New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

Reported COVID-19 cases and associated mortality remain low in many sub-Saharan countries relative to global averages, but true impact is difficult to estimate given limitations around surveillance and mortality registration. In Lusaka, Zambia, burial registration and SARS-CoV-2 prevalence data during 2020 allow estimation of excess mortality and transmission. Relative to pre-pandemic patterns, we estimate age-dependent mortality increases, totalling 3212 excess deaths (95% CrI: 2104-4591), representing an 18.5% (95% CrI: 13.0-25.2%) increase relative to pre-pandemic levels. Using a dynamical model-based inferential framework, we find that these mortality patterns and SARS-CoV-2 prevalence data are in agreement with established COVID-19 severity estimates. Our results support hypotheses that COVID-19 impact in Lusaka during 2020 was consistent with COVID-19 epidemics elsewhere, without requiring exceptional explanations for low reported figures. For more equitable decision-making during future pandemics, barriers to ascertaining attributable mortality in low-income settings must be addressed and factored into discourse around reported impact differences.

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: Rotavirus vaccines are effective in preventing severe rotavirus. Haiti introduced 2-dose monovalent (G1P[8]) rotavirus vaccine recommended for infants at 6 and 10 weeks of age in 2014. We calculated the effectiveness of rotavirus vaccine against hospitalization for acute gastroenteritis in Haiti. METHODS: We enrolled children 6-59 months old admitted May 2014-September 2019 for acute watery diarrhea at any sentinel surveillance hospital. Stool was tested for rotavirus using enzyme immunoassay (EIA) and genotyped with multiplex one-step RT-PCR assay and Sanger sequencing for stratification by genotype. We used a case-negative design where cases were children positive for rotavirus and controls were negative for rotavirus. Only children eligible for vaccination were included and a child was considered vaccinated if vaccine was given ≥ 14 days before enrollment. We used unconditional logistic regression to calculate odds ratios and calculated 2-dose and 1-dose vaccine effectiveness (VE) as (1 - odds ratio) * 100. RESULTS: We included 129 (19%) positive cases and 543 (81%) negative controls. Among cases, 77 (60%) were positive for equine-like G3P[8]. Two doses of rotavirus vaccine were 66% (95% CI: 44, 80) effective against hospitalizations due to any strain of rotavirus and 64% (95% CI: 33, 81) effective against hospitalizations due to the equine-like G3P[8] genotype. CONCLUSIONS: These findings are comparable to other countries in the Americas region. To the best of our knowledge, this is the first VE estimate both against the equine-like G3P[8] genotype and from a Caribbean country. Overall, these results support rotavirus vaccine use and demonstrate the importance of complete vaccination.

Increases in injection drug use (IDU) as a result of increasing levels of opioid misuse in the United States may increase risk for new, rapidly transmitted HIV infections in communities with otherwise low HIV prevalence.1 Changing characteristics and geographic locations of persons at risk for HIV infection due to injection-related risk behavior present ongoing challenges to partner services for HIV prevention. These jurisdictions have historically had less need for HIV-related partner services and therefore less investment in HIV outbreak preparedness and prevention infrastructure. Jurisdictions with low HIV prevalence have also had to rely on cluster investigation methods that were developed for primary use in urban areas. In early 2019, the US strategic plan to end the HIV epidemic in the United States within 10 years was announced, which prioritizes the rapid detection and response to emerging clusters of HIV infection to further reduce new transmissions as 1 of the 4 main pillars of the initiative.2

BACKGROUND: Salmonella Enteritidis and Salmonella Typhimurium are major causes of bloodstream infection and diarrheal disease in East Africa. Sources of human infection, including the role of the meat pathway, are poorly understood. METHODS: We collected cattle, goat, and poultry meat pathway samples from December 2015 through August 2017 in Tanzania and isolated Salmonella using standard methods. Meat pathway isolates were compared with nontyphoidal Salmonella (NTS) isolated from persons with bloodstream infection and diarrheal disease from 2007 through 2017 from Kenya by core genome multi-locus sequence typing (cgMLST). Isolates were characterized for antimicrobial resistance, virulence genes, and diversity. RESULTS: We isolated NTS from 164 meat pathway samples. Of 172 human NTS isolates, 90 (52.3%) from stool and 82 (47.7%) from blood, 53 (30.8%) were Salmonella Enteritidis ST11 and 62 (36.0%) Salmonella Typhimurium ST313. We identified cgMLST clusters within Salmonella Enteritidis ST11, Salmonella Heidelberg ST15, Salmonella Typhimurium ST 19, and Salmonella II 42:r:- ST1208 that included both human and meat pathway isolates. Salmonella Typhimurium ST313 was isolated exclusively from human samples. Human and poultry isolates bore more antimicrobial resistance and virulence genes and were less diverse than isolates from other sources. CONCLUSIONS: Our findings suggest that the meat pathway may be an important source of human infection by some clades of Salmonella Enteritidis ST11 in East Africa, but not of human Salmonella Typhimurium ST313 infection. Research is needed to systematically examine the contribution of other types of meat, animal products, produce, water, and environmental exposures to nontyphoidal Salmonella disease in East Africa.

BACKGROUND: In the first 2 years after a nationwide mass vaccination campaign of 1-29-year-olds with a meningococcal serogroup A conjugate vaccine (MenAfriVac) in Burkina Faso, carriage and disease due to serogroup A Neisseria meningitidis were nearly eliminated. We aimed to assess the long-term effect of MenAfriVac vaccination on meningococcal carriage and herd immunity. METHODS: We did four cross-sectional studies of meningococcal carriage in people aged 9 months to 36 years in two districts of Burkina Faso between May 2, 2016, and Nov 6, 2017. Demographic information and oropharyngeal swabs were collected. Meningococcal isolates were characterised using whole-genome sequencing. FINDINGS: Of 14 295 eligible people, 13 758 consented and had specimens collected and laboratory results available, 1035 of whom were meningococcal carriers. Accounting for the complex survey design, prevalence of meningococcal carriage was 7.60% (95% CI 5.67-9.52), including 6.98% (4.86-9.11) non-groupable, 0.48% (0.01-0.95) serogroup W, 0.10% (0.01-0.18) serogroup C, 0.03% (0.00-0.80) serogroup E, and 0% serogroup A. Prevalence ranged from 5.44% (95% CI 4.18-6.69) to 9.14% (6.01-12.27) by district, from 4.67% (2.71-6.64) to 11.17% (6.75-15.59) by round, and from 3.39% (0.00-8.30) to 10.43% (8.08-12.79) by age group. By clonal complex, 822 (88%) of 934 non-groupable isolates were CC192, all 83 (100%) serogroup W isolates were CC11, and nine (69%) of 13 serogroup C isolates were CC10217. INTERPRETATION: Our results show the continued effect of MenAfriVac on serogroup A meningococcal carriage, for at least 7 years, among vaccinated and unvaccinated cohorts. Carriage prevalence of epidemic-prone serogroup C CC10217 and serogroup W CC11 was low. Continued monitoring of N meningitidis carriage will be crucial to further assess the effect of MenAfriVac and inform the vaccination strategy for future multivalent meningococcal vaccines. FUNDING: Bill & Melinda Gates Foundation and Gavi, the Vaccine Alliance.

BACKGROUND: In September, 2017, human monkeypox re-emerged in Nigeria, 39 years after the last reported case. We aimed to describe the clinical and epidemiological features of the 2017-18 human monkeypox outbreak in Nigeria. METHODS: We reviewed the epidemiological and clinical characteristics of cases of human monkeypox that occurred between Sept 22, 2017, and Sept 16, 2018. Data were collected with a standardised case investigation form, with a case definition of human monkeypox that was based on previously established guidelines. Diagnosis was confirmed by viral identification with real-time PCR and by detection of positive anti-orthopoxvirus IgM antibodies. Whole-genome sequencing was done for seven cases. Haplotype analysis results, genetic distance data, and epidemiological data were used to infer a likely series of events for potential human-to-human transmission of the west African clade of monkeypox virus. FINDINGS: 122 confirmed or probable cases of human monkeypox were recorded in 17 states, including seven deaths (case fatality rate 6%). People infected with monkeypox virus were aged between 2 days and 50 years (median 29 years [IQR 14]), and 84 (69%) were male. All 122 patients had vesiculopustular rash, and fever, pruritus, headache, and lymphadenopathy were also common. The rash affected all parts of the body, with the face being most affected. The distribution of cases and contacts suggested both primary zoonotic and secondary human-to-human transmission. Two cases of health-care-associated infection were recorded. Genomic analysis suggested multiple introductions of the virus and a single introduction along with human-to-human transmission in a prison facility. INTERPRETATION: This study describes the largest documented human outbreak of the west African clade of the monkeypox virus. Our results suggest endemicity of monkeypox virus in Nigeria, with some evidence of human-to-human transmission. Further studies are necessary to explore animal reservoirs and risk factors for transmission of the virus in Nigeria. FUNDING: None.

PURPOSE: To investigate HIV transmission potential from a cluster of HIV infections among men who have sex with men to persons who inject drugs in 15 West Virginia counties. These counties were previously identified as highly vulnerable to rapid HIV dissemination through injection drug use (IDU) associated with high levels of opioid misuse. METHODS: We interviewed persons with 2017 HIV diagnoses about past-year risk behaviors and elicited sexual, IDU, and social contacts. We tested contacts for HIV and assessed risk behaviors. To determine HIV transmission potential from persons with 2017 diagnoses to persons who inject drugs, we assessed viral suppression status, HIV status of contacts, and IDU risk behaviors of persons living with HIV and contacts. RESULTS: We interviewed 78 persons: 39 with 2017 diagnoses and 39 contacts. Overall, 13/78 (17%) injected drugs in the past year. Of 19 persons with 2017 diagnoses and detectable virus, 9 (47%) had more than or equal to 1 sexual or IDU contacts of negative or unknown HIV status. During the past year, 2/9 had injected drugs and shared equipment, and 1/9 had more than or equal to 1 partner who did so. CONCLUSIONS: We identified IDU risk behavior among persons with 2017 diagnoses and their contacts. West Virginia HIV prevention programs should continue to give high priority to IDU harm reduction.

Samples collected in 2012 through diarrheal disease surveillance in Haiti were tested for rotavirus by enzyme immunoassay and real time RT-PCR and positive samples were genotyped. The predominant genotypes were G1P[8] (29% prevalence) and G9P[8] (21%). The observed genotype prevalence is similar to that reported previously for other Caribbean countries.

BACKGROUND: An estimated 20,000 new hepatitis B virus (HBV) infections occur each year in the United States. We describe the results of enhanced surveillance for acute hepatitis B at seven federally funded sites over a six-year period. METHODS: Health departments in Colorado, Connecticut, Minnesota, Oregon, Tennessee, 34 counties in New York state, and New York City were supported to conduct enhanced, population-based surveillance for acute HBV from 2006 through 2011. Demographic and risk factor data were collected on symptomatic cases using a standardized form. Sera from a subset of cases were also obtained for molecular analysis. RESULTS: In the six-year period, 2,220 acute hepatitis B cases were reported from the seven sites. For all sites combined, the incidence rate of HBV infection declined by 19%, but in Tennessee incidence increased by 90%, mainly among persons of white race/ethnicity and those aged 40-49 years. Of all reported cases, 66.1% were male, 57.1% were white, 58.4% were aged 30-49 years, and 60.1% were born in the United States. The most common risk factor identified was any drug use, notably in Tennessee; healthcare exposure was also frequently reported. The most common genotype for all reported cases was HBV genotype A (82%). CONCLUSIONS: Despite an overall decline in HBV infection, attributable to successful vaccination programs, a rise in incident HBV infection related to drug use is an increasing concern in some localities.

National surveys indicate prevalence of chronic hepatitis B among foreign-born persons in the USA is 5.6 times higher than US-born. Centers for Disease Control and Prevention funded chronic hepatitis B surveillance in Emerging Infections Program sites. A case was any chronic hepatitis B case reported to participating sites from 2001 to 2010. Sites collected standardized demographic data on all cases. We tested differences between foreign- and US-born cases by age, sex, and pregnancy using Chi square tests. We examined trends by birth country during 2005-2010. Of 36,008 cases, 21,355 (59.3 %) reported birth in a country outside the USA, 2,323 (6.5 %) were US-born. Compared with US-born, foreign-born persons were 9.2 times more frequent among chronic hepatitis B cases. Foreign-born were more frequently female, younger, ever pregnant, and born in China. Percentages of cases among foreign-born persons were constant during 2005-2010. Our findings support information from US surveillance for Hepatitis B screening and vaccination efforts.

Worldwide, diarrhea is a major contributor to morbidity and mortality in children; however, there are few data on the burden of diarrheal disease in Haiti. We conducted a retrospective review of hospital discharge registries from 2010 to 2012 in the pediatric wards of four Haitian hospitals and recorded the number of all-cause hospitalizations and deaths as well as diarrheal hospitalizations and deaths by age (≤ 2 and 3-5 years) and epidemiological week. Diarrhea was associated with 3,582 (33.7%) of 10,621 hospitalizations and 62 (11.5%) of 540 in-hospital deaths in children ≤ 5 years old. Of these children, 88.5% and 96.8%, respectively, were among children ≤ 2 years old. The highest proportions of diarrhea-associated hospitalizations occurred from January to April. At four Haitian hospitals over a 3-year period, during which time a major epidemic of cholera occurred, diarrheal disease in children ≤ 5 years was a major contributor to pediatric hospitalizations and mortality.

Our understanding of the sources of Mycobacterium avium infection is partially based on genotypic matching of pathogen isolates from cases and environmental sources. These approaches assume that genotypic identity is rare in isolates from unlinked cases or sources. To test this assumption, a high-resolution PCR-based genotyping approach, LSP-MVR, was selected and used to analyze clinical and environmental isolates of M. avium from geographically diverse sources. Among 127 clinical isolates from seven locations in North America, South America, and Europe, 42 genotypes were observed. Among twelve of these genotypes, matches were seen in isolates from apparently unlinked patients in two or more geographic locations. Six of the twelve were also observed in environmental isolates. A subset of these isolates was further analyzed by alternative strain genotyping methods, PFGE and MIRU-VNTR, which confirmed the existence of geographically dispersed strain genotypes. These results suggest that caution should be exercised in interpreting high-resolution genotypic matches as evidence for an acquisition event.

INTRODUCTION: The risk of acute hepatitis B among adults with diabetes mellitus is unknown. We investigated the association between diagnosed diabetes and acute hepatitis B. METHODS: Confirmed acute hepatitis B cases were reported in 2009-2010 to eight Emerging Infections Program (EIP) sites; diagnosed diabetes status was determined. Behavioral Risk Factor Surveillance System respondents residing in EIP sites comprised the comparison group. Odds ratios (ORs) comparing acute hepatitis B among adults with diagnosed diabetes versus without diagnosed diabetes were determined by multivariate logistic regression, adjusting for age, sex, and race/ethnicity, and stratified by the presence or absence of risk behaviors for hepatitis B virus (HBV) infection. RESULTS: During 2009-2010, EIP sites reported 865 eligible acute hepatitis B cases among persons aged ≥23 years; 95 (11.0%) had diagnosed diabetes. Comparison group diabetes prevalence was 9.1%. Among adults without hepatitis B risk behaviors and with reported diabetes status, the OR for acute hepatitis B comparing adults with and without diabetes was 1.9 (95% confidence interval [CI] = 1.4, 2.6); ORs for adults ages 23-59 and ≥60 years were 2.1 (95% CI = 1.6, 2.8) and 1.5 (95% = CI 0.9, 2.5), respectively. CONCLUSIONS: Diabetes was independently associated with an increased risk for acute hepatitis B among adults without HBV risk behaviors.

Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) x BMI and SNP x physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (beta = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 x 10(-6)). All SNPs were associated with 2-h glucose (beta = 0.06-0.12 mmol/allele, P ≤ 1.53 x 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.