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INTRODUCTION: Suboptimal care is frequent in the management of severe bacterial infection. We aimed to evaluate the consequences of suboptimal care in the early management of severe bacterial infection in children and study the determinants. METHODS: A previously reported population-based confidential enquiry included all children (3 months- 16 years) who died of severe bacterial infection in a French area during a 7-year period. Here, we compared the optimality of the management of these cases to that of pediatric patients who survived a severe bacterial infection during the same period for 6 types of care: seeking medical care by parents, evaluation of sepsis signs and detection of severe disease by a physician, timing and dosage of antibiotic therapy, and timing and dosage of saline bolus. Two independent experts blinded to outcome and final diagnosis evaluated the optimality of these care types. The effect of suboptimal care on survival was analyzed by a logistic regression adjusted on confounding factors identified by a causal diagram. Determinants of suboptimal care were analyzed by multivariate multilevel logistic regression. RESULTS: Suboptimal care was significantly more frequent during early management of the 21 children who died as compared with the 93 survivors: 24% vs 13% (p = 0.003). The most frequent suboptimal care types were delay to seek medical care (20%), under-evaluation of severity by the physician (20%) and delayed antibiotic therapy (24%). Young age (under 1 year) was independently associated with higher risk of suboptimal care, whereas being under the care of a paediatric emergency specialist or a mobile medical unit as compared with a general practitioner was associated with reduced risk. CONCLUSIONS: Suboptimal care in the early management of severe bacterial infection had a global independent negative effect on survival. Suboptimal care may be avoided by better training of primary care physicians in the specifics of pediatric medicine.

Introduction: Maternal and newborn infections are important causes of mortality but morbidity data from low- and middle-income countries is limited. We used telephone surveillance to estimate infection incidence and risk factors in women and newborns following hospital childbirth in Dar es Salaam. Methods: We recruited postnatal women from two tertiary hospitals and conducted telephone interviews 7 and 28 days after delivery. Maternal infection (endometritis, caesarean or perineal wound, or urinary tract infection) and newborn infection (umbilical cord or possible severe bacterial infection) were identified using hospital case-notes at the time of birth and self-reported symptoms. Adjusted Cox regression models were used to assess the association between potential risk-factors and infection. Results: We recruited 879 women and interviewed 791 (90%). From day 0–7, 6.7% (49/791) women and 6.2% (51/762) newborns developed infection. Using full follow-up data, the infection rate was higher in women with caesarean childbirth versus women with a vaginal delivery (aHR 1.93, 95%CI 1.11–3.36). Only 24% of women received pre-operative antibiotic prophylaxis before caesarean section. Infection was higher in newborns resuscitated at birth versus newborns who were not resuscitated (aHR 4.45, 95%CI 2.10–9.44). At interview, 66% (37/56) of women and 88% (72/82) of newborns with possible infection had sought health-facility care. Conclusions: Telephone surveillance identified a substantial risk of postnatal infection, including cases likely to have been missed by hospital-based data-collection alone. Risk of maternal endometritis and newborn possible severe bacterial infection were consistent with other studies. Caesarean section was the most important risk-factor for maternal infection. Improved implementation of pre-operative antibiotic prophylaxis is urgently required to mitigate this risk. [ABSTRACT FROM AUTHOR]

Inflammation-induced cholestasis is a common problem in septic patients and results from cytokine-mediated inhibition of bile acid export including impaired expression of the bile salt export pump (BSEP) with a consecutive increase in intracellular bile acids mediating cell damage. The present study focuses on the mechanisms by which interleukin 1 β (IL-1β), as a critical mediator of sepsis-induced cholestasis, controls the expression of BSEP in hepatocytes. Notably, the treatment of hepatocytes with IL-1β leads to the upregulation of a broad chemokine pattern. Thereby, the IL-1β -induced expression of in particular the CXCR2 ligands CXCL1 and 2 is further enhanced by bile acids, whereas the FXR-mediated upregulation of BSEP induced by bile acids is inhibited by IL-1β. In this context, it is interesting to note that inhibitor studies indicate that IL-1β mediates its inhibitory effects on bile acid-induced expression of BSEP indirectly via CXCR2 ligands. Consistently, inhibition of CXCR2 with the inhibitor SB225002 significantly attenuated of the inhibitory effect of IL-1β on BSEP expression. These data suggest that part of the cholestasis-inducing effect of IL-1β is mediated via a CXCR2-dependent feedback mechanism. [ABSTRACT FROM AUTHOR]

Severe bacterial infections (SBIs) are a leading cause of neonatal deaths in low- and middle-income countries. World Health Organization's (WHO's) guideline for outpatient management of danger signs indicating possible serious bacterial infections (PSBI) when referral is not possible was adopted by three pilot district councils in Mbeya Region, in Tanzania (Busekelo, Kyela and Mbarali Districts) in 2018 (the PSBI project). This study documented changes in practice during the PSBI project, and lessons learned. A cross-sectional study was conducted using both qualitative and quantitative data collection methods between July 2021 and January 2022, post-implementation. The study participants comprised stakeholders, health workers, community health workers, and mothers/fathers/caregivers who had a young infant with PSBI. Study tools included record review, quantitative, in-depth, and key informant interviews. Quantitative data were analysed using STATA version 15 (STATACorp Inc., TX, USA), whereas qualitative data were analysed using a framework analysis approach. Our assessment showed that 2,228 young infants (0–59 days old) from the three districts were classified as having PSBI. The majority, 1,607 (72.1%) had fast breathing as the only danger sign, while 621 (27.9%) were classified as having severe illness. All 621 young infants with severe illness were counselled and offered referral to a higher-level health facility; however, only 174 of them (28%) accepted the referral. The remaining 447 severely ill infants, for whom referral was not possible, were treated at the primary health facilities with gentamicin injection and amoxicillin dispersible tablets (DT). When referral is not feasible, outpatient treatment for young infants with signs of PSBI is possible within existing health system in Tanzania, based on experience after this pilot project. However, successful scale-up of outpatient management for PSBI will require commitments from government and key stakeholders to strengthen healthcare systems. [ABSTRACT FROM AUTHOR]

Purpose: To identify characteristics of SARS-CoV-2 infection that are associated with hospitalization in children initially evaluated in a Pediatric Emergency Department (ED). Methods: We identified cases of SARS-CoV-2 positive patients seen in the Arkansas Children's Hospital (ACH) ED or hospitalized between May 27, 2020, and April 28, 2022, using ICD-10 codes within the Pediatric Hospital Information System (PHIS) Database. We compared infection waves for differences in patient characteristics and used logistic regressions to examine which features led to a higher chance of hospitalization. Findings: We included 681 pre-Delta cases, 673 Delta cases, and 970 Omicron cases. Almost 17% of patients were admitted to the hospital. Compared to Omicron-infected children, pre-Delta and Delta-infected children were twice as likely hospitalized (OR = 2.2 and 2.0, respectively; p<0.0001). Infants under one year were >3 times as likely to be hospitalized than children ages 5–14 years regardless of wave (OR = 3.42; 95%CI = 2.36–4.94). Rural children were almost three times as likely than urban children to be hospitalized across all waves (OR = 2.73; 95%CI = 1.97–3.78). Finally, those with a complex condition had nearly a 15-fold increase in odds of admission (OR = 14.6; 95%CI = 10.6–20.0). Conclusions: Children diagnosed during the pre-Delta or Delta waves were more likely to be hospitalized than those diagnosed during the Omicron wave. Younger and rural patients were more likely to be hospitalized regardless of the wave. We suspect lower vaccination rates and larger distances from medical care influenced higher hospitalization rates. [ABSTRACT FROM AUTHOR]

Objective: Underdosing of antibiotics is common in patients with sickle cell disease (SCD). We hypothesized that in critically-ill patients with SCD receiving cefotaxime during acute chest syndrome, the continuous infusion may outperform the intermittent administration in achieving pharmacokinetic/pharmacodynamic targets. Design: Prospective before-after study. Settings: Intensive-care unit of a French teaching hospital and sickle cell disease referral center. Patients: Sixty consecutive episodes of severe acute chest syndrome in 58 adult patients with sickle cell disease. Interventions: Patients were treated with intermittent administration during the first period (April 2016 –April 2018) and with continuous infusion during the second period (May 2018 –August 2019). Measurements and main results: We included 60 episodes of acute chest syndrome in 58 patients (29 [25–34] years, 37/58 (64%) males). Daily dose of cefotaxime was similar between groups (59 [48–88] vs. 61 [57–64] mg/kg/day, p = 0.84). Most patients (>75%) presented a glomerular hyperfiltration with no difference between groups (p = 0.25). More patients had a cefotaxime trough level ≥2 mg/L with continuous infusion than intermittent administration: 28 (93%) vs. 5 (16%), p<0.001. The median residual concentration was higher in the continuous infusion than intermittent administration group: 10.5 [7.4–13.3] vs. 0 [0–0] mg/L, p<0.001. No infection relapse was observed in the entire cohort. Hospital length of stay was similar between groups. Conclusion: As compared to intermittent administration, continuous infusion of cefotaxime maximizes the pharmacokinetic/pharmacodynamic parameters in patients with SCD. The clinical outcome did not differ between the two administration methods; however, the study was underpowered to detect such a difference. [ABSTRACT FROM AUTHOR]

Background: In Ethiopia, neonatal mortality is persistently high. The country has been implementing community-based treatment of possible serious bacterial infection (PSBI) in young infants when referral to a hospital is not feasible since 2012. However, access to and quality of PSBI services remained low and were worsened by COVID-19. From November 2020 to June 2022, we conducted implementation research to mitigate the impact of COVID-19 and improve PSBI management implementation uptake and delivery in two woredas in Ethiopia. Methods: In April-May 2021, guided by implementation research frameworks, we conducted formative research to understand the PSBI management implementation challenges, including those due to the COVID-19 pandemic. Through a participatory process engaging stakeholders, we designed adaptive implementation strategies to bridge identified gaps using mechanism mapping to achieve implementation outcomes. Strategies included training and coaching, supportive supervision and mentorship, technical support units, improved supply of essential commodities, and community awareness creation about PSBI and COVID-19. We conducted cross-sectional household surveys in the two woredas before (April 2021) and after the implementation of strategies (June 2022) to measure changes in targeted outcomes. Results: We interviewed 4,262 and 4,082 women who gave live birth 2–14 months before data collection and identified 374 and 264 PSBI cases in April 2021 and June 2022, respectively. The prevalence of PSBI significantly decreased (p-value = 0.018) from 8.7% in April 2021 to 6.4% while the mothers' care-seeking behavior from medical care for their sick newborns increased significantly from 56% to 91% (p-value <0.01). Effective coverage of severely ill young infants that took appropriate antibiotics significantly improved from 33% [95% CI: 25.5–40.7] to 62% [95% CI: 51.0–71.6]. Despite improvements in the uptake of PSBI treatment, persisting challenges at the facility and systems levels impeded optimal PSBI service delivery and uptake, including perceived low quality of service, lack of community trust, and shortage of supplies. Conclusion: The participatory design and implementation of adaptive COVID-19 strategies effectively improved the uptake and delivery of PSBI treatment. Support systems were critical for frontline health workers to deliver PSBI services and create a resilient community health system to provide quality PSBI care during the pandemic. Additional strategies are needed to address persistent gaps, including improvement in client-provider interactions, supply of essential drugs, and increased social mobilization strategies targeting families and communities to further increase uptake. [ABSTRACT FROM AUTHOR]

Objective: To document trends in invasive pneumococcal disease (IPD) in a central hospital in Malawi during the period of national scale-up of antiretroviral therapy (ART) and cotrimoxazole prophylaxis. Methods: Between 1 January 2000 and 31 December 2009 almost 100,000 blood cultures and 40,000 cerebrospinal fluid (CSF) cultures were obtained from adults and children admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi with suspected severe bacterial infection. Results: 4,445 pneumococcal isolates were obtained over the 10 year period. 1,837 were from children: 885 (19.9%) from blood and 952 (21.4%) from CSF. 2,608 were from adults: 1,813 (40.8%) from blood and 795 (17.9%) from CSF. At the start of the surveillance period cotrimoxazole resistance was 73.8% and at the end was 92.6%. Multidrug resistance (MDR) was present in almost one third of isolates and was constant over time. Free ART was introduced in Malawi in 2004. From 2005 onwards there was a decline in invasive pneumococcal infections with a negative correlation between ART scale-up and the decline in IPD (Pearson's correlation r =20.91; p,0.001). Conclusion: During 2004-2009, national ART scale-up in Malawi was associated with a downward trend in IPD at QECH. The introduction of cotrimoxazole prophylaxis in HIV-infected groups has not coincided with a further increase in pneumococcal cotrimoxazole or multidrug resistance. These data highlight the importance of surveillance for high disease burden infections such as IPD in the region, which will be vital for monitoring pneumococcal conjugate vaccine introduction into national immunisation programmes. [ABSTRACT FROM AUTHOR]

Background: Intensive care units are units where healthcare-associated infections (HAIs) are common and antimicrobial resistance rates are increasing. Microbial contamination in hospital environment plays an important role in the development of HAIs. Intervention-based improvements in infection prevention and control at national and facility level are critical for the containment of antimicrobial resistance and prevention of HAIs. Objectives: This study aimed to determine the distribution of multidrug-resistant and carbapenemase-producing critical gram negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and Acinetobacter species) and their antibiotic resistance in intensive care unit environmental surfaces at the University of Gondar and Felege Hiwot Comprehensive Specialized Hospitals. Methods: This was multicenter hospital-based cross sectional study. Environmental samples were swabbed from all intensive care units using a normal saline moistened-sterile cotton tip stick. Bacteria culturing and antibiotic susceptibility testing were performed following standard microbiological techniques. Selected meropenem-resistant isolates were phenotypically assessed for carbapenemase production using modified and simplified carbapenem inactivation methods. Results: From a total of 384 environmental samples analyzed, 126 (32.8%) showed growth and 162 isolates were identified. K. pneumoniae (79/162, 48.8%) was the commonest isolate followed by Acinetobacter species (51/162, 31.5%), E. coli (19/162, 11.7%) and P. aeruginosa (13/162, 8.0%). Multidrug-resistant and carbapenemase-producing isolates were detected on most hospital environment surface types, especially from the baby bed sets and incubators. The most common multidrug-resistant and principal carbapenemase producer was K. pneumoniae, with rates of 71(89.9%) and 24(85.7%), respectively. Conclusion: This study revealed the distribution of multidrug-resistant and carbapenemase-producing critical gram negative bacteria in the environment of intensive care unit. Higher detection rate of multidrug-resistant and carbapenemase-producing K. pneumoniae on most environmental surfaces calls for urgent control action and further attention. [ABSTRACT FROM AUTHOR]

Background: Improved tools are required to detect bacterial infection in children with fever without source (FWS), especially when younger than 3 years old. The aim of the present study was to investigate the diagnostic accuracy of a host signature combining for the first time two viral-induced biomarkers, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon γ-induced protein-10 (IP-10), with a bacterial-induced one, C-reactive protein (CRP), to reliably predict bacterial infection in children with fever without source (FWS) and to compare its performance to routine individual biomarkers (CRP, procalcitonin (PCT), white blood cell and absolute neutrophil counts, TRAIL, and IP-10) and to the Labscore. Methods: This was a prospective diagnostic accuracy study conducted in a single tertiary center in children aged less than 3 years old presenting with FWS. Reference standard etiology (bacterial or viral) was assigned by a panel of three independent experts. Diagnostic accuracy (AUC, sensitivity, specificity) of host individual biomarkers and combinatorial scores was evaluated in comparison to reference standard outcomes (expert panel adjudication and microbiological diagnosis). Results: 241 patients were included. 68 of them (28%) were diagnosed with a bacterial infection and 5 (2%) with invasive bacterial infection (IBI). Labscore, ImmunoXpert, and CRP attained the highest AUC values for the detection of bacterial infection, respectively 0.854 (0.804–0.905), 0.827 (0.764–0.890), and 0.807 (0.744–0.869). Labscore and ImmunoXpert outperformed the other single biomarkers with higher sensitivity and/or specificity and showed comparable performance to one another although slightly reduced sensitivity in children < 90 days of age. Conclusion: Labscore and ImmunoXpert demonstrate high diagnostic accuracy for safely discriminating bacterial infection in children with FWS aged under and over 90 days, supporting their adoption in the assessment of febrile patients. [ABSTRACT FROM AUTHOR]

The current study describes the biogenic synthesis of two metal oxides zinc oxide (ZnO), aluminum oxide (Al2O3) nanoparticles using Camellia sinensis, and Origanum vulgare L. leaves extract, respectively. The synthesized metal oxide nanoparticles were investigated using spectroscopic and microscopic techniques to confirm the formation of their nanostructures. Accurate and precise spectrofluorometric probes were proposed for the quantification of Ofloxacin (OFX) and Ciprofloxacin (CPFX) in their bulk and commercial formulations. The extraordinary properties of Zinc oxide and aluminum oxide nanoparticles (ZnONPs and Al2O3NPs) enhance the fluorescence intensity in the presence of 0.5 mL and 1.0 mL of sodium dodecyl sulfate (SDS, 1.0% w/v) as organizing agent for the detection of OFX and CPFX, respectively. The optical detection of both drugs at λex/em range 250–700 nm displayed linearity with a main correlation coefficient >0.999 at 1–300 (OFX-SDS-ZnONPs) and 0.5–100 (OFX-SDS-Al2O3NPs) ng mL-1,10–400 (CPFX-SDS-ZnONPs) and 0.1–50 (CPFX-SDS-Al2O3NPs) ng mL-1. The detection and quantification limits were found to be 0.04, 0.03, and 0.02, 0.04 ng mL-1, 0.13, 0.10, and 7.24, 0.09 ng mL-1 for the above-mentioned fluorescence systems, respectively. The suggested spectrofluorometric probes were validated and potentially applied for the estimation of OFX and CPFX in their bulk and commercial formulations. [ABSTRACT FROM AUTHOR]

Background: Reducing the burden of neonatal sepsis requires timely identification and initiation of suitable antibiotic treatment in primary health care (PHC) settings. Countries are encouraged to adopt simplified antibiotic regimens at the PHC level for treating sick young infants (SYI) with signs of possible serious bacterial infection (PSBI). As countries implement PSBI guidelines, more lessons on effective implementation strategies and outcome measurements are needed. We document pragmatic approaches used to design, measure and report implementation strategies and outcomes while adopting PSBI guidelines in Kenya. Methods: We designed implementation research using longitudinal mixed methods embedded in a continuous regular systematic learning and adoption of evidence in the PHC context. We synthesized formative data to co-create with stakeholders, implementation strategies to incorporate PSBI guidelines into routine service delivery for SYIs. This was followed by quarterly monitoring for learning and feedback on the effect of implementation strategies, documented lessons learned and tracked implementation outcomes. We collected endline data to measure the overall effect on service level outcomes. Results: Our findings show that characterizing implementation strategies and linking them with implementation outcomes, helps illustrate the pathway between the implementation process and outcomes. Although we have demonstrated that it is feasible to implement PSBI in PHC, effective investment in continuous capacity strengthening of providers through blended approaches, efficient use of available human resources, and improving the efficiency of service areas for managing SYIs optimizes timely identification and management of SYI. Sustained provision of commodities for management of SYI facilitates increased uptake of services. Strengthening facility-community linkages supports adherence to scheduled visits. Enhancing the caregiver's preparedness during postnatal contacts in the community or facility will facilitate the effective completion of treatment. Conclusion: Careful design, and definition of terms related to the measurement of implementation outcomes and strategies enable ease of interpretation of findings. Using the taxonomy of implementation outcomes help frame the measurement process and provides empirical evidence in a structured way to demonstrate causal relationships between implementation strategies and outcomes. Using this approach, we have illustrated that the implementation of simplified antibiotic regimens for treating SYIs with PSBI in PHC settings is feasible in Kenya. [ABSTRACT FROM AUTHOR]

Main objective: A cohort of adult Malawian people living with HIV (PLHIV) testing positive for cryptococcal antigenemia was observed and followed to determine the outcomes and risk factors for attrition. Methods concept: Eligible PLHIV were enrolled at 5 health facilities in Malawi, representing different levels of health care. ART naïve patients, ART defaulters returning to care, and patients with suspected or confirmed ART treatment failure with CD4 <200 cells/μL or clinical stage 3 or 4 were enrolled and received CrAg tests on whole blood specimens from August 2018 to August 2019. Hospitalized PLHIV were enrolled and tested for CrAg from January 2019 to August 2019, regardless of CD4 or clinical stage. Patients with cryptococcal antigenemia were managed per Malawian clinical guidelines and were followed up for six months. Survival and risk factors for attrition at six months were assessed. Results: A total of 2146 patients were screened and 112 (5.2%) had cryptococcal antigenemia. Prevalence ranged from 3.8% (Mzuzu Central Hospital) to 25.8% (Jenda Rural Hospital). Of the 112 patients with antigenemia, 33 (29.5%) were diagnosed with concurrent CM at the time of enrollment. Six-month crude survival of all patients with antigenemia (regardless of CM status) ranged from 52.3% (assuming lost-to-follow-up (LTFU) patients died) to 64.9% (if LTFU survived). Patients who were diagnosed with concurrent CM by CSF test had poor survival (27.3–39.4%). Patients with antigenemia who were not diagnosed with concurrent CM had 71.4% (if LTFU died)– 89.8% (if LTFU survived) survival at six months. In adjusted analyses, patients with cryptococcal antigenemia detected after admission to inpatient care (aHR: 2.56, 1.07–6.15) and patients with concurrent CM at the time of positive antigenemia result (aHR: 2.48, 1.04–5.92) had significantly higher hazard of attrition at six months. Conclusions: Overall, our findings indicate a need for routine access to CrAg screening and pre-emptive fluconazole treatment as a way to detect cryptococcal antigenemia and prevent CM in outpatient and inpatient settings. Rapid access to diagnosis and treatment for cryptococcal meningitis (CM) with gold-standard antifungals is needed to improve survival of patients with advanced HIV in Malawi. [ABSTRACT FROM AUTHOR]

Background: Neonatal mortality remains unacceptably high in many countries. WHO recommends that all newborns be assessed during the postnatal period and should seek prompt medical care if there is any danger sign. However, in many developing countries, only a small proportion of women receive postnatal care. Also, the quality of care in public health facilities is sub-optimal. Methods: We designed an intervention package that included community health worker-assisted pregnancy and birth surveillance, post-natal visits to assess newborns on the first, third, seventh and twenty-eighth days of birth, referral for facility-based care, and establishing a newborn stabilization unit at the first level referral health facility. We did a quasi-experimental, propensity-score matched, controlled study in the Sylhet region of Bangladesh. We used a cross-sectional survey method at baseline and endline to measure the effect of our intervention. We considered two indicators for the primary outcome–(a) all-cause neonatal mortality rate and (b) case fatality of severe illness. Secondary outcomes were the proportion of neonates with signs and symptoms of severe illness who sought care in a hospital or a medically qualified provider. Results: Our sample size was 9,940 live births (4,257 at baseline, 5,683 at end line). Our intervention was significantly associated with a 39% reduction (aRR = 0.61, 95% CI: 0.40–0.93; p = 0.046) in the risk of neonatal mortality and 45% reduction (aRR = 0.55, 95% CI: 0.35–0.86; p = 0.001) in the risk of case fatality of severe illness among newborns in rural Bangladesh. The intervention significantly increased the care-seeking for severe illness at the first-level referral facility (DID 36.6%; 95% CI % 27.98 to 45.22; p<0.001). Interpretation: Our integrated community-facility interventions model resulted in early identification of severely sick neonates, early care seeking and improved treatment. The interventions led to a significant reduction in all-cause neonatal mortality and case fatality from severe illness. [ABSTRACT FROM AUTHOR]

Background: In patients with COVID-19 and baseline soluble urokinase plasminogen receptor plasma (suPAR) levels ≥ 6ng/mL, early administration of anakinra, a recombinant interleukin-1 receptor antagonist, may prevent disease progression and death. In case of suPAR testing unavailability, the Severe COvid Prediction Estimate (SCOPE) score may be used as an alternative in guiding treatment decisions. Methods: We conducted a monocenter, retrospective cohort study, including patients with SARS-CoV2 infection and respiratory failure. Patients treated with anakinra (anakinra group, AG) were compared to two control groups of patients who did not receive anakinra, respectively with ≥ 6 ng/mL (CG1) and < 6 ng/mL (CG2) baseline suPAR levels. Controls were manually paired by age, sex, date of admission and vaccination status and, for patients with high baseline suPAR, propensity score weighting for receiving anakinra was applied. Primary endpoint of the study was disease progression at day 14 from admission, as defined by patient distribution on a simplified version of the 11-point World Health Organization Clinical Progression Scale (WHO-CPS). Results: Between July, 2021 and January, 2022, 153 patients were included, among which 56 were treated with off-label anakinra, 49 retrospectively fulfilled prescriptive criteria for anakinra and were assigned to CG1, and 48 presented with suPAR levels < 6ng/mL and were assigned to CG2. At day 14, when comparing to CG1, patients who received anakinra had significantly reduced odds of progressing towards worse clinical outcome both in ordinal regression analysis (OR 0.25, 95% CI 0.11–0.54, p<0.001) and in propensity-adjusted multiple logistic regression analysis (OR 0.32, 95% CI 0.12–0.82, p = 0.021) thus controlling for a wide number of covariates. Sensitivities of baseline suPAR and SCOPE score in predicting progression towards severe disease or death at day 14 were similar (83% vs 100%, p = 0.59). Conclusion: This real-word, retrospective cohort study confirmed the safety and the efficacy of suPAR-guided, early use of anakinra in hospitalized COVID-19 patients with respiratory failure. [ABSTRACT FROM AUTHOR]

Acute fever in the majority of children in resource-limited countries is attributable to malaria and often treated without laboratory evidence. The aim of the study was to characterize acute pediatric infectious fevers (APIF) in the pediatric department of the Douala Laquintinie Hospital. A cross-sectional study was conducted among children aged 2 months to 15 years who were admitted with an acute fever (anal temperature ≥ 37.5°C less than 5 days in infants and 7 days in adolescents). 200 children were included and followed up during their hospitalization. The mean age was 3.7 (IQ25-75: 1–4.6) years. More than 3 out of 5 patients (62.5%) came from another health facility and anemia accounted for 29% of the reasons for consultation associated with fever. The main symptoms were vomiting (28%), cough (26%), convulsions (21%) and diarrhea (20%). Skin-mucosal pallor (43.0%) and hepatosplenomegaly (26.0%) were the most common physical signs encountered. Among febrile children, 116/200 (58%) were infected with at least 1 pathogen, and 1/200 (0.5%) had a fever of unknown etiology. Malaria (53% vs 80.5% presumptive) associated with anemia (95.3% of cases) was the most common pathology associated with APIF, followed by pneumonia (19.5%), meningitis (11.5%) and urinary tract infections (10% vs 54.5% presumptive). Malaria was over-diagnosed on admission and over-treated as well as urinary tract infection. A better understanding of common pathogens carriage, a better capacity for improved diagnosis and a better applied clinical algorithm for febrile illnesses in children are needed. [ABSTRACT FROM AUTHOR]

Purpose: Differentiating between acute viral and bacterial infection is challenging due to the similarity in symptom presentation. Blood tests can assist in the diagnosis, but they reflect the immediate status and fail to consider the dynamics of an inflammatory response with time since symptom onset. We applied estimated C-reactive protein (CRP) velocity (eCRPv), as derived from the admission CRP level divided by time from symptom onset, in order to better distinguish between viral and bacterial infections. Methods: This cross-sectional study included patients admitted to the emergency department with a confirmed viral (n = 83) or bacterial (n = 181) infection. eCRPv was defined as the ratio between the absolute CRP level upon admission to time from symptom onset (in hours). Absolute CRP and eCRPv values were compared between the 3 groups. Results: Bacterial patients presented with higher CRP levels (133 mg/L) upon admission compared to viral patients (23.31 mg/L) (P < 0.001). Their median value of eCRPv velocity was 4 times higher compared to the viral patients (1.1 mg/L/h compared 0.25 mg/L/h, P < 0.001). Moreover, in intermediate values of CRP (100–150 mg/L) upon admission, in which the differential diagnosis is controversial, high eCRPv is indicative of bacterial infection, eCRPv >4 mg/L/h represents only bacterial patients. Conclusions: During an acute febrile illness, the eCRPv value can be used for rapid differentiation between bacterial and viral infection, especially in patients with high CRP values. This capability can potentially expedite the provision of appropriate therapeutic management. Further research and validation may open new applications of the kinetics of inflammation for rapid diagnosis of an infectious vs. a viral source of fever. [ABSTRACT FROM AUTHOR]

Background: Globally, three fourth of neonatal deaths occur during the early neonatal period, this makes it a critical time to reduce the burden of neonatal death. The survival status of a newborn is determined by the individual (neonatal and maternal), and facility-level factors. Several studies were conducted in Ethiopia to assess early neonatal death; however, most of the studies had limited participants and did not well address the two main determinant factors covered in this study. In response to this gap, this study attempted to examine factors related to early neonatal death based on perinatal death surveillance data in consideration of all the possible determinants of early neonatal death. Methods: The national perinatal death surveillance data were used for this study. A total of 3814 reviewed perinatal deaths were included in the study. Bayesian multilevel parametric survival analysis was employed to identify factors affecting the survival of newborns during the early neonatal period. Adjusted time ratio (ATR) with 95% Bayesian credible intervals (CrI) was reported and log-likelihood was used for model comparison. Statistical significance was declared based on the non-inclusion of 1.0 in the 95% CrI. Result: More than half (52.4%) of early neonatal deaths occurred within the first two days of birth. Per the final model, as gestational age increases by a week the risk of dying during the early neonatal period is reduced by 6% [ATR = 0.94,95%CrI:(0.93–0.96)]. There was an increased risk of death during the early neonatal period among neonates deceased due to birth injury as compared to neonates who died due to infection [ATR = 2.05,95%CrI:(1.30–3.32)]; however, perinates who died due to complication of an intrapartum event had a lower risk of death than perinates who died due to infection [ATR = 0.87,95%CrI:(0.83–0.90)]. As the score of delay one and delay three increases by one unit, the newborn's likelihood of surviving during the early neonatal period is reduced by 4% [ATR = 1.04,95%CrI:(1.01–1.07)] and 21% [ATR = 1.21,95%CrI:(1.15–1.27)] respectively. Neonates born from mothers living in a rural area had a higher risk of dying during the early neonatal period than their counterparts living in an urban area [ATR = 3.53,95%CrI:(3.34–3.69)]. As compared to neonates treated in a primary health facility, being treated in secondary [ATR = 1.14,95%CrI:(1.02–1.27)] and tertiary level of care [ATR = 1.15,95%CrI:(1.04–1.25)] results in a higher risk of death during the early neonatal period. Conclusion: The survival of a newborn during the early neonatal period is determined by both individual (gestational age, cause of death, and delay one) and facility (residence, type of health facility and delay three) level factors. Thus, to have a positive early neonatal outcome, a tailored intervention is needed for the three major causes of death (i.e Infection, birth injury, and complications of the intrapartum period). Furthermore, promoting maternal health, improving the health-seeking behaviour of mothers, strengthening facility readiness, and narrowing down inequalities in service provision are recommended to improve the newborn's outcomes during the early neonatal period. [ABSTRACT FROM AUTHOR]

Almost half of under-five deaths occur during the neonatal period. Delivery with a skilled attendant, adherence to essential newborn care (ENC) and postnatal care (PNC) standards, and immediate treatment of infections are essential to improve neonatal survival. This article uses Demographic and Health Survey data from 45 low- and middle-income countries to assess 1) levels of ENC and PNC that mothers and newborns receive and how this differs by place of delivery and 2) levels of and sources for care-seeking for neonates sick with fever. For five of the ten ENC and PNC indicators assessed, less than two-thirds of mothers and newborns received care in alignment with global standards. Adherence is higher in private facilities than public facilities for all indicators other than immediate breastfeeding and skin-to-skin contact. Except for immediate breastfeeding, adherence is lowest for newborns born at home with a skilled birth attendant (SBA). Socioeconomic disparities exist in access to skilled delivery and adherence to ENC and PNC, with the largest disparities among newborns delivered at home with a SBA. Private provider adherence to ENC and PNC standards was relatively high for newborns from the wealthiest families, indicating that meeting recommended guidelines is achievable. On average across the 45 countries, half of caregivers for neonates with fever sought care outside the home and 45 percent of those sought care from the private sector. There were substantial socioeconomic disparities in care-seeking for fever, but illness prevalence and sources of care seeking were consistent across wealth quintiles. Closing inequities in neonatal care and care seeking and ensuring that all families, including the poorest, can access high quality maternal and newborn care is crucial to ensure equity and accelerate reductions in neonatal and child mortality. [ABSTRACT FROM AUTHOR]

Introduction: Research on simplified antibiotic regimens for outpatient treatment of 'Possible Serious Bacterial Infection' (PSBI) and the subsequent World Health Organization (WHO) guidelines provide an opportunity to increase treatment coverage. This multi-country implementation research initiative aimed to learn how to implement the WHO guideline in diverse contexts. These experiences have been individually published; this overview paper provides a summary of results and lessons learned across sites. Methods summary: A common mixed qualitative and quantitative methods protocol for implementation research was used in eleven sites in the Democratic Republic of Congo (Equateur province), Ethiopia (Tigray and Oromia regions), India (Haryana, Himachal Pradesh, Maharashtra, and Uttar Pradesh states), Malawi (Central Region), Nigeria (Kaduna and Oyo states), and Pakistan (Sindh province). Key steps in implementation research were: i) policy dialogue with the national government and key stakeholders, ii) the establishment of a 'Technical Support Unit' with the research team and district level managers, and iii) development of an implementation strategy and its refinement using an iterative process of implementation, programme learning and evaluation. Results summary: All sites successfully developed and evaluated an implementation strategy to increase coverage of PSBI treatment. During the study period, a total of 6677 young infants from the study catchment area were identified and treated at health facilities in the study area as inpatients or outpatients among 88179 live births identified. The estimated coverage of PSBI treatment was 75.7% (95% CI 74.8% to 78.6%), assuming a 10% incidence of PSBI among all live births. The treatment coverage was variable, ranging from 53.3% in Lucknow, India to 97.3% in Ibadan, Nigeria. The coverage of inpatient treatment ranged from 1.9% in Zaria, Nigeria, to 33.9% in Tigray, Ethiopia. The outpatient treatment coverage ranged from 30.6% in Pune, India, to 93.6% in Zaria, Nigeria. Overall, the case fatality rate (CFR) was 14.6% (95% CI 11.5% to 18.2%) for 0-59-day old infants with critical illness, 1.9% (95% CI 1.5% to 2.4%) for 0-59-day old infants with clinical severe infection and 0.1% for fast breathing in 7–59 days old. Among infants treated as outpatients, CFR was 13.7% (95% CI 8.7% to 20.2%) for 0-59-day old infants with critical illness, 0.9% (95% CI 0.6% to 1.2%) for 0-59-day old infants with clinical severe infection, and 0.1% for infants 7–59 days old with fast breathing. Conclusion: Important lessons on how to conduct each step of implementation research, and the challenges and facilitators for implementation of PSBI management guideline in routine health systems are summarised and discussed. These lessons will be used to introduce and scale-up implementation in relevant Low- and middle-income countries. [ABSTRACT FROM AUTHOR]

Serious bacterial infection (SBI) in children, such as bacterial meningitis or sepsis, is an important condition that can lead to fatal outcomes. Therefore, since it is very important to accurately diagnose SBI, SBI prediction tools such as 'Refined Lab-score' or 'clinical prediction rule' have been developed and used. However, these tools can predict SBI only when there are values of all factors used in the tool, and if even one of them is missing, the tools become useless. Therefore, the purpose of this study was to develop and validate a machine learning-driven model to predict SBIs among febrile children, even with missing values. This was a multicenter retrospective observational study including febrile children <6 years of age who visited Emergency departments (EDs) of 3 different tertiary hospitals from 2016 to 2018. The SBI prediction model was trained with a derivation cohort (data from two hospitals) and externally tested with a validation cohort (data from a third hospital). A total of 11,973 and 2,858 patient records were included in the derivation and validation cohorts, respectively. In the derivation cohort, the area under the receiver operating characteristic curve (AUROC) of the RF model was 0.964 (95% confidence interval [CI], 0.943–0.986), and the area under the precision-recall curve (AUPRC) was 0.753 (95% CI, 0.681–0.824). The conventional LR (CLR) model showed corresponding values of 0.902 (95% CI, 0.894–0.910) and 0.573 (95% CI, 0.560–0.586), respectively. In the validation cohort, the AUROC (95% CI) of the RF model was 0.950 (95% CI, 0.945–0.956), the AUPRC was 0.605 (95% CI, 0.593–0.616), and the CLR presented corresponding values of 0.815 (95% CI, 0.789–0.841) and 0.586 (95% CI, 0.553–0.619), respectively. We developed a machine learning-driven prediction model for SBI among febrile children, which works robustly despite missing values. And it showed superior performance compared to CLR in both internal validation and external validation. [ABSTRACT FROM AUTHOR]

Background: Serious invasive infections in newborns are a major cause of death. Lack of data on etiological causes hampers progress towards reduction of mortality. This study aimed to identify pathogens responsible for such infections in young infants in sub-Saharan Africa and to describe their antibiotics resistance profile. Methods: Between September 2016 and April 2018 we implemented an observational study in two rural sites in Burkina Faso and Tanzania enrolling young infants aged 0–59 days old with serious invasive infection. Blood samples underwent blood culture and molecular biology. Results: In total 634 infants with clinical diagnosis of serious invasive infection were enrolled and 4.2% of the infants had a positive blood culture. The most frequent pathogens identified by blood culture were Klebsiella pneumonia and Staphylococcus aureus, followed by Escherichia coli. Gram-negative isolates were only partially susceptible to first line WHO recommended treatment for neonatal sepsis at community level. A total of 18.6% of the infants were PCR positive for at least one pathogen and Escherichia coli and Staphylococcus aureus were the most common bacteria detected. Among infants enrolled, 60/634 (9.5%) died. Positive blood culture but not positive PCR was associated with risk of death. For most deaths, no pathogen was identified either by blood culture or molecular testing, and hence a causal agent remained unclear. Mortality was associated with low body temperature, tachycardia, respiratory symptoms, convulsions, history of difficult feeding, movement only when stimulated or reduced level of consciousness, diarrhea and/or vomiting. Conclusion: While Klebsiella pneumonia and Staphylococcus aureus, as well as Escherichia coli were pathogens most frequently identified in infants with clinical suspicion of serious invasive infections, most cases remain without definite diagnosis, making more accurate diagnostic tools urgently needed. Antibiotics resistance to first line antibiotics is an increasing challenge even in rural Africa. [ABSTRACT FROM AUTHOR]

Sepsis, an important and preventable cause of death in the newborn, is associated with high out of pocket hospitalization costs for the parents/guardians. The government of Nepal's Free Newborn Care (FNC) service that covers hospitalization costs has set a maximum limit of Nepalese rupees (NPR) 8000 i.e. USD 73.5, the basis of which is unclear. We aimed to estimate the costs of treatment in neonates and young infants fulfilling clinical criteria for sepsis, defined as clinical severe infection (CSI) to identify determinants of increased cost. This study assessed costs for treatment of 206 infants 3–59 days old, enrolled in a clinical trial, and admitted to the Kanti Children's Hospital in Nepal through June 2017 to December 2018. Total costs were derived as the sum of direct costs for bed charges, investigations, and medicines and indirect costs calculated by using work time loss of parents. We estimated treatment costs for CSI, the proportion exceeding NPR 8000 and performed multivariable linear regression to identify determinants of high cost. Of the 206 infants, 138 (67%) were neonates (3–28 days). The median (IQR) direct costs for treatment of CSI in neonates and young infants (29–59 days) were USD 111.7 (69.8–155.5) and 65.17 (43.4–98.5) respectively. The direct costs exceeded NPR 8000 (USD 73.5) in 69% of neonates with CSI. Age <29 days, moderate malnutrition, presence of any sign of critical illness and documented treatment failure were found to be important determinants of high costs for treatment of CSI. According to this study, the average treatment cost for a newborn with CSI in a public tertiary level hospital is substantial. The maximum limit offered for free newborn care in public hospitals needs to be revised for better acceptance and successful implementation of the FNC service to avert catastrophic health expenditures in developing countries like Nepal. Trial Registration: CTRI/2017/02/007966 (Registered on: 27/02/2017). [ABSTRACT FROM AUTHOR]

Background: Low-level private health facilities (LLPHFs) handle a considerable magnitude of sick children in low-resource countries. We assessed capacity of LLPHFs to manage malaria, pneumonia, diarrhea, and, possible severe bacterial infections (PSBIs) in under-five-year-olds. Methods: We conducted a cross-sectional survey in 110 LLPHFs and 129 health workers in Mbarara District, Uganda between May and December 2019. Structured questionnaires and observation forms were used to collect data on availability of treatment guidelines, vital medicines, diagnostics, and equipment; health worker qualifications; and knowledge of management of common childhood infections. Results: Amoxicillin was available in 97%, parental ampicillin and gentamicin in 77%, zinc tablets and oral rehydration salts in >90% while artemether-lumefantrine was available in 96% of LLPHF. About 66% of facilities stocked loperamide, a drug contraindicated in the management of diarrhoea in children. Malaria rapid diagnostic tests and microscopes were available in 86% of the facilities, timers/clocks in 57% but only 19% of the facilities had weighing scales and 6% stocked oxygen. Only 4% of the LLPHF had integrated management of childhood illness (IMCI) booklets and algorithm charts for management of common childhood illnesses. Of the 129 health workers, 52% were certificate nurses/midwives and (26% diploma nurses/clinical officers; 57% scored averagely for knowledge on management of common childhood illnesses. More than a quarter (38%) of nursing assistants had low knowledge scores. No notable significant differences existed between rural and urban LLPHFs in most parameters assessed. Conclusion: Vital first-line medicines for treatment of common childhood illnesses were available in most of the LLPHFs but majority lacked clinical guidelines and very few had oxygen. Majority of health workers had low to average knowledge on management of the common childhood illnesses. There is need for innovative knowledge raising interventions in LLPHFs including refresher trainings, peer support supervision and provision of job aides. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization recommends inpatient hospital treatment of young infants up to two months old with any sign of possible serious infection. However, each sign may have a different risk of death. The current study aims to calculate the case fatality ratio for infants with individual or combined signs of possible serious infection, stratified by inpatient or outpatient treatment. Methods: We analysed data from the African Neonatal Sepsis Trial conducted in five sites in the Democratic Republic of the Congo, Kenya and Nigeria. Trained study nurses classified sick infants as pneumonia (fast breathing in 7–59 days old), severe pneumonia (fast breathing in 0–6 days old), clinical severe infection [severe chest indrawing, high (> = 38°C) or low body temperature (<35.5°C), stopped feeding well, or movement only when stimulated] or critical illness (convulsions, not able to feed at all, or no movement at all), and referred them to a hospital for inpatient treatment. Infants whose caregivers refused referral received outpatient treatment. The case fatality ratio by day 15 was calculated for individual and combined clinical signs and stratified by place of treatment. An infant with signs of clinical severe infection or severe pneumonia was recategorised as having low- (case fatality ratio ≤2%) or moderate- (case fatality ratio >2%) mortality risk. Results: Of 7129 young infants with a possible serious infection, fast breathing (in 7–59 days old) was the most prevalent sign (26%), followed by high body temperature (20%) and severe chest indrawing (19%). Infants with pneumonia had the lowest case fatality ratio (0.2%), followed by severe pneumonia (2.0%), clinical severe infection (2.3%) and critical illness (16.9%). Infants with clinical severe infection had a wide range of case fatality ratios for individual signs (from 0.8% to 11.0%). Infants with pneumonia had similar case fatality ratio for outpatient and inpatient treatment (0.2% vs. 0.3%, p = 0.74). Infants with clinical severe infection or severe pneumonia had a lower case fatality ratio among those who received outpatient treatment compared to inpatient treatment (1.9% vs. 6.5%, p<0.0001). We recategorised infants into low-mortality risk signs (case fatality ratio ≤2%) of clinical severe infection (high body temperature, or severe chest indrawing) or severe pneumonia and moderate-mortality risk signs (case fatality ratio >2%) (stopped feeding well, movement only when stimulated, low body temperature or multiple signs of clinical severe infection). We found that both categories had four times lower case fatality ratio when treated as outpatient than inpatient treatment, i.e., 1.0% vs. 4.0% (p<0.0001) and 5.3% vs. 22.4% (p<0.0001), respectively. In contrast, infants with signs of critical illness had nearly two times higher case fatality ratio when treated as outpatient versus inpatient treatment (21.7% vs. 12.1%, p = 0.097). Conclusions: The mortality risk differs with clinical signs. Young infants with a possible serious infection can be grouped into those with low-mortality risk signs (high body temperature, or severe chest indrawing or severe pneumonia); moderate-mortality risk signs (stopped feeding well, movement only when stimulated, low body temperature or multiple signs of clinical severe infection), or high-mortality risk signs (signs of critical illness). New treatment strategies that consider differential mortality risks for the place of treatment and duration of inpatient treatment could be developed and evaluated based on these findings. Clinical trial registration: This trial was registered with the Australian New Zealand Clinical Trials Registry under ID ACTRN 12610000286044. [ABSTRACT FROM AUTHOR]

Introduction: Neonatal infections contribute substantially to infant mortality in Nigeria and globally. Management requires hospitalization, which is not accessible to many in low resource settings. World Health Organization developed a guideline to manage possible serious bacterial infection (PSBI) in young infants up to two months of age when a referral is not feasible. We evaluated the feasibility of implementing this guideline to achieve high coverage of treatment. Methods: This implementation research was conducted in out-patient settings of eight primary health care centres (PHC) in Lagelu Local Government Area (LGA) of Ibadan, Oyo State, Nigeria. We conducted policy dialogue with the Federal and State officials to adopt the WHO guideline within the existing programme setting and held orientation and sensitization meetings with communities. We established a Technical Support Unit (TSU), built the capacity of health care providers, supervised and mentored them, monitored the quality of services and collected data for management and outcomes of sick young infants with PSBI signs. The Primary Health Care Directorate of the state ministry and the local government led the implementation and provided technical support. The enablers and barriers to implementation were documented. Results: From 1 April 2016 to 31 July 2017 we identified 5278 live births and of these, 1214 had a sign of PSBI. Assuming 30% of births were missed due to temporary migration to maternal homes for delivery care and approximately 45% cases came from outside the catchment area due to free availability of medicines, the treatment coverage was 97.3% (668 cases/6861 expected births) with an expected 10% PSBI prevalence within the first 2 months of life. Of 1214 infants with PSBI, 392 (32%) infants 7–59 days had only fast breathing (pneumonia), 338 (27.8%) infants 0–6 days had only fast breathing (severe pneumonia), 462 (38%) presented with signs of clinical severe infection (CSI) and 22 (1.8%) with signs of critical illness. All but two, 7–59 days old infants with pneumonia were treated with oral amoxicillin without a referral; 80% (312/390) adhered to full treatment; 97.7% (381/390) were cured, and no deaths were reported. Referral to the hospital was not accepted by 87.7% (721/822) families of infants presenting with signs of PSBI needing hospitalization (critical illness 5/22; clinical severe infection; 399/462 and severe pneumonia 317/338). They were treated on an outpatient basis with two days of injectable gentamicin and seven days of oral amoxicillin. Among these 81% (584/721) completed treatment; 97% (700/721) were cured, and three deaths were reported (two with critical illness and one with clinical severe infection). We identified health system gaps including lack of staff motivation and work strikes, medicines stockouts, sub-optimal home visits that affected implementation. Conclusions: When a referral is not feasible, outpatient treatment for young infants with signs of PSBI is possible within existing programme structures in Nigeria with high coverage and low case fatality. To scale up this intervention successfully, government commitment is needed to strengthen the health system, motivate and train health workers, provide necessary commodities, establish technical support for implementation and strengthen linkages with communities. Registration: Trial is registered on Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12617001373369. [ABSTRACT FROM AUTHOR]

Introduction: Serious bacterial neonatal infections are a major cause of global neonatal mortality. While hospitalized treatment is recommended, families cannot access inpatient treatment in low resource settings. Two parallel randomized control trials were conducted at five sites in three countries (Democratic Republic of Congo, Kenya, and Nigeria) to compare the effectiveness of treatment with experimental regimens requiring fewer injections with a reference regimen A (injection gentamicin plus injection procaine penicillin both once daily for 7 days) on the outpatient basis provided to young infants (0–59 days) with signs of possible serious bacterial infection (PSBI) when the referral was not feasible. Costs were estimated to quantify the financial implications of scaleup, and cost-effectiveness of these regimens. Methods: Direct economic costs (including personnel, drugs and consumable costs) were estimated for identification, prenatal and postnatal visits, assessment, classification, treatment and follow-up. Data on time spent by providers on each activity was collected from 83% of providers. Indirect marginal financial costs were estimated for non-consumables/capital, training, transport, communication, administration and supervision by considering only a share of the total research and health system costs considered important for the program. Total economic costs (direct plus indirect) per young infant treated were estimated based on 39% of young infants enrolled in the trial during 2012 and the number of days each treated during one year. The incremental cost-effectiveness ratio was calculated using treatment failure after one week as the outcome indicator. Experimental regimens were compared to the reference regimen and pairwise comparisons were also made. Results: The average costs of treating a young infant with clinical severe infection (a sub-category of PSBI) in 2012 was lowest with regimen D (injection gentamicin once daily for 2 days plus oral amoxicillin twice daily for 7 days) at US$ 20.9 (95% CI US$ 16.4–25.3) or US$ 32.5 (2018 prices). While all experimental regimens B (injection gentamicin once daily plus oral amoxicillin twice daily, both for 7 days), regimen C (once daily of injection gentamicin injection plus injection procaine penicillin for 2 days, thereafter oral amoxicillin twice daily for 5 days) and regimen D were found to be more cost-effective as compared with the reference regimen A; pairwise comparison showed regimen D was more cost-effective than B or C. For fast breathing, the average cost of treatment with regimen E (oral amoxicillin twice daily for 7 days) at US$ 18.3 (95% CI US$ 13.4–23.3) or US$ 29.0 (2018 prices) was more cost-effective than regimen A. Indirect costs were 32% of the total treatment costs. Conclusion: Scaling up of outpatient treatment for PSBI when the referral is not feasible with fewer injections and oral antibiotics is cost-effective for young infants and can lead to increased access to treatment resulting in potential reductions in neonatal mortality. Clinical trial registration: The trial was registered with Australian New Zealand Clinical Trials Registry under ID ACTRN 12610000286044. [ABSTRACT FROM AUTHOR]

Background: Despite the necessity of early recognition for an optimal outcome, sepsis often remains unrecognized. Available tools for early recognition are rarely evaluated in low- and middle-income countries. In this study, we analyzed the spectrum, treatment and outcome of sepsis at an Ethiopian tertiary hospital and evaluated recommended sepsis scores. Methods: Patients with an infection and ≥2 SIRS criteria were screened for sepsis by SOFA scoring. From septic patients, socioeconomic and clinical data as well as blood cultures were collected and they were followed until discharge or death; 28-day mortality was determined. Results: In 170 patients with sepsis, the overall mortality rate was 29.4%. The recognition rate by treating physicians after initial clinical assessment was low (12.4%). Increased risk of mortality was significantly associated with level of SOFA and qSOFA score, Gram-negative bacteremia (in comparison to Gram-positive bacteremia; 42.9 versus 16.7%), and antimicrobial regimen including ceftriaxone (35.7% versus 19.2%) or metronidazole (43.8% versus 25.0%), but not with an increased respiratory rate (≥22/min) or decreased systolic blood pressure (≤100mmHg). In Gram-negative isolates, extended antimicrobial resistance with expression of extended-spectrum beta-lactamase and carbapenemase genes was common. Among adult patients, sensitivity and specificity of qSOFA score for detection of sepsis were 54.3% and 66.7%, respectively. Conclusion: Sepsis is commonly unrecognized and associated with high mortality, showing the need for reliable and easy-applicable tools to support early recognition. The established sepsis scores were either of limited applicability (SOFA) or, as in the case of qSOFA, were significantly impaired in their sensitivity and specificity, demonstrating the need for further evaluation and adaptation to local settings. Regional factors like malaria endemicity and HIV prevalence might influence the performance of different scores. Ineffective empirical treatment due to antimicrobial resistance is common and associated with mortality. Local antimicrobial resistance statistics are needed for guidance of calculated antimicrobial therapy to support reduction of sepsis mortality. [ABSTRACT FROM AUTHOR]

Background: Community-based data on the prevalence of clinical signs of possible serious bacterial infection (PSBI) and the mortality associated with them are scarce. The aim was to examine the prevalence for each sign of infection and mortality associated with infants in the first two months of life, using community surveillance through community health workers (CHW). Methods: We used population-based surveillance data of infants up to two months of age from the African Neonatal Sepsis Trial (AFRINEST). In this study, CHWs visited infants up to 10 times during the first two months of life at five sites in three sub-Saharan African countries. CHW assessed the infant for signs of infection (local or systemic) and referred infants who presented with any sign of infection to a health facility. We used a longitudinal analysis to calculate the risk of death associated with the presence of a sign of infection at the time of the visit until the subsequent visit. Results: During the first two months of their life, CHWs visited 84,759 live-born infants at least twice. In 11,089 infants (13.1%), one or more signs of infection were identified, of which 237 (2.1%) died. A sign of infection was detected at 2.1% of total visits. In 52% of visits, infants had one or more sign of systemic infection, while 25% had fast breathing in 7–59 days period and 23% had a local infection. All signs of infection, including multiple signs, were more frequently seen in the first week of life. The risk of mortality was very low (0.2%) for local infections and fast breathing in 7–59 days old, it was low for fast breathing 0–6 days old (0.6%), high body temperature (0.7%) and severe chest indrawing (1.0%), moderate for low body temperature (4.9%) and stopped feeding well/not able to feed at all (5.0%) and high for movement only when stimulated or no movement at all (10%) and multiple signs of systemic infection (15.5%). The risk of death associated with most clinical signs was higher (1.5 to 9 times) in the first week of life than at later age, except for low body temperature (4 times lower) as well as high body temperature (2 times lower). Conclusion: Signs of infections are common in the first two months of life. The mortality risk differs with clinical signs and can be grouped as very low (local infections, fast breathing 7–59 days), low (fever, severe chest indrawing and fast breathing 0–6 days), moderate (low body temperature and stopped feeding well/not able to feed at all) and high (for movements only on stimulation or no movements at all and multiple signs of infection). New treatment strategies that consider differential mortality risk could be developed and evaluated based on these findings. Clinical trial registration: The trial was registered with Australian New Zealand Clinical Trials Registry under ID ACTRN 12610000286044. [ABSTRACT FROM AUTHOR]

The risk factors associated with mortality in patients with extremely high serum C-reactive protein (CRP) levels are controversial. In this retrospective single-center cross-sectional study, the clinical and laboratory data of patients with CRP levels ≥40 mg/dL treated in Saitama Medical Center, Japan from 2004 to 2017 were retrieved from medical records. The primary outcome was defined as 72-hour mortality after the final CRP test. Forty-four mortal cases were identified from the 275 enrolled cases. Multivariate logistic regression analysis (MLRA) was performed to explore the parameters relevant for predicting mortality. As an alternative method of prediction, we devised a novel risk predictor, "weighted average of risk scores" (WARS). WARS features the following: (1) selection of candidate risk variables for 72-hour mortality by univariate analyses, (2) determination of C-statistics and cutoff value for each variable in predicting mortality, (3) 0–1 scoring of each risk variable at the cutoff value, and (4) calculation of WARS by weighted addition of the scores with weights assigned according to the C-statistic of each variable. MLRA revealed four risk variables associated with 72-hour mortality—age, albumin, inorganic phosphate, and cardiovascular disease—with a predictability of 0.829 in C-statistics. However, validation by repeated resampling of the 275 records showed that a set of predictive variables selected by MLRA fluctuated occasionally because of the presence of closely associated risk variables and missing data regarding some variables. WARS attained a comparable level of predictability (0.837) by combining the scores for 10 risk variables, including age, albumin, electrolytes, urea, lactate dehydrogenase, and fibrinogen. Several mutually related risk variables are relevant in predicting 72-hour mortality in patients with extremely high CRP levels. Compared to conventional MLRA, WARS exhibited a favorable performance with flexible coverage of many risk variables while allowing for missing data. [ABSTRACT FROM AUTHOR]

Background: Neonatal bacterial infections are a common cause of death, which can be managed well with inpatient treatment. Unfortunately, many families in low resource settings do not accept referral to a hospital. The World Health Organization (WHO) developed a guideline for management of young infants up to 2 months of age with possible serious bacterial infection (PSBI) when referral is not feasible. Government of Ethiopia with WHO evaluated the feasibility of implementing this guideline to increase coverage of treatment. Objective: The objective of this study was to implement a simplified antibiotic regimen (2 days gentamicin injection and 7 days oral amoxicillin) for management of sick young infants with PSBI in a programme setting when referral was not feasible to identify at least 80% of PSBI cases, achieve an overall adequate treatment coverage of at least 80% and document the challenges and opportunities for implementation at the community level in two districts in Tigray, Ethiopia. Methods: Using implementation research, we applied the PSBI guideline in a programme setting from January 2016 to August 2017 in Raya Alamata and Raya Azebo Woredas (districts) in Southern Tigray, Ethiopia with a population of 260884. Policy dialogue was held with decision-makers, programme implementers and stakeholders at federal, regional and district levels, and a Technical Support Unit (TSU) was established. Health Extension Workers (HEWs) working at the health posts and supervisors working at the health centres were trained in WHO guideline to manage sick young infants when referral was not feasible. Communities were sensitized towards appropriate home care. Results: We identified 854 young infants with any sign of PSBI in the study population of 7857 live births. The expected live births during the study period were 9821. Assuming 10% of neonates will have any sign of PSBI within the first 2 months of life (n = 982), the coverage of appropriate treatment of PSBI cases in our study area was 87% (854/982). Of the 854 sick young infants, 333 (39%) were taken directly to a hospital and 521 (61%) were identified by HEW at health posts. Of the 521 young infants, 27 (5.2%) had signs of critical illness, 181 (34.7%) had signs of clinical severe infection, whereas 313 (60.1%) young infants 7–59 days of age had only fast breathing pneumonia. All young infants with critical illness accepted referral to a hospital, while 117/181 (64.6%) infants with clinical severe infection accepted referral. Families of 64 (35.3%) infants with clinical severe infection refused referral and were treated at the health post with injectable gentamicin for 2 days plus oral amoxicillin for 7 days. All 64 completed recommended gentamicin doses and 63/64 (98%) completed recommended amoxicillin doses. Of 313 young infants, 7–59 days with pneumonia who were treated by the HEWs without referral with oral amoxicillin for 7 days, 310 (99%) received all 14 doses. No deaths were reported among those treated on an outpatient basis at health posts. But 35/477 (7%) deaths occurred among young infants treated at hospital. Conclusions: When referral is not feasible, young infants with PSBI can be managed appropriately at health posts by HEWs in the existing health system in Ethiopia with high coverage, low treatment failure and a low case fatality rate. Moreover, fast breathing pneumonia in infants 7–59 days of age can be successfully treated at the health post without referral. Relatively higher mortality in sick young infants at the referral level health facilities warrants further investigation. [ABSTRACT FROM AUTHOR]

Objective: To describe the patient population, priority diseases and outcomes in newborns admitted <48 hours old to neonatal units in both Kenya and Nigeria. Study design: In a network of seven secondary and tertiary level neonatal units in Nigeria and Kenya, we captured anonymised data on all admissions <48 hours of age over a 6-month period. Results: 2280 newborns were admitted. Mean birthweight was 2.3 kg (SD 0.9); 57.0% (1214/2128) infants were low birthweight (LBW; <2.5kg) and 22.6% (480/2128) were very LBW (VLBW; <1.5 kg). Median gestation was 36 weeks (interquartile range 32, 39) and 21.6% (483/2236) infants were very preterm (gestation <32 weeks). The most common morbidities were jaundice (987/2262, 43.6%), suspected sepsis (955/2280, 41.9%), respiratory conditions (817/2280, 35.8%) and birth asphyxia (547/2280, 24.0%). 18.7% (423/2262) newborns died; mortality was very high amongst VLBW (222/472, 47%) and very preterm infants (197/483, 40.8%). Factors independently associated with mortality were gestation <28 weeks (adjusted odds ratio 11.58; 95% confidence interval 4.73–28.39), VLBW (6.92; 4.06–11.79), congenital anomaly (4.93; 2.42–10.05), abdominal condition (2.86; 1.40–5.83), birth asphyxia (2.44; 1.52–3.92), respiratory condition (1.46; 1.08–2.28) and maternal antibiotics within 24 hours before or after birth (1.91; 1.28–2.85). Mortality was reduced if mothers received a partial (0.51; 0.28–0.93) or full treatment course (0.44; 0.21–0.92) of dexamethasone before preterm delivery. Conclusion: Greater efforts are needed to address the very high burden of illnesses and mortality in hospitalized newborns in sub-Saharan Africa. Interventions need to address priority issues during pregnancy and delivery as well as in the newborn. [ABSTRACT FROM AUTHOR]

Liver stiffness is a reliable non-invasive predictor of Hepatic Venous Pressure Gradient (HVPG) above 10 mm Hg. However, it failed to predict higher thresholds of HVPG. Our aim was to investigate whether liver stiffness and selected previously published non-invasive blood biomarkers could predict higher HVPG thresholds in liver transplant candidates without ongoing alcohol use. One hundred and nine liver transplant candidates with liver cirrhosis of various aetiologies underwent direct HVPG measurement, liver stiffness measurement by 2D shear-wave elastography (Aixplorer Multiwave, Supersonic Imagine, France) and assessment of blood HVPG biomarkers (osteopontin, VCAM-1, IL-6, TNF-α, IL-1ra/IL-1F3 and ELF score). The correlation between liver stiffness and HVPG was linear up to 30 mm Hg of HVPG (r = 0.765, p < 0.0001). The regression lines had similar slopes for HVPG values below and above 16 mm Hg (p > 0.05) and the correlation in patients with HVPG <16 mm Hg (r = 0.456, p = 0.01) was similar to patients with HVPG ≥ 16 mm Hg (r = 0.499, p < 0.0001). The correlation was similar in the subgroup patients with alcoholic (r = 0.718, p < 0.0001), NASH (r = 0.740, p = 0.008), cryptogenic (r = 0.648, p = 0,0377), cholestatic and autoimmune (r = 0.706, p < 0.0001) and viral cirrhosis (r = 0.756, p < 0.0001). Liver stiffness distinguished patients with HVPG above 16, and 20 mm Hg with AUROCs 0.90243, and 0.86824, sensitivity 0.7656, and 0.7027, and specificity 0.9333, and 0.8750. All studied blood biomarkers correlated better with liver stiffness than with HVPG and their AUROCs did not exceed 0.8 at both HVPG thresholds. Therefore, a composite predictor superior to liver stiffness could not be established. We conclude that liver stiffness is a clinically reliable predictor of higher HVPG thresholds in non-drinking subjects with advanced liver cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Government of India and the World Health Organization have guidelines for outpatient management of young infants 0–59 days with signs of Possible Serious Bacterial Infection (PSBI), when referral is not feasible. Implementation research was conducted to identify facilitators and barriers to operationalizing these guidelines. Methods: Himachal Pradesh government implemented the guidelines in program settings supported by Centre for Health Research and Development, Society for Applied Studies. The strategy included community sensitization, skill enhancement of Accredited Social Health Activists (ASHA), Auxiliary Nurse Midwives (ANMs) and Medical Officers (MOs) to identify PSBI and treat when referral was not feasible. The research team collected information on facilitators and barriers. A technical support unit provided training and oversight. Findings: Among 1997 live births from June 2017 to January 2019, we identified 160 cases of PSBI in young infants resulting in a coverage of 80%, assuming an incidence of 10%. Of these,29(18.1%) had signs of critical illness (CI), 92 (57.5%) had clinical severe infection (CSI), 5 (3.1%)had severe pneumonia (only fast breathing in young infants 0–6 days), while 34 (21%) had pneumonia (only fast breathing in young infants 7–59 days). Hospital referral was accepted by 48/160 (30%), whereas 112/160 (70%) were treated with the simplified treatment regimens at primary level facilities. Of the 29 infants with CI, 18 (62%) accepted referral; 26 (90%) recovered while 3 (10%) who had accepted referral, died. Of the 92 infants who had CSI, 86 (93%) recovered, 65 (71%) received simplified treatment and one infant who had accepted referral, died. All the five infants who had severe pneumonia, recovered; 3 (60%) had received simplified treatment. Of the 34 pneumonia cases, 33 received simplified treatment of which 5 (15%) failed treatment; two out of these 5 died. Overall, 6/160 infants died (case-fatality-rate 3.4%); 2 in the simplified treatment (case-fatality-rate 1.8%) and 4 in the hospital group (case-fatality-rate 8.3%). Delayed identification and care-seeking by families and health system weaknesses like manpower gaps and interrupted supplies were challenges in implementation. Conclusions: Implementation of the guidelines in program settings is possible and acceptable. Scaling up would require creating community awareness, early identification and appropriate care-seeking, strengthening ASHA home-visitation program, building skills and confidence of MOs and ANMs, uninterrupted supplies and a dependable referral system. [ABSTRACT FROM AUTHOR]

Background: Understanding communities' beliefs about the causes of illnesses in sick young infants (SYIs) is key to strengthening interventions and improving newborn health outcomes. This study explored communities' perception of the etiology of illnesses in SYIs 0–59 days old in four counties in Kenya. Methods: We used an exploratory qualitative study design. Data were collected between August and September 2018 and involved 23 in-depth interviews with female caregivers aged 15-24years; 25 focus group discussions with female caregivers aged 15–18 years, 19–24 years and 25–45 years; and 7 focus group discussions with fathers aged 18–34 years and 35 or more years. Participants were purposely sampled, only those with SYIs 0–59 days old were eligible to participate. Data were analyzed using inductive thematic analysis framework approach. Results: Female caregivers and fathers attributed illnesses in SYIs 0–59 days old to natural (biomedical) and supernatural causes which sometimes co-existed. There were commonalities in perceived natural causes of illness in SYIs across sites, age groups and gender. Perceived natural causes of illness in SYIs include unfavorable environmental and hygiene conditions, poor maternal and child nutrition, and healthcare practices. Perceived supernatural causes of illness in SYIs such as 'evil eyes' were common across the four counties while others were geographically unique such as the belief that owls cause illnesses. Conclusion: Communities' understanding of the etiology of illnesses in SYIs in the study settings overlapped between natural and supernatural causes. There is need for child health programmes to take into consideration communities' beliefs and practices regarding disease and health to improve newborn health outcomes. [ABSTRACT FROM AUTHOR]

Background: Sepsis is one of the major causes of neonatal death worldwide as well as in Bangladesh. The objective of the present study was to identify the risk factors and causative organisms of neonatal sepsis after delivery in a tertiary care hospital, Bangladesh. Methods: This was a case-control study conducted in the neonatal ward of Rajshahi Medical College Hospital (RMCH), a 1000-bed tertiary hospital situated in Rajshahi, Bangladesh. Neonates diagnosed as neonatal sepsis by clinical and laboratory parameters were included as cases in this study. Admitted neonates unsuspected or undiagnosed for sepsis were considered as controls. Maternal and neonatal information and their laboratory reports were collected and analyzed. Both bivariate and multiple logistic regression models were used to identify the risk factors of neonatal sepsis. Results: A total of 91 cases and 193 controls were included in the study. Maternal history of urinary tract infection (UTI) during the third trimester of pregnancy (aOR 2.75, 95% CI: 1.04–7.23, p <0.05), premature birth (aOR 2.77, 95% CI: 1.08–7.13, p <0.05) and APGAR score <7 at five minutes (aOR 2.58, 95% CI: 1.04–6.39, p <0.05) were associated with onset of neonatal sepsis in multiple logistic regression model. All these factors were also associated with developing early-onset neonatal sepsis, while maternal UTI and male sex of neonates were associated with developing late-onset neonatal sepsis. Escherichia coli (40.7%), Staphylococcus aureus (27.5%), and Klebsiella pneumoniae (18.7%) were the commonly isolated organisms causing neonatal sepsis. All these organisms were highly resistant to common antibiotics like amoxicillin, cephalosporins, aminoglycosides and quinolones. Carbapenemase group of drugs along with amikacin, nitrofurantoin and linezolid were the most sensitive drugs. Conclusions: Strengthening the existing facility for antenatal screening for early diagnosis and treatment of maternal infection during pregnancy as well as identifying high-risk pregnancy for adequate perinatal management is necessary to prevent neonatal sepsis-related morbidity and mortality. Rational use of antibiotics according to local epidemiology and culture and sensitivity reports may minimize the increasing hazards of antibiotic resistance. [ABSTRACT FROM AUTHOR]

Introduction: Patients with community-acquired pneumonia (CAP) undergo a dysregulated host response that is related to mortality. MicroRNAs (miRNAs) participate in this response, but their expression pattern and their role as biomarkers in CAP have not been fully characterized. Methods: A prospective observational study was performed in a cohort of 153 consecutive patients admitted to hospital with CAP. Clinical and analytical variables were collected, and the main outcome variable was 30-day mortality. Small RNA was purified from plasma of these patients obtained on the first day of admission, and miRNA expression was analyzed by RT-PCR. Univariate and multivariate analyses were carried out through the construction of a logistic regression model. The proposed model was compared with established prognostic clinical scales using ROC curve analysis. Results: The mean age of the patients included was 74.7 years [SD 15.9]. Their mean PSI was 100.9 [SD 34.6] and the mean modified Charlson index was 2.9 [SD 3.0]. Both miR-146a and miR-16-5p showed statistically significant association with 30-day mortality after admission due to CAP (1.10 vs. 0.23 and 51.74 vs. 35.23, respectively), and this association remained for miR-16-5p in the multivariate analysis adjusted for age, gender and history of bronchoaspiration (OR 0.95, p = 0.021). The area-under-the-curve (AUC) of our adjusted multivariate model (AUC = 0.954 95%CI [0.91–0.99]), was better than those of prognostic scales such as PSI (AUC = 0.799 [0.69–0.91]) and CURB-65 (AUC = 0.722 [0.58–0.86]). Conclusions: High levels of miR-146a-5p and miR-16-5p upon admission due to CAP are associated with lower mortality at 30 days of follow-up. Both miRNAs could be used as biomarkers of good prognosis in subjects hospitalized with CAP. [ABSTRACT FROM AUTHOR]

Background: Infection, particularly in the first 5 years of life, is a major cause of childhood deaths globally, many deaths from infections such as pneumonia and meningococcal disease are avoidable, if treated in time. Some factors that contribute to morbidity and mortality can be modified. These include organisational and environmental factors as well as those related to the child, family or professional. Objective: Examine what organizational and environmental factors and individual child, family and professional factors affect timing of admission to hospital for children with a serious infectious illness. Design: Systematic review. Data sources: Key search terms were identified and used to search CINAHL Plus, Medline, ASSIA, Web of Science, The Cochrane Library, Joanna Briggs Institute Database of Systematic Review. Study appraisal methods: Primary research (e.g. quantitative, qualitative and mixed methods studies) and literature reviews (e.g., systematic, scoping and narrative) were included if participants included or were restricted to children under 5 years of age with serious infectious illnesses, included parents and/or first contact health care professionals in primary care, urgent and emergency care and where the research had been conducted in OECD high income countries. The Mixed Methods Appraisal Tool was used to review the methodological quality of the studies. Main findings: Thirty-six papers were selected for full text review; 12 studies fitted the inclusion criteria. Factors influencing the timing of admission to hospital included the variability in children's illness trajectories and pathways to hospital, parental recognition of symptoms and clinicians non-recognition of illness severity, parental help-seeking behaviour and clinician responses, access to services, use and non-use of 'gut feeling' by clinicians, and sub-optimal management within primary, secondary and tertiary services. Conclusions: The pathways taken by children with a serious infectious illness to hospital are complex and influenced by a variety of potentially modifiable individual, organisational, environmental and contextual factors. Supportive, accessible, respectful services that provide continuity, clear communication, advice and safety-netting are important as is improved training for clinicians and a mandate to attend to 'gut feeling'. Implications: Relatively simple interventions such as improved communication have the potential to improve the quality of care and reduce morbidity and mortality in children with a serious infectious illness. [ABSTRACT FROM AUTHOR]

Background: Skin and soft tissue infections (SSTI) are a common but preventable cause of morbidity and mortality among people who inject drugs (PWID). They can be severe, and hospitalisations of PWID with SSTI are rising. The most common SSTI presentations are abscesses and cellulitis. Methods: We used data from Care & Prevent, a cross-sectional community survey of PWID in London. We reported the lifetime prevalence of SSTI, severity of infections, key risk factors, and associated sequelae. Pictorial questions were used to assess SSTI severity. Results: We recruited 455 PWID. SSTI lifetime prevalence was high: 64% reported an abscess and/or cellulitis. Over one-third (37%) reported a severe infection, 137 (47%) reported hospitalisation. SSTIrisk factors were: aged 35+ years, injecting once or more times a day, subcutaneous or intra-muscular injections, and making four or more attempts to achieve an injection. Those who reported having other health conditions were at higher odds of having an abscess or cellulitis, with risk tending to increase with number of reported conditions. Half (46%) employed self-care for their worst SSTI, and 43% waited for ten or more days before seeking medical care or not seeking medical care at all. Conclusions: Abscess and cellulitis are very common among PWID in London. We corroborate findings indicating SSTIs are associated with risks, e.g. venous access problems, as well as other co-morbid conditions: septicaemia, endocarditis, DVT, and kidney disease. These co-morbidities may impact SSTIs severity and outcomes. Delayed healthcare seeking potentially exacerbates infection severity, which in turn increases poorer health outcomes and complications. [ABSTRACT FROM AUTHOR]

Background: Despite remarkable progress in the reduction of death in under-five children, neonatal mortality has shown little or no concomitant reduction globally. It is also one of the most common causes of neonatal death in Ethiopia. Little is known on predictors of neonatal sepsis. Risk based screening and commencement of treatment appreciably reduces neonatal death and illness. Therefore, the main aim of this study was to identify predictors of neonatal sepsis in public referral hospitals of Northwest Ethiopia. Methods: Institutional based unmatched case-control study was conducted among a total of 231 neonates in Debre Markos and Felege Hiwot referral hospitals from March 2018- April 2018. Neonates who fulfill the preseted criteria for sepsis were considered as cases and neonates diagnosed with other medical reasons except sepsis were controls. For each case, two consecutive controls were selected by simple random sampling method. Data were collected using structured pretested questionnaire through a face to face interview with index mothers and by reviewing neonatal record using checklist. The collected data were entered into Epi data version 3.1 and exported to STATA/ SE software version 14. Binary and multivariable logistic regression analyses were employed. Statistical significance was declared at P<0.05. Result: Multivariable logistic regression analysis showed that, duration of rupture of membrane ≥ 18hours was significantly associated with sepsis (AOR = 10.4, 95%CI = 2.3–46.5). The other independent predictors of neonatal sepsis were number of maternal antenatal care service ≤3 (AOR = 4.4, 95%CI = 1.7–11.5), meconium stained amniotic fluid (AOR = 3.9, 95%CI = 1.5–9.8), urinary tract infection during pregnancy (AOR = 10.8, 95% CI = 3.4–33.9), intranatal fever (AOR = 3.2, 95% CI = 1.1–9.5), first minute APGAR score <7 (AOR = 3.2, 95% CI = 1.3–7.7), resuscitation at birth (AOR = 5.4, 95% CI = 1.9–15.5), nasogastric tube insertion (AOR = 3.7, 95% CI = 1.4–10.2). Conclusion: Neonatal invasive procedures, ANC follow up during pregnancy, different conditions during birth like meconium stained amniotic fluid, low APGAR score and resuscitation at birth were the independent predictors of neonatal sepsis. [ABSTRACT FROM AUTHOR]

Background: Based on World Health Organization guidelines, Government of India recommended management of possible serious bacterial infection (PSBI) in young infants up to two months of age on an outpatient basis where referral is not feasible. We implemented the guideline in program setting to increase access to treatment with high treatment success and low resultant mortality. Methods: Implementation research was conducted in four rural blocks of Lucknow district in Uttar Pradesh, India. It included policy dialogues with the central and state government and district level officials. A Technical Support Unit was established. Thereafter, capacity building across all cadres of health workers in the implementation area was done for strengthening of home based newborn care (HBNC) program, skills enhancement for identification and management of PSBI, logistics management to ensure availability of necessary supplies, monitoring and evaluation as well as providing feedback. Data was collected by the research team. Results: From June 2017 to February 2019 there were 24,448 live births in a population of 856106. We identified 1302 infants, aged 0–59 days, with any sign of PSBI leading to a coverage of 53% (1302/2445), assuming an incidence of 10%. However, in the establishment phase the coverage was 33%, while it was 85% in the implementation phase. Accredited social health activists (ASHAs) identified 81.2% (1058/1302) cases while rest were identified by families. ASHAs increased home visits within first 7 days of life in home based newborn care program from 74.3% (2781/3738) to 89.0% (3128/3513) and detection of cases of PSBI from 1.6% (45/2781) to 8.7% (275/3128) in the first and last quarter of the project, respectively. Of these 18.7% (244/1302) refused referral to government health system and 6.7% (88/1302) were treated in a hospital. Among cases of PSBI, there were 13.3% (173/1302) cases of fast breathing in young infant aged 7–59 days in whom referral was not needed. Of these 147 were treated by oral amoxicillin and 95.2% (140/147) were cured. Among those who needed referral, simplified treatment was given when referral was refused. There were 2.9% (37/1302) cases of fast breathing at ages of 0–6 days of which 34 were treated by simplified treatment with100% (34/34) cured;66.5% (866/1302) were cases of clinical severe infection of which 685 treated by simplified treatment with94.2% (645/685)cured and 09 died;17.3% (226/1302) cases of critical illness of which 93 were treated by simplified treatment, as a last resort, 72% (67/93) cured and 16 died. Among 255 cases who either did not seek formal treatment or sought it at private facilities, 96 died. Conclusion: Simplified treatment for PSBI is feasible in public program settings in northern India with good cure rates. It required system strengthening and supportive supervision. [ABSTRACT FROM AUTHOR]

Background: Serious infections account for 25% of global newborn deaths annually, most in low-resource settings where hospital-based treatment is not accessible or feasible. In Bangladesh, one-third of neonatal deaths are attributable to serious infection; in 2014, the government adopted new policy for outpatient management of danger signs indicating possible serious bacterial infections (PSBI) when referral was not possible. We conducted implementation research to understand what it takes for a district health team to implement quality outpatient PSBI management per national guidelines. Methods: PSBI management was introduced as part of the Comprehensive Newborn Care Package in 2015. The study piloted this package through government health systems with limited partner support to inform scale-up efforts. Data collection included facility register reviews for cases seen at primary level facilities; facility readiness and provider knowledge and skills assessments; household surveys capturing caregiver knowledge of newborn danger signs and care-seeking for newborn illness; and follow-up case tracking, capturing treatment adherence and outcomes. Analysis consisted of descriptive statistics. Results: Over the 15-month implementation period, 1432 young infants received care, of which 649 (45%) were classified as PSBI. Estimated coverage of care-seeking increased from 22% to 42% during the implementation period. Although facility readiness and providers' skills increased, providers' adherence to guidelines was not optimal. Among locally managed PSBI cases, 75% completed the oral antibiotic course and 15% received the fourth day follow-up. Care-seeking remained high among private providers (95%), predominantly village health doctors (over 80%). Conclusions: Facility readiness, including health care provider knowledge and skills were strengthened; future efforts should focus on improving provider adherence to guidelines. Social and behavior change strategies targeting families and communities should explore shifting care-seeking from private, possibly less-qualified providers. Strategies to improve private sector management of PSBI cases and improved linkages between private and public sector providers could be explored. [ABSTRACT FROM AUTHOR]

Background: Bacterial infection is one of the leading causes of mortality in young infants globally. The standard practice to manage young infants with any sign of possible serious bacterial infection (PSBI) is in a hospital setting with parenteral antibiotics, which may not be feasible for majority of cases in most low resource settings. The World Health Organization developed a guideline on management of PSBI in young infants when referral is not feasible in 2016. Methods: We conducted implementation research in selected communities in Zaria Local Government Areas of Kaduna State with an estimated population of 50,000 with the aim of understanding how to implement the WHO PSBI treatment guideline to achieve high coverage with low case fatality and treatment failure rates. Implementation was within the programmatic settings using existing health structure. We conducted policy dialogue with decision makers to adapt the recommendations to their social, cultural and programmatic context in Nigeria, held orientation meetings with program managers, built capacity of the health workers and supported the implementation within the health system. We supported a non-government organization to conduct community sensitization to promote care seeking and adherence to treatment advice. The research team collected data systematically on all young infants identified to have PSBI, the treatment they received and the clinical outcome. Results: Between April 2016 and March 2017, we identified 347 young infants up to 2 months of age with signs of PSBI who received treatment either as an outpatient or in a hospital among 2,154 births in the study population. The coverage of PSBI treatment in the study area was 95.5% assuming that 10% of all births have an episode of PSBI in the first two months of life. Most (89%) sick young infants with PSBI were identified by the community-oriented resource persons and sent to the Primary Health Care Centres (PHCs). Most families (97%) refused referral and were treated at a primary health care centre on outpatient basis. There were 12 deaths (3.5%) and 17 non-death treatment failures (4.9%) in 343 infants in whom an outcome could be ascertained. While non-death treatment failure rate was highest in 0-6-day infants with fast breathing (14.4%), case fatality was highest in those with signs of critical illness (20%). Conclusion: We have demonstrated that outpatient treatment strategy for young infants with PSBI when referral is not feasible is implementable within the programmatic settings, achieving very high population coverage and relatively low treatment failure and case fatality rates. Implementation at scale will require government's commitment to strengthen the health system with trained, motivated health care providers and necessary commodities. [ABSTRACT FROM AUTHOR]

Background: Very few data are available on treatment in HIV Late presenter population that still represents a clinical challenge. Methods: Prospective, multicenter, randomized open-label, 2 arm, phase-3 trial comparing the 48-week virological response of two different regimens: abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir in antiretroviral naive with CD4+ counts < 200/mm3 and a viral load (VL)<500,000 copies/mL. The primary Endpoint was the proportion of patients with undetectable viremia (VL<50 copies/mL) after 48 weeks. The planned sample size for this trial was 350 patients. Results: In 3 years, 53 patients were screened and 46 enrolled: 22 randomized to raltegravir and 24 to darunavir/r; 7 patients were excluded, 4 because of a VL >500,000 copies/mL and 3 for HLAB5701 positivity. The snapshot analysis at 48 weeks showed a virologic success of 77.3% in raltegravir and 66.7% in darunavir/r. Time to starting treatment was 34.5 days in raltegravir and 53 days in darunavir/r. At the as treated analysis, the median CD4 counts at 48 weeks was 297 cells/μL in raltegravir and 239 cells/μL in darunavir/r. No difference in total cholesterol, while triglycerides were higher in the darunavir/r arm. No statistical analyses were performed due to the low number of patients enrolled. Conclusions: Late presenter patients are frequent but very difficult to enroll in clinical trials, especially in western countries. These regimens and the conditions of many patients could not allow the test and treat strategy. The rate of virologic success was higher than 65% in both arms with a median CD4 cell count >200/μL at week 48. Trial registration: EUDRACT number: [ABSTRACT FROM AUTHOR]

Severe-febrile-illness (SFI) is a common cause of morbidity and mortality across sub-Saharan Africa (SSA). The burden of SFI in SSA is currently unknown and its estimation is fraught with challenges. This is due to a lack of diagnostic capacity for SFI in SSA, and thus a dearth of baseline data on the underlying etiology of SFI cases and scant SFI-specific causative-agent prevalence data. To highlight the public health significance of SFI in SSA, we developed a Bayesian model to quantify the incidence of SFI hospital admissions in SSA. Our estimates indicate a mean population-weighted SFI-inpatient-admission incidence rate of 18.4 (6.8–31.1, 68% CrI) per 1000 people for the year 2014, across all ages within areas of SSA with stable Plasmodium falciparum transmission. We further estimated a total of 16,200,337 (5,993,249–27,321,779, 68% CrI) SFI hospital admissions. This analysis reveals the significant burden of SFI in hospitals in SSA, but also highlights the paucity of pathogen-specific prevalence and incidence data for SFI in SSA. Future improvements in pathogen-specific diagnostics for causative agents of SFI will increase the abundance of SFI-specific prevalence and incidence data, aid future estimations of SFI burden, and enable clinicians to identify SFI-specific pathogens, administer appropriate treatment and management, and facilitate appropriate antibiotic use. [ABSTRACT FROM AUTHOR]

Background: The quick sequential organ failure assessment (qSOFA) score has recently been introduced to the emergency department (ED) and wards, and it predicted a higher number of deaths among patients with sepsis compared with baseline risk. However, studies about the application of the qSOFA score are limited in prehospital settings. Thus, this study aimed to assess the performance of prehospital qSOFA score in predicting the risk of mortality among patients with infection. Methods: This single center, retrospective cohort study was conducted in a Japanese tertiary care teaching hospital between April 2016 and March 2017. We enrolled all consecutive adult patients transported to the hospital by ambulance and admitted to the ED due to a suspected infection. We calculated the prehospital qSOFA score using the first vital sign obtained at the scene by emergency medical service (EMS) providers. The primary outcome was in-hospital mortality. The Cox proportional hazards model was used to assess the association between prehospital qSOFA positivity and in-hospital mortality. Results: Among the 925 patients admitted to the ED due to a suspected infection, 51.1% (473/925) were prehospital qSOFA-positive and 48.9% (452/925) were prehospital qSOFA-negative. The in-hospital mortality rates were 14.0% (66/473) in prehospital qSOFA-positive patients and 6.0% (27/452) in prehospital qSOFA-negative patients. The Cox proportional hazard regression model revealed a strong association between prehospital qSOFA score and in-hospital mortality (adjusted hazard ratio: 2.41, 95% confidence interval: 1.51–3.98; p <0.01). Conclusions: Among the patients with suspected infection who were admitted at the ED, a strong association was observed between the prehospital qSOFA score and in-hospital mortality. In order to use this score in clinical practice, future study is necessary to evaluate how infection is suspected in the prehospital arena. [ABSTRACT FROM AUTHOR]

The availability of antibiotics presents medical practitioners with a prescribing dilemma. On the one hand, antibiotics provide a safe and effective treatment option for patients with bacterial infections, but at a population level, over-prescription reduces their effectiveness by facilitating the evolution of bacteria that are resistant to antibiotic medication. A game-theoretic investigation, including analysis of equilibrium strategies, evolutionarily stability, and replicator dynamics, reveals that rational doctors, motivated to attain the best outcomes for their own patients, will prescribe antibiotics irrespective of the level of antibiotic resistance in the population and the behavior of other doctors, although they would achieve better long-term outcomes if their prescribing were more restrained. Ever-increasing antibiotic resistance may therefore be inevitable unless some means are found of modifying the payoffs of this potentially catastrophic social dilemma. [ABSTRACT FROM AUTHOR]