OBJECTIVE: Estimate the incremental costs and benefits of scaling up hypertension care in adults in 24 select countries, using three different systolic blood pressure (SBP) treatment cut-off points-≥140, ≥150 and ≥160 mm Hg. INTERVENTION: Strengthening the hypertension care cascade compared with status quo levels, with pharmacological treatment administered at different cut-points depending on the scenario. TARGET POPULATION: Adults aged 30+ in 24 low-income and middle-income countries spanning all world regions. PERSPECTIVE: Societal. TIME HORIZON: 30 years. DISCOUNT RATE: 4%. COSTING YEAR: 2020 USD. STUDY DESIGN: DATA SOURCES: Institute for Health Metrics and Evaluation's Epi Visualisations database-country-specific cardiovascular disease (CVD) incidence, prevalence and death rates. Mean SBP and prevalence-National surveys and NCD-RisC. Treatment protocols-WHO HEARTS. Treatment impact-academic literature. Costs-national and international databases. OUTCOME MEASURES: Health outcomes-averted stroke and myocardial infarction events, deaths and disability-adjusted life-years; economic outcomes-averted health expenditures, value of averted mortality and workplace productivity losses. RESULTS OF ANALYSIS: Across 24 countries, over 30 years, incremental scale-up of hypertension care for adults with SBP≥140 mm Hg led to 2.6 million averted CVD events and 1.2 million averted deaths (7% of expected CVD deaths). 68% of benefits resulted from treating those with very high SBP (≥160 mm Hg). 10 of the 12 highest-income countries projected positive net benefits at one or more treatment cut-points, compared with 3 of the 12 lowest-income countries. Treating hypertension at SBP≥160 mm Hg maximised the net economic benefit in the lowest-income countries. LIMITATIONS: The model only included a few hypertension-attributable diseases and did not account for comorbid risk factors. Modelled scenarios assumed ambitious progress on strengthening the care cascade. CONCLUSIONS: In areas where economic considerations might play an outsized role, such as very low-income countries, prioritising treatment to populations with severe hypertension can maximise benefits net of economic costs.

Malnourished children are at higher risk of mortality and morbidity following diarrheal illness and certain enteropathogens have been associated with malnutrition in children. Very few studies have comprehensively looked at the etiology of diarrhea in malnourished children and most have used conventional diagnostic methods with suboptimal sensitivity. We used a highly sensitive molecular approach against a broad range of pathogens causing diarrhea and examined their association with malnutrition. In addition, we looked at the pathogen diversity of pediatric diarrhea, three years after the nationwide rotavirus vaccine introduction to understand the evolving landscape of pathogens, which is crucial for planning strategies to further reduce the diarrhea burden. Clinical details and diarrheal stool samples were collected from hospitalized children aged < 5 years from three sentinel sites in India for a period of one year. The samples were tested by qPCR for 16 established causes of diarrhea using TaqMan Array Cards. A total of 772 children were enrolled, from whom 482 (62.4%) stool specimens were tested. No specific pathogen was associated with diarrhea among children with acute or chronic malnutrition compared to those with better nutritional status. Overall, adenovirus was the leading pathogen (attributable fraction (AF) 16.9%; 95% CI 14.1 to 19.2) followed by rotavirus (AF 12.6%; 95% CI 11.8 to 13.1) and Shigella (AF 10.9%; 95% CI 8.4 to 16.4). The majority of diarrhea requiring hospitalization in children aged < 2 years could be attributed to viruses, while Shigella was the most common pathogen among children aged > 2 years. These data on the prevalence and epidemiology of enteropathogens identified potential pathogens for public health interventions.

After the introduction of the rotavirus vaccine into the Universal Immunization Program in India in 2016, relatively few studies have assessed the prevalence and epidemiological patterns of acute gastroenteritis (AGE) among hospitalized children ≤5 years of age. We used a uniform protocol to recruit children with AGE as well as standardized testing and typing protocols. Stool specimens from children with AGE younger than 5 years of age admitted to six hospitals in three cities in India were collected from January 2017 through December 2019. Norovirus was detected by real-time reverse transcription-polymerase chain reaction (RT-qPCR) followed by typing positive specimens by conventional RT-PCR and Sanger sequencing. Norovirus was detected in 322 (14.8%) of 2182 specimens with the highest rate in 2018 (17.6%, 146/829), followed by 2019 (14.4%, 122/849) and 2017 (10.7%, 54/504). Rotavirus vaccine status was known for 91.6% of the children of which 70.4% were vaccinated and 29.6% not. Norovirus positivity in rotavirus-vaccinated children was 16.3% and 12% in unvaccinated children. GII.4 Sydney[P16] (39.3%), GII.4 Sydney[P31] (18.7%), GII.2[P16] (10%), GI.3[P13] (6.8%), GII.3[P16] (5.9%), and GII.13[P16] (5%) accounted for 85.8% (188/219) of the typed strains. Our data highlight the importance of norovirus in Indian children hospitalized with AGE.

Long-term follow-up of a cohort of unmarried girls who received one, two, or three doses of quadrivalent HPV vaccine, between 10 and 18 years of age, in an Indian multi-centric study allowed us to compare antibody responses between the younger and older age cohorts at 10-years post-vaccination, and study the impact of initiation of sexual activity and cervical HPV infections on antibody levels. Among the younger (10-14 years) recipients of a single dose, 97.7% and 98.2% had detectable binding antibody titers against HPV 16 and HPV 18 respectively at ten years post-vaccination. The proportions among those receiving a single dose at age 15-18 years were 92.3% and 94.2% against HPV 16 and HPV 18 respectively. Mean HPV 16 binding antibody titers were 2.1 folds (95%CI 1.4 to 3.3) higher in those vaccinated at ages 10-14 years, and 1.9 folds (95%CI 1.2 to 3.0) higher in those vaccinated at 15-18 years compared to mean titers seen in the unvaccinated women. Compared to previous timepoints of 36 or 48 months, binding antibodies against HPV 16 and neutralizing antibodies against both HPV 16 and HPV 18 were significantly higher at 10 years. This rise was more pronounced in participants vaccinated at 15-18 years. No association of marital status or cervical HPV infections was observed with the rise in titer. Durability of antibody response in single dose recipients correlated well with the high efficacy of a single dose against persistent HPV 16/18 infections irrespective of age at vaccination, as we reported earlier.

A SARS-CoV-2 P.1 (Gamma) variant outbreak occurred at a skilled nursing facility in Washington, USA, in April 2021. Effectiveness of 2 doses of mRNA vaccines against P.1 infection among residents in this outbreak was 75.0% (95% CI 44.5%-88.7%), similar to effectiveness for other pre-Delta variants among long-term care residents.

In April 2021, we assessed mRNA vaccine effectiveness (VE) in the context of a COVID-19 outbreak in a skilled nursing facility. Among 28 cases, genomic sequencing was performed on four specimens on four different patients, and all were classified by sequence analysis as the Beta (B.1.351) variant. Adjusted VE among residents was 65% (95% Confidence Interval: 25-84%). These findings underscore the importance of vaccination for prevention of COVID-19 in skilled nursing facilities.

BACKGROUND: Invasive pneumococcal disease (IPD) isolates forming genomic clusters can reflect rapid disease transmission between vulnerable individuals. METHODS: We performed whole genome sequencing of 2820 IPD isolates recovered during 2019 through CDC's Active Bacterial Core surveillance (ABCs) to provide strain information (serotypes, resistance, genotypes), and 2778 of these genomes were analyzed to detect highly related genomic clusters. RESULTS: Isolates from persons experiencing homelessness (PEH) were more often within genomic clusters than those from persons not experiencing homelessness (PNEH) (105/198, 53.0% vs 592/2551, 23.2%, p<0.001). The 4 western sites accounted for 33.4% (929/2778) of isolates subjected to cluster analysis yet accounted for 48.7% (343/705) of clustering isolates (p<0.001) and 150/198 (75.8%) isolates recovered from PEH (p<0.001). Serotypes most frequent among PEH were (in rank order) 12F, 4, 3, 9N, 8, 20, and 22F, all of which were among the 10 serotypes exhibiting the highest proportions of clustering isolates among all cases. These serotypes accounted for 44.9% (1265/2820) of all IPD cases and are included within available vaccines. CONCLUSIONS: We identified serotype-specific and geographic differences in IPD transmission. We show the vulnerability of PEH within different regions to rapidly spreading IPD transmission networks representing several pneumococcal serotypes included in available vaccines.

In April 2016, an indigenous monovalent rotavirus vaccine (Rotavac) was introduced to the National Immunization Program in India. Hospital-based surveillance for acute gastroenteritis was conducted in five sentinel sites from 2012 to 2020 to monitor the vaccine impact on various genotypes and the reduction in rotavirus positivity at each site. Stool samples collected from children under 5 years of age hospitalized with diarrhea were tested for group A rotavirus using a commercial enzyme immunoassay, and rotavirus strains were characterized by RT-PCR. The proportion of diarrhea hospitalizations attributable to rotavirus at the five sites declined from a range of 56-29.4% in pre-vaccine years to 34-12% in post-vaccine years. G1P[8] was the predominant strain in the pre-vaccination period, and G3P[8] was the most common in the post-vaccination period. Circulating patterns varied throughout the study period, and increased proportions of mixed genotypes were detected in the post-vaccination phase. Continuous long-term surveillance is essential to understand the diversity and immuno-epidemiological effects of rotavirus vaccination.

OBJECTIVES: We aimed to characterize invasive pneumococcal disease (IPD) isolates collected from multistate surveillance in the USA during 2018 and examine within-serotype propensities of isolates to form related clusters. METHODS: We predicted strain features using whole genome sequence obtained from 2885 IPD isolates obtained through the Center for Disease Control and Prevention's Active Bacterial Core surveillance (ABCs) that has a surveillance population of approximately 34.5 million individuals distributed among 10 states. Phylogenetic analysis was provided for serotypes accounting for >27 isolates. RESULTS: Thirteen-valent conjugate vaccine (PCV13) serotypes together with 6C accounted for 23/105 (21.9%) of isolates from children aged <5 years and 820/2780 (29.5%) isolates from those aged >5 years. The most common serotypes from adult IPD isolates were serotypes 3 (413/2780, 14.9%), 22F (291/2780, 10.5%) and 9N (191/2780, 6.9%). Among children IPD isolates, serotypes 15BC (18/105, 17.1%), 3 (11/105, 10.5%) and 33F (10/105, 9.5%) were most common. Serotypes 4, 12F, 20, and 7F had the highest proportions of isolates that formed related clusters together with highest proportions of isolates from persons experiencing homelessness (PEH). Among 84 isolates from long-term care facilities, two instances of highly related isolate pairs from co-residents were identified. CONCLUSIONS: Non-PCV13 serotypes accounted for more than 70% of IPD in ABCs, however PCV13 serotype 3 is the most common IPD serotype overall. Serotypes most common among PEH were more often associated with temporally related clusters identified both among PEH and among persons not reportedly experiencing homelessness.

After 7-valent pneumococcal conjugate vaccine introduction in the US in 2000, invasive pneumococcal disease (IPD) due to serotype 4 greatly decreased in children and adults. Starting in 2013, serotype 4 IPD incidence increased among adults >18 years old within three of ten Active Bacterial Core surveillance sites. Of 325 serotype 4 cases among adults in 2010-2018, 36% were from persons experiencing homelessness (PEH); incidence of serotype 4 IPD among PEH was 100-300 times higher than in the general population within these 3 areas. Genome sequencing for isolates recovered during 2015-2018 (n=246), revealed that increases in serotype 4 IPD were driven by lineages, ST10172, ST244, and ST695. Within each lineage, clusters of near-identical isolates indicated close temporal relatedness. Increases in serotype 4 IPD were limited to Colorado, California, and New Mexico, with highest increases observed among PEH, who were at increased risk for exposure to and infections caused by these strains.

OBJECTIVES: We aimed to provide population and whole genome sequence (WGS)-based characterization of invasive pneumococcal disease (IPD) isolates collected from multistate surveillance in the United States during 2017. METHODS: We obtained short read WGS from 2881 isolates with associated bioinformatics pipeline strain feature predictions. For quality control, capsular serotypes and antimicrobial minimum inhibitory concentrations (MICs) were also obtained conventionally from 442 isolates. Annotated WGS was provided (inclusive of serotypes, MICs, multilocus sequence types, pilus type(s)) from 2723 isolates. For 158 isolates with suboptimal WGS, antimicrobial MICs were obtained conventionally. RESULTS: There were 127 isolates from children <5 years and 2754 isolates from those > 5 in 2017. One of 43 different serotypes were predicted for 2877 of the 2881 isolates. Serotypes in 13-valent conjugate vaccine together with 6C (PCV13+6C) accounted for 816 (28.3%) isolates, with PCV13 serotype 3 being the most common serotype overall. Non-PCV13-6C- serotypes accounted for 2,065 (71.7%) isolates, comprising 96 (75.6%) isolates from children < 5 and 1969 (61.4%) isolates from those > 5. Of 36 different categories of recently emerged serotype-switch variants, three showed marked increases relative to 2015-2016 in that the number from 2017 surpassed the number from 2015-2016 combined. Two of these included antimicrobial-resistant serotype 11A and 35B serotype-switch variants of the ST156 clonal complex. CONCLUSIONS: PCV13+6C strains are still identified in 2017 but non-PCV13-type strains impose considerable burden. This well-annotated year 2017 WGS/strain dataset will prove useful for a broad variety of analyses and improved our understanding of IPD-causing strains in the post-PCV13 era.

Early-childhood biomonitoring of persistent organic pollutants (POPs) is challenging due to the logistic and ethical limitations associated with blood sampling. We investigated using faeces as a non-invasive matrix to estimate internal exposure to POPs. The concentrations of selected POPs were measured in matched plasma and faecal samples collected from 20 infants/toddlers (aged 13+/-4.8months), including a repeat sample time point for 13 infants (~5months apart). We observed higher rates of POP quantification in faeces (2g dry weight) than in plasma (0.5mL). Among the five chemicals that had quantification frequencies over 50% in both matrices, except for HCB, log concentration in faeces (Cf) and blood (Cb) were correlated (r>0.74, P<0.05) for p.p'-dichlorodiphenyldichloroethylene (p,p'-DDE), 2,3',4,4',5-pentachlorobiphenyl (PCB118), 2,2',3,4,4',5'-pentachlorobiphenyl (PCB138) and 2,2',4,4',5,5'-pentachlorobiphenyl (PCB153). We determined faeces:plasma concentration ratios (Kfb), which can be used to estimate Cb from measurements of Cf for infants/toddlers. For a given chemical, the variation in Kfb across individuals was considerable (CV from 0.46 to 0.70). Between 5% and 50% of this variation was attributed to short-term intra-individual variability between successive faecal samples. This variability could be reduced by pooling faeces samples over several days. Some of the remaining variability was attributed to longer-term intra-individual variability, which was consistent with previously reported observations of a decrease in Kfb over the first year of life. The strong correlations between Cf and Cb demonstrate the promise of using faeces for biomonitoring of these compounds. Future research on the sources of variability in Kfb could improve the precision and utility of this technique.

Background.: The epidemiology and clinical features of human coronaviruses (HCoVs) in children are not fully characterized. Methods.: A retrospective study of children with HCoV detected by reverse-transcriptase polymerase chain reaction (RT-PCR) was performed for a community cohort and a children's hospital in the same community from January 2013 to December 2014. The RT-PCR assay detected HCoV 229E, HKU1, NL63, and OC43 in nasal swabs from symptomatic children ≤18 years. Factors associated with increased severity of illness in hospitalized children were assessed by multivariable logistic regression. Results.: Human coronavirus was detected in 261 children, 49 and 212 from the community and hospital, respectively. The distribution of HCoV types and seasonal trends were similar in the community and hospital. Community cases were older than hospitalized cases (median age, 4.4 versus 1.7 years, respectively; P < .01), and a minority of community cases (26.5%) sought medical attention. Among the hospitalized children with HCoV detected, 39 (18.4%) received respiratory support and 24 (11.3%) were admitted to the pediatric intensive care unit (PICU). Age <2 years (odds ratio [OR] = 5.0; 95% confidence interval [CI], 1.9-13.1) and cardiovascular (OR = 3.9; 95% CI, 1.6-9.5), genetic/congenital (OR = 2.8; 95% CI, 1.1-7.0), and respiratory chronic complex conditions ([CCCs] OR = 4.5; 95% CI, 1.7-12.0) were associated with receiving respiratory support. Genetic/congenital (OR = 2.8; 95% CI, 1.1-7.4) CCCs were associated with PICU admission. Severity of illness was similar among hospitalized children with different HCoV types. Conclusions.: Children in the community with HCoV detected generally had mild illness as demonstrated by few medically attended cases. In hospitalized children, young age and CCCs, but not HCoV type, were associated with increased severity of illness.

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naive individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 - A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F - were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.

BACKGROUND: Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. METHODS AND FINDINGS: We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naive individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions-a proxy for recent infection-yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs-K101E, K103N, Y181C, and G190A-accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. CONCLUSIONS: Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

Lymphatic filariasis (LF) is a mosquito-borne parasitic infection that causes lymphedema, elephantiasis, and hydrocele. Haiti is one of only four countries left in the Americas where transmission of lymphatic filariasis still occurs. The National Program to Eliminate LF (NPELF) was started in Haiti in 2000, and by 2005 a population of 1.6 million people in 24 communes, including the majority of high-prevalence communes, was targeted at least once for mass drug administration (MDA). An interruption in external funding at the end of 2005 paralyzed the program, but with new donor support the NPELF was able to scale up to achieve full geographic coverage, reaching more than 8 million people in 2012. The LF program in Haiti has faced many challenges, including political crises, hurricanes, a devastating earthquake, and a deadly cholera outbreak in the earthquake's aftermath. Despite these challenges, the NPELF and partners have persisted, and now the program is integrated with soil-transmitted helminth (STH) control, is national in scope, and provides appropriate supportive care for persons suffering from LF morbidity. Haiti serves as a model for successful program implementation in countries affected by political and social challenges and natural disasters.

We report the first whole-genome sequences for five strains, two carried and three pathogenic, of the emerging pathogen Haemophilus haemolyticus. Preliminary analyses indicate that these genome sequences encode markers that distinguish H. haemolyticus from its closest Haemophilus relatives and provide clues to the identity of its virulence factors.

Rotavirus is the most common cause of fatal childhood diarrhea worldwide. We provide the first estimates of the health care and economic burden of severe rotavirus disease in Oman. We conducted active, hospital-based surveillance of rotavirus disease at 11 regional public hospitals in Oman, using the guidelines suggested by the generic World Health Organization protocol. From July 2006 through June 2008, all children aged <5 years who were hospitalized for acute gastroenteritis were enrolled in the surveillance program, and their stool samples were tested for rotavirus using a commercially available enzyme immunoassay (ID EIA Rotavirus Test; Dako Diagnostics). Rotavirus was detected in samples from 1712 (49%) of 3470 children. These children were hospitalized for a median of 3 days for severe diarrhea. A marked seasonal peak was evident with a majority of the cases occurring from December through May. Of the rotavirus cases, 69% occurred in children aged 6-17 months. We identified a diverse strain pattern in Oman, with G2 (37%), G1 (38%), and G9 (11%) accounting for most of typeable strains. By our burden estimates, the Omani government spends an estimated US$791,817 and US$1.8 million annually to treat rotavirus-associated diarrhea in the outpatient and hospital settings, respectively. A rotavirus vaccination program might substantially reduce the burden of severe diarrhea among children in Oman.