The impact of disability on recruitment to higher surgical specialty training: A retrospective cohort study.

BACKGROUND: UK examining bodies are required to eliminate discrimination against people with protected characteristics. To achieve this in surgery, differential attainment (DA) in assessments used as gatekeepers to career progression must be ruled out. This study investigated the impact of disability status on the likelihood of success at national selection for Higher Surgical Training (HST). METHODS: A retrospective cohort study of all UK graduates in the UKMED database (https://www.ukmed.ac.uk) who underwent selection for HST (ST3) from 2012 to 2019 (n = 2875). Univariate analysis identified differences in success rates at first-application. Logistic regression models identified whether disability was a predictor of success after adjusting for sociodemographic factors and prior MRCS performance. RESULTS: There was no significant difference in success rates between candidates with and without disabilities (all p > 0.05) for any surgical specialty. Disability status was not a statistically significant predictor of success. Female candidates were 25 % more likely to be successful (OR 1.25 [95%CI 1.05 to 1.49]) and Non-White candidates were 20 % less likely to be successful (OR 0.80 [95%CI 0.68 to 0.96]). Candidates who passed MRCS Part A and Part B at the first attempt were 49 % (OR 1.49 [95%CI 1.25 to 1.77]) and 90 % (OR 1.90 [95%CI 1.58 to 2.28]) more likely to be successful. CONCLUSION: No significant difference was found in the likelihood of being successful at HST selection for any surgical specialty between applicants with and without disabilities, regardless of type of disability. DA was identified between other sociodemographic groups which requires further exploration.

Establishing the predictive validity of the intercollegiate membership of the Royal Colleges of surgeons written examination: MRCS part B.

The Intercollegiate Membership of the Royal Colleges of Surgeons (MRCS) is a high-stakes postgraduate examination taken by thousands of surgical trainees worldwide every year. The MRCS is a challenging assessment, highly regarded by surgical training programmes and valued as a gatekeeper to the surgical profession. The examination is taken at considerable personal, social and financial cost to surgical trainees, and failure has significant implications for career progression. Given the value placed on MRCS, it must be a reliable and valid assessment of the knowledge and skills of early-career surgeons. Our first article 'Establishing the Predictive Validity of the Intercollegiate Membership of the Royal Colleges of Surgeons Written Examination: MRCS Part A' discussed the principles of assessment reliability and validity and outlined the mounting evidence supporting the predictive validity of the MRCS Part A (the multiple-choice questionnaire component of the examination). This, the second article in the series discusses six recently published studies investigating the predictive validity of the MRCS Part B (the clinical component of the examination). All national longitudinal cohort studies reviewed have demonstrated significant correlations between MRCS Part B and other assessments taken during the UK surgical training pathway, supporting the predictive validity of MRCS Part B. This review will be of interest to trainees, trainers and Royal Colleges given the value placed on the examination by surgical training programmes.

Examining the diversity of MRCS examiners.

BACKGROUND: MRCS examiners are the face of the Royal College of Surgeons for early-career surgeons and should therefore represent the workforce they are examining as not to marginalise or negatively impact on the assessment experience of candidates from minoritised groups. This study aimed to explore the diversity of MRCS examiners and whether they represent the demographics of the MRCS candidates. METHODS: A retrospective observational study including all active examiners and examination candidates who attempted MRCS Part A or Part B between January 2020 and July 2021. Self-declared demographic data collected by the Intercollegiate Committee for Basic Surgical Examinations (ICBSE) included gender, sexual orientation, disability status and ethnicity. Following data anonymisation, total group response frequencies were made available to the research team for statistical analysis. RESULTS: Chi-squared analyses showed statistically significant differences in the representation of gender, disability and ethnicity between candidates and examiners (all p < 0.001). Men (83.9% (n = 1121) vs 70.9% (n = 6017) respectively), individuals without disability (98.7% (n = 917) vs 96.1% (n = 6847)) and individuals of White ethnicity (36.6% (n = 346) vs 20.4% (n = 1223)) were significantly overrepresented in the examiners compared to the examination candidates. There was no statistically significant difference in sexual orientation between examiners and candidates (p = 0.712). CONCLUSIONS: Broadly speaking, the socio-demographic profile of MRCS examiners reflects that seen in senior and leadership positions in surgery in the UK - that is, predominantly male and White - but not that seen in early-career surgeons. Positive action is now required in examiner recruitment by the Royal Colleges to ensure that the cohort of MRCS examiners reflects the modern surgical workforce.

Type I interferon regulates proteolysis by macrophages to prevent immunopathology following viral infection.

The ability to treat severe viral infections is limited by our understanding of the mechanisms behind virus-induced immunopathology. While the role of type I interferons (IFNs) in early control of viral replication is clear, less is known about how IFNs can regulate the development of immunopathology and affect disease outcomes. Here, we report that absence of type I IFN receptor (IFNAR) is associated with extensive immunopathology following mucosal viral infection. This pathology occurred independent of viral load or type II immunity but required the presence of macrophages and IL-6. The depletion of macrophages and inhibition of IL-6 signaling significantly abrogated immunopathology. Tissue destruction was mediated by macrophage-derived matrix metalloproteinases (MMPs), as MMP inhibition by doxycycline and Ro 28-2653 reduced the severity of tissue pathology. Analysis of post-mortem COVID-19 patient lungs also displayed significant upregulation of the expression of MMPs and accumulation of macrophages. Overall, we demonstrate that IFNs inhibit macrophage-mediated MMP production to prevent virus-induced immunopathology and uncover MMPs as a therapeutic target towards viral infections.

Use of the oral beta blocker bisoprolol to reduce the rate of exacerbation in people with chronic obstructive pulmonary disease (COPD): a randomised controlled trial (BICS).

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity, mortality and healthcare costs. Beta blockers are well-established drugs widely used to treat cardiovascular conditions. Observational studies consistently report that beta blocker use in people with COPD is associated with a reduced risk of COPD exacerbations. The bisoprolol in COPD study (BICS) investigates whether adding bisoprolol to routine COPD treatment has clinical and cost-effective benefits. A sub-study will risk stratify participants for heart failure to investigate whether any beneficial effect of bisoprolol is restricted to those with unrecognised heart disease. METHODS: BICS is a pragmatic randomised parallel group double-blind placebo-controlled trial conducted in UK primary and secondary care sites. The major inclusion criteria are an established predominant respiratory diagnosis of COPD (post-bronchodilator FEV1 < 80% predicted, FEV1/FVC < 0.7), a self-reported history of ≥ 2 exacerbations requiring treatment with antibiotics and/or oral corticosteroids in a 12-month period since March 2019, age ≥ 40 years and a smoking history ≥ 10 pack years. A computerised randomisation system will allocate 1574 participants with equal probability to intervention or control groups, stratified by centre and recruitment in primary/secondary care. The intervention is bisoprolol (1.25 mg tablets) or identical placebo. The dose of bisoprolol/placebo is titrated up to a maximum of 4 tablets a day (5 mg bisoprolol) over 4-7 weeks depending on tolerance to up-dosing of bisoprolol/placebo-these titration assessments are completed by telephone or video call. Participants complete the remainder of the 52-week treatment period on the final titrated dose (1, 2, 3, 4 tablets) and during that time are followed up at 26 and 52 weeks by telephone or video call. The primary outcome is the total number of participant reported COPD exacerbations requiring oral corticosteroids and/or antibiotics during the 52-week treatment period. A sub-study will risk stratify participants for heart failure by echocardiography and measurement of blood biomarkers. DISCUSSION: The demonstration that bisoprolol reduces the incidence of exacerbations would be relevant not only to patients and clinicians but also to healthcare providers, in the UK and globally. TRIAL REGISTRATION: Current controlled trials ISRCTN10497306 . Registered on 16 August 2018.

Differential attainment at MRCS according to gender, ethnicity, age and socioeconomic factors: a retrospective cohort study.

OBJECTIVE: A recent independent review on diversity and inclusivity highlighted concerns that barriers to surgical career progression exist for some groups of individuals and not others. Group-level differences in performance at the Intercollegiate Membership of the Royal Colleges of Surgeons (MRCS) examinations have been identified but are yet to be investigated. We aimed to characterise the relationship between sociodemographic differences and performance at MRCS. DESIGN: Retrospective cohort study. SETTING: Secondary care. PARTICIPANTS: All UK MRCS candidates attempting Part A (n = 5780) and Part B (n = 2600) between 2013 and 2019 with linked sociodemographic data in the UK Medical Education Database (https://www.ukmed.ac.uk). MAIN OUTCOME MEASURES: Chi-square tests established univariate associations with MRCS performance. Multiple logistic regression identified independent predictors of success, adjusted for medical school performance. RESULTS: Statistically significant differences in MRCS pass rates were found according to gender, ethnicity, age, graduate status, educational background and socioeconomic status (all p < 0.05). After adjusting for prior academic attainment, being male (odds ratio [OR] 2.34, 95% confidence interval [CI] 1.87-2.92) or a non-graduate (OR 1.98, 95% CI 1.44-2.74) were independent predictors of MRCS Part A success and being a non-graduate (OR 1.77, 95% CI 1.15-2.71) and having attended a fee-paying school (OR 1.51, 95% CI 1.08-2.10) were independent predictors of Part B success. Black and minority ethnic groups were significantly less likely to pass MRCS Part B at their first attempt (OR 0.41, 95% CI 0.18-0.92 for Black candidates and OR 0.49, 95% CI 0.35-0.69 for Asian candidates) compared to White candidates. CONCLUSIONS: There is significant group-level differential attainment at MRCS, likely to represent the accumulation of privilege and disadvantage experienced by individuals throughout their education and training. Those leading surgical education now have a responsibility to identify and address the causes of these attainment differences.

Does performance at the intercollegiate Membership of the Royal Colleges of Surgeons (MRCS) examination vary according to UK medical school and course type? A retrospective cohort study.

OBJECTIVES: The knowledge, skills and behaviours required of new UK medical graduates are the same but how these are achieved differs given medical schools vary in their mission, curricula and pedagogy. Medical school differences seem to influence performance on postgraduate assessments. To date, the relationship between medical schools, course types and performance at the Membership of the Royal Colleges of Surgeons examination (MRCS) has not been investigated. Understanding this relationship is vital to achieving alignment across undergraduate and postgraduate training, learning and assessment values. DESIGN AND PARTICIPANTS: A retrospective longitudinal cohort study of UK medical graduates who attempted MRCS Part A (n=9730) and MRCS Part B (n=4645) between 2007 and 2017, using individual-level linked sociodemographic and prior academic attainment data from the UK Medical Education Database. METHODS: We studied MRCS performance across all UK medical schools and examined relationships between potential predictors and MRCS performance using χ2 analysis. Multivariate logistic regression models identified independent predictors of MRCS success at first attempt. RESULTS: MRCS pass rates differed significantly between individual medical schools (p<0.001) but not after adjusting for prior A-Level performance. Candidates from courses other than those described as problem-based learning (PBL) were 53% more likely to pass MRCS Part A (OR 1.53 (95% CI 1.25 to 1.87) and 54% more likely to pass Part B (OR 1.54 (1.05 to 2.25)) at first attempt after adjusting for prior academic performance. Attending a Standard-Entry 5-year medicine programme, having no prior degree and attending a Russell Group university were independent predictors of MRCS success in regression models (p<0.05). CONCLUSIONS: There are significant differences in MRCS performance between medical schools. However, this variation is largely due to individual factors such as academic ability, rather than medical school factors. This study also highlights group level attainment differences that warrant further investigation to ensure equity within medical training.

A cross-sectional study examining MRCS performance by core surgical training location.

BACKGROUND: In the UK, core surgical training (CST) is the first specialty experience that early-career surgeons receive but training differs significantly across CST deaneries. To identify the impact these differences have on trainee performance, we assessed whether success at the Membership of the Royal College of Surgeons (MRCS) examinations is associated with CST deanery. METHODS: A retrospective cohort study of UK trainees in CST who attempted MRCS between 2014 and 2020 (n = 1104). Chi-squared tests examined associations between locality and first-attempt MRCS performance. Multivariate logistic regression models identified the likelihood of MRCS success depending on CST deanery. RESULTS: MRCS Part A and Part B pass rates were associated with CST deanery (p < 0.001 and p = 0.013, respectively). Candidates that trained in Thames Valley (Odds Ratio [OR] 2.52 (95% Confidence Interval [CI] 1.00-6.42), North Central and East London (OR 2.37 [95% CI 1.04-5.40]) or South London (OR 2.36 [95% CI 1.09-5.10]) were each more than twice as likely to pass MRCS Part A at first attempt. Trainees from North Central and East London were more than ten times more likely to pass MRCS Part B at first attempt (OR 10.59 [95% CI 1.23-51.00]). However, 68% of candidates attempted Part A prior to CST and 48% attempted Part B before or during the first year of CST. CONCLUSION: MRCS performance is associated with CST deanery; however, many candidates passed the exam with little or any CST experience suggesting that some deaneries attract high academic performers. MRCS performance is therefore not a suitable marker of CST training quality.

Performance at medical school selection correlates with success in Part A of the intercollegiate Membership of the Royal College of Surgeons (MRCS) examination.

Medical schools in the UK typically use prior academic attainment and an admissions test (University Clinical Aptitude Test (UCAT), Biomedical Admissions Test (BMAT) or the Graduate Medical School Admissions Test (GAMSAT)) to help select applicants for interview. To justify their use, more information is needed about the predictive validity of these tests. Thus, we investigated the relationship between performance in admissions tests and the Membership of the Royal College of Surgeons (MRCS) examination.The UKMED database (https://www.ukmed.ac.uk) was used to access medical school selection data for all UK graduates who attempted MRCS Part A (n=11 570) and Part B (n=5690) between 2007 and 2019. Univariate and multivariate logistic regression models identified independent predictors of MRCS success. Pearson correlation coefficients examined the linear relationship between test scores and MRCS performance.Successful MRCS Part A candidates scored higher in A-Levels, UCAT, BMAT and GAMSAT (p<0.05). No significant differences were observed for MRCS Part B. All admissions tests were found to independently predict MRCS Part A performance after adjusting for prior academic attainment (A-Level performance) (p<0.05). Admission test scores demonstrated statistically significant correlations with MRCS Part A performance (p<0.001).The utility of admissions tests is clear with respect to helping medical schools select from large numbers of applicants for a limited number of places. Additionally, these tests appear to offer incremental value above A-Level performance alone. We expect this data to guide medical schools' use of admissions test scores in their selection process.

Does performance at medical school predict success at the Intercollegiate Membership of the Royal College of Surgeons (MRCS) examination? A retrospective cohort study.

BACKGROUND: Identifying predictors of success in postgraduate examinations can help guide the career choices of medical students and may aid early identification of trainees requiring extra support to progress in specialty training. We assessed whether performance on the educational performance measurement (EPM) and situational judgement test (SJT) used for selection into foundation training predicted success at the Membership of the Royal College of Surgeons (MRCS) examination. METHODS: This was a longitudinal, cohort study using data from the UK Medical Education Database (https://www.ukmed.ac.uk). UK medical graduates who had attempted Part A (n=2585) and Part B (n=755) of the MRCS between 2014 and 2017 were included. χ2 and independent t-tests were used to examine the relationship between medical school performance and sociodemographic factors with first-attempt success at MRCS Part A and B. Multivariate logistic regression was employed to identify independent predictors of MRCS performance. RESULTS: The odds of passing MRCS increased by 55% for Part A (OR 1.55 (95% CI 1.48 to 1.61)) and 23% for Part B (1.23 (1.14 to 1.32)) for every additional EPM decile point gained. For every point awarded for additional degrees in the EPM, candidates were 20% more likely to pass MRCS Part A (1.20 (1.13 to 1.29)) and 17% more likely to pass Part B (1.17 (1.04 to 1.33)). For every point awarded for publications in the EPM, candidates were 14% more likely to pass MRCS Part A (1.14 (1.01 to 1.28)). SJT score was not a statistically significant independent predictor of MRCS success. CONCLUSION: This study has demonstrated the EPM's independent predictive power and found that medical school performance deciles are the most significant measure of predicting later success in the MRCS. These findings can be used by medical schools, training boards and workforce planners to inform evidence-based and contemporary selection and assessment strategies.

Use of proton pump inhibitors and histamine-2 receptor antagonists and risk of gastric cancer in two population-based studies.

BACKGROUND: Studies have shown increased gastric cancer risk in users of proton pump inhibitors (PPI) and histamine-2 receptor antagonists, questioning the safety of gastric acid suppression. Therefore, we conducted a case-control study within the Scottish Primary Care Clinical Informatics Unit (PCCIU) database and a cohort study in the UK Biobank. METHODS: In PCCIU, five controls were matched to cases diagnosed in 1999-2011, and medications were determined from GP records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. In the UK Biobank, medications were self-reported at cohort entry 2006-2010, and gastric cancer ascertained from cancer registries until 2014. Hazard ratios (HR) were calculated using Cox regression. RESULTS: PCCIU contained 1119 cases and 5394 controls. UK Biobank contained 250 cases in 471,779 participants. PPI users had a higher gastric cancer risk in PCCIU and UK Biobank when applying a 1-year lag (adjusted OR = 1.49, 95% CI 1.24, 1.80; adjusted HR = 1.28, 95% CI 0.86, 1.90, respectively), but these associations were attenuated when using a 2-year lag (adjusted OR = 1.13, 95% CI 0.91, 1.40; adjusted HR = 1.15, 95% CI 0.73, 1.82, respectively). CONCLUSIONS: Overall, we observed little consistent evidence of an increased risk of gastric cancer with PPI use.

The role of 5α-reductase inhibitors in gastro-oesophageal cancer risk: A nested case-control study.

PURPOSE: The strong male predominance of gastro-oesophageal cancer suggests that sex hormones play an important role. 5α-Reductase (5AR) inhibitors have antiandrogen effects and have been shown to decrease cancer cell proliferation and metastasis. We conducted the first epidemiologic investigation into the association between 5AR inhibitor use and gastro-oesophageal cancer risk. METHODS: We conducted a nested case-control study within the Scottish Primary Care Clinical Information Unit Research database. Male cases diagnosed with oesophageal or gastric cancer between 1999 and 2011 were matched to up to five male controls based on birth year, diagnosis year, and general practice. We used electronic prescribing records to ascertain medication use. We used conditional logistic regression to calculate odds ratios (ORs) for the association between 5AR inhibitor use and cancer risk, after adjusting for comorbidities and aspirin, statin, or proton pump inhibitor use. RESULTS: The study included 2003 gastro-oesophageal cancer cases and 9650 controls. There was some evidence of reduced gastro-oesophageal cancer risk among 5AR inhibitor users (adjusted OR = 0.75; 95% CI, 0.56-1.02), particularly for finasteride (adjusted OR = 0.68; 95% CI, 0.50-0.94). These decreases were more marked among those who received at least 3 years of 5AR inhibitors (adjusted OR = 0.54; 95% CI, 0.27-1.05; P value = .071) or finasteride (adjusted OR = 0.49; 95% CI, 0.24-0.99; P value = .046). CONCLUSIONS: We found evidence of reduced gastro-oesophageal cancer risk among users of 5AR inhibitors, particularly finasteride. However, larger epidemiological studies are required before randomised controlled trials are considered.

Statin use and risk of liver cancer: Evidence from two population-based studies.

Epidemiological studies of statin use and liver cancer risk have produced conflicting results. We examined the association between statin use and risk of primary liver cancer in two large independent study populations taking account of important covariates and main indications of statins such as high cholesterol and chronic liver disease. We performed a nested case-control study within the Scottish Primary Care Clinical Informatics Unit (PCCIU) database. Five controls were matched to cases with primary liver cancer and we used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations with statin use. We also conducted a prospective cohort study within the UK Biobank using self-reported statin use and cancer-registry recorded primary liver cancer outcomes. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs. In the PCCIU case-control analysis, 434 liver cancer cases were matched to 2,103 controls. In the UK Biobank cohort, 182 out of 475,768 participants developed incident liver cancer. Statin use was associated with 39% lower risk of liver cancer in the PCCIU (adjusted OR 0.61, 95% CI 0.43-0.87). When we examined specific subtypes of liver cancer in the UK Biobank, statin use was associated with lower risk of hepatocellular carcinoma (HCC; adjusted HR, 0.48; 95% CI, 0.24-0.94) but not intrahepatic bile duct carcinoma (IBDC; adjusted HR, 1.09; 95% CI, 0.45-2.64). In conclusion, we found a consistent inverse relationship between statin use and risk of primary liver cancer which was only seen for HCC but not IBDC.

IL-15 and IFN-γ signal through the ERK pathway to inhibit HCV replication, independent of type I IFN signaling.

Despite effective new treatments for Hepatitis C virus (HCV) infection, development of drug resistance, safety concerns and cost are remaining challenges. More importantly, there is no vaccine available against hepatitis C infection. Recent data suggest that there is a strong correlation between spontaneous HCV clearance and human NK cell function, particularly IFN-γ production. Further, IL-15 has innate antiviral activity and is also one of the main factors that activates NK cells to produce IFN-γ. To examine whether IL-15 and IFN-γ have direct antiviral activity against HCV, Huh7.5 cells were treated with either IFN-γ or IL-15 prior to HCV infection. Our data demonstrate that IFN-γ and IL-15 block HCV replication in vitro. Additionally, we show that IL-15 and IFN-γ do not induce anti-HCV effects through the type I interferon signaling pathway or nitric oxide (NO) production. Instead, IL-15 and IFN-γ provide protection against HCV via the ERK pathway. Treatment of Huh7.5 cells with a MEK/ERK inhibitor abrogated the anti-HCV effects of IL-15 and IFN-γ and overexpression of ERK1 prevented HCV replication compared to control transfection. Our in vitro data support the hypothesis that early production of IL-15 and activation of NK cells in the liver lead to control of HCV replication.

Expanded CD56superbrightCD16+ NK Cells from Ovarian Cancer Patients Are Cytotoxic against Autologous Tumor in a Patient-Derived Xenograft Murine Model.

Natural killer (NK) cells are useful for cancer immunotherapy and have proven clinically effective against hematologic malignancies. However, immunotherapies for poor prognosis solid malignancies, including ovarian cancer, have not been as successful due to immunosuppression by solid tumors. Although rearming patients' own NK cells to treat cancer is an attractive option, success of that strategy is limited by the impaired function of NK cells from cancer patients and by inhibition by self-MHC. In this study, we show that expansion converts healthy donor and immunosuppressed ovarian cancer patient NK cells to a cytotoxic CD56superbrightCD16+ subset with activation state and antitumor functions that increase with CD56 brightness. We investigated whether these expanded NK cells may overcome the limitations of autologous NK cell therapy against solid tumors. Peripheral blood- and ascites-derived NK cells from ovarian cancer patients were expanded and then adoptively transferred into cell-line and autologous patient-derived xenograft models of human ovarian cancer. Expanded ovarian cancer patient NK cells reduced the burden of established tumors and prolonged survival. These results suggest that CD56bright NK cells harbor superior antitumor function compared with CD56dim cells. Thus, NK cell expansion may overcome limitations on autologous NK cell therapy by converting the patient's NK cells to a cytotoxic subset that exerts a therapeutic effect against autologous tumor. These findings suggest that the value of expanded autologous NK cell therapy for ovarian cancer and other solid malignancies should be clinically assessed. Cancer Immunol Res; 6(10); 1174-85. ©2018 AACR.

Impact of rurality on processes and outcomes in melanoma care: results from a whole-Scotland melanoma cohort in primary and secondary care.

BACKGROUND: Those living in rural areas have poorer cancer outcomes, but current evidence on how rurality impacts melanoma care and survival is contradictory. AIM: To investigate the impact of rurality on setting of melanoma excision and mortality in a whole-nation cohort. DESIGN AND SETTING: Analysis of linked routine healthcare data comprising every individual in Scotland diagnosed with melanoma, January 2005-December 2013, in primary and secondary care. METHOD: Multivariate binary logistic regression was used to explore the relationship between rurality and setting of melanoma excision; Cox proportional hazards regression between rurality and mortality was used, with adjustments for key confounders. RESULTS: In total 9519 patients were included (54.3% [n = 5167] female, mean age 60.2 years [SD 17.5]). Of melanomas where setting of excision was known, 90.3% (n = 8598) were in secondary care and 8.1% (n = 771) in primary care. Odds of primary care excision increased with increasing rurality/remoteness. Compared with those in urban areas, those in the most remote rural locations had almost twice the odds of melanoma excision in primary care (adjusted odds ratio [aOR] 1.92; 95% confidence interval [CI] = 1.33 to 2.77). No significant association was found between urban or rural residency and all-cause mortality. Melanoma-specific mortality was significantly lower in individuals residing in accessible small towns than in large urban areas (adjusted hazards ratio [HR] 0.53; 95% CI = 0.33 to 0.87) with no trend towards poorer survival with increasing rurality. CONCLUSION: Patients in Scottish rural locations were more likely to have a melanoma excised in primary care. However, those in rural areas did not have significantly increased mortality from melanoma. Together these findings suggest that current UK melanoma management guidelines could be revised to be more realistic by recognising the role of primary care in the prompt diagnosis and treatment of those in rural locations.

Medications that relax the lower oesophageal sphincter and risk of oesophageal cancer: An analysis of two independent population-based databases.

Excessive lower oesophageal sphincter relaxation increases gastro-oesophageal acid reflux, an oesophageal adenocarcinoma risk factor. Medications that relax this sphincter (benzodiazepines, calcium channel blockers, nitrates, ß2 agonists and xanthines) could promote cancer. These medications were investigated in two independent datasets. In the Scottish Primary Care Clinical Informatics Unit (PCCIU) database, a nested case-control study of oesophageal cancer was performed using GP prescription records. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for medication use and oesophageal cancer. In UK Biobank, a cohort study was conducted using self-reported medication use. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs for medication use and oesophageal cancer, and by tumour subtype. Overall, 1,979 oesophageal cancer patients were matched to 9,543 controls in PCCIU, and 355 of 475,768 participants developed oesophageal cancer in UK Biobank. None of the medications investigated were significantly associated with oesophageal cancer risk apart from ß2 agonists, which were associated with increased oesophageal cancer risk in PCCIU (adjusted OR 1.38, 95% CI 1.12, 1.70) but not in UK Biobank (adjusted HR 1.21, 95% CI 0.70, 2.08). Medications that relax the lower oesophageal sphincter were not associated with oesophageal cancer, apart from ß2 agonists. This increased cancer risk in ß2 agonist users merits further investigation.

Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells.

Ovarian cancer (OC) is the leading cause of gynecological cancer-related death in North America. Most ovarian cancer patients (OCPs) experience disease recurrence after first-line surgery and chemotherapy; thus, there is a need for novel second-line treatments to improve the prognosis of OC. Although peripheral blood-derived NK cells are known for their ability to spontaneously lyse tumour cells without prior sensitization, ascites-derived NK cells (ascites-NK cells) isolated from OCPs exhibit inhibitory phenotypes, impaired cytotoxicity and may play a pro-tumourigenic role in cancer progression. Therefore, it is of interest to improve the cytotoxic effector function of impaired OCP ascites-NK cells at the tumour environment. We investigated the efficacy of using an artificial APC-based ex vivo expansion technique to generate cytotoxic, expanded NK cells from previously impaired OCP ascites-NK cells, for use in an autologous model of NK cell immunotherapy. We are the first to obtain a log-scale expansion of OCP ascites-NK cells that upregulate the surface expression of activating receptors NKG2D, NKp30, NKp44, produce robust amounts of anti-tumour cytokines in the presence of OC cells and mediate direct tumour cytotoxicity against ascites-derived, primary OC cells obtained from autologous patients. Our findings demonstrate that it is possible to generate cytotoxic OCP ascites-NK cells from previously impaired OCP ascites-NK cells, which presents a promising immunotherapeutic target for the second-line treatment of OC. Future work should focus on evaluating the in vivo efficacy of autologous NK cell immunotherapy through the intraperitoneal delivery of NK cell expansion factors to a preclinical xenograft mouse model of human OC.

Ex Vivo-expanded Natural Killer Cells Derived From Long-term Cryopreserved Cord Blood are Cytotoxic Against Primary Breast Cancer Cells.

With over 600,000 units of umbilical cord blood (CB) stored on a global scale, it is important to elucidate the therapeutic abilities of this cryopreserved reservoir. In the advancing field of natural killer (NK) cell cancer immunotherapy, CB has proven to be a promising and noninvasive source of therapeutic NK cells. Although studies have proven the clinical efficacy of using long-term cryopreserved CB in the context of hematopoietic stem cell transplantations, little is known about its use for the ex vivo expansion of effector immune cells. Therefore, our group sought to derive ex vivo-expanded NK cells from long-term cryopreserved CB, using an artificial antigen presenting cell-mediated expansion technique. We compared the expansion potential and antitumor effector function of CB-derived NK (CB-NK) cells expanded from fresh (n=4), short-term cryopreserved (<1-year old, n=5), and long-term cryopreserved (1-10-year old, n=5) CB. Here, we demonstrated it is possible to obtain an exponential amount of expanded CB-NK cells from long-term cryopreserved CB. Ex vivo-expanded CB-NK cells had an increased surface expression of activating markers and showed potent antitumor function by producing robust levels of proinflammatory cytokines, interferon-γ, and tumor necrosis factor-α. Moreover, expanded CB-NK cells (n=3-5) demonstrated cytotoxicity towards primary breast cancer cells (n=2) derived from a triple-negative breast cancer and an estrogen receptor-positive/progesterone receptor-positive breast cancer patient. Long-term cryopreservation had no effect on the expansion potential or effector function of expanded CB-NK cells. Therefore, we propose that long-term cryopreserved CB remains clinically useful for the ex vivo expansion of therapeutic NK cells.

A controlled trial of screening, brief intervention and referral for treatment (SBIRT) implementation in primary care in the United Arab Emirates.

Aim This project evaluated the effectiveness of screening brief intervention and referral for treatment (SBIRT) in primary care in Abu Dhabi to manage patients with problematic substance use. This study aimed to determine whether: (i) training primary care physicians on the SBIRT model increased the identification of patients using substances at a harmful, hazardous or dependent level; (ii) training improved physicians' knowledge, attitudes and beliefs in self-efficacy in managing substance use. BACKGROUND: Substance use is increasing in the United Arab Emirates yet there has been no formal primary care intervention. SBIRT was considered an appropriate model given its endorsement by the WHO. METHODS: A controlled trial (two intervention and two matched control clinics) was undertaken. Intervention physicians (n=17) were trained in SBIRT. Physicians' attitudes were measured before and after training and eight months after implementation. Target recruitment was 900 patients. Inclusion criteria were: consenting UAE national, ⩾18 years, using the 'walk-in' primary care clinic. Patient data was collected by physician-administered questionnaire. Prevalence of drug use was measured through electronic patient records. Findings A total of 906 patients were screened, aged 18-82 years and 496 (55%) were female. Of these, 5.7% reported use of amphetamine, 3.9% alcohol, 3.3%, sedatives, 1.7% opioids and 1.1% cannabis. In all, 21 people had a moderate/high ASSIST score and received a brief intervention, but did not attend follow-up; three high-risk people were referred for specialist treatment. Physicians' attitudes towards patients with problematic substance use and providing treatment improved after training, but returned to pre-training levels after eight months. Including the 21 individuals identified from intervention screening, the prevalence of substance use increased to 0.208% (95% CI 0.154-0.274), significantly higher than in control clinics (P<0.001). In conclusion, physicians were generally positive towards SBIRT and SBIRT increased recorded drug related conditions at a practice level. However, poor patient attendance at follow-up requires investigation.