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Abstract Image-based prediction models for disease detection are sensitive to changes in data acquisition such as the replacement of scanner hardware or updates to the image processing software. The resulting differences in image characteristics may lead to drifts in clinically relevant performance metrics which could cause harm in clinical decision making, even for models that generalise in terms of area under the receiver-operating characteristic curve. We propose Unsupervised Prediction Alignment, a generic automatic recalibration method that requires no ground truth annotations and only limited amounts of unlabelled example images from the shifted data distribution. We illustrate the effectiveness of the proposed method to detect and correct performance drift in mammography-based breast cancer screening and on publicly available histopathology data. We show that the proposed method can preserve the expected performance in terms of sensitivity/specificity under various realistic scenarios of image acquisition shift, thus offering an important safeguard for clinical deployment.

Abstract Background Double reading (DR) in screening mammography increases cancer detection and lowers recall rates, but has sustainability challenges due to workforce shortages. Artificial intelligence (AI) as an independent reader (IR) in DR may provide a cost-effective solution with the potential to improve screening performance. Evidence for AI to generalise across different patient populations, screening programmes and equipment vendors, however, is still lacking. Methods This retrospective study simulated DR with AI as an IR, using data representative of real-world deployments (275,900 cases, 177,882 participants) from four mammography equipment vendors, seven screening sites, and two countries. Non-inferiority and superiority were assessed for relevant screening metrics. Results DR with AI, compared with human DR, showed at least non-inferior recall rate, cancer detection rate, sensitivity, specificity and positive predictive value (PPV) for each mammography vendor and site, and superior recall rate, specificity, and PPV for some. The simulation indicates that using AI would have increased arbitration rate (3.3% to 12.3%), but could have reduced human workload by 30.0% to 44.8%. Conclusions AI has potential as an IR in the DR workflow across different screening programmes, mammography equipment and geographies, substantially reducing human reader workload while maintaining or improving standard of care. Trial registration ISRCTN18056078 (20/03/2019; retrospectively registered).

Abstract Invasive plants are a major problem for land managers and have widespread and lasting environmental impacts. The invasive shrub Amur honeysuckle (Lonicera maackii) is a pervasive and noxious plant in the Midwest region of the United States. Despite this, many land managers may be uncomfortable with herbicide control of this and other invasive plants due to unknown impacts on ecosystem components including soils. To examine if herbicide control of Amur honeysuckle impacts soil enzyme activity and soil communities, we treated Amur honeysuckle with Garlon® 4 (triclopyr) suspended in Basal Bark Oil, Basal Bark Oil alone and untreated controls, then assessed soil community, soil enzyme activity and arbuscular mycorrhizal density changes among treatments and across the subsequent growing season. We found that basal bark herbicide treatments of Amur honeysuckle do not negatively impact soil enzyme activity, nor do they impact fungal, prokaryotic or oomycotan diversity or community structure. There was a slight but likely ecologically unimportant effect on community structure associated with basal bark oil applications, but not with herbicide applications. Arbuscular mycorrhizal colonization was negatively affected by herbicide use but this is likely due to reduction in host health and/or mortality. Taken together, this suggests that herbicide control of Amur honeysuckle does not impact soils and land managers can treat these invasive plants without concern for negative soil outcomes.

Trauma and emergency care is a national priority in Uganda due to the high burden of injury, impacting a primarily young and rural population. With a significant gap in qualified emergency medicine professionals, a need exists to rapidly upskill the current health workforce and to strengthen access to learning for non-specialist emergency care providers nationally. This review was completed in partnership with the Ugandan Ministry of Health and a consortium of UK partners to support national emergency workforce capacity building in Uganda and East Africa. The review built on policy and practice expertise to explore the feasibility of using emerging digital solutions, such as virtual and augmented reality, to meet the challenges of delivering rapid and equitable access to emergency care training at scale. Data collection included a narrative literature review, key informant interviews, an expert focus group, a technical workshop and field observations. Findings included (1) the identification of local technology expertise and experience, in direct contrast to literature and global perceptions of low-resource environments, (2) high and broad levels of national engagement with digital solutions, (3) existing ambition and infrastructure available to feasibly deliver training at scale and (4) delivery implications for comparable contexts. The review concludes that these emerging technologies should be considered a practical option in the design and delivery of health workforce training at scale. A series of recommendations are proposed for the policy and practice of health professional education and training in Uganda and for comparable contexts., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Alternative funding programs (AFPs) seek to reduce health plan sponsor costs, for example by excluding specialty drugs from a beneficiary's plan coverage and requiring patients to obtain medications through alternative sources (typically, the manufacturer's patient assistance programs) via an AFP vendor as a third-party., Objective: To describe patients' experiences and specialty medication access with AFPs., Methods: A survey method consisting of 26 optional single-choice and multiple-choice questions with branching logic divided across 5 sections (related to patient challenges with AFPs) was administered to patients recruited from an experienced AFP online patient panel and a patient advocacy group. The survey assessed patients' awareness of AFPs from their employers, experience with the patient assistance program application process via the AFP vendor, timeliness of medication access (if granted), and/or the health impact of delay in access. All descriptive and exploratory subgroup analyses were conducted by disease area and reported income levels; statistical analyses were carried out for the exploratory analyses., Results: The final sample included 227 patients. Most patients (61% [136/223]) first heard of the AFP as part of their health benefit when trying to obtain their medication. Of 198 patients, 88% reported being stressed because of the medication coverage denial and the uncertainty of obtaining their medication. More than half of patients (54% [115/213]) reported being uncomfortable with the benefits manager from the AFP vendor. On average, patients reported waiting to receive their medication for 68.2 days (approximately 2 months); 24% (51/215) reported the wait for the medication worsened their condition and 64% (138/215) reported the wait led to stress and/or anxiety. Patients who indicated the wait time negatively affected them had considered a job change or left their job at a 3-5-fold higher rate than those who reported no impact from wait time. A significantly higher proportion of patients with hemophilia and other bleeding disorders reported receiving their prescribed medication less often than patients with other conditions (63% [19/30] vs 81% [52/64]; P = 0.022), whereas more patients with lower incomes (<$50,000 vs >$50,000) reported not receiving any medication (12% [7/57] vs 5% [7/129]; P = 0.657), although these differences were not significant., Conclusions: Most patients who obtain their specialty medicines via AFPs reported being uncomfortable with the process and experiencing treatment delays, which may have been linked to disease progression, worsened mental well-being, and consideration of a job change. Employers should be aware of the potential downstream impacts on employee health, retention, and the employee-employer relationship when considering implementing an AFP into their health plan.

Reducing preventable readmissions is important to help manage current strains on healthcare systems. The metric of 30-day readmissions is commonly cited in discussions regarding this topic. While such thresholds have contemporary funding implications, the rationale for individual cut-off points is partially historical in nature. Through the examination of the basis for the analysis of 30-day readmissions, greater insight into the possible benefits and limitations of such a metric may be obtained., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

This paper examines the impact of a key source of wealth (the stock market) on road traffic collisions. Using data on over 2 million road accidents we do not find a linear relationship between stock prices and road crashes (fatal or otherwise) in Great Britain. However, we do find a V-shaped effect - collisions respond to the absolute change in stock market returns. The results are robust to a series of falsification exercises that potentially support a causal interpretation. We also examine another source of wealth that has not previously been examined - house prices. Similarly, we do not find that changes in monthly house prices have an impact on accidents, but a symmetric V-shaped is also shown for slight and serious accidents., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Ultrasound-guided intervention is an essential skill for many radiologists and critical for accurate diagnosis and treatment in many radiology subspecialties. Simulation using phantoms have demonstrated statistically significant benefits for trainees within the literature. We propose a novel phantom model which the authors feel is ideal for training clinical radiology trainees in the performance of ultrasound-guided procedures., Methods: The recipe to prepare a homemade phantom is described. Results of a local survey from trainees preparing and using the phantom are also presented., Results: This realistic training simulation model can be adapted to suit a variety of biopsy devices and procedures including soft tissue biopsy and cyst aspiration. The phantom mimics the sonographic appearances of soft tissue and biopsy targets can be concealed within. The phantom was easily prepared by 22 trainees (Likert score 4.5) and it functioned well (Likert score of 4.7)., Conclusion: In summary, our phantom model is ideal for training clinical radiology trainees in the performance of ultrasound-guided core biopsy. The availability and low cost of the model, combined with the ease of preparation and reproducibility, make this an efficient and effective addition to the training process., Advances in Knowledge: A low cost easily handmade phantom recipe is described that could be easily implemented in training schemes.

A multichannel microfluidic platform for real-time monitoring of epithelial barrier integrity by electrical impedance has been developed. Growth and polarization of human epithelial cells from the airway or gastrointestinal tract was continuously monitored over 5 days in 8 parallel, individually perfused microfluidic chips. Electrical impedance data were continuously recorded to monitor cell barrier formation using a low-cost bespoke impedance analyser. Data was analysed using an electric circuit model to extract the equivalent transepithelial electrical resistance and epithelial cell layer capacitance. The cell barrier integrity steadily increased overtime, achieving an average resistance of 418 ± 121 Ω cm 2 (airway cells) or 207 ± 59 Ω cm 2 (gastrointestinal cells) by day 5. The utility of the polarized airway epithelial barrier was demonstrated using a 24 hour challenge with double stranded RNA to mimic viral infection. This caused a rapid decrease in barrier integrity in association with disruption of tight junctions, whereas simultaneous treatment with a corticosteroid reduced this effect. The platform is able to measure barrier integrity in real-time and is scalable, thus has the potential to be used for drug development and testing.

Objective: Contrast-enhanced spectral mammography (CESM) breast biopsy has been recently introduced into clinical practice. This short communication describes the technique and potential as an alternative to MRI-guided biopsy., Methods and Materials: An additional abnormality was detected on a breast MRI examination in a patient with lobular carcinoma. The lesion was occult on conventional mammography, tomosynthesis and ultrasound and required histological diagnosis. Traditionally, this would have necessitated an MRI-guided breast biopsy, but was performed under CESM guidance., Results: A diagnostic CESM study was performed to ensure the lesion visibility with CESM and then targeted under CESM guidance. A limited diagnostic study, CESM scout and paired images for stereotactic targeting were obtained within a 10 min window following a single injection of iodinated contrast agent. The time from positioning in the biopsy device to releasing compression after biopsy and marker clip placement was 15 min. The biopsy confirmed the presence of multifocal breast cancer., Conclusion: CESM-guided breast biopsy is a new technique that can be successfully used as an alternative to MRI-guided breast biopsy., Advances in Knowledge: CESM-guided biopsy can be used to sample breast lesions which remain occult on standard mammography and ultrasound.

Objectives: This study examined the relationship between maternal exposure to stress during pregnancy and children's food preferences and diet in a population of low socioeconomic status., Methods: Indices of exposure to stress were constructed based on retrospective self-reported experience of stressful events during pregnancy (e.g., death of close family member, relationship difficulties, legal issues, health issues, financial issues, or other potentially stressful event[s]). Data were collected for >200 mothers of a low socioeconomic status with a child age 2 to 12 y. Data on mothers' body mass index, current exposure to stress, current diet, and diet during pregnancy were collected at the same time, as well as data on children's food preferences and current diet as reported by the mothers. Indices of the healthiness of food preferences and diet were constructed and used as outcome variables., Results: Maternal exposure to stress during pregnancy significantly predicts children's food and taste preferences, as well as their diet, in regression models controlling for maternal diet, current maternal stress, and demographic characteristics of both the child and mother. Higher average stress during pregnancy is linked with significantly less healthy food preferences and diet, as well as with weaker preferences for sour and bitter foods. This relationship is observed across different age groups., Conclusions: Maternal exposure to stress during pregnancy could have long-term detrimental effects on dietary outcomes and thereby on health conditions related to diet. Prenatal care and preconception counseling could be critical to develop preventive strategies to improve public health., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Well differentiated liposarcoma (WD-LPS) is a relatively rare tumour, with fewer than 50 cases occurring per year in the UK. These tumours are both chemotherapy- and radiotherapy-resistant and present a significant treatment challenge requiring radical surgery. Little is known of the molecular landscape of these tumours and no current targets for molecular therapy exist. We aimed to carry out a comprehensive molecular characterisation of WD-LPS via whole genome sequencing, RNA sequencing, and methylation array analysis. A recurrent mutation within exon 1 of FOXD4L3 was observed (chr9:70,918,189A>T; c.322A>T; p.Lys108Ter). Recurrent mutations were also observed in Wnt signalling, immunity, DNA repair, and hypoxia-associated genes. Recurrent amplification of HGMA2 was observed, although this was in fact part of a general amplification of the region around this gene. Recurrent gene fusions in HGMA2, SDHA, TSPAN31, and MDM2 were also observed as well as consistent rearrangements between chromosome 6 and chromosome 12. Our study has demonstrated a recurrent mutation within FOXD4L3, which shows evidence of interaction with the PAX pathway to promote tumourigenesis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland., (© 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.)

Reducing drink drive limits is generally regarded an effective strategy to save lives on the road. Using several new administrative data sources, we evaluate the effect of a stricter limit introduced in Scotland in 2014. This reduction had no effect on drink driving and road collisions. Estimates from a supply-of-offenses function suggests that the reform did not have much ex-ante scope for sizeable effects. The unavailability of cheaper alternative means of transportation and weak law enforcement seem to have been the main channels behind the lack of an impact. We find no externality on a wide range of domains, from alcohol consumption to criminal activities other than drink driving., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Pathological complete response (pathCR) in rectal cancer is beneficial, as up to 75% of patients do not experience regrowth of the primary tumour, but it is poorly understood. We hypothesised that the changes seen in the pre-treatment biopsies of pathCR but not seen in residual tumour after chemoradiotherapy were the determinants of responsiveness., Methods: Two groups of patients with either complete response (pathCR group, N = 24) or no response (poor response group, N = 24) were retrieved. Pre-treatment biopsies of cancers from these patients underwent high read depth amplicon sequencing for a targeted panel, exome sequencing, methylation profiling and immunohistochemistry for DNA repair pathway proteins., Results: Twenty four patients who underwent pathCR and twenty-four who underwent poor response underwent molecular characterisation. Patients in the pathCR group had significantly higher tumour mutational burden and neoantigen load, frequent copy number alterations but fewer structural variants and enrichment for driver mutations in the PI3K/AKT/mTOR signalling pathway. There were no significant differences in tumour heterogeneity as measured by MATH score. Methylation analysis demonstrated enrichment for hypomethyation in the PI3K/AKT/mTOR signalling pathway., Discussion: The phenomenon of pathCR in rectal cancer may be related to immunovisibility caused by a high tumour mutational burden phenotype. Potential therapy resistance mechanisms involve the PI3K/AKT/mTOR signalling pathway, but tumour heterogeneity does not seem to play a role in resistance., (© 2021. The Author(s).)

Background: Researchers and developers are evaluating the use of mammogram readers that use artificial intelligence (AI) in clinical settings., Objectives: This study examines the attitudes of women, both current and future users of breast screening, towards the use of AI in mammogram reading., Methods: We used a cross-sectional, mixed methods study design with data from the survey responses and focus groups. We researched in four National Health Service hospitals in England. There we approached female workers over the age of 18 years and their immediate friends and family. We collected 4096 responses., Results: Through descriptive statistical analysis, we learnt that women of screening age (≥50 years) were less likely than women under screening age to use technology apps for healthcare advice (likelihood ratio=0.85, 95% CI 0.82 to 0.89, p<0.001). They were also less likely than women under screening age to agree that AI can have a positive effect on society (likelihood ratio=0.89, 95% CI 0.84 to 0.95, p<0.001). However, they were more likely to feel positive about AI used to read mammograms (likelihood ratio=1.09, 95% CI 1.02 to 1.17, p=0.009)., Discussion and Conclusions: Women of screening age are ready to accept the use of AI in breast screening but are less likely to use other AI-based health applications. A large number of women are undecided, or had mixed views, about the use of AI generally and they remain to be convinced that it can be trusted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Clinical-grade whole-genome sequencing (cWGS) has the potential to become the standard of care within the clinic because of its breadth of coverage and lack of bias towards certain regions of the genome. Colorectal cancer presents a difficult treatment paradigm, with over 40% of patients presenting at diagnosis with metastatic disease. We hypothesised that cWGS coupled with 3' transcriptome analysis would give new insights into colorectal cancer., Methods: Patients underwent PCR-free whole-genome sequencing and alignment and variant calling using a standardised pipeline to output SNVs, indels, SVs and CNAs. Additional insights into the mutational signatures and tumour biology were gained by the use of 3' RNA-seq., Results: Fifty-four patients were studied in total. Driver analysis identified the Wnt pathway gene APC as the only consistently mutated driver in colorectal cancer. Alterations in the PI3K/mTOR pathways were seen as previously observed in CRC. Multiple private CNAs, SVs and gene fusions were unique to individual tumours. Approximately 30% of patients had a tumour mutational burden of > 10 mutations/Mb of DNA, suggesting suitability for immunotherapy., Conclusions: Clinical whole-genome sequencing offers a potential avenue for the identification of private genomic variation that may confer sensitivity to targeted agents and offer patients new options for targeted therapies.

This paper evaluates a method of generating a unique dataset that has been underused-a Freedom of Information (FOI) request. The UK's FOI Act came into force in 2005, allowing the public to make requests of publicly held data. We set out to understand the determinants of the quality responses to FOI requests. We also explain how requests can be made and provide suggestions to construct effective data-driven requests. We applied for data on hate crime from all police forces and on uptake of maternity leave from all universities. We find that observable characteristics of the local area, police force and universities neither determine whether the request was fulfilled, nor the speed of response, suggesting that the data from these FOI requests are representative of the institutions from which they were requested., Competing Interests: The authors have declared that no competing interests exist.

The primary objective of this study was to describe and compare the modus operandi, and associated contextual and situational factors, of French serial sexual murderers (SSMs) and nonserial sexual murderers (NSMs). A further objective was to verify the generalizability of the conclusions of James and Proulx's 2016 systematic review of the modus operandi of sexual murderers, the majority of whom were American or English. Detailed data on the precrime, modus operandi, postcrime, and victimology factors of 120 French sexual murderers (SSMs: n = 33; NSMs: n = 87) were compared. The results suggest that choice-structuring properties that shape the modus operandi of French sexual murderers are similar to those reported by James and Proulx: The modus operandi of French SSMs was shaped by homicidal, sadistic, and rape fantasies, while that of NSMs was shaped by the need to satisfy immediate, especially sexual, needs. However, it should be noted that while the modus operandi of American and English NSMs is primarily shaped by general deviance, that of French NSMs appear be primarily shaped by sexual deviance.

Sexual homicide typically implies a crime involving two people: perpetrator and victim. Thus, multiple-perpetrator and multiple concurrent victim sexual murderers are unusual, empirically invisible due to their exclusion from (or burying within) research samples. The present study examines 21 such cases of male sexual murderers having perpetrated at least one sexual homicide either together with a co-offender or alone but killing two victims at once. The aim was to investigate just how unusual, or not, these cases may be in relation to current scientific understanding of sexual murderers and their crimes. A descriptive analysis of offenses (co-offender and offender-victim dynamics, modus operandi) and offender characteristics is presented. Main findings, that multiple-perpetrator and multiple concurrent victim sexual murderers are not so unusual in that they are well conceptualized through application of the established sexualized, grievance, and rape murderer typology, are discussed in relation to clinical and empirical implications.

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are first-line antidepressants but require several weeks to elicit their actions. Chronic SSRI treatment induces desensitization of 5-HT1A autoreceptors to enhance 5-HT neurotransmission. Mice (both sexes) with gene deletion of 5-HT1A autoreceptors in adult 5-HT neurons ( 1AcKO ) were tested for response to SSRIs. Tamoxifen-induced recombination in adult 1AcKO mice specifically reduced 5-HT1A autoreceptor levels. The 1AcKO mice showed a loss of 5-HT1A autoreceptor-mediated hypothermia and electrophysiological responses, but no changes in anxiety- or depression-like behavior. Subchronic fluoxetine (FLX) treatment induced an unexpected anxiogenic effect in 1AcKO mice in the novelty suppressed feeding and elevated plus maze tests, as did escitalopram in the novelty suppressed feeding test. No effect was seen in wild-type ( WT ) mice. Subchronic FLX increased 5-HT metabolism in prefrontal cortex, hippocampus, and raphe of 1AcKO but not WT mice, suggesting hyperactivation of 5-HT release. To detect chronic cellular activation, FosB + cells were quantified. FosB + cells were reduced in entorhinal cortex and hippocampus (CA2/3) and increased in dorsal raphe 5-HT cells of 1AcKO mice, suggesting increased raphe activation. In WT but not 1AcKO mice, FLX reduced FosB + cells in the median raphe, hippocampus, entorhinal cortex, and median septum, which receive rich 5-HT projections. Thus, in the absence of 5-HT1A autoreceptors, SSRIs induce a paradoxical anxiogenic response. This may involve imbalance in activation of dorsal and median raphe to regulate septohippocampal or fimbria-fornix pathways. These results suggest that markedly reduced 5-HT1A autoreceptors may provide a marker for aberrant response to SSRI treatment. SIGNIFICANCE STATEMENT Serotonin-selective reuptake inhibitors (SSRIs) are effective in treating anxiety and depression in humans and mouse models. However, in some cases, SSRIs can increase anxiety, but the mechanisms involved are unclear. Here we show that, rather than enhancing SSRI benefits, adulthood knockout (KO) of the 5-HT1A autoreceptor, a critical negative regulator of 5-HT activity, results in an SSRI-induced anxiety effect that appears to involve a hyperactivation of the 5-HT system in certain brain areas. Thus, subjects with very low levels of 5-HT1A autoreceptors, such as during childhood or adolescence, may be at risk for an SSRI-induced anxiety response., (Copyright © 2019 the authors 0270-6474/19/391334-13$15.00/0.)

Objective: To develop and evaluate a low-cost computer-based tool to elicit dietary choices in an incentive compatible manner, which can be used on-line or as part of a laboratory study., Methods: The study was conducted with around 255 adults. Respondents were asked to allocate a fixed monetary budget across a choice of around a hundred grocery items with the prospect of receiving these items with some probability delivered to their home by a real supermarket. The tool covers a broad range of food items, allows inference of macro-nutrients and calories, and allows the researcher to fix the choice set participants can choose from. We compare the information derived from our incentivized tool, and compare it to alternative low-cost ways of measuring dietary intake, namely the food frequency questionnaire and a one-shot version of the 24-hour dietary recall, which are both based on self-reports. We compare the calorie intake indicators derived from each tool with a number of biometric measures for each subject, namely weight, body-mass-index (BMI) and waist size., Results: The results show that the dietary information collected is only weakly correlated across the three methods. We find that only the calorie intake measure from our incentivized tool is positively and significantly related to each of the biometric indicators. Specifically, a 10% increase in calorie intake is associated with a 1.5% increase in BMI. By contrast, we find no significant correlations for either of the two measures based on self-reports., Conclusion: The computer-based tool is a promising new, low-cost measure of dietary choices, particularly in one-shot situations where such behaviours are only observed once, whereas other tools like 24-hour dietary recalls and food frequency questionnaires may be more suited when they are administered repeatedly. The tool may be useful for research conducted with limited time and budget., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: Ulcerative colitis (UC) is associated with a higher background risk of dysplasia and/or neoplasia due to chronic inflammation. There exist few biomarkers for identification of patients with dysplasia, and targeted biopsies in this group of patients are inaccurate in reliably identifying dysplasia. We aimed to examine the epigenome of UC dysplasia and to identify and validate potential biomarkers., Methods: Colonic samples from patients with UC-associated dysplasia or neoplasia underwent epigenome-wide analysis on the Illumina 450K methylation array. Markers were validated by bisulphite pyrosequencing on a secondary validation cohort and accuracy calculated using logistic regression and receiver-operator curves., Results: Twelve samples from 4 patients underwent methylation array analysis and 6 markers (GNG7, VAV3, KIF5C, PIK3R5, TUBB6, and ZNF583) were taken forward for secondary validation on a cohort of 71 colonic biopsy samples consisting of normal uninflamed mucosa from control patients, acute and chronic colitis, "field" mucosa in patients with dysplasia/neoplasia, dysplasia, and neoplasia. Methylation in the beta-tubulin TUBB6 correlated with the presence of dysplasia (P < 0.0001) and accurately discriminated between dysplasia and nondysplastic tissue, even in the apparently normal field mucosa downstream from dysplastic lesions (AUC 0.84, 95% CI 0.81-0.87)., Conclusions: Methylation in TUBB6 is a potential biomarker for UC- associated dysplasia. Further validation is needed and is ongoing as part of the ENDCAP-C study.

The 5-HT1A autoreceptor mediates feedback inhibition of serotonin (5-HT) neurons, and is implicated in major depression. The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription. Since chronic stress alters HTR1A methylation and expression, we addressed whether recruitment of methyl-binding protein MeCP2 may alter Deaf1 regulation at the HTR1A locus. We show that MeCP2 enhances Deaf1 binding to its HTR1A site and co-immunoprecipitates with Deaf1 in cells and brain tissue. Chromatin immunoprecipitation assays showed Deaf1-dependent recruitment of MeCP2 to the mouse HTR1A promoter, and MeCP2 modulated human and mouse HTR1A gene transcription in a Deaf1-dependent fashion, enhancing Deaf1-induced repression at the Deaf1 site. To address the role of MeCP2 in HTR1A regulation in vivo, mice with conditional knockout of MeCP2 in adult 5-HT neurons (MeCP2 cKO) were generated. These mice exhibited increased 5-HT1A autoreceptor levels and function, consistent with MeCP2 enhancement of Deaf1 repression in 5-HT neurons. Interestingly, female MeCP2-cKO mice displayed reduced anxiety, while males showed increased anxiety and reduced depression-like behaviors. These data uncover a novel role for MeCP2 in 5-HT neurons to repress HTR1A expression and drive adult anxiety- and depression-like behaviors in a sex-specific manner.

Freud-1/Cc2d1a represses the gene transcription of serotonin-1A (5-HT1A) autoreceptors, which negatively regulate 5-HT tone. To test the role of Freud-1 in vivo , we generated mice with adulthood conditional knock-out of Freud-1 in 5-HT neurons ( cF1ko ). In cF1ko mice, 5-HT1A autoreceptor protein, binding and hypothermia response were increased, with reduced 5-HT content and neuronal activity in the dorsal raphe. The cF1ko mice displayed increased anxiety- and depression-like behavior that was resistant to chronic antidepressant (fluoxetine) treatment. Using conditional Freud-1/5-HT1A double knock-out ( cF1/1A dko ) to disrupt both Freud-1 and 5-HT1A genes in 5-HT neurons, no increase in anxiety- or depression-like behavior was seen upon knock-out of Freud-1 on the 5-HT1A autoreceptor-negative background; rather, a reduction in depression-like behavior emerged. These studies implicate transcriptional dysregulation of 5-HT1A autoreceptors by the repressor Freud-1 in anxiety and depression and provide a clinically relevant genetic model of antidepressant resistance. Targeting specific transcription factors, such as Freud-1, to restore transcriptional balance may augment response to antidepressant treatment. SIGNIFICANCE STATEMENT Altered regulation of the 5-HT1A autoreceptor has been implicated in human anxiety, major depression, suicide, and resistance to antidepressants. This study uniquely identifies a single transcription factor, Freud-1, as crucial for 5-HT1A autoreceptor expression in vivo Disruption of Freud-1 in serotonin neurons in mice links upregulation of 5-HT1A autoreceptors to anxiety/depression-like behavior and provides a new model of antidepressant resistance. Treatment strategies to reestablish transcriptional regulation of 5-HT1A autoreceptors could provide a more robust and sustained antidepressant response., (Copyright © 2017 the authors 0270-6474/17/3711967-12$15.00/0.)

We conduct a field experiment in 31 primary schools in England to test the effectiveness of different temporary incentives on increasing choice and consumption of fruit and vegetables at lunchtime. In each treatment, pupils received a sticker for choosing a fruit or vegetable at lunch. They were eligible for an additional reward at the end of the week depending on the number of stickers accumulated, either individually (individual scheme) or in comparison to others (competition). Overall, we find no significant effect of the individual scheme, but positive effects of competition. For children who had margin to increase their consumption, competition increases choice of fruit and vegetables by 33% and consumption by 48%. These positive effects generally carry over to the week immediately following the treatment, but are not sustained effects six months later. We also find large differences in effectiveness across demographic characteristics such as age and gender., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Community-based studies of patellofemoral pain (PFP) need a questionnaire tool that discriminates between those with and those without the condition. To overcome these issues, we have designed a self-report questionnaire which aims to identify people with PFP in the community., Study Designs: comparative study and cross-sectional study., Study Population: comparative study: PFP patients, soft-tissue injury patients and adults without knee problems. Cross-sectional study: adults attending a science festival., Intervention: comparative study participants completed the questionnaire at baseline and two weeks later. Cross-sectional study participants completed the questionnaire once. The optimal scoring system and threshold was explored using receiver operating characteristic curves, test-retest reliability using Cohen's kappa and measurement error using Bland-Altman plots and standard error of measurement. Known-group validity was explored by comparing PFP prevalence between genders and age groups., Results: Eighty-four participants were recruited to the comparative study. The receiver operating characteristic curves suggested limiting the questionnaire to the clinical features and knee pain map sections (AUC 0.97 95 % CI 0.94 to 1.00). This combination had high sensitivity and specificity (over 90 %). Measurement error was less than the mean difference between the groups. Test-retest reliability estimates suggest good agreement (N = 51, k = 0.74, 95 % CI 0.52-0.91). The cross-sectional study (N = 110) showed expected differences between genders and age groups but these were not statistically significant., Conclusion: A shortened version of the questionnaire, based on clinical features and a knee pain map, has good measurement properties. Further work is needed to validate the questionnaire in community samples.

Background: Formalin fixation, duration of tissue storage and tissue enrichment techniques can affect DNA methylation yield but these effects have not been quantitatively measured. The aim is to investigate the relative impact of these conditions on DNA methylation in rectal cancer., Methods: 10 rectal cancers with matched undissected fresh frozen tissues, laser capture microdissected (LCM) formalin-fixed paraffin-embedded (FFPE) tissues, manual macrodissected FFPE tissues, adjacent normal mucosa and stromal tissues were analysed for APC and LINE-1 methylation using bisulphite pyrosequencing., Results: FFPE cancer tissues, which had been stored for at least 4 years showed similar APC and LINE-1 methylation changes to matched fresh frozen cancer tissues. Laser capture microdissection did not increase the degree of methylation detected compared to manual macrodissection. Analysis of stromal tissues showed that they had undergone significant methylation changes compared to adjacent macroscopically normal mucosa, but not to the same extent as cancer tissues., Conclusion: Reliable DNA methylation results can be obtained from FFPE rectal cancer tissues, which have been in long-term storage. Because only minor differences in methylation between macrodissected and LCM cancer tissues were found, our results do not support the routine use of LCM to enrich for cancer cells for DNA methylation studies., (© 2013.)

Aim: Current guidelines recommend that mucocele-like lesions (MLL) of the breast diagnosed on needle core biopsy (NCB) should be categorized as a lesion of uncertain malignant potential (B3). However, data on the outcome of MLL diagnosed on NCB remains limited due to the rarity of this lesion. The aim of this study was to assess the outcome of pure MLL without atypia diagnosed on NCB using a large series of cases and a review of the literature to provide evidence that can guide management., Methods and Results: Patients who underwent diagnostic excision biopsy after a core biopsy diagnosis of MLL without atypia were identified from several centres. Two of 54 patients (4%) with MLL without atypia on core biopsy had ductal carcinoma in situ in the subsequent excision specimen. This is similar to the rate in previous studies of 4% (four of 106). If there is atypia in the core biopsy, previous studies found that the frequency of malignancy is much higher at 21% (seven of 33)., Conclusions: Our results provide evidence that pure MLL without atypia diagnosed on NCB is usually associated with a benign outcome., (© 2013 Blackwell Publishing Ltd.)

This paper provides field evidence on the effects of diet on educational outcomes, exploiting a campaign lead in the UK in 2004, which introduced drastic changes in the meals offered in the schools of one borough - Greenwich - shifting from low-budget processed meals towards healthier options. We evaluate the effect of the campaign on educational outcomes in primary schools using a difference in differences approach; comparing educational outcomes in primary schools (Key Stage 2 outcomes more specifically) before and after the reform, using the neighbouring Local Education Authorities as a control group. We find evidence that educational outcomes did improve significantly in English and Science. We also find that authorized absences - which are most likely linked to illness and health - fell by 14%., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The mechanisms underlying Golgi targeting and vesiculation are unknown, although the responsible phosphatidylinositol 4-phosphate (PtdIns(4)P) ligand and four-phosphate-adaptor protein (FAPP) modules have been defined. The micelle-bound structure of the FAPP1 pleckstrin homology domain reveals how its prominent wedge independently tubulates Golgi membranes by leaflet penetration. Mutations compromising the exposed hydrophobicity of full-length FAPP2 abolish lipid monolayer binding and compression. The trafficking process begins with an electrostatic approach, phosphoinositide sampling and perpendicular penetration. Extensive protein contacts with PtdIns(4)P and neighbouring phospholipids reshape the bilayer and initiate tubulation through a conserved wedge with features shared by diverse protein modules.

Background: The sensitivity of screening mammography for the detection of small breast cancers is higher when the mammogram is read by two readers rather than by a single reader. We conducted a trial to determine whether the performance of a single reader using a computer-aided detection system would match the performance achieved by two readers., Methods: The trial was designed as an equivalence trial, with matched-pair comparisons between the cancer-detection rates achieved by single reading with computer-aided detection and those achieved by double reading. We randomly assigned 31,057 women undergoing routine screening by film mammography at three centers in England to double reading, single reading with computer-aided detection, or both double reading and single reading with computer-aided detection, at a ratio of 1:1:28. The primary outcome measures were the proportion of cancers detected according to regimen and the recall rates within the group receiving both reading regimens., Results: The proportion of cancers detected was 199 of 227 (87.7%) for double reading and 198 of 227 (87.2%) for single reading with computer-aided detection (P=0.89). The overall recall rates were 3.4% for double reading and 3.9% for single reading with computer-aided detection; the difference between the rates was small but significant (P<0.001). The estimated sensitivity, specificity, and positive predictive value for single reading with computer-aided detection were 87.2%, 96.9%, and 18.0%, respectively. The corresponding values for double reading were 87.7%, 97.4%, and 21.1%. There were no significant differences between the pathological attributes of tumors detected by single reading with computer-aided detection alone and those of tumors detected by double reading alone., Conclusions: Single reading with computer-aided detection could be an alternative to double reading and could improve the rate of detection of cancer from screening mammograms read by a single reader. (ClinicalTrials.gov number, NCT00450359.), (2008 Massachusetts Medical Society)

This study investigated the suitability of juvenile three-spined sticklebacks, Gasterosteus aculeatus L., for detecting both androgen- and oestrogen-induced endocrine disruption. The investigated endpoints were kidney hypertrophy and the induction of the protein markers spiggin and vitellogenin. Juveniles were exposed to steroid hormones 17 beta-oestradiol (E2: nominal 0.01, 1.0 and 10 microg/L), 17 alpha-ethinylestradiol (EE2: nominal 0.05 microg/L) and 17 alpha-methyltestosterone (MT: nominal 1.0 microg/L) from the day of hatching until the termination of the experiments between 39 and 58 days after hatching. E2 (10 microg/L) and MT were applied during different time windows: (a) 14 days after hatching only and (b) continuously with start 14 days after hatching. Kidney hypertrophy is an androgen-dependent secondary sexual character in adult male sticklebacks and corresponds to the production of the glue protein spiggin during the breeding season. The kidneys were hypertrophied and spiggin levels were elevated in juvenile sticklebacks after treatment with MT. Paradoxically, slightly elevated spiggin levels and kidney hypertrophy were observed also in fish treated with high dose E2. Levels of vitellogenin, the oestrogen-inducible yolk precursor protein, were elevated in juvenile sticklebacks after E2 medium and high dose and EE2 treatment. The tested endpoints are suitable for the study of endocrine disruption in juvenile sticklebacks, a fish species that is easy to handle in laboratory and relevant for temperate geographical regions.