Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

"There should be one spot that you can go:" BRCA mutation carriers' perspectives on cancer risk management and a hereditary cancer registry.

Individuals who carry BRCA1 or BRCA2 pathogenic variants are recommended to have extensive cancer prevention screening and risk-reducing surgeries. Uptake of these recommendations is variable, and there remains room for improvement in the risk management of BRCA carriers. This paper explores female BRCA carriers' experiences with the current model of care and their perspectives on (and interest in) an inherited cancer registry. Findings can inform the development of a dedicated high-risk screening and management program for these patients. Quantitative and qualitative data were gathered through a provincial descriptive survey and semi-structured qualitative interviews to assess BRCA carriers' opinions toward risk management services in the province of Newfoundland and Labrador (NL), Canada. Survey (n = 69) and interview data (n = 15) revealed continuity and coordination challenges with the current system of care of high-risk individuals. Respondents suggested an inherited cancer registry would help identify high-risk individuals and provide a centralized system of risk management for identified carriers. Respondents identified concerns about the privacy of their registry data, including who could access it. Findings suggest BRCA carriers see great value in an inherited cancer registry. Specifically, participants noted it could provide a centralized system to help improve the coordination of burdensome, life-long risk management. Important patient concerns about protecting their privacy and their health data confidentiality must be addressed in patient and public information and informed consent documents about a registry.

Effects of Saccharomyces cerevisiae boulardii (CNCM I-1079) on feed intake, blood parameters, and production during early lactation.

The periparturient period is a metabolically demanding time for dairy animals because of increased nutrient requirements for milk yield. The objective of this study was to investigate the effect of feeding Saccharomyces cerevisiae boulardii (CNCM I-1079), a commercial active dry yeast (ADY), in dairy cows on productive and metabolic measures during the periparturient period. Primiparous (n = 33) and multiparous (n = 35) cows were fed a close-up total mixed ration (TMR) before calving and a lactation TMR postpartum. Three weeks before expected calving time, animals were blocked by parity and body weight and then randomly assigned to either control group (control; n = 34) or treatment (ADY; n = 34). All animals were housed in a tie-stall barn with individual feed bunks; the ADY animals received supplementary Saccharomyces cerevisiae boulardii (CNCM I-1079), top dressed daily at a predicted dosage of 1.0 × 1010 cfu (12.5 g) per head. Blood samples were collected weekly along with milk yield and milk composition data; feed intake data were collected daily. Serum samples were analyzed for glucose, nonesterified fatty acid, ß-hydroxybutyrate, haptoglobin (Hp), and the cytokines tumor necrosis factor-α, IL-6, and IL-18. Colostrum samples collected within the first 6 to 10 h were analyzed for somatic cell score and IgG, IgA, and IgM concentrations. Data were analyzed using PROC GLIMMIX in SAS with time as a repeated measure; model included time, parity, treatment, and their interactions. The ADY groups had greater milk yield (39.0 ± 2.4 vs. 36.7 ± 2.3 kg/d) and tended to produce more energy-corrected milk with better feed efficiency. There was no difference in plasma glucose, serum nonesterified fatty acid, serum ß-hydroxybutyrate, Hp, IL-6, or IL-18 due to ADY treatment. The tumor necrosis factor-α increased in ADY-supplemented animals (1.17 ± 0.69 vs. 4.96 ± 7.7 ng/mL), though week, parity, and their interactions had no effect. Serum amyloid A tended to increase in ADY-supplemented animals when compared to control animals and was additionally affected by week and parity; there were no significant interactions. No difference in colostrum IgG, IgA, and IgM was observed between treatments. Supplementing transition cow TMR with ADY (CNCM I-1079) improved milk production and tended to improve efficiency in early lactation; markers of inflammation were also influenced by ADY treatment, though the immunological effect was inconsistent.

Audit of waist measurement methods during statutory diving medical assessments.

BACKGROUND: Measurement of waist circumference is used to assess abdominal fat and risk of heart disease, type 2 diabetes, cancer and stroke. It is performed in several clinical settings for health promotion and medical assessment purposes, including statutory medical assessments where results may influence decisions on fitness to work. Under the Diving at Work Regulations 1997, working divers must have an annual assessment of their fitness to dive performed by an approved medical examiner of divers (AMED), appointed by the Health and Safety Executive (HSE). The assessment includes measurement of height, weight and waist circumference, the latter used as an indicator of central adiposity and associated health risks. AIMS: To establish the practice of AMEDs in measuring waist circumference of working divers undergoing medical assessment to determine their fitness to dive. METHODS: Ninety-seven AMEDs were sent a questionnaire and asked to describe their current practice in measuring waist circumference. The response rate was 79%. The audit standard used was the consensus document published by the World Health Organization (WHO). RESULTS: Of the 77 responses, 76 were completed sufficiently to allow analysis. When the waist was measured, there was consistency in the diver's level of clothing, stage of breathing and posture for the procedure but variability in the site of measurement. Only 7/76 (9%) respondents carried out waist measurement fully in line with WHO guidance. CONCLUSIONS: The audit has identified that there is a need for guidance for AMEDs on measuring waist circumference in the statutory medical assessment of working divers.

Moral distress revisited: the viewpoints and responses of nurses.

AIM: To present and discuss the main themes that were revealed following an analysis of the qualitative research findings that were extracted from a national survey regarding the causes and effects of moral distress amongst New Zealand nurses. BACKGROUND/INTRODUCTION: Moral distress continues to be a major concern amongst nurses around the world. In New Zealand, a country where nurses have just been on strike over their working conditions and the deteriorating state of their roles within the health services, it remains a major issue. METHOD: In the original research project, large numbers of nurses supplied not only quantitative data that revealed the extent and impact of moral distress on their practices, but also extensive notes that more specifically explained the causes and effects of their moral distress. This material has since been thematically analysed and is now presented. FINDINGS/RESULTS: The data strongly suggested that New Zealand nurses experienced and attempted to respond to several major issues; that is, they were not properly supported by 'the system', frequently experienced problems with managers and bullying, witnessing poor care practices and collegial incompetence, and suffered from ongoing problems caused by moral residue. CONCLUSION: Under current working conditions, nurses are struggling under an increasing weight of moral residue to maintain their ethical standards within an increasingly difficult ethical climate. IMPLICATIONS FOR NURSING AND HEALTH POLICY: This research suggests that although nurses clearly seek out and use various ways to cope with moral distress in their practices, there is a continuing need for moral courage and strengthening of moral resilience that involves greater input from not just nurses themselves, but nurse managers, educators and other health services representatives.

Penile Paget's Disease: A Case Report and Review of the Literature.

Extramammary Paget's Disease (EMPD) is a rare cutaneous, slow growing, intraepithelial adenocarcinoma that can be either primary (intraepithelial arising within the epidermis) or secondary (intraepithelial spread of a visceral carcinoma). Here we present the case of a 63-year-old male with EMPD of the glans penis stemming from underlying urothelial carcinoma. Our treatment decision elected for management with chemotherapy and local treatment with radiation therapy. Subsequent, review of the literature demonstrated a rare disease with a variety of underlying malignancies causing this secondary pathology. Caregivers should be aware of the association of Paget's disease and urothelial cancer and should have a high index of suspicion that erythematous penile lesions may represent Paget's disease and that penile biopsies should be performed early in this setting.

Integrative radiomics expression predicts molecular subtypes of primary clear cell renal cell carcinoma.

AIM: To identify combined positron-emission tomography (PET)/magnetic resonance imaging (MRI)-based radiomics as a surrogate biomarker of intratumour disease risk for molecular subtype ccA and ccB in patients with primary clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: PET/MRI data were analysed retrospectively from eight patients. One hundred and sixty-eight radiomics features for each tumour sampling based on the regionally sampled tumours with 23 specimens were extracted. Sparse partial least squares discriminant analysis (SPLS-DA) was applied to feature screening on high-throughput radiomics features and project the selected features to low-dimensional intrinsic latent components as radiomics signatures. In addition, multilevel omics datasets were leveraged to explore the complementing information and elevate the discriminative ability. RESULTS: The correct classification rate (CCR) for molecular subtype classification by SPLS-DA using only radiomics features was 86.96% with permutation test p=7×10-4. When multi-omics datasets including mRNA, microvascular density, and clinical parameters from each specimen were combined with radiomics features to refine the model of SPLS-DA, the best CCR was 95.65% with permutation test, p<10-4; however, even in the case of generating the classification based on transcription features, which is the reference standard, there is roughly 10% classification ambiguity. Thus, this classification level (86.96-95.65%) of the proposed method represents the discriminating level that is consistent with reality. CONCLUSION: Featured with high accuracy, an integrated multi-omics model of PET/MRI-based radiomics could be the first non-invasive investigation for disease risk stratification and guidance of treatment in patients with primary ccRCC.

Customized headgear for the management of recurrent temporomandibular joint dislocations.

Chronic recurrent temporomandibular joint (TMJ) dislocation is both an uncommon and debilitating condition of the facial skeleton. Various conservative management strategies have been tried, but these have often been associated with poor and transient outcomes. The use of a simple, innovative, and non-invasive solution is presented herein. A co-ordinated multidisciplinary approach was used in which the oral and maxillofacial laboratory technicians produced a customized headgear appliance that utilizes a 'seat belt'-like technology. This headgear was used successfully to manage the condition.

A cross-sectional analysis of factors associated with the intention to engage in tobacco treatment among inpatients in a state psychiatric hospital.

WHAT IS KNOWN ON THE SUBJECT?: People admitted to psychiatric facilities have high rates of tobacco use and hospitalizations present an opportunity for patients to have conversations about tobacco use treatment. Clinicians may believe that people with mental illnesses are not interested in quitting or that they do not understand the importance of treatment. Positive attitudes towards tobacco treatment, viewing that participating in treatment is normal care, and feeling that one is quite able to participate in such treatment predicts intentions to participate in treatment, which, in turn, predicts actual participation. WHAT DOES THIS PAPER ADD TO EXISTING KNOWLEDGE?: Psychiatric patients who use tobacco use report poor prior involvement with tobacco treatment. Positive attitudes towards, encouraging opinions of other people about, and having a sense of control over taking part in tobacco treatment increases plans to engage in treatment. Having a sense of control in taking part in tobacco treatment is strongly associated with prior experiences with evidence-based treatment. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Because psychiatric hospitalizations are an opportunity for addressing tobacco use and treatment, clinicians should be prepared to support willing patients, especially those with prior substance use histories. Support should include providing them with information regarding tobacco treatment options during their hospital stay and ways that they can continue to receive care after discharge. Clinicians should be promoters of pro-tobacco treatment attitudes and supporting patients' sense of control over participating in treatment during hospitalization. ABSTRACT: Introduction Hospitalized tobacco users with mental illnesses (MI) may face several barriers to stopping smoking. However, motivational factors that affect the intention to engage in tobacco treatment have been shown to predict actual engagement. Aim To use the Theory of Planned Behavior to assess intentions to and prior experiences of engaging in evidence-based tobacco treatment among hospitalized individuals with MI. Method A cross-sectional survey was conducted among 115 patients in a state psychiatric hospital. Multivariate analyses were used to examine associations with the intentions and prior experiences of engaging in tobacco treatment. Results After controlling for demographic and smoking history, attitudes, subjective norms and perceived behavioural control towards engaging in tobacco treatment were significantly associated with intentions towards treatment engagement. Only higher scores on perceived behavioural control and lower education levels were associated with reported prior experiences of tobacco treatment. Discussion The low prior treatment engagement scores, but relatively higher intention to engage scores among participants suggests the need for deliberate support for evidence-based tobacco treatment during psychiatric hospitalizations. Implications for practice Clinician training in tobacco treatment can promote self-efficacy to engage patients while supporting patients' control so that tobacco treatment is an expected component of psychiatric care.

The mandibular muscles in contemporary orthodontic practice: a review.

It is widely accepted that all dentists should have a thorough understanding of the muscles involved in moving or stabilizing the mandible. However, there is still much discussion regarding the influence of the mandibular muscles on normal facial growth and dental development, as well as on orthodontic treatment and post-treatment stability. Potential patients with different underlying vertical muscle patterns will have differences in the expected directions of future mandibular growth, lateral profile shape, facial and arch widths and vertical occlusal relationships. In turn, thorough diagnoses are likely to lead to differences in individual aims and objectives, treatment plans, timing of commencement, mechanical design, lateral profile and smile-aesthetics outcomes, choice of retention and plans for long-term maintenance. The potential influence of the mandibular muscles on normal morphologic variation and the soft tissue implications on contemporary orthodontic treatment and stability will be addressed in this review.

Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer.

PURPOSE: To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases. METHODS: A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion. RESULTS: The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients. CONCLUSIONS: The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.

Observations and Modelling of the Pre-flare Period of the 29 March 2014 X1 Flare.

On 29 March 2014, NOAA Active Region (AR) 12017 produced an X1 flare that was simultaneously observed by an unprecedented number of observatories. We have investigated the pre-flare period of this flare from 14:00 UT until 19:00 UT using joint observations made by the Interface Region Imaging Spectrometer (IRIS) and the Hinode Extreme Ultraviolet Imaging Spectrometer (EIS). Spectral lines providing coverage of the solar atmosphere from the chromosphere to the corona were analysed to investigate pre-flare activity within the AR. The results of the investigation have revealed evidence of strongly blue-shifted plasma flows, with velocities up to 200 km s - 1 , being observed 40 minutes prior to flaring. These flows are located along the filament present in the active region and are both spatially discrete and transient. In order to constrain the possible explanations for this activity, we undertake non-potential magnetic field modelling of the active region. This modelling indicates the existence of a weakly twisted flux rope along the polarity inversion line in the region where a filament and the strong pre-flare flows are observed. We then discuss how these observations relate to the current models of flare triggering. We conclude that the most likely drivers of the observed activity are internal reconnection in the flux rope, early onset of the flare reconnection, or tether-cutting reconnection along the filament.

Evaluation of a population-based approach to familial colorectal cancer.

As Newfoundland has the highest rate of familial colorectal cancer (CRC) in the world, we started a population-based clinic to provide colonoscopic and Lynch syndrome (LS) screening recommendations to families of CRC patients based on family risk. Of 1091 incident patients 51% provided a family history. Seventy-two percent of families were at low or intermediate-low risk of CRC and colonoscopic screening recommendations were provided by letter. Twenty-eight percent were at high and intermediate-high risk and were referred to the genetic counsellor, but only 30% (N = 48) were interviewed by study end. Colonoscopy was recommended more frequently than every 5 years in 35% of families. Lower family risk was associated with older age of proband but the frequency of screening colonoscopy recommendations varied across all age groups, driven by variability in family history. Twenty-four percent had a high MMR predict score for a Lynch syndrome mutation, and 23% fulfilled the Provincial Program criteria for LS screening. A population-based approach in the provision of colonoscopic screening recommendations to families at risk of CRC was limited by the relatively low response rate. A family history first approach to the identification of LS families was inefficient.

Qualitative study of views and experiences of performance management for healthcare-associated infections.

BACKGROUND: Centrally led performance management regimes using standard setting, monitoring, and incentives have become a prominent feature of infection prevention and control (IPC) in health systems. AIM: To characterize views and experiences of regulation and performance management relating to IPC in English hospitals. METHODS: Two qualitative datasets containing 139 interviews with healthcare workers and managers were analysed. Data directly relevant to performance management and IPC were extracted. Data analysis was based on the constant comparative method. FINDINGS: Participants reported that performance management regimes had mobilized action around specific infections. The benefits of establishing organizational structures of accountability were seen in empirical evidence of decreasing infection rates. Performance management was not, however, experienced as wholly benign, and setting targets in one area was seen to involve risks of 'tunnel vision' and the marginalization of other potentially important issues. Financial sanctions were viewed especially negatively; performance management was associated with risks of creating a culture of fearfulness, suppressing learning and disrupting inter-professional relationships. CONCLUSION: Centrally led performance management may have some important roles in IPC, but identifying where it is appropriate and determining its limits is critical. Persisting with harsh regimes may affect relationships and increase resistance to continued improvement efforts, but leaving all improvement to local teams may also be a flawed strategy.

[Better Reporting of Interventions: Template for Intervention Description and Replication (TIDieR) Checklist and Guide]. / Die TIDieR Checkliste und Anleitung - ein Instrument für eine verbesserte Interventionsbeschreibung und Replikation.

Without a complete published description of interventions, clinicians and patients cannot reliably implement interventions that are shown to be useful, and other researchers cannot replicate or build on research findings. The quality of description of interventions in publications, however, is remarkably poor. To improve the completeness of reporting, and ultimately the replicability, of interventions, an international group of experts and stakeholders developed the Template for Intervention Description and Replication (TIDieR) checklist and guide. The process involved a literature review for relevant checklists and research, a Delphi survey of an international panel of experts to guide item selection, and a face-to-face panel meeting. The resultant 12-item TIDieR checklist (brief name, why, what (materials), what (procedure), who intervened, how, where, when and how much, tailoring, modifications, how well (planned), how well (actually carried out)) is an extension of the CONSORT 2010 statement (item 5) and the SPIRIT 2013 statement (item 11). While the emphasis of the checklist is on trials, the guidance is intended to apply across all evaluative study designs. This paper presents the TIDieR checklist and guide, with a detailed explanation of each item, and examples of good reporting. The TIDieR checklist and guide should improve the reporting of interventions and make it easier for authors to structure the accounts of their interventions, reviewers and editors to assess the descriptions, and readers to use the information.

RADIATION DOSE MEASUREMENTS FOR HIGH-INTENSITY LASER INTERACTIONS WITH SOLID TARGETS AT SLAC.

A systematic study of photon and neutron radiation doses generated in high-intensity laser-solid interactions is underway at SLAC National Accelerator Laboratory. These laser-solid experiments are being performed using a 25 TW (up to 1 J in 40 fs) femtosecond pulsed Ti:sapphire laser at the Linac Coherent Light Source's (LCLS) Matter in Extreme Conditions (MEC) facility. Radiation measurements were performed with passive and active detectors deployed at various locations inside and outside the target chamber. Results from radiation dose measurements for laser-solid experiments at SLAC MEC in 2014 with peak intensity between 1018 and 7.1 × 1019 W cm-2 are presented.

Simulating Bosonic Baths with Error Bars.

We derive rigorous truncation-error bounds for the spin-boson model and its generalizations to arbitrary quantum systems interacting with bosonic baths. For the numerical simulation of such baths, the truncation of both the number of modes and the local Hilbert-space dimensions is necessary. We derive superexponential Lieb-Robinson-type bounds on the error when restricting the bath to finitely many modes and show how the error introduced by truncating the local Hilbert spaces may be efficiently monitored numerically. In this way we give error bounds for approximating the infinite system by a finite-dimensional one. As a consequence, numerical simulations such as the time-evolving density with orthogonal polynomials algorithm (TEDOPA) now allow for the fully certified treatment of the system-environment interaction.

Factors affecting jump performance in professional Australian rules footballers.

AIM: This study examined factors contributing to jump performance in professional Australian Rules Football (ARF) players. METHODS: Thirty-two ARF players performed a countermovement jump (CMJ) and were divided into groups based on jump performance: high calibre (HC) or low calibre (LC). During CMJ assessment, force, rate of force development, movement velocity and power were measured. Physical measures included mass, height, age, lower body strength, eccentric utilization ratio and leg stiffness (Kleg). HC and LC groups were compared to determine the variables contributing to jump performance and correlation and regression analyses also aided in identifying such variables. CMJ height was higher in the HC group (P<0.001). RESULTS: The HC group demonstrated a higher CMJ velocity (9.8%, P=0.004) and CMJ power (14.4%, P=0.042) when compared to the LC group. Further, the HC group demonstrated 7.5% higher Kleg than the LC group (P=0.019). Spearman's rho correlations demonstrated moderate-large relationships between jump height and strength, velocity and power, while the regression analysis revealed velocity was the sole predictive variable of jump performance. Jumping performance clearly differs within a group of professional ARF athletes. CONCLUSION: Movement velocity appears to be an important factor contributing to jump performance; however, lower body power and Kleg are also important for jump performance.