'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.

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.

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.

A Poisson scaling approach to backward wave propagation in a tube.

A mathematical analysis of wave propagation along an elastic cylindrical tube is presented, with the aim of determining the range of Poisson's ratio for which backward wave propagation (i.e. at negative group velocity) can occur near the ring frequency. This range includes zero Poisson's ratio and a surrounding interval of positive and negative values, whose width depends on the thickness of the tube. The whole range of Poisson's ratio is considered, so that the work applies to modern materials, e.g. composites. All results are presented in simple analytic form by means of a dominant balance in parameter space. The identification of this balance, which is unique, is a main new result in the paper, which makes possible a new type of shell theory based on 'Poisson scaling'. The mathematical approach is deductive from the equations of motion, rather than being based on kinematic hypotheses. A key finding, accessible via the Poisson scaling, is that the regime of negative group velocities extends to high wavenumbers, while being confined to a narrow band of frequencies. Thus responses localized in space are possible for near-monochromatic forcing, an important fact for nonlinear theories of tube dynamics near the ring frequency. This article is part of the theme issue 'Wave generation and transmission in multi-scale complex media and structured metamaterials (part 1)'.

Effects of milk replacer feeding rate and fat content on Jersey calf nutrient digestion and performance to 4 months of age.

This study evaluated effects of milk replacer (MR) feeding rate and fat concentration in MR on total-tract digestion (TTD) and growth performance in Jersey calves. Jersey heifer calves (n = 100, 2 blocks of 50; initially 30 ± 3.0 kg of body weight; 4-11 d of age) were randomly assigned to 1 of 4 treatments in a 2 × 2 factorial arrangement of MR feeding rate [454 g for 42 d, and 227 g for 7 d (MOD); or 454 g for 7 d, 681 g for 35 d, and 341 g for 7 d (HI), as-fed basis] and MR fat content (17 or 24% fat as-fed basis). Milk replacers (24% crude protein as-fed basis) were reconstituted to 14% solids and fed in 2 equal feedings for 42 d, and then mornings only for 7 d. Textured calf starter (21% crude protein, 40% starch, dry matter basis) and water were offered for ad libitum consumption. From d 57 to 112, calf starter was mixed with 5% chopped grass hay. Calves were housed individually to d 56 and housed in groups (4-5 calves/pen) from d 57 to 112. Estimates of TTD were measured in 5 calves/treatment (block 1) at wk 3 of the study using acid-insoluble ash as an indigestible marker. From 0 to 56 d, calf starter intake (CSI) was greater for MOD vs. HI and 17 versus 24% fat; average daily gain was greater for HI versus MOD; and hip width change was greater for 17 versus 24% fat. Estimates of organic matter TTD were greater for HI versus MOD, but neutral detergent fiber TTD was greater for MOD versus HI and for 17 versus 24% fat. From 57 to 112 d, hip height change was greater for MOD versus HI, and hip width change was greater for 17 versus 24% fat. In this study, feeding Jersey calves more MR improved preweaning average daily gain, but had a negative effect on CSI and likely rumen development, as neutral detergent fiber TTD was reduced at 3 wk and frame growth was reduced from d 57 to 112. This resulted in similar final calf body weights between MR feeding rates at the end of the study. No benefits were observed for feeding more fat in MR as CSI or for NDF digestibility, and frame growth was reduced.

Models to predict dry feed intake in Holstein calves to 4 months of age.

Voluntary daily dry feed intake (DFI) in Holstein calves was predicted using 60,761 individual daily observations collected from 1,235 Holstein calves in 30 experiments from 4 research stations in the United States and Europe. Consumption of dry feed (calf starter and hay, kg/d or percent of body weight) was measured from 3 to 114 d of age. Linear models and 2- and 3-parameter nonlinear models were evaluated to predict DFI using age of calf, intake of milk replacer, ambient temperature, percent forage, and neutral detergent fiber concentration in ration dry matter (DM) as independent variables. The initial data set was randomly divided within study location into development (80% of all observations) and validation data sets, and initial screening was conducted using the development data set. Five nonlinear models and 3 linear models (candidate models) were identified and used in further model evaluation. Cross-validation studies (n = 20) with the validation data set were conducted by linear regression of DFI with predicted DFI as independent variable. Candidate models were subsequently evaluated with data from 12 published studies in 2 analyses. The exponential model that best predicted daily DFI in Holstein calves in original and external data sets was DFI (kg/d) = 1.3207 × e[(-5.3892 + 0.6376 × MEgap) × EXP(-0.0392 × Age)] - 0.0013 × Temp + 0.0032 × NDFDM + 0.0026 × Age × MEgap - 0.3646 × PctForage [coefficient of determination (R2) = 0.92, concordance correlation coefficient (CCC) = 0.96, and mean square error of prediction (MSEP) = 0.10 kg]; where MEgap (Mcal/d) = difference of daily metabolizable energy (ME) requirement and ME intake from milk replacer; Age = age of calf (d) from 3 to 114, Temp = mean daily ambient temperature (°C), NDFDM = ration neutral detergent fiber (% DM); PctForage = percent forage in ration DM. The linear model that best predicted DFI was DFI (kg/d = -0.1349 + 0.0106 × Age + 0.1808 × MEgap + 0.0013 × Age × MEgap + 0.0001 × Temp + 0.00002 × Age × Temp (R2 = 0.93, CCC = 0.96, and MSEP = 0.10 kg). When Temp and ration characteristics were not included, optimal models were 1.4362 × e[(-4.6646 + 0.5234 × MEgap) × EXP(-0.0361 × Age)] + 0.0025 × Age × MEgap (R2 = 0.92, CCC = 0.96, and MSEP = 0.11 kg) and -0.1344 + 0.0102 × Age + 0.1810 × MEgap + 0.0013 × Age × MEgap [R2 = 0.93, CCC = 0.96, and MSEP = 0.10 kg]. Models of daily DFI may improve prediction of nutrient supply to young Holstein calves to approximately 4 mo of age, thereby increasing prediction of growth performance.

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.

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.

Differential effects of the mode of touch, active and passive, on experience-driven plasticity in the S1 cutaneous digit representation of adult macaque monkeys.

This study compared the receptive field (RF) properties and firing rates of neurons in the cutaneous hand representation of primary somatosensory cortex (areas 3b, 1, and 2) of 9 awake, adult macaques that were intensively trained in a texture discrimination task using active touch (fingertips scanned over the surfaces using a single voluntary movement), passive touch (surfaces displaced under the immobile fingertips), or both active and passive touch. Two control monkeys received passive exposure to the same textures in the context of a visual discrimination task. Training and recording extended over 1-2 yr per animal. All neurons had a cutaneous receptive field (RF) that included the tips of the stimulated digits (D3 and/or D4). In area 3b, RFs were largest in monkeys trained with active touch, smallest in those trained with passive touch, and intermediate in those trained with both; i.e., the mode of touch differentially modified the cortical representation of the stimulated fingers. The same trends were seen in areas 1 and 2, but the changes were not significant, possibly because a second experience-driven influence was seen in areas 1 and 2, but not in area 3b: smaller RFs with passive exposure to irrelevant tactile inputs compared with recordings from one naive hemisphere. We suggest that added feedback during active touch and higher cortical firing rates were responsible for the larger RFs with behavioral training; this influence was tempered by periods of more restricted sensory feedback during passive touch training in the active + passive monkeys.NEW & NOTEWORTHY We studied experience-dependent sensory cortical plasticity in relation to tactile discrimination of texture using active and/or passive touch. We showed that neuronal receptive fields in primary somatosensory cortex, especially area 3b, are largest in monkeys trained with active touch, smallest in those trained with passive touch, and intermediate in those trained using both modes of touch. Prolonged, irrelevant tactile input had the opposite influence in areas 1 and 2, favoring smaller receptive fields.

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.

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.

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.

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.

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.

Optogenetic Activation of the Infralimbic Cortex Suppresses the Return of Appetitive Pavlovian-Conditioned Responding Following Extinction.

The infralimbic medial prefrontal cortex (IL) is important for suppressing learned behavior after extinction, but whether this function extends to responses acquired through appetitive Pavlovian conditioning is unclear. We trained male, Long-Evans rats to associate a white-noise conditional stimulus (CS; 10 s; 14 presentations per session) with 10% liquid sucrose (0.2 mL per CS presentation), and recorded entries into the fluid port during the CS. The CS was presented without sucrose in subsequent extinction and test sessions. Increasing IL activity with pretest microinfusions of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 0, 0.3 nmol; 0.3 µl/side) reduced the reinstatement of CS-elicited port entries. The same result was obtained when IL neurons that expressed Channelrhodopsin-2 (ChR2) were optically stimulated during CS presentations at test (473 nm, 5 ms pulses at 20 Hz for 10.2 s, unilateral). Optical stimulation of ChR2-expressing IL neurons during CS presentations also reduced spontaneous recovery and context-induced renewal. Furthermore, optical stimulation (1) during intertrial intervals had no impact on renewal, (2) depolarized ChR2-expressing IL pyramidal neurons in vitro, and (3) preferentially increased Fos in ChR2-expressing neurons. These novel converging data highlight a critical role for the IL in suppressing the return of appetitive Pavlovian-conditioned responding following extinction.

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.

Context-dependent tactile texture-sensitivity in monkey M1 and S1 cortex.

Caudal primary motor cortex (M1, area 4) is sensitive to cutaneous inputs, but the extent to which the physical details of complex stimuli are encoded is not known. We investigated the sensitivity of M1 neurons (4 Macaca mulatta monkeys) to textured stimuli (smooth/rough or rough/rougher) during the performance of a texture discrimination task and, for some cells, during a no-task condition (same surfaces; no response). The recordings were made from the hemisphere contralateral to the stimulated digits; the motor response (sensory decision) was made with the nonstimulated arm. Most M1 cells were modulated during surface scanning in the task (88%), but few of these were texture-related (24%). In contrast, 44% of M1 neurons were texture related in the no-task condition. Recordings from the neighboring primary somatosensory cortex (S1), the potential source of texture-related signals to M1, showed that S1 neurons were significantly more likely to be texture related during the task (57 vs 24%) than M1. No difference was observed in the no-task condition (52 vs. 44%). In these recordings, the details about surface texture were relevant for S1 but not for M1. We suggest that tactile inputs to M1 were selectively suppressed when the animals were engaged in the task. S1 was spared these controls, as the same inputs were task-relevant. Taken together, we suggest that the suppressive effects are most likely exerted directly at the level of M1, possibly through the activation of a top-down gating mechanism specific to motor set/intention. NEW & NOTEWORTHY Sensory feedback is important for motor control, but we have little knowledge of the contribution of sensory inputs to M1 discharge during behavior. We showed that M1 neurons signal changes in tactile texture, but mainly outside the context of a texture discrimination task. Tactile inputs to M1 were selectively suppressed during the task because this input was not relevant for the recorded hemisphere, which played no role in generating the discrimination response.

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.

Physicians' perspectives of pharmacist-physician collaboration in the United Arab Emirates: Findings from an exploratory study.

Interprofessional collaborative care has been shown to improve patient outcomes. Physicians' views on collaboration with pharmacists give an insight into what contributes to a well-functioning team. Little is known about these views from low and ​middle-income countries and nothing from the United Arab Emirates (UAE). The purpose of this study is to investigate physicians' opinions on collaborative relationships with community pharmacists in the UAE. Semi-structured individual interviews and group discussions are conducted with a purposive sample of physicians. Thematic analysis based on the framework approach is used to generate themes. A total of 53 physicians participated. Three themes about collaboration emerged: perceived benefits of collaboration, facilitators of collaboration and perceived barriers to collaboration. Perceived benefits include reducing the burden on physicians, having the pharmacist as an extra safety check within the system, having the pharmacist assist patients to manage their medications: coping with side effects, reducing drug waste and costs, and attaining professional and health-system gains. Perceived facilitators included awareness and trust building, professional role definition, pharmacists' access to patient records and effective communication. Perceived barriers included patient and physician acceptance, logistic and financial issues and perceived pharmacist competence. This study has, for the first time, provided useful information to inform the future development of pharmacist-physician collaboration in the UAE and other countries with similar healthcare systems.

The impact of direct-fed microbials and enzymes on the health and performance of dairy cows with emphasis on colostrum quality and serum immunoglobulin concentrations in calves.

Thirty-six cows were blocked by calving date and randomly assigned to one of three treatments. Cows were on treatments 3 weeks prepartum through 8 weeks post-partum. Treatments were as follows: (i) no direct-fed microbial (DFM) or cellulase and amylase enzymes (C), (ii) 45.4 g/day of DFM (D) or (iii) 45.4 g/day of DFM and 18.2 g/day of enzyme (DE). Total mixed ration fed and refused were measured daily to determine dry matter intake (DMI). Blood samples were taken three times weekly and analysed for ß-hydroxybutyrate, glucose and non-esterified fatty acids. Body weight (BW) was measured weekly. Colostrum was weighed and analysed for IgA and IgG concentration. Calves were fed 4 L of colostrum within 2 hr of birth. Calf blood samples were taken at 0 and 24 hr for analysis of IgA and IgG concentrations and apparent efficiency of absorption. Milk yield was measured daily and samples collected weekly. Initial BW was different among treatments with D being lesser than C or DE treatments. Body weight, weight gain, efficiency of gain, DMI and blood parameters were unaffected. Treatment did not affect colostrum yield. Ash percentage of colostrum tended to increase with D and DE, while IgA and total solids yield decreased with D. Colostrum fat yield was decreased in D and DE. Treatments did not impact BW, serum IgA and IgG concentrations or apparent efficiency of absorption of calves. Post-partum BW, DMI, blood parameters, milk production and composition were unaffected by treatment. However, cows on D gained more BW and tended to have greater efficiency of gain compared to those on DE, but were similar to C. Somatic cell scores were greatest for D. Results indicate that DFM and enzyme supplementation did not improve health and performance of dairy cattle during the pre- and post-partum periods under conditions of this study.