Stakeholder attitudes towards audit credibility in English local government: A post-audit commission analysis

In recent years, substantial changes have been implemented to the audit regimes for local authorities in several countries. Following the abolishment of the Audit Commission, a unique regime for the audit of local authorities has emerged in England, with external audit now fully conducted by private sector audit firms. Auditor appointments for the vast majority of local authorities are now managed by a new organisation, Public Sector Audit Appointments Limited (PSAA). Drawing on the determinants of audit credibility developed by Funnell, Wade and Jupe (2016), this paper examines how local authority stakeholders in the transformed landscape of local public audit in England perceive audit credibility, including the role of PSAA and other audit stakeholders. Findings show that the impact of current arrangements is positively perceived by stakeholders in relation to auditors’ technical competence and independence, at least in the short term, however significant concern is found amongst stakeholders regarding the usefulness of local public audits. Compared to Funnell et al. (2016), we ascribe these differences to the different context of audit in English local government and suggest the relative weighting of determinants of audit credibility are contingent

"We should be at the table together from the beginning": perspectives on partnership from stakeholders at four research institutions in sub-Saharan Africa.

BACKGROUND: Global health research partnerships have been scrutinised for how they operate and criticised for perpetuating inequities. Guidance to inform fair partnership practice has proliferated and the movement to decolonise global health has added momentum for change. In light of this evolving context, we sought in this study to document contemporary experiences of partnership from the perspective of stakeholders in four sub-Saharan African research institutions. METHODS: We conducted qualitative interviews with 20 stakeholders at research institutions in four countries in anglophone eastern and southern Africa. Interview questions were informed by published guidance on equitable research partnerships. Data was analysed through an iterative process of inductive and deductive coding, supported by NVivo software. RESULTS: Early-career, mid-career and senior researchers and research administrators from four sub-Saharan African research institutions described wide-ranging experiences of partnership with high-income country collaborators. Existing guidelines for partnership provided good coverage of issues that participants described as being the key determinants of a healthy partnership, including mutual respect, role clarity and early involvement of all partners. However, there was almost no mention of guidelines being used to inform partnership practice. Participants considered the key benefits of partnership to be capacity strengthening and access to research funding. Meanwhile, participants continued to experience a range of well-documented inequities, including exclusion from agenda setting, study design, data analysis and authorship; and relationships that were exploitative and dominated by high-income country partners' interests. Participants also reported emerging issues where their institution had been the prime recipient of funds. These included high-income country partners being unwilling to accept a subordinate role and failing to comply with reporting requirements. CONCLUSIONS: Insights from stakeholders in four sub-Saharan African research institutions suggest that contemporary global health research partnerships generate considerable benefits but continue to exhibit longstanding inequities and reveal emerging tensions. Our findings suggest that long-term support targeted towards institutions and national research systems remains essential to fulfil the potential of research led from sub-Saharan Africa. High-income country stakeholders need to find new roles in partnerships and stakeholders from sub-Saharan Africa must continue to tackle challenges presented by the resource-constrained contexts in which they commonly operate

Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes*

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen–DR4(DRB1*0401)–restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group’s daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell–specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation

GA4GH: International policies and standards for data sharing across genomic research and healthcare.

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

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

Mortality in British vegetarians.

OBJECTIVE: To compare the mortality of British vegetarians and non-vegetarians. DESIGN: Analysis of original data from two prospective studies each including a large proportion of vegetarians--the Oxford Vegetarian Study and the Health Food Shoppers Study. Standardised mortality ratios (SMRs) compared with the population of England and Wales were calculated from deaths before age 90 for vegetarians and non-vegetarians in each study. Death rate ratios (DRRs) for vegetarians compared with non-vegetarians within each study were calculated for each of 14 major causes of death. SETTING: UK. SUBJECTS: Twenty-one thousand men and women aged 16-89 years at recruitment, including more than 8,000 vegetarians. RESULTS: SMRs for all causes of death were significantly below the reference level of 100 in both studies: 52 (95% confidence interval (CI) 49-56) based on 1,131 deaths in the Oxford Vegetarian Study and 59 (57-61) based on 2,346 deaths in the Health Food Shoppers Study. For all causes of death, the DRR for vegetarians compared with non-vegetarians was close to one in both studies: 1.01 (95% CI 0.89-1.14) in the Oxford Vegetarian Study, 1.03 (0.95-1.13) in the Health Food Shoppers Study. CONCLUSIONS: British vegetarians have low mortality compared with the general population. Their death rates are similar to those of comparable non-vegetarians, suggesting that much of this benefit may be attributed to non-dietary lifestyle factors such as a low prevalence of smoking and a generally high socio-economic status, or to aspects of the diet other than the avoidance of meat and fish

Monitoring local government financial sustainability: a Dutch-English comparison

Monitoring of local public finance is an essential part of fiscal regulation, although national approaches interact with political and economic environments. England and the Netherlands provide telling similarities and differences in their local government contexts and approaches to such indicators. After a brief discussion of theoretical issues, this chapter compares the use of financial sustainability indicators (FSIs) in Dutch and English local government. It reviews the history, current use, bodies involved, the indicators themselves, and approaches to monitoring. In England, a long history of central oversight of local government, focused upon performance, came to an end in 2010. Ever since, there has been no systematic FSI monitoring, as central government has not implemented its own model, the NAO has not been legitimated, and the local government sector itself has only recently started focusing on financial resilience. The Netherlands has traditionally placed its focus with respect to FSI monitoring on fiscal rules, which are monitored at the regional level of the provinces. More than in England, the Dutch local government association has supported the development of FSIs whilst local government reporting on FSIs is mandatory. Finally, we show how different fiscal rules and governmental characteristics have resulted in contrasting developments of indicators and monitoring