Stroke, coronary and peripheral artery disease survey on antithrombotic treatment (START IT)

QUESTIONS UNDER STUDY: To determine the perception of primary care physicians regarding the risk of subsequent atherothrombotic events in patients with established cardiovascular (CV) disease, and to correlate this perception with documented antithrombotic therapy. METHODS: In a cross-sectional study of the general practice population in Switzerland, 381 primary care physicians screened 127 040 outpatients during 15 consecutive workdays in 2006. Perception of subsequent atherothrombotic events in patients with established CV disease was assessed using a tick box questionnaire allowing choices between low, moderate, high or very high risk. Logistic regression models were used to determine the relationship between risk perception and antithrombotic treatment. RESULTS: Overall, 13 057 patients (10.4%) were identified as having established CV disease and 48.8% of those were estimated to be at high to very high risk for subsequent atherothrombotic events. Estimated higher risk for subsequent atherothrombotic events was associated with a shift from aspirin monotherapy to clopidogrel, vitamin K antagonist or aspirin plus clopidogrel (p <0.001 for trend). Clopidogrel (12.7% vs 6.8%, p <0.001), vitamin K antagonist (24.5% vs 15.6%, p <0.001) or aspirin plus clopidogrel (10.2% vs 4.2%, p <0.001) were prescribed in patients estimated to be at high to very high risk more often than in those at low to moderate risk. CONCLUSIONS: Perception of primary care physicians regarding risk of subsequent atherothrombotic events varies in patients with CV disease, and as a result antithrombotic therapy is altered in patients with anticipated high to very high risk even though robust evidence and clear guidelines are lacking.

Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial (PROVASA)

Critical limb ischemia due to peripheral arterial occlusive disease is associated with a severely increased morbidity and mortality. There is no effective pharmacological therapy available. Injection of autologous bone marrow-derived mononuclear cells (BM-MNC) is a promising therapeutic option in patients with critical limb ischemia, but double-blind, randomized trials are lacking.

Randomised trial of a clinical dosing algorithm to start anticoagulation with phenprocoumon

Prospective validation of two algorithms for the initiation of phenprocoumon treatment.

Sendai virus RNA polymerase scanning for mRNA start sites at gene junctions

Mini-genomes expressing two reporter genes and a variable gene junction were used to study Sendai virus RNA polymerase (RdRp) scanning for the mRNA start signal of the downstream gene (gs2). We found that RdRp could scan the template efficiently as long as the initiating uridylate of gs2 (3' UCCCnnUUUC) was preceded by the conserved intergenic region (3' GAA) and the last 3 uridylates of the upstream gene end signal (ge1; 3' AUUCUUUUU). The end of the leader sequence (3' CUAAAA, which precedes gs1) could also be used for gene2 expression, but this sequence was considerably less efficient. Increasing the distance between ge1 and gs2 (up to 200 nt) led to the progressive loss of gene2 expression, in which half of gene2 expression was lost for each 70 nucleotides of intervening sequence. Beyond 200 nt, gene2 expression was lost more slowly. Our results suggest that there may be two populations of RdRp that scan at gene junctions, which can be distinguished by the efficiency with which they can scan the genome template for gs.

CD4+ T-cell count increase in HIV-1-infected patients with suppressed viral load within 1 year after start of antiretroviral therapy

BACKGROUND: CD4+ T-cell recovery in patients with continuous suppression of plasma HIV-1 viral load (VL) is highly variable. This study aimed to identify predictive factors for long-term CD4+ T-cell increase in treatment-naive patients starting combination antiretroviral therapy (cART). METHODS: Treatment-naive patients in the Swiss HIV Cohort Study reaching two VL measurements <50 copies/ml >3 months apart during the 1st year of cART were included (n=1816 patients). We studied CD4+ T-cell dynamics until the end of suppression or up to 5 years, subdivided into three periods: 1st year, years 2-3 and years 4-5 of suppression. Multiple median regression adjusted for repeated CD4+ T-cell measurements was used to study the dependence of CD4+ T-cell slopes on clinical covariates and drug classes. RESULTS: Median CD4+ T-cell increases following VL suppression were 87, 52 and 19 cells/microl per year in the three periods. In the multiple regression model, median CD4+ T-cell increases over all three periods were significantly higher for female gender, lower age, higher VL at cART start, CD4+ T-cell <650 cells/microl at start of the period and low CD4+ T-cell increase in the previous period. Patients on tenofovir showed significantly lower CD4+ T-cell increases compared with stavudine. CONCLUSIONS: In our observational study, long-term CD4+ T-cell increase in drug-naive patients with suppressed VL was higher in regimens without tenofovir. The clinical relevance of these findings must be confirmed in, ideally, clinical trials or large, collaborative cohort projects but could influence treatment of older patients and those starting cART at low CD4+ T-cell levels.

Retention in care of HIV-infected children from HIV test to start of antiretroviral therapy: systematic review

BACKGROUND In adults it is well documented that there are substantial losses to the programme between HIV testing and start of antiretroviral therapy (ART). The magnitude and reasons for loss to follow-up and death between HIV diagnosis and start of ART in children are not well defined. METHODS We searched the PubMed and EMBASE databases for studies on children followed between HIV diagnosis and start of ART in low-income settings. We examined the proportion of children with a CD4 cell count/percentage after after being diagnosed with HIV infection, the number of treatment-eligible children starting ART and predictors of loss to programme. Data were extracted in duplicate. RESULTS Eight studies from sub-Saharan Africa and two studies from Asia with a total of 10,741 children were included. Median age ranged from 2.2 to 6.5 years. Between 78.0 and 97.0% of HIV-infected children subsequently had a CD4 cell count/percentage measured, 63.2 to 90.7% of children with an eligibility assessment met the eligibility criteria for the particular setting and time and 39.5 to 99.4% of the eligible children started ART. Three studies reported an association between low CD4 count/percentage and ART initiation while no association was reported for gender. Only two studies reported on pre-ART mortality and found rates of 13 and 6 per 100 person-years. CONCLUSION Most children who presented for HIV care met eligibility criteria for ART. There is an urgent need for strategies to improve the access to and retention to care of HIV-infected children in resource-limited settings.

When to start antiretroviral therapy in children aged 2-5 years: a collaborative causal modelling analysis of cohort studies from southern Africa

BACKGROUND There is limited evidence on the optimal timing of antiretroviral therapy (ART) initiation in children 2-5 y of age. We conducted a causal modelling analysis using the International Epidemiologic Databases to Evaluate AIDS-Southern Africa (IeDEA-SA) collaborative dataset to determine the difference in mortality when starting ART in children aged 2-5 y immediately (irrespective of CD4 criteria), as recommended in the World Health Organization (WHO) 2013 guidelines, compared to deferring to lower CD4 thresholds, for example, the WHO 2010 recommended threshold of CD4 count <750 cells/mm(3) or CD4 percentage (CD4%) <25%. METHODS AND FINDINGS ART-naïve children enrolling in HIV care at IeDEA-SA sites who were between 24 and 59 mo of age at first visit and with ≥1 visit prior to ART initiation and ≥1 follow-up visit were included. We estimated mortality for ART initiation at different CD4 thresholds for up to 3 y using g-computation, adjusting for measured time-dependent confounding of CD4 percent, CD4 count, and weight-for-age z-score. Confidence intervals were constructed using bootstrapping. The median (first; third quartile) age at first visit of 2,934 children (51% male) included in the analysis was 3.3 y (2.6; 4.1), with a median (first; third quartile) CD4 count of 592 cells/mm(3) (356; 895) and median (first; third quartile) CD4% of 16% (10%; 23%). The estimated cumulative mortality after 3 y for ART initiation at different CD4 thresholds ranged from 3.4% (95% CI: 2.1-6.5) (no ART) to 2.1% (95% CI: 1.3%-3.5%) (ART irrespective of CD4 value). Estimated mortality was overall higher when initiating ART at lower CD4 values or not at all. There was no mortality difference between starting ART immediately, irrespective of CD4 value, and ART initiation at the WHO 2010 recommended threshold of CD4 count <750 cells/mm(3) or CD4% <25%, with mortality estimates of 2.1% (95% CI: 1.3%-3.5%) and 2.2% (95% CI: 1.4%-3.5%) after 3 y, respectively. The analysis was limited by loss to follow-up and the unavailability of WHO staging data. CONCLUSIONS The results indicate no mortality difference for up to 3 y between ART initiation irrespective of CD4 value and ART initiation at a threshold of CD4 count <750 cells/mm(3) or CD4% <25%, but there are overall higher point estimates for mortality when ART is initiated at lower CD4 values. Please see later in the article for the Editors' Summary.

Immunodeficiency at the start of combination antiretroviral therapy in low-, middle-, and high-income countries

OBJECTIVE To describe the CD4 cell count at the start of combination antiretroviral therapy (cART) in low-income (LIC), lower middle-income (LMIC), upper middle-income (UMIC), and high-income (HIC) countries. METHODS Patients aged 16 years or older starting cART in a clinic participating in a multicohort collaboration spanning 6 continents (International epidemiological Databases to Evaluate AIDS and ART Cohort Collaboration) were eligible. Multilevel linear regression models were adjusted for age, gender, and calendar year; missing CD4 counts were imputed. RESULTS In total, 379,865 patients from 9 LIC, 4 LMIC, 4 UMIC, and 6 HIC were included. In LIC, the median CD4 cell count at cART initiation increased by 83% from 80 to 145 cells/μL between 2002 and 2009. Corresponding increases in LMIC, UMIC, and HIC were from 87 to 155 cells/μL (76% increase), 88 to 135 cells/μL (53%), and 209 to 274 cells/μL (31%). In 2009, compared with LIC, median counts were 13 cells/μL [95% confidence interval (CI): -56 to +30] lower in LMIC, 22 cells/μL (-62 to +18) lower in UMIC, and 112 cells/μL (+75 to +149) higher in HIC. They were 23 cells/μL (95% CI: +18 to +28 cells/μL) higher in women than men. Median counts were 88 cells/μL (95% CI: +35 to +141 cells/μL) higher in countries with an estimated national cART coverage >80%, compared with countries with <40% coverage. CONCLUSIONS Median CD4 cell counts at the start of cART increased 2000-2009 but remained below 200 cells/μL in LIC and MIC and below 300 cells/μL in HIC. Earlier start of cART will require substantial efforts and resources globally.

WHEN DOES THE TROUBLE START? OBESITY, DIABETES RISKS AND METABOLIC DISTURBANCES IN YOUNG PEOPLE WITH PSYCHOSIS

People with psychotic disorders have higher mortality rates compared to the general population. Most deaths are due to cardiovascular (CV) disease, reflecting high rates of CV risk factors such as obesity and diabetes. Treatment with antipsychotic drugs is associated with weight gain in clinical trials. However, there is little information about how these drugs affect children and young people, and how early in the course of treatment the elevation in CV risk factors begins. This information is essential in understanding the costs and benefits of these treatments in young people, and establishing preventive and early intervention services to address physical health comorbidities. This symposium reports both prospective and naturalistic data from children and adolescents treated with antipsychotic drugs. These studies demonstrate that adverse effects on cardiometabolic measures, notably BMI and insulin resistance, become apparent very soon after treatment is initiated. Further, children and adolescents appear to be even more sensitive to these effects than adults. Population-wide studies are also informative. Danish data showing that young people exposed to antipsychotics have a higher risk of diabetes, compared with young people who had a psychiatric diagnosis but were not exposed to antipsychotic drugs, will be presented. In addition, an Australian comparison between a large, nationally representative sample of people with psychosis and a general population sample shows that higher rates of obesity and other cardiometabolic abnormalities are already evident in people with psychosis by the age of 25 years. Young people living with psychosis are already disadvantaged by the demands of living with mental illness, stigma, and social factors such as unemployment and low income. The addition of obesity, diabetes and other comorbidities adds a further burden. The data presented highlights the need for careful selection of antipsychotic drugs, regular monitoring of physical health and early intervention when weight gain, glucose dysregulation, or other cardiometabolic abnormalities are detected.

The effect of ego depletion on sprint start reaction time

In the current study, we consider that optimal sprint start performance requires the self-control of responses. Therefore, start performance should depend on athletes' self-control strength. We assumed that momentary depletion of self-control strength (ego depletion) would either speed up or slow down the initiation of a sprint start, where an initiation that was sped up would carry the increased risk of a false start. Applying a mixed between- (depletion vs. nondepletion) and within- (before vs. after manipulation of depletion) subjects design, we tested the start reaction times of 37 sport students. We found that participants' start reaction times decelerated after finishing a depleting task, whereas it remained constant in the nondepletion condition. These results indicate that sprint start performance can be impaired by unrelated preceding actions that lower momentary self-control strength. We discuss practical implications in terms of optimizing sprint starts and related overall sprint performance.