yield is crucial to ensure food security globally, and more importantly, in South Asia. Therefore, the present study assessed the changes in future projected drought metrics and evaluated the future risk of yield reduction under drought intensity. We characterized the magnitude, intensity, and duration of future drought by means of the SPEI drought index using CMIP6 (Coupled Model Inter-comparison Phase-6) climate models. The impact of future drought on crop yield was quantified from the ISI-MP (Inter-Sectoral Impact Model Inter-comparison Project) crop model by a proposed non-linear ensemble of Random Forest (RF) and Gradient Boosting Machine (GBM). Results suggested that high drought magnitude with a longer drought duration is projected in some regions of South Asia while high drought intensity comes with a shorter duration. It was also found that Afghanistan, Pakistan, and India will experience a longer drought duration in the future. Our proposed ensemble machine learning (EML) approach had high predictive skill with a minimum value of RMSE (0.358-0.390), MAE (0.222-0.299), and a maximum value of R 2 (0.705-0.918) compared to the stand-alone methods of RF and GBM for yield loss risk projection. The drought-driven impact on crop yield demonstrates a high risk of yield loss under extreme drought events, which will encounter 54.15%, 29.30%, and 50.66% loss in the future for rice, wheat, and maize crops, respectively. Furthermore, drought and yield loss risk dynamics suggested a one unit decrease in SPEI value would lead to a 14.2%, 7.5%, and 10.9% decrease in yield for rice, wheat, and maize crops, respectively. This study will provide a notable direction for policy agencies to build resistance to crop production against the drought impact in the regions that are critical to climate change., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

β-Coronaviruses such as SARS-CoV-2 hijack coatomer protein-I (COPI) for spike protein retrograde trafficking to the progeny assembly site in endoplasmic reticulum-Golgi intermediate compartment (ERGIC). However, limited residue-level details are available into how the spike interacts with COPI. Here we identify an extended COPI binding motif in the spike that encompasses the canonical K-x-H dibasic sequence. This motif demonstrates selectivity for αCOPI subunit. Guided by an in silico analysis of dibasic motifs in the human proteome, we employ mutagenesis and binding assays to show that the spike motif terminal residues are critical modulators of complex dissociation, which is essential for spike release in ERGIC. αCOPI residues critical for spike motif binding are elucidated by mutagenesis and crystallography and found to be conserved in the zoonotic reservoirs, bats, pangolins, camels, and in humans. Collectively, our investigation on the spike motif identifies key COPI binding determinants with implications for retrograde trafficking., (© 2022. The Author(s).)

Objective: We systematically reviewed the evidence of published original research to determine the role of remdesivir in the management of patients with COVID-19 and a moderate-to-severe course of illness., Methods: A systematic search of articles was conducted in scientific databases, with the latest update in May 2021. This paper systematically reviewed the clinical evidence available (randomized controlled trials, compassionate use studies, and case reports) on the use of remdesivir for patients with moderate or severe COVID-19., Results: A total of eleven studies were included: four studies based on compassionate use of remdesivir, three randomized, double-blind, placebo-controlled, multicentre trials, three randomized, open-label, phase III trials, and one case report. Clinical improvement and mortality rates in patients who used remdesivir varied across studies., Conclusion: Given the current evidence, there is insufficient data to confidently recommend the use of remdesivir alone for the treatment of adult hospitalized patients with moderate-to-severe COVID-19. However, remdesivir may be considered along with an anti-inflammatory agent in patients with pneumonia, on oxygen support, provided there is close monitoring of clinical and laboratory parameters and adverse events.

Background: Overactivation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome can lead to severe illness in patients with coronavirus disease-2019 (COVID-19). The NLRP3 inhibitor, colchicine, therefore, appears to be promising for the treatment of COVID-19., Aims: We aimed to perform a meta-analysis of randomized trials investigating the effect of colchicine in patients with COVID-19., Materials & Methods: We systematically searched electronic databases and clinical trial registries (up to October 17, 2021) for eligible studies. The outcomes of interest were all-cause mortality and duration of hospital stay. Meta-analysis with the random-effects model was used to estimate the pooled odds ratio (OR) of mortality and 95% confidence interval (CI). The pooled standardized mean difference of duration of hospital stay with 95% CI between colchicine users and non-colchicine users was estimated using Cohen's d index., Results: The meta-analyses revealed no significant difference in the odds of mortality (pooled OR = 0.76; 95% CI: 0.53-1.07), but a significant reduction in the duration of hospital stay with the use of colchicine (pooled standardized mean difference = -0.59; 95% CI: -1.06 to -0.13)., Discussion and Conclusion: The ability of colchicine to reduce the length of stay in hospitalized patients with COVID-19 is consistent with its potential to prevent clinical deterioration via inhibition of NLRP3 inflammasome. Nevertheless, such beneficial effects of colchicine did not translate into mortality benefits in patients with COVID-19., (© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Objective: We aimed to perform a meta-analysis to summarize the overall evidence from randomized controlled trials related to higher-intensity anticoagulation in hospitalized patients with COVID-19., Methods: A systematic literature search was performed in electronic databases to identify randomized controlled trials comparing the clinical outcomes between intermediate/ therapeutic anticoagulation and prophylactic anticoagulation. Meta-analyses with random-effects models were used to estimate the pooled odds ratio (OR) for outcomes of interest at a 95% confidence interval (CI)., Results: Eight randomized controlled trials were included, with a total of 5405 hospitalized patients with COVID-19. The meta-analysis revealed no statistically significant difference in the odds of mortality (pooled OR = 0.92; 95% CI 0.71-1.19) but a statistically significant reduction in the odds of development of thrombotic events (pooled OR = 0.55; 95% CI 0.42-0.72), and significantly increased odds of development of major bleeding (pooled OR = 1.81; 95% CI 1.20-2.72) with the use of intermediate/therapeutic anticoagulation, relative to prophylactic anticoagulation. Subgroup analysis in patients with a severe course of COVID-19 observed a statistically significant reduction in the odds of development of thrombotic events (pooled OR = 0.66; 95% CI 0.45-0.98) but no significant difference in the odds of development of major bleeding events (pooled OR = 1.37; 95% CI 0.74-2.56), with the use of intermediate/therapeutic anticoagulation, relative to prophylactic anticoagulation., Conclusion: There could be net clinical benefits with higher-intensity dosing of anticoagulation relative to prophylactic-dosing of anticoagulation among hospitalized patients with severe COVID-19., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: We investigated the prescription trends and adverse drug reactions (ADRs) of ADHD drugs in primary care, England between 2010 and 2019., Methods: The Prescription Cost Analysis database presenting the primary care prescriptions data and the Interactive Drug Analysis Profiles presenting all suspected ADRs reported for each drug were screened. The data were analyzed using linear regression analysis to examine the annual average change per year., Results: The prescription items dispensed for ADHD showed an average 11.07% (95% CI 10.54-11.60, p  = .001) increase per year and there was a mean 11.54% (95% CI 11.03-12.06, p  = .001) increase per year in the costs. The overall reporting of serious and fatal ADR was reduced by 1.79% per year for ADHD drugs. Guanfacine showed a 40% mean increase per year., Conclusion: The increasing use of ADHD drugs within primary care in England could be a result of multiple factors such as growing ADHD prevalence.

Aim: Several randomized trials have evaluated the effect of neutralizing monoclonal antibodies on the risk of hospital admission and risk of mortality in patients with COVID-19. We aimed to summarize the overall evidence in the form of a systematic review and meta-analysis., Methods: A systematic literature search with no language restriction was performed in electronic databases and preprint repositories to identify eligible studies published up to 29 June 2021. The outcomes of interest were hospital admission and all-cause mortality. A random-effects model was used to estimate the pooled odds ratio (OR) for outcomes of interest with the use of neutralizing monoclonal antibodies relative to nonuse of neutralizing monoclonal antibodies, at 95% confidence intervals (CI)., Results: Our systematic literature search identified nine randomized controlled trials. Three trials had an overall low risk of bias, while four trials had some concerns in the overall risk of bias. The meta-analysis revealed no statistically significant difference in the odds of mortality (pooled OR = 0.69; 95% CI 0.33-1.47), but a statistically significant reduction in the odds of hospital admission (pooled OR = 0.29; 95% CI 0.21-0.42), with the administration of a neutralizing monoclonal antibody among patients with COVID-19, relative to non-administration of a neutralizing monoclonal antibody, at the current sample size., Conclusion: The reduced risk of hospital admission with neutralizing monoclonal antibodies use suggests that the timing of neutralizing antibodies administration is key in preventing hospital admission and, ultimately, death. Future randomized trials should aim to determine if the clinical outcomes with neutralizing monoclonal antibodies differ based on serostatus.

Meta-analyses were utilized to determine the overall effectiveness of BNT162b2 mRNA vaccine (Pfizer vaccine) against COVID-19 caused by Delta variant from large real-world studies. A systematic literature search with no language restriction was performed in electronic databases to identify eligible observational studies that reported the effectiveness of the BNT162b2 mRNA vaccine to prevent reverse transcription-polymerase chain reaction (RT-PCR) confirmed COVID-19 caused by Delta variant of SARS-CoV-2 (B.1.617.2). Random-effects meta-analysis model was used to estimate the pooled odds ratio (OR) at a 95% confidence interval, and the vaccine effectiveness was indicated as (pooled OR - 1)/OR. Seven studies were included for this meta-analysis. The meta-analysis revealed that the administration of BNT162b2 mRNA vaccine protected against RT-PCR confirmed COVID-19 caused by Delta variant ≥ 21 days after the first dose, with vaccine effectiveness of 55% (95% confidence interval 46-63%), as well as ≥ 14 days after the second dose, with vaccine effectiveness of 81% (95% confidence interval 69-88%). In conclusion, the BNT162b2 mRNA vaccine offers a substantial protection rate against RT-PCR confirmed COVID-19 caused by the Delta variant upon full vaccination, albeit with slightly reduced effectiveness relative to other strains of SARS-CoV-2., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Abstract: Owing to the reported safety concerns, we aimed to perform a systematic review and meta-analysis to determine the effect of preadmission/prediagnosis use of calcium channel blockers (CCBs) on the clinical outcomes in patients with COVID-19. A systematic literature search with no language restriction was conducted in electronic databases in July 2021 to identify eligible studies. The outcomes of interest were all-cause mortality and severe illness. A random-effects model was used to estimate the pooled summary measure for outcomes of interest with the preadmission/prediagnosis use of CCBs relative to nonuse CCBs, at 95% confidence intervals (CIs). The meta-analyses revealed no significant difference in the odds of all-cause mortality [pooled odds ratio (OR) = 0.82; 95% CI 0.68-1.00; n = 58,355] and in the odds of severe illness (pooled OR = 0.83; 95% CI 0.61-1.15; n = 46,091) respectively, with preadmission/prediagnosis use of CCBs relative to nonuse of CCBs. Nevertheless, subgroup analysis of studies originated from East Asia reported a significant reduction in the odds of all-cause mortality (pooled OR = 0.50; 95% CI 0.37-0.68) and the odds of severe illness (pooled OR = 0.51; 95% CI 0.33-0.78). There may not be safety concerns with the use of CCBs in patients with COVID-19, but their potential protective effects in the East Asian patients merit further investigations., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

We aimed to perform a systematic review and meta-analysis to determine the overall effect of the preadmission/prediagnosis use of calcium channel blockers (CCBs) on the clinical outcomes in hypertensive patients with COVID-19. A systematic literature search with no language restriction was conducted in electronic databases in July 2021 to identify eligible studies. A random-effects model was used to estimate the pooled summary measure for outcomes of interest with the preadmission/prediagnosis use of CCBs relative to the nonuse of CCBs at 95% confidence intervals (CIs). The meta-analysis revealed a significant reduction in the odds of all-cause mortality with the preadmission/prediagnosis use of CCBs relative to the nonuse of CCBs (pooled OR = 0.65; 95% CI 0.49-0.86) and a significant reduction in the odds of severe illness with preadmission/prediagnosis use of CCBs relative to the nonuse of CCBs (pooled OR = 0.61; 95% CI 0.44-0.84), and is associated with adequate evidence to reject the model hypothesis of 'no significant difference' at the current sample size. The potential protective effects offered by CCBs in hypertensive patients with COVID-19 merit large-scale prospective investigations., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Competing Interests: Competing interests: None declared.

Background: Patients with coronavirus disease 2019 (COVID-19) could experience multiple coinfections, and judicial antimicrobials, including antibiotics, is paramount to treat these coinfections. This study evaluated physicians' perception, attitude, and confidence about antimicrobial resistance (AMR) and antimicrobial prescribing in patients with COVID-19. Methods: A self-administered and validated online questionnaire comprised of six sections was disseminated among physicians working in public sector hospitals in Punjab, Pakistan, using the convenience sampling method from April to May 2021. The study also assessed the validity and reliability of the study questionnaire using exploratory factor analysis and Cronbach's alpha. In addition, the descriptive and inferential statistics present survey results. Results: A total of 387 physicians participated in this study. The study showed that the questionnaire demonstrated good internal consistency (Cronbach's alpha = 0.77). Most physicians ( n = 221, 57.1%) believed that AMR is a considerable problem in Pakistan. Less than a quarter of respondents ( n = 91, 23.5%) consulted with local antibiotic resistance data to prescribe antibiotics in COVID-19 patients. However, the respondents were confident to select a suitable antibiotic ( n = 229, 59.2%). More than three-quarters of the respondents believed that advice from a senior colleague ( n = 336, 86.8%), infectious disease (ID) physician ( n = 315, 81.4%), and implementing antimicrobial stewardship programs (ASPs) could facilitate appropriate prescribing of antibiotics in COVID-19 patients. Multivariate logistic regression revealed that physicians with more than 10 years of experience had higher odds of consulting local guidelines for antibiotic therapy (OR, 4.71 95% CI: 1.62-13.73, p = 0.004) than physicians with less than 5 years of experience. Similar trends were found for consulting national guidelines and local resistance data to select an empiric antibiotic therapy. Conclusion: AMR-related awareness was optimal among physicians. Only a few physicians looked up local antibiotic resistance data before prescribing antibiotics to COVID-19 patients empirically. The significant approaches advised by physicians to reduce AMR risk among COVID-19 patients were the implementation of ASPs combined with advice from ID physicians., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hayat, Mustafa, Ikram, Ijaz-Ul-Haq, Noor, Rasool, Ishaq, Rehman, Hasan and Fang.)