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Tuberculous meningitis (TBM) is a devastating infection of the central nervous system lacking an adequate point-of-care diagnostic test. We conducted a prospective cohort study of 550 Zambian adults with suspected TBM to determine the diagnostic accuracy of cerebrospinal fluid (CSF) Xpert MTB/RIF, CSF lipoarabinomannan (LAM), urine LAM, CSF total protein, and CSF glucose compared with the gold standard of CSF culture. We categorized patients with a positive CSF tuberculosis (TB) culture as definite TBM. We also assessed inpatient and 1-year mortality on definite TBM patients when CSF Xpert MTB/RIF results were available in real time to treating physicians relative to a historical comparison cohort in whom Xpert results were not available in real time. Of the 550 patients, 474 (86.2%) were HIV-infected and 105/550 (19.1%) had definite TBM based on a positive CSF culture. The sensitivity/specificity of the diagnostic tests were CSF Xpert MTB/RIF, 52.9%/94.2%; CSF LAM, 21.9%/94.2%; urine LAM, 24.1%/76.1%; and CSF glucose 100 mg/dl, 66.3%/90%. A model including CSF Xpert MTB/RIF, CSF LAM, CSF glucose, and CSF total protein demonstrated an area under the receiver operating curve of 0.90. The inpatient and 1-year mortality for definite TBM was 43% and 57%, respectively. There was low sensitivity for the diagnosis of TBM across all diagnostics tests. CSF Xpert MTB/RIF and CSF LAM are highly specific for the diagnosis of TBM. Despite the use of Xpert MTB/RIF for diagnostic purpose in real time, TBM was still associated with a high mortality in Zambian patients.

Begg and Mazumdar proposed using a rank correlation test to test for publication bias when carrying out meta-analyses. The asymptotic variance of the rank correlation test statistic was derived under assumptions unmet by this application, often resulting in a loss of power. Low power when Begg's test is used to screen for publication bias may lead to false positives in a subsequent meta-analysis. We obtain the asymptotic bias under the common conditionally normal model as a function of the distribution of primary study variances. In simulations, we consider the performance of Begg's test using an approximation to the correct asymptotic variance. We consider this performance under the common fixed effects and random effects frameworks. We then examine several meta-analyses drawn from the literature where the standard and bias-corrected versions of Begg's test lead to different conclusions. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression.

Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic "signatures" within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.

Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that [CD4.sup.+] cytotoxic T cells and [CD8.sup.+] T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR-expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic [CD4.sup.+] T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction., Introduction Systemic sclerosis (SSc) is a systemic autoimmune inflammatory disorder of unknown etiology characterized by prominent fibrosis that may affect many organs including the skin, lungs, kidneys, and gastrointestinal tract [...]

CD8(+) T cells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8(+) T cell response, with limited bystander activation of non-HIV memory CD8(+) T cells. HIV-specific CD8(+) T cells secreted little interferon-γ, underwent rapid apoptosis, and failed to upregulate the interleukin-7 receptor, known to be important for T cell survival. The rapidity to peak CD8(+) T cell activation and the absolute magnitude of activation induced by the exponential rise in viremia were inversely correlated with set point viremia. These data indicate that rapid, high magnitude HIV-induced CD8(+) T cell responses are crucial for subsequent immune control of acute infection, which has important implications for HIV vaccine design.

Abstract Background HLA-B alleles are associated with viral control in chronic HIV-1 infection, however, their role in primary HIV-1 disease is unclear. This study sought to determine the role of HLA-B alleles in viral control during the acute phase of HIV-1 infection and establishment of the early viral load set point (VLSP). Findings Individuals identified during primary HIV-1 infection were HLA class I typed and followed longitudinally. Associations between HLA-B alleles and HIV-1 viral replication during acute infection and VLSP were analyzed in untreated subjects. The results showed that neither HLA-B*57 nor HLA-B*27 were significantly associated with viral control during acute HIV-1 infection (Fiebig stage I-IV, n=171). HLA-B*57 was however significantly associated with a subsequent lower VLSP (p

The human gut mucosa is a major site of human immunodeficiency virus (HIV) infection and infection-associated pathogenesis. Increasing evidence shows that natural killer (NK) cells have an important role in control of HIV infection, but the mechanism(s) by which they mediate antiviral activity in the gut is unclear. Here, we show that two distinct subsets of NK cells exist in the gut, one localized to intraepithelial spaces (intraepithelial lymphocytes, IELs) and the other to the lamina propria (LP). The frequency of both subsets of NK cells was reduced in chronic infection, whereas IEL NK cells remained stable in spontaneous controllers with protective killer immunoglobulin-like receptor/human leukocyte antigen genotypes. Both IEL and LP NK cells were significantly expanded in immunological non-responsive patients, who incompletely recovered CD4+ T cells on highly active antiretroviral therapy (HAART). These data suggest that both IEL and LP NK cells may expand in the gut in an effort to compensate for compromised CD4+ T-cell recovery, but that only IEL NK cells may be involved in providing durable control of HIV in the gut.

In this article, we compared the binormal and the Lehmann receiver operating characteristic (ROC) curves using extensive simulation studies and real data sets related to HIV. We ran a large set of simulation studies with a wide range of distributions, varying sample sizes, and different degrees of overlap between the diseased and non-diseased population distributions. Simulation results suggest that the binormal ROC model performs better for normal data. However, for non-normal data, the Lehman model outperforms the binormal model. The discrepancies between the performances of the two models were more apparent for larger sample sizes or larger degree of separation between the distributions of the diseased and non-diseased subjects. Like the binormal model, the Lehman model provides smooth estimates of ROC curves and a closed-form expression for the area under the ROC curve. Moreover, the Lehmann model can also be used to obtain covariate-adjusted ROC curves and accommodates inference of correlated and longitudinal biomarkers. Thus, the Lehman model should be considered as an alternative when the restrictive distributional assumptions of the binormal model are not met. [ABSTRACT FROM AUTHOR]

Background: The goals of this prospective longitudinal study were to monitor levels of psychosocial stress in children and adolescents with Tourette syndrome (TS) and/or obsessive-compulsive disorder (OCD) compared to healthy control subjects and to examine the relationship between measures of psychosocial stress and fluctuations in tic, obsessive-compulsive (OC), and depressive symptom severity. Methods: Consecutive ratings of tic, OC and depressive symptom severity were obtained for 45 cases and 41 matched healthy control subjects over a two-year period. Measures of psychosocial stress included youth self-report, parental report, and clinician ratings of long-term contextual threat. Structural equation modeling for unbalanced repeated measures was used to assess the temporal sequence of psychosocial stress with the severity of tic, OC and depressive symptoms. Results: Subjects with TS and OCD experienced significantly more psychosocial stress than did the controls. Estimates of psychosocial stress were predictive of future depressive symptoms. Current levels of psychosocial stress were also a significant predictor of future OC symptom severity, but not vice versa. Current OC symptom severity was a predictor of future depressive symptom severity, but not vice versa. Current levels of psychosocial stress and depression were independent predictors of future tic severity, even after controlling for the effect of advancing chronological age. Conclusions: The impact of antecedent psychosocial adversity is greater on future depressive symptoms than for tic and/or OC symptoms. Worsening OC symptoms are also a predictor of future depressive symptoms. Advancing chronological age is robustly associated with reductions in tic severity.

This study examined the longitudinal effects of coping on outcome one year following completion of a randomized, controlled trial of a group coping intervention for AIDS-related bereavement. Bereaved HIV-positive participants (N = 267) were administered measures of grief, psychiatric distress, quality of life, and coping at baseline, post-intervention, and at 4-, 8-, and 12-month follow-ups. Coping strategies directly impacted all outcome variables for both study conditions. Additionally, the coping intervention moderated the relationship between avoidant coping and the longitudinal course of grief and psychiatric distress, resulting in greater reductions in grief and distress for intervention participants after accounting for avoidant coping strategies. (Contains 4 tables and 1 figure.)