Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data

ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.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

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

ARIA digital anamorphosis: Digital transformation of health and care in airway diseases from research to practice

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed

The use of cytokine assays in the in vitro assessment of cell-mediated immune responses in sheep

The detection and measurement of cytokines produced by activated T cells now offers an alternative or complementary approach to the assessment and dissection of cell-mediated immunity in all species. The work described in this thesis involves the use and/or development of methods to detect, in particular, interleukin-2 (IL-2) production and interferon (IFN)-γ in sheep, and the application of these assays alongside the established lymphocyte proliferation assay. The relationships between these assays were investigated, and their association with humoral responses was also examined in some cases. An IL-2 bioassay was adapted from other workers and used routinely for the quantification of ovine IL-2. The development of antibodies against ovine IL-2 was concurrently attempted with a view to the establishment of a sandwich Enzyme- Linked Immunosorbent Assay (ELISA) for convenient analysis of IL-2. A strategy producing polyclonal antibodies against synthetic peptides corresponding to regions of the bovine IL-2 amino acid sequence resulted in one antiserum that recognised recombinant bovine IL-2 and a secretion of stimulated ovine lymphocytes. A sandwich ELISA for bovine IFN-γ developed by other workers was optimized for detection of ovine IFN-γ. A series of experiments incorporated some or all of these assays to examine (1) the effect of several adjuvants on cell-mediated responses to Keyhole Limpet Haemocyanin (KLH) and a recombinant vaccine against the sheep parasite, Taenia ovis, and (2) the effect of zinc deficiency on the cell-mediated immune responses of lambs. When the relationships between the assays were examined (by calculating Spearman’s rank correlation coefficients) it was demonstrated that while lymphocyte proliferation was associated with both IL-2 and IFN-γ production, it was also consistently associated with total Ig production. By contrast IL-2 and IFN-γ production were never associated with total Ig production, suggesting that these cytokine assays are more specific indicators of the cell-mediated immune response than lymphocyte proliferation. Low plasma zinc levels in lambs did not significantly depress antigen- or mitogen-induced lymphocyte proliferation or IFN-γ production, but there was a trend towards lower than normal responses in weaned ram lambs on low zinc diets. Qualitative reverse-transcription polymerase chain reaction (RT-PCR) detected the expression of ovine cytokine genes in mitogen-stimulated splenocytes and skin biopsy samples from delayed-type hypersensitivity reactions. The detection of expression of some of these genes in the control samples highlighted the need to include quantitative procedures to determine if there were differences in the levels of gene expression that were biologically significant

Relationship between cigarette smoking and blood pressure in adults in Nepal: A population-based cross-sectional study.

Smoking and hypertension are two major risk factors for cardiovascular disease, the leading cause of death in Nepal. The relationship between cigarette smoking and blood pressure (BP) in Nepal is unclear. This study analysed the data from the 2016 Nepal Demographic and Health Survey to explore the differences in systolic BP (SBP) and diastolic BP (DBP) between current daily cigarette smokers and non-smokers in Nepali adults aged 18 to 49 years. A total of 5518 women and 3420 men with valid BP measurements were included. Age, body mass index, wealth quintile (socio-economic status) and agricultural occupation (proxy for physical activity) were included as potential confounders in multivariable linear regression analysis. Women smokers were found to have significantly lower SBP (mean difference 2.8 mm, 95% CI 0.7-4.8 mm) and DBP (mean difference 2.2 mm, 95% CI 0.9-3.6 mm) than non-smokers after adjustment. There were no significant differences in BP between smokers and non-smokers in males, either before or after adjustment. The lower BP in female cigarette smokers in Nepal may be explained by the physiological effect of daily cigarette smoking per se in women, or unmeasured confounders associated with a traditional lifestyle that may lower BP (for example, diet and physical activity). In this nationally representative survey, daily cigarette smoking was not associated with increased BP in males or females in Nepal

Relationship between cigarette smoking and blood pressure in adults in Nepal: A population-based cross-sectional study

Smoking and hypertension are two major risk factors for cardiovascular disease, the leading cause of death in Nepal. The relationship between cigarette smoking and blood pressure (BP) in Nepal is unclear. This study analysed the data from the 2016 Nepal Demographic and Health Survey to explore the differences in systolic BP (SBP) and diastolic BP (DBP) between current daily cigarette smokers and non-smokers in Nepali adults aged 18 to 49 years. A total of 5518 women and 3420 men with valid BP measurements were included. Age, body mass index, wealth quintile (socio-economic status) and agricultural occupation (proxy for physical activity) were included as potential confounders in multivariable linear regression analysis. Women smokers were found to have significantly lower SBP (mean difference 2.8 mm, 95% CI 0.7–4.8 mm) and DBP (mean difference 2.2 mm, 95% CI 0.9–3.6 mm) than non-smokers after adjustment. There were no significant differences in BP between smokers and non-smokers in males, either before or after adjustment. The lower BP in female cigarette smokers in Nepal may be explained by the physiological effect of daily cigarette smoking per se in women, or unmeasured confounders associated with a traditional lifestyle that may lower BP (for example, diet and physical activity). In this nationally representative survey, daily cigarette smoking was not associated with increased BP in males or females in Nepal