Immediate Risk for Cardiovascular Events and Suicide Following a Prostate Cancer Diagnosis: Prospective Cohort Study

Background

Stressful life events have been shown to be associated with altered risk of various health consequences. The aim of the present study was to investigate whether the emotional stress evoked by a prostate cancer diagnosis increases the immediate risks of cardiovascular events and suicide.

Methods and Findings

We conducted a prospective cohort study by following all men in Sweden who were 30 y or older (n = 4,305,358) for a diagnosis of prostate cancer (n = 168,584) and their subsequent occurrence of cardiovascular events and suicide between January 1, 1961 and December 31, 2004. We used Poisson regression models to calculate relative risks (RRs) and 95% confidence intervals (CIs) of cardiovascular events and suicide among men who had prostate cancer diagnosed within 1 y to men without any cancer diagnosis. The risks of cardiovascular events and suicide were elevated during the first year after prostate cancer diagnosis, particularly during the first week. Before 1987, the RR of fatal cardiovascular events was 11.2 (95% CI 10.4–12.1) during the first week and 1.9 (95% CI 1.9–2.0) during the first year after diagnosis. From 1987, the RR for cardiovascular events, nonfatal and fatal combined, was 2.8 (95% CI 2.5–3.2) during the first week and 1.3 (95% CI 1.3–1.3) during the first year after diagnosis. While the RR of cardiovascular events declined, the RR of suicide was stable over the entire study period: 8.4 (95% CI 1.9–22.7) during the first week and 2.6 (95% CI 2.1–3.0) during the first year after diagnosis. Men 54 y or younger at cancer diagnosis demonstrated the highest RRs of both cardiovascular events and suicide. A limitation of the present study is the lack of tumor stage data, which precluded possibilities of investigating the potential impact of the disease severity on the relationship between a recent diagnosis of prostate cancer and the risks of cardiovascular events and suicide. In addition, we cannot exclude residual confounding as a possible explanation.

Conclusions

Men newly diagnosed with prostate cancer are at increased risks for cardiovascular events and suicide. Future studies with detailed disease characteristic data are warranted. Please see later in the article for the Editors'' Summary     

Long term relative survival after surgery for abdominal aortic aneurysm in Western Australia: population based study

Objective: To determine the long term relative survival of all patients who had surgery for abdominal aortic aneurysm in Western Australia during 1985-94. Design: Population based study. Setting: Western Australia. Subjects: All patients who had had surgery for abdominal aortic aneurysm in Western Australia during 1985-94. Main outcome measures: Morbidity and mortality data of patients admitted and surgically treated for abdominal aortic aneurysm in Western Australia during 1985-94. Elective, ruptured, and acute non-ruptured cases were analysed separately. Independent analyses for sex and patients aged 80 years or more were also undertaken. Postoperative (>30 days) relative survival was assessed against age and sex matched controls. Results: Overall, 1475 (1257 men, 218 women) cases were identified. The crude five year survival after elective surgery, including deaths within 30 days of surgery, was 79% for both men and women. When compared with a matched population the five year relative survival after elective surgery was 94.9% (95% confidence interval 89.9% to 99.9%) for men but only 88.0% (76.3% to 99.7%) for women. The five year relative survival of those aged 80 years and over was good: 116.6% (89.1% to 144.0%) compared with 92.4% (87.7% to 97.0%) for those under 80 years of age (men and women combined). Cardiovascular disease caused 57.8% of the 341 deaths after 30 days. Conclusion: In a condition such as abdominal aortic aneurysm, which occurs in elderly patients, relative survival is more clinically meaningful than crude survival. The five year relative survival in cases of elective and ruptured abdominal aortic aneurysm was better in men than in women. This is probably because of greater comorbidity in women with abdominal aortic aneurysm and this deserves more attention in the future. The long term survival outcome in octogenarians supports surgery in selected cases.

Key messages

• Background mortality for conditions such as abdominal aortic aneurysm in elderly patients needs to be taken into account when assessing long term survival after surgery
• Relative survival methodology can correct for background mortality
• The five year relative survival for patients surviving beyond 30 days of elective surgery for abdominal aortic aneurysm was 95% for men and 88% for women
• For octogenarians, five year survival after elective surgery was greater than that expected of an age matched population
• Age over 80 years should not preclude consideration for elective surgery for abdominal aortic aneurysm

     

Efficacy,tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials

ObjectiveTo determine the efficacy, gastrointestinal safety, and tolerability of celecoxib (a cyclo-oxygenase 2 (COX 2) inhibitor) used in the treatment of osteoarthritis and rheumatoid arthritis.DesignSystematic review of randomised trials that compared at least 12 weeks'' celecoxib treatment with another non-steroidal anti-inflammatory drug (NSAID) or placebo and reported efficacy, tolerability, or safety. Trials identified from manufacturer and by searching electronic databases and evaluated according to predefined inclusion and quality criteria. Data combined through meta-analysis.Participants15 187 patients with osteoarthritis or rheumatoid arthritis.ResultsNine randomised controlled trials were included. Celecoxib and NSAIDS were equally effective for all efficacy outcomes. Compared with those taking other NSAIDs, in patients taking celecoxib the rate of withdrawals due to adverse gastrointestinal events was 46% lower (95% confidence interval 29% to 58%; NNT 35 at three months), the incidence of ulcers detectable by endoscopy was 71% lower (59% to 79%; NNT 6 at three months), and the incidence of symptoms of ulcers, perforations, bleeds, and obstructions was 39% lower (4% to 61%; NNT 208 at six months). Subgroup analysis of patients taking aspirin showed that the incidence of ulcers detected by endoscopy was reduced by 51% (14% to 72%) in those given celecoxib compared with other NSAIDs. The reduction was greater (73%, 52% to 84%) in those not taking aspirin.ConclusionCelecoxib is as effective as other NSAIDs for relief of symptoms of osteoarthritis and rheumatoid arthritis and has significantly improved gastrointestinal safety and tolerability.

What is already known on this topic

Long term NSAID use is associated with the development of peptic and duodenal ulcersCOX 2 specific inhibitors are claimed to cause fewer gastrointestinal complicationsThe National Institute for Clinical Excellence has recently recommended that COX 2 specific inhibitors are used in patients with arthritis who are at risk of gastrointestinal complications but not in those taking prophylactic aspirin

What this study adds

Systematic review of randomised trials shows that celecoxib is as effective as other NSAIDs for osteoarthritis and rheumatoid arthritisCelecoxib has significantly improved gastrointestinal safety and tolerability compared with standard NSAIDsAn improvement in gastrointestinal safety was still evident in patients who were also taking aspirin     

The Effect of Rural-to-Urban Migration on Obesity and Diabetes in India: A Cross-Sectional Study

Background

Migration from rural areas of India contributes to urbanisation and may increase the risk of obesity and diabetes. We tested the hypotheses that rural-to-urban migrants have a higher prevalence of obesity and diabetes than rural nonmigrants, that migrants would have an intermediate prevalence of obesity and diabetes compared with life-long urban and rural dwellers, and that longer time since migration would be associated with a higher prevalence of obesity and of diabetes.

Methods and Findings

The place of origin of people working in factories in north, central, and south India was identified. Migrants of rural origin, their rural dwelling sibs, and those of urban origin together with their urban dwelling sibs were assessed by interview, examination, and fasting blood samples. Obesity, diabetes, and other cardiovascular risk factors were compared. A total of 6,510 participants (42% women) were recruited. Among urban, migrant, and rural men the age- and factory-adjusted percentages classified as obese (body mass index [BMI] >25 kg/m²) were 41.9% (95% confidence interval [CI] 39.1–44.7), 37.8% (95% CI 35.0–40.6), and 19.0% (95% CI 17.0–21.0), respectively, and as diabetic were 13.5% (95% CI 11.6–15.4), 14.3% (95% CI 12.2–16.4), and 6.2% (95% CI 5.0–7.4), respectively. Findings for women showed similar patterns. Rural men had lower blood pressure, lipids, and fasting blood glucose than urban and migrant men, whereas no differences were seen in women. Among migrant men, but not women, there was weak evidence for a lower prevalence of both diabetes and obesity among more recent (≤10 y) migrants.

Conclusions

Migration into urban areas is associated with increases in obesity, which drive other risk factor changes. Migrants have adopted modes of life that put them at similar risk to the urban population. Gender differences in some risk factors by place of origin are unexpected and require further exploration. Please see later in the article for the Editors'' Summary     

Is Audio Computer-Assisted Self-Interview (ACASI) Useful in Risk Behaviour Assessment of Female and Male Sex Workers,Mombasa, Kenya?

Background

Audio computer-assisted self-interview (ACASI) may elicit more frequent reporting of socially sensitive behaviours than face-to-face (FtF)-interview. However, no study compared responses to both methods in female and male sex workers (FSW; MSW) in Africa.

Methodology/Principal Findings

We sequentially enrolled adults recruited for an HIV-1 intervention trial into a comparative study of ACASI and FtF-interview, in a clinic near Mombasa, Kenya. Feasibility and acceptability of ACASI, and a comparative analysis of enrolment responses between ACASI and FtF on an identical risk assessment questionnaire were evaluated. In total, 139 women and 259 men, 81% of eligible cohort participants, completed both interviews. ACASI captured a higher median number of regular (2 vs. 1, p<0.001, both genders) and casual partners in the last week (3 vs. 2, p = 0.04 in women; 2 vs. 1, p<0.001 in men). Group sex (21.6 vs. 13.5%, p<0.001, in men), intravenous drug use (IDU; 10.8 vs. 2.3%, p<0.001 in men; 4.4 vs. 0%, p = 0.03 in women), and rape (8.9 vs. 3.9%, p = 0.002, in men) were reported more frequently in ACASI. A surprisingly high number of women reported in ACASI that they had paid for sex (49.3 vs. 5.8%, p<0.001). Behaviours for recruitment (i.e. anal sex, sex work, sex between males) were reported less frequently in ACASI. The majority of women (79.2%) and men (69.7%) felt that answers given in ACASI were more honest. Volunteers who were not able to take ACASI (84 men, and 37 women) mostly lacked reading skills.

Conclusions/Significance

About 1 in 5 cohort participants was not able to complete ACASI, mostly for lack of reading skills. Participants who completed ACASI were more likely to report IDU, rape, group sex, and payment for sex by women than when asked in FtF interview. ACASI appears to be a useful tool for high risk behaviour assessments in the African context.     

Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study

Background

Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.

Methods and Findings

We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.

Conclusions

Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing. Please see later in the article for the Editors'' Summary     

SAVVY? (C31G) Gel for Prevention of HIV infection in Women: A Phase 3, Double-Blind,Randomized, Placebo-Controlled Trial in Ghana

Objective

The objective of this trial was to determine the effectiveness of 1.0% C31G (SAVVY) in preventing male-to-female vaginal transmission of HIV infection among women at high risk.

Methodology/Principal Findings

This was a Phase 3, double-blind, randomized, placebo-controlled trial. Participants made up to 12 monthly visits for HIV testing, adverse event reporting, and study product supply. The study was conducted between March 2004 and February 2006 in Accra and Kumasi, Ghana. We enrolled 2142 HIV-negative women at high risk of HIV infection, and randomized them to SAVVY or placebo gel. Main outcome measures were the incidence of HIV-1 and HIV-2 infection as determined by detection of HIV antibodies from oral mucosal transudate specimens and adverse events. We accrued 790 person-years of follow-up in the SAVVY group and 772 person-years in the placebo group. No clinically significant differences in the overall frequency of adverse events, abnormal pelvic examination findings, or abnormal laboratory results were seen between treatment groups. However, more participants in the SAVVY group reported reproductive tract adverse events than in the placebo group (13.0% versus 9.4%). Seventeen HIV seroconversions occurred; eight in participants randomized to SAVVY and nine in participants receiving placebo. The Kaplan-Meier estimates of the cumulative probability of HIV infection through 12 months were 0.010 in the SAVVY group and 0.011 in the placebo group (p = 0.731), with a hazard ratio (SAVVY versus placebo) of 0.88 (95% confidence interval 0.33, 2.27). Because of a lower-than-expected HIV incidence, we were unable to achieve the required number of HIV infections (66) to obtain the desired study power.

Conclusions/Significance

SAVVY was not associated with increased adverse events overall, but was associated with higher reporting of reproductive adverse events. Our data are insufficient to conclude whether SAVVY is effective at preventing HIV infection relative to placebo.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00129532","term_id":"NCT00129532"}}NCT00129532     

A Randomised Controlled Trial of Artemether-Lumefantrine Versus Artesunate for Uncomplicated Plasmodium falciparum Treatment in Pregnancy

Background

To date no comparative trials have been done, to our knowledge, of fixed-dose artemisinin combination therapies (ACTs) for the treatment of Plasmodium falciparum malaria in pregnancy. Evidence on the safety and efficacy of ACTs in pregnancy is needed as these drugs are being used increasingly throughout the malaria-affected world. The objective of this study was to compare the efficacy, tolerability, and safety of artemether-lumefantrine, the most widely used fixed ACT, with 7 d artesunate monotherapy in the second and third trimesters of pregnancy.

Methods and Findings

An open-label randomised controlled trial comparing directly observed treatment with artemether-lumefantrine 3 d (AL) or artesunate monotherapy 7 d (AS7) was conducted in Karen women in the border area of northwestern Thailand who had uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy. The primary endpoint was efficacy defined as the P. falciparum PCR-adjusted cure rates assessed at delivery or by day 42 if this occurred later than delivery, as estimated by Kaplan-Meier survival analysis. Infants were assessed at birth and followed until 1 y of life. Blood sampling was performed to characterise the pharmacokinetics of lumefantrine in pregnancy. Both regimens were very well tolerated. The cure rates (95% confidence interval) for the intention to treat (ITT) population were: AS7 89.2% (82.3%–96.1%) and AL 82.0% (74.8%–89.3%), p = 0.054 (ITT); and AS7 89.7% (82.6%–96.8%) and AL 81.2% (73.6%–88.8%), p = 0.031 (per-protocol population). One-third of the PCR-confirmed recrudescent cases occurred after 42 d of follow-up. Birth outcomes and infant (up to age 1 y) outcomes did not differ significantly between the two groups. The pharmacokinetic study indicated that low concentrations of artemether and lumefantrine were the main contributors to the poor efficacy of AL.

Conclusion

The current standard six-dose artemether-lumefantrine regimen was well tolerated and safe in pregnant Karen women with uncomplicated falciparum malaria, but efficacy was inferior to 7 d artesunate monotherapy and was unsatisfactory for general deployment in this geographic area. Reduced efficacy probably results from low drug concentrations in later pregnancy. A longer or more frequent AL dose regimen may be needed to treat pregnant women effectively and should now be evaluated. Parasitological endpoints in clinical trials of any antimalarial drug treatment in pregnancy should be extended to delivery or day 42 if it comes later. Trial Registration: Current Controlled Trials ISRCTN86353884     

A Novel Method to Adjust Efficacy Estimates for Uptake of Other Active Treatments in Long-Term Clinical Trials

Background

When rates of uptake of other drugs differ between treatment arms in long-term trials, the true benefit or harm of the treatment may be underestimated. Methods to allow for such contamination have often been limited by failing to preserve the randomization comparisons. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, patients were randomized to fenofibrate or placebo, but during the trial many started additional drugs, particularly statins, more so in the placebo group. The effects of fenofibrate estimated by intention-to-treat were likely to have been attenuated. We aimed to quantify this effect and to develop a method for use in other long-term trials.

Methodology/Principal Findings

We applied efficacies of statins and other cardiovascular drugs from meta-analyses of randomized trials to adjust the effect of fenofibrate in a penalized Cox model. We assumed that future cardiovascular disease events were reduced by an average of 24% by statins, and 20% by a first other major cardiovascular drug. We applied these estimates to each patient who took these drugs for the period they were on them. We also adjusted the analysis by the rate of discontinuing fenofibrate. Among 4,900 placebo patients, average statin use was 16% over five years. Among 4,895 assigned fenofibrate, statin use was 8% and nonuse of fenofibrate was 10%. In placebo patients, use of cardiovascular drugs was 1% to 3% higher. Before adjustment, fenofibrate was associated with an 11% reduction in coronary events (coronary heart disease death or myocardial infarction) (P = 0.16) and an 11% reduction in cardiovascular disease events (P = 0.04). After adjustment, the effects of fenofibrate on coronary events and cardiovascular disease events were 16% (P = 0.06) and 15% (P = 0.008), respectively.

Conclusions/Significance

This novel application of a penalized Cox model for adjustment of a trial estimate of treatment efficacy incorporates evidence-based estimates for other therapies, preserves comparisons between the randomized groups, and is applicable to other long-term trials. In the FIELD study example, the effects of fenofibrate on the risks of coronary heart disease and cardiovascular disease events were underestimated by up to one-third in the original analysis.

Trial Registration

Controlled-Trials.com ISRCTN64783481     

The Average Body Surface Area of Adult Cancer Patients in the UK: A Multicentre Retrospective Study

The majority of chemotherapy drugs are dosed based on body surface area (BSA). No standard BSA values for patients being treated in the United Kingdom are available on which to base dose and cost calculations. We therefore retrospectively assessed the BSA of patients receiving chemotherapy treatment at three oncology centres in the UK between 1^st January 2005 and 31^st December 2005.A total of 3613 patients receiving chemotherapy for head and neck, ovarian, lung, upper GI/pancreas, breast or colorectal cancers were included. The overall mean BSA was 1.79 m² (95% CI 1.78–1.80) with a mean BSA for men of 1.91 m² (1.90–1.92) and 1.71 m² (1.70–1.72) for women. Results were consistent across the three centres. No significant differences were noted between treatment in the adjuvant or palliative setting in patients with breast or colorectal cancer. However, statistically significant, albeit small, differences were detected between some tumour groups.In view of the consistency of results between three geographically distinct UK cancer centres, we believe the results of this study may be generalised and used in future costings and budgeting for new chemotherapy agents in the UK.     

Safety and Efficacy of Methotrexate in Psoriasis: A Meta-Analysis of Published Trials

BackgroundMethotrexate (MTX) has been used to treat psoriasis for over half a century. Even so, clinical data characterising its efficacy and safety are sparse.ObjectiveIn order to enhance the available evidence, we conducted two meta-analyses, one for efficacy and one for safety outcomes, respectively, according to PRISMA checklist. (Data sources, study criteria, and study synthesis methods are detailed in Methods).ResultsIn terms of efficacy, only eleven studies met criteria for study design and passed a Cochrane risk of bias analysis. Based on this limited dataset, 45.2% [95% confidence interval 34.1–60.0] of patients achieve PASI75 at primary endpoint (12 or 16 weeks, respectively, n = 705 patients across all studies), compared to a calculated PASI75 of 4.4 [3.5–5.6] for placebo, yielding a relative risk of 10.2 [95% C.I. 7.1–14.7]. For safety outcomes, we extended the meta-analysis to include studies employing the same dose range of MTX for other chronic inflammatory conditions, e.g. rheumatoid arthritis, in order not to maximise capture of relevant safety data. Based on 2763 patient safety years, adverse events (AEs) were found treatment limiting in 6.9 ± 1.4% (mean ± s.e.) of patients treated for six months, with an adverse effect profile largely in line with that encountered in clinical practice. Finally, in order to facilitate prospective clinical audit and to help generate long-term treatment outcomes under real world conditions, we also developed an easy to use documentation form to be completed by patients without requirement for additional staff time.LimitationsMeta-analyses for efficacy and safety, respectively, employed non-identical selection criteria.ConclusionsThese meta-analyses summarise currently available evidence on MTX in psoriasis and should be of use to gauge whether local results broadly fall within outcomes.     

Efficacy and safety of nitazoxanide, albendazole, and nitazoxanide-albendazole against Trichuris trichiura infection: a randomized controlled trial

Background

The currently used anthelmintic drugs, in single oral application, have low efficacy against Trichuris trichiura infection, and hence novel anthelmintic drugs are needed. Nitazoxanide has been suggested as potential drug candidate.

Methodology

The efficacy and safety of a single oral dose of nitazoxanide (1,000 mg), or albendazole (400 mg), and a nitazoxanide-albendazole combination (1,000 mg–400 mg), with each drug administered separately on two consecutive days, were assessed in a double-blind, randomized, placebo-controlled trial in two schools on Pemba, Tanzania. Cure and egg reduction rates were calculated by per-protocol analysis and by available case analysis. Adverse events were assessed and graded before treatment and four times after treatment.

Principal Findings

Complete data for the per-protocol analysis were available from 533 T. trichiura-positive children. Cure rates against T. trichiura were low regardless of the treatment (nitazoxanide-albendazole, 16.0%; albendazole, 14.5%; and nitazoxanide, 6.6%). Egg reduction rates were 54.9% for the nitazoxanide-albendazole combination, 45.6% for single albendazole, and 13.4% for single nitazoxanide. Similar cure and egg reduction rates were calculated using the available case analysis. Children receiving nitazoxanide had significantly more adverse events compared to placebo recipients. Most of the adverse events were mild and had resolved within 24 hours posttreatment.

Conclusions/Significance

Nitazoxanide shows no effect on T. trichiura infection. The low efficacy of albendazole against T. trichiura in the current setting characterized by high anthelmintic drug pressure is confirmed. There is a pressing need to develop new anthelmintics against trichuriasis.

Trial Registration

Controlled-Trials.com ISRCTN08336605     

Evolution of Asthma Severity in a Cohort of Young Adults: Is There Any Gender Difference?

Introduction

Little is known about the distribution of asthma severity in men and women in the general population. The objective of our study was to describe asthma severity and change in severity according to gender in a cohort of adult asthmatics

Methods

Subjects with asthma were identified from random samples of the 22 to 44 year-olds from the general population, screened for asthma from 1991 to 1993 in 48 centers from 22 countries and followed-up during 1998–2002, as part of the European Community Respiratory Health Survey (ECRHS). All participants to follow-up with current asthma at baseline were eligible for the analysis. To assess change over the follow-up, asthma severity at the two surveys was defined using standardized data on respiratory symptoms, lung function and medication according to the Global Initiative for Asthma (GINA) Guidelines. Another quantitative score (Ronchetti) further considering hospitalizations was also analysed.

Results

The study included 685 subjects with asthma followed-up over a mean period of 8.65 yr (min 4.3-max 11.7). At baseline, asthma severity according to GINA was distributed as intermittent: 40.7%, 31.7% as mild persistent, 14% as moderate persistent, and 13.5% as severe persistent. Using the Ronchetti score derived classification, the distribution of asthma severity was 58% mild, (intermittent and mild persistent), 25.8% moderate, and 15.4% severe. Whatever the classification, there was no significant difference in the severity distribution between men and women. There was also no gender difference in the severity distribution among incident cases which developed asthma between the two surveys. Men with moderate-to-severe asthma at baseline were more likely than women to have moderate-to-severe asthma at follow-up. Using GINA, 69.2% of men vs. 53.1% of women (p = 0.09) with moderate-to-severe asthma at baseline were still moderate-to-severe at follow-up. Using Ronchetti score, 53.3% of men vs. 36.2% of women (p = 0.03) with moderate-to-severe asthma at baseline were still moderate-to-severe at follow-up.

Conclusions

There was no gender difference in asthma severity at the two surveys. However, our findings suggest that asthma severity might be less stable in women than in men.     

60 kD Ro and nRNP A Frequently Initiate Human Lupus Autoimmunity

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, humoral autoimmune disorder. The unifying feature among SLE patients is the production of large quantities of autoantibodies. Serum samples from 129 patients collected before the onset of SLE and while in the United States military were evaluated for early pre-clinical serologic events. The first available positive serum sample frequently already contained multiple autoantibody specificities (65%). However, in 34 SLE patients the earliest pre-clinical serum sample positive for any detectable common autoantibody bound only a single autoantigen, most commonly 60 kD Ro (29%), nRNP A (24%), anti-phospholipids (18%) or rheumatoid factor (15%). We identified several recurrent patterns of autoantibody onset using these pre-diagnostic samples. In the serum samples available, anti-nRNP A appeared before or simultaneously with anti-nRNP 70 K in 96% of the patients who had both autoantibodies at diagnosis. Anti-60 kD Ro antibodies appeared before or simultaneously with anti-La (98%) or anti-52 kD Ro (95%). The autoantibody response in SLE patients begins simply, often binding a single specific autoantigen years before disease onset, followed by epitope spreading to additional autoantigenic specificities that are accrued in recurring patterns.     

Rapid Assessment of Avoidable Blindness in the Occupied Palestinian Territories

Background

There are no recent data on the prevalence and causes of blindness in the Occupied Palestinian Territories. The aim of our study was to estimate the prevalence and causes of blindness and visual impairment in the population aged 50 years and above in the Occupied Palestinian Territories using the Rapid Assessment of Avoidable Blindness (RAAB) survey method.

Methods and Findings

Clusters of 40 people who were 50 years and above were selected with probability proportionate to size using a multistage cluster random sampling method. Participants received a comprehensive ophthalmic examination in their homes, including visual acuity testing by one of three experienced ophthalmologists. The principal cause for visual loss was determined by an experienced ophthalmologist using portable diagnostic instruments. Information about previous cataract surgery, satisfaction with surgery and barriers to cataract surgery were collected. The prevalence of self-reported diabetes was also determined. The prevalence of bilateral blindness (VA<3/60 in the better eye with available correction) was 3.4% (95% CI: 2.7–4.0), 2.0% (95% CI: 1.4–2.5) for severe visual impairment (VA≥3/60 and <6/60), and 7.4% (95% CI: 6.4–8.3) for visual impairment (VA≥6/60 and <6/18). Avoidable causes (i.e. cataract, refractive error, aphakia, surgical complications, corneal scarring and phthysis) accounted for 80.0% of bilateral blindness, severe visual impairment (70.7%) and visual impairment (86.2%). Cataract was the main cause of blindness (55.0%). The prevalence of blindness was higher in Gaza (4.9%, 95% CI: 3.7–6.1%) than in the West Bank (2.5%, 95% CI: 1.9–3.1%) and among women (4.3%,95% CI: 3.3–5.2%) compared to men (2.2%,95%CI:1.5–2.9%). Among people who had undergone cataract surgery in the past, only 54.5% of eyes obtained a good outcome (VA≥6/18), 23.2% had a borderline outcome (VA<6/18 and ≥6/60) and 22.3% had a poor outcome (VA<6/60) with available correction. The prevalence of self-reported diabetes mellitus in ≥50 year age group was 26.4% (95% CI: 24.9–27.9).

Conclusions

The prevalence of blindness suggests that significant numbers of people in the Occupied Palestinian Territories exist who do not access eye care - predominantly women and those residing in Gaza. Programmes need to focus on maximizing the use of current services by these excluded groups.     

Recent advances in understanding sex differences in cardiac repolarization

A number of gender differences exist in the human electrocardiogram (ECG): the P-wave and P-R intervals are slightly longer in men than in women, whilst women have higher resting heart rates than do men, but a longer rate-corrected QT (QT_C) interval. Women with the LQT1 and LQT2 variants of congenital long-QT syndrome (LQTS) are at greater risk of adverse cardiac events. Similarly, many drugs associated with acquired LQTS have a greater risk of inducing torsades de pointes (TdP) arrhythmia in women than in men. There are also male:female differences in Brugada syndrome, early repolarisation syndrome and sudden cardiac death. The differences in the ECG between men and women, and in particular those relating to the QT interval, have been explored experimentally and provide evidence of differences in the processes underlying ventricular repolarization. The data available from rabbit, canine, rat, mouse and guinea pig models are reviewed and highlight involvement of male:female differences in Ca and K currents, although the possible involvement of rapid and persistent Na current and Na–Ca exchange currents cannot yet be excluded. The mechanisms underlying observed differences remain to be elucidated fully, but are likely to involve the influence of gonadal steroids. With respect to the QT interval and risk of TdP, a range of evidence implicates a protective role of testosterone in male hearts, possibly by both genomic and non-genomic pathways. Evidence regarding oestrogen and progesterone is less unequivocal, although the interplay between these two hormones may influence both repolarization and pro-arrhythmic risk.     

Phase 1 Safety and Immunogenicity Evaluation of ADMVA,a Multigenic,Modified Vaccinia Ankara-HIV-1 B'/C Candidate Vaccine

Background

We conducted a Phase I dose-escalation trial of ADMVA, a Clade-B''/C-based HIV-1 candidate vaccine expressing env, gag, pol, nef, and tat in a modified vaccinia Ankara viral vector. Sequences were derived from a prevalent circulating HIV-1 recombinant form in Yunnan, China, an area of high HIV incidence. The objective was to evaluate the safety and immunogenicity of ADMVA in human volunteers.

Methodology/Principal Findings

ADMVA or placebo was administered intramuscularly at months 0, 1 and 6 to 50 healthy adult volunteers not at high risk for HIV-1. In each dosage group [1×10⁷ (low), 5×10⁷ (mid), or 2.5×10⁸ pfu (high)] volunteers were randomized in a 3∶1 ratio to receive ADMVA or placebo in a double-blinded design. Subjects were followed for local and systemic reactogenicity, adverse events including cardiac adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA, immunoflourescent staining, and HIV-1 neutralization. Cellular immunogenicity was assessed by a validated IFNγ ELISpot assay and intracellular cytokine staining. Anti-vaccinia binding titers were measured by ELISA.ADMVA was generally well-tolerated, with no vaccine-related serious adverse events or cardiac adverse events. Local or systemic reactogenicity events were reported by 77% and 78% of volunteers, respectively. The majority of events were of mild intensity. The IFNγ ELISpot response rate to any HIV antigen was 0/12 (0%) in the placebo group, 3/12 (25%) in the low dosage group, 6/12 (50%) in the mid dosage group, and 8/13 (62%) in the high dosage group. Responses were often multigenic and occasionally persisted up to one year post vaccination. Antibodies to gp120 were detected in 0/12 (0%), 8/13 (62%), 6/12 (50%) and 10/13 (77%) in the placebo, low, mid, and high dosage groups, respectively. Antibodies persisted up to 12 months after vaccination, with a trend toward agreement with the ability to neutralize HIV-1 SF162 in vitro. Two volunteers mounted antibodies that were able to neutralize clade-matched viruses.

Conclusions/Significance

ADMVA was well-tolerated and elicited durable humoral and cellular immune responses.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00252148","term_id":"NCT00252148"}}NCT00252148     

The Causal Cascade to Multiple Sclerosis: A Model for MS Pathogenesis

Background

MS pathogenesis seems to involve both genetic susceptibility and environmental risk factors. Three sequential factors are implicated in the environmental risk. The first acts near birth, the second acts during childhood, and the third acts long thereafter. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem well suited to the first two environmental events.

Methodology/Principal Findings

A mathematical Model for MS pathogenesis is developed, incorporating these environmental and genetic factors into a causal scheme that can explain some of the recent changes in MS-epidemiology (e.g., increasing disease prevalence, a changing sex-ratio, and regional variations in monozygotic twin concordance rates).

Conclusions/Significance

This Model suggests that genetic susceptibility is overwhelmingly the most important determinant of MS pathogenesis. Indeed, over 99% of individuals seem genetically incapable of developing MS, regardless of what environmental exposures they experience. Nevertheless, the contribution of specific genes to MS-susceptibility seems only modest. Thus, despite HLA DRB1*1501 being the most consistently identified genetic marker of MS-susceptibility (being present in over 50% of northern MS patient populations), only about 1% of individuals with this allele are even genetically susceptible to getting MS. Moreover, because genetic susceptibility seems so similar throughout North America and Europe, environmental differences principally determine the regional variations in disease characteristics. Additionally, despite 75% of MS-patients being women, men are 60% more likely to be genetically-susceptible than women. Also, men develop MS at lower levels of environmental exposure than women. Nevertheless, women are more responsive to the recent changes in environmental-exposure (whatever these have been). This explains both the changing sex-ratio and the increasing disease prevalence (which has increased by a minimum of 32% in Canada over the past 35 years). As noted, environmental risk seems to result from three sequential components of environmental exposure. The potential importance of this Model for MS pathogenesis is that, if correct, a therapeutic strategy, designed to interrupt one or more of these sequential factors, has the potential to markedly reduce or eliminate disease prevalence in the future.