Supporting Information Sharing in Families at Risk of Bowel Cancer Through a Secure Website

Background: Bowel cancer is a significant health threat as it is the third most commonly diagnosed cancer worldwide. Screening can detect tumours early, thus allowing treatment to reduce morbidity and mortality. However, many relatives who share a high lifetime risk of bowel cancer remain unaware of their familial diagnosis and so are unable to access genetic testing or screening. Providing family letters and verbal recommendations to patients diagnosed with a vulnerability to bowel cancer has not been sufficient to support effective communication in these families. Little is known about how electronic methods of communication could be used to facilitate communication in families affected by a genetic vulnerability to cancer. Aim: To investigate whether a secure website could support families with an increased risk of bowel cancer to share information with their relatives. Methods: A pragmatic mixed methods approach with four phases was used. First, patients at high risk of bowel cancer who had been advised to have regular colonoscopy were invited to participate in an anonymous cross-sectional survey administered online and through NHS clinical services (n=286). Second, more in depth qualitative data were elicited through telephone interviews with a purposive sample of volunteers (n=14). Third, a secure website was designed to help relatives share sensitive documents online, with content informed by the experiences and views of survey and interview participants. Fourth, reactions to the website from 12 volunteers were elicited through three phases of video recorded Think-Aloud interviews, which guided further refinement of the website. Findings: The survey showed that: 43% of those at risk were first informed of the familial diagnosis by their relatives. The majority of participants needed much more practical information after learning they had an increased risk of cancer. Key issues were: a healthy lifestyle, genetic testing, bowel surveillance and talking to children. These topics were endorsed in the interviews, which also identified four main themes: impact of the genetic diagnosis; the need for practical information; the importance of adaptation to sharing information; and appropriate communication in contacts with relatives. Reactions to the website were positive; access to tailored information, plus the opportunity to store and share personal information were all welcomed. Conclusion: A personalised web-based information resource and document sharing facility like www.familyweb.org/ could improve health communication within families. It requires further research to confirm that it is effective in practice. Such innovations could help improve early detection and treatment though increased awareness of familial cancer risk. Patients need more support from health professionals to adjust and then disseminate information about their diagnosis

Abdominal massage plus advice, compared with advice only, for neurogenic bowel dysfunction in MS:a RCT

This project was funded by the National Institute for Health Research Health TechnologyPeer reviewedPublisher PD

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Perehdytysmateriaalin laatiminen Kauhajoen terveyskeskuksen akuuttiosastolle

Tämän toiminnallisen opinnäytetyön tarkoituksena oli tuottaa perehdytysmateriaali Suupohjan peruspalveluliikelaitoskuntayhtymän Kauhajoen terveyskeskuksen akuuttiosastolle. Työn tilaajana oli akuuttiosaston osastonhoitaja. Perehdytysmateriaalin tarkoituksena on tukea uuden tulokkaan perehtymistä sekä perehdytystä. Perehdytysmateriaali toimii myös tietolähteenä, josta koko henkilökunta voi tarvittaessa tarkistaa asioita. Opinnäytetyön tavoitteina oli yhtenäistää perehdytys akuuttiosastolla, helpottaa uuden työntekijän organisaation tutustumista ja toimia materiaalina, jota kokeneet työntekijät voivat käyttää asioiden tarkistamiseen. Perehdytysmateriaali toteutettiin yhteistyössä akuuttiosaston yhteyshenkilön kanssa. Hyvän perehdytyksen onnistumiseen vaikuttavat monet eri tekijät. Teoreettisessa viitekehyksessä esitetään perehdytyksen onnistumiseen vaikuttavat tekijät, akuuttiosaston toiminta ja hyvän kirjallisen materiaalin tuottamiseen vaikuttavat tekijät. Opinnäytetyöprojekti aloitettiin keväällä 2014. Teoreettiseen viitekehykseen haettiin tutkittua tietoa ja muuta laadukasta näyttöä. Akuuttiosaston henkilökunnalle tehtiin kysely heidän näkemyksistään hyvästä perehdytyksestä ja perehdytysmateriaalista. Teoreettisen viitekehyksen ja kyselyn tulosten perusteella laadittiin perehdytysmateriaali yhteistyössä tilaajan kanssa. Tilaaja on hyväksynyt perehdytysmateriaalin ja sitä tullaan käyttämään akuuttiosastolla vierihoitomallin tukena perehdytyksessä. Opinnäytetyön valmistusvaiheessa ei ole vielä mahdollista arvioida opinnäytetyön tavoitteiden saavuttamista. Jatkotutkimusaiheeksi ehdotetaan tavoitteiden arviointia kyselyn avulla.The purpose of this practice-based bachelor´s thesis was to make orientation material for the acute inpatient ward in Kauhajoki health centre. The thesis was commissioned by the ward nurse. The purpose of the orientation material is to support the orientation process of a new employee. The material can also be used by the other staff. The aim of the material is also to standardize the orientation process on the acute inpatient ward. The material was made in cooperation with the contact person on the ward. A good orientation process is influenced by many factors. The theoretical frame deals with the factors that affect the success of the orientation process, with the work and processes on the acute inpatient ward and the factors that influence producing written material of a good quality. The thesis project was started in the spring of 2014. Research data and evidence-based data were used when writing the theoretical frame. An inquiry was carried out among the staff. The orientation material was made based on the theoretical frame and the inquiry in cooperation with the client. The client has approved the orientation material, and it will be used in the acute inpatient ward to support the rooming-in model. The process of writing the thesis has not yet been completed so it is difficult to estimate if the goals have been accomplished. A topic for further research could be to evaluate, by carrying out an inquiry, if the goals were reached

The brain’s response to reward anticipation and depression in adolescence: dimensionality, specificity and longitudinal predictions in a community-based sample

International audienceOBJECTIVE: The authors examined whether alterations in the brain's reward network operate as a mechanism across the spectrum of risk for depression. They then tested whether these alterations are specific to anhedonia as compared with low mood and whether they are predictive of depressive outcomes.METHOD: Functional MRI was used to collect blood-oxygen-level-dependent (BOLD) responses to anticipation of reward in the monetary incentive task in 1,576 adolescents in a community-based sample. Adolescents with current subthreshold depression and clinical depression were compared with matched healthy subjects. In addition, BOLD responses were compared across adolescents with anhedonia, low mood, or both symptoms, cross-sectionally and longitudinally.RESULTS: Activity in the ventral striatum was reduced in participants with subthreshold and clinical depression relative to healthy comparison subjects. Low ventral striatum activation predicted transition to subthreshold or clinical depression in previously healthy adolescents at 2-year follow-up. Brain responses during reward anticipation decreased in a graded manner between healthy adolescents, adolescents with current or future subthreshold depression, and adolescents with current or future clinical depression. Low ventral striatum activity was associated with anhedonia but not low mood; however, the combined presence of both symptoms showed the strongest reductions in the ventral striatum in all analyses.CONCLUSIONS: The findings suggest that reduced striatal activation operates as a mechanism across the risk spectrum for depression. It is associated with anhedonia in healthy adolescents and is a behavioral indicator of positive valence systems, consistent with predictions based on the Research Domain Criteria