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Cluster randomized trials (CRTs) often enroll large numbers of participants; yet due to resource constraints, only a subset of participants may be selected for outcome assessment, and those sampled may not be representative of all cluster members. Missing data also present a challenge: if sampled individuals with measured outcomes are dissimilar from those with missing outcomes, unadjusted estimates of arm-specific endpoints and the intervention effect may be biased. Further, CRTs often enroll and randomize few clusters, limiting statistical power and raising concerns about finite sample performance. Motivated by SEARCH-TB, a CRT aimed at reducing incident tuberculosis infection, we demonstrate interlocking methods to handle these challenges. First, we extend Two-Stage targeted minimum loss-based estimation to account for three sources of missingness: (i) subsampling; (ii) measurement of baseline status among those sampled; and (iii) measurement of final status among those in the incidence cohort (persons known to be at risk at baseline). Second, we critically evaluate the assumptions under which subunits of the cluster can be considered the conditionally independent unit, improving precision and statistical power but also causing the CRT to behave like an observational study. Our application to SEARCH-TB highlights the real-world impact of different assumptions on measurement and dependence; estimates relying on unrealistic assumptions suggested the intervention increased the incidence of TB infection by 18% (risk ratio [RR] = 1.18, 95% confidence interval [CI]: 0.85–1.63), while estimates accounting for the sampling scheme, missingness, and within community dependence found the intervention decreased the incident TB by 27% (RR = 0.73, 95% CI: 0.57–0.92). [ABSTRACT FROM AUTHOR]

Background Human immunodeficiency virus (HIV) treatment reduces tuberculosis (TB) disease and mortality; however, the population-level impact of universal HIV-test-and-treat interventions on TB infection and transmission remain unclear. Methods In a sub-study nested in the SEARCH trial, a community cluster-randomized trial (NCT01864603), we assessed whether a universal HIV-test-and-treat intervention reduced population-level incident TB infection in rural Uganda. Intervention communities received annual, population-level HIV testing and patient-centered linkage. Control communities received population-level HIV testing at baseline and endline. We compared estimated incident TB infection by arms, defined by tuberculin skin test conversion in a cohort of persons aged 5 and older, adjusting for participation and predictors of infection, and accounting for clustering. Results Of the 32 trial communities, 9 were included, comprising 90 801 participants (43 127 intervention and 47 674 control). One-year cumulative incidence of TB infection was 16% in the intervention and 22% in the control; SEARCH reduced the population-level risk of incident TB infection by 27% (adjusted risk ratio = 0.73; 95% confidence interval [CI]:.57–.92, P =.005). In pre-specified analyses, the effect was largest among children aged 5–11 years and males. Conclusions A universal HIV-test-and-treat intervention reduced incident TB infection, a marker of population-level TB transmission. Investments in community-level HIV interventions have broader population-level benefits, including TB reductions. [ABSTRACT FROM AUTHOR]

In patients with drug-resistant epilepsy, electrical stimulation of the brain in response to epileptiform activity can make seizures less frequent and debilitating. This therapy, known as closed-loop responsive neurostimulation (RNS), aims to directly halt seizure activity via targeted stimulation of a burgeoning seizure. Rather than immediately stopping seizures as they start, many RNS implants produce slower, long-lasting changes in brain dynamics that better predict clinical outcomes. Here we hypothesize that stimulation during brain states with less epileptiform activity drives long-term changes that restore healthy brain networks. To test this, we quantified stimulation episodes during low- and high-risk brain states—that is, stimulation during periods with a lower or higher risk of generating epileptiform activity—in a cohort of 40 patients treated with RNS. More frequent stimulation in tonic low-risk states and out of rhythmic high-risk states predicted seizure reduction. Additionally, stimulation events were more likely to be phase-locked to prolonged episodes of abnormal activity for intermediate and poor responders when compared to super-responders, consistent with the hypothesis that improved outcomes are driven by stimulation during low-risk states. These results support the hypothesis that stimulation during low-risk periods might underlie the mechanisms of RNS, suggesting a relationship between temporal patterns of neuromodulation and plasticity that facilitates long-term seizure reduction. [ABSTRACT FROM AUTHOR]

Fungal infections, especially due to Candida species, are on the rise. Multi-drug resistant organisms such as Candida auris are difficult and time consuming to identify accurately. Machine learning is increasingly being used in health care, especially in medical imaging. In this study, we evaluated the effectiveness of six convolutional neural networks (CNNs) to identify four clinically important Candida species. Wet-mounted images were captured using bright field live-cell microscopy followed by separating single-cells, budding-cells, and cell-group images which were then subjected to different machine learning algorithms (custom CNN, VGG16, ResNet50, InceptionV3, EfficientNetB0, and EfficientNetB7) to learn and predict Candida species. Among the six algorithms tested, the InceptionV3 model performed best in predicting Candida species from microscopy images. All models performed poorly on raw images obtained directly from the microscope. The performance of all models increased when trained on single and budding cell images. The InceptionV3 model identified budding cells of C. albicans, C. auris, C. glabrata (Nakaseomyces glabrata), and C. haemulonii in 97.0%, 74.0%, 68.0%, and 66.0% cases, respectively. For single cells of C. albicans, C. auris, C. glabrata , and C. haemulonii InceptionV3 identified 97.0%, 73.0%, 69.0%, and 73.0% cases, respectively. The sensitivity and specificity of InceptionV3 were 77.1% and 92.4%, respectively. Overall, this study provides proof of the concept that microscopy images from wet-mounted slides can be used to identify Candida yeast species using machine learning quickly and accurately. [ABSTRACT FROM AUTHOR]

Background Social network analysis can elucidate tuberculosis transmission dynamics outside the home and may inform novel network-based case-finding strategies. Methods We assessed the association between social network characteristics and prevalent tuberculosis infection among residents (aged ≥15 years) of 9 rural communities in Eastern Uganda. Social contacts named during a census were used to create community-specific nonhousehold social networks. We evaluated whether social network structure and characteristics of first-degree contacts (sex, human immunodeficiency virus [HIV] status, tuberculosis infection) were associated with revalent tuberculosis infection (positive tuberculin skin test [TST] result) after adjusting for individual-level risk factors (age, sex, HIV status, tuberculosis contact, wealth, occupation, and Bacillus Calmette–Guérin [BCG] vaccination) with targeted maximum likelihood estimation. Results Among 3 335 residents sampled for TST, 32% had a positive TST results and 4% reported a tuberculosis contact. The social network contained 15 328 first-degree contacts. Persons with the most network centrality (top 10%) (adjusted risk ratio, 1.3 [95% confidence interval, 1.1–1.1]) and the most (top 10%) male contacts (1.5 [1.3–1.9]) had a higher risk of prevalent tuberculosis, than those in the remaining 90%. People with ≥1 contact with HIV (adjusted risk ratio, 1.3 [95% confidence interval, 1.1–1.6]) and ≥2 contacts with tuberculosis infection were more likely to have tuberculosis themselves (2.6 [ 95% confidence interval: 2.2–2.9]). Conclusions Social networks with higher centrality, more men, contacts with HIV, and tuberculosis infection were positively associated with tuberculosis infection. Tuberculosis transmission within measurable social networks may explain prevalent tuberculosis not associated with a household contact. Further study on network-informed tuberculosis case finding interventions is warranted. [ABSTRACT FROM AUTHOR]

Background In generalized epidemic settings, strategies are needed to prioritize individuals at higher risk of human immunodeficiency virus (HIV) acquisition for prevention services. We used population-level HIV testing data from rural Kenya and Uganda to construct HIV risk scores and assessed their ability to identify seroconversions. Methods During 2013–2017, >75% of residents in 16 communities in the SEARCH study were tested annually for HIV. In this population, we evaluated 3 strategies for using demographic factors to predict the 1-year risk of HIV seroconversion: membership in ≥1 known "risk group" (eg, having a spouse living with HIV), a "model-based" risk score constructed with logistic regression, and a "machine learning" risk score constructed with the Super Learner algorithm. We hypothesized machine learning would identify high-risk individuals more efficiently (fewer persons targeted for a fixed sensitivity) and with higher sensitivity (for a fixed number targeted) than either other approach. Results A total of 75 558 persons contributed 166 723 person-years of follow-up; 519 seroconverted. Machine learning improved efficiency. To achieve a fixed sensitivity of 50%, the risk-group strategy targeted 42% of the population, the model-based strategy targeted 27%, and machine learning targeted 18%. Machine learning also improved sensitivity. With an upper limit of 45% targeted, the risk-group strategy correctly classified 58% of seroconversions, the model-based strategy 68%, and machine learning 78%. Conclusions Machine learning improved classification of individuals at risk of HIV acquisition compared with a model-based approach or reliance on known risk groups and could inform targeting of prevention strategies in generalized epidemic settings. Clinical Trials Registration NCT01864603. [ABSTRACT FROM AUTHOR]

Background and Aims Prior work has examined cuticle function, composition and ultrastructure in many plant species, but much remains to be learned about how these features are related. This study aims to elucidate relationships between these features via analysis of cuticle development in adult maize (Zea mays L.) leaves, while also providing the most comprehensive investigation to date of the composition and ultrastructure of adult leaf cuticles in this important crop plant. Methods We examined water permeability, wax and cutin composition via gas chromatography, and ultrastructure via transmission electron microscopy, along the developmental gradient of partially expanded adult maize leaves, and analysed the relationships between these features. Key Results The water barrier property of the adult maize leaf cuticle is acquired at the cessation of cell expansion. Wax types and chain lengths accumulate asynchronously over the course of development, while overall wax load does not vary. Cutin begins to accumulate prior to establishment of the water barrier and continues thereafter. Ultrastructurally, pavement cell cuticles consist of an epicuticular layer, and a thin cuticle proper that acquires an inner, osmiophilic layer during development. Conclusions Cuticular waxes of the adult maize leaf are dominated by alkanes and alkyl esters. Unexpectedly, these are localized mainly in the epicuticular layer. Establishment of the water barrier during development coincides with a switch from alkanes to esters as the major wax type, and the emergence of an osmiophilic (likely cutin-rich) layer of the cuticle proper. Thus, alkyl esters and the deposition of the cutin polyester are implicated as key components of the water barrier property of adult maize leaf cuticles. [ABSTRACT FROM AUTHOR]

Background: Daily trimethoprim-sulfamethoxazole (TMP-SMX) and insecticide-treated nets remain the main interventions for prevention of malaria in human immunodeficiency virus (HIV)-infected pregnant women in Africa. However, antifolate and pyrethroid resistance threaten the effectiveness of these interventions, and new ones are needed.Methods: We conducted a double-blinded, randomized, placebo-controlled trial comparing daily TMP-SMX plus monthly dihydroartemisinin-piperaquine (DP) to daily TMP-SMX alone in HIV-infected pregnant women in an area of Uganda where indoor residual spraying of insecticide had recently been implemented. Participants were enrolled between gestation weeks 12 and 28 and given an insecticide-treated net. The primary outcome was detection of active or past placental malarial infection by histopathologic analysis. Secondary outcomes included incidence of malaria, parasite prevalence, and adverse birth outcomes.Result: All 200 women enrolled were followed through delivery, and the primary outcome was assessed in 194. There was no statistically significant difference in the risk of histopathologically detected placental malarial infection between the daily TMP-SMX plus DP arm and the daily TMP-SMX alone arm (6.1% vs. 3.1%; relative risk, 1.96; 95% confidence interval, .50-7.61; P = .50). Similarly, there were no differences in secondary outcomes.Conclusions: Among HIV-infected pregnant women in the setting of indoor residual spraying of insecticide, adding monthly DP to daily TMP-SMX did not reduce the risk of placental or maternal malaria or improve birth outcomes.Clinical Trials Registration: NCT02282293. [ABSTRACT FROM AUTHOR]

Background: Optimal treatment of human immunodeficiency virus (HIV)-associated tuberculosis in patients with high CD4⁺ T-cell counts is unknown. Suppression of viral replication during therapy for tuberculosis may block effects of immune activation on T cells and slow HIV disease progression.Methods: We conducted a randomized trial in 214 HIV-infected patients with active tuberculosis and CD4⁺ T-cell counts of ≥ 350 cells/μL to determine whether 6 months of antiretroviral therapy given during tuberculosis treatment would improve clinical outcomes. Subjects were randomized to receive 6 months of abacavir-lamivudine-zidovudine concurrent with tuberculosis therapy or delayed antiretroviral therapy. Endpoints were CD4⁺ T-cell counts of < 250 cells/μL, AIDS, or death.Results: Intervention and comparison arms had similar median CD4⁺ counts (517 and 534 cells/μL, respectively) and HIV RNA levels (4.6 and 4.7 log₁₀ copies/μL, respectively). Viral suppression was achieved in 86% of patients allocated to intervention. Seventeen subjects (15.6%) in the intervention arm developed study outcome compared to 25 subjects (22.8%) in the comparison arm (P = .17). Grade 3 or 4 adverse events were less frequent in the intervention arm. By 2 months, 90% of subjects in both arms were culture-negative for tuberculosis.Conclusions: Short-term antiretroviral therapy during tuberculosis treatment in patients with CD4⁺T-cell counts of >350 cells/μL was safe and associated with clinical benefits. [ABSTRACT FROM AUTHOR]

Background. Noroviruses are responsible for at least 50% of all gastroenteritis outbreaks worldwide. Noroviruses GII can infect humans via multiple routes including direct contact with an infected person, fecal matter, or vomitus, and contact with contaminated surfaces. Although norovirus is an intestinal pathogen, aerosols could, if inhaled, settle in the pharynx and later be swallowed. The aims of this study were to investigate the presence of norovirus GII bioaerosols during gastroenteritis outbreaks in healthcare facilities and to study the in vitro effects of aerosolization and air sampling on the noroviruses using murine norovirus as a surrogate. Methods. A total of 48 air samples were collected during norovirus outbreaks in 8 healthcare facilities. Samples were taken 1 m away from each patient, in front of the patient's room and at the nurses' station. The resistance to aerosolization stress ofmurine norovirus type 1 (MNV-1) bioaerosols was also tested in vitro using an aerosol chamber. Results. Norovirus genomes were detected in 6 of 8 healthcare centers. The concentrations ranged from 1.35 × 10¹ to 2.35 × 10³ genomes/m3 in 47% of air samples.MNV-1 preserved its infectivity and integrity during in vitro aerosol studies. Conclusions. Norovirus genomes are frequently detected in the air of healthcare facilities during outbreaks, even outside patients' rooms. In addition, in vitro models suggest that this virus may withstand aerosolization. [ABSTRACT FROM AUTHOR]

Background Human immunodeficiency virus (HIV)–infected pregnant women are at increased risk of malaria and its complications. In vitro and in vivo data suggest that the HIV protease inhibitors lopinavir/ritonavir may have potent antimalarial activity. We sought to evaluate whether lopinavir/ritonavir-based antiretroviral therapy (ART) reduced the risk of placental malaria. Methods HIV-infected, ART-naive pregnant women were enrolled between gestational weeks 12 and 28 and randomly assigned to receive lopinavir/ritonavir-based or efavirenz-based ART. Women received daily trimethoprim-sulfamethoxazole prophylaxis and insecticide-treated bed nets at enrollment and were followed up to 1 year after delivery. The primary outcome was placental malaria, defined by the detection of malaria parasites, using microscopy or polymerase chain reaction (PCR) analysis of placental blood specimens. Secondary outcomes included placental malaria, defined by histopathologic results; adverse birth outcomes; incidence of malaria; and prevalence of asymptomatic parasitemia. Analyses were done using an intention-to-treat approach. Results Of 389 subjects randomly assigned to a treatment group, 377 were followed through to delivery. There was no significant difference in the risk of placental malaria, as defined by thick smear or PCR findings, between the lopinavir/ritonavir-based and efavirenz-based ART arms (7.4% vs 9.8%; P = .45). Similarly, there were no differences in secondary outcomes between the 2 treatment arms. Conclusions Lopinavir/ritonavir-based ART did not reduce the risk of placental or maternal malaria or improve birth outcomes, compared with efavirenz-based ART. Clinical Trials Registration NCT00993031. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV)-exposed uninfected children (HEU) have an increased risk of morbidity and mortality compared with HIV-unexposed uninfected children (HUU); however, prior studies have not fully accounted for the role of both breastfeeding and age on this association. In this cohort of HEU and HUU in Uganda, non-breastfeeding HEU, from 6–11 months compared with non-breastfeeding HUU had a higher risk of hospitalizations [relative risk (RR): 10.1, 95% confidence interval (CI): 3.70–27.6], severe febrile illness (RR: 3.84, 95% CI: 2.06–7.17), severe diarrhea (RR: 6.37, 95% CI: 2.32–17.4) and severe malnutrition (RR: 18.4, 95% CI: 4.68–72.0). There were no differences between morbidity outcomes between breastfeeding HEU and HUU children, aged 6–11 months. In the 12–24 month age group, the only difference in morbidity outcomes among non-breast feeding children was an increased risk of severe malnutrition for HEU. These data suggest that the increased risk of morbidity among HEU aged 6–11 years is partially explained by early cessation of breastfeeding. [ABSTRACT FROM AUTHOR]

Persons infected with human immunodeficiency virus (HIV) have cellular cytotoxicity defects. Interleukin (IL)-12 is a potent stimulator of cytotoxicity. Fifteen HIV-infected patients were studied in a phase 1, single-dose escalation trial of human recombinant IL-12. One day after subjects received an IL-12 dose of 300 or 1000 ng/kg, they had a reduction in absolute lymphocyte count and peripheral blood mononuclear cell recovery. In evaluable patients 24 h after IL-12 administration, there was a 31% reduction overall in NK cell cytotoxicity (NKC) to HIV-infected cells at all doses and a 52% reduction in antibody-dependent cellular cytotoxicity (ADCC) at doses of 300 and 1000 ng/kg. In vitro incubation of patients' cells with IL-12 (before IL-12 administration) for 24 h increased NKC but had no effect on ADCC. The paradoxic acute reduction in cell number and cytotoxicity in vivo may be due to NK cell trafficking or regulatory cytokine mechanisms not apparent in vitro. [ABSTRACT FROM AUTHOR]

Serum samples from 735 homosexual or bisexual men were tested for antibodies to hepatitis C virus (HCV) and serologic markers of hepatitis B virus (HBV), and risk factors for each infection were compared. Thirty-four (4.6%) were confirmed HCV-positive compared with 81% positive for one or more HBV serologic marker(s). History of intravenous drug use (IVDU) and blood transfusion were significantly associated with HCV positivity (odds ratio [OR] = 14.3 and 4.4, respectively), but neither was significantly associated with HBV positivity. Sexual behavior was significantly associated with infection with both viruses. When IVDU and blood transfusion were controlled for, HCV infection was marginally associated with > 50 sex partners/year (OR = 2.1), > 25 oral receptive partners (OR = 2.4), and > 25 anal receptive partners (OR = 1.9). HBV infection was more strongly associated with the same variables. HCV infection is uncommon in homosexual men and IVDU is the primary route of transmission, but sexual transmission also occurs, albeit infrequently. [ABSTRACT FROM AUTHOR]

Treatment of uncomplicated malaria with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine in HIV-infected children on antiretroviral therapy (ART) was safe and efficacious. However there was a high risk of recurrent parasitemia within 28 days following treatment with AL, varying with ART regimen.Background. Artemisinin-based combination therapies (ACTs) are highly efficacious and safe, but data from human immunodeficiency virus (HIV)–infected children concurrently receiving antiretroviral therapy (ART) and ACTs are limited.Methods. We evaluated 28-day outcomes following malaria treatment with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in 2 cohorts of HIV-infected Ugandan children taking various ART regimens. In one cohort, children <6 years of age were randomized to lopinavir/ritonavir (LPV/r) or nonnucleoside reverse transcriptase inhibitor–based ART and treated with AL for uncomplicated malaria. In another cohort, children <12 months of age were started on nevirapine-based ART if they were eligible, and randomized to AL or DP for the treatment of their first and all subsequent uncomplicated malaria episodes.Results. There were 773 and 165 treatments for malaria with AL and DP, respectively. Initial response to therapy was excellent, with 99% clearance of parasites and <1% risk of repeat therapy within 3 days. Recurrent parasitemia within 28 days was common following AL treatment. The risk of recurrent parasitemia was significantly lower among children taking LPV/r-based ART compared with children taking nevirapine-based ART following AL treatment (15.3% vs 35.5%, P = .009), and those treated with DP compared with AL (8.6% vs 36.2%, P < .001). Both ACT regimens were safe and well tolerated.Conclusions. Treatment of uncomplicated malaria with AL or DP was efficacious and safe in HIV-infected children taking ART. However, there was a high risk of recurrent parasitemia following AL treatment, which was significantly lower in children taking LPV/r-based ART compared with nevirapine-based ART. [ABSTRACT FROM PUBLISHER]

As human immunodeficiency virus (HIV)-infected women gain access to combination antiretroviral therapy throughout sub-Saharan Africa, a growing number of infants are being born HIV-exposed but uninfected. Data about neonatal mortality and the impact of premature delivery, in this population are limited. We describe the 28-day mortality outcomes in a cohort of HIV-exposed infants who had ultrasound-confirmed gestational age in rural Uganda. There were 13 deaths among 351 infants, including 9 deaths in the perinatal period. Premature delivery was a strong predictor of mortality. The prevention of HIV transmission to infants is now possible in rural low-resource settings but the frequency of neonatal death among HIV-exposed infants remains extremely high, calling for new comprehensive interventions to reduce mortality in this growing population. [ABSTRACT FROM AUTHOR]

Accounting for outcomes among those lost to follow-up in a Ugandan HIV treatment program among patients entering care with a CD4 count >350 cells/µL and not immediately eligible for antiretroviral therapy reveals retention to be higher than most prevailing estimates.Background. In Africa, human immunodeficiency virus (HIV)–infected patients who present to care with CD4 levels >350 cells/µL (ie, current antiretroviral treatment thresholds) are often thought to be poorly retained in care, but most estimates do not account for outcomes among patients lost to follow-up.Methods. We evaluated HIV-infected adults who had made a visit in the last 2.5 years in a program in Uganda. We identified a random sample of patients lost to follow-up (9 months without a visit). Ascertainers sought patients in the community in this sample and outcomes were incorporated into revised survival estimates of mortality and retention for the clinic population using a probability weight.Results. Of 6473 patients, (29% male, median age 29 years, median CD4 count 550 cells/µL), 1294 (20%) became lost to follow-up over 2.5 years. Two hundred seven (16%) randomly selected lost patients were sought, and in 175 (85%) vital status was ascertained. In 19 of 175 (11%), the patient had died. Of the 156 (89%) alive, 74 (47%) were interviewed in person, and 38 of 74 (51%) reported HIV care elsewhere, whereas 36 of 74 (49%) were not in care. Application of weights derived from sampling found that at 2.5 years, retention among patients who enrolled with CD4 levels >350 cells/µL was 88.2% and mortality was 2.5%. Lower income, unemployment, and rural residence were associated with failure to be retained.Conclusions. Retention in patients entering care with high CD4 counts under routine program conditions in Africa is high in a Ugandan care program and may be systematically underestimated in many other settings. [ABSTRACT FROM PUBLISHER]

Background. Infection with hepatitis C virus (HCV) is a burgeoning worldwide public health problem, with 170 million infected individuals and an estimated 20 million deaths in the coming decades. While 6 main genotypes generally distinguish the global geographic diversity of HCV, a multitude of closely related subtypes within these genotypes are poorly defined and may influence clinical outcome and treatment options. Unfortunately, the paucity of genetic data from many of these subtypes makes time-consuming primer walking the limiting step for sequencing understudied subtypes.Methods. Here we combined long-range polymerase chain reaction amplification with pyrosequencing for a rapid approach to generate the complete viral coding region of 31 samples representing poorly defined HCV subtypes.Results. Phylogenetic classification based on full genome sequences validated previously identified HCV subtypes, identified a recombinant sequence, and identified a new distinct subtype of genotype 4. Unlike conventional sequencing methods, use of deep sequencing also facilitated characterization of minor drug resistance variants within these uncommon or, in some cases, previously uncharacterized HCV subtypes.Conclusions. These data aid in the classification of uncommon HCV subtypes while also providing a high-resolution view of viral diversity within infected patients, which may be relevant to the development of therapeutic regimens to minimize drug resistance. [ABSTRACT FROM AUTHOR]

Population-based human immunodeficiency virus (HIV) RNA metrics can help estimate antiretroviral therapy effectiveness within a community. We developed a fingerprick-based viral load technique and measured population HIV RNA levels in a rural Ugandan community, providing the first report from a resource limited setting.Background. Population-based human immunodeficiency virus type 1 (HIV-1) RNA levels (viral load [VL]) are proposed metrics for antiretroviral therapy (ART) program effectiveness. We estimated population-based HIV RNA levels using a fingerprick-based approach in a rural Ugandan community implementing rapid ART scale-up.Methods. A fingerprick-based HIV RNA measurement technique was validated against standard phlebotomy. This technique was deployed during a 5-day community-wide health campaign in a 6300-person community. Assessments included rapid HIV antibody testing, VL, and CD4+ T-cell count via fingerprick. We estimated population HIV RNA levels and the prevalence of undetectable RNA, assessed predictors of VL via linear regression, and mapped RNA levels within community geographic units.Results. During the community-wide health campaign, 179 of 2282 adults (7.8%) and 10 of 1826 children (0.5%) tested seropositive for HIV. Fingerprick VL was determined in 174 of 189 HIV-positive persons (92%). The mean log(VL) was 3.67 log (95% confidence interval [CI], 3.50–3.83 log copies/mL), median VL was 2720 copies/mL (interquartile range, <486–38 120 copies/mL), and arithmetic mean VL was 64 064 copies/mL. Overall, 64 of 174 of individuals had undetectable RNA (37% [95% CI, 30%–44%]), 24% had VL 486–10 000; 25% had VL 10 001–100 000; and 15% had VL>100 000 copies/mL. Among participants taking ART, 83% had undetectable VL.Conclusions. We developed and implemented a fingerprick VL testing method and provide the first report of population HIV RNA levels in Africa. In a rural Ugandan community experiencing ART scale-up, we found evidence of population-level ART effectiveness, but found a substantial population to be viremic, in need of ART, and at risk for transmission. [ABSTRACT FROM AUTHOR]

Protein interaction networks play central roles in biological systems, from simple metabolic pathways through complex programs permitting the development of organisms. Multicellularity could only have arisen from a careful orchestration of cellular and molecular roles and responsibilities, all properly controlled and regulated. Disease reflects a breakdown of this organismal homeostasis. To better understand the evolution of interactions whose dysfunction may be contributing factors to disease, we derived the human protein coevolution network using our MatrixMatchMaker algorithm and using the Orthologous MAtrix project (OMA) database as a source for protein orthologs from 103 eukaryotic genomes. We annotated the coevolution network using protein–protein interaction data, many functional data sources, and we explored the evolutionary rates and dates of emergence of the proteins in our data set. Strikingly, clustering based only on the topology of the coevolution network partitions it into two subnetworks, one generally representing ancient eukaryotic functions and the other functions more recently acquired during animal evolution. That latter subnetwork is enriched for proteins with roles in cell–cell communication, the control of cell division, and related multicellular functions. Further annotation using data from genetic disease databases and cancer genome sequences strongly implicates these proteins in both ciliopathies and cancer. The enrichment for such disease markers in the animal network suggests a functional link between these coevolving proteins. Genetic validation corroborates the recruitment of ancient cilia in the evolution of multicellularity. [ABSTRACT FROM PUBLISHER]

Human immunodeficiency virus (HIV) infection causes neurocognitive or motor function deficits in children with advanced disease, but it is unclear whether children with CD4 cell measures above the World Health Organization (WHO) thresholds for antiretroviral therapy (ART) initiation suffer significant impairment. Methods. The neurocognitive and motor functions of HIV-infected ART-naive Ugandan children aged 6-12 years with CD4 cell counts of >350 cells/lL and CD4 cell percentage of >15% were compared with those of HIV-uninfected children, using the Test of Variables of Attention (TOVA), the Kaufman Assessment Battery for Children, second edition (KABC-2), and the Bruininks-Oseretsky Test of Motor Proficiency, second edition (BOT-2). Results. Ninety-three HIV-infected children (median CD4 cell count, 655 cells/&UML;L; plasma HIV RNA level, 4.7 log10 copies/mL) were compared to 106 HIV-uninfected children. HIV-infected children performed worse on TOVA visual reaction times (multivariate analysis of covariance; P = .006); KABC-2 sequential processing (P = .005), simultaneous processing (P = .039), planning/reasoning (P = .023), and global performance (P = .024); and BOT-2 total motor proficiency (P 5 .003). High plasma HIV RNA level was associated with worse performance in 10 cognitive measures and 3 motor measures. In analysis of only WHO clinical stage 1 or 2 HIV-infected children (n = 68), significant differences between the HIV-infected and HIV-uninfected groups (P < .05) remained for KABC-2 sequential processing, KABC-2 planning/reasoning, and BOT-2 motor proficiency. Conclusions. Significant motor and cognitive deficits were found in HIV-infected ART-naive Ugandan children with CD4 cell counts of 350 cells/lL and percentages of >15%. Study of whether early initiation of ART could prevent or reverse such deficits is needed. [ABSTRACT FROM AUTHOR]

Abstract: Background: The IBD5 locus is a genetic risk factor for IBD, particularly Crohn''s Disease, coding for the organic cation/carnitine transporters (OCTN1 and 2). Two variants of OCTN are associated with susceptibility to Crohn''s Disease. Modified transport of carnitine in vitro has been reported for a polymorphism of OCTN1. The aim was to investigate the function of intestinal OCTNs in IBD in relation to genetic polymorphisms. Methods: Intestinal tissue was obtained from endoscopic biopsies and surgical resections from IBD patients (n=33 and 14, resp.) and controls (n=22 and 14, resp.). OCTN protein levels were measured in intestinal biopsies and carnitine transport was quantified in intestinal resections. Results: OCTN1 protein levels were significantly higher in ileal versus colonic tissue (2.95%±0.4 vs 0.66%±0.2, resp.; p<0.0002). OCTN1 expression was higher in Crohn''s disease patients with mutant homozygous or heterozygous genotypes (0.6%±0.1 vs 3%±0.8, resp., p<0.02). Carnitine transport was very rapid and Na+ dependent (10s). It was not different comparing Crohn''s Disease and control groups (0.45±0.12 vs 0.51±0.12nM carnitine/mg prot/min, resp.). Carnitine transport tended to be higher in subjects with mutant homozygous and heterozygous OCTN1 and OCTN2 genotypes (0.19 vs 0.59 and 0.25 vs 0.6, respectively). Conclusions: The present data reveal that OCTN protein levels appear to be similar in intestinal tissue from Crohn''s Disease patients and controls. Overall, ileal carnitine transport appears to as well equal in Crohn''s Disease and control groups. However, there was a trend towards higher carnitine transport in subjects with OCTN1 and OCTN2 mutations. [Copyright &y& Elsevier]

Background. Optimal treatment of human immunodeficiency virus (HIV)-associated tuberculosis in patients with high CD4+ T-cell counts is unknown. Suppression of viral replication during therapy for tuberculosis may block effects of immune activation on T cells and slow HIV disease progression. Methods. We conducted a randomized trial in 214 HIV-infected patients with active tuberculosis and CD4+ T-cell counts of ≥350 cells/μL to determine whether 6 months of antiretroviral therapy given during tuberculosis treatment would improve clinical outcomes. Subjects were randomized to receive 6 months of abacavir-lamivudine-zidovudine concurrent with tuberculosis therapy or delayed antiretroviral therapy. Endpoints were CD4+ T-cell counts of <250 cells/μL, AIDS, or death. Results. Intervention and comparison arms had similar median CD4+ counts (517 and 534 cells/μL, respectively) and HIV RNA levels (4.6 and 4.7 log10 copies/μL, respectively). Viral suppression was achieved in 86% of patients allocated to intervention. Seventeen subjects (15.6%) in the intervention arm developed study outcome compared to 25 subjects (22.8%) in the comparison arm (P = .17). Grade 3 or 4 adverse events were less frequent in the intervention arm. By 2 months, 90% of subjects in both arms were culture-negative for tuberculosis. Conclusions. Short-term antiretroviral therapy during tuberculosis treatment in patients with CD4+ T-cell counts of >350 cells/μL was safe and associated with clinical benefits. [ABSTRACT FROM AUTHOR]

Background. HIV-infected women have lower HIV RNA levels and higher CD4-cell counts than do men. This observation has been attributed to the immunomodulatory effects of sex steroid hormones, such as estrogen and progesterone. Limited data exist regarding potential sex differences in HIV RNA level and CD4 parameters among prepubertal children with untreated HIV infection. Methods. We examined the relationship of sex to HIV RNA level and CD4 parameters among 670 perinatally HIV-infected, antiretroviral therapy-naive African children aged ,18 years (median age, 4.8 years) using multivariate linear regression. In a subset of 188 children, we used longitudinal data to compare changes in HIV RNA levels and CD4 percentage over time. Levels of CD4 and CD8 T-cell activation (CD381HLA-DR1) were also compared between boys and girls. Results. Female children had lower HIV RNA levels (P 5 .0004) and higher CD4 percentages (P , .0001), compared to male children. Multivariate linear regression demonstrated an independent association of sex with both HIV RNA level and CD4 percentage after controlling for other covariates. Multilevel mixed-effects linear regression analysis of longitudinal HIV RNA level and CD4 parameter data showed that sex differences persisted across all observed ages. Levels of T-cell activation did not differ between the sexes. Conclusions. Significant sex differences in HIV RNA levels and CD4 parameters are present in HIV-infected children before the onset of puberty. These data suggest that intrinsic genetic differences between male and female individuals, unrelated to sex steroid hormone levels, influence HIV RNA level and CD4 parameters in HIV-infected individuals. [ABSTRACT FROM AUTHOR]

Modeling of expanding antiretroviral treatment to all HIV infected adults already in care in San Francisco predicts reductions in new HIV infections at 5 years of 59% among men who have sex with men (MSM). Addition of annual HIV testing for MSM to universal treatment decreases new infections by 76%.(See editorial commentary by DeGruttola and Schooley on pages 1050–1052.)Modeling of expanding antiretroviral treatment to all HIV-infected adults already in care in San Francisco predicts reductions in new HIV infection at 5 years of 59% among men who have sex with men. Addition of annual HIV testing for men who have sex with men to universal treatment decreases new infections by 76%. [ABSTRACT FROM AUTHOR]

Background. Human immunodeficiency virus (HIV)–tuberculosis coinfection is associated with heightened immune activation, viral replication, and T cell dysfunction. We compared changes in T cell activation and function between patients receiving concurrent treatment for HIV-tuberculosis coinfection and those receiving treatment for tuberculosis alone.Methods. HIV-infected adults with tuberculosis and CD4+ T cell counts >350 cells/mm3 were randomized to receive tuberculosis treatment alone (control arm; n = 36) or 6 months of antiretroviral therapy (ART) concurrent with tuberculosis treatment (intervention arm; n = 38). HIV viral load, T cell subsets, T cell activation, and cytokine production were measured at enrollment and every 3 months for 12 months.Results. Differences in absolute CD4+ and CD8+ T cell counts were not observed between arms. Viral load was reduced while participants received ART; control patients maintained viral load at baseline levels. Both arms had significant reductions in T cell expression of CD38 and HLA-DR. Interferon-γ production in response to mitogen increased significantly in the intervention arm.Conclusions. In HIV-infected adults with tuberculosis and CD4+ T cell counts >350 cells/mm3, both tuberculosis treatment and concurrent HIV-tuberculosis treatment reduce T cell activation and stabilize T cell counts. Concurrent ART with tuberculosis treatment does not provide additional, sustained reductions in T cell activation among individuals with preserved immunologic function. [ABSTRACT FROM PUBLISHER]

The article presents a randomized clinical trial which examines the prehabilitation of patients about colorectal surgery. The study involves some 112 patients who were randomly chosen to perform prehabilitation to enhance their functional capacity in anticipation of a forthcoming surgery. It concludes that prehabilitation gives more valuable information to patients who are scheduled for colorectal surgery.

In a prospective randomized, controlled trial in Uganda comparing the efficacy of antiretroviral therapy during tuberculosis therapy with the efficacy of tuberculosis therapy alone in HIV-infected patients with tuberculosis who have a CD4+ cell count 1350 cells/mL, it was found that antiretroviral therapy did not accelerate microbiologic, radiographic, or clinical responses to tuberculosis therapy: 18% of participants had sputum smears positive for Mycobacterium tuberculosis after 5 months of tuberculosis therapy, despite having had negative culture results. [ABSTRACT FROM AUTHOR]

An enhanced, refocused research agenda is critical to reducing the burden of tuberculosis (TB) in the human immunodeficiency virus (HIV) epidemic in developing countries. TB threatens HIV-infected patients before and after initiation of antiretroviral therapy, is difficult to diagnose, is rapidly fatal when it is drug resistant, and is being spread in clinics and hospitals. Research priorities include improved and point-of-care TB diagnostics; TB treatment and prevention during HIV infection, drug-resistant TB, and childhood TB; and optimization of TB and HIV program integration. With new TB diagnostics and drugs reaching approval, research must focus on effectively deploying these advancements. Research must include evaluations of individual, household, health care, and community approaches. Studies must apply implementation science to determine how to increase and adapt effective interventions to reduce TB burden in the context of HIV infection. Investment in this research will improve the lives of persons infected with HIV and contribute to efforts to reduce the global TB burden. [ABSTRACT FROM AUTHOR]

Background. Nucleic acid amplification tests are sensitive and specific for identifying Mycobacterium tuberculosis in sputum smear-positive populations, but they are less sensitive in sputum smear-negative populations. Few studies have assessed their performance among patients infected with HIV, and no studies have assessed their performance with oral wash specimens, which may be easier to obtain than sputum samples. Methods. We performed a prospective study involving 127 adults from 2 populations who were undergoing evaluation for respiratory complaints at Mulago Hospital in Kampala, Uganda. We obtained and tested sputum samples for Mycobacterium tuberculosis, and we simultaneously obtained oral wash specimens to test for M. tuberculosis DNA by polymerase chain reaction (PCR) amplification of a novel locus, the secA1 gene. A positive mycobacterial culture of sputum was used to define cases of tuberculosis; we calculated the sensitivity and specificity of the PCR assay with sputum or oral wash specimens in reference to the standard of sputum culture results. Results. Tuberculosis (75 [59%] of 127 patients) and HIV infection (58 [46%] of 126 patients) were both common in the study population. PCR of sputum samples was highly sensitive (sensitivity, 99%; 95% confidence interval, 93%-100%) and specific (specificity, 88%; 95% confidence interval, 77%-96%) for detection of pulmonary tuberculosis and performed well among HIV-infected patients and among patients with negative sputum smear results. PCR of oral wash specimens was less sensitive (sensitivity, 73%; 95% confidence interval, 62%-83%) but also detected a substantial proportion of tuberculosis cases. Conclusions. PCR targeting the secA1 gene was highly sensitive and specific for identifying M. tuberculosis in sputum samples, independent of smear or HIV infection status. Oral washes showed promise as an easily obtained respiratory specimen for tuberculosis diagnosis. PCR of sputum for detection of the secA1 gene could be a rapid, effective diagnostic tool for tuberculosis referral centers. [ABSTRACT FROM AUTHOR]

Genome phylogenies are used to build tree-like representations of evolutionary relationships among genomes. However, in condensing the phylogenetic signals within a set of genomes down to a single tree, these methods generally do not explicitly take into account discordant signals arising due to lateral genetic transfer. Because conflicting vertical and horizontal signals can produce compromise trees that do not reflect either type of history, it is essential to understand the sensitivity of inferred genome phylogenies to these confounding effects. Using replicated simulations of genome evolution, we show that different scenarios of lateral genetic transfer have significant impacts on the ability to recover the “true” tree of genomes, even when corrections for phylogenetically discordant signals are used. [ABSTRACT FROM AUTHOR]

Background. Artemisinin-based combination therapies are rapidly being adopted for the treatment of malaria in Africa; however, there are limited data on their safety and efficacy among human immunodeficiency virus (HIV)-infected populations. Methods. We compared malaria treatment outcomes between cohorts of HIV-infected and HIV-uninfected children in Uganda who were observed for 18 and 29 months, respectively. Malaria was treated with artesunate plus amodiaquine, and outcomes were assessed using standardized guidelines. HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis and antiretroviral therapy in accordance with current guidelines. Results. Twenty-six HIV-infected participants experiencing 35 episodes of malaria and 134 HIV-uninfected children experiencing 258 episodes of malaria were included in the study. Twelve HIV-infected children were receiving antiretroviral therapy, 11 of whom were receiving zidovudine. Malaria treatment was highly efficacious in both the HIV-infected and HIV-uninfected cohorts (28-day risk of recrudescence, 0% and 3.6%, respectively); however, there was a trend towards increased risk of recurrent malaria among the HIV-uninfected children (2.9% vs. 13.2%; P = .08). Importantly, the risk of neutropenia 14 days after initiation of treatment with artesunate plus amodiaquine was higher among HIV-infected children than among HIV-uninfected children (45% vs. 6%; P<.001). The severity of all episodes of neutropenia in HIV-uninfected children was mild to moderate, and 16% of episodes of neutropenia in the HIV-infected cohort were severe or life-threatening (neutrophil count, <750 cells/mm3). In the HIV-infected cohort, the risk of neutropenia was significantly higher among children who received antiretroviral therapy than among those who did not receive antiretroviral therapy (75% vs. 26%; P=.001). Conclusions. Artesunate plus amodiaquine was highly efficacious for malaria treatment in HIV-infected children but was associated with a high risk of neutropenia, especially in the context of concurrent antiretroviral use. Our findings highlight an urgent need for evaluation of alternative antimalarial therapies for HIV-infected individuals. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) immunopathogenesis in children remains poorly understood. We assessed T cell immune activation in antiretroviral therapy-naive children in Uganda (n = 154). Increased CD4+ and CD8+ T cell activation strongly correlated with decreased CD4+ T cell percentage. Interestingly, no correlation between plasma HIV RNA level and T cell activation was observed after controlling for CD4+ T cell count. In addition, the presence of Gag-specific CD4+ T helper responses was associated with increased HIVspecific CD8+ T cells. Understanding the balance between immuneactivation and T cell immunity in HIV-infected children may provide further insights into the mechanisms leading to effective immune control. [ABSTRACT FROM AUTHOR]

Motivation: Microbial genomes undergo evolutionary processes such as gene family expansion and contraction, variable rates and patterns of sequence substitution and lateral genetic transfer. Simulation tools are essential for both the generation of data under different evolutionary models and the validation of analytical methods on such data. However, meaningful investigation of phenomena such as lateral genetic transfer requires the simultaneous consideration of many underlying evolutionary processes.Results: We have developed EvolSimulator, a software package that combines non-stationary sequence and gene family evolution together with models of lateral genetic transfer, within a customizable birth–death model of speciation and extinction. Here, we examine simulated data sets generated with EvolSimulator using existing statistical techniques from the evolutionary literature, showing in detail each component of the simulation strategy.Availability: Source code, manual and other information are freely available at www.bioinformatics.org.au/evolsimContact:beiko@cs.dal.caSupplementary information: Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA) plays a key role in the epidemiology and pathogenesis of disease. The purpose of this study was to determine the characteristics and dynamics of nasal strains of MRSA, as well as their relation to community-associated disease activity. METHODS: This study is a cross-sectional survey and molecular epidemiologic analysis of nasal colonization by S. aureus in homeless and runaway youths, an underserved population at high risk for staphylococcal disease. RESULTS: Of the 308 study participants, 27.6% carried S. aureus, and 6.2% carried MRSA. Subgroups of individuals with increased MRSA carriage rates were also at highest risk for community-associated MRSA infection; these subgroups included individuals with either HIV infection or AIDS, injection drug users, patients with abscesses, and those recently hospitalized. Multilocus sequence typing and pulsed-field gel electrophoresis identified 2 genotypes--ST59:P (USA1000) and ST8:S (USA300)--that accounted for 84.2% (16/19) of the MRSA isolates carried. The genotypes were distinct from nosocomial genotypes endemic in the hospital, although they originated from individuals with prior exposure to health care. CONCLUSIONS: Comparison of MRSA strains from asymptomatic carriers versus concurrently collected community-associated clinical strains from patients treated at local health-care facilities allowed for the identification of 3 population dynamics of nasal strains of MRSA: (1) endemic clones--for example, ST8:C and ST59:P--sustained asymptomatic carriage and infection over prolonged periods; (2) an epidemic clone, ST8:S, demonstrated enhanced capacity for rapid transmission and widespread infections; and (3) an outbreak clone, ST30:Z (USA1100), was highly infectious but exhibited poor asymptomatic transmission. Copyright © 2005 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

To define methicillin-resistant Staphylococcus aureus (MRSA) reservoirs in the community and their population dynamics, we studied the molecular epidemiology of a random sample (n = 490 ) from a collection of 2154 inpatient and outpatient MRSA isolates during a 7-year period in San Francisco. We noted a progressive replacement of type II staphylococcal chromosomal cassette (SCC)mec-bearing isolates with type IV SCCmec- bearing isolates, which coincided with >4-fold increase in methicillin resistance between 1998 and 2002. Type IV SCCmec-bearing isolates involved in the increase in methicillin resistance belonged to 4 molecular genotypes. These 4 genotypes were associated predominantly with community-onset disease, rather than hospitalor long-term-care facility-onset disease (76.9% vs. 19.4% vs. 3.7%; P = .0005 ), suggesting that they are not feral descendants of hospital isolates. The longitudinal results linked the dramatic increase in MRSA infections to an expanding community reservoir of MRSA genotypes with intrinsic community survival advantage. [ABSTRACT FROM AUTHOR]

To characterize methicillin-resistant Staphylococcus aureus (MRSA) strains circulating in the community, we identified predictors of isolating community MRSA and genotyped a sample of MRSA collected from a community-based, high-risk population. Computerized databases of the Community Health Network of San Francisco and the Clinical Microbiology Laboratory were searched electronically for the years 1992-1 999 to identify community-onset infections caused by MRSA. Sequential analyses were performed to identify predictors of MRSA strains. The majority (58%) of infections were caused by strains traceable to the hospital or to long- term care facilities. Injection drug use was associated with infections that were not associated with health care settings. Genotypes for 20 of 35 MRSA isolates recovered from injection drug users did not match any of >600 genotypes of clinical isolates. In a nonoutbreak setting, the hospital was the main source of community MRSA; however, the presence of genetically distinct and diverse MRSA strains indicates MRSA strains now also originate from the community. [ABSTRACT FROM AUTHOR]

The standard view postulates a bell-shaped relationship between adherence to therapy and development of drug-resistant human immunodeficiency virus (HIV), with a resistance peak at a moderate level of adherence. This relationship has not been confirmed empirically. We statistically modeled the relationship between adherence and development of drug resistance, using empirically defined relationships of the rate of viral suppression and drug-resistance-mutation accumulation derived from patients receiving protease-inhibitor-based therapy. We found that the maximal rate of drug resistance occurs at 87% adherence and declines modestly at 100% adherence. Higher levels of viral suppression at 100% adherence (a marker of greater regimen potency) progressively reduce the overall population rate of drug resistance and shift the peak resistance rate to lower levels of adherence. [ABSTRACT FROM AUTHOR]

Focuses on the longitudinal study of the methicillin-resistant Staphylococcus aureus (MRSA) in a jail setting in San Francisco, California. Increase of the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infection the jails; Results of the clinical isolates obtained from inmate patients; Tests on the MRSA for phenotypic resistance to several antibacterial agents.

We describe a query-based web-accessible system (www.neurogadgets.com/bws.php) for facilitating comparative microbial genomics. A variety of query pages are available, each with numerous options, that allow a biologist to pose relevant questions of genomic data. We illustrate with a characterization of species-specific protein-coding genes (so-called ‘ORFans’), finding that they are on average smaller, faster evolving, and less G+C-rich, and that they encode proteins more basic in their predicted isoelectric point, compared with non-species-specific genes. Using a dual-threshold approach, we conclude that these are characteristics of true species-specific genes, rather than artifacts of mis-annotation. [Copyright &y& Elsevier]

The study objective was to determine the prevalence and risk factors for nasal colonization with Staphylococcus aureus and methicillin resistance among the urban poor and to compare antibiotic resistance and genetic similarity to concurrently collected clinical isolates of methicillin-resistant S. aureus (MRSA). A population-based community sample of 833 homeless and marginally housed adults were cultured and compared with 363 clinical isolates of MRSA; 22.8% of the urban poor were colonized with S. aureus. Of S. aureus isolates, 12.0% were methicillin resistant. Overall prevalence of MRSA was 2.8%. Significant multivariate risk factors for MRSA were injection drug use (odds ratio [OR], 9.7), prior endocarditis (OR, 4.1), and prior hospitalization within 1 year (OR, 2.4). Resistance to antimicrobials other than β -lactams was uncommon. Only 2 individuals (0.24%) with MRSA had no known risk factors. A total of 22 of 23 community MRSA genotypically matched clinical MRSA isolates, with 15 of 23 isolates identical to MRSA clones endemic among hospitalized patients. [ABSTRACT FROM AUTHOR]

Examines the limited antibody-dependent cellular toxicity (ADDC) antibody response induced by herpes simplex virus type 2 subunit vaccine. Interaction between the F[sub c] domain and the F[sub c] receptor-bearing cell; Configuration of glycoproteinB and D on infected cells or whole virions; Association between ADDC antibody levels and less-severe neonatal diseases.

Carbamoylphosphate synthetase (CPS) catalyzes the first committed step in pyrimidine biosynthesis, arginine biosynthesis, or the urea cycle. Organisms may contain either one generalized or two specific CPS enzymes, and these enzymes may be heterodimeric (encoded by linked or unlinked genes), monomeric, or part of a multifunctional protein. In order to help elucidate the evolution of CPS, we have performed a comprehensive phylogenetic analysis using the 21 available complete CPS sequences, including a sequence from Sulfolobus solfataricus P2 which we report in this paper. This is the first report of a complete CPS gene sequence from an archaeon, and sequence analysis suggests that it encodes an enzyme similar to heterodimeric CPSII. We confirm that internal similarity within the synthetase domain of CPS is the result of an ancient gene duplication that preceded the divergence of the Bacteria, Archaea, and Eukarya, and use this internal duplication in phylogenetic tree construction to root the tree of life. Our analysis indicates with high confidence that this archaeal sequence is more closely related to those of Eukarya than to those of Bacteria. In addition to this ancient duplication which created the synthetase domain, our phylogenetic analysis reveals a complex history of further gene duplications, fusions, and other events which have played an integral part in the evolution of CPS. [ABSTRACT FROM PUBLISHER]

Because vertical transmission of human immunodeficiency virus type 1 (HIV-1) from mother to infant occurs in only 15%-35% of possible opportunities, natural immune defenses of the mother, fetus, or neonate may be protective against infection. The relation between antibody-dependent cellular cytotoxicity (ADCC) antibodies and HIV-1 infection was explored in 78 neonates born to HIV-infected women. More than 90% of sera had measurable ADCC titers against HIV-1IIIB Infant titers were closely correlated with maternal titers but were independent of total IgG and total antibody reactive to the same strain in whole virus ELISA. At birth, mean ADCC antibody levels of infants or their mothers were the same for infants who were infected and those who ultimately seroreverted and remained healthy. ADCC antibody titers against HIV-1SF2 were weakly correlated with anti-HIV-1IIIB titers and did not predict protection from HIV-1 infection. High levels of anti-HIV-1 ADCC antibody at birth are not protective against vertical transmission of HI V-I. [ABSTRACT FROM PUBLISHER]

Patients with AIDS and disseminated Mycobacterium avium complex (MAC) infection received rifampin (600 mg) plus ethambutol (25 mg/kg) plus ciprofloxacin (750 mg) or matching placebos daily for 8 weeks. Patients were monitored every 2 weeks clinically and by quantitating MAC colony-forming units (cfu) per milliliter of blood. Analysis of baseline characteristics revealed no significant differences between groups. After 8 weeks, MAC cfu had decreased by > or = 1 log/mL in 4 of 9 treated patients versus 0 of 10 placebo recipients while increasing by > or = 1 log/mL in 1 and 7, respectively (P = .006). While the average combined clinical response score declined in both groups, it tended to decrease less in treated patients (P = .36). On the other hand, dose-limiting toxicity (primarily nausea and adverse drug interactions) occurred in 9 of 12 treatment versus 1 of 12 placebo patients (P = .005). Combined rifampin [corrected]-ethambutol-ciprofloxacin therapy for disseminated MAC infection had significant microbiologic efficacy with some evidence of clinical efficacy but was associated with drug intolerance. [ABSTRACT FROM AUTHOR]

The epitopes on herpes simplex virus (HSV) glycoprotein B (gB) recognized by sera of 23 patients with well-characterized HSV infection were studied. Twelve epitope-specific monoclonal antibodies with neutralization (NT) or antibody-dependent cellular cytotoxicity (ADCC) activities were used in competitive ELISA binding inhibition studies. The sera were additionally analyzed for homologous viral type NT, ADCC activity, and gB-reactive antibody by ELISA. Seroconversion was observed in each assay during convalescence. Relative type specificity for sera from HSV-l-infected but not from HSV-2-infected individuals was demonstrated in the ADCC assay. Sera from HSV-infected patients contained antibodies recognizing 9 of 12 epitopes, representing 5 of the 6 characterized antigenic domains of gB tested. Two of the epitopes were blocked in a type-specific fashion. The incidence ofepitopic recognition increased gradually with time and was delayed compared with the detection of functional ADCC or NT activity and overall antibody recognition of gB in the ELISA. [ABSTRACT FROM PUBLISHER]