Evaluation of Effectiveness of Doxycycline as Empirical Therapy for Treatment in Acute Undifferentiated Febrile Illnesses in Routine Clinical Practice: A Retrospective, EMR-based, Real-world Study

Background: Tetracyclines, in particular doxycycline, are recommended for the treatment of patients with acute undifferentiated febrile illness (AUFI); however, real-world studies are scarce. Methods: This retrospective, multicenter, observational study reviewed electronic medical records (April 2018 to March 2021) of adult patients (outpatient and inpatient departments [OPD and IPD]) with AUFI, treated with doxycycline monotherapy (doxycycline group) or doxycycline in combination with other antimicrobials (combination therapy group), from 7 tertiary hospitals and clinics in India. Results: Overall, 473 patients were included; 73.8% and 26.2% patients were prescribed doxycycline alone or in combination with other antimicrobials, respectively. Defervescence was achieved in 65.6% and 57.3% patients, respectively at the second (8-14 days) follow-up visit. Clinical cure rate for symptomatic resolution varied between 89.6% and 100% in OPD settings. Time taken from treatment initiation to defervescence was 3.51 ± 3.16 days for the doxycycline group and 3.46 ± 3.07 days for the combination therapy group. Both groups showed improvements in body temperature in OPD settings (84.2% and 84.5%) as well as IPD settings (97.4% and 94.1%). Adverse events in OPD patients in both groups were nausea (7.8% and 8.7%), anorexia (1.6% and 33.0%) and dyspepsia (1.6% and 67.9%). Conclusion: Doxycycline appears to be a promising candidate for treating patients with AUFI due to its demonstrated real-world effectiveness and safety profile

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Characteristics of available antiretroviral drugs - part 2

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Pediatric AIDS - part 1

Much progress has been made in the therapy of pediatric HIV infection, which has been transformed from a usually fatal disease into that of a chronic disease model. Early, aggressive therapy with the goal of complete suppression of viral replication (undetectable plasma virus) should be the therapeutic goal, but this new, more hopeful environment has been created at the cost of complexity and compromises in quality of life. The rapid pace of new developments and therapeutic complexities argue strongly for care in specialized centers or, at least, frequent consultation. Principles of therapy in the pediatric intensive care unit remain unchanged. Efforts are ongoing to develop simpler, more effective therapeutic regimens that suppress and ultimately eradicate infection and that stimulate immune reconstitution and reduces need for frequent hospitalization

Original Article - Effect of low tidal volumes vs conventional tidal volumes on outcomes of acute respiratory distress syndrome in critically ill children

Background: Adult data have shown low tidal volume strategy to be beneficial to the outcome of acute respiratory distress syndrome (ARDS).There are little data regarding the effect of different tidal volume strategies on outcomes in children with ARDS. Aims and Objectives: The aim of this study was to learn the differences in outcomes from ARDS in children using low vs conventional tidal volumes. Methods: All patients with ARDS (aged 1 month to 16 years) admitted to the pediatric intensive care unit from March 98 to June 2004 were studied. Prospective data for low expired tidal volumes (6-8ml/kg) were collected from Jan 2001 to June 2004 (group 1). ARDS patients during March 1998 to December 2000, receiving conventional tidal volumes (10-15 ml/kg) were used as retrospective control (group 2). Etiologies, PRISMIII scores, interventions, and outcomes data were recorded. Standard supportive therapy for ARDS was used in all children using conventional mechanical ventilation. Results: A total of 153 (4.67%) patients had ARDS as defined by standard criteria. Groups 1 and 2 had 78 and 65 patients, respectively, with comparable PRISMIII scores. Mortality was 23% (group 1) vs 36.9% (group 2) ( P < 0.005). The mean duration of ventilation and hospitalization in group 1 was significantly lower when compared with group 2 (11± 1 vs 18± 2 days; P < 0.005) and group 1 (19± 2 vs 26± 3 days; P < 0.005), respectively. Incidence of pneumothorax was 5% (group 1) as compared with 12% (group 2) ( P < 0.01). Long-term follow-up for incidence of chronic lung disease could not be studied. Common etiologies of ARDS included pneumonia, sepsis, dengue shock syndrome, falciparum malaria, and fulminant hepatic failure. Conclusions: Low tidal volume strategy was found to be associated with significantly lower duration of ventilation, hospitalization, incidence of pneumothorax, and mortality when compared with conventional tidal volume strategy in children with ARDS

Inheritance and identification of molecular markers associated with spot blotch (Cochliobolus sativus L.) resistance through microsatellites analysis in barley

Spot blotch resistant (IBON 18) and susceptible (RD 2508) lines were crossed to investigate inheritance of resistance and to identify simple sequence repeats (SSRs) associated with resistance. F1 resistance was intermediate and suggested additive nature of inheritance. Three additive genes was noted in the distribution of F3, F4 and F5 generations. In F6 and F6-7, the quantitative and qualitative approaches also suggested the control of three resistance genes. The parents and the RILs (F6/F6-7) were grown in four environments and spot blotch severity recorded. Forty five SSR primers, specific for chromosomes 1 (7H) and 5 (1H), were applied. Of these, 12 were polymorphic between the parents, and between the resistant and susceptible bulks. Three markers BMS 32, BMS 90 and HVCMA showed association with resistance, which was further confirmed through selective genotyping. The co-segregation data on the molecular markers (BMS 32, BMS 90 and HVCMA) and spot blotch severity on 173 RILs was analyzed by single marker linear regression approach. Significant regression suggested linkage among BMS 32, BMS 90 and HVCMA and the three resistant genes (designated as Rcs-qtl-5H-1, Rcs-qtl-5H-2 and Rcs-qtl-1H-1.) respectively. These markers explained 28%, 19% and 12% of variation respectively, for spot blotch resistance among the RILs

Pediatric Sepsis Guidelines: Summary for resource-limited countries

Justification: Pediatric sepsis is a commonly encountered global issue. Existing guidelines for sepsis seem to be applicable to the developed countries, and only few articles are published regarding application of these guidelines in the developing countries, especially in resource-limited countries such as India and Africa. Process: An expert representative panel drawn from all over India, under aegis of Intensive Care Chapter of Indian Academy of Pediatrics (IAP) met to discuss and draw guidelines for clinical practice and feasibility of delivery of care in the early hours in pediatric patient with sepsis, keeping in view unique patient population and limited availability of equipment and resources. Discussion included issues such as sepsis definitions, rapid cardiopulmonary assessment, feasibility of early aggressive fluid therapy, inotropic support, corticosteriod therapy, early endotracheal intubation and use of positive end expiratory pressure/mechanical ventilation, initial empirical antibiotic therapy, glycemic control, and role of immunoglobulin, blood, and blood products. Objective: To achieve a reasonable evidence-based consensus on the basis of published literature and expert opinion to formulating clinical practice guidelines applicable to resource-limited countries such as India. Recommendations: Pediatric sepsis guidelines are presented in text and flow chart format keeping resource limitations in mind for countries such as India and Africa. Levels of evidence are indicated wherever applicable. It is anticipated that once the guidelines are used and outcomes data evaluated, further modifications will be necessary. It is planned to periodically review and revise these guidelines every 3-5 years as new body of evidence accumulates