Comparing research investment to United Kingdom institutions and published outputs for tuberculosis, HIV and malaria: A systematic analysis across 1997-2013

Background: The "Unfinished Agenda" of infectious diseases is of great importance to policymakers and research funding agencies that require ongoing research evidence on their effective management. Journal publications help effectively share and disseminate research results to inform policy and practice. We assess research investments to United Kingdom institutions in HIV, tuberculosis and malaria, and analyse these by numbers of publications and citations and by disease and type of science. Methods: Information on infection-related research investments awarded to United Kingdom institutions across 1997-2010 were sourced from funding agencies and individually categorised by disease and type of science. Publications were sourced from the Scopus database via keyword searches and filtered to include only publications relating to human disease and containing a United Kingdom-based first and/or last author. Data were matched by disease and type of science categories. Investment (United Kingdom pounds) and publications were compared to generate an 'investment per publication' metric; similarly, an 'investment per citation' metric was also developed as a measure of the usefulness of research. Results: Total research investment for all three diseases was £1.4 billion, and was greatest for HIV (£651.4 million), followed by malaria (£518.7 million) and tuberculosis (£239.1 million). There were 17,271 included publications, with 9,322 for HIV, 4,451 for malaria, and 3,498 for tuberculosis. HIV publications received the most citations (254,949), followed by malaria (148,559) and tuberculosis (100,244). According to UK pound per publication, tuberculosis (£50,691) appeared the most productive for investment, compared to HIV (£61,971) and malaria (£94,483). By type of science, public health research was most productive for HIV (£27,296) and tuberculosis (£22,273), while phase I-III trials were most productive for malaria (£60,491). According to UK pound per citation, tuberculosis (£1,797) was the most productive area for investment, compared to HIV (£2,265) and malaria (£2,834). Public health research was the most productive type of science for HIV (£2,265) and tuberculosis (£1,797), whereas phase I-III trials were most productive for malaria (£1,713). Conclusions: When comparing total publications and citations with research investment to United Kingdom institutions, tuberculosis research appears to perform best in terms of efficiency. There were more public health-related publications and citations for HIV and tuberculosis than other types of science. These findings demonstrate the diversity of research funding and outputs, and provide new evidence to inform research investment strategies for policymakers, funders, academic institutions, and healthcare organizations.Infectious Disease Research Networ

Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array.

BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/bjc.2016.5

The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

INTRODUCTION: The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9-32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer. METHODS: A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size. RESULTS: There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42-1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55-2.25; P = 0.8) for BRCA2 carriers. CONCLUSION: The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers

MRI-targeted or standard biopsy for prostate-cancer diagnosis

Background Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. Methods In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. Results A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001). Conclusions The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .)

Ethnic differences in oral health and use of dental services:cross-sectional study using the 2009 Adult Dental Health Survey

Background Oral health impacts on general health and quality of life, and oral diseases are the most common non-communicable diseases worldwide. Non-White ethnic groups account for an increasing proportion of the UK population. This study explores whether there are ethnic differences in oral health and whether these are explained by differences in sociodemographic or lifestyle factors, or use of dental services. Methods We used the Adult Dental Health Survey 2009 to conduct a cross-sectional study of the adult general population in England, Wales and Northern Ireland. Ethnic groups were compared in terms of oral health, lifestyle and use of dental services. Logistic regression analyses were used to determine whether ethnic differences in fillings, extractions and missing teeth persisted after adjustment for potential sociodemographic confounders and whether they were explained by lifestyle or dental service mediators. Results The study comprised 10,435 (94.6 %) White, 272 (2.5 %) Indian, 165 (1.5 %) Pakistani/Bangladeshi and 187 (1.7 %) Black participants. After adjusting for confounders, South Asian participants were significantly less likely, than White, to have fillings (Indian adjusted OR 0.25, 95 % CI 0.17-0.37; Pakistani/Bangladeshi adjusted OR 0.43, 95 % CI 0.26-0.69), dental extractions (Indian adjusted OR 0.33, 95 % CI 0.23-0.47; Pakistani/Bangladeshi adjusted OR 0.41, 95 % CI 0.26-0.63), and <20 teeth (Indian adjusted OR 0.31, 95 % CI 0.16-0.59; Pakistani/Bangladeshi adjusted OR 0.22, 95 % CI 0.08-0.57). They attended the dentist less frequently and were more likely to add sugar to hot drinks, but were significantly less likely to consume sweets and cakes. Adjustment for these attenuated the differences but they remained significant. Black participants had reduced risk of all outcomes but after adjustment for lifestyle the difference in fillings was attenuated, and extractions and tooth loss became non-significant. Conclusions Contrary to most health inequalities, oral health was better among non-White groups, in spite of lower use of dental services. The differences could be partially explained by reported differences in dietary sugar

Early discontinuation of endocrine therapy for breast cancer: Who is at risk in clinical practice?

Purpose: Despite evidence supporting at least five years of endocrine therapy for early breast cancer, many women discontinue therapy early. We investigated the impact of initial therapy type and specific comorbidities on discontinuation of endocrine therapy in clinical practice. Methods We identified women in a population-based cohort with a diagnosis of early breast cancer and an incident dispensing of anastrozole, letrozole or tamoxifen from 2003-2008 (N = 1531). Pharmacy and health service data were used to determine therapy duration, treatment for pre-existing and post-initiation comorbidities (anxiety, depression, hot flashes, musculoskeletal pain, osteoporosis, vaginal atrophy), demographic and other clinical characteristics. Time to discontinuation of initial, and any, endocrine therapy was calculated. Cox regression determined the association of different characteristics on early discontinuation. Results Initial endocrine therapy continued for a median of 2.2 years and any endocrine therapy for 4.8 years. Cumulative probability of discontinuing any therapy was 17% after one year and 58% by five years. Initial tamoxifen, pre-existing musculoskeletal pain and newly-treated anxiety predicted shorter initial therapy but not discontinuation of any therapy. Early discontinuation of any therapy was associated with newly-treated hot flashes (HR = 2.1, 95%CI = 1.3-3.3), not undergoing chemotherapy (HR = 1.4, 95%CI = 1.1-1.8) and not undergoing mastectomy (HR = 1.5, 95%CI = 1.2-1.8). Conclusions Less than half of women completed five years of endocrine therapy. Women at greatest risk of stopping any therapy early were those with newly-treated hot flashes, no initial chemotherapy, or no initial mastectomy. This suboptimal use means that the reductions in recurrence demonstrated in clinical trials may not be realised in practice

Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci.

BACKGROUND: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. METHODS: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. RESULTS: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). CONCLUSIONS: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. IMPACT: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.D F. Easton was recipient of the CR-UK grant C1287/A10118. R A. Eeles was recipient of the CR-UK grant C5047/A10692 and B E. Henderson was recipient of the NIH grant 1U19CA148537-01This is the author accepted manuscript. The final version is available via AACR at http://cebp.aacrjournals.org/content/early/2015/04/02/1055-9965.EPI-14-0317.long

Global estimates on the number of people blind or visually impaired by Uncorrected Refractive Error: a meta-analysis from 2000 to 2020

Background: Uncorrected refractive error (URE) is a readily treatable cause of visual impairment (VI). This study provides updated estimates of global and regional vision loss due to URE, presenting temporal change for VISION 2020 Methods: Data from population-based eye disease surveys from 1980–2018 were collected. Hierarchical models estimated prevalence (95% uncertainty intervals [UI]) of blindness (presenting visual acuity (VA) < 3/60) and moderate-to-severe vision impairment (MSVI; 3/60 ≤ presenting VA < 6/18) caused by URE, stratified by age, sex, region, and year. Near VI prevalence from uncorrected presbyopia was defined as presenting near VA < N6/N8 at 40 cm when best-corrected distance (VA ≥ 6/12). Results: In 2020, 3.7 million people (95%UI 3.10–4.29) were blind and 157 million (140–176) had MSVI due to URE, a 21.8% increase in blindness and 72.0% increase in MSVI since 2000. Age-standardised prevalence of URE blindness and MSVI decreased by 30.5% (30.7–30.3) and 2.4% (2.6–2.2) respectively during this time. In 2020, South Asia GBD super-region had the highest 50+ years age-standardised URE blindness (0.33% (0.26–0.40%)) and MSVI (10.3% (8.82–12.10%)) rates. The age-standardized ratio of women to men for URE blindness was 1.05:1.00 in 2020 and 1.03:1.00 in 2000. An estimated 419 million (295–562) people 50+ had near VI from uncorrected presbyopia, a +75.3% (74.6–76.0) increase from 2000 Conclusions: The number of cases of VI from URE substantively grew, even as age-standardised prevalence fell, since 2000, with a continued disproportionate burden by region and sex. Global population ageing will increase this burden, highlighting urgent need for novel approaches to refractive service delivery.publishedVersio

A cohort study of 30 day mortality after NON-EMERGENCY surgery in a COVID-19 cold site

BACKGROUND: Two million non-emergency surgeries are being cancelled globally every week due to the COVID-19 pandemic, which will have a major impact on patients and healthcare systems. METHODS: During the peak of the pandemic in the United Kingdom, we set up a multicentre cancer network amongst 14 National Health Service institutions, performing urological, thoracic, gynaecological and general surgical urgent and cancer operations at a central COVID-19 cold site. This is a cohort study of 500 consecutive patients undergoing surgery in this network. The primary outcome was 30-day mortality from COVID-19. Secondary outcomes included all-cause mortality and post-operative complications at 30-days. RESULTS: 500 patients underwent surgery with median age 62.5 (IQR 51-71). 65% were male, 60% had a known diagnosis of cancer and 61% of surgeries were considered complex or major. No patient died from COVID-19 at 30-days. 30-day all-cause mortality was 3/500 (1%). 10 (2%) patients were diagnosed with COVID-19, 4 (1%) with confirmed laboratory diagnosis and 6 (1%) with probable COVID-19. 33/500 (7%) of patients developed Clavien-Dindo grade 3 or higher complications, with 1/33 (3%) occurring in a patient with COVID-19. CONCLUSION: It is safe to continue cancer and urgent surgery during the COVID-19 pandemic with appropriate service reconfiguration