Development of a multimodal geomarker pipeline to assess the impact of social, economic, and environmental factors on pediatric health outcomes.

OBJECTIVES: We sought to create a computational pipeline for attaching geomarkers, contextual or geographic measures that influence or predict health, to electronic health records at scale, including developing a tool for matching addresses to parcels to assess the impact of housing characteristics on pediatric health. MATERIALS AND METHODS: We created a geomarker pipeline to link residential addresses from hospital admissions at Cincinnati Children's Hospital Medical Center (CCHMC) between July 2016 and June 2022 to place-based data. Linkage methods included by date of admission, geocoding to census tract, street range geocoding, and probabilistic address matching. We assessed 4 methods for probabilistic address matching. RESULTS: We characterized 124 244 hospitalizations experienced by 69 842 children admitted to CCHMC. Of the 55 684 hospitalizations with residential addresses in Hamilton County, Ohio, all were matched to 7 temporal geomarkers, 97% were matched to 79 census tract-level geomarkers and 13 point-level geomarkers, and 75% were matched to 16 parcel-level geomarkers. Parcel-level geomarkers were linked using our exact address matching tool developed using the best-performing linkage method. DISCUSSION: Our multimodal geomarker pipeline provides a reproducible framework for attaching place-based data to health data while maintaining data privacy. This framework can be applied to other populations and in other regions. We also created a tool for address matching that democratizes parcel-level data to advance precision population health efforts. CONCLUSION: We created an open framework for multimodal geomarker assessment by harmonizing and linking a set of over 100 geomarkers to hospitalization data, enabling assessment of links between geomarkers and hospital admissions.

Causal Mediation of Neighborhood-Level Pediatric Hospitalization Inequities.

BACKGROUND AND OBJECTIVES: Population-wide racial inequities in child health outcomes are well documented. Less is known about causal pathways linking inequities and social, economic, and environmental exposures. Here, we sought to estimate the total inequities in population-level hospitalization rates and determine how much is mediated by place-based exposures and community characteristics. METHODS: We employed a population-wide, neighborhood-level study that included youth <18 years hospitalized between July 1, 2016 and June 30, 2022. We defined a causal directed acyclic graph a priori to estimate the mediating pathways by which marginalized population composition causes census tract-level hospitalization rates. We used negative binomial regression models to estimate hospitalization rate inequities and how much of these inequities were mediated indirectly through place-based social, economic, and environmental exposures. RESULTS: We analyzed 50 719 hospitalizations experienced by 28 390 patients. We calculated census tract-level hospitalization rates per 1000 children, which ranged from 10.9 to 143.0 (median 45.1; interquartile range 34.5 to 60.1) across included tracts. For every 10% increase in the marginalized population, the tract-level hospitalization rate increased by 6.2% (95% confidence interval: 4.5 to 8.0). After adjustment for tract-level community material deprivation, crime risk, English usage, housing tenure, family composition, hospital access, greenspace, traffic-related air pollution, and housing conditions, no inequity remained (0.2%, 95% confidence interval: -2.2 to 2.7). Results differed when considering subsets of asthma, type 1 diabetes, sickle cell anemia, and psychiatric disorders. CONCLUSIONS: Our findings provide additional evidence supporting structural racism as a significant root cause of inequities in child health outcomes, including outcomes at the population level.

Patient-centered mild traumatic brain injury interventions in the emergency department.

INTRODUCTION: Traumatic brain injury (TBI) results in 2.5 million emergency department (ED) visits per year in the US, with mild traumatic brain injury (mTBI) accounting for 90% of cases. There is considerable evidence that many experience chronic symptoms months to years later. This population is rarely represented in interventional studies. Management of adult mTBI in the ED has remained unchanged, without consensus of therapeutic options. The aim of this review was to synthesize existing literature of patient-centered ED treatments for adults who sustain an mTBI, and to identify practices that may offer promise. METHODS: A systematic review was conducted using the PubMed and Cochrane databases, while following PRISMA guidelines. Studies describing pediatric patients, moderate to severe TBI, or interventions outside the ED were excluded. Two reviewers independently performed title and abstract screening. A third blinded reviewer resolved discrepancies. The Mixed Methods Appraisal Tool (MMAT) was employed to assess the methodological quality of the studies. RESULTS: Our search strategy generated 1002 unique titles. 95 articles were selected for full-text screening. The 26 articles chosen for full analysis were grouped into one of the following intervention categories: (1) predictive models for Post-Concussion Syndrome (PCS), (2) discharge instructions, (3) pharmaceutical treatment, (4) clinical protocols, and (5) functional assessment. Studies that implemented a predictive PCS model successfully identified patients at highest risk for PCS. Trials implementing discharge related interventions found the use of video discharge instructions, encouragement of daily light exercise or bed rest, and text messaging did not significantly reduce mTBI symptoms. The use of electronic clinical practice guidelines (eCPG) and longer leaves of absence from work following injury reduced symptoms. Ondansetron was shown to reduce nausea in mTBI patients. Studies implementing ED Observation Units found significant declines in inpatient admissions and length of hospital stay. The use of tablet-based tasks was found to be superior to many standard cognitive assessments. CONCLUSION: Validated instruments are available to aid clinicians in identifying patients at risk for PCS or serious cognitive impairment. EDOU management and evidence-based modifications to discharge instructions may improve mTBI outcomes. Additional research is needed to establish the therapeutic value of medications and lifestyle changes for the treatment of mTBI in the ED.

Perceptions of sugar-sweetened beverages among adolescents in North Carolina.

Introduction: Sugar-sweetened beverage (SSB) consumption among adolescents contributes to diet-related chronic disease including obesity, type 2 diabetes, and poor oral health. Objective: To better understand adolescents' perceptions, attitudes, and consumption behaviors around SSBs by conducting virtual workshop discussions with adolescents in NC. Materials and methods: Adolescents ages 11-17 in communities with a high proportion of Supplemental Nutrition Assistance Program (SNAP) eligible households were selected to participate in a series of virtual group workshops during summer 2021. A semi-structured discussion guide was used by a workshop facilitator. Workshop discussions centered around general health perceptions, SSB perceptions, and consumption behaviors. A thematic analysis was used to summarize knowledge, beliefs, attitudes, and perceptions around SSBs. Results: Approximately 36 adolescents participated across four group workshops. Parents and caregivers influenced adolescents most when it came to making beverage choices. Positive SSB perceptions included liking the taste and the association with special times and social events. Negative opinions focused on associated health risks (diet-related chronic disease and poor oral health). Some adolescents acknowledged SSBs were not healthy but suggested they could be consumed occasionally. Very few participants mentioned any benefits from SSBs; those that mentioned benefits stated they provided energy, replaced electrolytes, and tasted good. Conclusion: Findings provide several key insights that can contribute to the development of messages aimed at curbing SSB consumption among adolescents. For example, messages that focus on catching adolescents' attention and sharing short- and long-term health consequences of high SSB consumption resonated with adolescents, but because occasional SSB intake was not seen as consequential, messages that suggest abstinence from SSBs may not be helpful in reducing consumption.

Patient Perceptions of Switching to a Generic Dry Powder Inhaler - Increased Understanding Through Journey Mapping.

Purpose: This qualitative study explored patients' attitudes about and perceptions of generic dry powder inhaler (DPI) substitution for the brand product and patients' views of generic product quality, efficacy, design, and usability. Methods: Forty COPD and asthma patients (36 adults, four adolescents), who were actively using a brand DPI product, participated in one of six focus groups. Participants completed a journey mapping exercise to assess attitudes and opinions about a scenario where they refill their prescription and unexpectedly receive a generic DPI instead of their brand DPI. The focus groups were audio recorded, transcribed, and analyzed thematically. Results: The hypothetical scenario of unexpectedly receiving a generic DPI elicited mixed feelings including: happiness and relief about potential cost savings, confusion, disappointment, anger, and/or frustration with the unexpected switch. Participants in most groups anticipated anxiety or hesitation in using the generic DPI due to concerns about potential differences in usability, uncertainty about correct use, and questions about efficacy. Participants across all groups said they would ask a pharmacist or healthcare provider for information or answers to their questions, and some participants said they would use online resources. When participants held the brand and generic DPI devices, most preferred the brand DPI device and found it easier, less cumbersome, or more convenient to use (due to size and weight). However, many participants reiterated that the potential reduced cost of the generic DPI would be a primary factor in their decision-making related to generic DPI substitution for their brand DPI. Conclusion: Patients experienced a mixture of positive and negative feelings when faced with an unexpected generic DPI substitution. Some patients have doubts about their ability to successfully navigate differences in generic device design, and most expressed the desire to participate in discussions and decision-making with their HCP about generic DPI sameness and substitution.

Mental Models of Infectious Diseases and Public Understanding of COVID-19 Prevention.

The emergence of viral diseases such as Ebola virus disease, Zika virus disease, and the coronavirus disease (COVID-19) has posed considerable challenges to health care systems around the world. Public health strategy to address emerging infectious diseases has depended in part on human behavior change and yet the perceptions and knowledge motivating that behavior have been at times inconsistent with the latest consensus of peer-reviewed science. Part of that disjuncture likely involves the existence and persistence of past ideas about other diseases. To forecast and prepare for future epidemic and pandemic response, we need to better understand how people approach emerging infectious diseases as objects of public opinion during the periods when such diseases first become salient at a population level. In this essay, we explore two examples of how existing mental models of past infectious diseases appear to have conditioned and constrained public response to novel viral diseases. We review previously reported experiences related to Zika virus in Central America and discuss public opinion data collected in the early months of the COVID-19 pandemic. In the case of Zika virus disease, we assess how thinking about earlier mosquito-borne disease seems to have affected public consideration of the virus in Guatemala. In the case of COVID-19, we assess how previous vaccination behavior for a different disease is associated with intention to obtain vaccination for COVID-19 in the future.

Ultrasound measurement of change in kidney volume is a sensitive indicator of severity of renal parenchymal injury.

Noninvasive determination of the severity of parenchymal injury in acute kidney injury remains challenging. Edema is an early pathological process following injury, which may correlate with changes in kidney volume. The goal of the present study was to test the hypothesis that "increases in kidney volume measured in vivo using ultrasound correlate with the degree of renal parenchymal injury." Ischemia-reperfusion (IR) of varying length was used to produce graded tissue injury. We first determined 1) whether regional kidney volume in rats varied with the severity (0, 15, 30, and 45 min) of warm bilateral IR and 2) whether this correlated with tubular injury score. We then determined whether these changes could be measured in vivo using three-dimensional ultrasound. Finally, we evaluated cumulative changes in kidney volume up to 14 days post-IR in rats to determine whether changes in renal volume were predictive of latent tubular injury following recovery of filtration. Experiments concluded that noninvasive ultrasound measurements of change in kidney volume over 2 wk are predictive of tubular injury following IR even in animals in which plasma creatinine was not elevated. We conclude that ultrasound measurements of volume are a sensitive, noninvasive marker of tissue injury in rats and that the use of three-dimensional ultrasound measurements may provide useful information regarding the timing, severity, and recovery from renal tissue injury in experimental studies.

Epidemiologic Changes of Scrub Typhus in China, 1952-2016.

Scrub typhus, a miteborne rickettsiosis, has emerged in many areas globally. We analyzed the incidence and spatial-temporal distribution of scrub typhus in China during 1952-1989 and 2006-2016 using national disease surveillance data. A total of 133,623 cases and 174 deaths were recorded. The average annual incidence was 0.13 cases/100,000 population during 1952-1989; incidence increased sharply from 0.09/100,000 population in 2006 to 1.60/100,000 population in 2016. The disease, historically endemic to southern China, has expanded to all the provinces across both rural and urban areas. We identified 3 distinct seasonal patterns nationwide; infections peaked in summer in the southwest, summer-autumn in the southeast, and autumn in the middle-east. Persons >40 years of age and in nonfarming occupations had a higher risk for death. The changing epidemiology of scrub typhus in China warrants an enhanced disease control and prevention program.

The impact of a pharmacist-driven, collaborative practice on diabetes management in an Urban underserved population: a mixed method assessment.

The objective of this manuscript is to describe the results of a pharmacist-driven, Type 2 diabetes targeted, collaborative practice within an urban, underserved federally qualified health center. Pharmacists within a primary care team managed patients with chronic illnesses utilizing a collaborative practice agreement. Pharmacists, pharmacy residents, and supervised students provided care for patients with Type 2 diabetes. The first visit incorporated past medical history, medication reconciliation, determination of adherence and patient knowledge of diabetes pathophysiology, care plan, including diet and exercise, medications, and possible complications. Pharmacists had the authority to optimize medications and order laboratory tests and referrals. Diabetes, hypertension, and medication use outcomes data were collected and analyzed to assess the impact of clinical pharmacy services. Patient and provider satisfaction were assessed via surveys and focus group interviews. Ninety-nine patients were included in the evaluation. The mean A1c level was 9.8% at baseline and 8.4% at follow-up (p< .05). There were significant improvements in patient attainment of A1c <9%, ACE Inhibitor/angiotensin receptor blocker and statin use, and tobacco cessation at follow-up (p< .05). Eleven providers who responded to the satisfaction survey answered 73% of the questions with strongly agree. The seven patients who participated in the satisfaction survey, and focus group were satisfied with the care they received from the pharmacists. The focus group highlighted similar personal goals, barriers, and interests in nutrition education. Working as part of a collaborative care team, pharmacists were able to have a significant impact on improving the health outcomes of patients with Type 2 diabetes and patient and provider perceptions of the vital role of pharmacists.

Ischemic Renal Injury: Can Renal Anatomy and Associated Vascular Congestion Explain Why the Medulla and Not the Cortex Is Where the Trouble Starts?

The kidneys receive approximately 20% of cardiac output and have a low fractional oxygen extraction. Quite paradoxically, however, the kidneys are highly susceptible to ischemic injury (injury associated with inadequate blood supply), which is most evident in the renal medulla. The predominant proposal to explain this susceptibility has been a mismatch between oxygen supply and metabolic demand. It has been proposed that unlike the well-perfused renal cortex, the renal medulla normally operates just above the threshold for hypoxia and that further reductions in renal perfusion cause hypoxic injury in this metabolically active region. An alternative proposal is that the true cause of ischemic injury is not a simple mismatch between medullary metabolic demand and oxygen supply, but rather the susceptibility of the outer medulla to vascular congestion. The capillary plexus of the renal outer medullary region is especially prone to vascular congestion during periods of ischemia. It is the failure to restore the circulation to the outer medulla that mediates complete and prolonged ischemia to much of this region, leading to injury and tubular cell death. We suggest that greater emphasis on developing clinically useful methods to help prevent or reverse the congestion of the renal medullary vasculature may provide a means to reduce the incidence and cost of acute kidney injury.

Factors That Mattered in Helping Travelers From Countries With Ebola Outbreaks Participate in Post-Arrival Monitoring During the 2014-2016 Ebola Epidemic.

During the 2014-2016 Ebola epidemic in West Africa, the US Centers for Disease Control and Prevention (CDC) developed the CARE+ program to help travelers arriving to the United States from countries with Ebola outbreaks to meet US government requirements of post-arrival monitoring. We assessed 2 outcomes: (1) factors associated with travelers' intention to monitor themselves and report to local or state public health authority (PHA) and (2) factors associated with self-reported adherence to post-arrival monitoring and reporting requirements. We conducted 1195 intercept in-person interviews with travelers arriving from countries with Ebola outbreaks at 2 airports between April and June 2015. In addition, 654 (54.7%) of these travelers participated in a telephone interview 3 to 5 days after intercept, and 319 (26.7%) participated in a second telephone interview 2 days before the end of their post-arrival monitoring. We used regression modeling to examine variance in the 2 outcomes due to 4 types of factors: (1) programmatic, (2) perceptual, (3) demographic, and (4) travel-related factors. Factors associated with the intention to adhere to requirements included clarity of the purpose of screening (B = 0.051, 95% confidence interval [CI], 0.011-0.092), perceived approval of others (B = 0.103, 95% CI, 0.058-0.148), perceived seriousness of Ebola (B = 0.054, 95% CI, 0.031-0.077), confidence in one's ability to perform behaviors (B = 0.250, 95% CI, 0.193-0.306), ease of following instructions (B = 0.053, 95% CI, 0.010-0.097), and trust in CARE Ambassador (B = 0.056, 95% CI, 0.009-0.103). Respondents' perception of the seriousness of Ebola was the single factor associated with adherence to requirements (odds ratio [OR] = 0.81, 95% CI, 0.673-0.980, for non-adherent vs adherent participants and OR = 0.86, 95% CI, 0.745-0.997, for lost to follow-up vs adherent participants). Results from this assessment can guide public health officials in future outbreaks by identifying factors that may affect adherence to public health programs designed to prevent the spread of epidemics.

Developing and Testing the Detén El Zika Campaign in Puerto Rico.

Responding to an emerging health threat often requires rapid deployment of behavior change communication. Health communication best practices include developing and testing draft messages and materials to ensure that they resonate with and inspire priority groups to act. However, when faced with an emergency health threat, the timeline for these activities can be compressed from months to weeks. This article discusses the rapid development and implementation of a Zika virus prevention campaign for pregnant women in Puerto Rico. The goal of the campaign was to increase knowledge among and motivate pregnant women, their partners and family members, and the community to follow Zika virus prevention recommendations. The steps in campaign development include environmental scanning, concept development and testing, and message testing to ensure development of campaign materials that resonated with and were well-received by key audience groups. The materials adhere to principles of behavior change communication, and offer our insights for development of future campaigns when under time constraints.

Identifying residual hotspots and mapping lower respiratory infection morbidity and mortality in African children from 2000 to 2017.

Lower respiratory infections (LRIs) are the leading cause of death in children under the age of 5, despite the existence of vaccines against many of their aetiologies. Furthermore, more than half of these deaths occur in Africa. Geospatial models can provide highly detailed estimates of trends subnationally, at the level where implementation of health policies has the greatest impact. We used Bayesian geostatistical modelling to estimate LRI incidence, prevalence and mortality in children under 5 subnationally in Africa for 2000-2017, using surveys covering 1.46 million children and 9,215,000 cases of LRI. Our model reveals large within-country variation in both health burden and its change over time. While reductions in childhood morbidity and mortality due to LRI were estimated for almost every country, we expose a cluster of residual high risk across seven countries, which averages 5.5 LRI deaths per 1,000 children per year. The preventable nature of the vast majority of LRI deaths mandates focused health system efforts in specific locations with the highest burden.

The current and future global distribution and population at risk of dengue.

Dengue is a mosquito-borne viral infection that has spread throughout the tropical world over the past 60 years and now affects over half the world's population. The geographical range of dengue is expected to further expand due to ongoing global phenomena including climate change and urbanization. We applied statistical mapping techniques to the most extensive database of case locations to date to predict global environmental suitability for the virus as of 2015. We then made use of climate, population and socioeconomic projections for the years 2020, 2050 and 2080 to project future changes in virus suitability and human population at risk. This study is the first to consider the spread of Aedes mosquito vectors to project dengue suitability. Our projections provide a key missing piece of evidence for the changing global threat of vector-borne disease and will help decision-makers worldwide to better prepare for and respond to future changes in dengue risk.

Voltage gated proton channels modulate mitochondrial reactive oxygen species production by complex I in renal medullary thick ascending limb.

Hv1 is a voltage-gated proton channel highly expressed in immune cells where, it acts to maintain NAD(P)H oxidase activity during the respiratory burst. We have recently reported that Hv1 is expressed in cells of the medullary thick ascending limb (mTAL) of the kidney and is critical to augment reactive oxygen species (ROS) production by this segment. While Hv1 is associated with NOX2 mediated ROS production in immune cells, the source of the Hv1 dependent ROS in mTAL remains unknown. In the current study, the rate of ROS formation was quantified in freshly isolated mTAL using dihydroethidium and ethidium fluorescence. Hv1 dependent ROS production was stimulated by increasing bath osmolality and ammonium chloride (NH4Cl) loading. Loss of either p67phox or NOX4 did not abolish the formation of ROS in mTAL. Hv1 was localized to mitochondria within mTAL, and the mitochondrial superoxide scavenger mitoTEMPOL reduced ROS formation. Rotenone significantly increased ROS formation and decreased mitochondrial membrane potential in mTAL from wild-type rats, while treatment with this inhibitor decreased ROS formation and increased mitochondrial membrane potential in mTAL from Hv1-/- mutant rats. These data indicate that NADPH oxidase is not the primary source of Hv1 dependent ROS production in mTAL. Rather Hv1 localizes to the mitochondria in mTAL and modulates the formation of ROS by complex I. These data provide a potential explanation for the effects of Hv1 on ROS production in cells independent of its contribution to maintenance of cell membrane potential and intracellular pH.

Mapping diphtheria-pertussis-tetanus vaccine coverage in Africa, 2000-2016: a spatial and temporal modelling study.

BACKGROUND: Routine childhood vaccination is among the most cost-effective, successful public health interventions available. Amid substantial investments to expand vaccine delivery throughout Africa and strengthen administrative reporting systems, most countries still require robust measures of local routine vaccine coverage and changes in geographical inequalities over time. METHODS: This analysis drew from 183 surveys done between 2000 and 2016, including data from 881 268 children in 49 African countries. We used a Bayesian geostatistical model calibrated to results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017, to produce annual estimates with high-spatial resolution (5 ×    5 km) of diphtheria-pertussis-tetanus (DPT) vaccine coverage and dropout for children aged 12-23 months in 52 African countries from 2000 to 2016. FINDINGS: Estimated third-dose (DPT3) coverage increased in 72·3% (95% uncertainty interval [UI] 64·6-80·3) of second-level administrative units in Africa from 2000 to 2016, but substantial geographical inequalities in DPT coverage remained across and within African countries. In 2016, DPT3 coverage at the second administrative (ie, district) level varied by more than 25% in 29 of 52 countries, with only two (Morocco and Rwanda) of 52 countries meeting the Global Vaccine Action Plan target of 80% DPT3 coverage or higher in all second-level administrative units with high confidence (posterior probability ≥95%). Large areas of low DPT3 coverage (≤50%) were identified in the Sahel, Somalia, eastern Ethiopia, and in Angola. Low first-dose (DPT1) coverage (≤50%) and high relative dropout (≥30%) together drove low DPT3 coverage across the Sahel, Somalia, eastern Ethiopia, Guinea, and Angola. INTERPRETATION: Despite substantial progress in Africa, marked national and subnational inequalities in DPT coverage persist throughout the continent. These results can help identify areas of low coverage and vaccine delivery system vulnerabilities and can ultimately support more precise targeting of resources to improve vaccine coverage and health outcomes for African children. FUNDING: Bill & Melinda Gates Foundation.

Aging and Direct-to-Consumer Prescription Drug Television Ads: The Effects of Individual Differences and Risk Presentation.

To determine how individual difference (age, cognition, and hearing) and risk presentation (audio frequency, speed, and organization) variables affect viewing of direct-to-consumer (DTC) prescription drug television ads, participants (N = 1,075) from four age groups across the adult lifespan took an in-person hearing examination, watched a DTC television ad, and responded to survey questions. Results showed that increased age was related to reduced cognition and hearing ability, as well as lower ad comprehension and risk recall. Greater speed and more complex organization of the ad's risk information lowered risk recall and claim recognition. Audio frequency had no effect. Cognitive abilities mediated the relationship between age and risk recall. Our findings suggest that older adults are likely to have more difficulty recalling and understanding the risks presented in DTC television ads. Risk information can be presented in ways that facilitate or inhibit recall and recognition among individuals across the lifespan.

The association between Zika virus infection and microcephaly in Brazil 2015-2017: An observational analysis of over 4 million births.

BACKGROUND: In 2015, high rates of microcephaly were reported in Northeast Brazil following the first South American Zika virus (ZIKV) outbreak. Reported microcephaly rates in other Zika-affected areas were significantly lower, suggesting alternate causes or the involvement of arboviral cofactors in exacerbating microcephaly rates. METHODS AND FINDINGS: We merged data from multiple national reporting databases in Brazil to estimate exposure to 9 known or hypothesized causes of microcephaly for every pregnancy nationwide since the beginning of the ZIKV outbreak; this generated between 3.6 and 5.4 million cases (depending on analysis) over the time period 1 January 2015-23 May 2017. The association between ZIKV and microcephaly was statistically tested against models with alternative causes or with effect modifiers. We found no evidence for alternative non-ZIKV causes of the 2015-2017 microcephaly outbreak, nor that concurrent exposure to arbovirus infection or vaccination modified risk. We estimate an absolute risk of microcephaly of 40.8 (95% CI 34.2-49.3) per 10,000 births and a relative risk of 16.8 (95% CI 3.2-369.1) given ZIKV infection in the first or second trimester of pregnancy; however, because ZIKV infection rates were highly variable, most pregnant women in Brazil during the ZIKV outbreak will have been subject to lower risk levels. Statistically significant associations of ZIKV with other birth defects were also detected, but at lower relative risks than that of microcephaly (relative risk < 1.5). Our analysis was limited by missing data prior to the establishment of nationwide ZIKV surveillance, and its findings may be affected by unmeasured confounding causes of microcephaly not available in routinely collected surveillance data. CONCLUSIONS: This study strengthens the evidence that congenital ZIKV infection, particularly in the first 2 trimesters of pregnancy, is associated with microcephaly and less frequently with other birth defects. The finding of no alternative causes for geographic differences in microcephaly rate leads us to hypothesize that the Northeast region was disproportionately affected by this Zika outbreak, with 94% of an estimated 8.5 million total cases occurring in this region, suggesting a need for seroprevalence surveys to determine the underlying reason.

Global variation in bacterial strains that cause tuberculosis disease: a systematic review and meta-analysis.

BACKGROUND: The host, microbial, and environmental factors that contribute to variation in tuberculosis (TB) disease are incompletely understood. Accumulating evidence suggests that one driver of geographic variation in TB disease is the local ecology of mycobacterial genotypes or strains, and there is a need for a comprehensive and systematic synthesis of these data. The objectives of this study were to (1) map the global distribution of genotypes that cause TB disease and (2) examine whether any epidemiologically relevant clinical characteristics were associated with those genotypes. METHODS: We performed a systematic review of PubMed and Scopus to create a comprehensive dataset of human TB molecular epidemiology studies that used representative sampling techniques. The methods were developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We extracted and synthesized data from studies that reported prevalence of bacterial genotypes and from studies that reported clinical characteristics associated with those genotypes. RESULTS: The results of this study are twofold. First, we identified 206 studies for inclusion in the study, representing over 200,000 bacterial isolates collected over 27 years in 85 countries. We mapped the genotypes and found that, consistent with previously published maps, Euro-American lineage 4 and East Asian lineage 2 strains are widespread, and West African lineages 5 and 6 strains are geographically restricted. Second, 30 studies also reported transmission chains and 4 reported treatment failure associated with genotypes. We performed a meta-analysis and found substantial heterogeneity across studies. However, based on the data available, we found that lineage 2 strains may be associated with increased risk of transmission chains, while lineages 5 and 6 strains may be associated with reduced risk, compared with lineage 4 strains. CONCLUSIONS: This study provides the most comprehensive systematic analysis of the evidence for diversity in bacterial strains that cause TB disease. The results show both geographic and epidemiological differences between strains, which could inform our understanding of the global burden of TB. Our findings also highlight the challenges of collecting the clinical data required to inform TB diagnosis and treatment. We urge future national TB programs and research efforts to prioritize and reinforce clinical data collection in study designs and results dissemination.