Summary Background The Thai phase 3 HIV vaccine trial RV 144 showed modest efficacy of a vaccine against HIV acquisition. Baseline variables of age, sex, marital status, and risk did not modify ...vaccine efficacy. We did a post-hoc analysis of the trial's data to investigate behavioural risk and efficacy every 6 months after vaccination. Methods RV 144 was a randomised, multicentre, double-blind, placebo-controlled efficacy trial testing the combination of the HIV vaccines ALVAC-HIV (vCP1521) and AIDSVAX B/E to prevent HIV infection or reduce setpoint viral load. Male and female volunteers aged 18–30 years were recruited from the community. In this post-hoc analysis of the modified intention-to-treat population (16 395 participants), HIV risk behaviour was assessed with a self-administered questionnaire at the time of initial vaccination in the trial and every 6 months thereafter for 3 years. We classified participants' behaviour as low, medium, or high risk. Both the acquisition endpoint and the early viral-load endpoint were examined for interactions with risk status over time and temporal effects after vaccination. Multiple proportional hazards regression models with treatment and time-varying risk covariates were analysed. Findings Risk of acquisition of HIV was low in each risk group, but 9187 (58·2%) participants reported higher-risk behaviour at least once during the study. Participants classified as high or increasing risk at least once during follow-up were compared with those who maintained low-risk or medium-risk behaviour as a time-varying covariate, and the interaction of risk status and acquisition efficacy was significant (p=0·01), with greater benefit in low-risk individuals. Vaccine efficacy seemed to peak early—cumulative vaccine efficacy was estimated to be 60·5% (95% CI 22–80) through the 12 months after initial vaccination—and declined quickly. Vaccination did not seem to affect viral load in either early or late infections. Interpretation Future HIV vaccine trials should recognise potential interactions between challenge intensity and risk heterogeneity in both population and treatment effects. The regimen tested in the RV 144 phase 3 trial might benefit from extended immunisation schedules. Funding US Army Medical Research and Materiel Command and Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health.
Summary Background The limited data available for long-term Ebola virus disease health outcomes suggest that sequelae persist for longer than 1 year after infection. The magnitude of the present ...outbreak in west Africa necessitates a more complete understanding of the health effects and future medical needs of these patients. Methods We invited adult survivors of the 2007 Bundibugyo Ebola virus outbreak in Uganda and their contacts to take part in an observational study roughly 29 months after the outbreak. We collected information about health status, functional limitations, and demographics. We collected blood samples for clinical chemistry, haematology, and filovirus antibodies using ELISA. Analyses were restricted to probable and confirmed survivors and their seronegative contacts. Findings We recruited 70 survivors of the 2007 Bundibugyo Ebola virus and 223 contacts. We did analyses for 49 probable and confirmed survivors and 157 seronegative contacts. Survivors of the Bundibugyo Ebola virus were at significantly increased risk of ocular deficits (retro-orbital pain RR 4·3, 95% CI 1·9–9·6; p<0·0001, blurred vision 1·9, 1·1–3·2; p=0·018), hearing loss (2·3, 1·2–4·5; p=0·010), difficulty swallowing (2·1, 1·1–3·9; p=0·017), difficulty sleeping (1·9, 1·3–2·8; p=0·001), arthralgias (2·0, 1·1–3·6; p=0·020), and various constitutional symptoms controlling for age and sex. Chronic health problems (prevalence ratio PR 2·1, 95% CI 1·2–3·6; p=0·008) and limitations due to memory loss or confusion (PR 5·8, 1·5–22·4; p=0·010) were also reported more frequently by survivors of Bundibugyo Ebola virus. Interpretation Long-term sequelae persist for more than 2 years after Ebola virus disease. Definition of health consequences related to Ebola virus disease could improve patient care for survivors and contribute to understanding of disease pathogenesis. Funding Chemical Biological Technologies Directorate, Defense Threat Reduction Agency.
Abstract Context HIV infection has become a manageable chronic disease. There are few studies of pain and symptoms in the current treatment era. Objectives Our primary objective was to determine the ...prevalence of and risk factors for pain and physical and psychological symptoms in a population of ambulatory HIV patients. Methods We performed a cross-sectional study using the Brief Pain Inventory and the Memorial Symptom Assessment Scale-Short Form (MSAS). Results We evaluated 156 individuals with a median age of 47.5 years (range 21–71), median time since HIV diagnosis of 11 years (range <1 to 25), and median CD4+ cell count of 502 cells/mm3 (interquartile range IQR 308–683). Most (125, 80.6%) of the patients had an undetectable viral load. Seventy-six (48.7%) patients reported pain, of whom 39 (51.3%) had moderate to severe pain, and 43 (57.3%) had pain that caused moderate to severe interference with their lives. The median number of symptoms was eight (IQR 5–14.5) of 32 queried. In multivariable analyses, patients with psychiatric illness were 39.8% more likely to have pain ( P < 0.001). Psychiatric illness was associated with 0.7 and 1.2 point higher MSAS subscale scores, and IV drug use was associated with 0.4 and 0.5 higher subscale scores (out of four). Conclusion Pain and other physical and psychological symptoms were common among ambulatory HIV patients. Pain and symptoms were strongly associated with psychiatric illness and IV drug use. Future investigation should evaluate interventions that include psychiatric and substance abuse components for HIV patients with pain.
Summary Background Ebola virus and Marburg virus cause serious disease outbreaks with high case fatality rates. We aimed to assess the safety and immunogenicity of two investigational DNA vaccines, ...one (EBO vaccine) encoding Ebola virus Zaire and Sudan glycoproteins and one (MAR) encoding Marburg virus glycoprotein. Methods RV 247 was a phase 1b, double-blinded, randomised, placebo-controlled clinical trial in Kampala, Uganda to examine the safety and immunogenicity of the EBO and MAR vaccines given individually and concomitantly. Healthy adult volunteers aged 18–50 years were randomly assigned (5:1) to receive three injections of vaccine or placebo at weeks 0, 4, and 8, with vaccine allocations divided equally between three active vaccine groups: EBO vaccine only, MAR vaccine only, and both vaccines. The primary study objective was to investigate the safety and tolerability of the vaccines, as assessed by local and systemic reactogenicity and adverse events. We also assessed immunogenicity on the basis of antibody responses (ELISA) and T-cell responses (ELISpot and intracellular cytokine staining assays) 4 weeks after the third injection. Participants and investigators were masked to group assignment. Analysis was based on the intention-to-treat principle. This trial is registered at ClinicalTrials.gov , number NCT00997607. Findings 108 participants were enrolled into the study between Nov 2, 2009, and April 15, 2010. All 108 participants received at least one study injection (including 100 who completed the injection schedule) and were included in safety and tolerability analyses; 107 for whom data were available were included in the immunogenicity analyses. Study injections were well tolerated, with no significant differences in local or systemic reactions between groups. The vaccines elicited antibody and T-cell responses specific to the glycoproteins received and we detected no differences between the separate and concomitant use of the two vaccines. 17 of 30 (57%, 95% CI 37–75) participants in the EBO vaccine group had an antibody response to the Ebola Zaire glycoprotein, as did 14 of 30 (47%, 28–66) in the group that received both vaccines. 15 of 30 (50%, 31–69) participants in the EBO vaccine group had an antibody response to the Ebola Sudan glycoprotein, as did 15 of 30 (50%, 31–69) in the group that received both vaccines. Nine of 29 (31%, 15–51) participants in the MAR vaccine groups had an antibody response to the Marburg glycoprotein, as did seven of 30 (23%, 10–42) in the group that received both vaccines. 19 of 30 (63%, 44–80) participants in the EBO vaccine group had a T-cell response to the Ebola Zaire glycoprotein, as did 10 of 30 (33%, 17–53) in the group that received both vaccines. 13 of 30 (43%, 25–63) participants in the EBO vaccine group had a T-cell response to the Ebola Sudan glycoprotein, as did 10 of 30 (33%, 17–53) in the group that received both vaccines. 15 of 29 (52%, 33–71) participants in the MAR vaccine group had a T-cell response to the Marburg glycoprotein, as did 13 of 30 (43%, 25–63) in the group that received both vaccines. Interpretation This study is the first Ebola or Marburg vaccine trial done in Africa, and the results show that, given separately or together, both vaccines were well tolerated and elicited antigen-specific humoral and cellular immune responses. These findings have contributed to the accelerated development of more potent Ebola virus vaccines that encode the same wild-type glycoprotein antigens as the EBO vaccine, which are being assessed during the 2014 Ebola virus disease outbreak in west Africa. Funding US Department of Defense Infectious Disease Clinical Research Program and US National Institutes of Health Intramural Research Program.
...heterozygous dominant negative mutations in STAT1 cause mild disseminated mycobacterial infections.1 Recently, heterozygous dominant gain-of-function (GOF) mutations in STAT1 were described as ...causing impaired STAT1 dephosphorylation, diminished IL-17-producing T-cell numbers, and chronic mucocutaneous candidiasis (CMC).2 These GOF mutations have also been associated with intracellular dimorphic fungal infections, disseminated coccidioidomycosis, histoplasmosis,3 and cases of wild-type forkhead box protein 3 (FOXP3) immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like syndrome.4 Progressive multifocal leukoencephalopathy, autoimmunity, arterial aneurysms, and squamous cell cancers have also been reported.2-5 We identified a novel GOF STAT1 mutation in a patient with disseminated mucormycosis caused by Apophysomyces trapeziformis. Biopsy of the deltoid muscle and lymph node showed an eosinophilic infiltrate surrounding aseptate fungal hyphae with right-angle branching (Fig 1, D), which is consistent with mucormycosis.7 Cultures from the right deltoid muscle biopsy specimen and blood grew A trapeziformis, which was identified by using colony and microscopic morphology and confirmed by sequencing.
Abstract Context The extent to which patients take chronic pain medications as prescribed is not well studied, and there are no generally agreed-upon measures. The Quantitative Analgesic ...Questionnaire (QAQ) is a new instrument designed to comprehensively document patient-reported medication use, generate scores to quantify it (by individual drug, class, and/or overall), and compare it (qualitatively and/or quantitatively) to the regimen as prescribed. Objectives The aim of this study was to describe the development and preliminary validation of the QAQ. Methods The QAQ was studied in a convenience sample of 149 HIV-infected participants. Results We found that the QAQ scores computed for participants' chronic pain medication regimens were valid based on their correlation with 1) patient-reported pain intensity ( r = 0.38; P < 0.001) and 2) experienced pain management physicians' independent quantification of the regimens ( r = 0.89; P < 0.001). The QAQ also demonstrated high interrater reliability ( r = 0.957; P < 0.001). Detailed examination of the QAQ data in a subset of 34 participants demonstrated that the QAQ revealed suboptimal adherence in 44% of participants and contained information that would not have been gleaned from review of the medical record alone in 94%, including use of over-the-counter medications and quantification of “as needed” dosing. The QAQ also was found to be useful in quantifying change in the medication regimen over time, capturing a change in 50% of the participants from baseline to eight week follow-up. Conclusion The QAQ is a simple tool that can facilitate understanding of patient-reported chronic pain medication regimens, including calculation of percent adherence and generation of quantitative scores suitable for estimating and tracking change in medication use over time.
At a time of growing concern over the rising costs and long-term environmental impacts of the use of fossil fuels and nuclear energy, wind energy has become an increasingly important sector of the ...electrical power industry, largely because it has been promoted as being emission-free and is supported by government subsidies and tax credits. However, large numbers of bats are killed at utility-scale wind energy facilities, especially along forested ridgetops in the eastern United States. These fatalities raise important concerns about cumulative impacts of proposed wind energy development on bat populations. This paper summarizes evidence of bat fatalities at wind energy facilities in the US, makes projections of cumulative fatalities of bats in the Mid-Atlantic Highlands, identifies research needs, and proposes hypotheses to better inform researchers, developers, decision makers, and other stakeholders, and to help minimize adverse effects of wind energy development.
Aims/hypothesis
We determined whether empagliflozin altered renal sympathetic nerve activity (RSNA) and baroreflexes in a diabetes model in conscious rabbits.
Methods
Diabetes was induced by alloxan, ...and RSNA, mean arterial pressure (MAP) and heart rate were measured before and after 1 week of treatment with empagliflozin, insulin, the diuretic acetazolamide or the ACE inhibitor perindopril, or no treatment, in conscious rabbits.
Results
Four weeks after alloxan administration, blood glucose was threefold and MAP 9% higher than non-diabetic controls (
p
< 0.05). One week of treatment with empagliflozin produced a stable fall in blood glucose (−43%) and increased water intake (+49%) but did not change RSNA, MAP or heart rate compared with untreated diabetic rabbits. The maximum RSNA to hypotension was augmented by 75% (
p
< 0.01) in diabetic rabbits but the heart rate baroreflex was unaltered. Empagliflozin and acetazolamide reduced the augmentation of the RSNA baroreflex (
p
< 0.05) to be similar to the non-diabetic group. Noradrenaline (norepinephrine) spillover was similar in untreated diabetic and non-diabetic rabbits but twofold greater in empagliflozin- and acetazolamide-treated rabbits (
p
< 0.05).
Conclusions/interpretation
As empagliflozin can restore diabetes-induced augmented sympathetic reflexes, this may be beneficial in diabetic patients. A similar action of the diuretic acetazolamide suggests that the mechanism may involve increased sodium and water excretion.
Graphical abstract
Early antiretroviral therapy (ART) initiation (ie, within 3 months of infection) limits establishment of the HIV reservoir. However, the effect of early ART initiation on the long-term dynamics of ...the pool of infected cells remains unclear.
In this longitudinal analysis, we included cisgender men who have sex with men (MSM) and transgender women (aged 18–54 years) at high risk for HIV infection, enrolled in the ongoing longitudinal MERLIN study in Peru between Oct 28, 2014, and Nov 8, 2018. Participants were eligible if they had been infected with HIV less than 90 days before enrolment, and if they had cryopreserved peripheral blood mononuclear cell (PBMC) samples. Participants were stratified into three groups on the basis of whether they initiated ART at 30 days or less (acute group), at 31–90 days (early group), or more than 24 weeks (deferred group) after the estimated date of detectable infection. PBMC samples were collected before ART initiation and longitudinally for up to 4 years on ART. The main outcomes were to establish the size of the HIV reservoir before ART initiation and to assess the effect of the timing of ART initiation on the decay of the HIV reservoir over 4 years follow-up. We quantified viral load, and isolated CD4 cells to quantify total HIV DNA, integrated HIV DNA and 2-long terminal repeat circles. Longitudinal analysis of active and inducible HIV reservoirs were measured by quantifying the frequency of CD4 cells producing multiply-spliced HIV RNA ex vivo and after in-vitro stimulation with a tat/rev induced limiting dilution assay (TILDA). A mixed-effects model from the time of ART initiation was used to measure longitudinal decays in viral loads and each HIV reservoir measure in each of the three groups.
We included 56 participants in this analysis, all of whom were MSM: 15 were in the acute group, 19 were in the early group, and 22 were in the deferred group. Participants in all three groups had similar levels of all HIV reservoir markers before ART initiation. All participants, including those in the acute group, had a pool of transcriptionally silent HIV-infected cells before ART initiation, as indicated by a substantial increase in TILDA measures upon stimulation. Longitudinal analysis over 4 years of ART revealed a biphasic decay of all HIV persistence markers, with a rapid initial decline followed by a slower decay in all participants. During the first-phase decay, the half-lives of both total and integrated HIV DNA and TILDA measures were significantly shorter in the acute group than in the early and deferred groups. During the second-phase decay, HIV reservoir markers continued to decline only in participants in the acute group.
Participants who initiated ART within 30 days or less of HIV infection showed a steeper and more sustained decay in HIV reservoir measures, suggesting long-term benefit of acute ART initiation on reservoir clearance.
The US National Institutes of Health and the Canadian Institutes for Health Research.
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