Hemophilia B (HB) is caused by mutations in the human gene F9. The mutation type plays a pivotal role in genetic counseling and prediction of inhibitor development. To help the HB community understand the molecular etiology of HB, we have developed a listing of all F9 mutations that are reported to cause HB based on the literature and existing databases. The Centers for Disease Control and Prevention (CDC) Hemophilia B Mutation Project (CHBMP) mutation list is compiled in an easily accessible format of Microsoft Excel and contains 1083 unique mutations that are reported to cause HB. Each mutation is identified using Human Genome Variation Society (HGVS) nomenclature standards. The mutation types and the predicted changes in amino acids, if applicable, are also provided. Related information including the location of mutation, severity of HB, the presence of inhibitor, and original publication reference are listed as well. Therefore, our mutation list provides an easily accessible resource for genetic counselors and HB researchers to predict inhibitors. The CHBMP mutation list is freely accessible at http://www.cdc.gov/hemophiliamutations.

PURPOSE: Population-based prevalence surveys are essential for decision-making on interventions to achieve trachoma elimination as a public health problem. This paper outlines the methodologies of Tropical Data, which supports work to undertake those surveys. METHODS: Tropical Data is a consortium of partners that supports health ministries worldwide to conduct globally standardised prevalence surveys that conform to World Health Organization recommendations. Founding principles are health ministry ownership, partnership and collaboration, and quality assurance and quality control at every step of the survey process. Support covers survey planning, survey design, training, electronic data collection and fieldwork, and data management, analysis and dissemination. Methods are adapted to meet local context and needs. Customisations, operational research and integration of other diseases into routine trachoma surveys have also been supported. RESULTS: Between 29(th) February 2016 and 24(th) April 2023, 3373 trachoma surveys across 50 countries have been supported, resulting in 10,818,502 people being examined for trachoma. CONCLUSION: This health ministry-led, standardised approach, with support from the start to the end of the survey process, has helped all trachoma elimination stakeholders to know where interventions are needed, where interventions can be stopped, and when elimination as a public health problem has been achieved. Flexibility to meet specific country contexts, adaptation to changes in global guidance and adjustments in response to user feedback have facilitated innovation in evidence-based methodologies, and supported health ministries to strive for global disease control targets.

BACKGROUND: Regulatory organizations recommend assessing hospital-acquired (HA) venous thromboembolism (VTE) risk for medical inpatients. OBJECTIVES: To develop and validate a risk assessment model (RAM) for HA-VTE in medical inpatients using objective and assessable risk factors knowable at admission. PATIENTS/METHODS: The development cohort included people admitted to medical services at the University of Vermont Medical Center (Burlington, VT, USA) between 2010-19 and the validation cohorts people admitted to Hennepin County Medical Center (Minneapolis, MN, USA), University of Michigan Medical Center (Ann Arbor, MI, USA), and Harris Health Systems (Houston, TX, USA). Individuals with VTE at admission, <18-years old, and admitted for <1 midnight were excluded. We used a Bayesian penalized regression technique to selected candidate HA-VTE risk factors for final inclusion in the RAM. RESULTS: The development cohort included 60,633 admissions and 227 HA-VTE and the validation cohorts 111,269 admissions and 651 HA-VTE. Seven HA-VTE risk factors with t-statistics ≥1.5 were included in the RAM: prior history of VTE, low hemoglobin, elevated creatinine, active cancer, hyponatremia, elevated red cell distribution width, and malnutrition. The AUC and calibration slope were 0.72 and 1.10. The AUC and calibration slopes were 0.70 and 0.93 at Hennepin County Medical Center, 0.70 and 0.87 at the University of Michigan Medical Center, and 0.71 and 1.00 at Harris Health Systems. The RAM performed well stratified by age, sex, and race. CONCLUSIONS: We developed and validated a RAM for HA-VTE in medical inpatients. By quantifying risk, clinicians can determine the potential benefits of measures to reduce HA-VTE.

The association between thromboembolic events (TE) and COVID-19 infection is not completely understood at the population level in the United States. We examined their association using a large US healthcare database. We analyzed data from the Premier Healthcare Database Special COVID-19 Release and conducted a case-control study. Thestudy population consisted of men and non-pregnant women aged18years with (cases) or without (controls) an inpatient ICD-10-CM diagnosis of TE between 3/1/2020 and 6/30/2021. Using multivariable logistic regression, we assessed the association between TE occurrence and COVID-19 diagnosis, adjusting for demographic factors and comorbidities. Among 227,343 cases, 15.2% had a concurrent or prior COVID-19 diagnosis within 30days of their index TE. Multivariable regression analysis showed a statistically significant association between a COVID-19 diagnosis and TE among cases when compared to controls (adjusted odds ratio [aOR]1.75, 95% CI 1.72-1.78). The association was more substantial if a COVID-19 diagnosis occurred 1-30days prior to index hospitalization (aOR3.00, 95% CI 2.88-3.13) compared to the same encounter as the index hospitalization. Our findings suggest an increased risk of TE among persons within 30days of beingdiagnosed COVID-19, highlighting the need for careful consideration of the thrombotic risk among COVID-19 patients, particularly during the first month following diagnosis.

INTRODUCTION: Sickle cell disease (SCD), a group of inherited blood cell disorders that primarily affects Black or African American persons, is associated with severe complications and a >20-year reduction in life expectancy. In 2014, an expert panel convened by the National Heart, Lung, and Blood Institute issued recommendations to prevent or reduce complications in children and adolescents with the most severe SCD subtypes, known as sickle cell anemia (SCA); recommendations included 1) annual screening of children and adolescents aged 2-16 years with transcranial Doppler (TCD) ultrasound to identify those at risk for stroke and 2) offering hydroxyurea therapy to children and adolescents aged ≥9 months to reduce the risk for several life-threatening complications. METHODS: Data from the IBM MarketScan Multi-State Medicaid Database were analyzed. TCD screening and hydroxyurea use were examined for 3,352 children and adolescents with SCA aged 2-16 years and continuously enrolled in Medicaid during 2019. Percentage change during 2014-2019 and variation by health subgroups were assessed. Analyses were stratified by age. RESULTS: During 2014-2019, TCD screening increased 27% among children and adolescents aged 10-16 years; hydroxyurea use increased 27% among children aged 2-9 years and 23% among children and adolescents aged 10-16 years. However, in 2019, only 47% and 38% of children and adolescents aged 2-9 and 10-16 years, respectively, had received TCD screening and 38% and 53% of children and adolescents aged 2-9 years and 10-16 years, respectively, used hydroxyurea. For both prevention strategies, usage was highest among children and adolescents with high levels of health care utilization and evidence of previous complications indicative of severe disease. CONCLUSION AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Despite increases since 2014, TCD screening and hydroxyurea use remain low among children and adolescents with SCA. Health care providers should implement quality care strategies within their clinics and partner with patients, families, and community-based organizations to address barriers to delivering and receiving recommended care.

Sickle cell disease (SCD), a group of inherited disorders, is a bellwether example of a chronic, disabling, life-threatening condition that is disproportionately underserved by the medical community. SCD is arguably associated with the most significant health inequities of both the 20th and 21st centuries. Although these inequities, which are linked to historical interpersonal and institutional racism, have been long recognized, there has been scant progress in closing the healthcare gaps.1 SCD affects at least 100,000 individuals in the United States, the vast majority being Black or African American individuals.1 Abnormal hemoglobin produced in SCD causes red blood cells (RBCs) to sickle, clogging blood flow and leading to vaso-occlusive crises and potential impacts on every organ system. Persons with SCD experience numerous complications, including recurrent episodes of severe pain, pneumonia and acute chest syndrome, stroke, and organ damage. Estimated life expectancy of those with SCD in the US is >20 years shorter than the average expected and the deficit in quality-adjusted life expectancy is particularly stark (>30 years shorter).2 esting is a safe and feasible alternative to mandatory quarantine and can be used to maximize safe in-person learning time during the pandemic.

BACKGROUND: Population-based data about cerebral venous sinus thrombosis (CVST) are limited. OBJECTIVES: To investigate the epidemiology of CVST in the United States. PATIENTS/METHODS: Three administrative data systems were analyzed: the 2018 Healthcare Cost and Utilization Project National Inpatient Sample (NIS) the 2019 IBM MarketScan Commercial and Medicare Supplemental Claims Database, and the 2019 IBM MarketScan Multi-state Medicaid Database. CVST, thrombocytopenia, and numerous comorbidities were identified using the International Classification of Diseases, Tenth Revision, Clinical Modification codes. Incidence rates of CVST and CVST with thrombocytopenia were estimated (per 100,000 total US population [NIS] and per 100,000 population aged 0 to 64 years covered by relevant contributing health plans [MarketScan samples]). Comorbidity prevalence was estimated among CVST cases versus total inpatients in the NIS sample. Recent pregnancy prevalence was estimated for the Commercial sample. RESULTS: Incidence rates of CVST in NIS, Commercial, and Medicaid samples were 2.85, 2.45, and 3.16, respectively. Incidence rates of CVST with thrombocytopenia were 0.21, 0.22, and 0.16, respectively. In all samples, CVST incidence increased with age; however, peak incidence was reached at younger ages in females than males. Compared with the general inpatient population, persons with CVST had higher prevalences of hemorrhagic stroke, ischemic stroke, other venous thromboembolism (VTE), central nervous system infection, head or neck infection, prior VTE, thrombophilia, malignancy, head injury, hemorrhagic disorder, and connective tissue disorders. Women aged 18 to 49 years with CVST had a higher pregnancy prevalence than the same-aged general population. CONCLUSIONS: Our findings provide recent and comprehensive data on the epidemiology of CVST and CVST with thrombocytopenia.

Sickle cell disease (SCD) is associated with increased risk of poor health outcomes from respiratory infections, including COVID-19 illness. We used US death data to investigate changes in SCD-related mortality before and during the COVID-19 pandemic. We estimated annual age- and quarter-adjusted SCD-related mortality rates for 2014-2020. We estimated the number of excess deaths in 2020 compared with 2019 using the standardized mortality ratio (SMR). We found 1023 SCD-related deaths reported in the United States during 2020, of which 86 (8.4%) were associated with COVID-19. SCD-related deaths, both associated and not associated with COVID-19, occurred most frequently among adults aged 25-59 years. The SCD-related mortality rate changed <5% year to year from 2014 to 2019 but increased 12% in 2020; the sharpest increase was among adults aged 60 years. The SMR comparing 2020 with 2019 was 1.12 (95% CI, 1.06-1.19). Overall, 113 (95% CI, 54-166) excess SCD-related deaths occurred in 2020.

BACKGROUND: The prevalence and effects of inappropriate empirical antibiotic therapy for bloodstream infections are unclear. We aimed to establish the population-level burden, predictors, and mortality risk of in-vitro susceptibility-discordant empirical antibiotic therapy among patients with bloodstream infections. METHODS: Our retrospective cohort analysis of electronic health record data from 131 hospitals in the USA included patients with suspected-and subsequently confirmed-bloodstream infections who were treated empirically with systemic antibiotics between Jan 1, 2005, and Dec 31, 2014. We included all patients with monomicrobial bacteraemia caused by common bloodstream pathogens who received at least one systemic antibiotic either on the day blood cultures were drawn or the day after, and for whom susceptibility data were available. We calculated the prevalence of discordant empirical antibiotic therapy-which was defined as receiving antibiotics on the day blood culture samples were drawn to which the cultured isolate was not susceptible in vitro-overall and by hospital type by using regression tree analysis. We used generalised estimating equations to identify predictors of receiving discordant empirical antibiotic therapy, and used logistic regression to calculate adjusted odds ratios for the relationship between in-hospital mortality and discordant empirical antibiotic therapy. FINDINGS: 21 608 patients with bloodstream infections received empirical antibiotic therapy on the day of first blood culture collection. Of these patients, 4165 (19%) received discordant empirical antibiotic therapy. Discordant empirical antibiotic therapy was independently associated with increased risk of mortality (adjusted odds ratio 1·46 [95% CI, 1·28-1·66]; p<0·0001), a relationship that was unaffected by the presence or absence of resistance or sepsis or septic shock. Infection with antibiotic-resistant species strongly predicted receiving discordant empirical therapy (adjusted odds ratio 9·09 [95% CI 7·68-10·76]; p<0·0001). Most incidences of discordant empirical antibiotic therapy and associated deaths occurred among patients with bloodstream infections caused by Staphylococcus aureus or Enterobacterales. INTERPRETATION: Approximately one in five patients with bloodstream infections in US hospitals received discordant empirical antibiotic therapy, receipt of which was closely associated with infection with antibiotic-resistant pathogens. Receiving discordant empirical antibiotic therapy was associated with increased odds of mortality overall, even in patients without sepsis. Early identification of bloodstream pathogens and resistance will probably improve population-level outcomes. FUNDING: US National Institutes of Health, US Centers for Disease Control and Prevention, and US Agency for Healthcare Research and Quality.

Programs seeking to eliminate the eye disease trachoma use prevalence of the clinical sign trachomatous inflammation–follicular (TF) in 1- to 9-year-olds as a proxy for population-level transmission of ocular Chlamydia trachomatis (Ct). TF prevalence determines the need for the A, F, and E components of the “SAFE” (surgery, antibiotics, facial cleanliness, environmental improvement) strategy. Ocular Ct infection, like its associated signs of conjunctival inflammation, is most common and most intense in young children [1, 2] who are repeatedly infected in areas of active transmission [3]: a model suggests that people can be infected more than 150 times in their lifetime [4]. Repeated infection leads to multiple episodes of TF plus more intense conjunctival inflammation and eventually conjunctival scarring (trachomatous scarring [TS])[5, 6]. Contraction of conjunctival scar can, over a period of years or decades, cause the upper eyelid to turn in and the eyelashes to rub against the eyeball (trachomatous trichiasis [TT]), which can lead to corneal opacity (CO) and blindness.

STUDY OBJECTIVE: We provide an updated assessment of trends in sickle cell disease (SCD)-related mortality, a significant source of mortality in the United States among black persons, using 1979 to 2017 US mortality data. METHODS: SCD-related deaths were identified with International Classification of Diseases codes. Because SCD-related death is rare in other races, the analysis focused on black decedents. Age-specific and average annual SCD-related death rates were calculated. Causes of death codes were categorized into 20 groups relevant to SCD outcomes. SCD-related deaths were compared with non-SCD-related deaths after matching on race, sex, age group, and year of death. RESULTS: There were 25,665 SCD-related deaths reported among blacks in the United States from 1979 through 2017. During that period, the annual SCD-related death rate declined in children and increased in adults, and the median age at death increased from 28 to 43 years. Acute causes of death, such as infection and cerebrovascular complications, were more common in younger age groups. Chronic complications were more common in adults. SCD-related deaths were more likely to be related to acute cardiac, pulmonary, and cerebrovascular complications; acute infections; and chronic cardiac and pulmonary complications and renal disorders; and less likely to be related to drug overdose and chronic infections than non-SCD-related deaths. CONCLUSION: These data indicate SCD-related deaths are now more likely to be related to chronic complications of the disease than to acute complications. More research regarding prevention and treatment of chronic complications of SCD is necessary because persons with SCD are living longer.

PROBLEM/CONDITION: Hemophilia is an X-linked genetic disorder that primarily affects males and results in deficiencies in blood-clotting proteins. Hemophilia A is a deficiency in factor VIII, and hemophilia B is a deficiency in factor IX. Approximately one in 5,000 males are born with hemophilia, and hemophilia A is about four times as common as hemophilia B. Both disorders are characterized by spontaneous internal bleeding and excessive bleeding after injuries or surgery. Hemophilia can lead to repeated bleeding into the joints and associated chronic joint disease, neurologic damage, damage to other organ systems, and death. Although no precise national U.S. prevalence estimates for hemophilia exist because of the difficulty identifying cases among persons who receive care from various types of health care providers, two previous state-based studies estimated hemophilia prevalence at 13.4 and 19.4 per 100,000 males. In addition, these studies showed that 67% and 82% of persons with hemophilia received care in a federally funded hemophilia treatment center (HTC), and 86% and 94% of those with the most severe cases of hemophilia (i.e., those with the lowest levels of clotting factor activity in the circulating blood) received care in a federally funded HTC. As of January 2020, the United States had 144 HTCs. PERIOD COVERED: 1998-2019. DESCRIPTION OF THE SYSTEM: Surveillance for hemophilia, which is a complex, chronic condition, is challenging because of its low prevalence, the difficulty in ascertaining cases uniformly, and the challenges in routinely characterizing and tracking associated health complications. Over time, two systems involving many stakeholders have been used to conduct ongoing hemophilia surveillance. During 1998-2011, CDC and the HTCs collaborated to establish the Universal Data Collection (UDC) surveillance system. The purposes of the UDC surveillance system were to monitor human immunodeficiency virus (HIV) and bloodborne viral hepatitis in persons with hemophilia, thereby tracking blood safety, and to track the prevalence of and trends in complications associated with hemophilia. HTC staff collected clinical data and blood specimens from UDC participants and submitted them to CDC. CDC tested specimens for viral hepatitis and HIV. In 2011, the UDC surveillance system was replaced by a new hemophilia surveillance system called Community Counts. CDC and the HTCs established Community Counts to expand laboratory testing and the collection of clinical data to better identify and track emerging health issues in persons with hemophilia. RESULTS: This report is the first comprehensive summary of CDC's hemophilia surveillance program, which comprises both UDC and Community Counts. Data generated from these surveillance systems have been used in the development of public health and clinical guidelines and practices to improve the safety of U.S. blood products and either prevent hemophilia-related complications or identify complications early. Several factors have played a role in the effectiveness of the UDC and Community Counts systems, including 1) a stable data collection design that was developed and is continually reviewed in close partnership with HTC regional leaders and providers to ensure surveillance activities are focused on maximizing the scientific and clinical impact; 2) flexibility to respond to emerging health priorities through periodic updates to data collection elements and special studies; 3) high data quality for many clinical indicators and state-of-the-art laboratory testing methods for hemophilia treatment product inhibitors (developed and refined in part based on CDC research); 4) timely data and specimen collection and submission, laboratory specimen testing, analysis, and reporting; and 5) the largest and most representative sample of persons with hemophilia in the United States and one of the largest and most comprehensive data collection systems on hemophilia worldwide. INTERPRETATION: CDC has successfully developed, implemented, and maintained a surveillance system for hemophilia. The program can serve as an example of how to conduct surveillance for a complex chronic disease by involving stakeholders, improving and building new infrastructure, expanding data collection (e.g., new diagnostic assays), providing testing guidance, establishing a registry with specimen collection, and integrating laboratory findings in clinical practice for the individual patient. PUBLIC HEALTH ACTION: Hemophilia is associated with substantial lifelong morbidity, excess premature deaths, and extensive health care needs throughout life. Through monitoring data from Community Counts, CDC will continue to characterize the benefits and adverse events associated with existing or new hemophilia treatment products, thereby contributing to maximizing the health and longevity of persons with hemophilia.

A complete understanding of human immune responses to Ebola virus infection is limited by the availability of specimens and the requirement for biosafety level 4 (BSL-4) containment. In an effort to bridge this gap, we evaluated cryopreserved PBMCs from 4 patients who survived Ebola virus disease (EVD) using an established mass cytometry antibody panel to characterize various cell populations during both the acute and convalescent phases. Acute loss of nonclassical monocytes and myeloid DCs, especially CD1c+ DCs, was noted. Classical monocyte proliferation and CD38 upregulation on plasmacytoid DCs coincided with declining viral load. Unsupervised analysis of cell abundance demonstrated acute declines in monocytic, NK, and T cell populations, but some populations, many of myeloid origin, increased in abundance during the acute phase, suggesting emergency hematopoiesis. Despite cell losses during the acute phase, upregulation of Ki-67 correlated with recovery of cell populations over time. These data provide insights into the human immune response during EVD.

As elaborated by Sabatino et al,1 five decades of advances have brought us widespread availability of safe and effective haemophilia treatment. However, inhibitors, neutralizing alloantibodies to factor VIII, still occur in ~25%-30% of persons with severe haemophilia A. Within the US, it is estimated that there are over 1000 individuals with a factor VIII inhibitor.2 Inhibitors are associated with increased risk from bleeding and twice the rate of hospitalization for a bleeding complication, increased morbidity from joint disease and significantly increased rate of death due to bleeding-related causes compared to those without inhibitors. Over the last 30 years, we have gained insights on risk factors for inhibitor development from retrospective and parallel-cohort studies as well as meta-analyses.3 However, there is still much to be learned about the basic mechanisms underlying this immune response and few studies that have significantly impacted inhibitor prevention and eradication.

INTRODUCTION: The major complication of protein replacement therapy for haemophilia A is the development of anti-FVIII antibodies or inhibitors that occur in 25%-30% of persons with severe haemophilia A. Alternative therapeutics such as bypassing agents or immune tolerance induction protocols have additional challenges and are not always effective. AIM: Assemble a National Heart, Lung and Blood Institute (NHLBI) State of the Science (SOS) Workshop to generate a national blueprint for research on inhibitors to solve the problem of FVIII immunogenicity. METHODS: An Executive Steering Committee was formed in October 2017 to establish the scientific focus and Scientific Working Groups for the SOS Workshop in May 2018. Four working groups were assembled to address scientific priorities in basic, translational and clinical research on inhibitors. RESULTS: Working Group 1 was charged with determining the scientific priorities for clinical trials to include the integration of non-intravenous, non-factor therapeutics including gene therapy into the standard of care for people with haemophilia A with inhibitors. Working Group 2 established the scientific priorities for 21st-century data science and biospecimen collection for observational inhibitor cohort studies. The scientific priorities for acquiring an actionable understanding of FVIII immunogenicity and the immunology of the host response and FVIII tolerance were developed by Working Group 3. Working Group 4 designed prospective pregnancy/birth cohorts to study FVIII immunogenicity, inhibitor development and eradication. CONCLUSION: The NHLBI SOS Workshop generated a focused summary of scientific priorities and implementation strategies to overcome the challenges of eradicating and preventing inhibitors in haemophilia A.

In the U.S., deaths due to pulmonary embolism (PE) account for 9.2% of all pregnancy-related deaths or approximately 1.5 deaths per 100,000 live births. Maternal deaths and maternal morbidity due to PE are more common among women who deliver by cesarean section. In the past decade, the clinical community has increasingly adopted venous thromboembolism (VTE) guidelines and thromboprophylaxis recommendations for pregnant women. Although deep vein thrombosis rates have decreased during this time-period, PE rates have remained relatively unchanged in pregnancy hospitalizations and as a cause of maternal mortality. Changes in the health profile of women who become pregnant, particularly due to maternal age and co-morbidities, needs more attention to better understand the impact of VTE risk during pregnancy and the postpartum period.

Background: Clinicians increasingly utilize polymyxins for treatment of serious infections caused by multidrug-resistant gram-negative bacteria. Emergence of plasmid-mediated, mobile colistin resistance genes creates potential for rapid spread of polymyxin resistance. We investigated the possible transmission of Klebsiella pneumoniae carrying mcr-1 via duodenoscope and report the first documented healthcare transmission of mcr-1-harboring bacteria in the United States. Methods: A field investigation, including screening targeted high-risk groups, evaluation of the duodenoscope, and genome sequencing of isolated organisms, was conducted. The study site included a tertiary care academic health center in Boston, Massachusetts, and extended to community locations in New England. Results: Two patients had highly related mcr-1-positive K. pneumoniae isolated from clinical cultures; a duodenoscope was the only identified epidemiological link. Screening tests for mcr-1 in 20 healthcare contacts and 2 household contacts were negative. K. pneumoniae and E. coli were recovered from the duodenoscope; neither carried mcr-1. Evaluation of the duodenoscope identified intrusion of biomaterial under the sealed distal cap; devices were recalled to repair this defect. Conclusions: We identified transmission of mcr-1 in a United States acute care hospital that likely occurred via duodenoscope despite no identifiable breaches in reprocessing or infection control practices. Duodenoscope design flaws leading to transmission of multidrug-resistant organsisms persist despite recent initiatives to improve device safety. Reliable detection of colistin resistance is currently challenging for clinical laboratories, particularly given the absence of an FDA-cleared test; improved clinical laboratory capacity for colistin susceptibility testing is needed to prevent the spread of mcr-carrying bacteria in healthcare settings.

Background: Resistance to all first-line antibiotics necessitates the use of less effective or more toxic "reserve" agents. Gram-negative bloodstream infections (GNBSIs) harboring such difficult-to-treat resistance (DTR) may have higher mortality than phenotypes that allow for >/=1 active first-line antibiotic. Methods: The Premier Database was analyzed for inpatients with select GNBSIs. DTR was defined as intermediate/resistant in vitro to all ss-lactam categories, including carbapenems and fluoroquinolones. Prevalence and aminoglycoside resistance of DTR episodes were compared with carbapenem-resistant, extended-spectrum cephalosporin-resistant, and fluoroquinolone-resistant episodes using CDC definitions. Predictors of DTR were identified. The adjusted relative risk (aRR) of mortality was examined for DTR, CDC-defined phenotypes susceptible to >/=1 first-line agent, and graded loss of active categories. Results: Between 2009-2013, 471 (1%) of 45011 GNBSI episodes at 92 (53.2%) of 173 hospitals exhibited DTR, ranging from 0.04% for Escherichia coli to 18.4% for Acinetobacter baumannii. Among patients with DTR, 79% received parenteral aminoglycosides, tigecycline, or colistin/polymyxin-B; resistance to all aminoglycosides occurred in 33%. Predictors of DTR included urban healthcare and higher baseline illness. Crude mortality for GNBSIs with DTR was 43%; aRR was higher for DTR than for carbapenem-resistant (1.2; 95% confidence interval, 1.0-1.4; P = .02), extended-spectrum cephalosporin-resistant (1.2; 1.1-1.4; P = .001), or fluoroquinolone-resistant (1.2; 1.0-1.4; P = .008) infections. The mortality aRR increased 20% per graded loss of active first-line categories, from 3-5 to 1-2 to 0. Conclusion: Nonsusceptibility to first-line antibiotics is associated with decreased survival in GNBSIs. DTR is a simple bedside prognostic measure of treatment-limiting coresistance.

AIM: The study objectives were to investigate the association between selected CYP2C9 and VKORC1 single nucleotide polymorphisms with serious bleeding or thrombotic risk, and to estimate mean daily maintenance dose of warfarin and international normalized ratio measurements among Blacks receiving warfarin anticoagulation. METHODS: We conducted a retrospective cohort study among 230 Black adults receiving warfarin for a minimum of three consecutive months with a confirmed date of first dosage. RESULTS: A lower mean daily maintenance dosage of warfarin was required to maintain an international normalized ratio measurement within the therapeutic range among Blacks with the VKORC1-1639G>A variant alleles ([G/A vs G/G, p = 0.02], [A/A vs G/A, p = 0.008] and [A/A vs G/G, p = 0.001]). CONCLUSION: Data indicated that VKORC1-1639A variant allele influenced warfarin daily maintenance dosage among our small, likely admixed Black patient population.

Background: One previous pilot study suggested the association of low plasma glucosylceramide (GlcCer) levels with venous thrombosis (VTE) risk. Objective: We aimed to confirm and evaluate the association of low plasma GlcCer levels with VTE and myocardial infarction (MI) occurrence, respectively. Patients and Methods: We evaluated the association of GlcCer in two independent case-control studies of Caucasian VTE populations (N = 210 and 636) and one case-control study of Caucasian MI patients (N = 345). Result: Plasma GlcCer levels in VTE patients were lower compared to controls in two independent VTE populations (5.0 vs 5.8 mug/mL, p = 0.003 for the Scripps registry, and 5.6 vs 6.0 mug/mL, p = 0.001 for the Valencia registry, respectively). A low plasma GlcCer level (below 10th percentile of controls) was associated with increased VTE occurrence [odds ratio (OR) = 3.7 (95%CI, 1.8-7.9) for Scripps registry and OR = 2.1 (95%CI, 1.3-3.3) for Valencia registry, respectively). For the MI study, the median GlcCer plasma level was lower in MI patients than in controls (4.3 vs 5.6 mug/mL, p<0.001), and a low level of GlcCer (below 10th percentile of control) was associated with higher MI occurrence [OR = 7.7, (95%CI, 4.3-13.8)]. Conclusion: Lower concentration of GlcCer was associated with VTE occurrence in two independent studies and also with MI occurrence in one study.

RATIONALE: The impact of a broad range of occupational exposures on subclinical interstitial lung disease (ILD) has not been studied. OBJECTIVES: To determine whether occupational exposures to vapors, gas, dust, and fumes (VGDF) are associated with high-attenuation areas (HAA) and interstitial lung abnormalities (ILA), which are quantitative and qualitative computed tomography (CT)-based measurements of subclinical ILD, respectively. METHODS: We performed analyses of participants enrolled in MESA (Multi-Ethnic Study of Atherosclerosis), a population-based cohort aged 45-84 years at recruitment. HAA was measured at baseline and on serial cardiac CT scans in 5,702 participants. ILA was ascertained in a subset of 2,312 participants who underwent full-lung CT scanning at 10-year follow-up. Occupational exposures were assessed by self-reported VGDF exposure and by job-exposure matrix (JEM). Linear mixed models and logistic regression were used to determine whether occupational exposures were associated with log-transformed HAA and ILA. Models were adjusted for age, sex, race/ethnicity, education, employment status, tobacco use, and scanner technology. MEASUREMENTS AND MAIN RESULTS: Each JEM score increment in VGDF exposure was associated with 2.64% greater HAA (95% confidence interval [CI], 1.23-4.19%). Self-reported vapors/gas exposure was associated with an increased odds of ILA among those currently employed (1.76-fold; 95% CI, 1.09-2.84) and those less than 65 years old (1.97-fold; 95% CI, 1.16-3.35). There was no consistent evidence that occupational exposures were associated with progression of HAA over the follow-up period. CONCLUSIONS: JEM-assigned and self-reported exposures to VGDF were associated with measurements of subclinical ILD in community-dwelling adults.

BACKGROUND: Prenatal alcohol exposure can affect neurodevelopment, but few studies have examined associations with autism spectrum disorder (ASD). METHODS: We assessed the association between maternal alcohol use and ASD in the Study to Explore Early Development, a multi-site case-control study of children born between September 2003 and August 2006 in the US Regression analyses included 684 children with research clinician-confirmed ASD, 869 children with non-ASD developmental delays or disorders (DDs), and 962 controls ascertained from the general population (POP). Maternal alcohol exposure during each month from 3 months prior to conception until delivery was assessed by self-report. RESULTS: Mothers of POP children were more likely to report any prenatal alcohol use than mothers of children with ASD or DD. In trimester one, 21.2% of mothers of POP children reported alcohol use compared with 18.1% and 18.2% of mothers of children with ASD or DD, respectively (adjusted OR for ASD vs. POP 0.8, 95% confidence interval 0.6, 1.1). During preconception and the first month of pregnancy, one to two drinks on average per week was inversely associated with ASD risk. CONCLUSIONS: These results do not support an adverse association between low-level alcohol exposure and ASD, although these findings were based on retrospective self-reported alcohol use. Unmeasured confounding or exposure misclassification may explain inverse associations with one to two drinks per week. Pregnant or potentially pregnant women should continue to follow recommendations to avoid alcohol use because of other known effects on infant health and neurodevelopment.

Venous thromboembolism (VTE), blood clots occurring as deep vein thrombosis, pulmonary embolism, or both, is an important and growing public health issue. The precise number of people affected by VTE is unknown; however, estimates suggest that up to 900,000 events resulting in as many as 100,000 premature deaths occur in the United States yearly with healthcare costs as high as $10 billion.1–3 Although anyone can develop VTE, research has shown that half of VTE events occurring in the outpatient setting are directly linked to a recent hospitalization or surgery.4 In patients with cancer, VTE is a leading cause of death after the cancer itself.5,6 Fortunately, many of these healthcare-associated VTE (HA-VTE) cases can be prevented. Recent analyses have shown that as many as 70% of HA-VTE cases are preventable through appropriate prophylaxis,7–9 yet reports suggest that fewer than half of hospital patients receive VTE prophylaxis in accordance with accepted evidence-based guidelines.10 Appropriate prevention of HA-VTE can result in a significant reduction in overall VTE occurrence, thereby decreasing healthcare burden and unnecessary deaths. | In November 2015, the Centers for Disease Control and Prevention (CDC) released the Healthcare-Associated VTE Prevention Challenge (http://www.cdc.gov/ncbddd/dvt/ha-vte-challenge.html) to identify, highlight, and reward hospitals, managed care organizations, and hospital networks that implemented innovative, effective, and sustainable strategies to prevent HA-VTE.

INTRODUCTION: No study has examined how the relationship between polycystic ovary syndrome (PCOS) and atherosclerotic cardiovascular diseases (aCVD), of ischemic stroke (ISCH), acute myocardial infarction (AMI), and peripheral vascular disease (PAD), differ in the presence of venous thromboembolism (VTE). MATERIALS AND METHODS: We performed a cross-sectional analysis using Truven Health Analytics MarketScan(R) Commercial databases from 2004-2011. The association between women aged 18-64years with and without PCOS, and aCVD was assessed using VTE-stratified multivariable logistic regression models. RESULTS: Overall, women with PCOS were more likely to have aCVD, (aOR, 1.27; 95% CI, 1.10-1.46) especially ISCH (aOR, 1.56; 95% CI, 1.30-1.88), than women without PCOS. When stratified by VTE status, women with PCOS and a VTE diagnosis had a decreased odds of having any aCVD (aOR 0.67; 95% CI, 0.46-0.98), and VTE diagnosis more often preceded the occurrence of ISCH and AMI among women with PCOS compared with women without PCOS. CONCLUSIONS: Overall, women with PCOS were more likely to have aCVD, with stroke being the most prevalent manifestation. Although VTE often occurred before any aCVD, it appeared to have an inverse association with the development of ISCH, AMI, and PAD among women with PCOS, suggesting that aggressively treating VTE or aCVD early may limit the chances of developing the other thrombogenic condition among women with PCOS.

In June 2012, an academic haematologist in a tertiary health facility notified the Centers for Disease Control and Prevention (CDC) of new onset inhibitors during hospitalization in four previously treated people with haemophilia (PWH). The four patients were considered at low risk for this complication. Inhibitor onset occurred among patients hospitalized during a 14-month period, whereas no inhibitor cases had occurred among inpatients during the previous 12-month period. All four cases had received a recombinant clotting factor concentrate (CFC) from a single manufacturer, raising concern about a possible product-related issue. The situation was reported to the North Carolina Department of Health and Human Services who advised that an investigation be carried out and requested assistance from CDC. | This report summarizes the results of the investigation conducted with the following specific aims: (i) to determine whether the cases represented an increase in the baseline inhibitor incidence among inpatients with haemophilia at the index facility; (ii) to assess whether the cases were at greater risk for an inhibitor than other inpatients with haemophilia as a result of personal, clinical or treatment factors; and (iii) to evaluate the possible influence of changes in hospital practices related to CFC use during the period.

BACKGROUND: The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS: We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS: No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 35% of vaccinees. Vaccine viremia was detected within 3 days in 103 of 110 participants (94%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days; 2 self-limited cases occurred in 40 participants (5%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. CONCLUSIONS: In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099 , NCT02287480 , and NCT02296983 ; Pan African Clinical Trials Registry number, PACTR201411000919191 .).

OBJECTIVE: This study assessed the risk of venous thromboembolism (VTE) among privately insured adults in the U.S. with one or more of the following autoimmune diseases: autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). MATERIALS AND METHODS: Using the Truven Health MarketScan(R) Databases, patients 18-64 years of age with a diagnosis of AIHA, ITP, RA, or SLE in 2007 and a sex and age-group matched comparison group of enrollees were followed up through 2010 to identify VTE events. Survival curve and Cox proportional hazards analyses were conducted to assess differences between groups. RESULTS: Among patients with AIHA, ITP, RA, or SLE, or >1 of these diseases, the risk of at least one VTE event was 19.74, 7.72, 4.90, 9.89, and 13.35 per 1,000 person-years, respectively; among the comparison group, the risk was 1.91 per 1,000 person-years. The adjusted hazard ratios (aHRs) for VTE among patients with AIHA, ITP, RA, or SLE, or >1 of these diseases (when compared with the comparison group) tended to decline over follow-up time; at 1year, the aHRs were 6.30 (95% confidence interval [CI]: 4.44-8.94), 2.95 (95% CI: 2.18-4.00), 2.13 (95% CI: 1.89-2.40), 4.68 (95% CI: 4.10-5.33), and 5.11 (95% CI: 4.26-6.14), respectively. CONCLUSION: Having AIHA, ITP, RA, or SLE, or >1 of these diseases was associated with an increased likelihood of a VTE event. More research is necessary to develop better understanding of VTE occurrence among people with autoimmune diseases.

INTRODUCTION: Recurrent venous thromboembolism (VTE) occurs infrequently following a provoked event but occurs in up to 30% of individuals following an initial unprovoked event. There is limited understanding of the biological mechanisms that predispose patients to recurrent VTE. OBJECTIVES: To identify whole blood gene expression profiles that distinguished patients with clinically distinct patterns of VTE. PATIENTS/METHODS: We studied 107 patients with VTE separated into 3 groups: (1) 'low-risk' patients had one or more provoked VTE; (2) 'moderate-risk' patients had a single unprovoked VTE; (3) 'high-risk' patients had ≥2 unprovoked VTE. Each patient group was also compared to twenty-five individuals with no personal history of VTE. Total RNA from whole blood was isolated and hybridized to Illumina HT-12V4 Beadchips to assay whole genome expression. RESULTS: Using class prediction analysis, we distinguished high-risk patients from low-risk patients and healthy controls with good receiver operating curve characteristics (AUC=0.81 and 0.84, respectively). We also distinguished moderate-risk individuals and low-risk individuals from healthy controls with AUC's of 0.69 and 0.80, respectively. Using differential expression analysis, we identified several genes previously implicated in thrombotic disorders by genetic analyses, including SELP, KLKB1, ANXA5, and CD46. Protein levels for several of the identified genes were not significantly different between the different groups. CONCLUSION: Gene expression profiles are capable of distinguishing patients with different clinical presentations of VTE, and genes relevant to VTE risk are frequently differentially expressed in these comparisons.

OBJECTIVE: Stromal derived factor-1alpha/CXCL12 is a chemoattractant responsible for homing of progenitor cells to ischemic tissues. We aimed to investigate the association of plasma CXCL12 with long-term cardiovascular outcomes in patients with coronary artery disease (CAD). METHODS: 785 patients aged: 63 +/- 12 undergoing coronary angiography were independently enrolled into discovery (N = 186) and replication (N = 599) cohorts. Baseline levels of plasma CXCL12 were measured using Quantikine CXCL12 ELISA assay (R&D systems). Patients were followed for cardiovascular death and/or myocardial infarction (MI) for a mean of 2.6 yrs. Cox proportional hazard was used to determine independent predictors of cardiovascular death/MI. RESULTS: The incidence of cardiovascular death/MI was 13% (N = 99). High CXCL12 level based on best discriminatory threshold derived from the ROC analysis predicted risk of cardiovascular death/MI (HR = 4.81, p = 1 x 10(-6)) independent of traditional risk factors in the pooled cohort. Addition of CXCL12 to a baseline model was associated with a significant improvement in c-statistic (AUC: 0.67-0.73, p = 0.03). Addition of CXCL12 was associated with correct risk reclassification of 40% of events and 10.5% of non-events. Similarly for the outcome of cardiovascular death, the addition of the CXCL12 to the baseline model was associated with correct reclassification of 20.7% of events and 9% of non-events. These results were replicated in two independent cohorts. CONCLUSION: Plasma CXCL12 level is a strong independent predictor of adverse cardiovascular outcomes in patients with CAD and improves risk reclassification.

AIMS: Bradykinin (BK) stimulates tissue plasminogen activator (t-PA) release from human endothelium. Although BK stimulates both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) release, the role of EDHF in t-PA release remains unexplored. This study sought to determine the mechanisms of BK-stimulated t-PA release in the forearm vasculature of healthy human subjects. METHODS: In 33 healthy subjects (age 40.3 +/- 1.9 years), forearm blood flow (FBF) and t-PA release were measured at rest and after intra-arterial infusions of BK (400 ng/min) and sodium nitroprusside (3.2 mg/min). Measurements were repeated after intra-arterial infusion of tetraethylammonium chloride (TEA; 1 micromol/min), fluconazole (0.4 micromol.min(-1).l(-1)), and N(G)-monomethyl-L-arginine (L-NMMA, 8 micromol/min) to block nitric oxide, and their combination in separate studies. RESULTS: BK significantly increased net t-PA release across the forearm (p < 0.0001). Fluconazole attenuated both BK-mediated vasodilation (-23.3 +/- 2.7% FBF, p < 0.0001) and t-PA release (from 50.9 +/- 9.0 to 21.3 +/- 8.9 ng/min/100 ml, p = 0.02). TEA attenuated FBF (-14.7 +/- 3.2%, p = 0.002) and abolished BK-stimulated t-PA release (from 22.9 +/- 5.7 to -0.8 +/- 3.6 ng/min/100 ml, p = 0.0002). L-NMMA attenuated FBF (p < 0.0001), but did not inhibit BK-induced t-PA release (nonsignificant). CONCLUSION: BK-stimulated t-PA release is partly due to cytochrome P450-derived epoxides and is inhibited by K(+)Ca channel blockade. Thus, BK stimulates both EDHF-dependent vasodilation and t-PA release.