BACKGROUND: The role of histo-blood group on the burden and severity of norovirus gastroenteritis in young infants has not been well documented. METHODS: Norovirus gastroenteritis was assessed in 443 Nicaraguan children followed from birth until 3 years of age. Stool samples were tested for norovirus by RT-qPCR and histo-blood group antigens (HBGA) were determined by phenotyping of saliva and blood. Hazards ratios (95% CI) and predictors of norovirus AGE outcome stratified by HBGA were estimated using Cox proportional hazards models. RESULTS: Of 1,353 AGE episodes experienced by children, 229 (17%) tested positive for norovirus with an overall incidence of 21.9/100 child-years. Secretor children were infected as early as 2 months old and had a higher incidence of norovirus GII compared to non-secretor children (15.4 vs 4.1/100 child-years, P = 0.006). Furthermore, all GII.4 AGE episodes occurred in secretor children. Children infected with GI (adjusted OR=0.09, 95% CI 0.02-0.33) or non-GII.4 viruses (adjusted OR=0.2, 95% CI: 0.07-0.6) were less likely to have severe AGE compared to GII.4 infected children. CONCLUSION: Secretor status in children strongly influences the incidence of symptomatic norovirus infection in a genogroup or genotype-dependent manner and provides evidence that clinical severity in children depends on norovirus genotypes.

The molecular composition and binding epitopes of the immunoglobulin G (IgG) antibodies that circulate in blood plasma following SARS-CoV-2 infection are unknown. Proteomic deconvolution of the IgG repertoire to the spike glycoprotein in convalescent subjects revealed that the response is directed predominantly (>80%) against epitopes residing outside the receptor-binding domain (RBD). In one subject, just four IgG lineages accounted for 93.5% of the response, including an N-terminal domain (NTD)-directed antibody that was protective against lethal viral challenge. Genetic, structural, and functional characterization of a multi-donor class of "public" antibodies revealed an NTD epitope that is recurrently mutated among emerging SARS-CoV-2 variants of concern. These data show that "public" NTD-directed and other non-RBD plasma antibodies are prevalent and have implications for SARS-CoV-2 protection and antibody escape.

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.

The control of re-occurring pandemic pathogens requires understanding the origins of new pandemic variants and the factors that drive their global spread. This is especially important for GII.4 norovirus, where vaccines under development offer promise to prevent hundreds of millions of annual gastroenteritis cases. Previous studies have hypothesized that new GII.4 pandemic viruses arise when previously circulating pandemic or pre-pandemic variants undergo substitutions in antigenic regions that enable evasion of host population immunity, as described by conventional models of antigenic drift. In contrast, we show here that the acquisition of new genetic and antigenic characteristics cannot be the proximal driver of new pandemics. Pandemic GII.4 viruses diversify and spread over wide geographical areas over several years prior to simultaneous pandemic emergence of multiple lineages, indicating that the necessary sequence changes must have occurred before diversification, years prior to pandemic emergence. We confirm this result through serological assays of reconstructed ancestral virus capsids, demonstrating that by 2003, the ancestral 2012 pandemic strain had already acquired the antigenic characteristics that allowed it to evade prevailing population immunity against the previous 2009 pandemic variant. These results provide strong evidence that viral genetic changes are necessary but not sufficient for GII.4 pandemic spread. Instead, we suggest that it is changes in host population immunity that enable pandemic spread of an antigenically preadapted GII.4 variant. These results indicate that predicting future GII.4 pandemic variants will require surveillance of currently unsampled reservoir populations. Furthermore, a broadly acting GII.4 vaccine will be critical to prevent future pandemics.

The COVID-19 pandemic highlights the substantial public health, economic, and societal consequences of virus spillover from a wildlife reservoir. Widespread human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also presents a new set of challenges when considering viral spillover from people to naïve wildlife and other animal populations. The establishment of new wildlife reservoirs for SARS-CoV-2 would further complicate public health control measures and could lead to wildlife health and conservation impacts. Given the likely bat origin of SARS-CoV-2 and related beta-coronaviruses (β-CoVs), free-ranging bats are a key group of concern for spillover from humans back to wildlife. Here, we review the diversity and natural host range of β-CoVs in bats and examine the risk of humans inadvertently infecting free-ranging bats with SARS-CoV-2. Our review of the global distribution and host range of β-CoV evolutionary lineages suggests that 40+ species of temperate-zone North American bats could be immunologically naïve and susceptible to infection by SARS-CoV-2. We highlight an urgent need to proactively connect the wellbeing of human and wildlife health during the current pandemic and to implement new tools to continue wildlife research while avoiding potentially severe health and conservation impacts of SARS-CoV-2 "spilling back" into free-ranging bat populations.

BACKGROUND AND AIMS: Human norovirus infection is the leading cause of acute gastroenteritis. Genetic polymorphisms, mediated by the FUT2 gene (secretor enzyme), define strain susceptibility. Secretors express a diverse set of fucosylated histoblood group antigen carbohydrates (HBGA) on mucosal cells; non-secretors (FUT2(-/-)) express a limited array of HBGAs. Thus, non-secretors have less diverse norovirus strain infections, including resistance to the epidemiologically dominant GII.4 strains. As future human norovirus vaccines will be comprised of GII.4 antigen and since secretor phenotype impacts GII.4 infection and immunity, non-secretors may immunologically mimic young children in response to GII.4 vaccination, providing a needed model to study cross-protection in the context of limited pre-exposure. METHODS: Utilizing specimens collected from the first characterized non- secretor cohort naturally infected with GII.2 human norovirus, we evaluated the breadth of serological immunity by surrogate neutralization assays, and cellular activation and cytokine production by flow cytometry. RESULTS: GII.2 infection resulted in broad antibody and cellular immunity activation that persisted for at least 30 days for T cells, monocytes and dendritic cells and for 180 days for blocking antibody. Multiple cellular lineages expressing IFN-gamma and TNF-alpha dominated the response. Both T cell and B cell responses were cross-reactive with other GII strains, but not GI strains. To promote entry mechanisms, inclusion of bile acids was essential for GII.2 binding to non-secretor HBGAs. CONCLUSION: These data support development of within-genogroup cross-reactive antibody and T cell immunity, key outcomes that may provide the foundation for eliciting broad immune responses following GII.4 vaccination in individuals with limited GII.4 immunity, including young children.

Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Herein, we show that the ribonucleoside analog beta-D-N(4)-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (beta-D-N(4)-hydroxycytidine-5'-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple coronaviruses and oral bioavailability highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.

Background: Rotavirus (RV) is a leading cause of severe gastroenteritis globally and can cause substantial morbidity associated with gastroenteritis in children <5years of age. Orally administered live-attenuated RV vaccines offer protection against disease but vaccination efforts have been hampered by high manufacturing costs and the need to maintain a cold chain. Methods: A subset of Vero cell host genes was identified by siRNA that when knocked down increased RV replication and these anti-viral host genes were individually deleted using CRISPR-Cas9. Results: Fully-sequenced gene knockout Vero cell substrates were assessed for increased RV replication and RV vaccine antigen expression compared to wild type Vero cells. The results showed that RV replication and antigen production were logs higher in Vero cells having an EMX2 gene deletion compared to other Vero cell substrates tested. Conclusions: We used siRNAs to screen for host genes that negatively affected RV replication, then CRISPR-Cas9 gene editing to delete select genes. The gene editing led to the development of enhanced RV vaccine substrates supporting a potential path forward for improving RV vaccine production.

Rapidly evolving RNA viruses, such as the GII.4 strain of human norovirus (HuNoV), and their vaccines elicit complex serological responses associated with previous exposure. Specific correlates of protection, moreover, remain poorly understood. Here, we report the GII.4-serological antibody repertoire-pre- and post-vaccination-and select several antibody clonotypes for epitope and structural analysis. The humoral response was dominated by GII.4-specific antibodies that blocked ancestral strains or by antibodies that bound to divergent genotypes and did not block viral-entry-ligand interactions. However, one antibody, A1431, showed broad blockade toward tested GII.4 strains and neutralized the pandemic GII.P16-GII.4 Sydney strain. Structural mapping revealed conserved epitopes, which were occluded on the virion or partially exposed, allowing for broad blockade with neutralizing activity. Overall, our results provide high-resolution molecular information on humoral immune responses after HuNoV vaccination and demonstrate that infection-derived and vaccine-elicited antibodies can exhibit broad blockade and neutralization against this prevalent human pathogen.

Background: Human noroviruses are the leading cause of acute gastroenteritis. Strains of the GII.4 genotype cause pandemic waves associated with viral evolution and subsequent antigenic drift and ligand binding modulation. In November 2015, a novel GII.4 Sydney recombinant variant (GII.P16-GII.4 Sydney) emerged and replaced GII.Pe-GII.4 Sydney as the predominant cause of acute gastroenteritis in the 2016-2017 season in the United States. Methods: Virus-like particles of GII.4 2012 and GII.4 2015 were compared for ligand binding and antibody reactivity using a surrogate neutralization assay. Results: Residue changes in the capsid between GII.4 2012 and GII.4 2015 decreased potency of human polyclonal sera and monoclonal antibodies. Change in epitope A resulted in complete loss of reactivity of a class of blockade antibodies and reduction of a second class. Epitope D changes modulated monoclonal antibody potency and ligand binding patterns. Conclusions: Substitutions in blockade antibody epitopes between GII.4 2012 and GII.4 2015 impacted antigenicity and ligand binding properties. Although the impact of polymerases on fitness remains uncertain, antigenic variation resulting in decreased potency of antibodies to epitope A coupled with altered ligand binding, likely contributed significantly to the spread of GII.4 2015 and replacement of GII.4 2012 as the predominant norovirus outbreak strain.

Transportation investments have the potential to improve health, but readily available data to guide transportation decisions that could promote health are limited. In October 2015, the U.S. Department of Transportation (USDOT) and the Centers for Disease Control and Prevention (CDC) released the Transportation and Health Tool (THT). The tool is a resource to help transportation professionals in states and metropolitan areas access data about transportation and health in their jurisdictions and stimulate discussions on how to improve public health through transportation planning and policy. To develop the tool, a multidisciplinary team identified 190 possible data indicators. Using input from expert panel workshops and criteria that addressed data availability, geographic scale, timeliness, feasibility, validity, and topic area, the team selected 14 transportation and health indicators that covered the four priority topic areas of safety, active transportation, air quality, and connectivity. The THT contains the raw values for each indicator and a standardized score to enable comparisons. Additionally, the THT contains 25 evidence-based strategies that can help practitioners in states and metropolitan areas take action to improve health outcomes.

Respiratory Syncytial Virus (RSV) infects respiratory epithelial cells and deregulates host gene expression by many mechanisms including expression of RSV G protein (RSV G). RSV G protein encodes a central conserved region (CCR) containing a CX3C motif that functions as a fractalkine mimic. Disruption of the CX3C motif (a.a. 182-186) located in the CCR of the G protein has been shown to affect G protein function in vitro and the severity of RSV disease pathogenesis in vivo. We show that infection of polarized Calu3 respiratory cells with recombinant RSV having point mutations in Cys173 and 176 (C173/176S) (rA2-GC12), or Cys186 (C186S) (rA2-GC4) is associated with a decline in the integrity of polarized Calu-3 cultures and decreased virus production. This is accompanied with downregulation of miRNAs let-7f and miR-24 and upregulation of interferon lambda (IFNlambda), a primary antiviral cytokine for RSV in rA2-GC12/rA2-GC4 infected cells. These results suggest that residues in the cysteine noose region of RSV G protein can modulate IFN lambda expression accompanied by downregulation of miRNAs, and are important for RSV G protein function and targeting.

Control banding (CB) is a risk management strategy that has been used to identify and recommend exposure control measures to potentially hazardous substances for which toxicological information is limited. The application of CB and level of expertise required for implementation and management can differ depending on knowledge of the hazard potential, the likelihood of exposure, and the ability to verify the effectiveness of exposure control measures. A number of different strategies have been proposed for using CB in workplaces where exposure to engineered nanomaterials (ENMs) can occur. However, it is unclear if the use of CB can effectively reduce worker exposure to nanomaterials. A systematic review of studies was conducted to answer the question can control banding be useful to ensure adequate controls for the safe handling of nanomaterials. A variety of databases were searched to identify relevant studies pertaining to CB. Database search terms included control, hazard, exposure, and risk banding as well as the use of these terms in the context of nanotechnology or nanomaterials. Other potentially relevant studies were identified during the review of articles obtained in the systematic review process. Identification of studies and the extraction of data were independently conducted by the reviewers. Quality of the studies was assessed using the methodological index for nonrandomized studies. The quality of the evidence was evaluated using grading of recommendations assessment, development and evaluation (GRADE). A total of 235 records were identified in the database search in which 70 records were determined to be eligible for full-text review. Only two studies were identified that met the inclusion criteria. These studies evaluated the application of the CB Nanotool in workplaces where ENMs were being handled. A total of 32 different nanomaterial handling activities were evaluated in these studies by comparing the recommended exposure controls using CB to existing exposure controls previously recommended by an industrial hygienist. It was determined that the selection of exposure controls using CB were consistent with those recommended by an industrial hygienist for 19 out of 32 (59.4%) job activities. A higher level of exposure control was recommended for nine out of 32 (28.1%) job activities using CB, while four out of 32 (12.5%) job activities had in-place exposure controls that were more stringent than those recommended using CB. After evaluation using GRADE, evidence indicated that the use of CB Nanotool can recommend exposure controls for many ENM job activities that would be consistent with those recommended by an experienced industrial hygienist. The use of CB for reducing exposures to ENMs has the potential to be an effective risk management strategy when information is limited on the health risk to the nanomaterial and/or there is an absence of an occupational exposure limit. However, there remains a lack of evidence to conclude that the use of CB can provide adequate exposure control in all work environments. Additional validation work is needed to provide more data to support the use of CB for the safe handling of ENMs. 2016, Springer Science+Business Media Dordrecht.

Vaccine manufacturing costs prevent a significant portion of the world's population from accessing protection from vaccine-preventable diseases. To enhance vaccine production at reduced costs, a genome-wide RNAi screen was performed to identify gene knockdown events that enhanced poliovirus replication. Primary screen hits were validated in a Vero vaccine manufacturing cell line using attenuated and wild type poliovirus strains. Multiple single and dual gene silencing events increased poliovirus titers >20-fold and >50-fold, respectively. Host gene knockdown events did not affect virus antigenicity and CRISPR-Cas9-mediated knockout of the top candidates dramatically improved viral vaccine strain production. Interestingly, silencing of several genes that enhanced poliovirus replication also enhanced enterovirus 71, a clinically relevant virus for which vaccines are being targeted. The discovery that host gene modulation can markedly increase virus vaccine production dramatically alters mammalian cell-based vaccine manufacturing and should facilitate polio eradication using the inactivated poliovirus vaccine. IMPORTANCE: Using a genome-wide RNAi screen, a collection of host virus-resistance genes was identified that upon silencing increased poliovirus and enterovirus 71 production from 10-fold to >50-fold in a Vero vaccine manufacturing cell line. This study provides novel insights into enterovirus-host interactions, and describes an approach toward developing the next generation of vaccine manufacturing through engineered vaccine cell lines. The findings show that specific gene silencing and knockout events can enhance viral titers of both attenuated (Sabin) and wild polioviruses, a finding that should greatly facilitate global implementation of inactivated polio vaccine, as well as further reducing costs for live-attenuated oral polio vaccines. This work describes a platform-enabling technology applicable to most vaccine preventable diseases.

Autoimmune thyroid diseases (AITD) and Type 1 diabetes (T1D) frequently occur in the same individual pointing to a strong shared genetic susceptibility. Indeed, the co-occurrence of T1D and AITD in the same individual is classified as a variant of the autoimmune polyglandular syndrome type 3 (designated APS3v). Our aim was to identify new genes and mechanisms causing the co-occurrence of T1D + AITD (APS3v) in the same individual using a genome-wide approach. For our discovery set we analyzed 346 Caucasian APS3v patients and 727 gender and ethnicity matched healthy controls. Genotyping was performed using the Illumina Human660W-Quad.v1. The replication set included 185 APS3v patients and 340 controls. Association analyses were performed using the PLINK program, and pathway analyses were performed using the MAGENTA software. We identified multiple signals within the HLA region and conditioning studies suggested that a few of them contributed independently to the strong association of the HLA locus with APS3v. Outside the HLA region, variants in GPR103, a gene not suggested by previous studies of APS3v, T1D, or AITD, showed genome-wide significance (p < 5 x 10-8). In addition, a locus on 1p13 containing the PTPN22 gene showed genome-wide significant associations. Pathway analysis demonstrated that cell cycle, B-cell development, CD40, and CTLA-4 signaling were the major pathways contributing to the pathogenesis of APS3v. These findings suggest that complex mechanisms involving T-cell and B-cell pathways are involved in the strong genetic association between AITD and T1D.

Noroviruses are the leading cause of acute gastroenteritis outbreaks worldwide. The majority of norovirus outbreaks are caused by genogroup II.4 (GII.4) noroviruses. Novel GII.4 noroviruses emerge every 2-4 years and replace older variants as the dominant norovirus. The process of the emergence of novel variants is believed to be caused by a combination of recombination, genetic drift, and selection driven by population immunity, but how or where these novel variants emerge is not known. We detected two previously unknown novel GII.4 variants, termed GII.4 UNK1 and GII.4 UNK2, and a diverse norovirus population in fecal specimens from immunocompromised individuals with diarrhea after they had undergone bone-marrow transplantation. We hypothesized that immunocompromised individuals can serve as reservoirs for novel norovirus variants. To test our hypothesis, metagenomic analysis of viral RNA populations was combined with a full genome bioinformatic analysis of publicly available GII.4 noroviruses sequences from 1974 - 2014 to identify converging sites. Localization analysis indicated that variable sites were more likely to be within two amino acids (P< 0.05) of positively selected sites. Further analysis indicated polymorphic site distribution was random and its proximity to positively selected sites was dependent on the size of the norovirus genome and the number of positively selected sites. The results indicate that random mutations can have a positive impact on driving norovirus evolution and that immunocompromised individuals have the ability to serve as a potential reservoirs for novel GII.4 strains. IMPORTANCE: Norovirus is the most common cause of viral gastroenteritis in the US. Every two to three years novel norovirus variants emerge and rapidly disseminate throughout the world. The continual emergence of novel noroviruses is believed to be caused by a combination of genetic drift, population immunity, and recombination, but exactly how this emergence occurs remains unknown. In this study we identified two novel GII.4 variants in immunocompromised bone marrow transplant patients. Using metagenomic and bioinformatics analysis, we show that most genetic polymorphisms in the novel variants occur near, 0-2 amino acids, of positively selected sites, but the distribution of mutations was random; clustering of polymorphisms with positively selected sites was a result of genome size, number of mutations and positively selected sites. This study shows that immunocompromised patients can harbor infectious novel norovirus variants and although mutations in viruses are random they can have a positive effect in viral evolution.

Few studies have evaluated population-level risk factors for having a bedbug infestation. We describe characteristics associated with bedbug complaints among New York City Housing Authority (NYCHA) residents. Unique households receiving bedbug extermination services in response to a complaint during January 1, 2010 to December 31, 2011 were identified from NYCHA's central facilities work order database. We examined associations between household characteristics and having a bedbug complaint using a generalized estimating equation Poisson regression model, accounting for clustering by housing development. Of the 176,327 NYCHA households, 11,660 (6.6 %) registered a bedbug complaint during 2010-2011. Bedbug complaints were independently associated with households having five or more children versus no children (prevalence ratio [PR] = 2.0), five or more adults versus one adult (PR = 1.6), a head of household (HOH) with impaired mobility (PR = 1.3), a household member receiving public assistance (PR = 1.2), a household income below poverty level (PR = 1.1), and a female HOH (PR = 1.1). Infestations were less likely to be reported by households with employed members (PR = 0.9), and an HOH aged 30-44 years (PR = 0.9) or 45-61 years (PR = 0.9), compared with an HOH aged 18-29 years. These results indicate that bedbug control efforts in public housing should be targeted toward households with low income and high occupancy.

BACKGROUND: Parvovirus B19 (B19V) is a small, nonenveloped virus that typically causes a benign flu-like illness that occurs most frequently in childhood. The virus is resistant to current viral inactivation steps used in the manufacture of antihemophilic factor concentrates and B19V transmission through these products has been documented. Since 2000, B19V nucleic acid test (NAT) screening of plasma pools has been implemented to further decrease the viral burden in these products, but no study has examined populations using these products to assess the impact of the screening on B19V transmission. STUDY DESIGN AND METHODS: Blood specimens obtained from participants of a surveillance system established in federally supported specialized bleeding disorders clinics were used in a B19V seroprevalence study. RESULTS: A total of 1643 specimens from 1043 participants age 2 to 7 years born after B19V NAT screening was implemented were tested. Age-specific prevalence rates were generally higher for subjects exposed to either plasma-derived products alone or in combination with other products compared to subjects with no exposure to antihemophilic products. Overall, compared to participants unexposed to blood or blood products, those exposed to plasma-derived products alone were 1.7 times more likely to have antibodies to B19V (p = 0.002). CONCLUSION: These results are consistent with continued B19V transmission through plasma-derived factor concentrates. Effective viral inactivation and detection processes are needed to protect users of these products from infection with B19V or other new or emerging viruses.

BACKGROUND: Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). METHODS: Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. FINDINGS: Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350,000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient -0.37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. INTERPRETATION: Rates of YLDs per 100,000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. FUNDING: Bill & Melinda Gates Foundation.

BACKGROUND: Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time. METHODS: We calculated DALYs as the sum of years of life lost (YLLs) and years lived with disability (YLDs). DALYs were calculated for 291 causes, 20 age groups, both sexes, and for 187 countries, and aggregated to regional and global estimates of disease burden for three points in time with strictly comparable definitions and methods. YLLs were calculated from age-sex-country-time-specific estimates of mortality by cause, with death by standardised lost life expectancy at each age. YLDs were calculated as prevalence of 1160 disabling sequelae, by age, sex, and cause, and weighted by new disability weights for each health state. Neither YLLs nor YLDs were age-weighted or discounted. Uncertainty around cause-specific DALYs was calculated incorporating uncertainty in levels of all-cause mortality, cause-specific mortality, prevalence, and disability weights. FINDINGS: Global DALYs remained stable from 1990 (2.503 billion) to 2010 (2.490 billion). Crude DALYs per 1000 decreased by 23% (472 per 1000 to 361 per 1000). An important shift has occurred in DALY composition with the contribution of deaths and disability among children (younger than 5 years of age) declining from 41% of global DALYs in 1990 to 25% in 2010. YLLs typically account for about half of disease burden in more developed regions (high-income Asia Pacific, western Europe, high-income North America, and Australasia), rising to over 80% of DALYs in sub-Saharan Africa. In 1990, 47% of DALYs worldwide were from communicable, maternal, neonatal, and nutritional disorders, 43% from non-communicable diseases, and 10% from injuries. By 2010, this had shifted to 35%, 54%, and 11%, respectively. Ischaemic heart disease was the leading cause of DALYs worldwide in 2010 (up from fourth rank in 1990, increasing by 29%), followed by lower respiratory infections (top rank in 1990; 44% decline in DALYs), stroke (fifth in 1990; 19% increase), diarrhoeal diseases (second in 1990; 51% decrease), and HIV/AIDS (33rd in 1990; 351% increase). Major depressive disorder increased from 15th to 11th rank (37% increase) and road injury from 12th to 10th rank (34% increase). Substantial heterogeneity exists in rankings of leading causes of disease burden among regions. INTERPRETATION: Global disease burden has continued to shift away from communicable to non-communicable diseases and from premature death to years lived with disability. In sub-Saharan Africa, however, many communicable, maternal, neonatal, and nutritional disorders remain the dominant causes of disease burden. The rising burden from mental and behavioural disorders, musculoskeletal disorders, and diabetes will impose new challenges on health systems. Regional heterogeneity highlights the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account. Because of improved definitions, methods, and data, these results for 1990 and 2010 supersede all previously published Global Burden of Disease results. FUNDING: Bill & Melinda Gates Foundation.

Few population-based studies have addressed the role that family history of colorectal cancer (CRC) plays in clinician decision making or patient health choices. The objective of this study was to evaluate the effect of family history of CRC on clinician practice, patient CRC screening, and patient preventive behavior. We analyzed 2008 Oregon Behavioral Risk Factor Surveillance System data to examine associations between family history of CRC and 1) patient-reported clinician recommendations, 2) perceived risk of developing CRC, 3) adoption of preventive and screening behaviors, and 4) CRC risk factors among 1,795 respondents without CRC. A family history of CRC was positively associated with a higher likelihood of respondents reporting that their clinicians discussed colorectal cancer screening (OR, 4.2; 95% CI, 2.4-7.4) and of respondents having colorectal screening within the recommended time period (OR, 2.2; 95% CI, 1.3-3.9). A family history of CRC was also associated with respondents reporting lifestyle changes to prevent CRC (OR, 2.6; 95% CI, 1.7-4.0). A family history of CRC may prompt clinicians to recommend screening and preventive behavior changes and motivate patients to adopt such strategies.

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

Advances in genomics and related fields promise a new era of personalized medicine in the cancer care continuum. Nevertheless, there are fundamental challenges in integrating genomic medicine into cancer practice. We explore how multilevel research can contribute to implementation of genomic medicine. We first review the rapidly developing scientific discoveries in this field and the paucity of current applications that are ready for implementation in clinical and public health programs. We then define a multidisciplinary translational research agenda for successful integration of genomic medicine into policy and practice and consider challenges for successful implementation. We illustrate the agenda using the example of Lynch syndrome testing in newly diagnosed cases of colorectal cancer and cascade testing in relatives. We synthesize existing information in a framework for future multilevel research for integrating genomic medicine into the cancer care continuum.

We previously reported widespread differential expression of long non-protein-coding RNAs (ncRNAs) in response to virus infection. Here, we expanded the study through small RNA transcriptome sequencing analysis of the host response to both severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza virus infections across four founder mouse strains of the Collaborative Cross, a recombinant inbred mouse resource for mapping complex traits. We observed differential expression of over 200 small RNAs of diverse classes during infection. A majority of identified microRNAs (miRNAs) showed divergent changes in expression across mouse strains with respect to SARS-CoV and influenza virus infections and responded differently to a highly pathogenic reconstructed 1918 virus compared to a minimally pathogenic seasonal influenza virus isolate. Novel insights into miRNA expression changes, including the association with pathogenic outcomes and large differences between in vivo and in vitro experimental systems, were further elucidated by a survey of selected miRNAs across diverse virus infections. The small RNAs identified also included many non-miRNA small RNAs, such as small nucleolar RNAs (snoRNAs), in addition to nonannotated small RNAs. An integrative sequencing analysis of both small RNAs and long transcripts from the same samples showed that the results revealing differential expression of miRNAs during infection were largely due to transcriptional regulation and that the predicted miRNA-mRNA network could modulate global host responses to virus infection in a combinatorial fashion. These findings represent the first integrated sequencing analysis of the response of host small RNAs to virus infection and show that small RNAs are an integrated component of complex networks involved in regulating the host response to infection. IMPORTANCE: Most studies examining the host transcriptional response to infection focus only on protein-coding genes. However, mammalian genomes transcribe many short and long non-protein-coding RNAs (ncRNAs). With the advent of deep-sequencing technologies, systematic transcriptome analysis of the host response, including analysis of ncRNAs of different sizes, is now possible. Using this approach, we recently discovered widespread differential expression of host long (>200 nucleotide [nt]) ncRNAs in response to virus infection. Here, the samples described in the previous report were again used, but we sequenced another fraction of the transcriptome to study very short (about 20 to 30 nt) ncRNAs. We demonstrated that virus infection also altered expression of many short ncRNAs of diverse classes. Putting the results of the two studies together, we show that small RNAs may also play an important role in regulating the host response to virus infection.

The major factors that propelled the development of occupational epidemiology since the 1950s have been delineated (1). They include momentum to control occupational injury that gained national prominence in the wake of the Triangle Shirtwaist Fire of March 25, 1911, in which 146 young, mostly female immigrant garment workers fell to their deaths while escaping from a fire in a locked sweat shop. This tragedy was a turning point in the nationwide adoption of state-based occupational safety regulations, workers' compensation programs, and federal safety legislation. During the 1930s, federal initiatives in occupational safety and health required contractor compliance, not only with wage and hour laws, but also with federal occupational safety and health regulations. The New Deal built state capacity by funding state industrial hygiene programs. Levenstein (1) reports a diminution of interest in occupational safety and health, except for the Atomic Energy Act in the 1950s, until the 1960s' resurgence in organized labor's political voice. Also, societal reaction to the Farmington, West Virginia, mine disaster of 1968, which killed 78 miners, led to passage of the Federal Coal Mine Health and Safety Act of 1969 and introduced federal regulation and federal inspectors to the mining industry. | | To this brief history could be added the major scientific advances in the invention and commercialization of synthetic organic chemicals, such as organic dyes that caused epidemics of bladder cancer among industrial workers and anemia and leukemia among benzene-exposed workers. Interest among health-care students and the public probably was affected by growing concern about the health effects of environmental toxins communicated to the public through Rachel Carson's 1962 book, Silent Spring (2). This book vividly detailed the environmental consequences of pesticides and helped launch the environmental movement. In 1965, a parallel popular book by Ralph Nader, Unsafe at Any Speed (3), concerned the forces at play in industry and society that led to production of unsafe automobiles and failure to adopt new safety technology, such as seat belts, which vaulted consumer safety into the public agenda. These historical tides provided fertile ground for national-level development of occupational epidemiology midway through the 20th century.

Individuals with Lynch syndrome, sometimes referred to as hereditary non-polyposis colorectal cancer (HNPCC), have an increased risk of developing colorectal cancer (CRC) as well as other cancers. The increased risk is due to inherited mutations in mismatch repair (MMR) genes, which reduce the ability of cells to repair DNA damage. Screening for Lynch syndrome in individuals newly diagnosed with colorectal cancer has been proposed as part of a strategy that combines tests and interventions to reduce the risk of colorectal cancer in the relatives of the colorectal cancer patients with Lynch Syndrome.

Genomic copy number alterations (CNA) are common in breast cancer. Identifying characteristic CNAs associated with specific breast cancer subtypes is a critical step in defining potential mechanisms of disease initiation and progression. We used genome-wide array comparative genomic hybridization to identify distinctive CNAs in breast cancer subtypes from 259 young (diagnosed with breast cancer at <55 years) African American (AA) and Caucasian American (CA) women originally enrolled in a larger population-based study. We compared the average frequency of CNAs across the whole genome for each breast tumor subtype and found that estrogen receptor (ER)-negative tumors had a higher average frequency of genome-wide gain (P < 0.0001) and loss (P = 0.02) compared to ER-positive tumors. Triple-negative (TN) tumors had a higher average frequency of genome-wide gain (P < 0.0001) and loss (P = 0.003) than non-TN tumors. No significant difference in CNA frequency was observed between HER2-positive and -negative tumors. We also identified previously unreported recurrent CNAs (frequency >40%) for TN breast tumors at 10q, 11p, 11q, 16q, 20p, and 20q. In addition, we report CNAs that differ in frequency between TN breast tumors of AA and CA women. This is of particular relevance because TN breast cancer is associated with higher mortality and young AA women have higher rates of TN breast tumors compared to CA women. These data support the possibility that higher overall frequency of genomic alteration events as well as specific focal CNAs in TN breast tumors might contribute in part to the poor breast cancer prognosis for young AA women.

In spite of accelerating human genome discoveries in a wide variety of diseases of public health significance, the promise of personalized health care and disease prevention based on genomics has lagged behind. In a time of limited resources, public health agencies must continue to focus on implementing programs that can improve health and prevent disease now. Nevertheless, public health has an important and assertive leadership role in addressing the promise and pitfalls of human genomics for population health. Such efforts are needed not only to implement what is known in genomics to improve health but also to reduce potential harm and create the infrastructure needed to derive health benefits in the future.

BACKGROUND: Testing for mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 (BRCA) has been commercially available since 1996. PURPOSE: This study sought to determine, among U.S. primary care physicians, the level of awareness and utilization of BRCA testing and the 2005 U.S. Preventive Services Task Force (USPSTF) recommendations. METHODS: In 2009, data were analyzed on 1500 physician respondents to the 2007 DocStyles national survey (515 family practitioners, 485 internists, 250 pediatricians, and 250 obstetricians/gynecologists). RESULTS: Overall, 87% of physicians were aware of BRCA testing, and 25% reported having ordered testing for at least one patient in the past year. Ordering tests was most prevalent among obstetricians/gynecologists in practice for more than 10 years, with more affluent patients. Physicians were asked to select indications for BRCA testing from seven different clinical scenarios representing increased (4) or low-risk (3) situations consistent with the USPSTF guidelines. Among ordering physicians (pediatricians excluded), 45% chose at least one low-risk scenario as an indication for BRCA testing. Only 19% correctly selected all of the increased-risk and none of the low-risk scenarios. CONCLUSIONS: A substantial majority of primary care physicians are aware of BRCA testing and many report having ordered at least one test within the past year. A minority, however, appear to consistently recognize the family history patterns identified by the USPSTF as appropriate indications for BRCA evaluation. These results suggest the need to improve providers' knowledge about existing recommendations-particularly in this era of increased BRCA direct-to-consumer marketing.