INTRODUCTION: An error grid compares measured versus reference glucose concentrations to assign clinical risk values to observed errors. Widely used error grids for blood glucose monitors (BGMs) have limited value because they do not also reflect clinical accuracy of continuous glucose monitors (CGMs). METHODS: Diabetes Technology Society (DTS) convened 89 international experts in glucose monitoring to (1) smooth the borders of the Surveillance Error Grid (SEG) zones and create a user-friendly tool-the DTS Error Grid; (2) define five risk zones of clinical point accuracy (A-E) to be identical for BGMs and CGMs; (3) determine a relationship between DTS Error Grid percent in Zone A and mean absolute relative difference (MARD) from analyzing 22 BGM and nine CGM accuracy studies; and (4) create trend risk categories (1-5) for CGM trend accuracy. RESULTS: The DTS Error Grid for point accuracy contains five risk zones (A-E) with straight-line borders that can be applied to both BGM and CGM accuracy data. In a data set combining point accuracy data from 18 BGMs, 2.6% of total data pairs equally moved from Zones A to B and vice versa (SEG compared with DTS Error Grid). For every 1% increase in percent data in Zone A, the MARD decreased by approximately 0.33%. We also created a DTS Trend Accuracy Matrix with five trend risk categories (1-5) for CGM-reported trend indicators compared with reference trends calculated from reference glucose. CONCLUSION: The DTS Error Grid combines contemporary clinician input regarding clinical point accuracy for BGMs and CGMs. The DTS Trend Accuracy Matrix assesses accuracy of CGM trend indicators.

Respiratory viruses contribute to high morbidity and mortality in Africa. In 2020, the Ohio State University's Global One Health Initiative, in collaboration with the Ethiopian Public Health Institute and the US Centers for Disease Control and Prevention, took action to strengthen Ethiopia's existing respiratory virus surveillance system through decentralization of laboratory testing and scale-up of national and regional capacity for detecting respiratory viruses. In August 2022, four regional laboratories were established, thereby raising the number of reference laboratories conducting respiratory virus surveillance to five. This article highlights lessons learned during implementation and outlines processes undertaken for laboratory scale-up and decentralization.

Candida auris, initially identified in 2009, has rapidly become a critical concern due to its antifungal resistance and significant mortality rates in healthcare-associated outbreaks. To date, whole-genome sequencing (WGS) has identified five unique clades of C. auris, with some strains displaying resistance to all primary antifungal drug classes. In this study, we presented the first WGS analysis of C. auris from Bangladesh, describing its origins, transmission dynamics, and antifungal susceptibility testing (AFST) profile. Ten C. auris isolates collected from hospital settings in Bangladesh were initially identified by CHROMagar Candida Plus, followed by VITEK2 system, and later sequenced using Illumina NextSeq 550 system. Reference-based phylogenetic analysis and variant calling pipelines were used to classify the isolates in different clades. All isolates aligned ~90% with the Clade I C. auris B11205 reference genome. Of the 10 isolates, 8 were clustered with Clade I isolates, highlighting a South Asian lineage prevalent in Bangladesh. Remarkably, the remaining two isolates formed a distinct cluster, exhibiting >42,447 single-nucleotide polymorphism differences compared to their closest Clade IV counterparts. This significant variation corroborates the emergence of a sixth clade (Clade VI) of C. auris in Bangladesh, with potential for international transmission. AFST results showed that 80% of the C. auris isolates were resistant to fluconazole and voriconazole, whereas Clade VI isolates were susceptible to azoles, echinocandins, and pyrimidine analogue. Genomic sequencing revealed ERG11_Y132F mutation conferring azole resistance while FCY1_S70R mutation found inconsequential in describing 5-flucytosine resistance. Our study underscores the pressing need for comprehensive genomic surveillance in Bangladesh to better understand the emergence, transmission dynamics, and resistance profiles of C. auris infections. Unveiling the discovery of a sixth clade (Clade VI) accentuates the indispensable role of advanced sequencing methodologies.IMPORTANCECandida auris is a nosocomial fungal pathogen that is commonly misidentified as other Candida species. Since its emergence in 2009, this multidrug-resistant fungus has become one of the five urgent antimicrobial threats by 2019. Whole-genome sequencing (WGS) has proven to be the most accurate identification technique of C. auris which also played a crucial role in the initial discovery of this pathogen. WGS analysis of C. auris has revealed five distinct clades where isolates of each clade differ among themselves based on pathogenicity, colonization, infection mechanism, as well as other phenotypic characteristics. In Bangladesh, C. auris was first reported in 2019 from clinical samples of a large hospital in Dhaka city. To understand the origin, transmission dynamics, and antifungal-resistance profile of C. auris isolates circulating in Bangladesh, we conducted a WGS-based surveillance study on two of the largest hospital settings in Dhaka, Bangladesh.

INTRODUCTION: the number of wild poliomyelitis cases, worldwide, dropped from 350,000 cases in 1988 to 33 in 2018. Acute flaccid paralysis (AFP) surveillance is a key strategy toward achieving global polio eradication. The 2014 Ebola virus disease (EVD) epidemic in West Africa infected over 28,000 people and had devastating effects on health systems in Guinea, Liberia, and Sierra Leone. We sought to assess the effects of the 2014 Ebola outbreak on AFP surveillance in Guinea and Liberia. METHODS: a retrospective cross-sectional analysis was performed for Guinea and Liberia to evaluate EVD´s impact on World Health Organization (WHO) AFP surveillance performance indicators during 2012-2015. RESULTS: both Guinea and Liberia met the WHO target non-polio AFP incidence rate nationally, and generally sub-nationally, prior to the EVD outbreak; rates decreased substantially during the outbreak in seven of eight regions in Guinea and 11 of 15 counties in Liberia. Throughout the study period, both Guinea and Liberia attained appropriate overall targets nationally for "notification" and "stool adequacy" indicators, but each country experienced periods of poor regional/county-specific indicator performance. CONCLUSION: these findings mirrored the negative effect of the Ebola outbreak on polio elimination activities in both countries and highlights the need to reinforce this surveillance system during times of crisis.

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of MIS-C patient samples (n=199) to identify a distinct set of host proteins that are differentially targeted by patient autoantibodies relative to matched controls. We identified an autoreactive epitope within SNX8, a protein expressed primarily in immune cells which regulates an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed the SARS-CoV-2 proteome-wide MIS-C patient antibody response and found it to be differentially reactive to a distinct domain of the SARS-CoV-2 nucleocapsid (N) protein relative to controls. This viral N region and the mapped SNX8 epitope bear remarkable biochemical similarity. Furthermore, we find that many children with anti-SNX8 autoantibodies also have T-cells cross-reactive to both SNX8 and this distinct domain of the SARS-CoV-2 N protein. Together, these findings suggest that MIS-C patients develop a distinct immune response against the SARS-CoV-2 N protein that is associated with cross reactivity to the self-protein SNX8, demonstrating a link from the infection to the inflammatory syndrome. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.

Background: We estimated SARS-CoV-2 Delta and Omicron-specific effectiveness of 2 and 3 mRNA COVID-19 vaccine doses in adults against symptomatic illness in US outpatient settings. Method(s): Between October 1, 2021, and February 12, 2022, research staff consented and enrolled eligible participants who had fever, cough, or loss of taste or smell and sought outpatient medical care or clinical SARS-CoV-2 testing within 10 days of illness onset. Using the test-negative design, we compared the odds of receiving 2 or 3 mRNA COVID-19 vaccine doses among SARS-CoV-2 cases versus controls using logistic regression. Regression models were adjusted for study site, age, onset week, and prior SARS-CoV-2 infection. Vaccine effectiveness (VE) was calculated as (1 - adjusted odds ratio) x 100%. Result(s): Among 3847 participants included for analysis, 574 (32%) of 1775 tested positive for SARS-CoV-2 during the Delta predominant period and 1006 (56%) of 1794 participants tested positive during the Omicron predominant period. When Delta predominated, VE against symptomatic illness in outpatient settings was 63% (95% CI: 51% to 72%) among mRNA 2-dose recipients and 96% (95% CI: 93% to 98%) for 3-dose recipients. When Omicron predominated, VE was 21% (95% CI: -6% to 41%) among 2-dose recipients and 62% (95% CI: 48% to 72%) among 3-dose recipients. Conclusion(s): In this adult population, 3 mRNA COVID-19 vaccine doses provided substantial protection against symptomatic illness in outpatient settings when the Omicron variant became the predominant cause of COVID-19 in the U.S. These findings support the recommendation for a 3rd mRNA COVID-19 vaccine dose. 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.

INTRODUCTION: Inequitable access to leisure-time physical activity (LTPA) resources may explain geographic disparities in type 2 diabetes (T2D). We evaluated whether the neighborhood socioeconomic environment (NSEE) affects T2D through the LTPA environment. RESEARCH DESIGN AND METHODS: We conducted analyses in three study samples: the national Veterans Administration Diabetes Risk (VADR) cohort comprising electronic health records (EHR) of 4.1 million T2D-free veterans, the national prospective cohort REasons for Geographic and Racial Differences in Stroke (REGARDS) (11 208 T2D free), and a case-control study of Geisinger EHR in Pennsylvania (15 888 T2D cases). New-onset T2D was defined using diagnoses, laboratory and medication data. We harmonized neighborhood-level variables, including exposure, confounders, and effect modifiers. We measured NSEE with a summary index of six census tract indicators. The LTPA environment was measured by physical activity (PA) facility (gyms and other commercial facilities) density within street network buffers and population-weighted distance to parks. We estimated natural direct and indirect effects for each mediator stratified by community type. RESULTS: The magnitudes of the indirect effects were generally small, and the direction of the indirect effects differed by community type and study sample. The most consistent findings were for mediation via PA facility density in rural communities, where we observed positive indirect effects (differences in T2D incidence rates (95% CI) comparing the highest versus lowest quartiles of NSEE, multiplied by 100) of 1.53 (0.25, 3.05) in REGARDS and 0.0066 (0.0038, 0.0099) in VADR. No mediation was evident in Geisinger. CONCLUSIONS: PA facility density and distance to parks did not substantially mediate the relation between NSEE and T2D. Our heterogeneous results suggest that approaches to reduce T2D through changes to the LTPA environment require local tailoring.

BACKGROUND: The B.1.167.2 (Delta) variant quickly became the predominant circulating SARS-CoV-2 strain in the United States during Summer 2021. Missouri identified a high number of outbreaks in long-term care facilities (LTCF) across the state with low vaccination rates among LTCF staff members and poor adherence to mitigation measures within local communities. AIM: This report aims to describe COVID-19 outbreaks that occurred in Missouri LTCFs impacting staff and residents during the surge of the Delta variant. METHODS: Outbreaks of COVID-19 in 178 LTCFs were identified by the Missouri Department of Health and Senior Services. Case data from LTCFs with the highest burden of disease were analyzed to assess disease transmission, vaccination status, and outcomes among residents and staff. Additional investigational measures included onsite visits to facilities with recent COVID-19 outbreaks in communities with substantial transmission to assess mitigation measures. FINDINGS: During 22(nd) April - 29(th) July 2021, 159 COVID-19 cases among 72 staff members and 87 residents, were identified in 10 LTCFs. Over 74.7% of resident cases were vaccinated compared to 23.6% of staff cases. Vaccinated residents had a lower proportion of hospitalizations and deaths reported compared to unvaccinated residents. Data analysis and contact tracing efforts from a sample of the facilities suggest staff members were likely a major factor in introducing SARS-CoV-2 virus into the facilities. Adherence to COVID-19 mitigation measures varied at the visited facilities. CONCLUSION: Data showed that vaccination rates varied between staff cases and resident cases in facilities with high burden outbreaks. Differences were identified in mitigation practices in at least two facilities.

This study seeks to find the correlation between case fatality rates (CFRs) and third-dose vaccination coverage in 244 counties (si/gun/gu) of South Korea during the omicron variant wave. Multivariate regression analyses report that the higher third-dose vaccination rates were correlated with lower regional CFRs, when controlling for age structure. If the third-dose vaccination rate of a county is higher by 10%, it would have a CFR lower by 0.05% (95% confidence interval, 0.03-0.08%). As the number of cumulative confirmed cases in South Korea was 16,353,495 as of April 20, 2022, a lower CFR by 0.03-0.08% is equivalent to 4,394-12,448 lives (8.6-24.4 per 100,000) spared. County-specific characteristics, such as age structure, intensive care unit availability, and the level of non-pharmaceutical interventions may also affect the extent of this correlation. The conclusion implicates the potential role of coronavirus disease 2019 vaccines in reducing the pressure on the regional healthcare capacity.

Evaluation of geographic disparities in type 2 diabetes (T2D) onset requires multidimensional approaches at a relevant spatial scale to characterize community types and features that could influence this health outcome. Using Geisinger electronic health records (2008-2016), we conducted a nested case-control study of new onset T2D in a 37-county area of Pennsylvania. The study included 15,888 incident T2D cases and 79,435 controls without diabetes, frequency-matched 1:5 on age, sex, and year of diagnosis or encounter. We characterized patients' residential census tracts by four dimensions of social determinants of health (SDOH) and into a 7-category SDOH census tract typology previously generated for the entire United States by dimension reduction techniques. Finally, because the SDOH census tract typology classified 83% of the study region's census tracts into two heterogeneous categories, termed rural affordable-like and suburban affluent-like, to further delineate geographies relevant to T2D, we subdivided these two typology categories by administrative community types (U.S. Census Bureau minor civil divisions of township, borough, city). We used generalized estimating equations to examine associations of 1) four SDOH indexes, 2) SDOH census tract typology, and 3) modified typology, with odds of new onset T2D, controlling for individual-level confounding variables. Two SDOH dimensions, higher socioeconomic advantage and higher mobility (tracts with fewer seniors and disabled adults) were independently associated with lower odds of T2D. Compared to rural affordable-like as the reference group, residence in tracts categorized as extreme poverty (odds ratio [95% confidence interval] = 1.11 [1.02, 1.21]) or multilingual working (1.07 [1.03, 1.23]) were associated with higher odds of new onset T2D. Suburban affluent-like was associated with lower odds of T2D (0.92 [0.87, 0.97]). With the modified typology, the strongest association (1.37 [1.15, 1.63]) was observed in cities in the suburban affluent-like category (vs. rural affordable-like-township), followed by cities in the rural affordable-like category (1.20 [1.05, 1.36]). We conclude that in evaluating geographic disparities in T2D onset, it is beneficial to conduct simultaneous evaluation of SDOH in multiple dimensions. Associations with the modified typology showed the importance of incorporating governmentally, behaviorally, and experientially relevant community definitions when evaluating geographic health disparities.

Before the emergence of SARS-CoV-2, the virus that causes COVID-19, influenza activity in the United States typically began to increase in the fall and peaked in February. During the 2021-22 season, influenza activity began to increase in November and remained elevated until mid-June, featuring two distinct waves, with A(H3N2) viruses predominating for the entire season. This report summarizes influenza activity during October 3, 2021-June 11, 2022, in the United States and describes the composition of the Northern Hemisphere 2022-23 influenza vaccine. Although influenza activity is decreasing and circulation during summer is typically low, remaining vigilant for influenza infections, performing testing for seasonal influenza viruses, and monitoring for novel influenza A virus infections are important. An outbreak of highly pathogenic avian influenza A(H5N1) is ongoing; health care providers and persons with exposure to sick or infected birds should remain vigilant for onset of symptoms consistent with influenza. Receiving a seasonal influenza vaccine each year remains the best way to protect against seasonal influenza and its potentially severe consequences.

Humans will set foot on the Moon again soon. The lunar dust (LD) is potentially reactive and could pose an inhalation hazard to lunar explorers. We elucidated LD toxicity and investigated the toxicological impact of particle surface reactivity (SR) using three LDs, quartz, and TiO(2). We first isolated the respirable-size-fraction of an Apollo-14 regolith and ground two coarser samples to produce fine LDs with increased SR. SR measurements of these five respirable-sized dusts, determined by their in-vitro ability to generate hydroxyl radicals (OH), showed that ground LDs>unground LDTiO(2) quartz. Rats were each intratracheally instilled with 0, 1, 2.5, or 7.5mg of a test dust. Toxicity biomarkers and histopathology were assessed up to 13weeks after the bolus instillation. All dusts caused dose-dependent-increases in pulmonary lesions and toxicity biomarkers. The three LDs, which possessed mineral compositions/properties similar to Arizona volcanic ash, were moderately toxic. Despite a 14-fold OH difference among these three LDs, their toxicities were indistinguishable. Quartz produced the lowest OH amount but showed the greatest toxicity. Our results showed no correlation between the toxicity of mineral dusts and their ability to generate free radicals. We also showed that the amounts of oxidants per neutrophil increased with doses, time and the cytotoxicity of the dusts in the lung, which supports our postulation that dust-elicited neutrophilia is the major persistent source of oxidative stress. These results and the discussion of the crucial roles of the short-lived, continuously replenished neutrophils in dust-induced pathogenesis are presented.

We recently reported a lack of interference between inactivated rotavirus vaccine (IRV) and inactivated poliovirus vaccine (IPV) and their potential dose sparing when the two vaccines were administered intramuscularly either in combination or standalone in rats and guinea pigs. In the present study, we optimized the formulations of both vaccines and investigated the feasibility of manufacturing a combined IRV-IPV dissolving microneedle patch (dMNP), assessing its compatibility and immunogenicity in rats. Our results showed that IRV delivered by dMNP alone or in combination with IPV induced similar levels of RV-specific IgG and neutralizing antibody. Likewise, IPV delivered by dMNP alone or in combination with IRV induced comparable levels of neutralizing antibody of poliovirus types 1, 2, and 3. We further demonstrated high stability of IRV-dMNP at 5, 25, and 40 °C and IPV-dMNP at 5 and 25 °C, and found that three doses of IRV or IPV when co-administered at a quarter dose was as potent as a full target dose in inducing neutralizing antibodies against corresponding rotavirus or poliovirus. We conclude that IRV-IPV dMNP did not interfere with each other in triggering an immunologic response and were highly immunogenic in rats. Our findings support the further development of this innovative approach to deliver a novel combination vaccine against rotavirus and poliovirus in children throughout the world.

At the start of the COVID-19 pandemic, the Centers for Disease Control and Prevention (CDC) designed, manufactured, and distributed the CDC 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel for SARS-CoV-2 detection. The diagnostic panel targeted three viral nucleocapsid gene loci (N1, N2, and N3 primers and probes) to maximize sensitivity and to provide redundancy for virus detection if mutations occurred. After the first distribution of the diagnostic panel, state public health laboratories reported fluorescent signal in the absence of viral template (false-positive reactivity) for the N3 component and to a lesser extent for N1. This report describes the findings of an internal investigation conducted by the CDC to identify the cause(s) of the N1 and N3 false-positive reactivity. For N1, results demonstrate that contamination with a synthetic template, that occurred while the "bulk" manufactured materials were located in a research lab for quality assessment, was the cause of false reactivity in the first lot. Base pairing between the 3' end of the N3 probe and the 3' end of the N3 reverse primer led to amplification of duplex and larger molecules resulting in false reactivity in the N3 assay component. We conclude that flaws in both assay design and handling of the "bulk" material, caused the problems with the first lot of the 2019-nCoV Real-Time RT-PCR Diagnostic Panel. In addition, within this study, we found that the age of the examined diagnostic panel reagents increases the frequency of false positive results for N3. We discuss these findings in the context of improvements to quality control, quality assurance, and assay validation practices that have since been improved at the CDC.

Background: While there are known individual-level risk factors for kidney disease at time of type 2 diabetes diagnosis, little is known regarding the role of community context. We evaluated the association of community socioeconomic deprivation (CSD) and community type with estimated glomerular filtration rate (eGFR) when type 2 diabetes is diagnosed. Method(s): This was a retrospective cohort study of 13,144 adults with newly diagnosed type 2 diabetes in Pennsylvania. The outcome was the closest eGFR measurement within one year prior to and two weeks after type 2 diabetes diagnosis, calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation. We used adjusted multinomial regression models to estimate associations of CSD (quartile 1, least deprivation) and community type (township, borough, city) with eGFR and used adjusted generalized estimating equation models to evaluate whether community features were associated with the absence of diabetes screening in the years prior to type 2 diabetes diagnosis. Result(s): Of the participants, 1279 (9.7%) had hyperfiltration and 1377 (10.5%) had reduced eGFR. Women were less likely to have hyperfiltration and more likely to have reduced eGFR. Black (versus White) race was positively associated with hyperfiltration when the eGFR calculation was corrected for race but inversely associated without the correction. Medical Assistance (ever versus never) was positively associated with reduced eGFR. Higher CSD and living in a city were each positively associated (odds ratio [95% confidence interval]) with reduced eGFR (CSD quartiles 3 and 4 versus quartile 1, 1.23 [1.04, 1.46], 1.32 [1.11, 1.58], respectively; city versus township, 1.38 [1.15, 1.65]). These features were also positively associated with the absence of a type 2 diabetes screening measure. Conclusion(s): In a population-based sample, more than twenty percent had hyperfiltration or reduced eGFR at time of type 2 diabetes diagnosis. Individual- and community-level factors were associated with these outcomes. Copyright © 2021 The Authors

IMPORTANCE: Multiple inflammatory syndrome in children (MIS-C) occurs in association with the COVID-19 pandemic. OBJECTIVE: To describe the clinical characteristics and geographic and temporal distribution of the largest cohort of patients with MIS-C in the United States to date. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis was conducted on clinical and laboratory data collected from patients with MIS-C. The analysis included patients with illness onset from March 2020 to January 2021 and met MIS-C case definition. MAIN OUTCOMES AND MEASURES: Geographic and temporal distribution of MIS-C was compared with that of COVID-19 nationally, by region, and level of urbanicity by county. Clinical and laboratory findings and changes over time were described by age group and by presence or absence of preceding COVID-19. RESULTS: A total of 1733 patients with MIS-C were identified; 994 (57.6%) were male and 1117 (71.3%) were Hispanic or non-Hispanic Black. Gastrointestinal symptoms, rash, and conjunctival hyperemia were reported by 53% (n = 931) to 67% (n = 1153) of patients. A total of 937 patients (54%) had hypotension or shock, and 1009 (58.2%) were admitted for intensive care. Cardiac dysfunction was reported in 484 patients (31.0%), pericardial effusion in 365 (23.4%), myocarditis in 300 (17.3%), and coronary artery dilatation or aneurysms in 258 (16.5%). Patients aged 0 to 4 years had the lowest proportion of severe manifestations, although 171 patients (38.4%) had hypotension or shock and 197 (44.3%) were admitted for intensive care. Patients aged 18 to 20 years had the highest proportions with myocarditis (17 [30.9%]), pneumonia (20 [36.4%]), acute respiratory distress syndrome (10 [18.2%]), and polymerase chain reaction positivity (39 [70.9%]). These older adolescents also had the highest proportion reporting preceding COVID-19-like illness (63%). Nationally, the first 2 MIS-C peaks followed the COVID-19 peaks by 2 to 5 weeks. The cumulative MIS-C incidence per 100 000 persons younger than 21 years was 2.1 and varied from 0.2 to 6.3 by state. Twenty-four patients (1.4%) died. CONCLUSIONS AND RELEVANCE: In this cross-sectional study of a large cohort of patients with MIS-C, 2 peaks that followed COVID-19 peaks by 2 to 5 weeks were identified. The geographic and temporal association of MIS-C with the COVID-19 pandemic suggested that MIS-C resulted from delayed immunologic responses to SARS-CoV-2 infection. The clinical manifestations varied by age and by presence or absence of preceding COVID-19.

In December 2020, the B.1.1.7 genetic variant of SARS-CoV-2, the virus that causes COVID-19, was first reported after emergence and rapid circulation in the United Kingdom (1). Evidence suggests that the B.1.1.7 variant is more efficiently transmitted than are other SARS-CoV-2 variants, and widespread circulation could thereby increase SARS-CoV-2 infection and hospitalization rates (1,2). The first reported SARS-CoV-2 B.1.1.7 variant case in the United States was confirmed by sequencing in Colorado on December 29, 2020.* This report describes a person who traveled from the United Kingdom to the United States after experiencing COVID-19-compatible symptoms(†) and was eventually confirmed to be infected with the B.1.1.7 variant.

OBJECTIVES: To evaluate associations of community types and features with new onset type 2 diabetes in diverse communities. Understanding the location and scale of geographic disparities can lead to community-level interventions. DESIGN: Nested case-control study within the open dynamic cohort of health system patients. SETTING: Large, integrated health system in 37 counties in central and northeastern Pennsylvania, USA. PARTICIPANTS AND ANALYSIS: We used electronic health records to identify persons with new-onset type 2 diabetes from 2008 to 2016 (n=15 888). Persons with diabetes were age, sex and year matched (1:5) to persons without diabetes (n=79 435). We used generalised estimating equations to control for individual-level confounding variables, accounting for clustering of persons within communities. Communities were defined as (1) townships, boroughs and city census tracts; (2) urbanised area (large metro), urban cluster (small cities and towns) and rural; (3) combination of the first two; and (4) county. Community socioeconomic deprivation and greenness were evaluated alone and in models stratified by community types. RESULTS: Borough and city census tract residence (vs townships) were associated (OR (95% CI)) with higher odds of type 2 diabetes (1.10 (1.04 to 1.16) and 1.34 (1.25 to 1.44), respectively). Urbanised areas (vs rural) also had increased odds of type 2 diabetes (1.14 (1.08 to 1.21)). In the combined definition, the strongest associations (vs townships in rural areas) were city census tracts in urban clusters (1.41 (1.22 to 1.62)) and city census tracts in urbanised areas (1.33 (1.22 to 1.45)). Higher community socioeconomic deprivation and lower greenness were each associated with increased odds. CONCLUSIONS: Urban residence was associated with higher odds of type 2 diabetes than for other areas. Higher community socioeconomic deprivation in city census tracts and lower greenness in all community types were also associated with type 2 diabetes.

The genus Rotavirus comprises eight species, designated A to H, and two recently identified tentative species I in dogs and J in bats. Species Rotavirus A, B, C and H (RVA, RVB, RVC and RVH) have been detected in humans and animals. While human and animal RVA are well characterized and defined, complete porcine genome sequences in the GenBank are limited compared to human strains. Here, we used a metagenomic approach to sequence the 11 segments of RVA, RVC and RVH strains from piglets in the United States (US) and explore the evolutionary relations of these RV species. Metagenomics identified Astroviridae, Picornaviridae, Caliciviridae, Coronoviridae in samples MN9.65 and OK5.68 while Picobirnaviridae and Arteriviridae were only identified in sample OK5.68. Whole genome sequencing and phylogenetic analyses identified multiple genotypes with the RVA of strain MN9.65 and OK5.68, with the genome constellation of G5/G9-P[7]/P[13]-I5/I5- R1/R1-C1-M1-A8-N1-T7-E1/E1-H1 and G5/G9-P[6]/P[7]-I5-R1/R1-C1-M1-A8-N1-T1/T7-E1/E1-H1, respectively. The RVA strains had a complex evolutionary relationship with other mammalian strains. The RVC strain OK5.68 had a genome constellation of G9-P[6]-I1-R1-C5-M6-A5-N1-T1-E1-H1, and shared an evolutionary relationship with porcine strains from the US. The RVH strains MN9.65 and OK5.68 had the genome constellation of G5-P1-I1-R1-C1-M1-A5-N1-T1-E4-H1 and G5-P1-I1-R1-C1-M1-A5-N1-T1-E1-H1, indicating multiple RVH genome constellations are circulating in the US. These findings allow us to understand the complexity of the enteric virome, develop improved screening methods for RVC and RVH strains, facilitate expanded rotavirus surveillance in pigs, and increase our understanding of the origin and evolution of rotavirus species.

Zika virus (ZIKV) infection remains a public health concern necessitating demand for long-term virus production for diagnostic assays and R&D activities. Inactivated virus constitutes an important component of the Trioplex rRT-PCR assay and serological IgM assay (MAC-ELISA). The aim of our study is to establish standard methods of ZIKV inactivation while maintaining antigenicity and RNA integrity. We tested viral supernatants by four different inactivation methods: 1. Heat inactivation at 56 °C and 60 °C; 2. Gamma-Irradiation; 3. Chemical inactivation by Beta-propiolactone (BPL) and 4. Fast-acting commercial disinfecting agents. Effectivity was measured by cytopathic effect (CPE) and plaque assay. RNA stability and antigenicity were measured by RT-PCR and MAC-ELISA, respectively. Results: Heat inactivation: Low titer samples, incubated at 56 °C for 2 hrs, showed neither CPE or plaques compared to high titer supernatants that required 2.5 hrs. Inactivation occurred at 60 °C for 60 min with all virus titers. Gamma irradiation: Samples irradiated at ≥3 Mrad for low virus concentrations and ≥5Mrad for high virus titer completely inactivated virus. Chemical Inactivation: Neither CPE nor plaques were observed with ≥0.045% BPL inactivation of ZIKV. Disinfectant: Treatment of viral supernatants with Micro-Chem Plus(TM), inactivated virus in 2 min, whereas, Ethanol (70%) and STERIS Coverage® Spray TB inactivated the virus in 5 min.

Human papilloma virus (HPV) causes a subset of head and neck squamous cell carcinomas (HNSCC) of the oropharynx. We combined targeted DNA- and genome-wide RNA-sequencing to identify genetic variants and gene expression signatures respectively from patients with HNSCC including oropharyngeal squamous cell carcinomas (OPSCC). DNA and RNA were purified from 35- formalin fixed and paraffin embedded (FFPE) HNSCC tumor samples. Immuno-histochemical evaluation of tumors was performed to determine the expression levels of p16INK4A and classified tumor samples either p16+ or p16-. Using ClearSeq Comprehensive Cancer panel, we examined the distribution of somatic mutations. Somatic single-nucleotide variants (SNV) were called using GATK-Mutect2 ("tumor-only" mode) approach. Using RNA-seq, we identified a catalog of 1,044 and 8 genes as significantly expressed between p16+ and p16-, respectively at FDR 0.05 (5%) and 0.1 (10%). The clinicopathological characteristics of the patients including anatomical site, smoking and survival were analyzed when comparing p16+ and p16- tumors. The majority of tumors (65%) were p16+. Population sequence variant databases, including gnomAD, ExAC, COSMIC and dbSNP, were used to identify the mutational landscape of somatic sequence variants within sequenced genes. Hierarchical clustering of The Cancer Genome Atlas (TCGA) samples based on HPV-status was observed using differentially expressed genes. Using RNA-seq in parallel with targeted DNA-seq, we identified mutational and gene expression signatures characteristic of p16+ and p16- HNSCC. Our gene signatures are consistent with previously published data including TCGA and support the need to further explore the biologic relevance of these alterations in HNSCC.

Since February 12, 2020, approximately 6.5 million cases of SARS-CoV-2 infection, the cause of coronavirus disease 2019 (COVID-19), and 190,000 SARS-CoV-2-associated deaths have been reported in the United States (1,2). Symptoms associated with SARS-CoV-2 infection are milder in children compared with adults (3). Persons aged <21 years constitute 26% of the U.S. population (4), and this report describes characteristics of U.S. persons in that population who died in association with SARS-CoV-2 infection, as reported by public health jurisdictions. Among 121 SARS-CoV-2-associated deaths reported to CDC among persons aged <21 years in the United States during February 12-July 31, 2020, 63% occurred in males, 10% of decedents were aged <1 year, 20% were aged 1-9 years, 70% were aged 10-20 years, 45% were Hispanic persons, 29% were non-Hispanic Black (Black) persons, and 4% were non-Hispanic American Indian or Alaska Native (AI/AN) persons. Among these 121 decedents, 91 (75%) had an underlying medical condition,* 79 (65%) died after admission to a hospital, and 39 (32%) died at home or in the emergency department (ED).(†) These data show that nearly three quarters of SARS-CoV-2-associated deaths among infants, children, adolescents, and young adults have occurred in persons aged 10-20 years, with a disproportionate percentage among young adults aged 18-20 years and among Hispanics, Blacks, AI/ANs, and persons with underlying medical conditions. Careful monitoring of SARS-CoV-2 infections, deaths, and other severe outcomes among persons aged <21 years remains particularly important as schools reopen in the United States. Ongoing evaluation of effectiveness of prevention and control strategies will also be important to inform public health guidance for schools and parents and other caregivers.

Coronavirus disease 2019 (COVID-19), the respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in Wuhan, China and has since become pandemic. In response to the first cases identified in the United States, close contacts of confirmed COVID-19 cases were investigated to enable early identification and isolation of additional cases and to learn more about risk factors for transmission. Close contacts of nine early travel-related cases in the United States were identified and monitored daily for development of symptoms (active monitoring). Selected close contacts (including those with exposures categorized as higher risk) were targeted for collection of additional exposure information and respiratory samples. Respiratory samples were tested for SARS-CoV-2 by real-time reverse transcription polymerase chain reaction at the Centers for Disease Control and Prevention. Four hundred four close contacts were actively monitored in the jurisdictions that managed the travel-related cases. Three hundred thirty-eight of the 404 close contacts provided at least basic exposure information, of whom 159 close contacts had ≥1 set of respiratory samples collected and tested. Across all actively monitored close contacts, two additional symptomatic COVID-19 cases (i.e., secondary cases) were identified; both secondary cases were in spouses of travel-associated case patients. When considering only household members, all of whom had ≥1 respiratory sample tested for SARS-CoV-2, the secondary attack rate (i.e., the number of secondary cases as a proportion of total close contacts) was 13% (95% CI: 4-38%). The results from these contact tracing investigations suggest that household members, especially significant others, of COVID-19 cases are at highest risk of becoming infected. The importance of personal protective equipment for healthcare workers is also underlined. Isolation of persons with COVID-19, in combination with quarantine of exposed close contacts and practice of everyday preventive behaviors, is important to mitigate spread of COVID-19.

To identify facilities at risk of receiving patients colonized or infected with multidrug-resistant organisms (MDROs), we developed an interactive web-based interface for visualization of patient-sharing networks among healthcare facilities in Tennessee, USA. Using hospital discharge data and the Centers for Medicare and Medicaid Services' claims and Minimum Data Set, we constructed networks among hospitals and skilled nursing facilities. Networks included direct and indirect transfers, which accounted for <365 days in the community outside of facility admissions. Authorized users can visualize a facility of interest and tailor visualizations by year, network dataset, length of time in the community, and minimum number of transfers. The interface visualizes the facility of interest with its connected facilities that receive or send patients, the number of interfacility transfers, and facilities at risk of receiving transfers from the facility of interest. This tool will help other health departments enhance their MDRO outbreak responses.

In 2014, trained health care provider capacity was insufficient to deliver care to an estimated 70,000 persons in Maryland with chronic hepatitis C virus (HCV) infection. The goal of Maryland Community Based Programs to Test and Cure Hepatitis C, a public health implementation project, was to improve HCV treatment access by expanding the workforce. Sharing the Cure (STC) was a package of services deployed 10/1/14 to 9/30/18 that included enhanced information technology and public health infrastructure, primary care provider training, and practice transformation. Nine primary care sites enrolled. HCV clinical outcomes were documented among individuals who presented for care at sites and met criteria for HCV testing including risk factor or birth cohort (born between 1945 and 1965) based testing. Fifty-three providers completed the STC training. STC providers identified 3,237 HCV antibody positive patients of which 2,624 (81%) were RNA+. Of those HCV RNA+, 1,739 (66%) were staged, 932 (36%) were prescribed treatment, 838 (32%) started treatment, 721 (28%) completed treatment, and 543 (21%) achieved cure. Among 1,739 patients staged, 693 (40%) patients had a liver fibrosis assessment score < F2, rendering them ineligible for treatment under Maryland Medicaid guidelines. HCV RNA testing among HCV antibody positive people increased from 40% (baseline) to 95% amongst STC providers. Of 554 patients with virologic data reported, 543 (98%) achieved cure. Primary care practices can effectively serve as HCV treatment centers to expand treatment access. However, criteria by insurance providers in Maryland was a major barrier to treatment.

BACKGROUND: Irradiative sterilization of clinical specimens prior to chemical laboratory testing provides a way to not only sterilize pathogens and ensure laboratorian safety but also preserve sample volume and maintain compatibility with quantitative chemical diagnostic protocols. Since the compatibility of clinical biomarkers with gamma irradiation is not well characterized, a subset of diagnostic biomarkers ranging in molecular size, concentration, and clinical matrix was analyzed to determine recovery following gamma irradiation. METHODS: Sample irradiation of previously characterized quality control materials (QCs) at 5 Mrad was carried out at the Gamma Cell Irradiation Facility at the Centers for Disease Control and Prevention (CDC) in Atlanta, GA. Following irradiation, the QCs were analyzed alongside non-irradiated QCs to determine analyte recovery between dosed and control samples. RESULTS: Biomarkers for exposure to abrin, ricin, and organophosphorus nerve agents (OPNAs) were analyzed for their stability following gamma irradiation. The diagnostic biomarkers included adducts to butyrylcholinesterase, abrine, and ricinine, respectively, and were recovered at over 90% of their initial concentration. CONCLUSIONS: The results from this pilot study support the implementation of an irradiative sterilization protocol for possible mixed-exposure samples containing both chemical and biological threat agents (mixed CBTs). Furthermore, irradiative sterilization significantly reduces a laboratorian's risk of infection from exposure to an infectious agent without compromising chemical diagnostic testing integrity, particularly for diagnostic assays in which the chemical analyte has been shown to be fully conserved following a 5 Mrad irradiative dose.

Live oral rotavirus vaccines have been developed by serial passaging in cell culture and found safe in infants. However, mechanisms for the adaptation and attenuation of rotavirus vaccines are not fully understood. We have prepared a human rotavirus vaccine strain CDC-9 (G1P[8]) which when grown in MA104 cells to passages 11 or 12 (P11/P12), had no nucleotide and amino acid sequence changes from the original virus in stool. Upon adaptation and passages in Vero cells, the strain underwent five amino acid changes at passage 28 (P28) and one additional change at P44/P45 in VP4 gene. We performed virologic, immunological and pathogenic characterization of wild-type CDC-9 virus P11/P12 and its two mutants at P28 or P44/P45 using in vitro- and in vivo-model systems. We found that mutants CDC-9 P28 and P44 induced upregulated expression of immunomodulatory cytokines. On the other hand, the two mutant viruses induced lower STAT-1 phosphorylation and grew to two logs higher titers than wild-type virus in human CaCo-2 cells and simian Vero cells. In neonatal rats, CDC-9 P45 showed reduced rotavirus shedding in fecal specimens and did not induce diarrhea compared to wild-type virus, and modulated cytokine responses comparable to Rotarix infection. These findings indicate that mutant CDC-9 is attenuated and safe. Our study is the first to provide insight into the possible mechanisms of human rotavirus adaptation and attenuation and supports ongoing efforts to develop CDC-9 as a new generation of rotavirus vaccine for live oral or parenteral administration.IMPORTANCE Mechanisms for in vitro adaptation and in vivo attenuation of human rotavirus vaccines are not known. The present study is the first to comprehensively compare the in vitro growth characteristics, virulence, and host response of a wild-type and an attenuated human rotavirus CDC-9 strain in CaCo-2 cells and neonatal rats. Our study identifies critical sequence changes in the genome that render human rotavirus adapted to high growth in Vero cells and attenuated and safe in neonatal rats thus supports clinical development of CDC-9 for oral or parenteral vaccination in children.

Streptococcus pneumoniae (pneumococcus) is a major human pathogen producing structurally diverse capsular polysaccharides. Widespread use of highly successful pneumococcal conjugate vaccines (PCVs) targeting pneumococcal capsules has greatly reduced infections by the vaccine types but increased infections by nonvaccine serotypes. Herein, we report a new and the 100th capsule type, named serotype 10D, by determining its unique chemical structure and biosynthetic roles of all capsule synthesis locus (cps) genes. The name 10D reflects its serologic cross-reaction with serotype 10A and appearance of cross-opsonic antibodies in response to immunization with 10A polysaccharide in a 23-valent pneumococcal vaccine. Genetic analysis showed that 10D cps has three large regions syntenic to and highly homologous with cps loci from serotype 6C, serotype 39, and an oral streptococcus strain (S. mitis SK145). The 10D cps region syntenic to SK145 is about 6 kb and has a short gene fragment of wciNalpha at the 5' end. The presence of this nonfunctional wciNalpha fragment provides compelling evidence for a recent interspecies genetic transfer from oral streptococcus to pneumococcus. Since oral streptococci have a large repertoire of cps loci, widespread PCV usage could facilitate the appearance of novel serotypes through interspecies recombination.IMPORTANCE The polysaccharide capsule is essential for the pathogenicity of pneumococcus, which is responsible for millions of deaths worldwide each year. Currently available pneumococcal vaccines are designed to elicit antibodies to the capsule polysaccharides of the pneumococcal isolates commonly causing diseases, and the antibodies provide protection only against the pneumococcus expressing the vaccine-targeted capsules. Since pneumococci can produce different capsule polysaccharides and therefore reduce vaccine effectiveness, it is important to track the appearance of novel pneumococcal capsule types and how these new capsules are created. Herein, we describe a new and the 100th pneumococcal capsule type with unique chemical and serological properties. The capsule type was named 10D for its serologic similarity to 10A. Genetic studies provide strong evidence that pneumococcus created 10D capsule polysaccharide by capturing a large genetic fragment from an oral streptococcus. Such interspecies genetic exchanges could greatly increase diversity of pneumococcal capsules and complicate serotype shifts.

Data on the detailed clinical progression of COVID-19 in conjunction with epidemiological and virological characteristics are limited. In this case series, we describe the first 12 US patients confirmed to have COVID-19 from 20 January to 5 February 2020, including 4 patients described previously(1-3). Respiratory, stool, serum and urine specimens were submitted for SARS-CoV-2 real-time reverse-transcription polymerase chain reaction (rRT-PCR) testing, viral culture and whole genome sequencing. Median age was 53 years (range: 21-68); 8 patients were male. Common symptoms at illness onset were cough (n = 8) and fever (n = 7). Patients had mild to moderately severe illness; seven were hospitalized and demonstrated clinical or laboratory signs of worsening during the second week of illness. No patients required mechanical ventilation and all recovered. All had SARS-CoV-2 RNA detected in respiratory specimens, typically for 2-3 weeks after illness onset. Lowest real-time PCR with reverse transcription cycle threshold values in the upper respiratory tract were often detected in the first week and SARS-CoV-2 was cultured from early respiratory specimens. These data provide insight into the natural history of SARS-CoV-2. Although infectiousness is unclear, highest viral RNA levels were identified in the first week of illness. Clinicians should anticipate that some patients may worsen in the second week of illness.

This report details the proceedings and conclusions from the 3rd International Congress on Unexplained Deaths in Infants and Children, held November 26-27, 2018 at the Radcliffe Institute at Harvard University. The Congress was motivated by the increasing rejection of the diagnosis Sudden Infant Death Syndrome (SIDS) in the medical examiner community, leading to falsely depressed reported SIDS rates and undermining the validity and reliability of the diagnosis, which remains a leading cause of infant and child mortality. We describe the diagnostic shift away from SIDS and the practical issues contributing to it. The Congress was attended by major figures and opinion leaders in this area from countries significantly engaged in this problem. Four categories (International Classification of Diseases (ICD)-11 categories of MH11, MH12, MH14, PB00-PB0Z) were recommended for classification, and explicit definitions and guidance were provided for death certifiers. SIDS was reframed as unexplained sudden death in infancy or SIDS/MH11 to emphasize that either term signifies the lack of explanation following a rigorous investigation. A distinct category for children over the age of 1 was recommended (MH12). Definitions and exclusions were provided for the alternative categories of accidental asphyxia and undetermined. As recommended, unexplained sudden death in infancy or SIDS on a death certificate will code a unique, trackable entity, accurately reflecting the inability to determine a definitive explanation, while satisfying surveillance needs and reliable identification for research efforts. The conclusions will be submitted to the World Health Organization for inclusion in the upcoming ICD-11.