A systematic evaluation of the robustness of the evidence supporting current guidelines on myocardial revascularization using the Fragility Index

Background: RCTs (randomized controlled trials) are the preferred source of evidence to support professional societies’ guidelines. The fragility index (FI), defined as the minimum number of patients whose status would need to switch from nonevent to event to render a statistically significant result nonsignificant, quantitatively estimates the robustness of RCT results. We evaluate RCTs supporting current guidelines on myocardial revascularization using the FI and FI minus number of patients lost to follow-up. Methods and Results: The FI and FI minus number of patients lost to follow-up of RCTs supporting the 2012 American College of Cardiology/American Heart Association Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease, the 2014 Focused Update of the American College of Cardiology/American Heart Association Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease, and the 2018 European Society of Cardiology/European Association for Cardio-Thoracic Surgery Guidelines for Myocardial Revascularization were calculated. Of 414 RCTs identified, 160 were eligible for FI calculation. The median FI was 8.0 (95% CI, 5.0–9.0) and the median FI minus number of patients lost to follow-up was 1.0 (95% CI, 0.0–3.0). FI was ≤3, indicating very limited robustness, in 44 (27.5%) RCTs, and was lower than the number LTF, indicating limited robustness, in 68 (42.5%) RCTs. FI was significantly (all P<0.05) correlated with the sample size, number of events, statistical power, journal impact factor, use of intention-to-treat analysis, and of composite end points and negatively correlated with the use of percutaneous interventions in the treatment arm and the P-value level. Conclusions: More than a quarter of RCTs that support current guidelines on myocardial revascularization have a FI of 3 or lower, and over 40% of trials reveal a FI that is lower than the number of patients lost to follow-up. These findings suggest that the robustness of the findings that support current myocardial revascularization guidelines is tenuous and vulnerable to change as new evidence from RCTs appears

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation

Monitoring Inequalities in the Health Workforce: The Case Study of Brazil 1991–2005

Introduction: Both the quantity and the distribution of health workers in a country are fundamental for assuring equitable access to health services. Using the case of Brazil, we measure changes in inequalities in the distribution of the health workforce and account for the sources of inequalities at sub-national level to identify whether policies have been effectiv

Is HIV Infection a Risk Factor for Multi-Drug Resistant Tuberculosis? A Systematic Review

BACKGROUND:Tuberculosis (TB) is an important cause of human suffering and death. Human immunodeficiency virus (HIV), multi-drug resistant TB (MDR-TB), and extensive drug resistant tuberculosis (XDR-TB) have emerged as threats to TB control. The association between MDR-TB and HIV infection has not yet been fully investigated. We conducted a systematic review and meta-analysis to summarize the evidence on the association between HIV infection and MDR-TB. METHODS AND RESULTS:Original studies providing Mycobacterium tuberculosis resistance data stratified by HIV status were identified using MEDLINE and ISI Web of Science. Crude MDR-TB prevalence ratios were calculated and analyzed by type of TB (primary or acquired), region and study period. Heterogeneity across studies was assessed, and pooled prevalence ratios were generated if appropriate. No clear association was found between MDR-TB and HIV infection across time and geographic locations. MDR-TB prevalence ratios in the 32 eligible studies, comparing MDR-TB prevalence by HIV status, ranged from 0.21 to 41.45. Assessment by geographical region or study period did not reveal noticeable patterns. The summary prevalence ratios for acquired and primary MDR-TB were 1.17 (95% CI 0.86, 1.6) and 2.72 (95% CI 2.03, 3.66), respectively. Studies eligible for review were few considering the size of the epidemics. Most studies were not adjusted for confounders and the heterogeneity across studies precluded the calculation of a meaningful overall summary measure. CONCLUSIONS:We could not demonstrate an overall association between MDR-TB and HIV or acquired MDR-TB and HIV, but our results suggest that HIV infection is associated with primary MDR-TB. Future well-designed studies and surveillance in all regions of the world are needed to better clarify the relationship between HIV infection and MDR-TB

Clinical and laboratory experience of vorinostat (suberoylanilide hydroxamic acid) in the treatment of cutaneous T-cell lymphoma

The most common cutaneous T-cell lymphomas (CTCLs) – mycosis fungoides (MF) and Sézary Syndrome – are characterised by the presence of clonally expanded, skin-homing helper-memory T cells exhibiting abnormal apoptotic control mechanisms. Epigenetic modulation of genes that induce apoptosis and differentiation of malignant T cells may therefore represent an attractive new strategy for targeted therapy for T-cell lymphomas. In vitro studies show that vorinostat (suberoylanilide hydroxamic acid or SAHA), an oral inhibitor of class I and II histone deacetylases, induces selective apoptosis of malignant CTCL cell lines and peripheral blood lymphocytes from CTCL patients at clinically achievable doses. In a Phase IIa clinical trial, vorinostat therapy achieved a meaningful partial response (>50% reduction in disease burden) in eight out of 33 (24%) patients with heavily pretreated, advanced refractory CTCL. The most common major toxicities of oral vorinostat therapy were fatigue and gastrointestinal symptoms (diarrhoea, altered taste, nausea, and dehydration from not eating). Thrombocytopenia was dose limiting in patients receiving oral vorinostat at the higher dose induction levels of 300 mg twice daily for 14 days. These studies suggest that vorinostat represents a promising new agent in the treatment of CTCL patients. Additional studies are underway to define the exact mechanism (s) of by which vorinostat induces selective apoptosis in CTCL cells and to further evaluate the antitumour efficacy of vorinostat in a Phase IIb study in CTCL patients

Incident Tuberculosis during Antiretroviral Therapy Contributes to Suboptimal Immune Reconstitution in a Large Urban HIV Clinic in Sub-Saharan Africa

Antiretroviral therapy (ART) effectively decreases tuberculosis (TB) incidence long-term, but is associated with high TB incidence rates in the first 6 months. We sought to determine the incidence and the long-term effects of TB during ART on HIV treatment outcome, and the risk factors for incident TB during ART in a large urban HIV clinic in Uganda.Routinely collected longitudinal clinical data from all patients initiated on first-line ART was retrospectively analysed. 5,982 patients were included with a median baseline CD4+ T cell count (CD4 count) of 117 cells/mm(3) (interquartile range [IQR]; 42, 182). In the first 2 years, there were 336 (5.6%) incident TB events in 10,710 person-years (py) of follow-up (3.14 cases/100 pyar [95% CI 2.82-3.49]); incidence rates at 0-3, 3-6, 6-12 and 12-24 months were 11.25 (9.58-13.21), 6.27 (4.99-7.87), 2.47 (1.87-3.36) and 1.02 (0.80-1.31), respectively. Incident TB during ART was independently associated with baseline CD4 count of <50 cells/mm(3) (hazard ratio [HR] 1.84 [1.25-2.70], P = 0.002) and male gender (HR 1.68 [1.34-2.11], P<0.001). After two years on ART, the patients who had developed TB in the first 12 months had a significantly lower median CD4 count increase (184 cells/mm(3) [IQR; 107, 258, n = 118] vs 209 cells/mm(3) [124, 309, n = 2166], P = 0.01), a larger proportion of suboptimal immune reconstitution according to two definitions (increase in CD4 count <200 cells/mm(3): 57.4% vs 46.9%, P = 0.03, and absolute CD4 count <200 cells/mm(3): 30.4 vs 19.9%, P = 0.006), and a higher percentage of immunological failure according to the WHO criteria (13.6% vs 6.5%, P = 0.003). Incident TB during ART was independently associated with poor CD4 count recovery and fulfilling WHO immunological failure definitions.Incident TB during ART occurs most often within 3 months and in patients with CD4 counts less than 50 cells/mm(3). Incident TB during ART is associated with long-term impairment in immune recovery

The Effect of Tuberculosis on Mortality in HIV Positive People: A Meta-Analysis

Tuberculosis is a leading cause of death in people living with HIV (PLWH). We conducted a meta analysis to assess the effect of tuberculosis on mortality in people living with HIV. Meta-analysis of cohort studies assessing the effect of tuberculosis on mortality in PLWH. To identify eligible studies we systematically searched electronic databases (until December 2008), performed manual searches of citations from relevant articles, and reviewed conference proceedings. Multivariate hazard ratios (HR) of mortality in PLWH with and without tuberculosis, estimated in individual cohort studies, were pooled using random effect weighting according to "Der Simonian Laird method" if the p-value of the heterogeneity test was <0.05. Fifteen cohort studies were systematically retrieved. Pooled overall analysis of these 15 studies estimating the effect of tuberculosis on mortality in PLWH showed a Hazard Ratio (HR) of 1.8 (95% confidence interval (CI): 1.4-2.3). Subanalysis of 8 studies in which the cohort was not exposed to highly active antiretroviral therapy (HAART) showed an HR of 2.6 (95% CI: 1.8-3.6). Subanalysis of 6 studies showed that tuberculosis did not show an effect on mortality in PLWH exposed to HAART: HR 1.1 (95% CI: 0.9-1.3). These results provide an indication of the magnitude of benefit to an individual that could have been expected if tuberculosis had been prevented. It emphasizes the need for additional studies assessing the effect of preventing tuberculosis or early diagnosis and treatment of tuberculosis in PLWH on reducing mortality. Furthermore, the results of the subgroup analyses in cohorts largely exposed to HAART provide additional support to WHO's revised guidelines, which include promoting the initiation of HAART for PLWH co-infected with tuberculosis. The causal effect of tuberculosis on mortality in PLWH exposed to HAART needs to be further evaluated once the results of more cohort studies become availabl

Tailored design of NKT-stimulatory glycolipids for polarization of immune responses

Natural killer T (NKT) cell is a distinct population of T lymphocytes that can rapidly release massive amount of Th1 and Th2 cytokines upon the engagement of their T cell receptor with glycolipids presented by CD1d. The secreted cytokines can promote cell-mediated immunity to kill tumor cells and intracellular pathogens, or suppress autoreactive immune cells in autoimmune diseases. Thus, NKT cell is an attractive target for developing new therapeutics to manipulate immune system. The best-known glycolipid to activate NKT cells is α-galactosylceramide (α-GalCer), which has been used as a prototype for designing new NKT stimulatory glycolipids. Many analogues have been generated by modification of the galactosyl moiety, the acyl chain or the phytosphingosine chain of α-GalCer. Some of the analogues showed greater abilities than α-GalCer in polarizing immune responses toward Th1 or Th2 dominance. Among them, several analogues containing phenyl groups in the lipid tails were more potent in inducing Th1-skewed cytokines and exhibited greater anticancer efficacy than α-GalCer. Analyses of the correlation between structure and activity of various α-GalCer analogues on the activation of iNKT cell revealed that CD1d–glycolipid complexes interacted with the same population of iNKT cell expressing similar T-cell receptor Vβ as α-GalCer. On the other hand, those phenyl glycolipids with propensity for Th1 dominant responses showed greater binding avidity and stability than α-GalCer for iNKT T-cell receptor when complexed with CD1d. Thus, it is the avidity and stability of the ternary complexes of CD1d-glycolipid-iNKT TCR that dictate the polarity and potency of immune responses. These findings provide a key to the rationale design of immune modulating glycolipids with desirable Th1/Th2 polarity for clinical application. In addition, elucidation of α-GalCer-induced anergy, liver damage and accumulation of myeloid derived suppressor cells has offered explanation for its lacklustre anti-cancer activities in clinical trials. On other hand, the lack of such drawbacks in glycolipid analogues containing phenyl groups in the lipid tails of α-GalCer coupled with the greater binding avidity and stability of CD1d-glycolipid complex for iNKT T-cell receptor, account for their superior anti-cancer efficacy in tumor bearing mice. Further clinical development of these phenyl glycolipids is warranted

Small RNA-based antimicrobial immunity

Protection against microbial infection in eukaryotes is provided by diverse cellular and&nbsp;molecular mechanisms. Here, we present a comparative view of the antiviral activity of virus-derived small interfering RNAs in fungi, plants, invertebrates and mammals, detailing the&nbsp;mechanisms for their production, amplification and activity. We also highlight the recent discovery of viral PIWI-interacting RNAs in animals and a new role for mobile host and pathogen small RNAs in plant defence against eukaryotic pathogens. In turn, viruses that infect plants, insects and mammals, as well as eukaryotic pathogens of plants, have evolved specific virulence proteins that suppress RNA interference (RNAi). Together, these advances suggest that an antimicrobial function of the RNAi pathway is conserved across eukaryotic kingdoms