Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19. OBJECTIVES: To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes. MAIN RESULTS: This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022.  The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies.  Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence).  The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain. AUTHORS' CONCLUSIONS: In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review.

Impact of exercise on brain-bone marrow interactions in chronic stress: potential mechanisms preventing stress-induced hypertension.

We examined the effect of chronic restraint stress and the counteractive effects of daily exercise on the molecular basis of the brain-bone marrow (BM) interactions, by especially focusing on the paraventricular nucleus (PVN) of the hypothalamus. Male Wistar rats were assigned into control, restraint stress, and stress + daily spontaneous exercise (SE) groups. BM and hypothalamic gene expression profiles were examined through the undertaking of RT-PCR and microarrays, respectively. The inflammatory blood cell population was investigated through flow cytometry. Through the use of immunohistochemistry, we examined the presence of BM-derived C-C chemokine receptor type 2 (CCR2)-expressing microglial cells in the rat PVN. The gene expression levels of BM inflammatory factors such as those of interleukin 1 beta and CCR2, and the inflammatory blood cell population were found to be significantly higher in both restrained groups compared with control group. Interestingly, chronic restraint stress alone activated the recruitment of BM-derived CCR2-expressing microglial cells into the PVN, whereas daily spontaneous exercise prevented it. A notable finding was that restraint stress upregulated relative gene expression of hypothalamic matrix metalloproteinase 3 (MMP3), which increases the permeability of the blood-brain barrier (BBB), and that exercise managed to normalize it. Moreover, relative expression of some hypothalamic genes directly involved in the facilitation of cell migration was downregulated by daily exercise. Our findings suggest that daily spontaneous exercise can reduce the numbers of BM-derived CCR2-expressing microglial cells into the PVN through the prevention of stress-induced changes in the hypothalamic gene expression.NEW & NOTEWORTHY Chronic restraint stress can upregulate MMP3 gene expression in the rat hypothalamus, whereas daily spontaneous exercise can prevent this stress-induced effect. Stress-induced BM-derived inflammatory cell recruitment into the rat PVN can be prevented by daily spontaneous exercise. Stress-induced increase of hypothalamic MMP3 gene expression may be responsible for BBB injury, thereby allowing for BM-derived inflammatory cells to be recruited and to accumulate in the rat PVN, and to be subsequently involved in the onset of stress-induced hypertension.

PSMA-PET/CT-Guided Intensification of Radiation Therapy for Prostate Cancer (PSMAgRT): Findings of Detection Rate, Effect on Cancer Management, and Early Toxicity From a Phase 2 Randomized Controlled Trial.

PURPOSE: Prostate-specific membrane antigen (PSMA) ligand positron emission tomography (PET) is increasingly integrated in prostate cancer management because of its diagnostic performance. We sought to evaluate the effect of PSMA-PET/computed tomography (CT)-guided intensification of radiation therapy (PSMAgRT) on patient outcomes. Here, we report secondary trial endpoints including the rate of new lesion detection, effect on prostate cancer management, and treatment-related toxicities. METHODS AND MATERIALS: In this phase 2 cohort multiple randomized controlled trial across 2 institutions, men with prostate cancer planned for RT were randomly selected for PSMAgRT across 4 strata: oligometastatic, high risk (Cancer of the Prostate Risk Assessment ≥6 or cN1), salvage post-RT, and salvage postprostatectomy (RP). Primary endpoint was failure-free survival at 5 years, with analysis pending further follow-up. Secondary endpoints included new lesion detection yield of PSMA-PET/CT, acute and delayed toxicities, effect on prostate cancer management, and health-related quality-of-life outcomes. This trial is registered with ClinicalTrials.gov, identifier NCT03525288, companion to registry NCT03378856. RESULTS: Between May 2018 and February 2021, 262 patients were enrolled and randomized. Nine patients were later excluded (5 control, 4 PSMAgRT), leaving 253 patients for analysis (23 oligometastatic, 86 high risk, 16 salvage post-RT, and 128 salvage post-RP). New lesions were detected in 45.5% of oligometastatic, 39.5% of high risk, 14.3% of salvage post-RT, and 51.6% of salvage post-RP. Overall, PSMA-PET/CT led to intensification of RT in over half of patients (52.0%), with minimal intensification of systemic therapy (4.0%). With a median follow-up of 12.9 months, this intensification was associated with 3 attributable grade 3+ events (2.5% of patients undergoing PSMAgRT) but no difference in the rate of grade 2+ events attributable to RT compared with controls (43%, both arms). CONCLUSIONS: In this randomized trial, PSMA-PET/CT led to intensification of RT in more than half of patients. Longer follow-up is required to determine whether this intensification translates to effect on cancer control and long-term toxicity and health-related quality-of-life outcomes.

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance. OBJECTIVES: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events. MAIN RESULTS: We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes. AUTHORS' CONCLUSIONS: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).

Platelet activation in rabbits with decompression sickness.

Platelets are the most easily altered type of peripheral blood cell in decompression sickness (DCS), which can feature decreased platelet count and the appearance of platelet microparticles in plasma. We hypothesized that DCS results in platelet activation in the bloodstream. The present study was carried out on 45 rabbits. The platelet count and concentration of plasma platelet markers were determined in 35 rabbits; the platelet shape was observed under scanning electron microscope in 10 rabbits. All indexes were collected at two points: 24 hours before the simulated dive and 30 minutes after the simulated dive. Platelet count decreased noticeably after DCS, from 380.10 ± 73.61 (G/L) to 330.23 ± 115.72 (G/L), a change of approximately -13.49 ± 25.57 (%). Platelet count was further decreased in the severe DCS group (a change of -45.99 ± 18.57%). Platelet count after DCS was proportional to the survival time of the rabbits after DCS. The concentration of two plasma platelet markers (PF4 and BTG) did not demonstrate statistically significant change at 30 minutes after DCS. However, platelet shape was changed, and the following features were observed: oblong, distortion, flattening shape, sticking together, mixing of membrane, and abundance of pseudopods with a 100- to 200-nm diameter. We conclude there is platelet activation in the bloodstream in cases of DCS.

Prediction of enteric methane emission from beef cattle in Southeast Asia.

We conducted a meta-data analysis to develop prediction equations to estimate enteric methane (CH4 ) emission from beef cattle in Southeast Asia. The dataset was obtained from 25 studies, which included 332 individual observations on nutrient intakes, digestibilities, and CH4 emissions. Cattle were provided tropical forage or rice straw, with or without concentrates in individual pens equipped with indirect open-circuit head hood apparatus. The simplest and best equation to predict daily CH4 emission was CH4 (g/day) = 22.71 (±1.008) × dry matter intake (DMI, kg/day) + 8.91 (±10.896) [R2  = 0.77; root mean square error (RMSE) = 19.363 g/day]. The best equation to predict CH4 energy as a proportion of gross energy intake (CH4 -E/GEI, J/100 J) was obtained using DMI per body weight (DMIBW, kg/100 kg), content (g/100 g DM) of ether extract (EE) and crude protein (CP), and DM digestibility (DMD, g/100 g); CH4 -E/GEI = -0.782 (±0.2526) DMIBW - 0.436 (±0.0548) EE - 0.073 (±0.0218) CP + 0.049 (±0.0097) DMD + 8.654 (±0.6517) (R2  = 0.39; RMSE = 1.3479 J/100 J GEI). It was indicated that CH4 emissions from beef cattle in Southeast Asia are predictable using present developed models including simple indices.

Public reporting and the quality of care of German nursing homes.

OBJECTIVES: Since 2009, German nursing homes have been evaluated regularly by an external institution with quality report cards published online. We follow recent debates and argue that most of the information in the report cards does not reliably measure quality of care. However, a subset of up to seven measures does. Do these measures that reflect "risk factors" improve over time? METHOD: Using a sample of more than 3000 German nursing homes with information on two waves, we assume that the introduction of public reporting is an exogenous institutional change and apply before-after-estimations to obtain estimates for the relation between public reporting and quality. RESULTS: We find a significant improvement of the identified risk factors. Also, the two employed outcome quality indicators improve significantly. The improvements are driven by nursing homes with low quality in the first evaluation. CONCLUSION: To the extent that this can be interpreted as evidence that public reporting positively affects the (reported) quality in nursing homes, policy makers should carefully choose indicators reflecting care-sensitive quality.

Cervical necrosis after chemoradiation for cervical cancer: case series and literature review.

BACKGROUND: The aim of this study was to assess the management of cervical necrosis (CN) following radiotherapy (RT) and the impact of smoking status. This rare complication mimics a neoplastic recurrence, and causes concern among attending physicians. METHODS: Between July 2008 and March 2013, 5 women on 285 with localized cervical cancer had a CN following RT. Patients were treated with concomitant chemoradiation. The medical records were reviewed to abstract demographic and clinical information until March 2013. RESULTS: 1.75% (95% confidence interval: 0.23 to 3.28%) developed CN. All patients were smokers with a mean of 19.5 pack-years (range: 7.5-45 pack-years). All patients were treated with weekly Cisplatin chemotherapy and external beam radiation to the pelvis, 45 Gy in 25 fractions. Four patients received an extra boost with a median dose of 7.2 Gy (range: 5.4-10 Gy). All patients had intracavitary brachytherapy (range: 27.9 to 30 Gy). Clinical presentation was similar for all the cases: vaginal discharge associated with pain. Mean time for time post-radiation therapy to necrosis was 9.3 months (range: 2.2-20.5 months). Standard workup was done to exclude cancer recurrence: biopsies and radiologic imaging. Conservative treatment was performed with excellent results. Resolution of the necrosis was complete after a few months (range: 1 to 4 months). Median follow-up until March 2013 was 19 months. All the patients were alive with no clinical evidence of disease. CONCLUSIONS: This study, the largest to date, shows that conservative management of CN after RT is effective, and should be attempted. This complication is more common in smokers, and counseling intervention should result in fewer complications of CN.

Impact of concurrent androgen deprivation on fiducial marker migration in external-beam radiation therapy for prostate cancer.

PURPOSE: To determine the extent of gold fiducial marker (FM) migration in patients treated for prostate cancer with concurrent androgen deprivation and external-beam radiation therapy (EBRT). METHODS AND MATERIALS: Three or 4 gold FMs were implanted in 37 patients with prostate adenocarcinoma receiving androgen deprivation therapy (ADT) in conjunction with 70-78 Gy. Androgen deprivation therapy was started a median of 3.9 months before EBRT (range, 0.3-12.5 months). To establish the extent of FM migration, the distance between each FM was calculated for 5-8 treatments once per week throughout the EBRT course. For each treatment, the distance between FMs was compared with the distance from the digitally reconstructed radiographs generated from the planning CT. A total of 281 treatments were analyzed. RESULTS: The average daily migration was 0.8 ± 0.3 mm, with distances ranging from 0.2 mm-2.6 mm. Two of the 281 assessed treatments (0.7%) showed migrations >2 mm. No correlation between FM migration and patient weight or time delay between ADT and start of EBRT was found. There was no correlation between the extent of FM migration and prostate volume. CONCLUSION: This is the largest report of implanted FM migration in patients receiving concomitant ADT. Only 0.7% of the 281 treatments studied had significant marker migrations (>2 mm) throughout the course of EBRT. Consequently, the use of implanted FMs in these patients enables accurate monitoring of prostate gland position during treatment.

The importance of an exponential prostate-specific antigen decline after external beam radiotherapy for intermediate risk prostate cancer.

BACKGROUND: To study the influence of an exponential prostate-specific antigen (PSA) decline on biochemical failure after external-beam radiotherapy (EBRT). METHODS: We analyzed 114 patients with intermediate risk prostate cancer (Gleason≤6 and PSA 10-20 or Gleason 7 and PSA <10). Patients were randomized between EBRT doses of either 70.2 Gy or 79.2 Gy (1.8 Gy per day). All patients had a follow up of at least six PSA measurements post-EBRT. Exponential decline and PSA half life were included in a Cox regression analysis for factors associated with biochemical failure. RESULTS: A total of 80/114 (70.2%) patterns were classified as having an exponential PSA decline. Both exponential decline (HR 0.115, 95%CI 0.03-0.44, p=0.0016) and PSA half life ratio were statistically significant predictors (HR 1.03 (95% CI 1.01-1.06)) of biochemical failure. In the model predicting for exponential decline, none of the factors were significant. CONCLUSION: Patients with an exponential PSA decline show a better biochemical outcome in the long term.

Efficacy of a low-cost, inactivated whole-cell oral cholera vaccine: results from 3 years of follow-up of a randomized, controlled trial.

BACKGROUND: Killed oral cholera vaccines (OCVs) have been licensed for use in developing countries, but protection conferred by licensed OCVs beyond two years of follow-up has not been demonstrated in randomized, clinical trials. METHODS/PRINCIPAL FINDINGS: We conducted a cluster-randomized, placebo-controlled trial of a two-dose regimen of a low-cost killed whole cell OCV in residents 1 year of age and older living in 3,933 clusters in Kolkata, India. The primary endpoint was culture-proven Vibrio cholerae O1 diarrhea episodes severe enough to require treatment in a health care facility. Of the 66,900 fully dosed individuals (31,932 vaccinees and 34,968 placebo recipients), 38 vaccinees and 128 placebo-recipients developed cholera during three years of follow-up (protective efficacy 66%; one-sided 95%CI lower bound = 53%, p<0.001). Vaccine protection during the third year of follow-up was 65% (one-sided 95%CI lower bound = 44%, p<0.001). Significant protection was evident in the second year of follow-up in children vaccinated at ages 1-4 years and in the third year in older age groups. CONCLUSIONS/SIGNIFICANCE: The killed whole-cell OCV conferred significant protection that was evident in the second year of follow-up in young children and was sustained for at least three years in older age groups. Continued follow-up will be important to establish the vaccine's duration of protection. TRIAL REGISTRATION: ClinicalTrials.gov NCT00289224.

Efficacy and safety of a modified killed-whole-cell oral cholera vaccine in India: an interim analysis of a cluster-randomised, double-blind, placebo-controlled trial.

BACKGROUND: Oral cholera vaccines consisting of killed whole cells have been available for many years, but they have not been used extensively in populations with endemic disease. An inexpensive, locally produced oral killed-whole-cell vaccine has been used in high-risk areas in Vietnam. To expand the use of this vaccine, it was modified to comply with WHO standards. We assessed the efficacy and safety of this modified vaccine in a population with endemic cholera. METHODS: In this double-blind trial, 107 774 non-pregnant residents of Kolkata, India, aged 1 year or older, were cluster-randomised by dwelling to receive two doses of either modified killed-whole-cell cholera vaccine (n=52 212; 1966 clusters) or heat-killed Escherichia coli K12 placebo (n=55 562; 1967 clusters), both delivered orally. Randomisation was done by computer-generated sequence in blocks of four. The primary endpoint was prevention of episodes of culture-confirmed Vibrio cholerae O1 diarrhoea severe enough for the patient to seek treatment in a health-care facility. We undertook an interim, per-protocol analysis at 2 years of follow-up that included individuals who received two completely ingested doses of vaccine or placebo. We assessed first episodes of cholera that occurred between 14 days and 730 days after receipt of the second dose. This study is registered with ClinicalTrials.gov, number NCT00289224. FINDINGS: 31 932 participants assigned to vaccine (1721 clusters) and 34 968 assigned to placebo (1757 clusters) received two doses of study treatment. There were 20 episodes of cholera in the vaccine group and 68 episodes in the placebo group (protective efficacy 67%; one-tailed 99% CI, lower bound 35%, p<0.0001). The vaccine protected individuals in age-groups 1.0-4.9 years, 5.0-14.9 years, and 15 years and older, and protective efficacy did not differ significantly between age-groups (p=0.28). We recorded no vaccine-related serious adverse events. INTERPRETATION: This modified killed-whole-cell oral vaccine, compliant with WHO standards, is safe, provides protection against clinically significant cholera in an endemic setting, and can be used in children aged 1.0-4.9 years, who are at highest risk of developing cholera in endemic settings. FUNDING: Bill & Melinda Gates Foundation, Swedish International Development Cooperation Agency, Governments of South Korea, Sweden, and Kuwait.

Factors influencing treatment decisions in patients with low risk prostate cancer referred to a brachytherapy clinic.

OBJECTIVE: The present study aimed to analyze factors influencing treatment decisions in patients diagnosed with low risk prostate cancer who were referred to a brachytherapy clinic and had to choose from four treatment options: expectant management (watchful waiting), radical prostatectomy, external beam radiation therapy, and permanent seed brachytherapy. METHODS: We analyzed factors that influenced the treatment decisions of 110 consecutive patients with low risk prostate cancer who were referred to a brachytherapy clinic in a hospital in Montreal, Canada. These factors included patient age, marital status, and profession, as well as referral source (a urologist or a radiation oncologist), and distance and driving time from the patient's home to the medical center. Cost was not a factor as the procedure is covered under the Canadian healthcare system. RESULTS: Of the 110 patients, 53 patients (48.2%) chose permanent seed brachytherapy, 33 patients (31.8%) chose expectant management, 12 patients (10.9%) chose external beam radiation therapy, and 10 patients (9.1%) chose radical prostatectomy. Patients who chose brachytherapy were significantly younger than those who chose external beam radiation therapy (p = 0.011). Patients living further away from the hospital than the median distance of 19.85 miles were more likely to choose brachytherapy than expectant management (p = 0.017).

Hepatitis B infection in rural Vietnam and the implications for a national program of infant immunization.

To ascertain hepatitis B virus (HBV) infection rates for Vietnam, we surveyed HBV markers in two districts of Thanh Hoa province. We randomly selected 536 infants (9- < or = 18 months old), 228 children (4 to < or = 6 years old), 219 adolescents (14 to < or = 16 years old), and 596 adults (25 to < or = 40 years old). On questioning, none of those surveyed had received vaccine against HBV. Hepatitis B virus surface antigen (HBsAg) and total HBV core antibody (anti-HBc) were measured in all specimens, and HBV e antigen (HBeAg) in those positive for HBsAg, and HBV surface antibody (anti-HBs) were measured in all others. Current infection (HBsAg+) rates were infants = 12.5%, children = 18.4%, adolescents = 20.5%, and adults = 18.8%. Current or previous infection (HBsAg+, anti-HBc+, or anti-HBs+) increased with age (infants = 19.6%, children = 36.4%, adolescents = 55.3%, adults = 79.2%). Rates of HBeAg among those HBsAg+ were infants = 85.1%, children = 88.1%, adolescents = 71.1%, and adults = 30.4%. The epidemiology of HBV in Vietnam resembles that of many southeast Asian nations before introduction of vaccine. Immunization of newborns will have enormous impact on HBV-related morbidity and mortality there.