Examining temporal trends in psychological distress and the co-occurrence of common substance use in a population-based sample of grade 7-12 students from 2013 to 2019.

PURPOSE: Characterizing trends and correlates of adolescent psychological distress is important due to observed global increases over the last 20 years. Substance use is a commonly discussed correlate, though we lack an understanding about how co-occurrence of these concerns has been changing over time. METHODS: Data came from repeated, representative, cross-sectional surveys of grade 7-12 students across Ontario, Canada conducted biennially from 2013 to 2019. Poisson regression with robust standard errors was used to examine changes in the joint association between psychological distress (operationalized as Kessler-6 [K6] scores ≥ 13) and substance use over time. Weighted prevalence ratios (PR) and their 99% confidence intervals were estimated, where p < 0.01 denotes statistical significance. RESULTS: The prevalence of psychological distress doubled between 2013 and 2019, with adjusted increases of about 1.2 times each survey year. This biennial increase did not differ based on sex, perceived social standing, school level, or any substance use. Students using substances consistently reported a higher prevalence of psychological distress (between 1.2 times and 2.7 times higher). There were similarly no differential temporal trends based on substance use for very high distress (K6 ≥ 19) or K6 items explored individually. CONCLUSION: Psychological distress steeply increased among adolescents and substance use remains important to assess and address alongside distress. However, the magnitude of temporal increases appears to be similar for adolescents reporting and not reporting substance use.

'Low' faecal immunochemical test (FIT) colorectal cancer: a 4-year comparison of the Nottingham '4F' protocol with FIT10 in symptomatic patients.

AIM: The aim of this work was to evaluate colorectal cancer (CRC) outcomes after 'low' (sub-threshold) faecal immunochemical test (FIT) results in symptomatic patients tested in primary care. METHOD: This work comprised a retrospective audit of 35 289 patients with FIT results who had consulted their general practitioner with lower gastrointestinal symptoms and had subsequent CRC diagnoses. The Rapid Colorectal Cancer Diagnosis pathway was introduced in November 2017 to allow incorporation of FIT into clinical practice. The local '4F' protocol combined FIT results with blood tests and digital rectal examination (DRE): FIT, full blood count, ferritin and finger [DRE]. The outcome used was detection rates of CRC, missed CRC and time to diagnosis in local 4F protocols for patients with a subthreshold faecal haemoglobin (fHb) result compared with thresholds of 10 and 20 µg Hb/g faeces. RESULTS: A single threshold of 10 µg Hb/g faeces identifies a population in whom the risk of CRC is 0.2%, but this would have missed 63 (10.5%) of 599 CRCs in this population. The Nottingham 4F protocol would have missed fewer CRCs [42 of 599 (7%)] despite using a threshold of 20 µg Hb/g faeces for patients with normal blood tests. Subthreshold FIT results in patients subsequently diagnosed with a palpable rectal tumour yielded the longest delays in diagnosis. CONCLUSION: A combination of FIT with blood results and DRE (the 4F protocol) reduced the risk of missed or delayed diagnosis. Further studies on the impact of such protocols on the diagnostic accuracy of FIT are expected. The value of adding blood tests to FIT may be restricted to specific parts of the fHb results spectrum.

Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Ovariectomy reduces cholinergic modulation of excitatory synaptic transmission in the rat entorhinal cortex.

Estrogens are thought to contribute to cognitive function in part by promoting the function of basal forebrain cholinergic neurons that project to the hippocampus and cortical regions including the entorhinal cortex. Reductions in estrogens may alter cognition by reducing the function of cholinergic inputs to both the hippocampus and entorhinal cortex. In the present study, we assessed the effects of ovariectomy on proteins associated with cholinergic synapses in the entorhinal cortex. Ovariectomy was conducted at PD63, and tissue was obtained on PD84 to 89 to quantify changes in the degradative enzyme acetylcholinesterase, the vesicular acetylcholine transporter, and muscarinic M1 receptor protein. Although the vesicular acetylcholine transporter was unaffected, ovariectomy reduced both acetylcholinesterase and M1 receptor protein, and these reductions were prevented by chronic replacement of 17ß-estradiol following ovariectomy. We also assessed the effects of ovariectomy on the cholinergic modulation of excitatory transmission, by comparing the effects of the acetylcholinesterase inhibitor eserine on evoked excitatory synaptic field potentials in brain slices obtained from intact rats, and from ovariectomized rats with or without 17ß-estradiol replacement. Eserine is known to prolong the effects of endogenously released acetylcholine, resulting in an M1-like mediated reduction of glutamate release at excitatory synapses. The reduction in excitatory synaptic potentials in layer II of the entorhinal cortex induced by 15-min application of 10 µM eserine was greatly reduced in slices from ovariectomized rats as compared to intact rats and ovariectomized rats with replacement of 17ß-estradiol. The reduced modulatory effect of eserine is consistent with the observed changes in cholinergic proteins, and suggests that reductions in 17ß-estradiol following ovariectomy lead to impaired cholinergic function within the entorhinal cortex.

Quantitative FIT stratification is superior to NICE referral criteria NG12 in a high-risk colorectal cancer population.

BACKGROUND: Guidelines for urgent investigation of colorectal cancer (CRC) are based on age and symptom-based criteria. This study aims to compare the diagnostic value of clinical features and faecal immunochemical test (FIT) results to identify those at a higher risk of CRC, thereby facilitating effective triage of patients. METHODS: We undertook a review of all patients referred for investigation of CRC at our centre between September 2016 and June 2018. Patients were identified using a prospectively recorded local database. We performed a logistic regression analysis of factors associated with a diagnosis of CRC. RESULTS: One-thousand-and-seven-hundred-eighty-four patients with FIT results were included in the study. Change in bowel habit (CIBH) was the most common referring clinical feature (38.3%). Patients diagnosed with CRC were significantly older than those without malignancy (74.0 years vs 68.9 years, p = 0.0007). Male patients were more likely to be diagnosed with CRC than females (6.5% vs 2.5%, Chi-squared 16.93, p < 0.0001). CRC was diagnosed in 3.5% (24/684) with CIBH compared to 8.1% (6/74) with both CIBH and iron deficiency anaemia. No individual or combination of referring clinical features was associated with an increased diagnosis of CRC (Chi-squared, 8.03, p = 0.155). Three patients with negative FIT results (< 4 µg Hb/g faeces) were diagnosed with CRC (3/1027, 0.3%). The highest proportion of cancers detected was in the ≥ 100 µg Hb/g faeces group (55/181, 30.4%). CONCLUSION: In a multivariate model, FIT outperforms age, sex and all symptoms prompting referral. FIT has greater stratification value than any referral symptoms. FIT does have value in patients with iron deficiency anaemia.

Faecal immunochemical testing and blood tests for prioritization of urgent colorectal cancer referrals in symptomatic patients: a 2-year evaluation.

BACKGROUND: A novel pathway incorporating faecal immunochemical testing (FIT) for rapid colorectal cancer diagnosis (RCCD) was introduced in 2017. This paper reports on the service evaluation after 2 years of pathway implementation. METHODS: The RCCD protocol was based on FIT, blood results and symptoms to stratify adult patients in primary care. Two-week-wait (2WW) investigation was indicated for patients with rectal bleeding, rectal mass and faecal haemoglobin (fHb) level of 10 µg Hb/g faeces or above or 4 µg Hb/g faeces or more in the presence of anaemia, low ferritin or thrombocytosis, in all other symptom groups. Patients with 100 µg Hb/g faeces or above had expedited investigation . A retrospective audit of colorectal cancer detected between 2017 and 2019 was conducted, fHb thresholds were reviewed and critically assessed for cancer diagnoses. RESULTS: In 2 years, 14788 FIT tests were dispatched with 13361 (90.4 per cent) completed returns. Overall, fHb was less than 4 µg Hb/g faeces in 9208 results (68.9 per cent), 4-9.9 µg Hb/g in 1583 (11.8 per cent), 10-99.9 µg Hb/g in 1850 (13.8 per cent) and 100 µg Hb/g faeces or above in 720 (5.4 per cent). During follow-up (median 10.4 months), 227 colorectal cancers were diagnosed. The cancer detection rate was 0.1 per cent in patients with fHb below 4 µg Hb/g faeces, 0.6 per cent in those with fHb 4-9.9 µg Hb/g faeces, 3.3 per cent for fHb 10-99.9 µg Hb/g faeces and 20.7 per cent for fHb 100 µg Hb/g faeces or above. The detection rate in the cohort with 10-19.9 µg Hb/g faeces was 1.4 per cent, below the National Institute for Health and Care Excellence threshold for urgent referral. The colorectal cancer rate in patients with fHb below 20 µg Hb/g faeces was less than 0.3 per cent. CONCLUSION: Use of FIT to "rule out" urgent referral from primary care misses a small number of cases. The threshold for referral may be adjusted with blood results to improve stratification .

Towards Better Perioperative Pain Management in Mexico: A Study in a Network of Hospitals Using Quality Improvement Methods from PAIN OUT.

OBJECTIVE: This was a pre-post study in a network of hospitals in Mexico-City, Mexico. Participants developed and implemented Quality Improvement (QI) interventions addressing perioperative pain management. METHODS: PAIN OUT, an international QI and research network, provided tools for web-based auditing and feedback of pain management and patient-reported outcomes (PROs) in the clinical routine. Ward- and patient-level factors were evaluated with multi-level models. Change in proportion of patients reporting worst pain ≥6/10 between project phases was the primary outcome. RESULTS: Participants created locally adapted resources for teaching and pain management, available to providers in the form of a website and a special issue of a national anesthesia journal. They offered teaching to anesthesiologists, surgeons, including residents, and nurses. Information was offered to patients and families. A total of 2658 patients were audited in 9 hospitals, between July 2016 and December 2018. Participants reported that the project made them aware of the importance of: training in pain management; auditing one's own patients to learn about PROs and that QI requires collaboration between multi-disciplinary teams. Participants reported being unaware that their patients experienced severe pain and lacked information about pain treatment options. Worst pain decreased significantly between the two project phases, as did PROs related to pain interfering with movement, taking a deep breath/coughing or sleep. The opportunity of patients receiving information about their pain treatment options increased from 44% to 77%. CONCLUSIONS: Patients benefited from improved care and pain-related PROs. Clinicians appreciated gaining increased expertise in perioperative pain management and methods of QI.

GP access to FIT increases the proportion of colorectal cancers detected on urgent pathways in symptomatic patients in Nottingham.

OBJECTIVE: Service evaluation of GP access to Faecal Immunochemical Test (FIT) for colorectal cancer (CRC) detection in Nottinghamshire and use of FIT for "rule out", "rule in" and "first test selection". DESIGN: Retrospective audit of FIT results, CRC outcomes and resource utilisation before and after introduction of FIT in Primary Care in November 2017. Data from the new pathway up to December 2018 was compared with previous experience. RESULTS: Between November 2017 and December 2018, 6747 GP FIT test requests yielded 5733 FIT results, of which 4082 (71.2%) were <4.0 µg Hb/g faeces, 579 (10.1%) were 4.0-9.9 µg Hb/g faeces, 836 (14.6%) were 10.0-149.9 µg Hb/g faeces, and 236 (4.1%) were ≥150.0 µg Hb/g faeces. The proportion of "rule out" results <4.0 µg Hb/g faeces was significantly higher than in the Getting FIT cohort (71.2% vs 60.4%, Chi squared 42.8, p < 0.0001) and the proportion of "rule in" results ≥150.0 µg Hb/g faeces was significantly lower (4.1% vs 8.1%, Chi squared 27.3,P < 0.0001). There was a 33% rise in urgent referrals across Nottingham overall during the evaluation period. 2 CRC diagnoses were made in 4082 patients who had FIT<4.0 µg Hb/g faeces. 58.4% of new CRC diagnoses associated with a positive FIT were early stage cancers (Stage I and II). The proportion of all CRC diagnoses that follow an urgent referral s rose after introduction of FIT. CONCLUSIONS: FIT allows GP's to select a more appropriate cohort for urgent investigation without a large number of missed diagnoses. FIT appears to promise a "stage migration" effect which may ultimately improve CRC outcomes.

Randomised trial of population-based BRCA testing in Ashkenazi Jews: long-term outcomes.

OBJECTIVE: Unselected population-based BRCA testing provides the opportunity to apply genomics on a population-scale to maximise primary prevention for breast-and-ovarian cancer. We compare long-term outcomes of population-based and family-history (FH)/clinical-criteria-based BRCA testing on psychological health and quality of life. DESIGN: Randomised controlled trial (RCT) (ISRCTN73338115) GCaPPS, with two-arms: (i) population-screening (PS); (ii) FH/clinical-criteria-based testing. SETTING: North London Ashkenazi-Jewish (AJ) population. POPULATION/SAMPLE: AJ women/men. METHODS: Population-based RCT (1:1). Participants were recruited through self-referral, following pre-test genetic counselling from the North London AJ population. INCLUSION CRITERIA: AJ women/men >18 years old; exclusion-criteria: prior BRCA testing or first-degree relatives of BRCA-carriers. INTERVENTIONS: Genetic testing for three Jewish BRCA founder-mutations: 185delAG (c.68_69delAG), 5382insC (c.5266dupC) and 6174delT (c.5946delT), for (i) all participants in PS arm; (ii) those fulfilling FH/clinical criteria in FH arm. Linear mixed models and appropriate contrast tests were used to analyse the impact of BRCA testing on psychological and quality-of-life outcomes over 3 years. MAIN OUTCOME MEASURES: Validated questionnaires (HADS/MICRA/HAI/SF12) used to analyse psychological wellbeing/quality-of-life outcomes at baseline/1-year/2-year/3-year follow up. RESULTS: In all, 1034 individuals (691 women, 343 men) were randomised to PS (n = 530) or FH (n = 504) arms. There was a statistically significant decrease in anxiety (P = 0.046) and total anxiety-&-depression scores (P = 0.0.012) in the PS arm compared with the FH arm over 3 years. No significant difference was observed between the FH and PS arms for depression, health-anxiety, distress, uncertainty, quality-of-life or experience scores associated with BRCA testing. Contrast tests showed a decrease in anxiety (P = 0.018), health-anxiety (P < 0.0005) and quality-of-life (P = 0.004) scores in both PS and FH groups over time. Eighteen of 30 (60%) BRCA carriers identified did not fulfil clinical criteria for BRCA testing. Total BRCA prevalence was 2.9% (95% CI 1.97-4.12%), BRCA1 prevalence was 1.55% (95% CI 0.89-2.5%) and BRCA2 prevalence was 1.35% (95% CI 0.74-2.26%). CONCLUSION: Population-based AJ BRCA testing does not adversely affect long-term psychological wellbeing or quality-of-life, decreases anxiety and could identify up to 150% additional BRCA carriers. TWEETABLE ABSTRACT: Population BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life.

The role of the paraventricular nucleus of the thalamus in the augmentation of heroin seeking induced by chronic food restriction.

Drug addiction is a chronic disorder that is characterized by compulsive drug seeking and involves cycling between periods of compulsive drug use, abstinence, and relapse. In both human addicts and animal models of addiction, chronic food restriction has been shown to increase rates of relapse. Previously, our laboratory has demonstrated a robust increase in drug seeking following a period of withdrawal in chronically food-restricted rats compared with sated rats. To date, the neural mechanisms that mediate the effect of chronic food restriction on drug seeking have not been elucidated. However, the paraventricular nucleus of the thalamus (PVT) appears to be a promising target to investigate. The objective of the current study was to examine the role of the PVT in the augmentation of heroin seeking induced by chronic food restriction. Male Long-Evans rats were trained to self-administer heroin for 10 days. Rats were then removed from the training chambers and experienced a 14-day withdrawal period with either unrestricted (sated) or mildly restricted (FDR) access to food. On day 14, rats underwent a 1-hour heroin-seeking test under extinction conditions, during which neural activity in the PVT was either inhibited or increased using pharmacological or chemogenetic approaches. Unexpectedly, inhibition of the PVT did not alter heroin seeking in food-restricted or sated rats, while enhancing neural activity in the PVT-attenuated heroin seeking in food-restricted rats. These results indicate that PVT activity can modulate heroin seeking induced by chronic food restriction.

Early clinical outcomes of a rapid colorectal cancer diagnosis pathway using faecal immunochemical testing in Nottingham.

AIM: We introduced primary care access to faecal immunochemical testing (FIT) as a stratification tool for symptomatic patients considered to be at risk of colorectal cancer (CRC) prior to urgent referral. We aimed to evaluate clinical and pathway outcomes during the first 6 months of this novel approach. METHOD: FIT was recommended for all patients who consulted their general practitioner with lower gastrointestinal symptoms other than rectal bleeding and rectal mass. We undertook a retrospective audit of the results of FIT, related clinical outcomes and resource utilization on prospectively logged cases between November 2017 and May 2018. RESULTS: Of the 1862 FIT kits dispatched by post 91.4% were returned, with a median return time of 7 days (range 2-110 days); however, 1.3% of returned kits could not be analysed. FIT results ≥ 150.0 µg haemoglobin (Hb)/g faeces identified patients with a significantly higher risk of CRC (30.9% vs 1.4%, chi-square 167.1, P < 0.0001). FIT results ≥ 10.0 µg Hb/g faeces identified patients with significantly higher risk of significant noncancer bowel pathology (24.1% vs 4.9%, chi-square 73.6, P < 0.0001) and FIT results < 4.0 µg Hb/g faeces identified a group more likely to have non-CRC pathology (5.1% vs 2.4%, chi-square 3.9, P < 0.05). The CRC detection rate in 531 patients investigated after a FIT result of < 4.0 µg Hb/g faeces was 0.2%. In 899 investigated patients, a FIT result with a threshold of 4.0 µg Hb/g faeces had sensitivity 97.2% (85.5-99.9% CI), specificity 61.4% (58.1-64.7% CI), negative predictive value 99.8% (98.7-100.0% CI) and positive predictive value 9.5% (8.7-10.4% CI). CONCLUSION: A symptomatic pathway incorporating FIT is feasible and appears more clinically effective than pathways based on age and symptoms alone.

Service evaluation of faecal immunochemical testing and anaemia for risk stratification in the 2-week-wait pathway for colorectal cancer.

Background: New national guidance on urgent referral for investigation of colorectal cancer included faecal occult blood testing in 2015. A service evaluation of faecal immunochemical testing (FIT) and anaemia as risk stratification tools in symptomatic patients suspected of having CRC was undertaken. Methods: Postal FIT was incorporated into the colorectal cancer 2-week wait (2WW) pathway for all patients without rectal bleeding in 2016. Patients were investigated in the 2WW pathway as normal, and outcomes of investigations were recorded prospectively. Anaemia was defined as a haemoglobin level below 120 g/l in women and 130 g/l in men. Results: FIT kits were sent to 1106 patients, with an 80·9 per cent return rate; 810 patients completed investigations and 40 colorectal cancers were diagnosed (4·9 per cent). FIT results were significantly higher in patients with anaemia (median (i.q.r.) 4·8 (0·8-34·1) versus 1·2 (0-6·4) µg Hb/g faeces in those without anaemia; P < 0·001). Some 60·4 per cent of patients (538 of 891) had a result lower than 4 µg haemoglobin (Hb) per g faeces (limit of detectability), and 69·7 per cent (621 of 891) had less than 10 µg Hb/g faeces. Some 60 per cent of patients with colorectal cancer had a FIT reading of 150 µg Hb/g faeces or more. For five colorectal cancers diagnosed in patients with a FIT value below 10 µg Hb/g faeces, there was either a palpable rectal mass or the patient was anaemic. A FIT result of more than 4 µg Hb/g faeces had 97·5 per cent sensitivity and 64·5 per cent specificity for a diagnosis of colorectal cancer. A FIT result above 4 µg Hb/g faeces and/or anaemia had a 100 per cent sensitivity and 45·3 per cent specificity for colorectal cancer diagnosis. Conclusion: FIT is most useful at the extremes of detectability; strongly positive readings predict high rates of colorectal cancer and other significant pathology, whereas very low readings in the absence of anaemia or a palpable rectal mass identify a group with very low risk. High return rates for FIT within this 2WW pathway indicate its acceptability.

Partially Covered Versus Uncovered Self-Expandable Metal Stents: Coating Nor Diameter Affect Clinical Outcomes.

INTRODUCTION: Jaundice is a common initial presentation of malignant biliary stricture. In patients with life expectancies that are greater than 3 months, self-expanding metal stents (SEMS) offer a larger diameter stent with longer patency and fewer complications compared to plastic stents. There have been conflicting results in the published literature as to efficacy and safety between the various SEMS types and diameters. We compared stent coating (PCSEMS vs USEMS) and diameter on clinical outcomes regarding management of malignant biliary obstruction. METHODS: A retrospective cohort study was conducted using a database of consecutive patients who underwent an ERCP with biliary SEMS placement (only 8 and 10 mm) between 2009 and 2017. RESULTS: In total, 278 patients who had SEMS at ERCP for malignant biliary obstruction were included (213 PCSEMS vs 65 USEMS). The groups were demographically evenly matched. Clinical success rates and patency duration were not statistically significant between PCSEMS and USEMS (98.1% vs 95.5%, P = 0.36, and 302.5 vs 225.5 days, P = 0.72, respectively). Adverse event rates were similar between both PCSEMS and USEMS with regard to overall adverse events. Stent diameter did not have an impact on overall clinical success (98.9% vs 95.3%, P = 0.11) or patency duration (239 days vs 336 days, P = 0.51). CONCLUSIONS: Our comparison of PCSEMS versus USEMS and 8 mm versus 10 mm showed no difference in clinical efficacy or adverse events between the two SEMS coatings and diameter, illustrating that coating and size do not matter in regard to stent choice, despite prior suggestive data.

Improving perioperative pain management: a preintervention and postintervention study in 7 developing countries.

INTRODUCTION: The burden of untreated postoperative pain is high. OBJECTIVE: This study assessed feasibility of using quality improvement (QI) tools to improve management of perioperative pain in hospitals in multiple developing countries. METHODS: The International Pain Registry and Developing Countries working groups, from the International Association for the Study of Pain (IASP), sponsored the project and PAIN OUT, a QI and research network, coordinated it, and provided the research tools. The IASP published a call about the project on its website. Principal investigators (PIs) were responsible for implementing a preintervention and postintervention study in 1 to 2 surgical wards in their hospitals, and they were free to choose the QI intervention. Trained surveyors used standardized and validated web-based tools for collecting findings about perioperative pain management and patient reported outcomes (PROs). Four processes and PROs, independent of surgery type, assessed effectiveness of the interventions. RESULTS: Forty-three providers responded to the call; 13 applications were selected; and PIs from 8 hospitals, in 14 wards, in 7 countries, completed the study. Interventions focused on teaching providers about pain management. Processes improved in 35% and PROs in 37.5% of wards. CONCLUSIONS: The project proved useful on multiple levels. It offered PIs a framework and tools to perform QI work and findings to present to colleagues and administration. Management practices and PROs improved on some wards. Interpretation of change proved complex, site-dependent, and related to multiple factors. PAIN OUT gained experience coordinating a multicentre, international QI project. The IASP promoted research, education, and QI work.

Attitude towards and factors affecting uptake of population-based BRCA testing in the Ashkenazi Jewish population: a cohort study.

OBJECTIVE: To evaluate factors affecting unselected population-based BRCA testing in Ashkenazi Jews (AJ). DESIGN: Cohort-study set within recruitment to the GCaPPS trial (ISRCTN73338115). SETTING: North London AJ population. POPULATION OR SAMPLE: Ashkenazi Jews women/men >18 years, recruited through self-referral. METHODS: Ashkenazi Jews women/men underwent pre-test counselling for BRCA testing through recruitment clinics (clusters). Consenting individuals provided blood samples for BRCA testing. Data were collected on socio-demographic/family history/knowledge/psychological well-being along with benefits/risks/cultural influences (18-item questionnaire measuring 'attitude'). Four-item Likert-scales analysed initial 'interest' and 'intention-to-test' pre-counselling. Uni- and multivariable logistic regression models evaluated factors affecting uptake/interest/intention to undergo BRCA testing. Statistical inference was based on cluster robust standard errors and joint Wald tests for significance. Item-Response Theory and graded-response models modelled responses to 18-item questionnaire. MAIN OUTCOME MEASURES: Interest, intention, uptake, attitude towards BRCA testing. RESULTS: A total of 935 individuals (women = 67%/men = 33%; mean age = 53.8 (SD = 15.02) years) underwent pre-test genetic-counselling. During the pre-counselling, 96% expressed interest in and 60% indicated a clear intention to undergo BRCA testing. Subsequently, 88% opted for BRCA testing. BRCA-related knowledge (P = 0.013) and degree-level education (P = 0.01) were positively and negatively (respectively) associated with intention-to-test. Being married/cohabiting had four-fold higher odds for BRCA testing uptake (P = 0.009). Perceived benefits were associated with higher pre-counselling odds for interest in and intention to undergo BRCA testing. Reduced uncertainty/reassurance were the most important factors contributing to decision-making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional impact/inability to prevent cancer/marriage ability/ethnic focus/stigmatisation) were significantly associated with lower odds of uptake of BRCA testing, and discriminated between acceptors and decliners. Male gender/degree-level education (P = 0.001) had weaker correlations, whereas having children showed stronger (P = 0.005) associations with attitudes towards BRCA testing. CONCLUSIONS: BRCA testing in the AJ population has high acceptability. Pre-test counselling increases awareness of disadvantages/limitations of BRCA testing, influencing final cost-benefit perception and decision-making on undergoing testing. TWEETABLE ABSTRACT: BRCA testing in Ashkenazi Jews has high acceptability and uptake. Pre-test counselling facilitates informed decision-making.

Expression of Lamin A/C in early-stage breast cancer and its prognostic value.

PURPOSE: Lamins A/C, a major component of the nuclear lamina, play key roles in maintaining nuclear integrity, regulation of gene expression, cell proliferation and apoptosis. Reduced lamin A/C expression in cancer has been reported to be a sign of poor prognosis. However, its clinical significance in breast cancer remains to be defined. This study aimed to evaluate expression and prognostic significance of lamin A/C in early-stage breast cancer. METHODS: Using immunohistochemical staining of tissue microarrays, expression of lamin A/C was evaluated in a large well-characterised series of early-stage operable breast cancer (n = 938) obtained from Nottingham Primary Breast Carcinoma Series. Association of lamin A/C expression with clinicopathological parameters and outcome was evaluated. RESULTS: Positive expression rate of lamin A/C in breast cancer was 42.2% (n = 398). Reduced/loss of expression of lamin A/C was significantly associated with high histological grade (p < 0.001), larger tumour size (p = 0.004), poor Nottingham Prognostic Index score (p < 0.001), lymphovascular invasion (p = 0.014) and development of distant metastasis (p = 0.027). Survival analysis showed that reduced/loss of expression of lamin A/C was significantly associated with shorter breast cancer-specific survival (p = 0.008). CONCLUSION: This study suggests lamin A/C plays a role in breast cancer and loss of its expression is associated with variables of poor prognosis and shorter outcome.

Pain after orthopaedic surgery: differences in patient reported outcomes in the United States vs internationally. An observational study from the PAIN OUT dataset.

BACKGROUND: A previous PAIN OUT study found that American orthopaedic-surgical patients rated 'worst pain' higher than did similar European patients. This study aims to confirm these findings in a larger, international patient sample, explore whether risk factors for greater postoperative pain exist disproportionately in the American population, and confirm the findings for one procedure. METHODS: Surveyors collected patient reported outcomes (PROs) and perioperative pain management practices using PAIN OUT methodology. Most PROs used 11-point numerical rating scales (0=null, 10=worst possible). Risk factors included: female gender, younger age, high BMI, chronic pain, and opioid use before surgery. Initial analysis used a mixed patient cohort. A secondary analysis used only patients undergoing total knee replacement (TKR). Inference was based primarily on effect size using Cohen's d. RESULTS: 13,770 patients in 13 European and non-European countries (international ) and 564 patients from the United States (US) contributed data on the 1st postoperative day. Three of 11 PROs differed between the cohorts: 'worst pain' {US 7.5 (2.5) vs international 5.6 (2.8); d=0.66 [confidence interval (CI) 0.58-0.75]}; proportion 'receiving information about treatment options' [US 0.86 vs international 0.66; d=0.53 (CI 0.39-0.66)]; reporting adverse effects and their severity [US 0.87 vs international 0.73; d=0.52 (CI 0.38-0.66)]. Risk factors did not differ between the two cohorts. PROs and management patterns in TKR patients were similar to the mixed cohort. CONCLUSIONS: Three PROs differed between international and US patients, with higher 'worst pain' for US patients. Neither risk factors, nor patient mix accounted for the observed differences for 'worst pain'. CLINICAL TRIAL REGISTRATION: NCT 02083835.

Could stool collection devices help increase uptake in bowel cancer screening programmes?

OBJECTIVE: To understand the usage and acceptability of a faecal collection device amongst participants in the National Health Service Bowel Cancer Screening Programme, with the aim of influencing future uptake. SETTING: Participants completing faecal occult blood test retests as part of the routine Bowel Cancer Screening Programme in Eastern England. METHODS: A faecal collection device and questionnaire were sent to all potential retest participants during a one-month period to collect information on prior stool collection methods and ease of use and usefulness of the enclosed faecal collection device. RESULTS: Out of 1087 participants invited, 679 (62.5%) returned their questionnaire. Of these, 429 (63.2%) trialled the faecal collection device at least once, 163 (38.4%) found the device made collecting their sample easier than previously, 189 (44.6%) found it made collection more difficult and 72 (17.0%) said it made no difference. Similar numbers reported finding that the faecal collection device made collecting the sample more pleasant (130, 31.5%), less pleasant (103, 25.0%) and no different (179, 43.4%) compared with previous collection without a faecal collection device. CONCLUSION: Although a small proportion of participants found the faecal collection device helpful, a considerable majority did not or did not use it at all. Offering faecal collection devices is unlikely to produce a substantial increase in bowel cancer screening uptake.

Prospective evaluation of chronic pain disorders and treatments.

BACKGROUND: The incidence of chronic pain is variable among individuals who have sustained traumatic or surgical injury. Also, treatments for pain rarely are effective consistently for a procedure or agent, and no therapies are considered effective for pain that is chronic. NEW METHOD: Difficulties with standard methods for conducting clinical trials call attention to a need for protocols that provide a new understanding of the development of and control over chronic pain. Prospective single-subject research designs can document varieties of pain progression over time for individuals. Subsequent grouping of individuals with common characteristics directs a mechanism-based approach to therapy. RESULTS: Tracking of individuals' pain and associated influences over time is consistent with clinical practice, noting and adapting to changes that occur. COMPARISON WITH EXISTING METHODS: Grouping patients with diverse characteristics and variable effects of therapy is problematic. Conventional evaluation of pain assesses patients with similar injuries or surgery without characterizations of individuals who develop chronic pain or recover over time. Also, classical evaluation of therapies involves comparison of groups receiving treatment or a placebo without characterization of patients with successful and unsuccessful results. CONCLUSIONS: Single-subject prospective studies can inform clinical trials according to individual differences that would be obscured by comparison of groups with unknown variation in characteristics that influence pain and therapeutic effectiveness.