Effects of fecal microbiome transfer in adolescents with obesity: the gut bugs randomized controlled trial

Peer reviewe

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). Interpretation: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Serious skin infections in New Zealand children

Skin infections are a common and widespread ailment among children. While these infections have generally been considered benign, the number requiring overnight hospitalisation for treatment, termed ‘serious skin infections’, has risen markedly in recent years with the incidence in NZ children thought to be significantly higher than that in children of comparatively developed countries. This study aimed to define serious skin infections and describe their epidemiology in the NZ setting. Increased awareness of serious skin infections has resulted in a number of national and regional reports being released over the past decade. However, the accuracy of these existing skin infection data has been limited by the lack of a consistent and valid case definition. By assessing the screening performance of various case definitions when applied in the setting of 4 years of paediatric admissions to a provincial NZ hospital, a new definition for serious skin infection was produced which improved sensitivity from 61% to 99% with negligible loss in specificity. This new case definition was then applied to national hospitalisation data to identify all 0-14 year old children admitted overnight to a NZ hospital with a serious skin infection between January 1990 and December 2007. During this 18-year period the incidence of infection almost doubled from 294.1/100 000 in 1990 to 562.3/100 000 in 2007. Seasonality showed consistent peaks in late Summer and early Autumn. The highest rates were observed in boys, children under 5 years old, Māori (NZ Indigenous peoples) and Pacific children, those living in deprived neighbourhoods, in urban areas and in Northern districts of the country. Trends over time showed the distribution of disease changed with evidence of worsening ethnic and socioeconomic disparities in infection rates. The highest regional incidence was found in the Tairawhiti (Gisborne) Region, where during the same 18-year period admissions rose even more rapidly from 414.5/100 000 in 1990 to 993.3/100 000 in 2007. A closer comparison of hospitalisation data between Tairawhiti and NZ found ethnic disparities in serious skin infection rates were greater in the Tairawhiti Region than nationally. In addition, the overall disease incidence was significantly higher than that expected even after controlling for differences in the population distribution of age, ethnicity and deprivation. This finding suggests the involvement of other unknown aetiological factors. To better understand factors contributing to the need for inpatient treatment, a chart review was conducted of all 163 children admitted to Gisborne Hospital with a serious skin infection between January 2006 and December 2007. Compared to studies in other NZ settings, types, sites and causal organisms of infections were similar. However, there were longer delays to seek medical attention with only 77% of children seeing a GP after a median of 2 days of symptoms, resulting in 60% requiring immediate hospitalisation. In hospital, 70% of cases received intravenous antibiotics and 31% required surgical treatment for their infection. One third of children had suffered a previous skin infection with 12% requiring hospitalisation. Finally, to investigate the hypothesis that trends in serious skin infections reflect corresponding patterns of infection in the community, and to estimate the often hidden burden of skin infection in primary care, a sample of Tairawhiti general practitioners recorded all cases of skin infection in children diagnosed over a 10-week period in 2008. There were 110 incident cases of infection during the study period; through age and ethnicity standardisation this was found to be equivalent to an annual incidence rate of 106.7 (95%CI 85.2-127.2) cases per 1000 children. For every one hospitalisation there were 14 cases seen in primary care. Comparing analogous primary care and hospital demographic data showed that three quarters of skin infections in both primary care and hospital settings occurred in Māori children. There was no gender predominance in either setting, however hospitalised cases of serious skin infection were more likely to occur in the preschool age group with children aged 5-9 years predominating at the primary care level. Serious skin infections are a significant and increasing source of morbidity in NZ children. They now contribute to over 4,500 hospitalisations annually and, based on extrapolations from Tairawhiti data, an estimated 60,000 general practice presentations each year. In addition, they contribute to health disparities with evidence of worsening ethnicity and deprivation-related inequalities over time. Efforts need to be both directed towards effective and sustainable prevention of these infections and towards ongoing research to better understand the aetiology of disease and opportunities for reducing their incidence

Serious skin infections in New Zealand children

Skin infections are a common and widespread ailment among children. While these infections have generally been considered benign, the number requiring overnight hospitalisation for treatment, termed ‘serious skin infections’, has risen markedly in recent years with the incidence in NZ children thought to be significantly higher than that in children of comparatively developed countries. This study aimed to define serious skin infections and describe their epidemiology in the NZ setting. Increased awareness of serious skin infections has resulted in a number of national and regional reports being released over the past decade. However, the accuracy of these existing skin infection data has been limited by the lack of a consistent and valid case definition. By assessing the screening performance of various case definitions when applied in the setting of 4 years of paediatric admissions to a provincial NZ hospital, a new definition for serious skin infection was produced which improved sensitivity from 61% to 99% with negligible loss in specificity. This new case definition was then applied to national hospitalisation data to identify all 0-14 year old children admitted overnight to a NZ hospital with a serious skin infection between January 1990 and December 2007. During this 18-year period the incidence of infection almost doubled from 294.1/100 000 in 1990 to 562.3/100 000 in 2007. Seasonality showed consistent peaks in late Summer and early Autumn. The highest rates were observed in boys, children under 5 years old, Māori (NZ Indigenous peoples) and Pacific children, those living in deprived neighbourhoods, in urban areas and in Northern districts of the country. Trends over time showed the distribution of disease changed with evidence of worsening ethnic and socioeconomic disparities in infection rates. The highest regional incidence was found in the Tairawhiti (Gisborne) Region, where during the same 18-year period admissions rose even more rapidly from 414.5/100 000 in 1990 to 993.3/100 000 in 2007. A closer comparison of hospitalisation data between Tairawhiti and NZ found ethnic disparities in serious skin infection rates were greater in the Tairawhiti Region than nationally. In addition, the overall disease incidence was significantly higher than that expected even after controlling for differences in the population distribution of age, ethnicity and deprivation. This finding suggests the involvement of other unknown aetiological factors. To better understand factors contributing to the need for inpatient treatment, a chart review was conducted of all 163 children admitted to Gisborne Hospital with a serious skin infection between January 2006 and December 2007. Compared to studies in other NZ settings, types, sites and causal organisms of infections were similar. However, there were longer delays to seek medical attention with only 77% of children seeing a GP after a median of 2 days of symptoms, resulting in 60% requiring immediate hospitalisation. In hospital, 70% of cases received intravenous antibiotics and 31% required surgical treatment for their infection. One third of children had suffered a previous skin infection with 12% requiring hospitalisation. Finally, to investigate the hypothesis that trends in serious skin infections reflect corresponding patterns of infection in the community, and to estimate the often hidden burden of skin infection in primary care, a sample of Tairawhiti general practitioners recorded all cases of skin infection in children diagnosed over a 10-week period in 2008. There were 110 incident cases of infection during the study period; through age and ethnicity standardisation this was found to be equivalent to an annual incidence rate of 106.7 (95%CI 85.2-127.2) cases per 1000 children. For every one hospitalisation there were 14 cases seen in primary care. Comparing analogous primary care and hospital demographic data showed that three quarters of skin infections in both primary care and hospital settings occurred in Māori children. There was no gender predominance in either setting, however hospitalised cases of serious skin infection were more likely to occur in the preschool age group with children aged 5-9 years predominating at the primary care level. Serious skin infections are a significant and increasing source of morbidity in NZ children. They now contribute to over 4,500 hospitalisations annually and, based on extrapolations from Tairawhiti data, an estimated 60,000 general practice presentations each year. In addition, they contribute to health disparities with evidence of worsening ethnicity and deprivation-related inequalities over time. Efforts need to be both directed towards effective and sustainable prevention of these infections and towards ongoing research to better understand the aetiology of disease and opportunities for reducing their incidence

Critical analysis of hydrogen production from mixed culture fermentation under thermophilic condition (60 °C)

Bio-hydrogen production from mixed culture fermentation (MCF) of glucose was studied by conducting a comprehensive product measurement and detailed mass balance analysis of their contributions to the final H yield. The culture used in this study was enriched on glucose at 60Â\ua0°C through a sequential batch operation consisting of daily glucose feeds, headspace purging and medium replacement every third day in serum bottles for over 2Â\ua0years. 2-Bromoethanesulfonate (BES) was only required during the first three 3-day cycles to permanently eliminate methanogenic activity. Daily glucose feeds were fully consumed within 24Â\ua0h, with a persistent H yield of 2.7Â\ua0±Â\ua00.1Â\ua0mol H/mol glucose, even when H was allowed to accumulate over the 3-day cycle. The measured H production exceeded by 14Â\ua0% the theoretical production of H associated with the fermentation products, dominated by acetate and butyrate. Follow-up experiments using acetate with a C-labelled methyl group showed that the excess H production was not due to acetate oxidation. Chemical formula analysis of the biomass showed a more reduced form of CHON suggesting that the biomass formation may even consume produced H from fermentation