Understanding decision-making for and against oncoplastic breast-conserving surgery as an alternative to a mastectomy in early breast cancer: UK ANTHEM qualitative study.

BACKGROUND: Oncoplastic breast-conserving surgery may allow women with early breast cancer to avoid a mastectomy, but many women undergo more extensive surgery, even when breast-conserving options are offered. The aim of the ANTHEM qualitative study was to explore factors influencing women's surgical decision-making for and against oncoplastic breast-conserving surgery. METHODS: Semi-structured interviews were conducted with a purposive sample of women who had received either oncoplastic breast-conserving surgery or a mastectomy with or without immediate breast reconstruction to explore their rationale for procedure choice. Interviews were transcribed verbatim and analysed thematically. Trial registration number: ISRCTN18238549. RESULTS: A total of 27 women from 12 centres were interviewed. Out of these, 12 had chosen oncoplastic breast-conserving surgery and 15 had chosen a mastectomy with or without immediate breast reconstruction. Overwhelmingly, women's decisions were guided by their surgical teams. Decision-making for and against oncoplastic breast-conserving surgery was influenced by three key inter-related factors: perceptions of oncological safety; the importance of maintaining/restoring femininity and body image; and practical issues. Oncological safety was paramount. Women who reported feeling reassured that oncoplastic breast-conserving surgery was oncologically safe were happy to choose this option. Those who were not reassured were more likely to opt for a mastectomy, as a perceived 'safer' option. Most women wished to maintain/restore femininity, with the offer of immediate breast reconstruction essential to make a mastectomy an acceptable option. Practical issues such as the perceived magnitude of the surgery were a lesser concern. CONCLUSION: Decision-making is complex and heavily influenced by the surgical team. High-quality, accurate information about surgical options, including appropriate reassurance about the short- and long-term oncological safety of oncoplastic breast-conserving surgery is vital if women are to make fully informed decisions.

Current practice and provision of oncoplastic breast-conserving surgery in the UK: results of the ANTHEM national practice questionnaire.

PURPOSE: Oncoplastic breast-conserving surgery (OPBCS) may be a better option than mastectomy ± immediate breast reconstruction (IBR) for women with breast cancer but studies directly comparing the techniques are lacking. We surveyed UK breast units to determine the current practice of OPBCS to inform the design of a future comparative study. METHODS: An electronic survey was developed to explore the current practice of OPBCS. This included the local availability of volume displacement and/or replacement techniques; number of cases performed; contraindications and approach to contralateral symmetrisation. Summary data for each survey item were calculated and overall provision of care examined. RESULTS: 58 UK centres completed the survey, including 43 (74%) stand-alone breast and 15 (26%) combined breast/plastics units. Over 40% of units (n = 24) treated more than 500 cancers/year. Most units offered volume displacement techniques (TMs) (97%). Over two-thirds (n = 39. 67%) of units offered local perforator flaps (LPF). Approximately a half of units (10/19) not performing LPF were planning to introduce them in the next 12-24 months. A third (n = 19, 33%) of units routinely performed simultaneous contralateral symmetrisation mostly with two-surgeon operating. There were limited oncological restrictions to OPBCS with no contraindications for multifocal cancers in most centres; 65% of units (36/55) offered OPBCS for multicentric disease. Extensive DCIS was a contraindication in a minority of units. CONCLUSIONS: OPBCS is widely available in the UK but contraindications and approaches to contralateral symmetrisation were variable. Work is now needed to prospectively evaluate the outcomes of OPBCS vs mastectomy ± IBR to support informed decision-making.

Assessing competition in the hip implant industry in the light of recent policy guidance.

NHS procurement is a highly topical area, attracting a great deal of recent policy focus. The pivotal report by Lord Carter of Coles (2016) highlighted unwarranted variation, estimating it to be worth approximately £5bn in efficiency savings. In relation to hip replacement surgery, recent procurement policy guidance has recommended the use of cemented hip implants for all patients aged 68 years and over in England and Wales. Previous work established that the hip implant supplying market was very concentrated, with only a few large suppliers, especially for cemented implants. The advocated major shift towards cemented implants would almost certainly increase further the market share of the dominant manufacturer of cemented sector thus raising potential competition and welfare issues. We carry out a market study to establish whether there might be a potential competition concern, using data from the National Joint Registry (2005-2018, 37 suppliers, nearly 700 models). We first establish the structure of the industry with a specific focus on seller concentration. Secondly we evaluate the dynamics underlying concentration in the market, assessing the innovative performance of the sector using a novel statistical analysis of the dynamics of market shares. We then look to three comparable but alternative markets for similarities or differences to the THR implant industry. We find a high and increasingly concentrated oligopolistic and static market structure, largely devoid of dynamics and with no real sign of innovation. These findings are further emphasized when compared with the three close alternative markets. Although this stability could just be a mature market where technical advances have already taken place, our findings highlight the potential welfare and policy implications of concentrating on cemented fixation. Given the current emphasis on efficiency in procurement, it is essential that there should also be scrutiny of the firms dealing with public procurement.

Protocol for a mixed-method study to inform the feasibility of undertaking a large-scale multicentre study comparing the clinical and patient-reported outcomes of oncoplastic breast conservation as an alternative to mastectomy with or without immediate breast reconstruction in women unsuitable for standard breast-conserving surgery (the ANTHEM Feasibility Study).

INTRODUCTION: Approximately 40% of the 55 000 women diagnosed with breast cancer each year in the UK undergo mastectomy because they are considered unsuitable for standard breast-conserving surgery (BCS) due to tumour size or multiple tumour foci. Mastectomy can significantly impact women's quality of life, and only one in four women currently undergo immediate breast reconstruction (IBR).Level 2 oncoplastic breast-conserving surgery (OPBCS) combines removing the cancer with a range of plastic surgical volume replacement (eg, local perforator flaps) and volume displacement techniques (eg, therapeutic mammaplasty) that can extend the role of BCS and may allow some women not suitable for standard BCS to avoid mastectomy. High-quality research to determine whether OPBCS offers a safe and effective alternative to mastectomy±IBR is currently lacking. Preliminary work is needed to ensure a future large-scale study is feasible and well designed and addresses questions important to patients and the National Health Service. METHODS AND ANALYSIS: Mixed methods will be used to inform feasibility and design of a future large-scale study comparing the clinical effectiveness and cost-effectiveness of OPBCS and mastectomy±IBR. It will have four parts: (1) a National Practice Questionnaire to determine current practice and provision of oncoplastic breast and reconstructive surgery in the UK; (2) a pilot multicentre prospective cohort study to explore the proportion of patients choosing OPBCS versus mastectomy, the proportion in OPBCS is successful and clinical and patient-reported outcomes of different techniques at 3 and 12 months postsurgery; (3) a qualitative interview study to explore patients' attitudes to different procedures, rationale for decision-making and perceptions of outcomes; and (4) design of the future study.All centres offering OPBCS and mastectomy in the UK will be invited to participate. Recruitment is planned to commence winter 2020 and continue for 12 months. ETHICS AND DISSEMINATION: The study has ethical approval from the Wales Research Ethics Committee 6 National Research Ethics Service (REC Ref 20/WA/0225). Results will be presented at national and international meetings and published in peer-reviewed journals. We will work with patients to develop lay summaries and share these through patient groups and breast cancer charities. TRIAL REGISTRATION NUMBER: ISRCTN18238549.

Comparison of laser power output from the fiber tip during endovenous laser ablation against displayed power and the "first treatment" effect.

OBJECTIVE: International guidelines recommend endovenous laser ablation as one of the first-line treatments for truncal venous reflux associated with varicose veins. Clinicians use linear endovenous energy density to measure the energy used during treatment. The aim of this study was to investigate the power output from the fiber tip and to see if this changed with use. METHODS: We placed 15 mL of water in a thermally insulated 25-mL beaker. Two thermocouples were placed equidistantly adjacent to the laser fiber tip. A 1470-nm laser was fired at 5W for 2 minutes and the temperature change was measured. Three fibers were used on different days to allow the laser to cool for 24 hours between fibers. Each fiber was tested three times in a row. We also tested the "first treatment" effect by comparing the power output when the fiber was fired immediately after the laser was switched on, compared with treatments when the laser had been switched on for 1 hour. To assess whether this was due to the console being "cold" on the first firing of the day, we repeated the experiment having switched on the laser console 1 hour before firing to "prewarm" the console. However, the diode was not fired during this hour. To measure fiber degradation, three runs of the experiment were performed successively before firing the laser continuously for 20 minutes, then three more runs were conducted, resulting in delivery of approximately 10,000 J. RESULTS: The actual power output seemed to be lower than the console suggested. The power output from the first fiber used in a succession of three with the same laser had a significantly lower power output than the following two runs (P = .0004 and P < .0001, respectively). When the laser was prewarmed for 1 hour without firing, no change in this output pattern was noted (P = .293). Fiber degradation was not found in any of the fibers that were tested within the maximum recommended for the fiber (10,000 J). CONCLUSIONS: The first use of a fiber in a treatment session has a significantly lower power output from the treatment tip than subsequent uses, even if the machine is prewarmed and the console displays the same power for each. The authors believe that this phenomenon is due to the diode being less efficient when first used after switching it on. Clinicians need to be aware that the true power output at the fiber tip may not be as indicated by the console display and may be variable during a treatment session.

Effects and cost of different strategies to eliminate hepatitis C virus transmission in Pakistan: a modelling analysis.

BACKGROUND: The WHO elimination strategy for hepatitis C virus advocates scaling up screening and treatment to reduce global hepatitis C incidence by 80% by 2030, but little is known about how this reduction could be achieved and the costs of doing so. We aimed to evaluate the effects and cost of different strategies to scale up screening and treatment of hepatitis C in Pakistan and determine what is required to meet WHO elimination targets for incidence. METHODS: We adapted a previous model of hepatitis C virus transmission, treatment, and disease progression for Pakistan, calibrating using available data to incorporate a detailed cascade of care for hepatitis C with cost data on diagnostics and hepatitis C treatment. We modelled the effect on various outcomes and costs of alternative scenarios for scaling up screening and hepatitis C treatment in 2018-30. We calibrated the model to country-level demographic data for 1960-2015 (including population growth) and to hepatitis C seroprevalence data from a national survey in 2007-08, surveys among people who inject drugs (PWID), and hepatitis C seroprevalence trends among blood donors. The cascade of care in our model begins with diagnosis of hepatitis C infection through antibody screening and RNA confirmation. Diagnosed individuals are then referred to care and started on treatment, which can result in a sustained virological response (effective cure). We report the median and 95% uncertainty interval (UI) from 1151 modelled runs. FINDINGS: One-time screening of 90% of the 2018 population by 2030, with 80% referral to treatment, was projected to lead to 13·8 million (95% UI 13·4-14·1) individuals being screened and 350 000 (315 000-385 000) treatments started annually, decreasing hepatitis C incidence by 26·5% (22·5-30·7) over 2018-30. Prioritised screening of high prevalence groups (PWID and adults aged ≥30 years) and rescreening (annually for PWID, otherwise every 10 years) are likely to increase the number screened and treated by 46·8% and decrease incidence by 50·8% (95% UI 46·1-55·0). Decreasing hepatitis C incidence by 80% is estimated to require a doubling of the primary screening rate, increasing referral to 90%, rescreening the general population every 5 years, and re-engaging those lost to follow-up every 5 years. This approach could cost US$8·1 billion, reducing to $3·9 billion with lowest costs for diagnostic tests and drugs, including health-care savings, and implementing a simplified treatment algorithm. INTERPRETATION: Pakistan will need to invest about 9·0% of its yearly health expenditure to enable sufficient scale up in screening and treatment to achieve the WHO hepatitis C elimination target of an 80% reduction in incidence by 2030. FUNDING: UNITAID.

The use of micro-costing in economic analyses of surgical interventions: a systematic review.

BACKGROUND: Compared with conventional top down costing, micro-costing may provide a more accurate method of resource-use assessment in economic analyses of surgical interventions, but little is known about its current use. The aim of this study was to systematically-review the use of micro-costing in surgery. METHODS: Comprehensive searches identified complete papers, published in English reporting micro-costing of surgical interventions up to and including 22nd June 2018. Studies were critically appraised using a modified version of the Consensus on Health Economic Criteria (CHEC) Checklist. Study demographics and details of resources identified; methods for measuring and valuing identified resources and any cost-drivers identified in each study were summarised. RESULTS: A total of 85 papers were identified. Included studies were mainly observational comparative studies (n = 42, 49.4%) with few conducted in the context of a randomised trial (n = 5, 5.9%). The majority of studies were single-centre (n = 66, 77.6%) and almost half (n = 40, 47.1%) collected data retrospectively. Only half (n = 46, 54.1%) self-identified as being 'micro-costing' studies. Rationale for the use of micro-costing was most commonly to compare procedures/techniques/processes but over a third were conducted specifically to accurately assess costs and/or identify cost-drivers. The most commonly included resources were personnel costs (n = 76, 89.4%); materials/disposables (n = 76, 89.4%) and operating-room costs (n = 62,72.9%). No single resource was included in all studies. Most studies (n = 72, 84.7%) identified key cost-drivers for their interventions. CONCLUSIONS: There is lack of consistency regarding the current use of micro-costing in surgery. Standardising terminology and focusing on identifying and accurately costing key cost-drivers may improve the quality and value of micro-costing in future studies. TRIAL REGISTRATION: PROSPERO registration CRD42018099604.

International development and implementation of a core measurement set for research and audit studies in implant-based breast reconstruction: a study protocol.

INTRODUCTION: Outcome reporting in research studies of breast reconstruction is inconsistent and lacks standardisation. The results of individual studies therefore cannot be meaningfully compared or combined limiting their value. A core outcome set (COS) has been developed to address these issues and identified 11 key outcomes to be measured and reported in all future research and audit studies in reconstructive breast surgery (RBS). A COS represents what key outcomes should be measured. The next step is to determine how and when this should be done. The aim of this study is to develop a core measurement set (CMS) for use in research and audit studies in implant-based breast reconstruction. METHODS AND ANALYSIS: The CMS will be developed in accordance with the guidance developed by the Core Outcome Measures in Effectiveness Trials initiative (COMET) and COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) group for the selection of outcome measurement instruments (OMIs) for relevant outcome domains included in the RBS COS. This will involve three phases with strategies to promote implementation as a final additional phase. The phases are (1) conceptual considerations in which the target population, procedures and settings are defined; (2) systematic reviews to identify existing clinical, patient-reported and cosmetic OMIs and, if appropriate, assess their quality using COSMIN methodology; (3) a modified Delphi process including sequential Delphi surveys involving approximately 100 healthcare professionals and a face to face consensus meeting to agree and ratify which outcome definitions and OMIs should be used and standardised time points for assessment; (4) strategies to promote dissemination and adoption of the CMS. ETHICS AND DISSEMINATION: Ethical approval has been granted by University of Bristol Faculty Research Ethics Committee FREC ID 60221. Dissemination strategies will include scientific meeting presentations and peer-reviewed journal publications. Implementation activities will include engagement with journal editors and funders to promote uptake and use of the CMS.

Spatial and temporal disease dynamics of the parasite Hematodinium sp. in shore crabs, Carcinus maenas.

BACKGROUND: The parasitic dinoflagellates of the genus Hematodinium represent the causative agent of so-called bitter or pink crab disease in a broad range of shellfish taxa. Outbreaks of Hematodinium-associated disease can devastate local fishing and aquaculture efforts. The goal of our study was to examine the potential role of the common shore (green) crab Carcinus maenas as a reservoir for Hematodinium. Carcinus maenas is native to all shores of the UK and Ireland and the North East Atlantic but has been introduced to, and subsequently invaded waters of, the USA, South Africa and Australia. This species is notable for its capacity to harbour a range of micro- and macro-parasites, and therefore may act as a vector for disease transfer. METHODS: Over a 12-month period, we interrogated 1191 crabs across two distinct locations (intertidal pier, semi-closed dock) in Swansea Bay (Wales, UK) for the presence and severity of Hematodinium in the haemolymph, gills, hepatopancreas and surrounding waters (eDNA) using PCR-based methods, haemolymph preparations and histopathology. RESULTS: Overall, 13.6% were Hematodinium-positive via PCR and confirmed via tissue examination. Only a small difference was observed between locations with 14.4% and 12.8% infected crabs in the Dock and Pier, respectively. Binomial logistic regression models revealed seasonality (P < 0.002) and sex (P < 0.001) to be significant factors in Hematodinium detection with peak infection recorded in spring (March to May). Male crabs overall were more likely to be infected. Phylogenetic analyses of the partial ITS and 18S rRNA gene regions of Hematodinium amplified from crabs determined the causative agent to be the host generalist Hematodinium sp., which blights several valuable crustaceans in the UK alone, including edible crabs (Cancer pagurus) and langoustines (Nephrops norvegicus). CONCLUSIONS: Shore crabs were infected with the host generalist parasite Hematodinium sp. in each location tested, thereby enabling the parasite to persist in an environment shared with commercially important shellfish.

Evaluation of an educational intervention to increase HIV-testing in high HIV prevalence general practices: a pilot feasibility stepped-wedged randomised controlled trial.

BACKGROUND: HIV-infected patients often present to primary care several times with HIV-indicator conditions before diagnosis but the opportunity to test by healthcare professionals (HCPs) is frequently missed. Current HIV testing rates in primary care are low and educational interventions to facilitate HCPs to increase testing and awareness of HIV are needed. METHOD: We implemented a pilot feasibility stepped-wedged randomised controlled trial of an educational intervention in high HIV prevalence practices in Bristol. The training delivered to HCPs including General Practitioners (GP) aimed to increase HIV testing and included why, who, and how to test. The intervention was adapted from the Medical Foundation for HIV and Sexual Health HIV Testing in Practice (MEDFASH) educational tool. Questionnaires assessed HCP feedback and perceived impacts of the intervention. HIV testing rates were compared between control and intervention practices using 12 monthly laboratory totals. RESULTS: 169 HCPs (from 19 practices) received the educational intervention. 127 (75%) questionnaires were completed. Delivery of the intervention was received positively and was perceived as valuable for increasing awareness, confidence and consideration of testing, with HCPs gaining more awareness of HIV testing guidelines. The main pre-training HIV testing barrier reported by GPs was the patient not considering themselves at risk, whilst for nurses it was a concern about embarrassing or offending the patient. Most HCPs reported the intervention addressed these barriers. The HIV testing rate increased more in the control than in the intervention practices: mean difference 2.6 (95% CI 0.5,4.7) compared with 1.9 (- 0.5,4.3) per 1000 patients, respectively. The number of HIV tests across all practices increased from 1154 in the first 6 months to 1299 in the second 6 months, an annual increase in testing rate of 2.0 (0.7,3.4) from 16.3 to 18.3 per 1000 patients. CONCLUSION: There was a small increase in HIV testing rates over the study period, but this could not be attributed to the educational intervention. More effective and sustainable programmes tailored to each practice context are needed to change testing culture and HCP behaviour. Repeated training, supported by additional measures, such as testing prompts, may be needed to influence primary care HIV testing.

Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality: The CAP Randomized Clinical Trial.

Importance: Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment. Objective: To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer-specific mortality. Design, Setting, and Participants: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016. Intervention: An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice. Main Outcomes and Measures: Primary outcome: prostate cancer-specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic. Results: Among 415 357 randomized men (mean [SD] age, 59.0 [5.6] years), 189 386 in the intervention group and 219 439 in the control group were included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%) attended the PSA testing clinic and 67 313 (36%) underwent PSA testing. Of 64 436 with a valid PSA test result, 6857 (11%) had a PSA level between 3 ng/mL and 19.9 ng/mL, of whom 5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, -0.013 per 1000 person-years [95% CI, -0.047 to 0.022]; rate ratio [RR], 0.96 [95% CI, 0.85 to 1.08]; P = .50). The number diagnosed with prostate cancer was higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95% CI, 1.14 to 1.25]; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lower were identified in the intervention group (n = 3263/189 386 [1.7%]) than in the control group (n = 2440/219 439 [1.1%]) (difference per 1000 men, 6.11 [95% CI, 5.38 to 6.84]; P < .001). In the analysis of all-cause mortality, there were 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR, 0.99 [95% CI, 0.94 to 1.03]; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence-adjusted causal RR was 0.93 (95% CI, 0.67 to 1.29; P = .66). Conclusions and Relevance: Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening. Trial Registration: ISRCTN Identifier: ISRCTN92187251.

Importance and Contribution of Community, Social, and Healthcare Risk Factors for Hepatitis C Infection in Pakistan.

Pakistan has a high prevalence of hepatitis C virus (HCV) infection, estimated at 4.9% (2,290/46,843) in the 2007 national HCV seroprevalence survey. We used data from this survey to assess the importance of risk factor associations with HCV prevalence in Pakistan. Exposures were grouped as community (going to the barbers, sharing smoking equipment, having an ear/nose piercing, tattoo, or acupuncture), healthcare (ever having hemodialysis, blood transfusion, or ≥ 5 injections in the last year), demographic (marital status and age), and socio-economic (illiterate or laborer). We used mutually adjusted multivariable regression analysis, stratified by sex, to determine associations with HCV infection, their population attributable fraction, and how risk of infection accumulates with multiple exposures. Strength of associations was assessed using adjusted odds ratios (aOR). Community [aOR females 1.5 (95% confidence interval [CI]: 1.2, 1.8); males 1.2 (1.1, 1.4)] and healthcare [females 1.4 (1.2, 1.6); males 1.2 (1.1, 1.4)] exposures, low socio-economic status [females 1.6 (1.3, 1.80); males 1.3 (1.2, 1.5)], and marriage [females 1.5 (1.2, 1.9); males 1.4 (1.1, 1.8)] were associated with increased HCV infection. Among married women, the number of children was associated with an increase in HCV infection; linear trend aOR per child 1.06 (1.01, 1.11). Fewer infections could be attributed to healthcare exposures (females 13%; males 6%) than to community exposures (females 25%; males 9%). Prevalence increased from 3% to 10% when cumulative exposures increased from 1 to ≥ 4 [aOR per additional exposure for females 1.5 (1.4, 1.6); males 1.2 (1.2, 1.3)]. A combination of community, healthcare, and other factors appear to drive the Pakistan HCV epidemic, highlighting the need for a comprehensive array of prevention strategies.

Impact of opioid substitution therapy on the HIV prevention benefit of antiretroviral therapy for people who inject drugs.

OBJECTIVE: A recent meta-analysis suggested that opioid substitution therapy (OST) increased uptake of antiretroviral treatment (ART) and HIV viral suppression. We modelled whether OST could improve the HIV prevention benefit achieved by ART among people who inject drugs (PWID). METHODS: We modelled how introducing OST could improve the coverage of ART across a PWID population for different baseline ART coverage levels. Using existing data on how yearly HIV-transmission risk is related to HIV plasma viral load, changes in the level of viral suppression across the population were used to project the relative reduction in yearly HIV-transmission risk achieved by ART, with or without OST, compared with if there was no ART - defined here as the prevention effectiveness of ART. RESULTS: Owing to OST use increasing the chance of being on ART and achieving viral suppression if on ART, the prevention effectiveness of ART for PWID on OST (compared with PWID not on OST) increases by 44, 31, or 20% for a low (20%), moderate (40%), or high (60%) baseline ART coverage, respectively. Improvements in the population-level prevention effectiveness of ART are also achieved across all PWID, compared with if OST was not introduced. For instance, if OST is introduced at 40% coverage, the population-level prevention effectiveness of ART could increase by 27, 20, or 13% for a low (20%), moderate (40%), or high (60%) baseline ART coverage, respectively. CONCLUSION: OST could improve the HIV prevention benefit of ART; supporting strategies that aim to concurrently scale-up OST with ART.

Outcomes from massive paracetamol overdose: a retrospective observational study.

LINKED ARTICLE: This article is commented on by Bateman DN and Dear JW. Should we treat very large paracetamol overdose differently? Br J Clin Pharmacol 2017; 83: 1163-5. https://doi.org/10.1111/bcp.13279 AIMS: Treatment of paracetamol (acetaminophen) overdose with acetylcysteine is standardized, with dose determined only by patient weight. The validity of this approach for massive overdoses has been questioned. We systematically compared outcomes in massive and non-massive overdoses, to guide whether alternative treatment strategies should be considered, and whether the ratio between measured timed paracetamol concentrations (APAPpl ) and treatment nomogram thresholds at those time points (APAPt ) provides a useful assessment tool. METHODS: This is a retrospective observational study of all patients (n = 545) between 2005 and 2013 admitted to a tertiary care toxicology service with acute non-staggered paracetamol overdose. Massive overdoses were defined as extrapolated 4-h plasma paracetamol concentrations >250 mg l-1 , or reported ingestions ≥30 g. Outcomes (liver injury, coagulopathy and kidney injury) were assessed in relation to reported dose and APAPpl :APAPt ratio (based on a treatment line through 100 mg l-1 at 4 h), and time to acetylcysteine. RESULTS: Ingestions of ≥30 g paracetamol correlated with higher peak serum aminotransferase (r = 0.212, P < 0.0001) and creatinine (r = 0.138, P = 0.002) concentrations. Acute liver injury, hepatotoxicity and coagulopathy were more frequent with APAPpl :APAPt  ≥ 3 with odds ratios (OR) and 95% confidence intervals (CI) of 9.19 (5.04-16.68), 35.95 (8.80-158.1) and 8.34 (4.43-15.84), respectively (P < 0.0001). Heightened risk persisted in patients receiving acetylcysteine within 8 h of overdose. CONCLUSION: Patients presenting following massive paracetamol overdose are at higher risk of organ injury, even when acetylcysteine is administered early. Enhanced therapeutic strategies should be considered in those who have an APAPpl :APAPt  ≥ 3. Novel biomarkers of incipient liver injury and abbreviated acetylcysteine regimens require validation in this patient cohort.

Contemporary accuracy of death certificates for coding prostate cancer as a cause of death: Is reliance on death certification good enough? A comparison with blinded review by an independent cause of death evaluation committee.

BACKGROUND: Accurate cause of death assignment is crucial for prostate cancer epidemiology and trials reporting prostate cancer-specific mortality outcomes. METHODS: We compared death certificate information with independent cause of death evaluation by an expert committee within a prostate cancer trial (2002-2015). RESULTS: Of 1236 deaths assessed, expert committee evaluation attributed 523 (42%) to prostate cancer, agreeing with death certificate cause of death in 1134 cases (92%, 95% CI: 90%, 93%). The sensitivity of death certificates in identifying prostate cancer deaths as classified by the committee was 91% (95% CI: 89%, 94%); specificity was 92% (95% CI: 90%, 94%). Sensitivity and specificity were lower where death occurred within 1 year of diagnosis, and where there was another primary cancer diagnosis. CONCLUSIONS: UK death certificates accurately identify cause of death in men with prostate cancer, supporting their use in routine statistics. Possible differential misattribution by trial arm supports independent evaluation in randomised trials.

Are European lobsters (Homarus gammarus) susceptible to infection by a temperate Hematodinium sp.?

Hematodinium spp. infect over 40 species of crustaceans worldwide, but have not been reported to infect the European lobster, Homarus gammarus. In this study, Hematodinium parasites (a mixture of uni- and multinucleate trophont-like stages) were taken from donor crabs (Cancer pagurus) and injected into juvenile H. gammarus. Juvenile C. pagurus were also injected with the same inoculum. Haemolymph was taken at regular intervals and examined for the presence of Hematodinium using light microscopy and PCR, in two separate experiments of duration 4 and 8months. All lobsters were negative for Hematodinium whilst the C. pagurus challenged became infected. It is concluded that European lobsters are not susceptible to infection with a clade of Hematodinium that infects C. pagurus.

Standardisation of information submitted to an endpoint committee for cause of death assignment in a cancer screening trial ­ lessons learnt from CAP (Cluster randomised triAl of PSA testing for Prostate cancer).

BACKGROUND: In cancer screening trials where the primary outcome is target cancer-specific mortality, the unbiased determination of underlying cause of death (UCD) is crucial. To minimise bias, the UCD should be independently verified by expert reviewers, blinded to death certificate data and trial arm. We investigated whether standardising the information submitted for UCD assignment in a population-based randomised controlled trial of prostate-specific antigen (PSA) testing for prostate cancer reduced the reviewers' ability to correctly guess the trial arm. METHODS: Over 550 General Practitioner (GP) practices (>415,000 men aged 50-69 years) were cluster-randomised to PSA testing (intervention arm) or the National Health Service (NHS) prostate cancer risk management programme (control arm) between 2001 and 2007. Assignment of UCD was by independent reviews of researcher-written clinical vignettes that masked trial arm and death certificate information. A period of time after the process began (the initial phase), we analysed whether the reviewers could correctly identify trial arm from the vignettes, and the reasons for their choice. This feedback led to further standardisation of information (second phase), after which we re-assessed the extent of correct identification of trial arm. RESULTS: 1099 assessments of 509 vignettes were completed by January 2014. In the initial phase (n = 510 assessments), reviewers were unsure of trial arm in 33% of intervention and 30% of control arm assessments and were influenced by symptoms at diagnosis, PSA test result and study-specific criteria. In the second phase (n = 589), the respective proportions of uncertainty were 45% and 48%. The percentage of cases whereby reviewers were unable to determine the trial arm was greater following the standardisation of information provided in the vignettes. The chances of a correct guess and an incorrect guess were equalised in each arm, following further standardisation. CONCLUSIONS: It is possible to mask trial arm from cause of death reviewers, by using their feedback to standardise the information submitted to them. TRIAL REGISTRATION: ISRCTN92187251.

Differential regulation of macropinocytosis in macrophages by cytokines: implications for foam cell formation and atherosclerosis.

A key event during the formation of lipid-rich foam cells during the progression of atherosclerosis is the uptake of modified low-density lipoproteins (LDL) by macrophages in response to atherogenic mediators in the arterial intima. In addition to scavenger receptor-dependent uptake of LDL, macropinocytosis is known to facilitate the uptake of LDL through the constitutive and passive internalization of large quantities of extracellular solute. In this study we confirm the ability of macropinocytosis to facilitate the uptake of modified LDL by human macrophages and show its modulation by TGF-ß, IFN-γ, IL-17A and IL-33. Furthermore we show that the TGF-ß-mediated inhibition of macropinocytosis is a Smad-2/-3-independent process.

Can choices between alternative hip prostheses be evidence based? a review of the economic evaluation literature.

BACKGROUND: Total hip replacement surgery places a considerable financial burden on health services and society. Given the large number of hip prostheses available to surgeons, reliable economic evidence is crucial to inform resource allocation decisions. This review summarises published economic evidence on alternative hip prostheses to examine the potential for the literature to inform resource allocation decisions in the UK. METHODS: We searched nine medical and economics electronic databases. 3,270 studies were initially identified, 17 studies were included in the review. Studies were critically appraised using three separate guidelines. RESULTS: Several methodological problems were identified including a lack of observed long term prosthesis survival data, limited up-to-date and UK based evidence and exclusion of patient and societal perspectives. CONCLUSIONS: More clinical trials including long term follow-up and economic evaluation are needed. These should compare the cost-effectiveness of different prostheses with longer-term follow-up and including a wider perspective.