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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.

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.

The contribution of respiratory viruses to acute febrile illness (AFI) burden is poorly characterized. We describe the prevalence, seasonality, and clinical features of respiratory viral infection among AFI admissions in Sri Lanka. We enrolled AFI patients ≥ 1 year of age admitted to a tertiary care hospital in southern Sri Lanka, June 2012-October 2014. We collected epidemiologic/clinical data and a nasal or nasopharyngeal sample that was tested using polymerase chain reaction (Luminex NxTAG, Austin, TX). We determined associations between weather data and respiratory viral activity using the Spearman correlation and assessed respiratory virus seasonality using a Program for Appropriate Technology definition. Bivariable and multivariable regression analyses were conducted to identify features associated with respiratory virus detection. Among 964 patients, median age was 26.2 years (interquartile range 14.6-39.9) and 646 (67.0%) were male. One-fifth (203, 21.1%) had respiratory virus detected: 13.9% influenza, 1.4% human enterovirus/rhinovirus, 1.4% parainfluenza virus, 1.1% respiratory syncytial virus, and 1.1% human metapneumovirus. Patients with respiratory virus identified were younger (median 9.8 versus 27.7 years, P < 0.001) and more likely to have respiratory signs and symptoms. Influenza A and respiratory viral activity peaked in February-June each year. Maximum daily temperature was associated with influenza and respiratory viral activity (P = 0.03 each). Patients with respiratory virus were as likely as others to be prescribed antibiotics (55.2% versus 52.6%, P = 0.51), and none reported prior influenza vaccination. Respiratory viral infection was a common cause of AFI. Improved access to vaccines and respiratory diagnostics may help reduce disease burden and inappropriate antibiotic use.

Preventing burnout and promoting positive mental health among medical students is important. Relevant research is lacking on positive mental health in medical students, particularly in low- and middle-income countries. We conducted a cross-sectional survey of Sri Lankan students enrolled in a five-year medical program. Measures included the Mental Health Continuum-Short Form, Kessler 10 Psychological Distress Scale, and Oldenburg Burnout Inventory. We investigated relationships between year in program, mental health indicators, and academic performance. Three hundred twenty-seven students participated (35% response rate). Most students had moderate positive mental health (64.8%) and severe psychological distress (40.4%). Final year students reported more psychological distress and burnout than first year students. Female students had higher burnout scores than males. In multivariable models, fourth and fifth year students evidenced lower positive mental health than first year students. Mental health indicators were unassociated with academic performance. Overall, distress rates were higher than those reported among students in other countries. Higher burnout and distress may be driven by increased responsibilities in the final clinical years of training. Bolstering positive mental health through positive emotions, meaning, and social connection may minimize burnout and distress, although extracurricular activities require time. Interventions to reduce medical student distress in Sri Lanka are needed.

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 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.

Summary Background Early and accurate identification of individuals with viral infections is crucial for clinical management and public health interventions. We aimed to assess the ability of transcriptomic biomarkers to identify naturally acquired respiratory viral infection before typical symptoms are present. Methods In this index-cluster study, we prospectively recruited a cohort of undergraduate students (aged 18–25 years) at Duke University (Durham, NC, USA) over a period of 5 academic years. To identify index cases, we monitored students for the entire academic year, for the presence and severity of eight symptoms of respiratory tract infection using a daily web-based survey, with symptoms rated on a scale of 0–4. Index cases were defined as individuals who reported a 6-point increase in cumulative daily symptom score. Suspected index cases were visited by study staff to confirm the presence of reported symptoms of illness and to collect biospecimen samples. We then identified clusters of close contacts of index cases (ie, individuals who lived in close proximity to index cases, close friends, and partners) who were presumed to be at increased risk of developing symptomatic respiratory tract infection while under observation. We monitored each close contact for 5 days for symptoms and viral shedding and measured transcriptomic responses at each timepoint each day using a blood-based 36-gene RT-PCR assay. Findings Between Sept 1, 2009, and April 10, 2015, we enrolled 1465 participants. Of 264 index cases with respiratory tract infection symptoms, 150 (57%) had a viral cause confirmed by RT-PCR. Of their 555 close contacts, 106 (19%) developed symptomatic respiratory tract infection with a proven viral cause during the observation window, of whom 60 (57%) had the same virus as their associated index case. Nine viruses were detected in total. The transcriptomic assay accurately predicted viral infection at the time of maximum symptom severity (mean area under the receiver operating characteristic curve [AUROC] 0·94 [95% CI 0·92–0·96]), as well as at 1 day (0·87 [95% CI 0·84–0·90]), 2 days (0·85 [0·82–0·88]), and 3 days (0·74 [0·71–0·77]) before peak illness, when symptoms were minimal or absent and 22 (62%) of 35 individuals, 25 (69%) of 36 individuals, and 24 (82%) of 29 individuals, respectively, had no detectable viral shedding. Interpretation Transcriptional biomarkers accurately predict and diagnose infection across diverse viral causes and stages of disease and thus might prove useful for guiding the administration of early effective therapy, quarantine decisions, and other clinical and public health interventions in the setting of endemic and pandemic infectious diseases. Funding US Defense Advanced Research Projects Agency.

ObjectivesThe role of follow-up blood cultures (FUBCs) in the management of Gram-negative bacteraemia (GNB) is poorly understood. We aimed to determine the utility of FUBCs in identifying patients with increased mortality risk.MethodsAn observational study with a prospectively enrolled cohort of adult inpatients with GNB was conducted at Duke University Health System from 2002 to 2015. FUBCs were defined as blood cultures performed from 24hours to 7days from initial positive blood culture.ResultsAmong 1702 patients with GNB, 1164 (68%) had FUBCs performed. When performed, FUBCs were positive in 20% (228/1113) of cases. FUBC acquisition was associated with lower all-cause in-hospital mortality (108/538, 20%, vs. 176/1164, 15%; p 0.01) and attributable in-hospital mortality (78/538, 15%, vs. 98/1164, 8%; p&nbsp

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.

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.

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 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

Farmworkers experience many work-related hazards, including exposure to neurotoxicants. We compared neurobehavioral performance of 288 farmworkers in central Florida who had done farm work for at least 1 month with 51 controls who had not. Most of the farmworkers had worked in one or more of three types of agriculture: ornamental ferns, nurseries, or citrus fruit. We collected information on farm work history in a structured interview and evaluated neurobehavioral performance using a battery of eight tests. Analyses were adjusted for established confounders including age, sex, education, and acculturation. Ever having done farm work was associated with poor performance on four tests--digit span [odds ratio (OR) = 1.90; 95% confidence interval (CI), 1.02-3.53], tapping (coefficient = 4.13; 95% CI, 0.00-8.27), Santa Ana test (coefficient = 1.34; 95% CI, 0.29-2.39), and postural sway (coefficient = 4.74; 95% CI, -2.20 to 11.7)--but had little effect on four others: symbol digit latency, vibrotactile threshold, visual contrast sensitivity, and grip strength. Associations with farm work were similar in magnitude to associations with personal characteristics such as age and sex. Longer duration of farm work was associated with worse performance. Associations with fern work were more consistent than associations with nursery or citrus work. Deficits related to the duration of work experience were seen in former as well as current farmworkers, and decreased performance was related to chronic exposure even in the absence of a history of pesticide poisoning. We conclude that long-term experience of farm work is associated with measurable deficits in cognitive and psychomotor function.

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.

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 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.

Zidovudine has been shown to prolong survival in patients with the acquired immunodeficiency syndrome (AIDS) and, in persons with human immunodeficiency virus (HIV) infection but not AIDS, to delay the progression to AIDS. However, it is still uncertain whether treatment before the development of AIDS prolongs survival.We analyzed data from a cohort of 2162 high-risk men who were already seropositive for HIV type 1 (HIV-1) and 406 men who seroconverted from October 1986 through April 1991. There were 306 deaths. The probabilities of death were compared among men at similar stages of disease who began zidovudine therapy before the diagnosis of AIDS and among those who did not. Relative risks of death were calculated for each of five initial disease states on the basis of CD4+ cell counts and clinical symptoms and signs appearing over follow-up periods of 6, 12, 18, and 24 months. Adjustments were also made for the use of prophylaxis against Pneumocystis carinii pneumonia (PCP).After we controlled for CD4+ cell count and symptoms, the use of zidovudine with or without PCP prophylaxis before the development of AIDS significantly reduced mortality in all follow-up periods. The relative risks of death were 0.43 (95 percent confidence interval, 0.23 to 0.78) at 6 months, 0.54 (95 percent confidence interval, 0.38 to 0.78) at 12 months, 0.59 (95 percent confidence interval, 0.44 to 0.79) at 18 months, and 0.67 (95 percent confidence interval, 0.52 to 0.86) at 24 months. After we adjusted for the effects of PCP prophylaxis, zidovudine alone significantly reduced mortality at 6, 12, and 18 months (relative risks, 0.45, 0.59, and 0.70, respectively), but not at 24 months (relative risk, 0.81). Among zidovudine users, those who also used PCP prophylaxis before the development of AIDS had significantly lower mortality at 18 and 24 months than those who did not (relative risks, 0.62 and 0.60, respectively).The results of this study support the hypothesis that in HIV-1 infection, early treatment with zidovudine and PCP prophylaxis improves survival in addition to slowing the progression to AIDS.

International audience; BACKGROUND: The significance of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) is unknown. Using a multinational collection of isolates from methicillin-resistant S. aureus (MRSA) infective endocarditis (IE), we characterized patients with IE with and without hVISA, and we genotyped the infecting strains. METHODS: MRSA bloodstream isolates from 65 patients with definite IE from 8 countries underwent polymerase chain reaction (PCR) for 31 virulence genes, pulsed-field gel electrophoresis, and multilocus sequence typing. hVISA was defined using population analysis profiling. RESULTS: Nineteen (29.2%) of 65 MRSA IE isolates exhibited the hVISA phenotype by population analysis profiling. Isolates from Oceania and Europe were more likely to exhibit the hVISA phenotype than isolates from the United States (77.8% and 35.0% vs 13.9%; P < .001). The prevalence of hVISA was higher among isolates with a vancomycin minimum inhibitory concentration of 2 mg/L (P = .026). hVISA-infected patients were more likely to have persistent bacteremia (68.4% vs 37.0%; P = .029) and heart failure (47.4% vs 19.6%; P = .033). Mortality did not differ between hVISA- and non-hVISA-infected patients (42.1% vs 34.8%, P = .586). hVISA and non-hVISA isolates were genotypically similar. CONCLUSIONS: In these analyses, the hVISA phenotype occurred in more than one-quarter of MRSA IE isolates, was associated with certain IE complications, and varied in frequency by geographic region.

HLA-specific antibodies (HSA) and soluble CD30 (sCD30) were measured in 208 renal transplant recipients with functioning grafts at least 1 year after transplantation (median 8.2 years) to investigate the predictive value of HSA and sCD30 on subsequent graft outcome. HSA (class I and class II) were detected by both ELISA LAT-M and Luminex LabScreen assays. Data on graft outcome was collected with a median follow-up time of 3.5 years after antibody and sCD30 measurement. Recipients with post-transplant HLA class II antibodies had particularly poor graft outcome with a hazard ratio (HR) of 7.8 (p < 0.0001) when detected by ELISA, and a HR of 6.0 (p < 0.0001) when detected by Luminex. A high post-transplant sCD30 level ≥100 U/mL was associated with increased risk of subsequent graft failure (HR 2.7, p = 0.03). sCD30 and HSA had an independent and additive association with graft outcome. Recipients with HLA class II antibody and high sCD30 had the highest risk of subsequent graft failure (HR 43.4, p < 0.0001 and HR 18.1, p = 0.0008 for ELISA and Luminex, respectively). These data show that detection of HSA and serum sCD30 measured at least 1-year post-transplant provides valuable and predictive information regarding subsequent graft outcome.

Background Nonsynonymous single nucleotide polymorphisms (SNPs) in fibronectin binding protein A (fnbA) of Staphylococcus aureus are associated with cardiac device infections. However, the role of fnbA SNPs in S. aureus arthroplasty infection is unknown. Methods Bloodstream S. aureus isolates from a derivation cohort of patients at a single U.S. medical center with S. aureus bacteremia (SAB) and prosthetic hip or knee arthroplasties that were infected (PJI, n = 27) or uninfected (PJU, n = 43) underwent sequencing of fnbA and fnbB. A validation cohort of S. aureus bloodstream PJI (n = 12) and PJU (n = 58) isolates from Germany also underwent fnbA and fnbB sequencing. Results Overall, none of the individual fnbA or fnbB SNPs were significantly associated with the PJI or PJU clinical groups within the derivation cohort. Similarly, none of the individual fnbA or fnbB SNPs were associated with PJI or PJU when the analysis was restricted to patients with either early SAB (i.e., bacteremia occurring 1 year after placement or manipulation of prostheses). Conclusions In contrast to cardiac device infections, there is no association between nonsynonymous SNPs in fnbA or fnbB of bloodstream S. aureus isolates and arthroplasty infection. These results suggest that initial steps leading to S. aureus infection of cardiovascular and orthopedic prostheses may arise by distinct processes.

Cellular immune responses are an important correlate of hepatitis C virus (HCV) infection outcome. These responses are governed by the host's human leukocyte antigen (HLA) type, and HLA-restricted viral escape mutants are a critical aspect of this host-virus interaction. We examined the driving forces of HCV evolution by characterizing the in vivo selective pressure(s) exerted on single amino acid residues within nonstructural protein 3 (NS3) by the HLA types present in two host populations. Associations between polymorphisms within NS3 and HLA class I alleles were assessed in 118 individuals from Western Australia and Switzerland with chronic hepatitis C infection, of whom 82 (69%) were coinfected with human immunodeficiency virus. The levels and locations of amino acid polymorphisms exhibited within NS3 were remarkably similar between the two cohorts and revealed regions under functional constraint and selective pressures. We identified specific HCV mutations within and flanking published epitopes with the correct HLA restriction and predicted escaped amino acid. Additional HLA-restricted mutations were identified that mark putative epitopes targeted by cell-mediated immune responses. This analysis of host-virus interaction reveals evidence of HCV adaptation to HLA class I-restricted immune pressure and identifies in vivo targets of cellular immune responses at the population level.

Continuing uncertainty exists about standardized procedures for the placement of electrocardiographic (ECG) chest electrodes, technical variability being the largest error source for short-term variations in amplitudes and waveforms of the chest lead ECGs. To avoid presumed attenuation of ECG amplitudes by abundant breast tissue, anterolateral chest electrodes in women are often placed under the breasts and too low. There is also considerable uncertainty about locating the midclavicular line and the V4 electrode, particularly in obese persons and in women. We examined the effect of breast tissue protuberance on ECG amplitudes using ECG and anthropometric data on 6,814 women included in the Atherosclerosis Research in Communities Study (ARIC). The R wave amplitudes in anterolateral chest leads and the Sokolow-Lyon voltage decreased (P < .001 for all), and RaVL and the Cornell voltage increased significantly with increasing breast protuberance (P < .001 for all). However, these effects were small (15 microV or less for each 1-cm increment in breast protuberance), and R2 values were less than .01, indicating that breast protuberance alone explained less than 1% of ECG amplitude variations. When chest size and breast protuberance estimates were entered simultaneously into a multivariate regression model, chest size appeared to dominate, and model R2 values increased for positive associations with RaVL (R2 = .12) and the Cornell voltage (R2 = .04). Combined model R2 values remained < or =.01 for all other ECG amplitudes. A detailed step-by-step standardized electrode placement procedure was formulated. Because of the difficulties encountered in locating the left midclavicular line by visual inspection, we introduced well-defined procedures for identification and documentation of lateral chest electrode placement locations as a quality control method for clinical trials. Population data from the Third National Health and Nutrition Survey on the distributions by sex and race of chest electrode V4 and V6 locations and anthropometric data on chest size and shape are presented in order to facilitate evaluation of the comparability of electrode placement procedures in various studies and for quality control in clinical trials. It is concluded that standardized procedures to document chest electrode placement locations are feasible. Breast tissue appears to have a practically negligible effect on ECG amplitudes, and in women, the placement of chest electrodes on the breast rather than under the breast is recommended in order to facilitate the precision of electrode placement at the correct horizontal level and at the correct lateral positions.

Major histocompatibility complex (MHC) genes (HLA in humans) regulate the immune response to foreign antigens. Molecular and serologic techniques were used to identify products of HLA class I, class II and transporter (TAP) genes (also part of the MHC) in homosexual seroconverters to human immunodeficiency virus type 1 (HIV-1). Comprehensive statistical analysis produced an HLA profile that predicted time from HIV-1 infection to the onset of AIDS. The profile was developed in a cohort of 139 men and evaluated in a second unrelated cohort of 102 men. In the evaluation cohort, the profile discriminated a sixfold difference between groups with the shortest and longest times to AIDS (P = 0.001). These findings support current theory about control of antigen processing by HLA genes and have implications for immunopathogenesis of HIV-1 and other infections.

Considerable efforts have been invested recently to improve electrocardiographic (ECG) classification accuracy for left ventricular hypertrophy (LVH). This study examines how LVH classification accuracy is influenced by (1) the selection of an echocardiographic standard for LVH, (2) LVH severity level in the test groups, and (3) the adjustment of LVH criteria for obesity and age. Using data obtained from large, community-based populations, this study explores prospects for improving ECG models for LVH classification and examines some of the general characteristics of newer ECG models for estimating left ventricular mass (LVM) on a continuous scale. The results indicate that the apparent ECG classification accuracy for LVH is substantially influenced by echocardiographic standards and criteria for LVH, LVH severity level, and selection criteria for test populations, and these differences explain some of the often substantial differences in test results from clinical versus community-based evaluation studies. The low reproducibility of echocardiographic LVM as the standard is a limiting factor in attempts to improve ECG criteria for LVH and LVM prediction models. Adjustment of ECG amplitudes to anthropometric factors that simultaneously influence LVM may result in confounding effects and may lead to the development of inappropriate models. The performance of ECG models for LVM prediction improved substantially by the inclusion of body weight as a covariate with ECG variables. The addition of standing height and various covariates reflecting obesity did not improve LVM prediction accuracy. Compared to the older LVM prediction models of the Novacode ECG program, the correlation between echocardiographic and ECG estimates of LVM increased sufficiently (from 0.33 to 0.54 in women and from 0.46 to 0.62 in men) to suggest that these improved ECG models are suitable for monitoring LVH progression/ regression in study groups participating in hypertension intervention trials.

Changes in the use of antiretroviral drugs and factors associated with changes from monotherapy with zidovudine (ZDV) to other regimens were quantified in the Multicenter AIDS Cohort Study. Participants who had been receiving monotherapy with ZDV were categorized as (1) discontinuing ZDV monotherapy ; (2) switching to didanosine (ddl), zalcitabine (ddC), or stavudine (d4T) monotherapy ; (3) switching to combination therapy (ZDV with ddl, ddC, or d4T) ; or (4) continuing ZDV monotherapy. From 1990 to 1994, the percentage of participants using ZDV monotherapy decreased from 27% to 17% (among participants without AIDS) and from 60% to 17% (among those with AIDS). At the same time, the proportion of participants using combination therapy increased from zero to 11% (no AIDS) and from 2% to 21% (AIDS), and the proportion switching to a different monotherapy increased from zero to 8% (no AIDS) and from 8% to 26% (AIDS). Polychotomous logistic regression methods were used to identify the factors predicting changes from ZDV monotherapy. Among participants without AIDS, indicators of drug failure (such as a lower CD4 lymphocyte count or symptoms of human immunodeficiency virus type 1 infection) were predictive of the initiation of combination therapy, while among patients with AIDS they were predictive of a switch to an alternative monotherapy. A decrease in hemoglobin levels, a marker of ZDV toxicity, was predictive for all patients of a switch to other monotherapy. In addition, private health insurance coverage was associated with reduced odds of the discontinuation of antiretroviral therapy. These data show that clinicians and patients are opting for more aggressive antiretroviral regimens and that changes in CD4 lymphocyte count and in the status of symptoms remain the primary guides for changes in therapy.

To clarify useful clinical parameters for determining the need for changes in antiretroviral regimens, 586 persons who were seropositive for the human immunodeficiency virus (HIV) and who had intermediate-stage HIV disease underwent follow-up semiannually for a median of 3.1 years after zidovudine monotherapy was instituted. The strongest predictors of time to the development of AIDS and of survival were an increased CD4 lymphocyte count (> 50/microL), a decreased neopterin level (> 2.4 nmol/L), and no increase in the number of symptoms after 7-12 months of zidovudine therapy. Men who had the best quartile CD4 lymphocyte and neopterin responses and who also had no increase in the number of symptoms were 23 times less likely to die (reflecting a 96% increase in survival) than were men who had the worst responses in these variable categories. After 7-12 months of zidovudine therapy, 5-year survival rates were 63% for men with good responses in all three variable categories, 47%-49% for those with good CD4 lymphocyte responses and good responses in one other variable category, 31% for those with only a good CD4 lymphocyte response, and 0 for those with poor responses in all three variable categories.

To examine the effect of acyclovir use on disease progression and survival in human immunodeficiency virus (HIV)-seropositive persons treated with zidovudine.Four university-based or -affiliated clinics.Prospective cohort study of homosexual and bisexual men with semi-annual follow-up. Intent-to-treat Cox models were fit to determine the relation between the use of acyclovir (modeled as a time-dependent covariate) and disease progression, controlling for baseline and time-dependent clinical and laboratory prognostic variables. The acquired immunodeficiency syndrome (AIDS)-free duration and survival time were calculated from the first use of zidovudine. Analysis included study visits 7 to 17 (from 1987 to 1992).786 HIV-seropositive participants in the Multicenter AIDS Cohort Study who began zidovudine therapy before a clinical diagnosis of AIDS; of these, 515 subsequently received acyclovir. Participants were asked at each visit whether they had "used any medication for health reasons not related to AIDS or if they had taken any medication to help fight AIDS or the HIV virus"; 488 patients indicated acyclovir use under either or both questions, and 242 patients indicated only the latter use.The use of acyclovir for any indication was not associated with an effect on progression to AIDS but was associated with a 26% decrease in the risk for death (relative hazard, 0.74; P = 0.07). The use of acyclovir for HIV infection was also not associated with an effect on progression to AIDS but was associated with a 36% decrease in the risk for death (relative hazard, 0.64; P = 0.01). To further investigate these findings, we examined dose, constancy, and timing of acyclovir use. The median daily dose of acyclovir used for HIV infection was between 600 and 800 mg. No apparent dose effect on survival was found. Longer uninterrupted use of acyclovir for any indication was associated with an 18% decrease in the risk for death for three or more consecutive visits (relative hazard, 0.82; P = 0.23), a 28% decrease for four or more consecutive visits (relative hazard, 0.72; P = 0.09), and a 7% decrease per visit based on the cumulative number of visits while the patient received acyclovir (relative hazard, 0.93 per visit increase; P = 0.03). Use of acyclovir for any indication and use of acyclovir for HIV infection were each associated with a 44% decreased probability of death if the drug was used after AIDS developed (P = 0.007 and P = 0.005, respectively) but not before. To further investigate the prolongation of survival, two landmark analyses were done. The first analysis began at a landmark of 1 year after initiation of zidovudine therapy and compared three groups of patients: those who used acyclovir at or before this landmark, those who had never started acyclovir or started the drug after the landmark, and those who had never used acyclovir. The 90% survival times were 1325, 1059, and 982 days, respectively. The second analysis began at a landmark of developing either a CD4 count less than 50 cells/microL or clinical AIDS. The 90% survival times for the three groups were 398, 261, and 176 days, respectively.Our analysis suggests that consistent use of acyclovir at a dose sufficient to suppress herpetic recurrences (that is, 600 to 800 mg/d) has a clinically significant effect on prolonging survival in a well-characterized cohort with extensive previous exposure to herpesvirus infections. Further clinical investigation of low-dose acyclovir with concomitant antiretroviral therapy is warranted.

Repeat episodes of infective endocarditis (IE) can occur in patients who survive an initial episode. We analysed risk factors and 1-year mortality of patients with repeat IE. We considered 1874 patients enrolled in the International Collaboration on Endocarditis – Prospective Cohort Study between January 2000 and December 2006 (ICE-PCS) who had definite native or prosthetic valve IE and 1-year follow-up. Multivariable analysis was used to determine risk factors for repeat IE and 1-year mortality. Of 1874 patients, 1783 (95.2%) had single-episode IE and 91 (4.8%) had repeat IE: 74/91 (81%) with new infection and 17/91 (19%) with presumed relapse. On bivariate analysis, repeat IE was associated with haemodialysis (p 0.002), HIV (p 0.009), injection drug use (IDU) (p < 0.001), Staphylococcus aureus IE (p 0.003), healthcare acquisition (p 0.006) and previous IE before ICE enrolment (p 0.001). On adjusted analysis, independent risk factors were haemodialysis (OR, 2.5; 95% CI, 1.2–5.3), IDU (OR, 2.9; 95% CI, 1.6–5.4), previous IE (OR, 2.8; 95% CI, 1.5–5.1) and living in the North American region (OR, 1.9; 95% CI, 1.1–3.4). Patients with repeat IE had higher 1-year mortality than those with single-episode IE (p 0.003). Repeat IE is associated with IDU, previous IE and haemodialysis. Clinicians should be aware of these risk factors in order to recognize patients who are at risk of repeat IE.