A retrospective review on antibiotic use in acute watery diarrhea in children in a tertiary care hospital of Karachi, Pakistan

Introduction: Responsible for at least one in nine pediatric deaths, diarrheal diseases are the leading, global cause of death. Further abetted by improper antibiotic use in a hospital setting, children with acute watery diarrhea can see prolonged hospital stays, and unwanted adverse effects such as antibiotic resistance. Hence, this study is aimed to identify the association between antibiotic usage for the treatment of acute watery diarrhea in children, and the impact this line of management has on the duration of their hospital stay.Methods: A retrospective review was conducted at the department of Pediatric of Aga Khan University Hospital (AKUH) in Karachi. A total of 305 records of children aged 6 months to 5 years who were admitted with a diagnosis of acute watery diarrhea from June 2017 -December 2018 was screened, of which 175 fulfilled the eligibility criteria. A predesigned questionnaire was used to collect demographic information, comorbidities, and clinical features, severity of dehydration, clinical examination, treatment received, and laboratory investigations. The primary outcome of this study was the length of hospital stay measured against the number of hours a child stayed in hospital for treatment of acute watery diarrhea. The statistical analysis was carried out using STATA version 14 to reach conclusive results.Results: 175 patients presented with acute watery diarrhea, out of which 106 (60.6%) did not receive antibiotics. The median (IQR) age of the group that did not receive antibiotics was 12.0 (12.0) months compared to 15.0 (12.0) months for the group that did receive antibiotics. In both groups, there were more males than females, less than 15% of the patients were severely malnourished (WHZ score -3SD) and less than 10% of the patients were severely dehydrated. The median (IQR) length of hospital stay (hours) was 32.0 (19.0) respectively for the group that did not receive antibiotic and 41.0 (32.0) for the group that did receive antibiotic therapy. The expected length of hospital stay for the group that received antibiotic therapy was 0.22 hours higher than the group that did not. Finally, as compared to females, hospital stay for males was longer by 0.25 hours.Conclusion: In conclusion, antibiotic use was associated with a prolonged hospital stay in children with acute watery diarrhea as compared to children who did not receive antibiotics. Large scale robust prospective studies are needed to establish this association using this observational data

The spectrum of primary immunodeficiencies at a tertiary care hospital in Pakistan

Background: Primary Immunodeficiency Disorders (PIDs) are well-known disorders in the West. but the recognition and diagnosis of these disorders is challenging in developing countries. We present the spectrum of PIDs seen at a tertiary care center in Pakistan, identified using clinical case definitions and molecular methods.Methods: A retrospective chart review of children suspected to have PID was conducted at the Aga Khan University Hospital (AKUH) Karachi, Pakistan from 2010 to 2016. Data on demographics, clinical features, family history of consanguinity, sibling death, details of laboratory workup done for PID and molecular tests targeted panel next generation sequencing (NGS) or whole exome sequencing (WES) performed at the Geha laboratory at Boston Children\u27s Hospital, USA was collected. The study was exempted from the Ethical Review Committee of AKUH.Results: A total of 43 children visited the hospital with suspected PID during the study period. Genetic testing was performed in 31/43 (72.1%) children. A confirmed diagnosis of PID was established in 20/43 (46.5%) children. A pathogenic gene variant was identified in 17(85%) of the 20 confirmed cases (Table 1). Twelve (60%) of the confirmed cases of PID were male. The most common presenting symptom was recurrent diarrhea 11/20 (55%). The mean (±S.D) age of the cases at the time of diagnosis was 4.2 (±4.1) years. Chronic granulomatous disease (CGD) was the most common 6/20 (30%) disorder, followed by severe combined immunodeficiency (SCID) 3/20 (15%), leukocyte adhesion deficiency (LAD) 3/20 (15%), agammaglobulinemia/hypogammaglobulinemia 3/20 (15%), and Hermansky-Pudlak Syndrome (HPS) 2/20 (10%). Wiskott-Aldrich Syndrome, Immunodeficiency Centromeric Instability and Facial Anomalies Syndrome (ICF 2), Trichohepatoenteric syndrome (TRES), and C3 deficiency were each diagnosed once {1/20 (4.3%) each} (Table 1). Of these 20 confirmed cases, almost all 19/20 (95%) had a family history of consanguinity. Sibling death was reported in 5/20 (25%) of these cases. Five out of the 20 (25%) children died over the 7-year period for various reasons.Conclusion: PIDs are not uncommon in Pakistan; their diagnosis may be missed or delayed due to the overlapping of clinical features of PID with other diseases and a lack of diagnostic facilities. There is a need to build capacity for early recognition and diagnosis of PIDs to decrease morbidity and mortality

Response of extensively drug resistant salmonella typhi to treatment with meropenem and azithromycin, in Pakistan

Introduction: Salmonella Typhi is one of the leading health problems in Pakistan. With the emergence of extensively drug resistant (XDR) Salmonella Typhi, treatment options are limited. Here we report the clinical manifestations and the response to treatment of patients with XDR Typhoid fever. The patients were treated with either Meropenem or Azithromycin or a combination of both.Methods: We reviewed the records of culture confirmed XDR typhoid who visited Aga Khan University Hospital (AKUH), Karachi and Aga Khan Secondary Care Hospital, Hyderabad from April 2017 to June 2018. Symptoms developed during disease, unplanned treatment extension and complications developed while on antimicrobials was recorded. Means with standard deviation were calculated for duration of treatment, time to defervescence, and cost of treatment.Results: Records of 81 culture confirmed XDR typhoid patients admitted at the AKU hospitals were reviewed. Most, (n = 45; 56%) were male. Mean age of the cases was 8.03 years with range (1-40). About three quarter (n = 66) of the patients were treated as inpatient. Fever and vomiting were the most common symptoms at the time of presentation. Oral azithromycin alone (n = 22; 27%), intravenous meropenem alone (n = 20; 25%), or a combination of azithromycin and meropenem (n = 39; 48%) were the options used for treatment. Average (95% confidence interval) time to defervescence was 7.1(5.5-8.6), 6.7(4.7-8.7), and 6.7(5.5-7.9) days for each treatment option respectively whereas there were 1,0 and 3 treatment failures in each treatment option respectively. Average cost of treatment per day for azithromycin was US$5.87 whereas it was US$88.46 for meropenem.Conclusion: Patients treated with either Azithromycin, Meropenem alone or in combination showed similar time to defervescence. Because of the lower cost of azithromycin, it is preferable in lower socio-economic areas. Background estimates for power calculation can be made for more robust clinical trials using this observational data

Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Abstract: Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate

Global prevalence and genotype distribution of hepatitis C virus infection in 2015 : A modelling study

Publisher Copyright: © 2017 Elsevier LtdBackground The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of—and expansion on—the 2014 analysis, which reported 80 million (95% CI 64–103) viraemic infections in 2013. Methods We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Findings Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1·0% (95% uncertainty interval 0·8–1·1) in 2015, corresponding to 71·1 million (62·5–79·4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). Interpretation The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections. Funding John C Martin Foundation.publishersversionPeer reviewe

Subnational mapping of HIV incidence and mortality among individuals aged 15–49 years in sub-Saharan Africa, 2000–18 : a modelling study

Background: High-resolution estimates of HIV burden across space and time provide an important tool for tracking and monitoring the progress of prevention and control efforts and assist with improving the precision and efficiency of targeting efforts. We aimed to assess HIV incidence and HIV mortality for all second-level administrative units across sub-Saharan Africa. Methods: In this modelling study, we developed a framework that used the geographically specific HIV prevalence data collected in seroprevalence surveys and antenatal care clinics to train a model that estimates HIV incidence and mortality among individuals aged 15–49 years. We used a model-based geostatistical framework to estimate HIV prevalence at the second administrative level in 44 countries in sub-Saharan Africa for 2000–18 and sought data on the number of individuals on antiretroviral therapy (ART) by second-level administrative unit. We then modified the Estimation and Projection Package (EPP) to use these HIV prevalence and treatment estimates to estimate HIV incidence and mortality by second-level administrative unit. Findings: The estimates suggest substantial variation in HIV incidence and mortality rates both between and within countries in sub-Saharan Africa, with 15 countries having a ten-times or greater difference in estimated HIV incidence between the second-level administrative units with the lowest and highest estimated incidence levels. Across all 44 countries in 2018, HIV incidence ranged from 2 ·8 (95% uncertainty interval 2·1–3·8) in Mauritania to 1585·9 (1369·4–1824·8) cases per 100 000 people in Lesotho and HIV mortality ranged from 0·8 (0·7–0·9) in Mauritania to 676· 5 (513· 6–888·0) deaths per 100 000 people in Lesotho. Variation in both incidence and mortality was substantially greater at the subnational level than at the national level and the highest estimated rates were accordingly higher. Among second-level administrative units, Guijá District, Gaza Province, Mozambique, had the highest estimated HIV incidence (4661·7 [2544·8–8120·3]) cases per 100000 people in 2018 and Inhassunge District, Zambezia Province, Mozambique, had the highest estimated HIV mortality rate (1163·0 [679·0–1866·8]) deaths per 100 000 people. Further, the rate of reduction in HIV incidence and mortality from 2000 to 2018, as well as the ratio of new infections to the number of people living with HIV was highly variable. Although most second-level administrative units had declines in the number of new cases (3316 [81· 1%] of 4087 units) and number of deaths (3325 [81·4%]), nearly all appeared well short of the targeted 75% reduction in new cases and deaths between 2010 and 2020. Interpretation: Our estimates suggest that most second-level administrative units in sub-Saharan Africa are falling short of the targeted 75% reduction in new cases and deaths by 2020, which is further compounded by substantial within-country variability. These estimates will help decision makers and programme implementers expand access to ART and better target health resources to higher burden subnational areas

Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990-2019 : a systematic analysis from the Global Burden of Disease Study 2019

Background Ending the global tobacco epidemic is a defining challenge in global health. Timely and comprehensive estimates of the prevalence of smoking tobacco use and attributable disease burden are needed to guide tobacco control efforts nationally and globally. Methods We estimated the prevalence of smoking tobacco use and attributable disease burden for 204 countries and territories, by age and sex, from 1990 to 2019 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. We modelled multiple smoking-related indicators from 3625 nationally representative surveys. We completed systematic reviews and did Bayesian meta-regressions for 36 causally linked health outcomes to estimate non-linear dose-response risk curves for current and former smokers. We used a direct estimation approach to estimate attributable burden, providing more comprehensive estimates of the health effects of smoking than previously available. Findings Globally in 2019, 1.14 billion (95% uncertainty interval 1.13-1.16) individuals were current smokers, who consumed 7.41 trillion (7.11-7.74) cigarette-equivalents of tobacco in 2019. Although prevalence of smoking had decreased significantly since 1990 among both males (27.5% [26. 5-28.5] reduction) and females (37.7% [35.4-39.9] reduction) aged 15 years and older, population growth has led to a significant increase in the total number of smokers from 0.99 billion (0.98-1.00) in 1990. Globally in 2019, smoking tobacco use accounted for 7.69 million (7.16-8.20) deaths and 200 million (185-214) disability-adjusted life-years, and was the leading risk factor for death among males (20.2% [19.3-21.1] of male deaths). 6.68 million [86.9%] of 7.69 million deaths attributable to smoking tobacco use were among current smokers. Interpretation In the absence of intervention, the annual toll of 7.69 million deaths and 200 million disability-adjusted life-years attributable to smoking will increase over the coming decades. Substantial progress in reducing the prevalence of smoking tobacco use has been observed in countries from all regions and at all stages of development, but a large implementation gap remains for tobacco control. Countries have a dear and urgent opportunity to pass strong, evidence-based policies to accelerate reductions in the prevalence of smoking and reap massive health benefits for their citizens. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Measuring routine childhood vaccination coverage in 204 countries and territories, 1980-2019 : a systematic analysis for the Global Burden of Disease Study 2020, Release 1

Background Measuring routine childhood vaccination is crucial to inform global vaccine policies and programme implementation, and to track progress towards targets set by the Global Vaccine Action Plan (GVAP) and Immunization Agenda 2030. Robust estimates of routine vaccine coverage are needed to identify past successes and persistent vulnerabilities. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020, Release 1, we did a systematic analysis of global, regional, and national vaccine coverage trends using a statistical framework, by vaccine and over time. Methods For this analysis we collated 55 326 country-specific, cohort-specific, year-specific, vaccine-specific, and dosespecific observations of routine childhood vaccination coverage between 1980 and 2019. Using spatiotemporal Gaussian process regression, we produced location-specific and year-specific estimates of 11 routine childhood vaccine coverage indicators for 204 countries and territories from 1980 to 2019, adjusting for biases in countryreported data and reflecting reported stockouts and supply disruptions. We analysed global and regional trends in coverage and numbers of zero-dose children (defined as those who never received a diphtheria-tetanus-pertussis [DTP] vaccine dose), progress towards GVAP targets, and the relationship between vaccine coverage and sociodemographic development. Findings By 2019, global coverage of third-dose DTP (DTP3; 81.6% [95% uncertainty interval 80.4-82 .7]) more than doubled from levels estimated in 1980 (39.9% [37.5-42.1]), as did global coverage of the first-dose measles-containing vaccine (MCV1; from 38.5% [35.4-41.3] in 1980 to 83.6% [82.3-84.8] in 2019). Third- dose polio vaccine (Pol3) coverage also increased, from 42.6% (41.4-44.1) in 1980 to 79.8% (78.4-81.1) in 2019, and global coverage of newer vaccines increased rapidly between 2000 and 2019. The global number of zero-dose children fell by nearly 75% between 1980 and 2019, from 56.8 million (52.6-60. 9) to 14.5 million (13.4-15.9). However, over the past decade, global vaccine coverage broadly plateaued; 94 countries and territories recorded decreasing DTP3 coverage since 2010. Only 11 countries and territories were estimated to have reached the national GVAP target of at least 90% coverage for all assessed vaccines in 2019. Interpretation After achieving large gains in childhood vaccine coverage worldwide, in much of the world this progress was stalled or reversed from 2010 to 2019. These findings underscore the importance of revisiting routine immunisation strategies and programmatic approaches, recentring service delivery around equity and underserved populations. Strengthening vaccine data and monitoring systems is crucial to these pursuits, now and through to 2030, to ensure that all children have access to, and can benefit from, lifesaving vaccines. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe