OBJECTIVES: To propose a framework for adoption of privacy-preserving record linkage (PPRL) for public health applications. METHODS: Twelve interviews with subject matter experts (SMEs) were conducted virtually and coded using an inductive approach. A collaborative session was conducted with SMEs to identify key steps in the PPRL project lifecycle which informed development of a PPRL implementation checklist. RESULTS: This framework has 2 decision-making levels: the organization level and the project or program level. Organization-level considerations include PPRL governance, the optimal choice among approved PPRL solutions, the need for longitudinal linkages, the potential issue of vendor lock-in, and costs. Program-level considerations include characteristics of the PPRL use case, linkage quality and accuracy, data privacy and use, security thresholds, compatibility with data owners' data architecture, and trade-offs between open-source and commercial PPRL solutions. A PPRL implementation checklist was developed to guide public health practitioners considering PPRL for data linkage. CONCLUSIONS: The framework may be considered by public health entities to guide adoption and implementation of PPRL in public health research and surveillance. Public health experts may refer to this framework and the PPRL implementation checklist when determining the appropriateness of PPRL for specific use cases and implementation planning.

BACKGROUND: In 2022, the U.S. Centers for Disease Control and Prevention collaborated with implementing partners, African Field Epidemiology Network and Sydani Group, to support COVID-19 vaccination efforts in Nigeria. To characterize the costs of COVID-19 vaccination, this study evaluated financial costs per dose for activities implemented to support the intensification campaign for COVID-19 vaccination. METHODS: This retrospective evaluation collected secondary data from existing expenditure and programmatic records on resource utilization to roll out COVID-19 vaccination during 2022. The study included incremental financial costs of the activities implemented to support an intensification campaign for COVID-19 vaccination across nine states and six administrative levels in Nigeria from the perspective of the external donor (U.S. Government). Costs for vaccines and injection supplies, transport of vaccines, and any economic costs, including government in-kind contributions, were not included. All costs were converted from Nigerian Naira to 2022 U.S. Dollars (US$). RESULTS: The estimated financial delivery cost of the COVID-19 vaccination intensification campaign was US$0.84 per dose (total expenditure of US$6.29 million to administer 7,461,971 doses). Most of the financial resources were used for fieldwork activities (86%), followed by monitoring and supervision activities (8%), coordination activities (5%), and training-related activities (1%). Labor (58%) and travel (37%) were the resource inputs that accounted for the majority of the cost, while shares of other resource inputs were marginal (1% for each). Most labor costs (79%) were spent on payments for mass vaccination campaign teams, including pay-for-performance incentives. By administrative level, the largest share of costs (46%) was for pay-for-performance incentives at the community, health facility, or campus levels combined, followed by local government area level (24%), community level only (15%), state level (9%), national level (3%), campus level only (1%), and health facility level only (< 1%). CONCLUSIONS: Findings from the evaluation can help to inform resources needed for vaccination activities to respond to future outbreaks and pandemics in resource-limited settings, particularly to reach new target populations not regularly included in routine childhood immunization delivery.

During routine clinical practice, infectious disease physicians encounter patients with difficult-to-diagnose clinical syndromes and may order advanced molecular testing to detect pathogens. These tests may identify potential infectious causes for illness and allow clinicians to adapt treatments or stop unnecessary antimicrobials. Cases of pathogen-agnostic disease testing also provide an important window into known, emerging, and reemerging pathogens and may be leveraged as part of national sentinel surveillance. A survey of Emerging Infections Network members, a group of infectious disease providers in North America, was conducted in May 2023. The objective of the survey was to gain insight into how and when infectious disease physicians use advanced molecular testing for patients with difficult-to-diagnose infectious diseases, as well as to explore the usefulness of advanced molecular testing and barriers to use. Overall, 643 providers answered at least some of the survey questions; 478 (74%) of those who completed the survey had ordered advanced molecular testing in the last two years, and formed the basis for this study. Respondents indicated that they most often ordered broad-range 16S rRNA gene sequencing, followed by metagenomic next-generation sequencing and whole genome sequencing; and commented that in clinical practice, some, but not all tests were useful. Many physicians also noted several barriers to use, including a lack of national guidelines and cost, while others commented that whole genome sequencing had potential for use in outbreak surveillance. Improving frontline physician access, availability, affordability, and developing clear national guidelines for interpretation and use of advanced molecular testing could potentially support clinical practice and public health surveillance.

Mortality surveillance systems can have limitations, including reporting delays, incomplete reporting, missing data, and insufficient detail on important risk or sociodemographic factors that can impact the accuracy of estimates of current trends, disease severity, and related disparities across subpopulations. The Centers for Disease Control and Prevention used multiple data systems during the COVID-19 emergency response-line-level case‒death surveillance, aggregate death surveillance, and the National Vital Statistics System-to collectively provide more comprehensive and timely information on COVID-19‒associated mortality necessary for informed decisions. This article will review in detail the line-level, aggregate, and National Vital Statistics System surveillance systems and the purpose and use of each. This retrospective review of the hybrid surveillance systems strategy may serve as an example for adaptive informational approaches needed over the course of future public health emergencies. (Am J Public Health. Published online ahead of print July 25, 2024:e1-e10. https://doi.org/10.2105/AJPH.2024.307743).

OBJECTIVES: To understand the landscape of privacy preserving record linkage (PPRL) applications in public health, assess estimates of PPRL accuracy and privacy, and evaluate factors for PPRL adoption. MATERIALS AND METHODS: A literature scan examined the accuracy, data privacy, and scalability of PPRL in public health. Twelve interviews with subject matter experts were conducted and coded using an inductive approach to identify factors related to PPRL adoption. RESULTS: PPRL has a high level of linkage quality and accuracy. PPRL linkage quality was comparable to that of clear text linkage methods (requiring direct personally identifiable information [PII]) for linkage across various settings and research questions. Accuracy of PPRL depended on several components, such as PPRL technique, and the proportion of missingness and errors in underlying data. Strategies to increase adoption include increasing understanding of PPRL, improving data owner buy-in, establishing governance structure and oversight, and developing a public health implementation strategy for PPRL. DISCUSSION: PPRL protects privacy by eliminating the need to share PII for linkage, but the accuracy and linkage quality depend on factors including the choice of PPRL technique and specific PII used to create encrypted identifiers. Large-scale implementations of PPRL linking millions of observations-including PCORnet, National Institutes for Health N3C, and the Centers for Disease Control and Prevention COVID-19 project have demonstrated the scalability of PPRL for public health applications. CONCLUSIONS: Applications of PPRL in public health have demonstrated their value for the public health community. Although gaps must be addressed before wide implementation, PPRL is a promising solution to data linkage challenges faced by the public health ecosystem.

OBJECTIVE: This study is to compare socio-demographic, HIV testing, and prevention factors experienced by insured low-income heterosexual Black women and men. METHODS: We examined cross-sectional data from Black women and men (n = 5837) recruited in 23 U.S. cities for National HIV Behavioral Surveillance June-December 2019. We compared socio-demographic and behavioral factors between groups using log-linked Poisson regression models, producing adjusted prevalence ratios and 95% confidence intervals. RESULTS: Black women were less likely than Black men to have private insurance (aPR 0.61, 95% CI 0.50-0.74, p < 0.0001). Black women were more likely than Black men to have incomes at or below the poverty line (aPR 1.04, 95% CI 1.01-1.07, p = 0.02), be aware of PrEP (aPR 1.20, 95% CI 1.12-1.28, p < 0.0001), and have been recently tested for HIV (aPR 1.12, 95% CI 1.04, 1.20, p < 0.01). CONCLUSIONS: Despite insured status, many Black women and men experienced suboptimal access to and utilization of HIV testing and prevention services. Understanding how social conditions produce differential access to care may help inform HIV prevention interventions.

To better identify emerging or reemerging pathogens in patients with difficult-to-diagnose infections, it is important to improve access to advanced molecular testing methods. This is particularly relevant for cases where conventional microbiologic testing has been unable to detect the pathogen and the patient's specimens test negative. To assess the availability and utility of such testing for human clinical specimens, a literature review of published biomedical literature was conducted. From a corpus of more than 4,000 articles, a set of 34 reports was reviewed in detail for data on where the testing was being performed, types of clinical specimens tested, pathogen agnostic techniques and methods used, and results in terms of potential pathogens identified. This review assessed the frequency of advanced molecular testing, such as metagenomic next generation sequencing that has been applied to clinical specimens for supporting clinicians in caring for difficult-to-diagnose patients. Specimen types tested were from cerebrospinal fluid, respiratory secretions, and other body tissues and fluids. Publications included case reports and series, and there were several that involved clinical trials, surveillance studies, research programs, or outbreak situations. Testing identified both known human pathogens (sometimes in new sites) and previously unknown human pathogens. During this review, there were no apparent coordinated efforts identified to develop regional or national reports on emerging or reemerging pathogens. Therefore, development of a coordinated sentinel surveillance system that applies advanced molecular methods to clinical specimens which are negative by conventional microbiological diagnostic testing would provide a foundation for systematic characterization of emerging and underdiagnosed pathogens and contribute to national biodefense strategy goals.

The surveillance and identification of emerging, reemerging, and unknown infectious disease pathogens is essential to national public health preparedness and relies on fluidity, coordination, and interconnectivity between public and private pathogen surveillance systems and networks. Developing a national sentinel surveillance network with existing resources and infrastructure could increase efficiency, accelerate the identification of emerging public health threats, and support coordinated intervention strategies that reduce morbidity and mortality. However, implementing and sustaining programs to detect emerging and reemerging pathogens in humans using advanced molecular methods, such as metagenomic sequencing, requires making large investments in testing equipment and developing networks of clinicians, laboratory scientists, and bioinformaticians. In this study, we sought to gain an understanding of how federal government agencies currently support such pathogen agnostic testing of human specimens in the United States. We conducted a landscape analysis of federal agency websites for publicly accessible information on the availability and type of pathogen agnostic testing and details on flow of clinical specimens and data. The website analysis was supplemented by an expert review of results with representatives from the federal agencies. Operating divisions within the US Department of Health and Human Services and the US Department of Veterans Affairs have developed and sustained extensive clinical and research networks to obtain patient specimens and perform metagenomic sequencing. Metagenomic facilities supported by US agencies were not equally geographically distributed across the United States. Although many entities have work dedicated to metagenomics and/or support emerging infectious disease surveillance specimen collection, there was minimal formal collaboration across agencies.

BACKGROUND: Early administration of antibiotics in sepsis is associated with improved patient outcomes, but safe and generalizable approaches to de-escalate or discontinue antibiotics after suspected sepsis events are unknown. METHODS: We used a modified Delphi approach to identify safety criteria for an opt-out protocol to guide de-escalation or discontinuation of antibiotic therapy after 72 hours in non-ICU patients with suspected sepsis. An expert panel with expertise in antimicrobial stewardship and hospital epidemiology rated 48 unique criteria across 3 electronic survey rating tools. Criteria were rated primarily based on their impact on patient safety and feasibility for extraction from electronic health record review. The 48 unique criteria were rated by anonymous electronic survey tools, and the results were fed back to the expert panel participants. Consensus was achieved to either retain or remove each criterion. RESULTS: After 3 rounds, 22 unique criteria remained as part of the opt-out safety checklist. These criteria included high-risk comorbidities, signs of severe illness, lack of cultures during sepsis work-up or antibiotic use prior to blood cultures, or ongoing signs and symptoms of infection. CONCLUSIONS: The modified Delphi approach is a useful method to achieve expert-level consensus in the absence of evidence suifficient to provide validated guidance. The Delphi approach allowed for flexibility in development of an opt-out trial protocol for sepsis antibiotic de-escalation. The utility of this protocol should be evaluated in a randomized controlled trial.

BACKGROUND: Violence is a serious public health concern disproportionately experienced by American Indian and Alaska Native (AIAN) people. While the burden and impact of violence may be explained by the presence of risk factors among this group, AIAN communities benefit from unique protective factors and universal strategies which may be tailored with tribal adaptations. We sought to identify and explore violence prevention strategies specific to AIAN populations. METHODS: A review was conducted to systematically identify violence prevention programs, policies, and practices implemented in AIAN communities. We searched nine electronic databases and relevant gray literature released between January 1980 and June 2018. We included intervention-focused records targeting at least one violence topic area (child abuse/neglect, elder abuse, intimate partner violence, sexual violence, youth violence, and suicide) in a majority (> 50%) AIAN population. RESULTS: A total of 5220 non-duplicate records were screened, yielding 318 full-text records. After applying exclusion criteria, 57 records describing 60 program, policy, or practice implementations of 43 unique interventions were identified. All six violence types were represented, although more than half (58%; n = 25/43) focused on suicide prevention. Among suicide prevention programs, the most common strategies were identifying and supporting people at risk (80%; n = 20), teaching coping and problem-solving skills (56%; n = 14), and promoting connectedness (48%; n = 12). Two-thirds of the implementations (67%; n = 40/60) were in fully (100%) AIAN communities. Programs were implemented across many settings, though schools were the most common (35%, n = 21/60) setting. Of the 60 total implementations, a majority (80%; n = 48) were new approaches developed by and for AIAN communities, while the remainder were AIAN adaptations of programs previously created for non-AIAN populations. Most implementations (60%; n = 36/60) provided some evaluation data although less than half (45%; n = 27/60) reported evaluation results. CONCLUSIONS: This review identified many violence prevention strategies specific to AIAN populations. While programs developed in one tribe may not be completely generalizable to others, shared tribal risk and protective factors suggest programs could be successful across diverse communities. Findings indicate there is a need to develop and evaluate violence prevention programs, policies and practices for AIAN populations.

Severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) is a novel human coronavirus that was identified in 2019. SARS-CoV-2 infection results in an acute, severe respiratory disease called coronavirus disease 2019 (COVID-19). The emergence and rapid spread of SARS-CoV-2 has led to a global public health crisis, which continues to affect populations across the globe. Real time reverse transcription polymerase chain reaction (rRT-PCR) is the reference standard test for COVID-19 diagnosis. Serological tests are valuable tools for serosurveillance programs and establishing correlates of protection from disease. This study evaluated the performance of one in-house enzyme linked immunosorbent assay (ELISA) utilizing the pre-fusion stabilized ectodomain of SARS-CoV-2 spike (S), two commercially available chemiluminescence assays Ortho VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack and Abbott SARS-CoV-2 IgG assay and one commercially available Surrogate Virus Neutralization Test (sVNT), GenScript USA Inc., cPass SARS-CoV-2 Neutralization Antibody Detection Kit for the detection of SARS-CoV-2 specific antibodies. Using a panel of rRT-PCR confirmed COVID-19 patients' sera and a negative control group as a reference standard, all three immunoassays demonstrated high comparable positivity rates and low discordant rates. All three immunoassays were highly sensitive with estimated sensitivities ranging from 95.4-96.6 %. ROC curve analysis indicated that all three immunoassays had high diagnostic accuracies with area under the curve (AUC) values ranging from 0.9698 to 0.9807. High positive correlation was demonstrated among the conventional microneutralization test (MNT) titers and the sVNT inhibition percent values. Our study indicates that independent evaluations are necessary to optimize the overall utility and the interpretation of the results of serological tests. Overall, we demonstrate that all serological tests evaluated in this study are suitable for the detection of SARS-CoV-2 antibodies.

INTRODUCTION: The National Spina Bifida Patient Registry (NSBPR) assesses bladder and bowel incontinence using ordinal categories, but prior NSBPR analyses employed binary classification. Our aims were to 1) perform the first NSBPR analysis of bladder and bowel incontinence as ordinal outcomes to compare to the binary definition and subject variables; 2) explore the correlation of incontinence with undergarment usage, and 3) assess incontinence status following continence surgeries. METHODS: Data from NSBPR participants' most recent clinic visit from 2013 to 2020 were analyzed. Ordinal categories of incontinence were compared to previously used binary definitions. Incontinence surgical outcomes were analyzed for those with data at least three months post-operatively. Chi-square tests evaluated associations among categorical variables. Univariate and ordinal logistic regression models were used to test associations of ordinal incontinence status with patient and condition factors. Statistical tests were 2-sided; p values < 0.05 were considered significant. RESULTS: Analysis of 7217 individuals using ordinal incontinence outcomes showed little difference from previously used binary outcomes. The final multivariable logistic regression models with ordinal multinomial outcomes showed that associations of incontinence with age, sex, race/ethnicity, health insurance, level of lesion, and continence management technique were similar to prior studies. Among those reporting never being incontinent of both bladder and bowel, 14% reported using protective undergarments. Of the 500 individuals who had bladder outlet surgery, 38% reported never being incontinent of urine. Of 1416 individuals who had appendicostomy (ACE) bowel surgery, 48% reported never being incontinent of stool. DISCUSSION: Our current analysis showed that ordinal continence outcome classification had similar continence findings as previous studies using the binary definition of continence. Expanding the binary definition of continence to include monthly episodes of incontinence did not greatly increase the proportion of continent individuals and, therefore, would have not likely made meaningful differences in continence outcomes in prior NSBPR analyses. However, it is known that even mild incontinence can affect quality of life, therefore, capturing any level of incontiennce is of clinical importance. Confirmation of the association of continence outcomes with sociodemographic, condition-related, and interventional factors with both approaches further validates previous analyses using the binary definition of continence. CONCLUSION: The previously used binary definition of bladder and bowel continence appears robust. Undergarment choice was a poor surrogate for reported incontinence. After bladder and bowel continence surgeries, 38% and 48%, respectively, reported never being incontinent.

The first coronavirus, avian infectious bronchitis virus, was discovered in 1937 by Fred Beaudette and Charles Hudson. In 1967, June Almeida and David Tyrrell performed electron microscopy on specimens from cultures of viruses known to cause colds in humans and identified particles that resembled avian infectious bronchitis virus. Almeida coined the term “coronavirus,” from the Latin corona (“crown”), because the glycoprotein spikes of these viruses created an image similar to a solar corona (Figure).

Coronavirus virions are spherical or variable in shape and composed of an outer layer of lipid covered with a crown of club-shaped peplomers or spikes. Within each spike is a helical single-stranded RNA-containing structural protein. Although the term corona was first used in English in the 1500s, it was borrowed directly from the Latin word for “crown.” Corona is derived from the Ancient Greek κορώνη (korōnè), meaning “garland” or “wreath,” coming from a proto-Indo-European root, sker- or ker-, meaning “to turn” or “to bend.” | | In the 1967 initial description of an electron microscopic image of a human common cold virus, June Almeida (née Hart) and David Tyrrell described the surface of coronavirus particles as being “covered with a distinct layer of projections roughly 200Ǻ [20 nm] long….[with] a narrow stalk just in the limit of resolution of the microscope and a ‘head’ roughly 100Ǻ across”. In micrographs, the club-shaped spikes that stud the surface of coronaviruses are glycoproteins that give the appearance of a radiate crown.

Folate is a source of one-carbons necessary for DNA methylation, a critical epigenetic modification necessary for genomic structure and function. The use of supplemental folic acid is widespread however; the potential influence on DNA methylation is unclear. We measured global DNA methylation using DNA extracted from samples from a population-based, double-blind randomized trial of folic acid supplementation (100, 400, 4000 µg per day) taken for 6 months; including a 3 month post-supplementation sample. We observed no changes in global DNA methylation in response to up to 4,000 µg/day for 6 months supplementation in DNA extracted from uncoagulated blood (approximates circulating blood). However, when DNA methylation was determined in coagulated samples from the same individuals at the same time, significant time, dose, and MTHFR genotype-dependent changes were observed. The baseline level of DNA methylation was the same for uncoagulated and coagulated samples; marked differences between sample types were observed only after intervention. In DNA from coagulated blood, DNA methylation decreased (-14%; P<0.001) after 1 month of supplementation and 3 months after supplement withdrawal, methylation decreased an additional 23% (P<0.001) with significant variation among individuals (max+17%; min-94%). Decreases in methylation of ≥25% (vs. <25%) after discontinuation of supplementation were strongly associated with genotype: MTHFR CC vs. TT (adjusted odds ratio [aOR] 12.9, 95%CI 6.4, 26.0). The unexpected difference in DNA methylation between DNA extracted from coagulated and uncoagulated samples in response to folic acid supplementation is an important finding for evaluating use of folic acid and investigating the potential effects of folic acid supplementation on coagulation.

Vaccine development against hepatitis C virus (HCV) is hindered by poor understanding of factors defining cross-immunoreactivity among heterogeneous epitopes. Using synthetic peptides and mouse immunization as a model, we conducted a quantitative analysis of cross-immunoreactivity among variants of the HCV hypervariable region 1 (HVR1). Analysis of 26,883 immunological reactions among pairs of peptides showed that the distribution of cross-immunoreactivity among HVR1 variants was skewed, with antibodies against a few variants reacting with all tested peptides. The HVR1 cross-immunoreactivity was accurately modeled based on amino acid sequence alone. The tested peptides were mapped in the HVR1 sequence space, which was visualized as a network of 11,319 sequences. The HVR1 variants with a greater network centrality showed a broader cross-immunoreactivity. The entire sequence space is explored by each HCV genotype and subtype. These findings indicate that HVR1 antigenic diversity is extensively convergent and effectively limited, suggesting significant implications for vaccine development.

The majority of malaria rapid diagnostic tests (RDTs) detect Plasmodium falciparum histidine-rich protein 2 (PfHRP2), encoded by the pfhrp2 gene. Recently, P. falciparum isolates from Peru were found to lack pfhrp2 leading to false-negative RDT results. We hypothesized that pfhrp2-deleted parasites in Peru derived from a single genetic event. We evaluated the parasite population structure and pfhrp2 haplotype of samples collected between 1998 and 2005 using seven neutral and seven chromosome 8 microsatellite markers, respectively. Five distinct pfhrp2 haplotypes, corresponding to five neutral microsatellite-based clonal lineages, were detected in 1998-2001; pfhrp2 deletions occurred within four haplotypes. In 2003-2005, outcrossing among the parasite lineages resulted in eight population clusters that inherited the five pfhrp2 haplotypes seen previously and a new haplotype; pfhrp2 deletions occurred within four of these haplotypes. These findings indicate that the genetic origin of pfhrp2 deletion in Peru was not a single event, but likely occurred multiple times.

BACKGROUND: In May 2011, the first trivalent inactivated influenza vaccine exclusively for intradermal administration (TIV-ID) was licensed in the US for adults aged 18-64 years. OBJECTIVE: To characterize adverse events (AEs) after TIV-ID reported to the US Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting surveillance system. METHODS: We searched VAERS for US reports after TIV-ID among persons vaccinated from July 1, 2011-February 28, 2013. Medical records were requested for reports coded as serious (death, hospitalization, prolonged hospitalization, disability, life-threatening-illness), and those suggesting anaphylaxis. Clinicians reviewed available information and assigned a primary clinical category to each report. Empirical Bayesian data mining was used to identify disproportional AE reporting following TIV-ID. Causality was not assessed. RESULTS: VAERS received 466 reports after TIV-ID; 9 (1.9%) were serious, including one reported fatality in an 88-year-old vaccinee. Median age was 43 years (range 4-88 years). The most common AE categories were: 218 (46.8%) injection site reactions; 89 (19.1%) other non-infectious (comprised mainly of constitutional signs and symptoms); and 74 (15.9%) allergy. Eight reports (1.7%) of anaphylaxis were verified by the Brighton criteria or a documented physician diagnosis. Disproportional reporting was identified for three AEs: 'injection site nodule', 'injection site pruritus', and 'drug administered to patient of inappropriate age'. The findings for the first two AEs were expected. Twenty-four reports of vaccinees <18 years or ≥ 65 years were reported, and 14 of 24 were coded with the AE 'drug administered to patient of inappropriate age'. CONCLUSIONS: Review of VAERS reports did not identify any new or unexpected safety concerns after TIV-ID. Injection site reactions were the most commonly reported AEs, similar to the pre-licensure clinical trials. Use of TIV-ID in younger and older individuals outside the approved age range highlights the need for education of healthcare providers regarding approved TIV-ID use.

Cardiovascular diseases (CVDs) are a major source of morbidity and mortality worldwide. Despite a decline of ≈30% over the past decade, heart disease remains the leading killer of Americans.1 For rare and familial forms of CVD, we are increasingly recognizing single-gene mutations that impart relatively large effects on individual phenotype. Examples include inherited forms of cardiomyopathy, arrhythmias, and aortic diseases. However, the prevalence of monogenic disorders typically accounts for a small proportion of the total CVD observed in the population. CVDs in the general population are complex diseases, with several contributing genetic and environmental factors. Although recent progress in monogenic disorders has occurred, we have seen a period of intense investigation to identify the genetic architecture of more common forms of CVD and related traits. | | Genomics serves several roles in cardiovascular health and disease, including disease prediction, discovery of genetic loci influencing CVD, functional evaluation of these genetic loci to understand mechanisms, and identification of therapeutic targets. For single-gene CVDs, progress has led to several clinically useful diagnostic tests, extending our ability to inform the management of afflicted patients and their family members. However, there has been little progress in developing genetic testing for complex CVD because individual common variants have only a modest impact on risk. The study of the genomics of complex CVDs is further challenged by the influence of environmental variables, phenotypic heterogeneity, and pathogenic complexity. Characterization of the clinical phenotype requires consideration of the clinical details of the diseases and traits under study.

BACKGROUND: The Middle East respiratory syndrome coronavirus (MERS-CoV) was discovered September 2012 in the Kingdom of Saudi Arabia (KSA). The first US case of MERS-CoV was confirmed on 2 May 2014. METHODS: We summarize the clinical symptoms and signs, laboratory and radiologic findings, and MERS-CoV-specific tests. RESULTS: The patient is a 65-year-old physician who worked in a hospital in KSA where MERS-CoV patients were treated. His illness onset included malaise, myalgias, and low-grade fever. He flew to the United States on day of illness (DOI) 7. His first respiratory symptom, a dry cough, developed on DOI 10. On DOI 11, he presented to an Indiana hospital as dyspneic, hypoxic, and with a right lower lobe infiltrate on chest radiography. On DOI 12, his serum tested positive by real-time reverse transcription polymerase chain reaction (rRT-PCR) for MERS-CoV and showed high MERS-CoV antibody titers, whereas his nasopharyngeal swab was rRT-PCR negative. Expectorated sputum was rRT-PCR positive the following day, with a high viral load (5.31 × 10(6) copies/mL). He was treated with antibiotics, intravenous immunoglobulin, and oxygen by nasal cannula. He was discharged on DOI 22. The genome sequence was similar (>99%) to other known MERS-CoV sequences, clustering with those from KSA from June to July 2013. CONCLUSIONS: This patient had a prolonged nonspecific prodromal illness before developing respiratory symptoms. Both sera and sputum were rRT-PCR positive when nasopharyngeal specimens were negative. US clinicians must be vigilant for MERS-CoV in patients with febrile and/or respiratory illness with recent travel to the Arabian Peninsula, especially among healthcare workers.

BACKGROUND: Scaling-up antiretroviral therapy (ART) in resource-limited settings has raised concerns of emerging HIV drug resistance (DR) and its transmission to newly infected individuals. To assess the prevalence of transmitted drug resistance (TDR) in recently HIV-infected individuals, a WHO TDR threshold survey was conducted among young adults in Kigali, Rwanda. METHODS: Between May and July 2011, HIV subtype and genotyping were performed on dried blood spots (DBS) prepared from blood specimens collected from newly HIV-diagnosed and ART-naive individuals aged 15 to 21 years in eight HIV voluntary counselling and testing (VCT) sites in Kigali. RESULTS: In total, 57 of the 68 DBS collected from eligible participants were successfully amplified. The median age of participants was 20 years and 86% were female. Most participants (96%) were infected with subtype A1 virus. Two participants (4%) had the K103N non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation and one (2%) had the M46L protease inhibitor (PI) mutation. The TDR prevalence was 3.5% (95% CI 0.4, 12.1) for NNRTI and 1.8% (95% CI 0.0, 9.4) for PI. CONCLUSIONS: The prevalence of HIV TDR in VCT attendees in Kigali was characterized as low (<5%) for all drug classes according to the WHO HIV DR threshold survey methodology. Despite a decade of widespread ART in Rwanda, TDR prevalence remains low, and so the current first-line ART regimens should continue to be effective. However, as scale-up of ART continues, frequent HIV DR surveillance is needed to monitor the effectiveness of available ART regimens at the population level.

Viral metagenomics sequencing of fecal samples from outbreaks of acute gastroenteritis from the US revealed the presence of small circular ssDNA viral genomes encoding a replication initiator protein (Rep). Viral genomes were ∼2.5 kb in length, with bi-directionally oriented Rep and capsid (Cap) encoding genes and a stem loop structure downstream of Rep. Several genomes showed evidence of recombination. By digital screening of an in-house virome database (1.04 billion reads) using BLAST, we identified closely related sequences from cases of unexplained diarrhea in France. Deep sequencing and PCR detected such genomes in 7 of 25 US (28 percent) and 14 of 21 French outbreaks (67 percent). One of eighty-five sporadic diarrhea cases in the Gambia was positive by PCR. Twenty-two complete genomes were characterized showing that viruses from patients in the same outbreaks were closely related suggesting common origins. Similar genomes were also characterized from the stools of captive chimpanzees, a gorilla, a black howler monkey, and a lemur that were more diverse than the human stool-associated genomes. The name smacovirus is proposed for this monophyletic viral clade. Possible tropism include mammalian enteric cells or ingested food components such as infected plants. No evidence of viral amplification was found in immunodeficient mice orally inoculated with smacovirus-positive stool supernatants. A role for smacoviruses in diarrhea, if any, remains to be demonstrated.

The development of resistance of Neisseria gonorrhoeae to available first-line antibiotics, including penicillins, tetracyclines, fluoroquinolones and cephalosporins, has led to the circulation of multidrug-resistant gonorrhea at a global scale. Advancements in high-throughput whole-genome sequencing (WGS) provide useful tools that can be used to enhance gonococcal detection, treatment and management capabilities, which will ultimately aid in the control of antimicrobial resistant gonorrhea worldwide. In this minireview, we discuss the application of WGS of N. gonorrhoeae to strain typing, phylogenomic, molecular surveillance and transmission studies. We also examine the application of WGS analyses to the public health sector as well as the potential usage of WGS-based transcriptomic and epigenetic methods to identify novel gonococcal resistance mechanisms.

A clear understanding of the genetic basis of antibiotic resistance in Mycobacterium tuberculosis is required to accelerate the development of rapid drug susceptibility testing methods based on genetic sequence.Raw genotype-phenotype correlation data were extracted as part of a comprehensive systematic review to develop a standardised analytical approach for interpreting resistance associated mutations for rifampicin, isoniazid, ofloxacin/levofloxacin, moxifloxacin, amikacin, kanamycin, capreomycin, streptomycin, ethionamide/prothionamide and pyrazinamide. Mutation frequencies in resistant and susceptible isolates were calculated, together with novel statistical measures to classify mutations as high, moderate, minimal or indeterminate confidence for predicting resistance.We identified 286 confidence-graded mutations associated with resistance. Compared to phenotypic methods, sensitivity (95% CI) for rifampicin was 90.3% (89.6-90.9%), while for isoniazid it was 78.2% (77.4-79.0%) and their specificities were 96.3% (95.7-96.8%) and 94.4% (93.1-95.5%), respectively. For second-line drugs, sensitivity varied from 67.4% (64.1-70.6%) for capreomycin to 88.2% (85.1-90.9%) for moxifloxacin, with specificity ranging from 90.0% (87.1-92.5%) for moxifloxacin to 99.5% (99.0-99.8%) for amikacin.This study provides a standardised and comprehensive approach for the interpretation of mutations as predictors of M. tuberculosis drug-resistant phenotypes. These data have implications for the clinical interpretation of molecular diagnostics and next-generation sequencing as well as efficient individualised therapy for patients with drug-resistant tuberculosis.

After the hurricanes in 2017 in the U.S. Caribbean, it was essential to rebuild, strengthen, and sustain essential environmental health (EH) services and systems. The National Environmental Health Association, in partnership with the Centers for Disease Control and Prevention, developed an online mentorship program for newly hired and existing EH staff and health department leadership in Caribbean health departments. Participants were provided with both practical and didactic learning and were allowed to evaluate the program. Both mentors and mentees were highly satisfied with the knowledge and skills acquired, and mentees expressed it was relevant to their daily work. Based on the findings, we recommend both an online and a hybrid mentorship program for leadership- and inspector-level workforces in EH and potentially in other fields.

Background Under the Global Programme to Eliminate Lymphatic Filariasis (LF), American Samoa conducted mass drug administration (MDA) from 2000-2006. Despite passing Transmission Assessment Surveys (TAS) in 2011/2012 and 2015, American Samoa failed TAS-3 in 2016, with antigen (Ag) prevalence of 0.7% (95%CI 0.3-1.8%) in 6-7 year-olds. A 2016 community survey (Ag prevalence 6.2% (95%CI 4.4-8.5%) in age ≥8 years) confirmed resurgence. Here, we explore the potential of targeted strategies to strengthen post-MDA surveillance.Methodology/Principal Findings Using Ag data plus new antibody data (Wb123, Bm14, Bm33) from the 2016 surveys, we identified risk factors for seropositivity using multivariable logistic regression. We compared TAS with strategies that targeted high-risk subpopulations (older ages, householders of Ag-positive TAS children [index children]) and/or known hotspots, and used NNTestav (average number needed to test to identify one positive) to compare sampling efficiency.Antibody prevalence in TAS-3 (n=1143) were 1.6% for Bm14 (95%CI 0.9-2.9%), 7.9% for Wb123 (95%CI 6.4-9.6%), and 20.2% for Bm33 (95%CI 16.7-24.3%); and in the community survey (n=2507), 13.9% for Bm14 (95%CI 11.2-17.2%), 27.9% for Wb123 (95%CI 24.6-31.4%), and 47.3% for Bm33 (95%CI 42.1-52.6%). Ag prevalence was 20.7% (95%CI 9.7-53.5%) in households of index children. Higher Ag prevalence was found in males (adjusted odds ratio [aOR] 3.01), age ≥18 years (aOR 2.18), residents of Fagali’i (aOR 15.81), and outdoor workers (aOR 2.61). Using Ag, NNTestav ranged from 142.5 for TAS, to &lt;5 for households of index children. NNTestav was lower in older ages, and highest for Ag, followed by Bm14, Wb123 and Bm33 antibodies.Conclusions/Significance We propose a multi-stage surveillance strategy, starting with population-representative sampling (e.g. TAS), followed by targeted strategies in subgroups and locations with low NNTestav. This approach could potentially improve the efficiency of identifying remaining infected persons and residual hotspots. The utility of antibodies in surveillance should also be explored.AUTHOR SUMMARY Lymphatic filariasis (LF) is a parasitic infection transmitted by mosquito bites. Globally, tens of millions are infected, with many disfigured and disabled by severe damage to their lymphatic systems, such as severe swelling of the legs (elephantiasis) or scrotum (hydrocele). The Global Programme to Eliminate LF (GPELF) aims to interrupt disease transmission through mass drug administration (MDA), and to control illness and suffering in affected persons. The World Health Organization recommends conducting Transmission Assessment Surveys (TAS) in school children aged 6 to 7 years, to determine if infection rates have dropped to levels where disease transmission is no longer sustainable. From 2000-2006, American Samoa conducted MDA and made significant progress towards eliminating LF. However, despite passing TAS in 2011/2012 and 2015, surveys in 2016 showed evidence of resurgence. Our study explored alternative surveillance strategies and compared their efficiency with TAS. Based on our findings, we recommended that in addition to TAS, strategies that target high-risk populations and hotspots would strengthen surveillance and help countries achieve their goals of LF elimination.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work received financial support from the Coalition for Operational Research on Neglected Tropical Diseases (COR-NTD), which is funded at The Task Force for Global Health primarily by the Bill &amp; Melinda Gates Foundation [OPP1053230], the United Kingdom Department for International Development, and by the United States Agency for International Development through its Neglected Tropical Diseases Program. CLL was supported by an Australian National Health and Medical Research Council Fellowship (1109035). MS was supported by a fellowship funded by the Westpac Scholars Trust. The funders had no role in study design, data collection and analysis, decisi n to publish, or preparation of the manuscript.Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe datasets generated and analysed during the present study are available from the corresponding author upon reasonable request.

Parasitic nematodes (roundworms) and platyhelminths (flatworms) cause debilitating chronic infections of humans and animals, decimate crop production and are a major impediment to socioeconomic development. Here we compare the genomes of 81 nematode and platyhelminth species, including those of 76 parasites. From 1.4 million genes, we identify gene family births and hundreds of large expanded gene families at key nodes in the phylogeny that are relevant to parasitism. Examples include gene families that modulate host immune responses, enable parasite migration though host tissues or allow the parasite to feed. We use a wide-ranging in silico screen to identify and prioritise new potential drug targets and compounds for testing. We also uncover lineage-specific differences in core metabolism and in protein families historically targeted for drug development. This is the broadest comparative study to date of the genomes of parasitic and non-parasitic worms. It provides a transformative new resource for the research community to understand and combat the diseases that parasitic worms cause.

Background The extent to which vaccinated persons who become infected with SARS-CoV-2 contribute to transmission is unclear. During a SARS-CoV-2 Delta variant outbreak among incarcerated persons with high vaccination rates in a federal prison, we assessed markers of viral shedding in vaccinated and unvaccinated persons. Methods Consenting incarcerated persons with confirmed SARS-CoV-2 infection provided mid-turbinate nasal specimens daily for 10 consecutive days and reported symptom data via questionnaire. Real-time reverse transcription-polymerase chain reaction (RT-PCR), viral whole genome sequencing, and viral culture was performed on these nasal specimens. Duration of RT-PCR positivity and viral culture positivity was assessed using survival analysis. Results A total of 978 specimens were provided by 95 participants, of whom 78 (82%) were fully vaccinated and 17 (18%) were not fully vaccinated. No significant differences were detected in duration of RT-PCR positivity among fully vaccinated participants (median: 13 days) versus those not fully vaccinated (median: 13 days; p=0.50), or in duration of culture positivity (medians: 5 days and 5 days; p=0.29). Among fully vaccinated participants, overall duration of culture positivity was shorter among Moderna vaccine recipients versus Pfizer (p=0.048) or Janssen (p=0.003) vaccine recipients. Conclusions As this field continues to develop, clinicians and public health practitioners should consider vaccinated persons who become infected with SARS-CoV-2 to be no less infectious than unvaccinated persons. These findings are critically important, especially in congregate settings where viral transmission can lead to large outbreaks. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

BACKGROUND A classic debate concerns whether absolute or relative income is more salient. Absolute values resources as constant across time and place while relative contextualizes one’s hierarchical location in the distribution of a time and place. OBJECTIVE This study investigates specifically whether absolute income or relative income matters more for health and well-being. METHODS We exploit within-person, within-age, and within-time variation with higher-quality income measures and multiple health and well-being outcomes in the United States. Using the Panel Study of Income Dynamics and the Cross-National Equivalent File, we estimate three-way fixed effects models of self-rated health, poor health, psychological distress, and life satisfaction. RESULTS For all four outcomes, relative income has much larger standardized coefficients than absolute income. Robustly, the confidence intervals for relative income do not overlap with zero. By contrast, absolute income mostly has confidence intervals that overlap with zero, and its coefficient is occasionally signed in the wrong direction. A variety of robustness checks support these results. CONCLUSIONS Relative income has far greater predictive validity than absolute income for self-reported health and well-being. CONTRIBUTION Compared to earlier studies, this study provides a more rigorous comparison and test of the predictive validity of absolute and relative income that is uniquely conducted with data on the United States. This informs debates on income measurement, the sources of health and well-being, and inequalities generally. Plausibly, these results can guide any analysis that includes income in models. © 2023 David Brady, Michaela Curran & Richard M. Carpiano. All Rights Reserved.