IMPORTANCE: Examining racial and ethnic disparities in pediatric COVID-19 hospitalizations is critical to inform public health efforts to reduce those disparities. OBJECTIVE: To characterize trends in pediatric COVID-19 hospitalizations by race and ethnicity from March 2020 to September 2023, focusing on recent epidemiologic findings (October 2022 to September 2023). DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data from the COVID-19 Hospitalization Surveillance Network (COVID-NET) including 13 555 hospitalizations among patients aged 17 years or younger with a laboratory-confirmed SARS-CoV-2 infection who are residents of the COVID-NET catchment area in 12 states, covering approximately 10% of the US population. EXPOSURE: Laboratory-confirmed SARS-CoV-2 infection within 14 days prior to or during hospitalization. MAIN OUTCOMES AND MEASURES: Pediatric COVID-19-associated hospitalization rates by race and ethnicity and characteristics associated with COVID-19-associated hospitalizations. RESULTS: Between March 2020 and September 2023, COVID-NET identified 13 555 pediatric hospitalizations (median patient age, 3.3 years [IQR, 0.6-12.5 years]; 7110 boys [52.5%]; 780 non-Hispanic Asian or Pacific Islander children [5.8%], 3837 non-Hispanic Black children [28.3%], 4131 Hispanic children [30.5%], and 4807 non-Hispanic White children [35.5%]). Hospitalization rates were 2.15 (95% CI, 2.01-2.34) times higher for Black children and 2.06 (95% CI, 1.91-2.23) times higher for Hispanic children compared with Asian or Pacific Islander children, who had the lowest rates. Despite overall decreased pediatric hospitalization rates between October 2022 and September 2023, higher rates of intensive care unit admissions among Black and Hispanic children persisted, at 1.88 (95% CI, 1.28-2.74) times higher for Black children and 2.13 (95% CI, 1.47-3.10) times higher for Hispanic children compared with Asian or Pacific Islander children. Among hospitalized children, 61.4% (95% CI, 57.0%-65.8%) of Black patients and 45.5% (95% CI, 41.9%-49.3%) of Hispanic patients had 1 or more underlying medical condition compared with 45.6% (95% CI, 42.1%-49.1%) of White children and 45.0% (95% CI, 41.9%-49.3%) of Asian or Pacific Islander children. Obesity (17.8%; 95% CI, 15.3%-20.5%) and neurologic disorders (15.2%; 95% CI, 13.7%-16.8%) were the most common conditions overall; 11.9% (95% CI, 9.1%-15.1%) of Black children had sickle cell disease, the fourth most common condition in this group. CONCLUSIONS AND RELEVANCE: This study found that among pediatric patients hospitalized with COVID-19, Black and Hispanic children were disproportionately more likely to be hospitalized for COVID-19 and experience severe disease compared with White and Asian or Pacific Islander children. A higher proportion of hospitalized Black children had underlying medical conditions. This study underlines the need for targeted interventions, particularly for children with underlying medical conditions, and the need for equitable access and use of vaccines and therapeutics for disproportionately affected populations.

PROBLEM/CONDITION: Candidemia, a bloodstream infection caused by Candida spp., is a common cause of health care-associated bloodstream infections in the United States. Candidemia is associated with substantial health care costs, morbidity, and mortality. PERIOD COVERED: 2017-2021. DESCRIPTION OF SYSTEM: CDC's Emerging Infections Program (EIP), a collaboration among CDC, state health departments, and academic partners, was used to conduct active, population-based laboratory surveillance for candidemia at city or county sites located in 10 states (California, Colorado, Connecticut, Georgia, Maryland, Minnesota, New Mexico, New York, Oregon, and Tennessee), representing a combined population of approximately 21.5 million persons, or 7% of the U.S. population in 2019. Connecticut began reporting cases on January 1, 2019, and conducts statewide surveillance. Although candidemia is not a nationally notifiable condition, cases of Candida auris infection are nationally notifiable, and cases of candidemia caused by C. auris could be included in both national case counts and EIP surveillance. A culture-confirmed candidemia case is defined as a positive blood culture for any Candida sp. from a resident in the surveillance catchment area. Subsequent positive blood cultures for Candida within 30 days of the initial positive culture (index date) in the same patient are considered part of the same case. Clinical laboratories serving each catchment area report candidemia cases, and trained surveillance officers abstract information from medical charts for all cases. Corresponding isolates are sent to CDC for species confirmation and antifungal susceptibility testing. RESULTS: A total of 7,381 candidemia cases were identified during the surveillance period (2017-2021). The overall incidence was 7.4 cases per 100,000 population. Across age groups, sexes, racial and ethnic groups, and surveillance sites, incidence was generally stable or increased slightly from 2017 to 2021, with the lowest overall incidence in 2019 (6.8) and the highest in 2021 (7.9). In 2021, candidemia incidence was highest in patients aged ≥65 years (22.7) and infants (aged <1 year) (8.0). Incidence was higher in males (8.7) compared with females (7.0) and higher in non-Hispanic Black or African American (Black) patients (12.8) compared with non-Black patients (5.6). Incidence was highest in Maryland (14.5), followed by Tennessee (10.1) and Georgia (10.0); incidence was lowest in Oregon (4.8). Increases occurred in the percentage of cases classified as health care onset (52.2% in 2017 to 58.0% in 2021). Overall, among 7,381 cases (in 6,235 patients), 63.7% occurred in patients who had a central venous catheter, 80.7% involved recent systemic antibiotic receipt, and 9.0% occurred in patients who had a history of injection drug use. The percentage of cases with a positive SARS-CoV-2 test during the 90 days before or after the index date increased from 10.4% in 2020 to 17.7% in 2021. From 2017 to 2021, the percentage of cases involving an intensive care unit stay before the index date increased from 38.3% to 44.9%. Echinocandins (e.g., micafungin) were used as treatment in 49.8% of cases, and azoles were used in 47.7%. The all-cause in-hospital mortality rate was 32.6%; this increased from 26.8% in 2019 to 36.1% in 2021. Overall, Candida albicans accounted for 37.1% of cases, followed by Candida glabrata (30.4%) and Candida parapsilosis (13.5%); however, C. glabrata was the most frequent species in California (38.4%) and Maryland (32.9%). Candida auris infections accounted for 0.4% of cases. Among 6,576 Candida isolates for which interpretive breakpoints exist and isolates were available for testing, 5.6% were fluconazole resistant, and <1% were echinocandin resistant. Antifungal resistance was stable for all antifungals tested across years. INTERPRETATION: Candidemia remains an important health care-associated infection. The disproportionate incidence among older adults, males, and Black patients is consistent with previous reports, and the overall incidence of candidemia has not changed substantially compared with previous EIP findings based on data collected during 2012-2016 (8.7 per 100,000 population). The higher mortality rate associated with candidemia during 2020-2021 likely reflects consequences of the COVID-19 pandemic, including strained health care systems and an increased population of patients who were susceptible to candidemia because of COVID-19-related critical illness. PUBLIC HEALTH ACTION: Strict implementation of measures to prevent health care-associated bloodstream infections is important to help prevent candidemia cases. Health care officials and providers should be vigilant for candidemia as a complication of critical illness. Continued surveillance is needed to monitor for emerging populations at risk for candidemia and changes in antifungal resistance patterns, which can help guide antifungal treatment selection.

Maternal respiratory syncytial virus (RSV) vaccine and nirsevimab, a long-acting monoclonal antibody for infants aged 0-7 months and children aged 8-19 months who are at increased risk for severe RSV disease, became widely available for prevention of severe RSV disease among infants and young children during the 2024-25 RSV season. To evaluate the association between availability of these products and infant and child RSV-associated hospitalization rates, the rates among children aged <5 years were compared for the 2024-25 and 2018-20 RSV seasons using data from the RSV-Associated Hospitalization Surveillance Network (RSV-NET) and New Vaccine Surveillance Network (NVSN). Among infants aged 0-7 months (eligible for protection with maternal vaccination or nirsevimab), 2024-25 RSV-associated hospitalization rates were lower compared with 2018-20 pooled rates (estimated relative rate reductions of 43% [RSV-NET: 95% CI = 40%-46%] and 28% [NVSN: 95% CI = 18%-36%]). The largest estimated rate reduction was observed among infants aged 0-2 months (RSV-NET: 52%, 95% CI = 49%-56%; NVSN: 45%, 95% CI = 32%-57%) and during peak hospitalization periods (December-February). These findings support Advisory Committee on Immunization Practices' recommendations for maternal vaccination or nirsevimab to protect against severe RSV disease in infants and highlight the importance of implementing the recommendations to protect infants as early in the RSV season as possible, before peak transmission, and for infants born during the RSV season, within the first week of life, ideally during the birth hospitalization.

BACKGROUND: Patients hospitalised with influenza have heterogeneous clinical presentations and disease severity, which may complicate epidemiologic study design or interpretation. We applied latent class analysis to identify clinically distinct subgroups of adults hospitalised with influenza. METHODS: We analysed cross-sectional study data on adults (≥18 years) hospitalised with laboratory-confirmed influenza from the population-based U.S. Influenza Hospitalization Surveillance Network (FluSurv-NET) including 13 states during 2017-2018 and 2018-2019 influenza seasons (October 1 through April 30). Adults were included if they were residents of the FluSurv-NET catchment area, hospitalised with laboratory-confirmed influenza during these two seasons, and had both the main case report form and the supplemental disease severity case report form completed. We constructed a latent class model to identify subgroups from multiple observed variables including baseline characteristics (age and comorbidities) and clinical course (symptoms at admission, respiratory support requirement, and development of new complications and exacerbations of underlying conditions). FINDINGS: Among the 43,811 influenza-associated hospitalizations reported during the 2017-2018 and 2018-2019 influenza seasons, 15,873 (36.2%) were included in our analytic population: among them, 7069 (44.5%) were male and 8804 (55.5%) were female. We identified five subgroups. Subgroup A included persons of all ages with few comorbidities and 87.9% (255/290) of pregnant women. Subgroup B included older adults with comorbidities (cardiovascular disease (79.7% [3650/4581]) and diabetes (50.6% [2320/4581])). Almost all patients in subgroups C and D had asthma or chronic lung disease and high proportions with exacerbations of underlying conditions (59.7% [889/1489] and 65.1% [2274/3496], respectively). Subgroup E had the highest proportion with new complications (90.3% [1383/1531]). Subgroups D and E had the highest proportions with severe disease indicators: 21.0% (733/3496) and 50.4% (771/1531) required ICU admission, 7.2% (253/3496) and 28.0% (428/1531) required invasive mechanical ventilation, and 3.3% (116/3496) and 11.4% (174/1531) died in-hospital, respectively. INTERPRETATION: The five identified subgroups of adults hospitalised with influenza had varying distributions of age, comorbid conditions, and clinical courses characterized by new complications versus exacerbations of existing conditions. Stratifying by these subgroups may strengthen analyses that assess the impact of influenza vaccination and antiviral treatment on risk of severe disease. Limitations included that results were based on a convenience sample within FluSurv-NET sites and were likely not representative of all adults hospitalised with influenza in the United States. Influenza testing was also clinician-driven, likely leading to under-ascertainment. FUNDING: Centers for Disease Control and Prevention.

BACKGROUND: Pneumonia is common in adults hospitalized with laboratory-confirmed influenza, but the association between timeliness of influenza antiviral treatment and severe clinical outcomes in patients with influenza-associated pneumonia is not well characterized. METHODS: We included adults aged ≥18 years hospitalized with laboratory-confirmed influenza and a discharge diagnosis of pneumonia over 7 influenza seasons (2012-2019) sampled from a multistate population-based surveillance network. We evaluated 3 treatment groups based on timing of influenza antiviral initiation relative to admission date (day 0, day 1, days 2-5). Baseline characteristics and clinical outcomes were compared across groups using unweighted counts and weighted percentages accounting for the complex survey design. Logistic regression models were generated to evaluate the association between delayed treatment and 30-day all-cause mortality. RESULTS: A total of 26 233 adults were sampled in the analysis. Median age was 71 years and most (92.2%) had ≥1 non-immunocompromising condition. Overall, 60.9% started antiviral treatment on day 0, 29.5% on day 1, and 9.7% on days 2-5 (median, 2 days). Baseline characteristics were similar across groups. Thirty-day mortality occurred in 7.5%, 8.5%, and 10.2% of patients who started treatment on day 0, day 1, and days 2-5, respectively. Compared to those treated on day 0, adjusted odds ratio for death was 1.14 (95% confidence interval [CI], 1.01-1.27) in those starting treatment on day 1 and 1.40 (95% CI, 1.17-1.66) in those starting on days 2-5. CONCLUSIONS: Delayed initiation of antiviral treatment in patients hospitalized with influenza-associated pneumonia was associated with higher risk of death, highlighting the importance of timely initiation of antiviral treatment at admission.

IMPORTANCE: Seasonal influenza is associated with substantial disease burden. The relationship between census tract-based social vulnerability and clinical outcomes among patients with influenza remains unknown. OBJECTIVE: To characterize associations between social vulnerability and outcomes among patients hospitalized with influenza and to evaluate seasonal influenza vaccine and influenza antiviral utilization patterns across levels of social vulnerability. DESIGN, SETTING, AND PARTICIPANTS: This retrospective repeated cross-sectional study was conducted among adults with laboratory-confirmed influenza-associated hospitalizations from the 2014 to 2015 through the 2018 to 2019 influenza seasons. Data were from a population-based surveillance network of counties within 13 states. Data analysis was conducted in December 2023. EXPOSURE: Census tract-based social vulnerability. MAIN OUTCOMES AND MEASURES: Associations between census tract-based social vulnerability and influenza outcomes (intensive care unit admission, invasive mechanical ventilation and/or extracorporeal membrane oxygenation support, and 30-day mortality) were estimated using modified Poisson regression as adjusted prevalence ratios. Seasonal influenza vaccine and influenza antiviral utilization were also characterized across levels of social vulnerability. RESULTS: Among 57 964 sampled cases, the median (IQR) age was 71 (58-82) years; 55.5% (95% CI, 51.5%-56.0%) were female; 5.2% (5.0%-5.4%) were Asian or Pacific Islander, 18.3% (95% CI, 18.0%-18.6%) were Black or African American, and 64.6% (95% CI, 64.2%-65.0%) were White; and 6.6% (95% CI, 6.4%-68%) were Hispanic or Latino and 74.7% (95% CI, 74.3%-75.0%) were non-Hispanic or Latino. High social vulnerability was associated with higher prevalence of invasive mechanical ventilation and/or extracorporeal membrane oxygenation support (931 of 13 563 unweighted cases; adjusted prevalence ratio [aPR], 1.25 [95% CI, 1.13-1.39]), primarily due to socioeconomic status (790 of 11 255; aPR, 1.31 [95% CI, 1.17-1.47]) and household composition and disability (773 of 11 256; aPR, 1.20 [95% CI, 1.09-1.32]). Vaccination status, presence of underlying medical conditions, and respiratory symptoms partially mediated all significant associations. As social vulnerability increased, the proportion of patients receiving seasonal influenza vaccination declined (-19.4% relative change across quartiles; P < .001) as did the proportion vaccinated by October 31 (-6.8%; P < .001). No differences based on social vulnerability were found in in-hospital antiviral receipt, but early in-hospital antiviral initiation (-1.0%; P = .01) and prehospital antiviral receipt (-17.3%; P < .001) declined as social vulnerability increased. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, social vulnerability was associated with a modestly increased prevalence of invasive mechanical ventilation and/or extracorporeal membrane oxygenation support among patients hospitalized with influenza. Contributing factors may have included worsened baseline respiratory health and reduced receipt of influenza prevention and prehospital or early in-hospital treatment interventions among persons residing in low socioeconomic areas.

PROBLEM/CONDITION: Seasonal influenza accounts for 9.3 million-41 million illnesses, 100,000-710,000 hospitalizations, and 4,900-51,000 deaths annually in the United States. Since 2003, the Influenza Hospitalization Surveillance Network (FluSurv-NET) has been conducting population-based surveillance for laboratory-confirmed influenza-associated hospitalizations in the United States, including weekly rate estimations and descriptions of clinical characteristics and outcomes for hospitalized patients. However, a comprehensive summary of trends in hospitalization rates and clinical data collected from the surveillance platform has not been available. REPORTING PERIOD: 2010-11 through 2022-23 influenza seasons. DESCRIPTION OF SYSTEM: FluSurv-NET conducts population-based surveillance for laboratory-confirmed influenza-associated hospitalizations among children and adults. During the reporting period, the surveillance network included 13-16 participating sites each influenza season, with prespecified geographic catchment areas that covered 27 million-29 million persons and included an estimated 8.8%-9.5% of the U.S. population. A case was defined as a person residing in the catchment area within one of the participating states who had a positive influenza laboratory test result within 14 days before or at any time during their hospitalization. Each site abstracted case data from hospital medical records into a standardized case report form, with selected variables submitted to CDC on a weekly basis for rate estimations. Weekly and cumulative laboratory-confirmed influenza-associated hospitalization rates per 100,000 population were calculated for each season from 2010-11 through 2022-23 and stratified by patient age (0-4 years, 5-17 years, 18-49 years, 50-64 years, and ≥65 years), sex, race and ethnicity, influenza type, and influenza A subtype. During the 2020-21 season, only the overall influenza hospitalization rate was reported because case counts were insufficient to estimate stratified rates. RESULTS: During the 2010-11 to 2022-23 influenza seasons, laboratory-confirmed influenza-associated hospitalization rates varied significantly across seasons. Before the COVID-19 pandemic, hospitalization rates per 100,000 population ranged from 8.7 (2011-12) to 102.9 (2017-18) and had consistent seasonality. After SARS-CoV-2 emerged, the hospitalization rate for 2020-21 was 0.8, and the rate did not return to recent prepandemic levels until 2022-23. Inconsistent seasonality also was observed during 2020-21 through 2022-23, with influenza activity being very low during 2020-21, extending later than usual during 2021-22, and occurring early during 2022-23. Molecular assays, particularly multiplex standard molecular assays, were the most common influenza test type in recent seasons, increasing from 12% during 2017-18 for both pediatric and adult cases to 43% and 55% during 2022-23 for pediatric and adult cases, respectively. During each season, adults aged ≥65 years consistently had the highest influenza-associated hospitalization rate across all age groups, followed in most seasons by children aged 0-4 years. Black or African American and American Indian or Alaska Native persons had the highest age-adjusted influenza-associated hospitalization rates across these seasons. Among patients hospitalized with influenza, the prevalence of at least one underlying medical condition increased with increasing age, ranging from 36.9% among children aged 0-4 years to 95.4% among adults aged ≥65 years. Consistently across each season, the most common underlying medical conditions among children and adolescents were asthma, neurologic disorders, and obesity. The most common underlying medical conditions among adults were hypertension, obesity, chronic metabolic disease, chronic lung disease, and cardiovascular disease. The proportion of FluSurv-NET patients with acute respiratory signs and symptoms at hospital admission decreased from 90.6% during 2018-19 to 83.2% during 2022-23. Although influenza antiviral use increased during the 2010-11 through the 2017-18 influenza seasons, it decreased from 90.2% during 2018-19 to 79.1% during 2022-23, particularly among children and adolescents. Admission to the intensive care unit, need for invasive mechanical ventilation, and in-hospital death ranged from 14.1% to 22.3%, 4.9% to 11.1%, and 2.2% to 3.5% of patients hospitalized with influenza, respectively, during the reported surveillance period. INTERPRETATIONS: Influenza continues to cause severe morbidity and mortality, particularly in older adults, and disparities have persisted in racial and ethnic minority groups. Persons with underlying medical conditions represented a large proportion of patients hospitalized with influenza. Increased use of multiplex tests and other potential changes in facility-level influenza testing practices (e.g., influenza screening at all hospital admissions) could have implications for the detection of influenza infections among hospitalized patients. Antiviral use decreased in recent seasons, and explanations for the decrease should be further evaluated. PUBLIC HEALTH ACTION: Continued robust influenza surveillance is critical to monitor progress in efforts to encourage antiviral treatment and improve clinical outcomes for persons hospitalized with influenza. In addition, robust influenza surveillance can potentially reduce disparities by informing efforts to increase access to preventive measures for influenza and monitoring any subsequent changes in hospitalization rates.

The COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) was established in March 2020 to monitor trends in hospitalizations associated with SARS-CoV-2 infection. COVID-NET is a geographically diverse population-based surveillance system for laboratory-confirmed COVID-19-associated hospitalizations with a combined catchment area covering approximately 10% of the US population. Data collected in COVID-NET includes monthly counts of hospitalizations for persons with confirmed SARS-CoV-2 infection who reside within the defined catchment area. A Bayesian modeling approach is proposed to estimate US national COVID-associated hospital admission rates based on information reported in the COVID-NET system. A key component of the approach is the ability to estimate uncertainty resulting from extrapolation of hospitalization rates observed within COVID-NET to the US population. In addition, the proposed model enables estimation of other contributors to uncertainty including temporal dependence among reported COVID-NET admission counts, the impact of unmeasured site-specific factors, and the frequency and accuracy of testing for SARS-CoV-2 infection. Based on the proposed model, an estimated 6.3 million (95% uncertainty interval (UI) 5.4-7.3 million) COVID-19-associated hospital admissions occurred in the United States from September 2020 through December 2023. Between April 2020 and December 2023, model-based monthly admission rate estimates ranged from a minimum of 1 per 10,000 population (95% UI 0.7-1.2) in June of 2023 to a highest monthly level of 16 per 10,000 (95% UI 13-19) in January 2022.

Among adults, COVID-19 hospitalization rates increase with age. Data from the COVID-19-Associated Hospitalization Surveillance Network were analyzed to estimate population-based COVID-19-associated hospitalization rates during October 2023-April 2024 and identify demographic and clinical characteristics of adults aged ≥18 years hospitalized with COVID-19. Adults aged ≥65 years accounted for 70% of all adult COVID-19-associated hospitalizations, and their COVID-19-associated hospitalization rates were higher than those among younger adult age groups. Cumulative rates of COVID-19-associated hospitalization during October 2023-April 2024 were the lowest for all adult age groups during an October-April surveillance period since 2020-2021. However, hospitalization rates among all adults aged ≥75 years approached one COVID-19-associated hospitalization for every 100 persons. Among adults hospitalized with COVID-19, 88.1% had not received the 2023-2024 formula COVID-19 vaccine before hospitalization, 80.0% had multiple underlying medical conditions, and 16.6% were residents of long-term care facilities (LTCFs). Guidance for adults at high risk for severe COVID-19 illness, including adults aged ≥65 years and residents of LTCFs, should continue to focus on adopting measures to reduce risk for contracting COVID-19, advocating for receipt of recommended COVID-19 vaccinations, and seeking prompt outpatient antiviral treatment after receipt of a positive SARS-CoV-2 test result.

BACKGROUND: Reports of fluconazole-resistant Candida parapsilosis bloodstream infections are increasing. We describe a cluster of fluconazole-resistant C parapsilosis bloodstream infections identified in 2021 on routine surveillance by the Georgia Emerging Infections Program in conjunction with the Centers for Disease Control and Prevention. METHODS: Whole-genome sequencing was used to analyze C parapsilosis bloodstream infections isolates. Epidemiological data were obtained from medical records. A social network analysis was conducted using Georgia Hospital Discharge Data. RESULTS: Twenty fluconazole-resistant isolates were identified in 2021, representing the largest proportion (34%) of fluconazole-resistant C parapsilosis bloodstream infections identified in Georgia since surveillance began in 2008. All resistant isolates were closely genetically related and contained the Y132F mutation in the ERG11 gene. Patients with fluconazole-resistant isolates were more likely to have resided at long-term acute care hospitals compared with patients with susceptible isolates (P = .01). There was a trend toward increased mechanical ventilation and prior azole use in patients with fluconazole-resistant isolates. Social network analysis revealed that patients with fluconazole-resistant isolates interfaced with a distinct set of healthcare facilities centered around 2 long-term acute care hospitals compared with patients with susceptible isolates. CONCLUSIONS: Whole-genome sequencing results showing that fluconazole-resistant C parapsilosis isolates from Georgia surveillance demonstrated low genetic diversity compared with susceptible isolates and their association with a facility network centered around 2 long-term acute care hospitals suggests clonal spread of fluconazole-resistant C parapsilosis. Further studies are needed to better understand the sudden emergence and transmission of fluconazole-resistant C parapsilosis.

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information.

This case study is part of a series centered on the Centers for Disease Control and Prevention/National Healthcare Safety Network (NHSN) healthcare-associated infection (HAI) surveillance definitions. This specific case study focuses on the application of common surveillance concepts included in Laboratory-Identified (LabID) Event Reporting [Chapter 12 of the NHSN Patient Safety Manual - Multidrug-Resistant Organism &Clostridioides difficile Infection (MDRO/CDI) Module] used with validation efforts. The intent of the case study series is to foster standardized application of the NHSN surveillance definitions and encourage accurate event determination among Infection Preventionists (IPs).

BACKGROUND: Machine learning has the potential to help researchers better understand and close the gap in HIV care delivery in large metropolitan regions such as Mecklenburg County, North Carolina, USA. OBJECTIVES: We aim to identify important risk factors associated with delayed linkage to care for HIV patients with novel machine learning models and identify high-risk regions of the delay. METHODS: Deidentified 2013-2017 Mecklenburg County surveillance data in eHARS format were requested. Both univariate analyses and machine learning random forest model (developed in R 3.5.0) were applied to quantify associations between delayed linkage to care (>30 days after diagnosis) and various risk factors for individual HIV patients. We also aggregated linkage to care by zip codes to identify high-risk communities within the county. RESULTS: Types of HIV-diagnosing facility significantly influenced time to linkage; first diagnosis in hospital was associated with the shortest time to linkage. HIV patients with lower CD4+ cell counts (<200/ml) were twice as likely to link to care within 30 days than those with higher CD4+ cell count. Random forest model achieved high accuracy (>80% without CD4+ cell count data and >95% with CD4+ cell count data) to predict risk of delay in linkage to care. In addition, we also identified top high-risk zip codes of delayed linkage. CONCLUSION: The findings helped public health teams identify high-risk communities of delayed HIV care continuum across Mecklenburg County. The methodology framework can be applied to other regions with HIV epidemic and challenge of delayed linkage to care.

BACKGROUND: Clinicians confront numerous practical issues in optimizing the use of anticoagulants to treat venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and other health care professionals in their decisions about the use of anticoagulants in the management of VTE. These guidelines assume the choice of anticoagulant has already been made. METHODS: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 25 recommendations and 2 good practice statements to optimize management of patients receiving anticoagulants. CONCLUSIONS: Strong recommendations included using patient self-management of international normalized ratio (INR) with home point-of-care INR monitoring for vitamin K antagonist therapy and against using periprocedural low-molecular-weight heparin (LMWH) bridging therapy. Conditional recommendations included basing treatment dosing of LMWH on actual body weight, not using anti-factor Xa monitoring to guide LMWH dosing, using specialized anticoagulation management services, and resuming anticoagulation after episodes of life-threatening bleeding.

Many antineoplastic drugs used to treat cancer, particularly alkylating agents and topoisomerase inhibitors, are known to induce genetic damage in patients. Elevated levels of chromosomal aberrations, micronuclei, and DNA damage have been documented in cancer patients. Elevations in these same biomarkers of genetic damage have been reported in numerous studies of healthcare workers, such as nurses and pharmacists, who routinely handle these drugs, but results vary across studies. To obtain an overall assessment of the exposure effect, we performed a meta-analysis on data obtained from peer-reviewed publications reporting chromosomal aberration levels in healthcare workers exposed to antineoplastic drugs. A literature search identified 39 studies reporting on occupational exposure to antineoplastic drugs and measurement of chromosomal aberrations in healthcare workers. After applying strict inclusion criteria for data quality and presentation, data from 17 studies included in 16 publications underwent meta-analysis using Hedges' bias-corrected g and a random-effects model. Results showed the level of chromosomal aberrations in healthcare workers exposed to antineoplastic drugs was significantly higher than in controls. The standardized mean differences (difference of means divided by within sd) from all studies were pooled, yielding a value 1.006 (unitless) with p< 0.001. Thus, in addition to the documented genotoxic effects of antineoplastic drugs in cancer patients, this meta-analysis confirmed a significant association between occupational exposure to antineoplastics during the course of a normal work day and increases in chromosomal aberrations in healthcare workers. Based on the studies reviewed, we were unable to accurately assess whether appropriate use of protective measures might reduce the incidence of genetic damage in healthcare workers. However, given the potential for increased cancer risk linked to increases in chromosomal aberrations, the results of this study support the need to limit occupational exposure of healthcare workers to antineoplastic drugs as much as possible.

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.

In the 15 June 2012 issue of Clinical Infectious Diseases, Witt et al reported that vaccine effectiveness (VE) of acellular pertussis vaccines was 41% for children aged 2–7 years, 24% for 8- to 12-year-olds, and 79% for 13- to 18-year-olds [1]. The authors conclude that their data “confirms markedly lower than expected protection afforded by the pre-school series of acellular pertussis vaccinations in the 8–12 year age group” and poor durability of protection from the vaccine. While we agree that protection wanes over time, there are important limitations to the Witt et al analysis. | VE estimates are predicated on comparing disease risk in a vaccinated group with disease risk in an unvaccinated group. When calculating VE for multiple dose vaccines, partially vaccinated persons should not be grouped with unvaccinated individuals [2, 3]. Doing so compromises the vaccine-naive comparison group and lowers VE estimates. Although the authors do not specify how undervaccinated individuals were handled in the analyses, the results presented in their Tables 1 and 2 indicate that undervaccinated and unvaccinated individuals were inappropriately categorized together, rather than excluding undervaccinated persons from the analysis. This bias explains the surprisingly low estimates in the 2 younger and combined overall age groups.

The effect of training instruction, whether presented as the manufacturer's printed instructions, a short video training session specific to the product, or as a one-on-one training session was evaluated using four hearing protection devices with eight groups of subjects. Naive subjects were recruited and tested using three different forms of training: written, video, and individual training. The group averages for A-weighted attenuation were not statistically significant when compared between the video or the written instruction conditions, regardless of presentation order. The experimenter-trained A-weighted attenuations were significantly greater than the written and video instruction for most of the protectors and groups. For each earplug, the noise reduction statistic for A-weighting (NRS A ) and the associated confidence intervals were calculated for the 80 th and 20 th percentiles of protection. Across subject groups for each protector, the differences between NRS A ratings were found to be not statistically significant. Several comparisons evaluating the order of testing, the type of testing, and statistical tests of the performance across the groups are presented.