Publications

IMPORTANCE

Several randomized clinical trials have demonstrated the efficacy of preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) acquisition. Little is known about adherence to the regimen, sexual practices, and overall effectiveness when PrEP is implemented in clinics that treat sexually transmitted infections (STIs) and community-based clinics serving men who have sex with men (MSM).

OBJECTIVE

To assess PrEP adherence, sexual behaviors, and the incidence of STIs and HIV infection in a cohort of MSM and transgender women initiating PrEP in the United States.

DESIGN, SETTING, AND PARTICIPANTS

Demonstration project conducted from October 1, 2012, through February 10, 2015 (last date of follow-up), among 557 MSM and transgender women in 2 STI clinics in San Francisco, California, and Miami, Florida, and a community health center in Washington, DC. Data were analyzed from December 18, 2014, through August 8, 2015.

INTERVENTIONS

A combination of daily, oral tenofovir disoproxil fumarate and emtricitabine was provided free of charge for 48 weeks. All participants received HIV testing, brief client-centered counseling, and clinical monitoring.

MAIN OUTCOMES AND MEASURES

Concentrations of tenofovir diphosphate in dried blood spot samples, self-reported numbers of anal sex partners and episodes of condomless receptive anal sex, and incidence of STI and HIV acquisition.

RESULTS

Overall, 557 participants initiated PrEP, and 437 of these (78.5%) were retained through 48 weeks. Based on the findings from the 294 participants who underwent measurement of tenofovir diphosphate levels, 80.0% to 85.6% had protective levels (consistent with ≥4 doses/wk) at follow-up visits. African American participants (56.8% of visits; P = .003) and those from the Miami site (65.1% of visits; P < .001) were less likely to have protective levels, whereas those with stable housing (86.8%; P = .02) and those reporting at least 2 condomless anal sex partners in the past 3 months (88.6%; P = .01) were more likely to have protective levels. The mean number of anal sex partners declined during follow-up from 10.9 to 9.3, whereas the proportion engaging in condomless receptive anal sex remained stable at 65.5% to 65.6%. Overall STI incidence was high (90 per 100 person-years) but did not increase over time. Two individuals became HIV infected during follow-up (HIV incidence, 0.43 [95% CI, 0.05-1.54] infections per 100 person-years); both had tenofovir diphosphate levels consistent with fewer than 2 doses/wk at seroconversion.

CONCLUSIONS AND RELEVANCE

The incidence of HIV acquisition was extremely low despite a high incidence of STIs in a large US PrEP demonstration project. Adherence was higher among those participants who reported more risk behaviors. Interventions that address racial and geographic disparities and housing instability may increase the impact of PrEP.

AIMS

We recently reported that immunosuppression with FTY720 improves cardiac function and extends longevity in Hypomorphic ApoE mice deficient in scavenger receptor Type-BI expression, also known as the HypoE/SR-BI(–/–) mouse model of diet-induced coronary atherosclerosis and myocardial infarction (MI). In this study, we tested the impact of FTY720 on cardiac dysfunction in HypoE/SR-BI(–/–) mice that survive MI and subsequently develop chronic heart failure.

METHODS/RESULTS

HypoE/SR-BI(–/–) mice were bred to Mx1-Cre transgenic mice, and offspring were fed a high-fat diet (HFD) for 3.5 weeks to provoke hyperlipidemia, coronary atherosclerosis, and recurrent MIs. In contrast to our previous study, hyperlipidemia was rapidly reversed by inducible Cre-mediated gene repair of the HypoE allele and switching mice to a normal chow diet. Mice that survived the period of HFD were subsequently given oral FTY720 in drinking water or not, and left ventricular (LV) function was monitored using serial echocardiography for up to 15 weeks. In untreated mice, LV performance progressively deteriorated. Although FTY720 treatment did not initially prevent a decline of heart function among mice 6 weeks after Cre-mediated gene repair, it almost completely restored normal LV function in these mice by 15 weeks. Reversal of heart failure did not result from reduced atherosclerosis as the burden of aortic and coronary atherosclerosis actually increased to similar levels in both groups of mice. Rather, FTY720 caused systemic immunosuppression as assessed by reduced numbers of circulating T and B lymphocytes. In contrast, FTY720 did not enhance the loss of T cells or macrophages that accumulated in the heart during the HFD feeding period, but it did enhance the loss of B cells soon after plasma lipid lowering. Moreover, FTY720 potently reduced the expression of matrix metalloproteinase-2 and genes involved in innate immunity-associated inflammation in the heart.

CONCLUSIONS

Our data demonstrate that immunosuppression with FTY720 prevents postinfarction myocardial remodeling and chronic heart failure.

Scleroderma, also called systemic sclerosis (SSc), is an autoimmune connective tissue disease characterized by abnormality of the immune system, cardiovascular disorder, and fibrosis of the skin, lung, kidney, and other internal organs. Skin symptom and stiffness of the skin with accumulation of collagen cause severe disability, and cardiovascular and lung complications lead to high mortality. Despite recent progress, therapies for these complications in SSc are limited and the underlying mechanisms are poorly understood. Animal models are one strategy to identify molecular mechanisms and pathways underlying these complications of SSc and could provide a mechanistic basis for a design of clinical trials. However, although several animal models have been reported to reproduce some aspects of SSc, none of them recapitulates all of the pathological features of SSc. In this review, we describe previously reported animal models of scleroderma and discuss their utility and limitations in efforts to understand the mechanisms underlying scleroderma and develop new treatments for this disease.

OBJECTIVE

Fatigue is a major concern for individuals with rheumatoid arthritis (RA). However, in order to treat fatigue adequately, its sources need to be identified.

METHODS

Data were collected during a single home visit (number of participants = 158). All participants had physician-diagnosed RA. Assessments of self-reported sleep quality, depression, physical activity, RA disease activity, muscle strength, functional limitations, and body composition were made. Information on demographics, medications, and smoking was collected. The Fatigue Severity Inventory (FSI; measuring average fatigue over the past 7 days) was used as the primary outcome. Analyses were first conducted to evaluate bivariate relationships with fatigue. Correlations among risk factors were examined. Multivariate analyses identified independent predictors of fatigue.

RESULTS

The mean ± SD age was 59 ± 11 years, the mean ± SD disease duration was 21 ± 13 years, and 85% of subjects were female. The mean ± SD FSI rating was 3.8 ± 2.0 (range 0-10). In multivariate analyses, self-reported disease activity, poor sleep, depression, and obesity were independently associated with fatigue. Physical inactivity was correlated with poor sleep, depression, and obesity. Mediation analyses indicated that physical inactivity had an indirect association with fatigue, mediated by poor sleep, depression, and obesity.

CONCLUSION

This cross-sectional study suggests that fatigue may not be solely a result of RA disease activity, but may result from a constellation of factors that includes RA disease activity or pain, but also includes inactivity, depression, obesity, and poor sleep. The results suggest new avenues for interventions to improve fatigue in individuals with RA, such as increasing physical activity or addressing depression or obesity.

CONTEXT

The optimal pharmacologic treatment for early convulsive status epilepticus is unclear.

OBJECTIVE

To analyze efficacy, tolerability and safety data for anticonvulsant treatment of children and adults with convulsive status epilepticus and use this analysis to develop an evidence-based treatment algorithm.

DATA SOURCES

Structured literature review using MEDLINE, Embase, Current Contents, and Cochrane library supplemented with article reference lists.

STUDY SELECTION

Randomized controlled trials of anticonvulsant treatment for seizures lasting longer than 5 minutes.

DATA EXTRACTION

Individual studies were rated using predefined criteria and these results were used to form recommendations, conclusions, and an evidence-based treatment algorithm.

RESULTS

A total of 38 randomized controlled trials were identified, rated and contributed to the assessment. Only four trials were considered to have class I evidence of efficacy. Two studies were rated as class II and the remaining 32 were judged to have class III evidence. In adults with convulsive status epilepticus, intramuscular midazolam, intravenous lorazepam, intravenous diazepam and intravenous phenobarbital are established as efficacious as initial therapy (Level A). Intramuscular midazolam has superior effectiveness compared to intravenous lorazepam in adults with convulsive status epilepticus without established intravenous access (Level A). In children, intravenous lorazepam and intravenous diazepam are established as efficacious at stopping seizures lasting at least 5 minutes (Level A) while rectal diazepam, intramuscular midazolam, intranasal midazolam, and buccal midazolam are probably effective (Level B). No significant difference in effectiveness has been demonstrated between intravenous lorazepam and intravenous diazepam in adults or children with convulsive status epilepticus (Level A). Respiratory and cardiac symptoms are the most commonly encountered treatment-emergent adverse events associated with intravenous anticonvulsant drug administration in adults with convulsive status epilepticus (Level A). The rate of respiratory depression in patients with convulsive status epilepticus treated with benzodiazepines is lower than in patients with convulsive status epilepticus treated with placebo indicating that respiratory problems are an important consequence of untreated convulsive status epilepticus (Level A). When both are available, fosphenytoin is preferred over phenytoin based on tolerability but phenytoin is an acceptable alternative (Level A). In adults, compared to the first therapy, the second therapy is less effective while the third therapy is substantially less effective (Level A). In children, the second therapy appears less effective and there are no data about third therapy efficacy (Level C). The evidence was synthesized into a treatment algorithm.

CONCLUSIONS

Despite the paucity of well-designed randomized controlled trials, practical conclusions and an integrated treatment algorithm for the treatment of convulsive status epilepticus across the age spectrum (infants through adults) can be constructed. Multicenter, multinational efforts are needed to design, conduct and analyze additional randomized controlled trials that can answer the many outstanding clinically relevant questions identified in this guideline.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after an initial diagnosis of prostate cancer and management options for localized, regional, and metastatic disease. Recommendations for disease monitoring, treatment of recurrent disease, and systemic therapy for metastatic castration-recurrent prostate cancer also are included. This article summarizes the NCCN Prostate Cancer Panel's most significant discussions for the 2016 update of the guidelines, which include refinement of risk stratification methods and new options for the treatment of men with high-risk and very-high-risk disease and progressive castration-naïve disease.