Estimating the Impact of Plasma HIV-1 RNA Reductions on Heterosexual HIV-1 Transmission Risk

Background

The risk of sexual transmission of HIV-1 is strongly associated with the level of HIV-1 RNA in plasma making reduction in HIV-1 plasma levels an important target for HIV-1 prevention interventions. A quantitative understanding of the relationship of plasma HIV-1 RNA and HIV-1 transmission risk could help predict the impact of candidate HIV-1 prevention interventions that operate by reducing plasma HIV-1 levels, such as antiretroviral therapy (ART), therapeutic vaccines, and other non-ART interventions.

Methodology/Principal Findings

We use prospective data collected from 2004 to 2008 in East and Southern African HIV-1 serodiscordant couples to model the relationship of plasma HIV-1 RNA levels and heterosexual transmission risk with confirmation of HIV-1 transmission events by HIV-1 sequencing. The model is based on follow-up of 3381 HIV-1 serodiscordant couples over 5017 person-years encompassing 108 genetically-linked HIV-1 transmission events. HIV-1 transmission risk was 2.27 per 100 person-years with a log-linear relationship to log₁₀ plasma HIV-1 RNA. The model predicts that a decrease in average plasma HIV-1 RNA of 0.74 log₁₀ copies/mL (95% CI 0.60 to 0.97) reduces heterosexual transmission risk by 50%, regardless of the average starting plasma HIV-1 level in the population and independent of other HIV-1-related population characteristics. In a simulated population with a similar plasma HIV-1 RNA distribution the model estimates that 90% of overall HIV-1 infections averted by a 0.74 copies/mL reduction in plasma HIV-1 RNA could be achieved by targeting this reduction to the 58% of the cohort with plasma HIV-1 levels ≥4 log₁₀ copies/mL.

Conclusions/Significance

This log-linear model of plasma HIV-1 levels and risk of sexual HIV-1 transmission may help estimate the impact on HIV-1 transmission and infections averted from candidate interventions that reduce plasma HIV-1 RNA levels.     

Independent Component Analysis-Based Identification of Covariance Patterns of Microstructural White Matter Damage in Alzheimer’s Disease

The existing DTI studies have suggested that white matter damage constitutes an important part of the neurodegenerative changes in Alzheimer’s disease (AD). The present study aimed to identify the regional covariance patterns of microstructural white matter changes associated with AD. In this study, we applied a multivariate analysis approach, independent component analysis (ICA), to identify covariance patterns of microstructural white matter damage based on fractional anisotropy (FA) skeletonised images from DTI data in 39 AD patients and 41 healthy controls (HCs) from the Alzheimer’s Disease Neuroimaging Initiative database. The multivariate ICA decomposed the subject-dimension concatenated FA data into a mixing coefficient matrix and a source matrix. Twenty-eight independent components (ICs) were extracted, and a two sample t-test on each column of the corresponding mixing coefficient matrix revealed significant AD/HC differences in ICA weights for 7 ICs. The covariant FA changes primarily involved the bilateral corona radiata, the superior longitudinal fasciculus, the cingulum, the hippocampal commissure, and the corpus callosum in AD patients compared to HCs. Our findings identified covariant white matter damage associated with AD based on DTI in combination with multivariate ICA, potentially expanding our understanding of the neuropathological mechanisms of AD.     

Limitations to antiarrhythmic drug use in patients with atrial fibrillation

Background

Of the antiarrhythmic agents currently marketed in Canada, 5 are commonly used to treat atrial fibrillation (AF). The impact of contraindications, warnings and precautions for the use of these drugs in patients with AF is not known. We evaluated the proportion of patients with AF for whom contraindications, warnings and/or precautions might limit the use of these commonly prescribed drugs and the proportion of patients actually receiving antiarrhythmic drugs despite the presence of contraindications and/or warnings.

Methods

A total of 723 patients with electrocardiographically confirmed, new-onset paroxysmal AF who were enrolled in the Canadian Registry of Atrial Fibrillation were used in this analysis. The 1996 Compendium of Pharmaceuticals and Specialties was used to obtain contraindications, warnings and precautions for use of 5 antiarrhythmic drugs: flecainide, quinidine, sotalol, amiodarone and propafenone. Proportions of patients with contraindications, warnings and/or precautions for use of any of these drugs owing to comorbid conditions or concomitant drug therapy were calculated, regardless of whether the drugs had been prescribed. We then calculated the proportion of patients taking each antiarrhythmic drug at 3 months despite contraindications and/or warnings.

Results

At baseline, when conditions for contraindications and warnings were combined, 414 (57%), 235 (33%), 327 (45%), 285 (39%) and 272 (38%) patients had restrictions for the use of flecainide, quinidine, sotalol, amiodarone and propafenone respectively. Among 465 patients actually taking these medications at 3-month follow-up, 33.3% (2/6), 83.3% (40/48), 36.4% (92/253), 64.1% (25/39) and 34.5% (41/119) respectively had contraindications and/or warnings against their use. The burden of comorbid disease among patients with AF was noteworthy: 404 (56%) had structural heart disease, which included 227 (31%) with ischemic heart disease, 158 (22%) with left ventricular systolic dysfunction and 106 (15%) with heart failure.

Interpretation

The high burden of comorbid disease and concomitant drug use in a large proportion of patients with AF limits the suitability of existing antiarrhythmic drugs. Over one-third of patients with new-onset AF received antiarrhythmic drugs despite the presence of contraindications or warnings. Although such restrictions may not preclude the use of these drugs, the results demonstrate the need for new antiarrhythmic drugs with fewer limitations.Atrial fibrillation (AF) is the most frequently encountered sustained arrhythmia in clinical practice and accounts for more physician visits and hospital days than any other cardiac arrhythmia.¹ Although it is usually not life-threatening, AF is associated with substantial morbidity and increased mortality, largely because of the increased risk of stroke and thromboembolic events.^2,3,4Maintenance of sinus rhythm by means of cardioversion and use of antiarrhythmic drugs is often the initial therapy for AF,⁵ although the results of recent randomized controlled trials have cast doubt on whether rhythm control should be routinely applied in patients with atrial fibrillation or flutter.^6,7 Several factors are offered as justification for the use of antiarrhythmic drug therapy: symptoms can substantially impair quality of life,^8,9 lack of active atrial transport and irregular, frequently rapid ventricular rates may result in reduced exercise capacity, dyspnea and cardiomyopathy; and the risk of stroke and thromboembolism is increased, owing to incomplete atrial emptying and stasis in the noncontracting atria.¹⁰Of the antiarrhythmic agents approved for use in Canada, 5 are prescribed relatively commonly. All 5 are indicated for ventricular arrhythmias, and 2 (flecainide and quinidine) are approved for supraventricular arrhythmias (SVA) in patients without structural heart disease. Sotalol, propafenone and amiodarone, although not officially approved for SVA in Canada, are the antiarrhythmic agents most commonly prescribed for AF.^7,11 Each drug has labelling that identifies contraindications, warnings and precautions for use in the setting of cardiac and noncardiac conditions. The frequency of these restrictions and the extent to which these drugs are used despite restrictions among patients with AF are not known. To address this problem we sought to describe the frequency and impact of contraindications and warnings among patients in whom the use of antiarrhythmic drugs would likely be contemplated.     

甲/福流/8/58(H2N2)血凝素基因对该病毒在地鼠鼻甲中繁殖性状的影响

用在地鼠鼻甲繁殖不好、但在肺中繁殖较好的甲/福流/8/58(H2N2)流感病毒,与在地鼠的上下呼吸道均能较好地繁殖的H3N2型病毒重组,所获重组株(福R3),除HA基因是来自H2N2外,其它基因均来自H3N2。该重组病毒像亲本株H2N2株一样,在地鼠鼻甲繁不好。结果表明,编码甲/福流/8/58病毒的H2血凝素的基因影响着地鼠的组织嗜性。     

鸣禽白腰文鸟前脑发声控制核团的性双态性

应用神经示踪、放射免疫测定及组织学方法,对成体鸣禽白腰文鸟前脑发声控制核团的性双态性及血中的睾酮水平进行了研究。结果发现,前脑高级发声中枢、古纹状体粗核和Ｘ区三个发声控制核团均存在明显的性双态性,雄性的上述三个发声控制核团体积分别比雌性大５．３１、４．０１和１．９２倍,在三个选定的平面上,雄性个体的前两个核团神经元数量超过雌性,但神经元分布的密度则小于雌性,差异均显著（Ｐ〈０．０５）。从高级发声中     

Quantitation of human immunodeficiency virus type 1 DNA forms with the second template switch in peripheral blood cells predicts disease progression independently of plasma RNA load

There are several forms of human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood T cells and lymph nodes in untreated HIV-1-infected individuals and in patients whose plasma HIV-1 RNA levels are suppressed by long-term combination antiretroviral therapy. However, it remains to be established whether the concentration of HIV-1 DNA in cells predicts the clinical outcome of HIV-1 infection. In this report, we measured the concentration of HIV-1 DNA forms which has undergone the second template switch (STS DNA) and 2-long-terminal-repeat DNA circles in peripheral blood mononuclear cell (PBMC) samples. To do this, we used molecular-beacon-based real-time PCR assays and studied 130 patients with hemophilia in the Multicenter Hemophilia Cohort Study. We assessed the influence of baseline HIV-1 STS DNA levels on the progression of HIV-1 disease in the absence of combination antiretroviral therapy by Kaplan-Meier and Cox regression analysis. Among the patients who progressed to AIDS, the median levels (interquartile ranges) of STS HIV-1 DNA in PBMC were significantly higher than those of patients who remained AIDS free during the 16 years of follow-up (1,017 [235 to 6,059] and 286 [31 to 732] copies per 10(6) PBMC, respectively; P < 0.0001). Rates of progression to death and development of AIDS varied significantly (log rank P < 0.001) by quartile distribution of HIV-1 STS DNA levels. After adjustment for age at seroconversion, baseline CD4(+) T-cell counts, plasma viral load, and T-cell-receptor excision circles, the relative hazards (RH) of death and AIDS were significantly increased with higher HIV-1 STS DNA levels (adjusted RH, 1.84 [95% confidence interval (CI), 1.30 to 2.59] and 2.62 [95% CI, 1.75 to 3.93] per 10-fold increase per 10(6) PBMC, respectively). HIV-1 STS DNA levels in each individual remained steady in longitudinal PBMC samples during 16 years of follow-up. Our findings show that the concentration of HIV-1 STS DNA in PBMC complements the HIV-1 RNA load in plasma in predicting the clinical outcome of HIV-1 disease. This parameter may have important implications for understanding the virological response to combination antiretroviral therapy.     

REST/ACTIVITY RHYTHMS AND MORTALITY RATES IN OLDER MEN: MROS SLEEP STUDY

An association between increased risk of mortality and disruptions in rest/activity circadian rhythms (RAR) has been shown among adults with dementia and with metastatic colorectal cancer. However, the association among a more general population of older adults has not been studied. Our study population consisted of 2964 men aged?≥?67 yrs of age enrolled in the Outcomes of Sleep Disorders in Older Men (MrOS Sleep) Study. Rest/activity patterns were measured with wrist actigraphy. RAR parameters were computed and expressed as quintiles, and included acrophase (time of peak activity level), amplitude (peak-to-nadir difference), mesor (middle of the peak), pseudo F-value (overall circadian rhythmicity), beta (steepness), and alpha (peak-to-trough width). After adjustment for multiple potential confounders, men in the lowest quintile of pseudo F-value had a 57% higher mortality rate (hazard ratio [HR]?=?1.57, 95% CI, 1.03–2.39) than men in the highest quintile. This association was even stronger with increased risk of cardiovascular disease-related mortality (CVD) (HR?=?2.32, 95% CI, 1.04–5.22). Additionally, men in the lowest quintile of acrophase had a 2.8-fold higher rate of CVD-related mortality (HR?=?2.84, 95% CI, 1.29–6.24). There was no evidence of independent associations with amplitude, mesor, alpha, beta, and mortality risk. Older men with less robust RAR and earlier acrophase timing have modestly higher all-cause and CVD-related mortality rates. Further research should examine potential biological mechanisms underlying this association. (Author correspondence: ames0047@umn.edu)     

Elderly Peritoneal Dialysis Compared with Elderly Hemodialysis Patients and Younger Peritoneal Dialysis Patients: Competing Risk Analysis of a Korean Prospective Cohort Study

The outcomes of peritoneal dialysis (PD) in elderly patients have not been thoroughly investigated. We aimed to investigate the clinical outcomes and risk factors associated with PD in elderly patients. We conducted a prospective observational nationwide adult end-stage renal disease (ESRD) cohort study in Korea from August 2008 to March 2013. Among incident patients (n = 830), patient and technical survival rate, quality of life, and Beck’s Depression Inventory (BDI) scores of elderly PD patients (≥65 years, n = 95) were compared with those of PD patients aged ≤49 years (n = 205) and 50~64 years (n = 192); and elderly hemodialysis (HD) patients (n = 315). The patient death and technical failure were analyzed by cumulative incidence function. Competing risk regressions were used to assess the risk factors for survival. The patient survival rate of elderly PD patients was inferior to that of younger PD patients (P<0.001). However, the technical survival rate was similar (P = 0.097). Compared with elderly HD patients, the patient survival rate did not differ according to dialysis modality (P = 0.987). Elderly PD patients showed significant improvement in the BDI scores, as compared with the PD patients aged ≤49 years (P = 0.003). Low albumin, diabetes and low residual renal function were significant risk factors for the PD patient survival; and peritonitis was a significant risk factor for technical survival. Furthermore, low albumin and hospitalization were significant risk factors of patient survival among the elderly. The overall outcomes were similar between elderly PD and HD patients. PD showed the benefit in BDI and quality of life in the elderly. Additionally, the technical survival rate of elderly PD patients was similar to that of younger PD patients. Taken together, PD may be a comparable modality for elderly ESRD patients.