PURPOSE: The 2018 Kenya Population-based HIV Impact Assessment revealed gaps in HIV care among adolescents and young people living with HIV (AYPLHIV) aged 10-24 years, with only 70.6% aware of their status, of these, 93.1% on antiretroviral therapy (ART), and 79.2% of those on treatment had achieved viral load suppression (VLS). Operation Triple Zero (OTZ) aims to address these gaps by fostering intrinsic motivation in AYPLHIV to achieve good health outcomes, emphasizing zero missed appointments, zero missed medication, and zero viral load. We examine clinical outcomes of VLS, ART adherence, and retention among AYPLHIV aged 10-24 enrolled in OTZ from 2017 to 2021. METHODS: Data from 20 early adopter OTZ sites were analyzed for ART adherence, retention, viral load testing, and VLS. We compared demographic and clinical characteristics at enrollment and end line by sex, using Pearson's chi-square test for categorical variables, McNemar chi-square test, and Wilcoxon rank-sum for baseline versus end-line comparisons. RESULTS: Of 1,569 AYPLHIV enrolled in OTZ, 1,372 (87.4%) had complete records. The median age at OTZ enrollment was 12 years (interquartile range: 14-16). VLS improved from 72.7% to 88.5% (p < .001), and 96% of AYPLHIV were retained on ART. Among virally suppressed AYPLHIV at baseline (n = 958), 92.4% sustained VLS (91.9% females, 92.9% males), notably 100% among those on once-a-day dolutegravir or atazanavir. Re-suppression rate for viremic AYPLHIV at baseline (n = 360) was 78.3%. Satisfactory adherence correlated with higher re-suppression rates. DISCUSSION: OTZ implementation led to improved HIV treatment outcomes among AYPLHIV, contributing to sustained epidemic control efforts complementing other interventions.

BACKGROUND: The RTS,S/AS01(E) malaria vaccine (RTS,S) was introduced by national immunisation programmes in Ghana, Kenya, and Malawi in 2019 in large-scale pilot schemes. We aimed to address questions about feasibility and impact, and to assess safety signals that had been observed in the phase 3 trial that included an excess of meningitis and cerebral malaria cases in RTS,S recipients, and the possibility of an excess of deaths among girls who received RTS,S than in controls, to inform decisions about wider use. METHODS: In this prospective evaluation, 158 geographical clusters (66 districts in Ghana; 46 sub-counties in Kenya; and 46 groups of immunisation clinic catchment areas in Malawi) were randomly assigned to early or delayed introduction of RTS,S, with three doses to be administered between the ages of 5 months and 9 months and a fourth dose at the age of approximately 2 years. Primary outcomes of the evaluation, planned over 4 years, were mortality from all causes except injury (impact), hospital admission with severe malaria (impact), hospital admission with meningitis or cerebral malaria (safety), deaths in girls compared with boys (safety), and vaccination coverage (feasibility). Mortality was monitored in children aged 1-59 months throughout the pilot areas. Surveillance for meningitis and severe malaria was established in eight sentinel hospitals in Ghana, six in Kenya, and four in Malawi. Vaccine uptake was measured in surveys of children aged 12-23 months about 18 months after vaccine introduction. We estimated that sufficient data would have accrued after 24 months to evaluate each of the safety signals and the impact on severe malaria in a pooled analysis of the data from the three countries. We estimated incidence rate ratios (IRRs) by comparing the ratio of the number of events in children age-eligible to have received at least one dose of the vaccine (for safety outcomes), or age-eligible to have received three doses (for impact outcomes), to that in non-eligible age groups in implementation areas with the equivalent ratio in comparison areas. To establish whether there was evidence of a difference between girls and boys in the vaccine's impact on mortality, the female-to-male mortality ratio in age groups eligible to receive the vaccine (relative to the ratio in non-eligible children) was compared between implementation and comparison areas. Preliminary findings contributed to WHO's recommendation in 2021 for widespread use of RTS,S in areas of moderate-to-high malaria transmission. FINDINGS: By April 30, 2021, 652 673 children had received at least one dose of RTS,S and 494 745 children had received three doses. Coverage of the first dose was 76% in Ghana, 79% in Kenya, and 73% in Malawi, and coverage of the third dose was 66% in Ghana, 62% in Kenya, and 62% in Malawi. 26 285 children aged 1-59 months were admitted to sentinel hospitals and 13 198 deaths were reported through mortality surveillance. Among children eligible to have received at least one dose of RTS,S, there was no evidence of an excess of meningitis or cerebral malaria cases in implementation areas compared with comparison areas (hospital admission with meningitis: IRR 0·63 [95% CI 0·22-1·79]; hospital admission with cerebral malaria: IRR 1·03 [95% CI 0·61-1·74]). The impact of RTS,S introduction on mortality was similar for girls and boys (relative mortality ratio 1·03 [95% CI 0·88-1·21]). Among children eligible for three vaccine doses, RTS,S introduction was associated with a 32% reduction (95% CI 5-51%) in hospital admission with severe malaria, and a 9% reduction (95% CI 0-18%) in all-cause mortality (excluding injury). INTERPRETATION: In the first 2 years of implementation of RTS,S, the three primary doses were effectively deployed through national immunisation programmes. There was no evidence of the safety signals that had been observed in the phase 3 trial, and introduction of the vaccine was associated with substantial reductions in hospital admission with severe malaria. Evaluation continues to assess the impact of four doses of RTS,S. FUNDING: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.

BACKGROUND: All countries are required to implement International Health Regulations (IHR) through development and implementation of multi-year National Action Plans for Health Security (NAPHS). IHR implementation requires annual operational planning which involves several tools such as NAPHS, State Party Annual Report (SPAR), Joint External Evaluation (JEE) and WHO IHR Benchmarks tool. Sierra Leone has successfully improved IHR capacities across the years through successful annual operational planning using the above tools. We conducted a study to document and share the country's unique approach to implementation of NAPHS. METHODS: This was an observational study where the process of implementing and monitoring NAPHS in Sierra Leone was observed at the national level from 2018 to 2021. Data was obtained through review and analysis of NAPHS annual operational plans, quarterly review reports and annual IHR assessment reports. Available data was supplemented by information from key informants. Qualitative data was captured as notes and analysed for various themes while quantitative data was analyzed mainly for means and proportions. RESULTS: The overall national IHR Joint External Evaluation self-assessment score for human health improved from 44% in 2018 to 51% in 2019 and 57% in 2020. The score for the animal sector improved from 32% in 2018 to 43% in 2019 and 52% in 2020. A new JEE tool with new indicators was used in 2021 and the score for both human and animal sectors declined slightly to 51%. Key enablers of success included strong political commitment, whole-of-government approach, annual assessments using JEE tool, annual operational planning using WHO IHR Benchmarks tool and real time online monitoring of progress. Key challenges included disruption created by COVID-19 response, poor health infrastructure, low funding and inadequate health workforce. CONCLUSION: IHR annual operational planning and implementation using evidence-based data and tools can facilitate strengthening of IHR capacity and should be encouraged.

BACKGROUND AND AIMS: In the United States, overdose deaths resulting from methamphetamine and other amphetamine-type stimulants (METH/AMPH) have been increasing. We describe rates and characterize patients hospitalized after a METH/AMPH-involved overdose in Washington State, to guide prevention and control measures. DESIGN SETTING PARTICIPANTS: We conducted a trend analysis of hospitalized Washington State residents aged ≥15 years who received a METH/AMPH-involved overdose diagnosis in Washington's civilian hospitals and reported in the Comprehensive Hospital Abstract Reporting System. MEASUREMENTS: We used Joinpoint regression analysis to study trends in rates of hospitalized patients who received a METH/AMPH-involved overdose diagnosis during 2010-2017. We used 2016-2017 data to describe characteristics of patients with nonfatal and fatal outcomes and used chi-square test (for categorical variables) and Wilcoxon rank-sum test (for continuous variables) to compare characteristics of patients by outcome. FINDINGS: During 2010-2017, 3587 patients were hospitalized and received a METH/AMPH-involved overdose diagnosis. The age-adjusted rate for METH/AMPH-involved overdose hospitalization increased from 6.3/100,000 persons in 2010 to 8.5/100,000 persons in 2017. Patients aged ≥55 years had the greatest increase in rate of overdose hospitalizations. Among these patients, 86% also had a substance use disorder diagnosis involving substances other than METH/AMPH, and 35% experienced a polysubstance overdose. CONCLUSIONS: We observed increasing rates of METH/AMPH-involved overdose hospitalizations in Washington State, particularly among persons aged ≥55 years. Approximately a third of patients also experienced a polysubstance overdose, which can be considered when designing interventions to address increasing rates of overdose hospitalizations in Washington State.

BACKGROUND: In resource-limited settings, acute respiratory infections continue to be the leading cause of death in young children. We conducted postmortem investigations in children <5 years hospitalized with a clinical diagnosis of respiratory disease at Kenya's largest referral hospital. METHODS: We collected respiratory and other tissues postmortem to examine pathologic processes using histology, molecular and immunohistochemistry assays. Nasopharyngeal, trachea, bronchi and lung specimens were tested using 21-target respiratory pathogen real-time reverse transcription polymerase chain reaction assays deployed on Taqman Array Cards. Expert panels reviewed all findings to determine causes of death and associated pathogens. RESULTS: From 2014 to 2015, we investigated 64 pediatric deaths (median age 7 months). Pneumonia was determined as cause of death in 70% (42/52) of cases where death was associated with an infectious disease process. The main etiologies of pneumonia deaths were respiratory syncytial virus (RSV) (n = 7, 19%), Pneumocystis jirovecii (n = 7, 19%), influenza A (n = 5, 14%) and Streptococcus pneumoniae (n = 5, 14%)-10% of cases had multi-pathogen involvement. Among the other 10 deaths associated with a nonpneumonia infectious process, 4 did not have an etiology assigned, the others were associated with miliary tuberculosis (2), cerebral thrombosis due to HIV (1), Enterobacteriaceae (1), rotavirus (1), and 1 case of respiratory infection with severe hypokalemia associated with RSV. CONCLUSIONS: In spite of well-established vaccination programs in Kenya, some deaths were still vaccine preventable. Accelerated development of RSV monoclonal antibodies and vaccines, introduction of seasonal influenza vaccination, and maintenance or improved uptake of existing vaccines can contribute to further reductions in childhood mortality.

To assess transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a detention facility experiencing a coronavirus disease outbreak and evaluate testing strategies, we conducted a prospective cohort investigation in a facility in Louisiana, USA. We conducted SARS-CoV-2 testing for detained persons in 6 quarantined dormitories at various time points. Of 143 persons, 53 were positive at the initial test, and an additional 58 persons were positive at later time points (cumulative incidence 78%). In 1 dormitory, all 45 detained persons initially were negative; 18 days later, 40 (89%) were positive. Among persons who were SARS-CoV-2 positive, 47% (52/111) were asymptomatic at the time of specimen collection; 14 had replication-competent virus isolated. Serial SARS-CoV-2 testing might help interrupt transmission through medical isolation and quarantine. Testing in correctional and detention facilities will be most effective when initiated early in an outbreak, inclusive of all exposed persons, and paired with infection prevention and control.

Introduction: South Africa has the world's largest antiretroviral treatment programme, which may contribute to the adverse drug reaction (ADR) burden. We aimed to determine the proportion of adult non-trauma emergency unit (EU) presentations attributable to ADRs and to characterise ADR-related EU presentations, stratified according to HIV status, to determine the contribution of drugs used in management of HIV and its complications to ADR-related EU presentations, and identify factors associated with ADR-related EU presentation. Methods: We conducted a retrospective folder review on a random 1.7% sample of presentations over a 12-month period in 2014/2015 to the EUs of two hospitals in Cape Town, South Africa. We identified potential ADRs with the help of a trigger tool. A multidisciplinary panel assessed potential ADRs for causality, severity, and preventability. Results: We included 1010 EU presentations and assessed 80/1010 (7.9%) as ADR-related, including 20/239 (8.4%) presentations among HIV-positive attendees. Among HIV-positive EU attendees with ADRs 17/20 (85%) were admitted, versus 22/60 (37%) of HIV-negative/unknown EU attendees. Only 5/21 (24%) ADRs in HIV-positive EU attendees were preventable, versus 24/63 (38%) in HIV-negative/unknown EU attendees. On multivariate analysis, only increasing drug count was associated with ADR-related EU presentation (adjusted odds ratio 1.10 per additional drug, 95% confidence interval 1.03 to 1.18), adjusted for age, sex, HIV status, comorbidity, and hospital. Conclusions: ADRs caused a significant proportion of EU presentations, similar to findings from other resource-limited settings. The spectrum of ADR manifestations in our EUs reflects South Africa's colliding epidemics of infectious and non-communicable diseases. ADRs among HIV-positive EU attendees were more severe and less likely to be preventable.

BACKGROUND: Although many viral respiratory illnesses are transmitted within households, the evidence base for SARS-CoV-2 is nascent. We sought to characterize SARS-CoV-2 transmission within US households and estimate the household secondary infection rate (SIR) to inform strategies to reduce transmission. METHODS: We recruited laboratory-confirmed COVID-19 patients and their household contacts in Utah and Wisconsin during March 22-April 25, 2020. We interviewed patients and all household contacts to obtain demographics and medical histories. At the initial household visit, 14 days later, and when a household contact became newly symptomatic, we collected respiratory swabs from patients and household contacts for testing by SARS-CoV-2 rRT-PCR and sera for SARS-CoV-2 antibodies testing by enzyme-linked immunosorbent assay (ELISA). We estimated SIR and odds ratios (OR) to assess risk factors for secondary infection, defined by a positive rRT-PCR or ELISA test. RESULTS: Thirty-two (55%) of 58 households had evidence of secondary infection among household contacts. The SIR was 29% (n = 55/188; 95% confidence interval [CI]: 23-36%) overall, 42% among children (<18 years) of the COVID-19 patient and 33% among spouses/partners. Household contacts to COVID-19 patients with immunocompromised conditions had increased odds of infection (OR: 15.9, 95% CI: 2.4-106.9). Household contacts who themselves had diabetes mellitus had increased odds of infection (OR: 7.1, 95% CI: 1.2-42.5). CONCLUSIONS: We found substantial evidence of secondary infections among household contacts. People with COVID-19, particularly those with immunocompromising conditions or those with household contacts with diabetes, should take care to promptly self-isolate to prevent household transmission.

Identifying determinants of HIV reservoir levels may inform novel viral eradication strategies. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) co-infections were assessed as predictors of HIV proviral DNA level in 26 HIV RNA-suppressed Kenyan children starting antiretroviral therapy (ART) before 7 months of age. Earlier acquisition of CMV and EBV, and higher cumulative burden of systemic EBV DNA viremia were each associated with higher HIV DNA level in the reservoir after 24 months of ART, independent of HIV RNA levels over time. These data suggest delaying or containing CMV and EBV viremia may be novel strategies to limit HIV reservoir formation.

BACKGROUND AND OBJECTIVES: Limited data exist on severe acute respiratory syndrome coronavirus 2 in children. We described infection rates and symptom profiles among pediatric household contacts of individuals with coronavirus disease 2019. METHODS: We enrolled individuals with coronavirus disease 2019 and their household contacts, assessed daily symptoms prospectively for 14 days, and obtained specimens for severe acute respiratory syndrome coronavirus 2 real-time reverse transcription polymerase chain reaction and serology testing. Among pediatric contacts (<18 years), we described transmission, assessed the risk factors for infection, and calculated symptom positive and negative predictive values. We compared secondary infection rates and symptoms between pediatric and adult contacts using generalized estimating equations. RESULTS: Among 58 households, 188 contacts were enrolled (120 adults; 68 children). Secondary infection rates for adults (30%) and children (28%) were similar. Among households with potential for transmission from children, child-to-adult transmission may have occurred in 2 of 10 (20%), and child-to-child transmission may have occurred in 1 of 6 (17%). Pediatric case patients most commonly reported headache (79%), sore throat (68%), and rhinorrhea (68%); symptoms had low positive predictive values, except measured fever (100%; 95% confidence interval [CI]: 44% to 100%). Compared with symptomatic adults, children were less likely to report cough (odds ratio [OR]: 0.15; 95% CI: 0.04 to 0.57), loss of taste (OR: 0.21; 95% CI: 0.06 to 0.74), and loss of smell (OR: 0.29; 95% CI: 0.09 to 0.96) and more likely to report sore throat (OR: 3.4; 95% CI: 1.04 to 11.18). CONCLUSIONS: Children and adults had similar secondary infection rates, but children generally had less frequent and severe symptoms. In two states early in the pandemic, we observed possible transmission from children in approximately one-fifth of households with potential to observe such transmission patterns.

BACKGROUND: Improved understanding of SARS-CoV-2 spectrum of disease is essential for clinical and public health interventions. There are limited data on mild or asymptomatic infections, but recognition of these individuals is key as they contribute to viral transmission. We describe the symptom profiles from individuals with mild or asymptomatic SARS-CoV-2 infection. METHODS: From March 22 to April 22, 2020 in Wisconsin and Utah, we enrolled and prospectively observed 198 household contacts exposed to SARS-CoV-2. We collected and tested nasopharyngeal (NP) specimens by RT-PCR two or more times during a 14-day period. Contacts completed daily symptom diaries. We characterized symptom profiles on the date of first positive RT-PCR test and described progression of symptoms over time. RESULTS: We identified 47 contacts, median age 24 (3-75) years, with detectable SARS-CoV-2 by RT-PCR. The most commonly reported symptoms on the day of first positive RT-PCR test were upper respiratory (n=32, 68%) and neurologic (n=30, 64%); fever was not commonly reported (n=9, 19%). Eight (17%) individuals were asymptomatic at the date of first positive RT-PCR collection; two (4%) had preceding symptoms that resolved and six (13%) subsequently developed symptoms. Children less frequently reported lower respiratory symptoms (age <18: 21%, age 18-49: 60%, age 50+ years: 69%; p=0.03). CONCLUSIONS: Household contacts with lab-confirmed SARS-CoV-2 infection reported mild symptoms. When assessed at a single time-point, several contacts appeared to have asymptomatic infection; however, over time all developed symptoms. These findings are important to inform infection control, contact tracing, and community mitigation strategies.

Transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), by asymptomatic and presymptomatic persons poses important challenges to controlling spread of the disease, particularly in congregate settings such as correctional and detention facilities (1). On March 29, 2020, a staff member in a correctional and detention facility in Louisiana developed symptoms(dagger) and later had a positive test result for SARS-CoV-2. During April 2-May 7, two additional cases were detected among staff members, and 36 cases were detected among incarcerated and detained persons at the facility; these persons were removed from dormitories and isolated, and the five dormitories that they had resided in before diagnosis were quarantined. On May 7, CDC and the Louisiana Department of Health initiated an investigation to assess the prevalence of SARS-CoV-2 infection among incarcerated and detained persons residing in quarantined dormitories. Goals of this investigation included evaluating COVID-19 symptoms in this setting and assessing the effectiveness of serial testing to identify additional persons with SARS-CoV-2 infection as part of efforts to mitigate transmission. During May 7-21, testing of 98 incarcerated and detained persons residing in the five quarantined dormitories (A-E) identified an additional 71 cases of SARS-CoV-2 infection; 32 (45%) were among persons who reported no symptoms at the time of testing, including three who were presymptomatic. Eighteen cases (25%) were identified in persons who had received negative test results during previous testing rounds. Serial testing of contacts from shared living quarters identified persons with SARS-CoV-2 infection who would not have been detected by symptom screening alone or by testing at a single time point. Prompt identification and isolation of infected persons is important to reduce further transmission in congregate settings such as correctional and detention facilities and the communities to which persons return when released.

Maternal and neonatal tetanus* (MNT) remains a major public health problem, with an 80%-100% case-fatality rate among neonates, especially in areas with poor immunization coverage and limited access to clean deliveries (i.e., delivery in a health facility or assisted by medically trained attendants in sanitary conditions) and umbilical cord care (1). In 1989, the World Health Assembly endorsed the elimination(dagger) of neonatal tetanus (NT), and in 1999, the initiative was relaunched and renamed the MNT elimination( section sign) initiative, targeting 59( paragraph sign) priority countries (1). Elimination strategies include 1) achieving >/=80% coverage with >/=2 doses of tetanus toxoid-containing vaccine (TTCV) among women of reproductive age through routine immunization of pregnant women and supplementary immunization activities (SIAs)** in high-risk areas and districts(daggerdagger); 2) achieving care at >/=70% of deliveries by a skilled birth attendant (SBA)( section sign section sign); and 3) enhancing surveillance for NT cases (1). This report summarizes progress toward achieving MNT elimination during 2000-2018. Coverage with >/=2 doses of TTCV (2 doses of tetanus toxoid [TT2+] or 2 doses of tetanus-diphtheria toxoid [Td2+]) among women of reproductive age increased by 16%, from 62% in 2000 to 72% in 2018. By December 2018, 52 (88%) of 59 priority countries had conducted TTCV SIAs, vaccinating 154 million (77%) of 201 million targeted women of reproductive age with TT2+/Td2+. Globally, the percentage of deliveries assisted by SBAs increased from 62% during 2000-2005 to 81% during 2013-2018, and estimated neonatal tetanus deaths decreased by 85%, from 170,829 in 2000 to 25,000 in 2018. By December 2018, 45 (76%) of 59 priority countries were validated by WHO as having achieved MNT elimination. To achieve elimination in the remaining 14 countries and sustain elimination in countries that have achieved it, implementation of MNT elimination strategies needs to be maintained and strengthened, and TTCV booster doses need to be included in country immunization schedules as recommended by the World Health Organization (WHO) (2). In addition, integration of maternal, newborn, and child health services with vaccination services is needed, as well as innovative approaches to target hard-to-reach areas for tetanus vaccination and community engagement to strengthen surveillance.

Tropical splenomegaly is often associated with malaria and schistosomiasis. In 2014 and 2015, 145 Congolese refugees in western Uganda diagnosed with splenomegaly during predeparture medical examinations underwent enhanced screening for various etiologies. After anecdotal reports of unresolved splenomegaly and complications after U.S. arrival, patients were reassessed to describe long-term clinical progression after arrival in the United States. Post-arrival medical information was obtained through medical chart abstraction in collaboration with state health partners in nine participating states. We evaluated observed splenomegaly duration and associated clinical sequelae between 130 case patients from eastern Congo and 102 controls through adjusted hierarchical Poisson models, accounting for familial clustering. Of the 130 case patients, 95 (73.1%) had detectable splenomegaly after arrival. Of the 85 patients with records beyond 6 months, 45 (52.9%) had persistent splenomegaly, with a median persistence of 14.7 months (range 6.0-27.9 months). Of the 112 patients with available results, 65 (58.0%) patients had evidence of malaria infection, and the mean splenomegaly duration did not differ by Plasmodium species. Refugees with splenomegaly on arrival were 43% more likely to have anemia (adjusted relative risk [aRR]: 1.43, 95% CI: 1.04-1.97). Those with persistent splenomegaly were 60% more likely (adjusted relative risk [aRR]: 1.60, 95% CI: 1.15-2.23) to have a hematologic abnormality, particularly thrombocytopenia (aRR: 5.53, 95% CI: 1.73-17.62), and elevated alkaline phosphatase (aRR: 1.57, 95% CI: 1.03-2.40). Many patients experienced persistent splenomegaly, contradicting literature describing resolution after treatment and removal from an endemic setting. Other possible etiologies should be investigated and effective treatment, beyond treatment for malaria and schistosomiasis, explored.

The Global Health Security Agenda aims to improve countries' ability to prevent, detect, and respond to infectious disease threats by building or strengthening core capacities required by the International Health Regulations (2005). One of those capacities is the development of surveillance systems to rapidly detect and respond to occurrences of diseases with epidemic potential. Since 2015, the US Centers for Disease Control and Prevention (CDC) has worked with partners in Sierra Leone to assist the Ministry of Health and Sanitation in developing an Integrated Disease Surveillance and Response (IDSR) system. Beginning in 2016, CDC, in collaboration with the World Health Organization and eHealth Africa, has supported the ministry in the development of Android device mobile data entry at the health facility for electronic IDSR (eIDSR), also known as health facility-based eIDSR. Health facility-based eIDSR was introduced via a pilot program in 1 district, and national rollout began in 2018. With more than 1,100 health facilities now reporting, the Sierra Leone eIDSR system is substantially larger than most mobile-device health (mHealth) projects found in the literature. Several technical innovations contributed to the success of health facility-based eIDSR in Sierra Leone. Among them were data compression and dual-mode (internet and text) message transmission to mitigate connectivity issues, user interface design tailored to local needs, and a continuous-feedback process to iteratively detect user or system issues and remediate challenges identified. The resultant system achieved high user acceptance and demonstrated the feasibility of an mHealth-based surveillance system implemented on a national scale.

BACKGROUND: We assessed the safety and immunogenicity of the RTS,S/AS01 malaria vaccine in a subset of children identified as HIV-infected during a large phase III randomized controlled trial conducted in seven sub-Saharan African countries. METHODS: Infants 6-12 weeks and children 5-17 months old were randomized to receive 4 RTS,S/AS01 doses (R3R group), 3 RTS,S/AS01 doses plus 1 comparator vaccine dose (R3C group), or 4 comparator vaccine doses (C3C group) at study months 0, 1, 2 and 20. Infants and children with WHO stage III/IV HIV disease were excluded but HIV testing was not routinely performed on all participants; our analyses included children identified as HIV-infected based on medical history or clinical suspicion and confirmed by polymerase chain reaction or antibody testing. Serious adverse events (SAEs) and anti-circumsporozoite (CS) antibodies were assessed. RESULTS: Of 15459 children enrolled in the trial, at least 1953 were tested for HIV and 153 were confirmed as HIV-infected (R3R: 51; R3C: 54; C3C: 48). Among these children, SAEs were reported for 92.2% (95% CI: 81.1-97.8) in the R3R, 85.2% (72.9-93.4) in the R3C and 87.5% (74.8-95.3) in the C3C group over a median follow-up of 39.3, 39.4 and 38.3 months, respectively. Fifteen HIV-infected participants in each group (R3R: 29.4%, R3C: 27.8%, C3C: 31.3%) died during the study. No deaths were considered vaccination-related. In a matched case-control analysis, 1 month post dose 3 anti-CS geometric mean antibody concentrations were 193.3 EU/mL in RTS,S/AS01-vaccinated HIV-infected children and 491.5 EU/mL in RTS,S/AS01-vaccinated immunogenicity controls with unknown or negative HIV status (p=0.0001). CONCLUSIONS: The safety profile of RTS,S/AS01 in HIV-infected children was comparable to that of the comparator (meningococcal or rabies) vaccines. RTS,S/AS01 was immunogenic in HIV-infected children but antibody concentrations were lower than in children with an unknown or negative HIV status. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00866619.

Molecular diagnostic methods are becoming increasingly available for assessment of acute lower respiratory illnesses (ALRI). However, nasopharyngeal/oropharyngeal (NP/OP) swabs may not accurately reflect etiologic agents from the lower respiratory tract where sputum specimens are considered as a more representative sample. The pathogen yields from NP/OP against sputum specimens have not been extensively explored, especially in tropical countries. We compared pathogen yields from NP/OP swabs and sputum specimens from patients ≥18 years hospitalized with ALRI in rural Western Kenya. Specimens were tested for 30 pathogens using TaqMan Array Cards (TAC) and results compared using McNemar’s test. The agreement for pathogen detection between NP/OP and sputum specimens ranged between 85–100%. More viruses were detected from NP/OP specimens whereas Klebsiella pneumoniae and Mycobacterium tuberculosis were more common in sputum specimens. There was no clear advantage in using sputum over NP/OP specimens to detect pathogens of ALRI in adults using TAC in the context of this tropical setting.

BACKGROUND: Clinical autopsies are not often part of routine care, despite their role in clarifying cause of death. In fact, autopsy rates across the world have declined and are especially low in sub-Saharan Africa. OBJECTIVES: We set out to identify factors associated with acceptance of pediatric autopsies among parents of deceased children less than five years old, and examined local preferences for minimally invasive tissue sampling (MITS) procedures during post-mortem (PM) examinations. METHODS: From December 2016 to September 2017, we contacted 113 parents/next of kin who had been previously approached to consent to a PM examination of their deceased child as part of a Kenyan study on cause of death. Interviews occurred up to three years after the death of their child. FINDINGS: Seventy-three percent (83/113) of eligible study participants were enrolled, of whom 62/83 (75%) had previously consented to PM examination of their child. Those who previously consented to PM had higher levels of education, were more likely employed, and had more knowledge about certain aspects of autopsies than non-consenters. The majority (97%) of PM consenters did so because they wanted to know the cause of death of their child, and up to a third believed autopsy studies helped advance medical knowledge. Reasons for non-consent to PM examination included: parents felt there was no need for further examination (29%) or they were satisfied with the clinical diagnosis (24%). Overall, only 40% of study participants would have preferred MITS procedures to conventional autopsy. However, 81% of autopsy non-consenters would have accepted PM examination if it only involved MITS techniques. CONCLUSION: There is potential to increase autopsy rates by strengthening reasons for acceptance and addressing modifiable reasons for refusals. Although MITS procedures have the potential to improve autopsy acceptance rates, they were not significantly preferred over conventional autopsies in our study population.

A phase III, double-blind, randomized, controlled trial (NCT00866619) in sub-Saharan Africa showed RTS,S/AS01 vaccine efficacy against malaria. We now present in-depth safety results from this study. 8922 children (enrolled at 5-17 months) and 6537 infants (enrolled at 6-12 weeks) were 1:1:1-randomized to receive 4 doses of RTS,S/AS01 (R3R) or non-malaria control vaccine (C3C), or 3 RTS,S/AS01 doses plus control (R3C). Aggregate safety data were reviewed by a multi-functional team. Severe malaria with Blantyre Coma Score </=2 (cerebral malaria [CM]) and gender-specific mortality were assessed post-hoc. Serious adverse event (SAE) and fatal SAE incidences throughout the study were 24.2%-28.4% and 1.5%-2.5%, respectively across groups; 0.0%-0.3% of participants reported vaccination-related SAEs. The incidence of febrile convulsions in children was higher during the first 2-3 days post-vaccination with RTS,S/AS01 than with control vaccine, consistent with the time window of post-vaccination febrile reactions in this study (mostly the day after vaccination). A statistically significant numerical imbalance was observed for meningitis cases in children (R3R: 11, R3C: 10, C3C: 1) but not in infants. CM cases were more frequent in RTS,S/AS01-vaccinated children (R3R: 19, R3C: 24, C3C: 10) but not in infants. All-cause mortality was higher in RTS,S/AS01-vaccinated versus control girls (2.4% vs 1.3%, all ages) in our setting with low overall mortality. The observed meningitis and CM signals are considered likely chance findings, that - given their severity - warrant further evaluation in phase IV studies and WHO-led pilot implementation programs to establish the RTS,S/AS01 benefit-risk profile in real-life settings.

OBJECTIVES: We compared minimally invasive tissue sampling (MITS) with conventional autopsy (CA) in detection of respiratory pathology/pathogens among Kenyan children younger than 5 years who were hospitalized with respiratory disease and died during hospitalization. METHODS: Pulmonary MITS guided by anatomic landmarks was followed by CA. Lung tissues were triaged for histology and molecular testing using TaqMan Array Cards (TACs). MITS and CA results were compared for adequacy and concordance. RESULTS: Adequate pulmonary tissue was obtained by MITS from 54 (84%) of 64 respiratory deaths. Comparing MITS to CA, full histologic diagnostic concordance was present in 23 (36%) cases and partial concordance in 19 (30%), an overall 66% concordance rate. Pathogen detection using TACs had full concordance in 27 (42%) and partial concordance in 24 (38%) cases investigated, an overall 80% concordance rate. CONCLUSIONS: MITS is a viable alternative to CA in respiratory deaths in resource-limited settings, especially if combined with ancillary tests to optimize diagnostic accuracy.

During January 22-March 23, 2018, a local health department in Washington was notified of two patients who received a diagnosis of acute hepatitis C virus (HCV) infection. Neither patient had behavioral risk factors associated with HCV acquisition; however, both had received injectable narcotic (opioid) drugs from the same nurse during separate visits to an emergency department (ED) at a local hospital on December 6 and December 16, 2017. Investigation revealed that the nurse had accessed the automated drug dispensing system at a higher frequency than had other staff members, admitted diverting* patients' injectable narcotic and antihistamine drugs for personal use, and tested positive for HCV antibodies (anti-HCV) on March 19, 2018, but did not have quantifiable HCV RNA. Specimens from both patients were sent to CDC for genetic testing, and HCV viral variants analysis found a significant level of genetically similar HCV variants in both patients, indicating a common source of infection. Further investigation was conducted to confirm the infection source, identify other potentially exposed patients, and treat any new patients who received an HCV diagnosis. Monitoring frequency of access to drug dispensing systems can help identify staff members with abnormal dispensing patterns, including diversion activities (1). U.S. health care facilities are required to prevent, identify, and report any loss, diversion, or theft of controlled substances (2).

BACKGROUND: In sub-Saharan Africa, where the burden of respiratory disease-related deaths is the highest, information on the cause of death remains inadequate because of poor access to health care and limited availability of diagnostic tools. Postmortem examination can aid in the ascertainment of causes of death. This manuscript describes the study protocol for the Pediatric Respiratory Etiology Surveillance Study (PRESS). OBJECTIVE: This study protocol aims to identify causes and etiologies associated with respiratory disease-related deaths among children (age 1-59 months) with respiratory illness admitted to the Kenyatta National Hospital (KNH), the largest public hospital in Kenya, through postmortem examination coupled with innovative approaches to laboratory investigation. METHODS: We prospectively followed children hospitalized with respiratory illness until the end of clinical care or death. In case of death, parents or guardians were offered grief counseling, and postmortem examination was offered. Lung tissue specimens were collected using minimally invasive tissue sampling and conventional autopsy where other tissues were collected. Tissues were tested using histopathology, immunohistochemistry, and multipathogen molecular-based assays to identify pathogens. For each case, clinical and laboratory data were reviewed by a team of pathologists, clinicians, laboratorians, and epidemiologists to assign a cause of and etiology associated with death. RESULTS: We have enrolled pediatric cases of respiratory illness hospitalized at the KNH at the time of this submission; of those, 14.8% (140/945) died while in the hospital. Both analysis and interpretation of laboratory results and writing up of findings are expected in 2019-2020. CONCLUSIONS: Postmortem studies can help identify major pathogens contributing to respiratory-associated deaths in children. This information is needed to develop evidence-based prevention and treatment policies that target important causes of pediatric respiratory mortality and assist with the prioritization of local resources. Furthermore, PRESS can provide insights into the interpretation of results using multipathogen testing platforms in resource-limited settings. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/10854.

OBJECTIVE: To describe available models of HIV and noncommunicable disease (NCD) care integration in sub-Saharan Africa (SSA). DESIGN: Narrative review of published articles describing various models of HIV and NCD care integration in SSA. RESULTS: We identified five models of care integration across various SSA countries. These were integrated community-based screening for HIV and NCDs in the general population; screening for NCDs and NCD risk factors among HIV patients enrolled in care; integration of HIV and NCD care within clinics; differentiated care for patients with HIV and/or NCDs; and population healthcare for all. We illustrated these models with descriptive case studies highlighting the lessons learned and evidence gaps from the various models. CONCLUSION: Leveraging existing HIV infrastructure for NCD care is feasible with various approaches possible depending on available program capacity. Process and clinical outcomes for existing models of care integration are not yet described but are urgently required to further advise policy decisions on HIV/NCD care integration.

Serosurveys are useful for assessing population susceptibility to vaccine-preventable disease outbreaks. Although at-risk populations in remote areas could benefit from this type of information, they face several logistical barriers to implementation, such as lack of access to centralized laboratories, cold storage, and transport of samples. We describe a potential solution: a compact and portable, field-deployable, point-of-care system relying on digital microfluidics that can rapidly test a small volume of capillary blood for disease-specific antibodies. This system uses inexpensive, inkjet-printed digital microfluidic cartridges together with an integrated instrument to perform enzyme-linked immunosorbent assays (ELISAs). We performed a field validation of the system's analytical performance at Kakuma refugee camp, a remote setting in northwestern Kenya, where we tested children aged 9 to 59 months and caregivers for measles and rubella immunoglobulin G (IgG). The IgG assays were determined to have sensitivities of 86% [95% confidence interval (CI), 79 to 91% (measles)] and 81% [95% CI, 73 to 88% (rubella)] and specificities of 80% [95% CI, 49 to 94% (measles)] and 91% [95% CI, 76 to 97% (rubella)] (measles, n = 140; rubella, n = 135) compared with reference tests (measles IgG and rubella IgG ELISAs from Siemens Enzygnost) conducted in a centralized laboratory. These results demonstrate a potential role for this point-of-care system in global serological surveillance, particularly in remote areas with limited access to centralized laboratories.

BACKGROUND: Influenza-associated respiratory illness was substantial during the emergence of the 2009 influenza pandemic. Estimates of influenza burden in the post-pandemic period are unavailable to guide Kenyan vaccine policy. OBJECTIVES: To update estimates of hospitalized and non-hospitalized influenza-associated severe acute respiratory illness (SARI) during a post-pandemic period (2012-2014) and describe the incidence of disease by narrow age categories. METHODS: We used data from Siaya County Referral Hospital to estimate age-specific base rates of SARI. We extrapolated these base rates to other regions within the country by adjusting for regional risk factors for acute respiratory illness (ARI), regional healthcare utilization for acute respiratory illness, and the proportion of influenza-positive SARI cases in each region, so as to obtain region-specific rates. RESULTS: The mean annual rate of hospitalized influenza-associated SARI among all ages was 21 (95% CI 19-23) per 100 000 persons. Rates of non-hospitalized influenza-associated SARI were approximately 4 times higher at 82 (95% CI 74-90) per 100 000 persons. Mean annual rates of influenza-associated SARI were highest in children <2 years of age with annual hospitalization rates of 147 (95% CI of 134-160) per 100 000 persons and non-hospitalization rates of 469 (95% CI 426-517) per 100 000 persons. For the period 2012-2014, there were between 8153 and 9751 cases of hospitalized influenza-associated SARI and 31 785-38 546 cases of non-hospitalized influenza-associated SARI per year. CONCLUSIONS: The highest burden of disease was observed among children <2 years of age. This highlights the need for strategies to prevent influenza infections in this age group.

BACKGROUND: Respiratory diseases cause substantial morbidity and mortality worldwide, with sub-Saharan Africa bearing the greatest burden. Identifying etiologies of respiratory disease is important to inform cost effective treatment, prevention and control strategies. Testing for all of the different pathogens that are potentially associated with respiratory illnesses is challenging. We piloted the use of a multi-pathogen respiratory Taqman Array Cards (TAC) to identify pathogens in respiratory samples collected from non-fatal and fatal cases and their matched asymptomatic controls. METHODS: This is a case control study comparing viral and bacterial pathogens detected among non-fatal and fatal cases to those detected among age and time matched asymptomatic controls. We used McNemar's test to compare proportions of pathogens detected among cases (non-fatal and fatal) to their matched asymptomatic controls. We used Mann-Whitney test to compare the distribution of median Cycle threshold (Ct) values among non-fatal and fatal cases to their corresponding asymptomatic controls. RESULTS: There were 72 fatal and 72 non-fatal cases matched to 72 controls. We identified at least one pathogen in 109/144 (76%) cases and 59/72 (82%) controls. For most pathogens, the median Ct values were lower among cases (fatal and non-fatal) compared to asymptomatic controls. CONCLUSIONS: Similar rates of pathogen detection among cases and controls make interpretation of results challenging. Ct-values might be helpful in interpreting clinical relevance of detected pathogens using multi-pathogen diagnostic tools.

BACKGROUND: In order to better understand respiratory syncytial virus (RSV) epidemiology and burden in tropical Africa, optimal case definitions for detection of RSV cases need to be identified. METHODS: We used data collected between September 2009 - August 2013 from children aged <5 years hospitalized with acute respiratory Illness at Siaya County Referral Hospital. We evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of individual signs, symptoms and standard respiratory disease case definitions (severe acute respiratory illness [SARI]; hospitalized influenza-like illness [hILI]; integrated management of childhood illness [IMCI] pneumonia) to detect laboratory-confirmed RSV infection. We also evaluated an alternative case definition of cough or difficulty breathing plus hypoxia, in-drawing, or wheeze. RESULTS: Among 4714 children hospitalized with ARI, 3810 (81 %) were tested for RSV; and 470 (12 %) were positive. Among individual signs and symptoms, cough alone had the highest sensitivity to detect laboratory-confirmed RSV [96 %, 95 % CI (95-98)]. Hypoxia, wheezing, stridor, nasal flaring and chest wall in-drawing had sensitivities ranging from 8 to 31 %, but had specificities >75 %. Of the standard respiratory case definitions, SARI had the highest sensitivity [83 %, 95 % CI (79-86)] whereas IMCI severe pneumonia had the highest specificity [91 %, 95 % CI (90-92)]. The alternative case definition (cough or difficulty breathing plus hypoxia, in-drawing, or wheeze) had a sensitivity of [55 %, 95 % CI (50-59)] and a specificity of [60 %, 95 % CI (59-62)]. The PPV for all case definitions and individual signs/symptoms ranged from 11 to 20 % while the negative predictive values were >87 %. When we stratified by age <1 year and 1- < 5 years, difficulty breathing, severe pneumonia and the alternative case definition were more sensitive in children aged <1 year [70 % vs. 54 %, p < 0.01], [19 % vs. 11 %, p = 0.01] and [66 % vs. 43 %, p < 0.01] respectively, while non-severe pneumonia was more sensitive [14 % vs. 26 %, p < 0.01] among children aged 1- < 5 years. CONCLUSION: The sensitivity and specificity of different commonly used case definitions for detecting laboratory-confirmed RSV cases varied widely, while the positive predictive value was consistently low. Optimal choice of case definition will depend upon study context and research objectives.

Although the severe acute respiratory illness (SARI) case definition is increasingly used for inpatient influenza surveillance, pneumonia is a more familiar term to clinicians and policymakers. We evaluated WHO case definitions for severe acute respiratory illness (SARI) and pneumonia (Integrated Management of Childhood Illnesses (IMCI) for children aged <5 years and Integrated Management of Adolescent and Adult Illnesses (IMAI) for patients aged ≥13 years) for detecting laboratory-confirmed influenza among hospitalized ARI patients. Sensitivities were 84% for SARI and 69% for IMCI pneumonia in children aged <5 years and 60% for SARI and 57% for IMAI pneumonia in patients aged ≥13 years. Clinical pneumonia case definitions may be a useful complement to SARI for inpatient influenza surveillance.

Limited data exist on the burden of serious adverse drug reactions (ADRs) in sub-Saharan Africa, which has high HIV and tuberculosis prevalence. We determined the proportion of adult admissions attributable to ADRs at 4 hospitals in South Africa. We characterized drugs implicated in, risk factors for, and the preventability of ADR-related admissions.We prospectively followed patients admitted to 4 hospitals' medical wards over sequential 30-day periods in 2013 and identified suspected ADRs with the aid of a trigger tool. A multidisciplinary team performed causality, preventability, and severity assessment using published criteria. We categorized an admission as ADR-related if the ADR was the primary reason for admission.There were 1951 admissions involving 1904 patients: median age was 50 years (interquartile range 34-65), 1057 of 1904 (56%) were female, 559 of 1904 (29%) were HIV-infected, and 183 of 1904 (10%) were on antituberculosis therapy (ATT). There were 164 of 1951 (8.4%) ADR-related admissions. After adjustment for age and ATT, ADR-related admission was independently associated (P ≤ 0.02) with female sex (adjusted odds ratio [aOR] 1.51, 95% confidence interval [95% CI] 1.06-2.14), increasing drug count (aOR 1.14 per additional drug, 95% CI 1.09-1.20), increasing comorbidity score (aOR 1.23 per additional point, 95% CI 1.07-1.41), and use of antiretroviral therapy (ART) if HIV-infected (aOR 1.92 compared with HIV-negative/unknown, 95% CI 1.17-3.14). The most common ADRs were renal impairment, hypoglycemia, liver injury, and hemorrhage. Tenofovir disoproxil fumarate, insulin, rifampicin, and warfarin were most commonly implicated, respectively, in these 4 ADRs. ART, ATT, and/or co-trimoxazole were implicated in 56 of 164 (34%) ADR-related admissions. Seventy-three of 164 (45%) ADRs were assessed as preventable.In our survey, approximately 1 in 12 admissions was because of an ADR. The range of ADRs and implicated drugs reflect South Africa's high HIV and tuberculosis burden. Identification and management of these ADRs should be considered in HIV and tuberculosis care and treatment programs and should be emphasized in health care worker training programmes.

BACKGROUND: In Africa, recent surveillance has demonstrated a high burden of influenza, but influenza vaccine is rarely used. In Kenya, a country with a tropical climate, influenza has been shown to circulate year-round, like in other tropical countries. METHODS: During three months in 2010 and 2011, and two months in 2012, the Kenya Medical Research Institute/CDC-Kenya offered free injectable trivalent inactivated influenza vaccine to children 6 months-10 years old in two resource-poor communities in Kenya - Kibera andLwak (total population ~50,000). We conducted a case-control study to evaluate vaccine effectiveness (VE)in preventing laboratory-confirmed influenza associated with influenza-like illness and acute lower respiratory illness. RESULTS: Of 52,000 eligible children, 41%, 48%, and 51% received at least one vaccine in 2010, 2011, and 2012, respectively; 30%, 36%, and 38% were fully vaccinated. VE among fully vaccinated children was 57% (95% CI = 29-74%) during a 6-month follow-up period, 39% (95% CI = 17-56%) during a 9-month follow-up period, and 48% (95% CI = 32-61%) during a 12-month follow-up period. For the 12-month follow-up period, VE was statistically significant in children < 5 years and children 5 years old < 10 years old (50% and 46%, respectively). CONCLUSIONS: In Kenya, parents of nearly half of eligible children under 10 years old chose to get their children vaccinated with a free influenza vaccine. During a 12-month follow-up period the vaccine was moderately effective in preventing medically attended influenza-associated respiratory illness.