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The complement system is a vital component of the innate immune system, though its role in bacteremia is poorly understood. We present complement levels in Staphylococcus aureus bacteremia (SAB) and Gram-negative bacteremia (GNB) and describe observed associations of complement levels with clinical outcomes. Complement and cytokine levels were measured in serum samples from 20 hospitalized patients with SAB, 20 hospitalized patients with GNB, 10 non-infected hospitalized patients, and 10 community controls. C5a levels were significantly higher in patients with SAB as compared to patients with GNB. Low C4 and C3 levels were associated with septic shock and 30-day mortality in patients with GNB, and elevated C3 was associated with a desirable outcome defined as absence of (1) septic shock, (2) acute renal failure, and (3) death within 30 days of bacteremia. Low levels of C9 were associated with septic shock in patients with GNB but not SAB. Elevated IL-10 was associated with increased 30-day mortality in patients with SAB. Complement profiles differ in patients with SAB and those with GNB. Measurement of IL-10 in patients with SAB and of C4, C3, and C9 in patients with GNB may help to identify those at higher risk for poor outcomes. Electronic supplementary material The online version of this article (10.1007/s10096-020-03955-z) contains supplementary material, which is available to authorized users.

Background To understand the clinical, bacterial, and host characteristics associated with recurrent Staphylococcus aureus bacteremia (R-SAB), patients with R-SAB were compared to contemporaneous patients with a single episode of SAB (S-SAB). Methods All SAB isolates underwent spa genotyping. All isolates from R-SAB patients underwent pulsed-field gel electrophoresis (PFGE). PFGE-indistinguishable pairs from 40 patients underwent whole genome sequencing (WGS). Acute phase plasma from R-SAB and S-SAB patients was matched 1:1 for age, race, sex, and bacterial genotype, and underwent cytokine quantification using 25-analyte multiplex bead array. Results R-SAB occurred in 69 (9.1%) of the 756 study patients. Of the 69 patients, 30 experienced relapse (43.5%) and 39 reinfection (56.5%). Age, race, hemodialysis dependence, presence of foreign body, methicillin-resistant Staphyloccus aureus, and persistent bacteremia were individually associated with likelihood of recurrence. Multivariate risk modeling revealed that black hemodialysis patients were nearly 2 times more likely (odds ratio [OR] = 9.652 [95% confidence interval [CI], 5.402–17.418]) than white hemodialysis patients (OR = 4.53 [95% CI, 1.696–10.879]) to experience R-SAB. WGS confirmed PFGE interpretations in all cases. Median RANTES (regulated on activation, normal T cell expressed and secreted) levels in acute phase plasma from the initial episode of SAB were higher in R-SAB than in matched S-SAB controls (P = .0053, false discovery rate Conclusion This study identified several risk factors for R-SAB. The largest risk for R-SAB is among black hemodialysis patients. Higher RANTES levels in R-SAB compared to matched controls warrants further study.

Significance The severity and duration of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia varies widely between individuals. Host factors predisposing to persistent MRSA bacteremia are poorly understood, although genetic association studies are beginning to identify potentially influential variants. We found an association between the A/C heterozygous genotype in the DNMT3A correlating with shorter time to resolution of MRSA bacteremia. Using in vitro macrophage assays and murine sepsis models, we demonstrated that DNMT3A variants may alter host response to infection through increased methylation of key regulatory genes, resulting in reduced interleukin-10 production and in turn, allowing for a more protective immune response that clears infection. An improved understanding of the factors predisposing to persistent MRSA bacteremia may help to discover better treatment options., The role of the host in development of persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is not well understood. A cohort of prospectively enrolled patients with persistent methicillin-resistant S. aureus bacteremia (PB) and resolving methicillin-resistant S. aureus bacteremia (RB) matched by sex, age, race, hemodialysis status, diabetes mellitus, and presence of implantable medical device was studied to gain insights into this question. One heterozygous g.25498283A > C polymorphism located in the DNMT3A intronic region of chromosome 2p with no impact in messenger RNA (mRNA) expression was more common in RB (21 of 34, 61.8%) than PB (3 of 34, 8.8%) patients (P = 7.8 × 10−6). Patients with MRSA bacteremia and g.25498283A > C genotype exhibited significantly higher levels of methylation in gene-regulatory CpG island regions (Δmethylation = 4.1%, P < 0.0001) and significantly lower serum levels of interleukin-10 (IL-10) than patients with MRSA bacteremia without DNMT3A mutation (A/C: 9.7038 pg/mL vs. A/A: 52.9898 pg/mL; P = 0.0042). Expression of DNMT3A was significantly suppressed in patients with S. aureus bacteremia and in S. aureus-challenged primary human macrophages. Small interfering RNA (siRNA) silencing of DNMT3A expression in human macrophages caused increased IL-10 response upon S. aureus stimulation. Treating macrophages with methylation inhibitor 5-Aza-2′-deoxycytidine resulted in increased levels of IL-10 when challenged with S. aureus. In the murine sepsis model, methylation inhibition increased susceptibility to S. aureus. These findings indicate that g.25498283A > C genotype within DNMT3A contributes to increased capacity to resolve MRSA bacteremia, potentially through a mechanism involving increased methylation of gene-regulatory regions and reduced levels of antiinflammatory cytokine IL-10.

Background We conducted a longitudinal study to evaluate changes in the clinical presentation and epidemiology of Staphylococcus aureus bacteremia (SAB) in an academic, US medical center. Methods Consecutive patients with monomicrobial SAB were enrolled from January 1995 to December 2015. Each person’s initial bloodstream S. aureus isolate was genotyped using spa typing. Clonal complexes (CCs) were assigned using Ridom StaphType software. Changes over time in both the patient and bacterial characteristics were estimated with linear regression. Associations between genotypes or clinical characteristics and complications were estimated using multivariable regression models. Results Among the 2348 eligible participants, 54.2% had an implantable, foreign body of some type. This proportion increased significantly during the 21-year study period, by 0.96% annually (P = .002), as did comorbid conditions and acquisition outside of the hospital. Rates of any metastatic complication also significantly increased, by 0.94% annually (P = .019). Among the corresponding bloodstream S. aureus isolates, spa-CC012 (multi-locus sequence type [MLST] CC30), -CC004 (MLST CC45), -CC189 (MLST CC1), and -CC084 (MLST CC15) all significantly declined during the study period, while spa-CC008 (MLST CC8) significantly increased. Patients with SAB due to spa-CC008 were significantly more likely to develop metastatic complications in general, and abscesses, septic emboli, and persistent bacteremia in particular. After adjusting for demographic, racial, and clinical variables, the USA300 variant of spa-CC008 was independently associated with metastatic complications (odds ratio 1.42; 95% confidence interval 1.02–1.99). Conclusions Systematic approaches for monitoring complications of SAB and genotyping the corresponding bloodstream isolates will help identify the emergence of hypervirulent clones and likely improve clinical management of this syndrome.

Background Microbial cell-free DNA (mcfDNA) sequencing of plasma can identify the presence of a pathogen in a host. In this study, we evaluated the duration of pathogen detection by mcfDNA sequencing vs conventional blood culture in patients with bacteremia. Methods Blood samples from patients with culture-confirmed bloodstream infection were collected within 24 hours of the index positive blood culture and 48 to 72 hours thereafter. mcfDNA was extracted from plasma, and next-generation sequencing was applied. Reads were aligned against a curated pathogen database. Statistical significance was defined with Bonferroni adjustment for multiple comparisons (P Results A total of 175 patients with Staphylococcus aureus bacteremia (n = 66), gram-negative bacteremia (n = 74), or noninfected controls (n = 35) were enrolled. The overall sensitivity of mcfDNA sequencing compared with index blood culture was 89.3% (125 of 140), and the specificity was 74.3%. Among patients with bacteremia, pathogen-specific mcfDNA remained detectable for significantly longer than conventional blood cultures (median 15 days vs 2 days; P Conclusions Pathogen mcfDNA identified the bacterial etiology of bloodstream infection for a significantly longer interval than conventional cultures, and its duration of detection was associated with increased risk for metastatic infection. mcfDNA could play a role in the diagnosis of partially treated endovascular infections.

This study evaluated the impact of didactic videos and service user testimonial videos on mental illness stigma among medical students. Two randomized controlled trials were conducted in Nepal. Study 1 examined stigma reduction for depression. Study 2 examined depression and psychosis. Participants were Nepali medical students (Study 1:n=94, Study 2:¬n=213) randomized to three conditions: a didactic video based on the mental health Gap Action Programme (mhGAP), a service user video about living with mental illness, or a control condition with no videos. In Study 1, videos only addressed depression. In Study 2, videos addressed depression and psychosis. In Study 1, both didactic and service user videos reduced stigma compared to the control (F2,91=6.37, p=0.003). In Study 2 (depression and psychosis), there were no differences among the three arms (F2,210=2.07, p=0.13). When comparing Study 1 and 2, there was greater stigma reduction in the service user video arm with only depression versus service user videos with depression and psychosis (t(31)=-3.04, p=0.005). In summary, didactic and service user videos were associated with decreased stigma when content addressed only depression. However, no stigma reduction was seen when including depression and psychosis. This calls for different strategies based on types of mental illnesses. ClinicalTrials.gov identifier: NCT03231761

BackgroundWhile factors that drive early mortality among people living with HIV (PLWH) initiating antiretroviral therapy (ART) in sub-Saharan Africa (SSA) have been described, less is known about the predictors of long-term mortality for those with ART experience.MethodsPLWH and on ART attending two HIV treatment clinics in Moshi, Tanzania were enrolled from 2008 through 2009 and followed for 3.5 years. Demographic, psychosocial, and clinical information were collected at enrollment. Plasma HIV RNA measurements were collected annually. Cause of death was adjudicated by two independent reviewers based on verbal autopsy information and medical records. Bivariable and multivariable analyses were conducted using Cox proportional hazard models to identify predictors of mortality.ResultsThe analysis included 403 participants. The median (IQR) age in years was 42 (36-48) and 277 (68.7%) participants were female. The proportion of participants virologically suppressed during the 4 collection time points was 88.5%, 94.7%, 91.5%, and 94.5%. During follow-up, 24 participants died; the overall mortality rate was 1.8 deaths per 100 person-years. Of the deaths, 14 (58.3%) were suspected to be HIV/AIDS related. Predictors of mortality (adjusted hazard ratio, 95% confidence interval) were male sex (2.63, 1.01-6.83), secondary or higher education (7.70, 3.02-19.60), receiving care at the regional referral hospital in comparison to the larger zonal referral hospital (6.33, 1.93-20.76), and moderate to severe depression symptoms (6.35, 1.69-23.87).ConclusionsAs ART coverage continues to expand in SSA, HIV programs should recognize the need for interventions to promote HIV care engagement for men and the integration of mental health screening and treatment with HIV care. Facility-level barriers may contribute to challenges faced by PLWH as they progress through the HIV care continuum, and further understanding of these barriers is needed. The association of higher educational attainment with mortality merits further investigation.

Background: Response-guided hepatitis C therapy was standard with interferon-based regimens but is not used for direct-acting antivirals (DAAs). Week 4 viral kinetics may predict sustained virological response (SVR) with DAAs, but it is unclear whether extending therapy in slow responders affects outcomes. Objectives: The primary objective was to compare SVR rates between traditional and extended duration groups. Secondary objectives were to compare SVR rates among subgroups and to determine factors associated with SVR. Methods: This institutional review board–approved, retrospective, single-center study identified patients with chronic hepatitis C virus (HCV) infection with detectable week 4 HCV RNA who were treated with DAAs. Patients were excluded for early discontinuation, treatment regimen not recommended first-line, or missing HCV RNA labs. Patients were stratified into traditional and extended duration groups. The primary end point was SVR. Secondary end points included factors associated with SVR and rationale for extension of therapy duration. Results: A total of 363 patients were included; 58 (16%) received extended therapy. Patients were primarily genotype 1a (70%) and treatment naïve (80%). More than half had advanced fibrosis or cirrhosis. SVR12 rates were 100% in the extended duration group and 96.7% in the traditional duration group ( P = 0.37). There were no associations with SVR and prespecified patient-specific factors. Sample size was limited. Conclusion and Relevance: Based on these findings, a recommendation for extension of therapy cannot be made for patients with detectable HCV RNA at week 4 of treatment at this time. Cost analyses may help guide recommendations to re-treat rare failures versus extend therapy in all slow responders.

Background Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased sustained viral response rate (SVR) in patients taking ledipasvir/sofosbuvir (LDV/SOF). The relationship between PPI usage and SVR is less clear in patients with HIV/HCV coinfection, where concomitant antiretrovirals may result in more complex drug interactions. Aims Evaluate the effects of acid suppression medications (PPI or H2 -receptor antagonist [H2 B]) use and SVR rates in patients with HIV/HCV or HCV and taking LDV/SOF in a large multi-center veteran cohort. Methods Retrospective analysis of all veterans in the Veterans Affairs Health Care System who received LDV/SOF ± ribavirin from 10/10/2014 to 12/31/2015. The odds ratios (OR) of PPI or H2 B use for SVR were adjusted for clinical factors and with inverse probability of treatment weighting for non-random treatment selection for acid suppression medication use. Results There were 9703 veterans included in our final analysis. After adjustment of other clinical factors, PPI use is associated with a lower SVR in the overall cohort (95.0% vs. 96.1%, OR:0.86, 95% CI: 0.74-0.99, P=0.03, number needed to harm 90.9) and HIV/HCV co-infection subgroup (93.4% vs. 96.9%, OR:0.47, 95% CI: 0.26-0.85, P=0.01, number needed to harm 28.6). Conclusion PPI use is associated with reduced SVR after LDV/SOF treatment, with a more significant impact in the subgroup of patients with HIV/HCV coinfection. Precautions need to be taken when using PPI and LDV/SOF in this group of patients.

Rationale & Objective Staphylococcus aureus (S aureus) bacteremia (SAB) is associated with morbidity and mortality in patients receiving maintenance hemodialysis (HD). We evaluated changes in clinical and bacterial characteristics, and their associations with clinical outcomes with SAB in this population over a 21-year period. Study Design Prospective cohort study. Setting & Participants 453 hospitalized, non-neutropenic adults receiving maintenance HD who developed monomicrobial SAB between 1995 and 2015. Exposure Clinical characteristics and bacterial genotype. Outcome All-cause and SAB-attributable mortality, persistent bacteremia, and metastatic complications. Analytical Approach Proportions of participants experiencing each outcome were calculated overall and by calendar year. Secular trends were estimated using binomial risk regression, a generalized linear model with the log link function for a binomial outcome. Associations with outcomes were estimated using logistic regression. Results Over the 21-year study period, patients receiving maintenance HD experienced significant increases in age- and diabetes-adjusted SAB-attributable mortality (0.45% [95% CI, 0.36%-0.46%] per year), persistent bacteremia (0.86% [95% CI, 0.14%-1.55%] per year), metastatic complications (0.84% [95% CI, 0.11%-1.56%] per year), and infection with the virulent S aureus clone USA300 (1.47% [95% CI, 0.33%-2.52%] per year). Over time, the suspected source of SAB was less likely to be a central venous catheter (−1.32% [95% CI, −2.05 to −0.56%] per year) or arteriovenous graft (−1.08% [95% CI, −1.54 to −0.56] per year), and more likely to be a nonvascular access source (1.89% [95% CI, 1.29%-2.43%] per year). Patients with a nonvascular access suspected source of infection were more likely to die as a result of their S aureus infection (OR, 3.20 [95% CI, 1.36-7.55]). The increase in USA300 infections may have contributed to the observed increase in persistent bacteremia (OR, 2.96 [95% CI, 1.12-7.83]) but did not explain the observed increases in SAB-attributable mortality (OR, 0.83 [95% CI, 0.19-3.61]) or metastatic complications (OR, 1.34 [95% CI, 0.53-3.41]). Limitations Single-center, inpatient cohort. Conclusions The clinical and molecular epidemiology of SAB in patients receiving maintenance HD has changed over time, with an increase in SAB-attributable mortality and morbidity despite a decline in catheter-related infections.

Background Long-term data on outcomes of participants hospitalized with heart failure (HF) from low- and middle-income countries are limited. Methods and Results In the Trivandrum Heart Failure Registry (THFR) in 2013, 1205 participants from 18 hospitals in Trivandrum, India, were enrolled. Data were collected on demographics, clinical presentation, treatment, and outcomes. We performed survival analyses, compared groups and evaluated the association between heart failure (HF) type and mortality, adjusting for covariates that predicted mortality in a global HF risk score. The mean (standard deviation) age of participants was 61.2 (13.7) years. Ischemic heart disease was the most common cause (72%). The in-hospital mortality rate was higher for participants with HF with reduced ejection fraction (HFrEF; 9.7%) compared with those with HF with preserved ejection fraction (HFpEF; 4.8%; P = .003). After 3 years, 540 (44.8%) participants had died. The all-cause mortality rate was lower for participants with HFpEF (40.8%) compared with HFrEF (46.2%; P = .049). In multivariable models, older age (hazard ratio [HR] 1.24 per decade, 95% confidence interval [CI] 1.15-1.33), New York Heart Association functional class IV symptoms (HR 2.80, 95% CI 1.43-5.48), and higher serum creatinine (HR 1.12 per mg/dL, 95% CI 1.04-1.22) were associated with all-cause mortality. Conclusions Participants with HF in the THFR have high 3-year all-cause mortality. Targeted hospital-based quality improvement initiatives are needed to improve survival during and after hospitalization for HF.

BACKGROUND Naloxone-an opioid antagonist that reverses the effects of opioids-is increasingly being distributed in non-medical settings. We sought to identify the facilitators of, and barriers to, opioid users using naloxone kits in North Carolina.METHODS In 2015, we administered a 15-item survey to a convenience sample of 100 treatment seekers at 4 methadone/buprenorphine Medication Assisted Therapy (MAT) clinics in North Carolina.RESULTS Seventy-four percent of participants reported having ever gotten a naloxone kit; this percentage was higher for females (81%) than males (63%) (P = .06). The primary reason given for not having a kit was not knowing where to get one. Only 6% had heard of kits from the media and only 5% received one from a medical provider. Among kit recipients, 56% of both females and males reported mostly or sometimes carrying the kit, with additional participants reporting always. Reasons for not carrying a kit were no longer being around drugs, forgetting it, and the kit being too large. Men discussed the difficulties of carrying the naloxone kits, which are currently too large to fit in a pocket. Ninety-four percent of naloxone users reported intending to call emergency services in case of an overdose emergency.LIMITATIONS Study limitations included a small sample, participants limited to MAT clinics, and a predominantly white sample.CONCLUSIONS MAT treatment seekers reported a willingness to carry and use naloxone kits. Education, outreach, media, and medical providers need to promote naloxone kits. A smaller kit may increase the likelihood of men carrying one.

ObjectiveTo identify health systems-level barriers to treatment for women who screened positive for high-risk human papillomavirus (hrHPV) in a cervical cancer prevention program in Kenya.MethodsIn a trial of implementation strategies for hrHPV-based cervical cancer screening in western Kenya in 2018-2019, women underwent hrHPV testing offered through community health campaigns, and women who tested positive were referred to government health facilities for cryotherapy. The current analysis draws on treatment data from this trial, as well as two observational studies that were conducted: 1) periodic assessments of the treatment sites to ascertain availability of resources for treatment and 2) surveys with treatment providers to elicit their views on barriers to care. Bivariate analyses were performed for the site assessment data, and the provider survey data were analyzed descriptively.ResultsSeventeen site assessments were performed across three treatment sites. All three sites reported instances of supply stockouts, two sites reported treatment delays due to lack of supplies, and two sites reported treatment delays due to provider factors. Of the 16 providers surveyed, ten (67%) perceived lack of knowledge of HPV and cervical cancer as the main barrier in women's decision to get treated, and seven (47%) perceived financial barriers for transportation and childcare as the main barrier to accessing treatment. Eight (50%) endorsed that providing treatment free of cost was the greatest facilitator of treatment.ConclusionPatient education and financial support to reach treatment are potential areas for intervention to increase rates of hrHPV+ women presenting for treatment. It is also essential to eliminate barriers that prevent treatment of women who present, including ensuring adequate supplies and staff for treatment.

Background Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections are associated with increased risk of cardiovascular disease (CVD). The potential impact of recently updated cholesterol guidelines on treatment of HIV- and HCV-infected veterans is unknown. Methods We performed a retrospective cohort study to assess statin use and recommendations among 13 579 HIV-infected, 169 767 HCV-infected, and 6628 HIV/HCV-coinfected male veterans aged 40-75 years. Prior 2004 Adult Treatment Panel (ATP-III) guidelines were compared with current 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines and 2014 US Department of Veterans Affairs (VA)/US Department of Defense (DoD) joint clinical practice guidelines using laboratory, medication, and comorbidity data from the VA Clinical Case Registry from 2008 through 2010. Results Using risk criteria delineated by the ATP-III guidelines, 50.6% of HIV-infected, 45.9% of HCV-infected, and 33.8% of HIV/HCV-coinfected veterans had an indication for statin therapy. However, among those eligible, 22.7%, 30.5%, and 31.5%, respectively, were not receiving ATP-III recommended statin therapy. When current cholesterol guidelines were applied by VA/DoD and ACC/AHA criteria, increases in recommendations for statins were found in all groups (57.3% and 66.1% of HIV-infected, 64.4% and 73.7% of HCV-infected, 49.1% and 58.5% of HIV/HCV-coinfected veterans recommended). Conclusions Statins were underutilized among veterans infected with HIV, HCV, and HIV/HCV according to previous ATP-III guidelines. Current VA/DoD and ACC/AHA guidelines substantially expand statin recommendations and widen the gap of statin underutilization in all groups. These gaps in care present an opportunity to improve CVD prevention efforts in these at-risk populations.

Background Hematogenous vertebral osteomyelitis (HVOM) is a rare, but devastating complication of Staphylococcus aureus bacteremia (SAB). Risk factors and outcomes associated with HVOM among patients with SAB remain incompletely understood. Methods All adult, hospitalized, non-neutropenic patients with SAB were prospectively enrolled from 1995 to 2015. Additional data was subsequently collected on all patients with HVOM. Diagnosis of HVOM was made either radiographically or microbiologically by culture from the infection site. Patients who underwent lumbar puncture or spinal surgery within 30 days prior to the diagnosis of HVOM were excluded. Results Of 2,475 cases of prospectively enrolled patients with SAB, 90 (3.6%) developed HVOM. The most common site of involvement was the lumbar spine (65.6%). MRI was used in the diagnosis of 90% of patients and although only 28.9% underwent bone biopsy, 88.5% of these bone cultures grew S. aureus. Patients with HVOM were more likely to have community-acquired SAB (22.2% vs. 9.9%, P < 0.0001) and persistent bacteremia (47.8% vs. 20.5%, P < 0.0001). Patients with HVOM who required surgical intervention were more likely to have motor deficit (60.9% vs. 21.4%, P = 0.0013) and have associated epidural abscesses (69.6% vs. 44.8%, P = 0.0400). Prolonged antibiotic use for HVOM was common, with 13.3% remaining on therapeutic antibiotics and 16.6% on suppressive therapy at 6 months. This dropped to 2.2% on therapeutic and 15.5% on suppressive therapy at 12 months. All-cause mortality was high in the HVOM cohort at 14.4% at 90-days, increasing to a cumulative 18.9% and 20.0% at 6 and 12-months, respectively. Rates of readmission, recurrent bacteremia, paralysis, and mortality at 6 and 12-months were similar for those who required surgical intervention and those who did not. Demographics, comorbidities, and clinical characteristics of patients with and without hematogenous vertebral osteomyelitis (HVOM) Conclusion HVOM in patients with SAB was associated with high rates of all-cause mortality up to 12 months following date of diagnosis. Patients with community-acquired bacteremia and persistent bacteremia were more likely to develop HVOM. Disclosures Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Actavis (Grant/Research Support)Advanced Liquid Logics (Grant/Research Support)Affinergy (Consultant, Research Grant or Support)Affinium (Consultant)Allergan (Grant/Research Support)Ampliphi Biosciences (Consultant)Basilea (Consultant, Research Grant or Support)Bayer (Consultant)C3J (Consultant)Cerexa (Consultant, Research Grant or Support)Contrafect (Consultant, Research Grant or Support)Cubist (Grant/Research Support)Debiopharm (Consultant)Destiny (Consultant)Durata (Consultant)Forest (Grant/Research Support)Genentech (Consultant, Research Grant or Support)Integrated Biotherapeutics (Consultant)Janssen (Consultant, Research Grant or Support)Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)Medimmune (Consultant, Research Grant or Support)Merck (Consultant, Research Grant or Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis (Consultant, Research Grant or Support)Pfizer (Grant/Research Support)Regeneron (Consultant, Research Grant or Support)Tetraphase (Consultant)Theravance (Consultant, Research Grant or Support)Trius (Consultant)xBiotech (Consultant)

Background: In patients with active infective endocarditis (IE), the relationship between timing of surgery and survival is uncertain. The objective was to evaluate clinical characteristics associated with timing of surgery and the association between surgical timing and 6-month survival in complicated, left-sided IE. Methods: In a prospective, multicenter, observational registry (The International Collaboration on Endocarditis-PLUS, registry from 2008 to 2012), clinical factors associated with timing of surgery during the index hospitalization were determined among 485 adult patients with definite, complicated, left-sided IE who underwent cardiac surgery during their index hospitalization. The relationship between early surgical intervention (

Alpha-toxin is a major Staphylococcus aureus virulence factor. This study evaluated potential relationships between in vitro alpha-toxin expression of S. aureus bloodstream isolates, anti-alpha-toxin antibody in serum of patients with S. aureus bacteremia (SAB), and clinical outcomes in 100 hemodialysis and 100 postsurgical SAB patients. Isolates underwent spa typing and hla sequencing. Serum anti-alpha-toxin IgG and neutralizing antibody levels were measured by using an enzyme-linked immunosorbent assay and a red blood cell (RBC)-based hemolysis neutralization assay. Neutralization of alpha-toxin by an anti-alpha-toxin monoclonal antibody (MAb MEDI4893) was tested in an RBC-based lysis assay. Most isolates encoded hla (197/200; 98.5%) and expressed alpha-toxin (173/200; 86.5%). In vitro alpha-toxin levels were inversely associated with survival (cure, 2.19 μg/ml, versus failure, 1.09 μg/ml; P < 0.01). Both neutralizing (hemodialysis, 1.26 IU/ml, versus postsurgical, 0.95; P < 0.05) and IgG (hemodialysis, 1.94 IU/ml, versus postsurgical, 1.27; P < 0.05) antibody levels were higher in the hemodialysis population. Antibody levels were also significantly higher in patients infected with alpha-toxin-expressing S. aureus isolates ( P < 0.05). Levels of both neutralizing antibodies and IgG were similar among patients who were cured and those not cured (failures). Sequence analysis of hla revealed 12 distinct hla genotypes, and all genotypic variants were susceptible to a neutralizing monoclonal antibody in clinical development (MEDI4893). These data demonstrate that alpha-toxin is highly conserved in clinical S. aureus isolates. Higher in vitro alpha-toxin levels were associated with a positive clinical outcome. Although patients infected with alpha-toxin-producing S. aureus exhibited higher anti-alpha-toxin antibody levels, these levels were not associated with a better clinical outcome in this study.

We evaluated the syphilis reverse sequence algorithm (RSA) in a Veteran Affairs facility, finding 5.5% reactive Treponema pallidum enzyme immunoassay (EIA) tests. In a subset of EIA+/VDRL-/TP-PA+ cases, 48% were previously treated. Of veterans with unknown/no prior therapy, only 45% had documentation of subsequent treatment, suggesting suboptimal interpretation of RSA results.

Background: Bartonella species are important emerging pathogens in human and veterinary medicine. In the context of their daily activities, veterinary professionals have frequent animal contact and arthropod exposures. Detection of Bartonella spp. using traditional culture methods has been limited by poor sensitivity, making it difficult to determine the prevalence of infection in this population. We have developed a detection method combining enrichment culture and molecular amplification, which increases testing sensitivity. Methods: We performed a cross-sectional study to determine the prevalence of detectable Bartonella spp. in the blood of veterinary personnel and nonveterinary control subjects. Bartonella was detected by enrichment blood culture with conventional PCR followed by DNA sequencing. Results were correlated with epidemiological variables and symptoms. Results: We detected DNA from at least one Bartonella species in 32 (28%) of the 114 veterinary subjects. After DNA sequencing, the Bartonella species could be determined for 27 of the 32 infected subjects, including B. henselae in 15 (56%), B. vinsonii subsp. berkhoffii in seven (26%), B. koehlerae in six (22%), and a B. volans–like sequence in one (4%). Seventy percent of Bartonella-positive subjects described headache compared with 40% of uninfected veterinarians (p=0.009). Irritability was also reported more commonly by infected subjects (68% vs. 43%, p=0.04). Conclusions: Our study supports an emerging body of evidence that cryptic Bartonella bloodstream infection may be more frequent in humans than previously recognized and may induce symptoms. Longitudinal studies are needed to determine the natural course and clinical features of Bartonella infection.

ObjectiveTo identify patient factors associated with whether women who screened positive for high-risk human papillomavirus (hrHPV) successfully accessed treatment in a cervical cancer prevention program in Kenya.MethodsA prospective cohort study was conducted as part of a trial of implementation strategies for hrHPV-based cervical cancer screening in western Kenya from January 2018 to February 2019. In this larger trial, women underwent hrHPV testing during community health campaigns (CHCs), and hrHPV+ women were referred to government facilities for cryotherapy. For this analysis, we looked at rates of and predictors of presenting for treatment and presenting within 30 days of receiving positive hrHPV results ("timely" presentation). Data came from questionnaires completed at the time of screening and treatment. Multivariable logistic regression was used to identify factors associated with each outcome.ResultsOf the 505 hrHPV+ women, 266 (53%) presented for treatment. Cryotherapy was performed in 236 (89%) of the women who presented, while 30 (11%) were not treated: 15 (6%) due to gas outage, six (2%) due to pregnancy, five (2%) due to concern for cervical cancer, and four (2%) due to an unknown or other reason. After adjusting for other factors in the multivariable analysis, higher education level and missing work to come to the CHC were associated with presenting for treatment. Variables that were associated with increased likelihood of timely presentation were missing work to come to the CHC, absence of depressive symptoms, told by someone important to come to the CHC, and shorter distance to the treatment site.ConclusionThe majority of hrHPV+ women who did not get treated were lost at the stage of decision-making or accessing treatment, with a small number encountering barriers at the treatment sites. Patient education and financial support are potential areas for intervention to increase rates of hrHPV+ women seeking treatment.

Background The unmet surgical need, specifically neurosurgical need, in Uganda is significant, yet only 2 public hospitals currently perform neurosurgery in the country. This study examines the epidemiology and outcomes of neurosurgical conditions presenting to 1 of 12 regional referral hospitals in Uganda, in an effort to understand the neurosurgical needs of this population. Methods The study was conducted at Mbarara Regional Referral Hospital (MRRH), in southwestern Uganda. Demographics, clinical characteristics, and outcomes were retrospectively collected for all patients who presented to MRRH with a neurosurgical condition between January 2012 and September 2015. Results During the study period, 1854 patients presented to MRRH with a neurosurgical condition. More than half of the patients were between 19 and 40 years old, and the majority were males (76.1%). The overall median length of stay was 5 days (interquartile range: 2.5–10). The majority of admissions were due to trauma (87%), with almost 60% due to road traffic incidents. The overall mortality rate was 12.8%. A multivariable Cox proportional hazards model revealed that age, closed head injury, and admission Glasgow Coma Scale have a strong positive correlation with mortality while getting a diagnostic image and neurosurgical procedure were negatively correlated with mortality. Conclusion Traumatic brain injury represented the majority of neurosurgical admissions at MRRH, disproportionately affecting young males. Age, closed head injury, admission Glasgow Coma Scale, getting a diagnostic image, and neurosurgical procedure were all independent predictors of mortality. Resource appropriate interventions throughout the health system are needed to meet the demand and improve outcomes.

Traumatic brain injury (TBI) is a leading cause of death and disability. Patients with TBI in low and middle-income countries have worse outcomes than patients in high-income countries. We evaluated important clinical indicators associated with mortality for patients with TBI at University Teaching Hospital of Kigali, Kigali, Rwanda.A prospective consecutive sampling of patients with TBI presenting to University Teaching Hospital of Kigali Accident and Emergency Department was screened for inclusion criteria: reported head trauma, alteration in consciousness, headache, and visible head trauma. Exclusion criteria were age10 years,48 hours after injury, and repeat visit. Data were assessed for association with death using logistic regression. Significant variables were included in a multivariate logistic regression model and refined via backward elimination.Between October 7, 2013, and April 6, 2014, 684 patients were enrolled; 14 (2%) were excluded because of incomplete data. Of patients, 81% were male with mean age of 31 years (range, 10-89 years; SD 11.8). Most patients (80%) had mild TBI (Glasgow Coma Scale [GCS] score 13-15); 10% had moderate (GCS score 9-12) and 10% had severe (GCS score 3-8) TBI. Multivariate logistic regression determined that GCS score13, hypoxia, bradycardia, tachycardia, and age50 years were significantly associated with death.GCS score13, hypoxia, bradycardia, tachycardia, and age50 years were associated with mortality. These findings inform future research that may guide clinicians in prioritizing care for patients at highest risk of mortality.

Clostridium difficile infection (CDI) is a common cause of nosocomial diarrhea and colitis. The incidence and prognostic significance of thrombocytopenia as related to mode of acquisition (hospital vs. community), NAP1/027 strain, and disease severity has not been examined. We performed a single-institution retrospective analysis of all adult inpatients from 2013 to 2014 diagnosed with CDI during their hospitalization to document the incidence/prevalence of thrombocytopenia and associated outcomes. Severe disease was defined by a composite endpoint of inpatient death, death within 30 days of discharge, presence of septic shock, or need for colectomy during hospitalization. Of the 533 patients diagnosed with CDI, moderate thrombocytopenia (platelet count

International audience; Echocardiography is essential for the diagnosis and management of ă infective endocarditis (IE). However, the reproducibility for the ă echocardiographic assessment of variables relevant to IE is unknown. ă Objectives of this study were: (1) To define the reproducibility for IE ă echocardiographic variables and (2) to describe a methodology for ă assessing quality in an observational cohort containing site-interpreted ă data. IE reproducibility was assessed on a subset of echocardiograms ă from subjects enrolled in the International Collaboration on ă Endocarditis registry. Specific echocardiographic case report forms were ă used. Intra-observer agreement was assessed from six site readers on ten ă randomly selected echocardiograms. Inter-observer agreement between ă sites and an echocardiography core laboratory was assessed on a separate ă random sample of 110 echocardiograms. Agreement was determined using ă intraclass correlation (ICC), coverage probability (CP), and limits of ă agreement for continuous variables and kappa statistics ă (kappa(weighted)) and CP for categorical variables. Intra-observer ă agreement for LVEF was excellent [ICC = 0.93 +/- 0.1 and all pairwise ă differences for LVEF (CP) were within 10 %]. For IE categorical ă echocardiographic variables, intra-observer agreement was best for ă aortic abscess (kappa(weighted) = 1.0, CP = 1.0 for all readers). ă Highest inter-observer agreement for IE categorical echocardiographic ă variables was obtained for vegetation location (kappa(weighted) = 0.95; ă 95 % CI 0.92-0.99) and lowest agreement was found for vegetation ă mobility (kappa(weighted) = 0.69; 95 % CI 0.62-0.86). Moderate to ă excellent intra- and inter-observer agreement is observed for ă echocardiographic variables in the diagnostic assessment of IE. A ă pragmatic approach for determining echocardiographic data ă reproducibility in a large, multicentre, site interpreted observational ă cohort is feasible.

Background. Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and the primary cause of liver transplantation in the United States, and coinfection with human immunodeficiency virus (HIV) increases the risk of comorbidities. However, healthcare utilization (HCU) patterns among HIV/HCV-coinfected patients are poorly understood. This study compared the rates of HCU and reasons for hospital admission among HCV-infected, HIV-infected, and HIV/HCV-coinfected veterans. Methods. Hepatitis C virus- and HIV-infected and HIV/HCV-coinfected veterans in care with the Department of Veterans Affairs (VA) from 1998 to 2009 (n = 335 371, n = 28 179, n = 13 471, respectively) were identified by HIV- and HCV-associated International Classification of Diseases, Ninth Revision codes from the clinical case registry. We assessed rates of HCU using emergency department (ED) visits, outpatient visits, and hospitalization and primary diagnoses associated with hospitalization. Independent risk factors associated with hospitalization were also examined. Results. Rates of outpatient and ED visits increased over the 11-year study period for all groups, with inpatient admission rates remaining stable. The HCU rates were consistently higher for the coinfected than other cohorts. The primary reason for hospital admission for all groups was psychiatric disease/substance use, accounting for 44% of all admissions. Nadir CD4 500 cells/mm3. Conclusions. As the current population of HCV-infected, HIV-infected, and HIV/HCV-coinfected veterans age, they will continue to place a substantial and increasing demand on the US healthcare system, particularly in their utilization of ED and outpatient services. These data suggest the need for an ongoing investment in mental health and primary care within the VA healthcare system.

Background Host factors and complications have been associated with higher mortality in infective endocarditis ( IE ). We sought to develop and validate a model of clinical characteristics to predict 6‐month mortality in IE . Methods and Results Using a large multinational prospective registry of definite IE (International Collaboration on Endocarditis [ ICE ]–Prospective Cohort Study [ PCS ], 2000–2006, n=4049), a model to predict 6‐month survival was developed by Cox proportional hazards modeling with inverse probability weighting for surgery treatment and was internally validated by the bootstrapping method. This model was externally validated in an independent prospective registry ( ICE ‐ PLUS , 2008–2012, n=1197). The 6‐month mortality was 971 of 4049 (24.0%) in the ICE ‐ PCS cohort and 342 of 1197 (28.6%) in the ICE ‐ PLUS cohort. Surgery during the index hospitalization was performed in 48.1% and 54.0% of the cohorts, respectively. In the derivation model, variables related to host factors (age, dialysis), IE characteristics (prosthetic or nosocomial IE , causative organism, left‐sided valve vegetation), and IE complications (severe heart failure, stroke, paravalvular complication, and persistent bacteremia) were independently associated with 6‐month mortality, and surgery was associated with a lower risk of mortality (Harrell's C statistic 0.715). In the validation model, these variables had similar hazard ratios (Harrell's C statistic 0.682), with a similar, independent benefit of surgery (hazard ratio 0.74, 95% CI 0.62–0.89). A simplified risk model was developed by weight adjustment of these variables. Conclusions Six‐month mortality after IE is ≈25% and is predicted by host factors, IE characteristics, and IE complications. Surgery during the index hospitalization is associated with lower mortality but is performed less frequently in the highest risk patients. A simplified risk model may be used to identify specific risk subgroups in IE .

Staphylococcus aureus is the most common cause of both infective endocarditis (IE) [1] and soft tissue infection (STI) [2] in the industrialized world. The frequency of S. aureus as a human pathogen is thought to be due in part to its diverse armamentarium of virulence-associated genes. Although substantial evidence suggests that clinical manifestations of S. aureus are influenced by the genetic characteristics of the infecting strain [3–7], the association between S. aureus genes and severity of illness is incompletely understood. Previously, we demonstrated a significant association between specific S. aureus isolates genotypes and infection severity [4]. We used multilocus sequence typing (MLST) to show that clonal complex (CC) 5 and CC30 were significantly associated with the presence of IE and bone and joint infection among 371 clinically well-characterized S. aureus isolates from a single geographical region. However, these findings must be confirmed prior to being considered broadly generalizable. The current investigation seeks to externally validate these previously observed associations between bacterial genotype and infection severity in S. aureus. To do this, we used bacterial isolates from 2 large multinational cohorts of patients with distinct forms of staphylococcal disease: IE and STI.

We appreciate the thoughtful comments of Drs Almonedro-Delia, Galvez-Acebal, and Rodriguez-Bano regarding our recent publication, “Association Between Surgical Indications, Operative Risk, and Clinical Outcome in Infective Endocarditis: a Prospective Study From the International Collaboration on Endocarditis.”1 These authors raise important issues for evaluating the impact of surgery on patient outcomes, particularly survival. We strongly agree that treatment selection bias and survivor bias are major issues when evaluating the impact of surgery on mortality and that the use of appropriate statistical methodologies is necessary to quantify an unbiased and causal association of the effect of surgical treatment on outcome. In our previous studies on …

Background: Phenol-soluble modulins (PSM) are amphipathic proteins produced by Staphylococcus aureus that promote virulence, inflammatory response, and biofilm formation. We previously showed that MRSA isolates from soft tissue infection (SSTI) produced significantly higher levels of PSM than MRSA isolates from hospital-acquired pneumonia (HAP) or infective endocarditis (IE). In this investigation, we sought to validate this finding in methicillin-susceptible S. aureus (MSSA) isolates. Methods: MSSA isolates (n = 162) from patients with SSTI, HAP, and IE were matched 1:1:1 based on geographic origin of the infection to form 54 triplets (North America n = 27, Europe n = 25, Australia n = 2). All isolates underwent spa typing and were classified using eGenomics. In vitro PSM production was quantified by high-performance liquid chromatography/mass spectrometry. Fischer's Exact Test and the Kruskal-Wallis test were used for statistical analysis. Results: Spa1 was more common in SSTI (14.81% SSTI, 3.70% HAP, 1.85% IE) (< 0.03). Spa2 was more common in HAP (0% SSTI, 12.96% HAP, 3.70% IE) (< 0.01). Levels of PSMα1-all differed significantly among the three clinical groups, with SSTI isolates producing the highest levels and IE producing the lowest levels of PSMα1-4. Spa1 isolates produced significantly more delta-toxin (< 0.03) than non-Spa1 isolates. No associations between PSM levels and clinical outcome of SSTI, HAP, or IE were identified. Conclusion: Production of PSMα1-is highest in SSTI MSSA isolates, supporting the hypothesis that these peptides are important for SSTI pathogenesis. These findings are similar to those described in MRSA, and demonstrate that associations between PSM levels and type of infection are independent of the methicillin-resistance status of the isolate.

Background— Staphylococcus aureus left-sided native valve infective endocarditis (LNVIE) has higher complication and mortality rates compared with endocarditis from other pathogens. Whether echocardiographic variables can predict prognosis in S aureus LNVIE is unknown. Methods and Results— Consecutive patients with LNVIE, enrolled between January 2000 and September 2006, in the International Collaboration on Endocarditis were identified. Subjects without S aureus IE were matched to those with S aureus IE by the propensity of having S aureus . Survival differences were determined using log-rank significance tests. Independent echocardiographic predictors of mortality were identified using Cox-proportional hazards models that included inverse probability of treatment weighting and surgery as a time-dependent covariate. Of 727 subjects with LNVIE and 1-year follow-up, 202 had S aureus IE. One-year survival rates were significantly lower for patients with S aureus IE overall (57% S aureus IE versus 80% non- S aureus IE; P S aureus IE versus 68% non- S aureus IE; P P P =0.004) were the only independent echocardiographic predictors of in-hospital mortality in S aureus LNVIE. Valve perforation (hazard ratio, 2.16; 95% confidence interval, 1.21–3.68; P =0.006) and intracardiac abscess (hazard ratio, 2.25; 95% confidence interval, 1.26–3.78; P =0.004) were the only independent predictors of 1-year mortality. Conclusions— S aureus is an independent predictor of 1-year mortality in subjects with LNVIE. In S aureus LNVIE, intracardiac abscess and left ventricular ejection fraction

Phenol-soluble modulins (PSMs) are amphipathic, pro-inflammatory proteins secreted by most Staphylococcus aureus isolates. This study tested the hypothesis that in vitro PSM production levels are associated with specific clinical phenotypes.177 methicillin-resistant S. aureus (MRSA) isolates from infective endocarditis (IE), skin and soft tissue infection (SSTI), and hospital-acquired/ventilator-associated pneumonia (HAP) were matched by geographic origin, then genotyped using spa-typing. In vitro PSM production was measured by high performance liquid chromatography/mass spectrometry. Statistical analysis was performed using Chi-squared or Kruskal-Wallis tests as appropriate.Spa type 1 was significantly more common in SSTI isolates (62.7% SSTI; 1.7% IE; 16.9% HAP; p 0.0001) while HAP and IE isolates were more commonly spa type 2 (0% SSTI; 37.3% IE; 40.7% HAP; p 0.0001). USA300 isolates produced the highest levels of PSMs in vitro. SSTI isolates produced significantly higher quantities of PSMα1-4, PSMβ1, and δ-toxin than other isolates (p 0.001). These findings persisted when USA300 isolates were excluded from analysis.Increased in vitro production of PSMs is associated with an SSTI clinical source. This significant association persisted after exclusion of USA300 genotype isolates from analysis, suggesting that PSMs play a particularly important role in the pathogenesis of SSTI as compared to other infection types.

Previous studies have suggested that lead exposure may be associated with increased risk of amyotrophic lateral sclerosis (ALS). Polymorphisms in the genes for delta-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR) may affect susceptibility to lead exposure. We used data from a case-control study conducted in New England from 1993 to 1996 to evaluate the relationship of ALS to polymorphisms in ALAD and VDR and the effect of these polymorphisms on the association of ALS with lead exposure. The ALAD 2 allele (177G to C; K59N) was associated with decreased lead levels in both patella and tibia, although not in blood, and with an imprecise increase in ALS risk [odds ratio (OR) = 1.9; 95% confidence interval (95% CI), 0.60-6.3]. We found a previously unreported polymorphism in ALAD at an Msp1 site in intron 2 (IVS2+299G>A) that was associated with decreased bone lead levels and with an imprecise decrease in ALS risk (OR = 0.35; 95% CI, 0.10-1.2). The VDR B allele was not associated with lead levels or ALS risk. Our ability to observe effects of genotype on associations of ALS with occupational exposure to lead or with blood or bone lead levels was limited. These findings suggest that genetic susceptibility conferred by polymorphisms in ALAD may affect ALS risk, possibly through a mechanism related to internal lead exposure.

International audience; Background - The impact of early valve surgery (EVS) on the outcome of Staphylococcus aureus (SA) prosthetic valve infective endocarditis (PVIE) is unresolved. The objective of this study was to evaluate the association between EVS, performed within the first 60 days of hospitalization, and outcome of SA PVIE within the International Collaboration on Endocarditis-Prospective Cohort Study. Methods - Participants were enrolled between June 2000 and December 2006. Cox proportional hazards modeling that included surgery as a time-dependent covariate and propensity adjustment for likelihood to receive cardiac surgery was used to evaluate the impact of EVS and 1-year all-cause mortality on patients with definite left-sided S. aureus PVIE and no history of injection drug use. Results - EVS was performed in 74 of the 168 (44.3%) patients. One-year mortality was significantly higher among patients with S. aureus PVIE than in patients with non-S. aureus PVIE (48.2% vs 32.9%; P = .003). Staphylococcus aureus PVIE patients who underwent EVS had a significantly lower 1-year mortality rate (33.8% vs 59.1%; P = .001). In multivariate, propensity-adjusted models, EVS was not associated with 1-year mortality (risk ratio, 0.67 [95% confidence interval, .39-1.15]; P = .15). Conclusions - In this prospective, multinational cohort of patients with S. aureus PVIE, EVS was not associated with reduced 1-year mortality. The decision to pursue EVS should be individualized for each patient, based upon infection-specific characteristics rather than solely upon the microbiology of the infection causing PVIE.

The validity of the reported high prevalence of left ventricular hypertrophy (LVH) among African-American men and women has been questioned owing to conflicting echocardiographic evidence. We used echocardiographic left ventricular mass (LVM) from M-mode measurements to evaluate associations between LVM, body size, and electrocardiographic (ECG) variables in 3,627 white and African-American men and women 65 years of age and older who were participants of the Cardiovascular Health Study (CHS), a multicenter cohort study of risk factors for coronary heart disease and stroke. ECG amplitudes used in LVH criteria were substantially higher in African-Americans, with apparent LVH prevalence 2 to 3 times higher in African American men and women than in white men and women, although there was no significant racial difference in echocardiographic LVM. The higher apparent LVH prevalence by Sokolow-Lyon criteria in African-American men is in part owing to smaller lateral chest diameter. In women, reasons for racial differences in ECG LVH prevalence remain largely unexplained although a small part of the excess LVH in African-American women by the Sokolow-Lyon criteria appears to be owing to a larger lateral chest semidiameter in white women. ECG variables alone were too inaccurate for LVM prediction, and it was necessary to incorporate in all ECG models body weight that was properly adjusted for race and sex. This resulted in modest LVM prediction accuracy, with R-square values ranging from .22 to .36. Race- and sex-specific ECG models introduced for LVM estimation with an appropriate adjustment for body size differences are expected to facilitate evaluation of LVH status in contrasting racial population groups.

Electrocardiographic (ECG) manifestations of clinical and subclinical cardiovascular disease are used as an important component in the evaluation of clinical trials, and there is an increasing demand for well-defined criteria for clinically significant evolution of ECG abnormalities. The Novacode ECG classification system provides a comprehensive hierarchical set of criteria for prevalent ECG abnormalities and for clinically significant serial ECG changes, both adverse and favorable, as a response to pharmacologic, surgical, and other interventions. These criteria are used to grade Q wave and ischemic abnormalities in order to achieve stable classification of both prevalent and incident myocardial infarctions by minimizing false classifications due to clinically insignificant ECG variations. This approach differs from the traditional Minnesota Code classification system, in which incident events are determined by changes in classification categories, with the application of additional elaborate validation rules to exclude frequent false classifications. Novacode hierarchy is so structured that for each abnormality, a general class is first determined with the simplest possible classification criteria and more specific abnormality subgroups are then classified with more elaborate criteria. This approach will satisfy differing needs of clinical trials for detail in classification. Explicit definition of ECG variables and condition statements for the classification criteria facilitate implementation of the Novacode with computer ECG programs.

Cigarette smoking as a risk factor in progression of HIV-1 disease was investigated in the Multicenter AIDS Cohort Study of homosexual men. Longitudinal data for T-cell subsets, HIV-related clinical symptoms, smoking behavior, and AIDS medication use were collected semiannually from 2,499 HIV-1-seropositive men for up to 9 years. Survival methods, including Kaplan-Meier analysis and multivariate Cox regression models, were used to assess the effect of cigarette smoking on development of Pneumocystis carinii pneumonia (PCP), AIDS, death, and self-reported oral thrush. After adjustment for CD4+ lymphocyte count and use of antiretroviral and anti-PCP medications, smoking was not significantly associated with progression to PCP, AIDS, or death in either the HIV-seroprevalent or-seroincident cohort members. Among men who had baseline CD4+ cell counts > 200/microliter, smoking was associated with a 40% increase in the hazard of oral thrush (p < or = 0.01). These data indicate that cigarette smoking does not have a major effect on the progression of HIV-1 infection to AIDS or death but may affect the incidence of oral thrush.

The use of daptomycin in Gram-positive left-sided infective endocarditis (IE) has significantly increased. The purpose of this study was to assess the influence of high-dose daptomycin on the outcome of left-sided IE due to Gram-positive pathogens. This was a prospective cohort study based on 1,112 cases from the International Collaboration on Endocarditis (ICE)-Plus database and the ICE-Daptomycin Substudy database from 2008 to 2010. Among patients with left-sided IE due to Staphylococcus aureus , coagulase-negative staphylococci, and Enterococcus faecalis , we compared those treated with daptomycin (cohort A) to those treated with standard-of-care (SOC) antibiotics (cohort B). The primary outcome was in-hospital mortality. Time to clearance of bacteremia, 6-month mortality, and adverse events (AEs) ascribable to daptomycin were also assessed. There were 29 and 149 patients included in cohort A and cohort B, respectively. Baseline comorbidities did not differ between the two cohorts, except for a significantly higher prevalence of diabetes and previous episodes of IE among patients treated with daptomycin. The median daptomycin dose was 9.2 mg/kg of body weight/day. Two-thirds of the patients treated with daptomycin had failed a previous antibiotic regimen. In-hospital and 6-month mortalities were similar in the two cohorts. In cohort A, median time to clearance of methicillin-resistant S. aureus (MRSA) bacteremia was 1.0 day, irrespective of daptomycin dose, representing a significantly faster bacteremia clearance compared to SOC (1.0 versus 5.0 days; P < 0.01). Regimens with higher daptomycin doses were not associated with increased incidence of AEs. In conclusion, higher-dose daptomycin may be an effective and safe alternative to SOC in the treatment of left-sided IE due to common Gram-positive pathogens.

Leukocyte counts and differentials are commonly acquired in patients with suspected respiratory viral infections and may contribute diagnostic information. However, most published work is limited to a single timepoint at initial presentation to a medical provider, which may correspond to widely varying points in the course of disease.To examine the temporal development and time-dependent utility of routine leukocyte differentials in the diagnosis of respiratory viral infections.We analyzed data from recent experimental human challenges with influenza A/H3N2, human rhinovirus (HRV), and respiratory syncytial virus (RSV). Routine clinical lab cell counts and differentials were measured daily from the time period immediately prior to inoculation through the eventual resolution of symptomatic disease.Approximately 50% of challenged individuals developed symptoms and viral shedding consistent with clinical disease. Subpopulations of WBC showed marked differences between symptomatic and asymptomatic individuals over time, but these changes were much more profound and consistent in influenza infection. Influenza-infected subjects develop both relative lymphopenia and relative monocytosis, both of which closely mirror symptom development in time. A lymphocyte:monocyte ratio of2 correctly classifies 100% of influenza (but not RSV or HRV) infected subjects at the time of maximal symptoms.Leukocyte differentials may suggest a viral etiology in patients with upper respiratory infection, but are not sufficient to allow differentiation between common viruses. Timing of data acquisition relative to the disease course is a key component in determining the utility of these tests.

Health care utilization for HIV-1-infected patients appears to be declining in the United States as a result of highly active antiviral therapy (HAART); yet the opposite appears true in the HIV/hepatitis C virus (HCV) coinfected population. The reasons for this difference are not well understood. We examined the rates and reasons for emergency department visits and hospital admissions at an academic tertiary care medical center for HIV/HCV coinfected patients as compared to HIV-1 monoinfected patients, using a retrospective matched cohort study design. HIV/HCV coinfected patients had higher rates of health care utilization (emergency department visits 43.9 versus 7.1 per 100 person-years; hospital admissions 18.2 versus 6.7 per 100 person-years, for HIV coinfected and monoinfected, respectively). This increase was not solely due to liver related events. Instead, comorbidities such as diabetes, renal disease, and psychiatric/substance abuse played a larger role in the health-care utilization in the HIV/HCV coinfected population.

Background: Using demographic and clinical measures from emergency department evaluations, we developed an automated surveillance system for influenza-like illness (ILI). Methods: We selected a random sample of patients who were seen at the Durham, NC Veterans Affairs Medical Center between May 2002 and October 2009 with fever or a respiratory ICD-9 diagnosis code and divided this into subsets for system development and validation. Comprehensive chart reviews identified patients who met a standard case definition for ILI. Logistic regression models predicting ILI were fit in the development sample. We applied the parameter estimates from these models to the validation sample and evaluated their utility using receiver-operator characteristic analysis. Results: The models discriminated ILI very well in the validation sample; the C-statistics were > 0.89. Conclusions: Risk estimates based on statistical models can be incorporated into electronic medical records systems to assist clinicians and could be used in real-time surveillance for disease outbreaks. Keywords: influenza-like illness; population surveillance; predictive modeling (Published: 20 April 2011) Citation: Emerging Health Threats Journal 2011, 4 : 7108 - DOI: 10.3402/ehtj.v4i0.7108

Previous family and twin studies indicate that genetic variation makes an important contribution to individual variation in high density lipoprotein cholesterol (HDL) levels, even after adjusment for covariates (such as obesity and alcohol consumption) that also cluster in families. However, most studies assume that genetic mechanisms affecting variation in HDL level are the same in all subgroups of the population (e.g., men versus women, by age). Using data from the Kaiser-Permanente Women Twins Study, we found different patterns of clustering for monozygotic (MZ) and dizygotic (DZ) twins depending on menopausal status

Background Circulating biomarkers can facilitate sepsis diagnosis, enabling early management and improved outcomes. Procalcitonin (PCT) has been suggested to have superior diagnostic utility compared to other biomarkers. Study Objectives To define the discriminative value of PCT, interleukin-6 (IL-6), and C-reactive protein (CRP) for suspected sepsis. Methods PCT, CRP, and IL-6 were correlated with infection likelihood, sepsis severity, and septicemia. Multivariable models were constructed for length-of-stay and discharge to a higher level of care. Results Of 336 enrolled subjects, 60% had definite infection, 13% possible infection, and 27% no infection. Of those with infection, 202 presented with sepsis, 28 with severe sepsis, and 17 with septic shock. Overall, 21% of subjects were septicemic. PCT, IL6, and CRP levels were higher in septicemia (median PCT 2.3 vs. 0.2 ng/mL; IL-6 178 vs. 72 pg/mL; CRP 106 vs. 62 mg/dL; p < 0.001). Biomarker concentrations increased with likelihood of infection and sepsis severity. Using receiver operating characteristic analysis, PCT best predicted septicemia (0.78 vs. IL-6 0.70 and CRP 0.67), but CRP better identified clinical infection (0.75 vs. PCT 0.71 and IL-6 0.69). A PCT cutoff of 0.5 ng/mL had 72.6% sensitivity and 69.5% specificity for bacteremia, as well as 40.7% sensitivity and 87.2% specificity for diagnosing infection. A combined clinical-biomarker model revealed that CRP was marginally associated with length of stay (p = 0.015), but no biomarker independently predicted discharge to a higher level of care. Conclusions In adult emergency department patients with suspected sepsis, PCT, IL-6, and CRP highly correlate with several infection parameters, but are inadequately discriminating to be used independently as diagnostic tools.

Sepsis is caused by a heterogeneous group of infectious etiologies. Early diagnosis and the provision of appropriate antimicrobial therapy correlate with positive clinical outcomes. Current microbiological techniques are limited in their diagnostic capacities and timeliness. Multiplex PCR has the potential to rapidly identify bloodstream infections and fill this diagnostic gap. We identified patients from two large academic hospital emergency departments with suspected sepsis. The results of a multiplex PCR that could detect 25 bacterial and fungal pathogens were compared to those of blood culture. The results were analyzed with respect to the likelihood of infection, sepsis severity, the site of infection, and the effect of prior antibiotic therapy. We enrolled 306 subjects with suspected sepsis. Of these, 43 were later determined not to have infectious etiologies. Of the remaining 263 subjects, 70% had sepsis, 16% had severe sepsis, and 14% had septic shock. The majority had a definite infection (41.5%) or a probable infection (30.7%). Blood culture and PCR performed similarly with samples from patients with clinically defined infections (areas under the receiver operating characteristic curves, 0.64 and 0.60, respectively). However, blood culture identified more cases of septicemia than PCR among patients with an identified infectious etiology (66 and 46, respectively; P = 0.0004). The two tests performed similarly when the results were stratified by sepsis severity or infection site. Blood culture tended to detect infections more frequently among patients who had previously received antibiotics ( P = 0.06). Conversely, PCR identified an additional 24 organisms that blood culture failed to detect. Real-time multiplex PCR has the potential to serve as an adjunct to conventional blood culture, adding diagnostic yield and shortening the time to pathogen identification.

Aggressive diagnosis and treatment of patients presenting to the emergency department (ED) with septic shock has been shown to reduce mortality. To enhance the ability to intervene in patients with lesser illness severity, a better understanding of the natural history of the early progression from simple infection to more severe illness is needed.The objectives were to 1) describe the clinical presentation of ED sepsis, including types of infection and causative microorganisms, and 2) determine the incidence, patient characteristics, and mortality associated with early progression to septic shock among ED patients with infection.This was a multicenter study of adult ED patients with sepsis but no evidence of shock. Multivariable logistic regression was used to identify patient factors for early progression to shock and its association with 30-day mortality.Of 472 patients not in shock at ED presentation (systolic blood pressure90 mm Hg and lactate4 mmol/L), 84 (17.8%) progressed to shock within 72 hours. Independent factors associated with early progression to shock included older age, female sex, hyperthermia, anemia, comorbid lung disease, and vascular access device infection. Early progression to shock (vs. no progression) was associated with higher 30-day mortality (13.1% vs. 3.1%, odds ratio [OR] = 4.72, 95% confidence interval [CI] = 2.01 to 11.1; por = 0.001). Among 379 patients with uncomplicated sepsis (i.e., no evidence of shock or any end-organ dysfunction), 86 (22.7%) progressed to severe sepsis or shock within 72 hours of hospital admission.A significant portion of ED patients with less severe sepsis progress to severe sepsis or shock within 72 hours. Additional diagnostic approaches are needed to risk stratify and more effectively treat ED patients with sepsis.