Do psychological harms result from being labelled with an unexpected diagnosis of abdominal aortic aneurysm or prostate cancer through screening? A systematic review

Objective A potential psychological harm of screening is unexpected diagnosistextemdashlabelling. We need to know the frequency and severity of this harm to make informed decisions about screening. We asked whether current evidence allows an estimate of any psychological harm of labelling. As case studies, we used two conditions for which screening is common: prostate cancer (PCa) and abdominal aortic aneurysm (AAA).Design Systematic review with narrative synthesis.Data sources and eligibility criteria We searched the English language literature in PubMed, PsychINFO and Cumulative Index of Nursing and Allied Health Literature (CINAHL) for research of any design published between 1 January 2002 and 23 January 2017 that provided valid data about the psychological state of people recently diagnosed with early stage PCa or AAA. Two authors independently used explicit criteria to review and critically appraise all studies for bias, applicability and the extent to which it provided evidence about the frequency and severity of harm from labelling.Results 35 quantitative studies (30 of PCa and 5 of AAA) met our criteria, 17 (48.6 of which showed possible or definite psychological harm from labelling. None of these studies, however, had either appropriate measures or relevant comparisons to estimate the frequency and severity of psychological harm. Four PCa and three AAA qualitative studies all showed clear evidence of at least moderate psychological harm from labelling. Seven population-based studies found increased suicide in patients recently diagnosed with PCa.Conclusions Although qualitative and population-based studies show that at least moderate psychological harm due to screening for PCa and AAA does occur, the current quantitative evidence is insufficient to allow a more precise estimation of frequency and severity. More sensitive measures and improved research designs are needed to fully characterise this harm. In the meantime, clinicians and recommendation panels should be aware of the occurrence of this harm.Peer reviewe

Regulation of T cell receptor signaling by activation-induced zinc influx

Zinc enhances TCR signaling in part by inhibiting Shp-1 recruitment to the TCR synapse

Cervix carcinoma is associated with an up-regulation and nuclear localization of the dual-specificity protein phosphatase VHR

BACKGROUND: The 21-kDa Vaccinia virus VH1-related (VHR) dual-specific protein phosphatase (encoded by the DUSP3 gene) plays a critical role in cell cycle progression and is itself regulated during the cell cycle. We have previously demonstrated using RNA interference that cells lacking VHR arrest in the G1 and G2 phases of the cell cycle and show signs of beginning of cell senescence. METHODS: In this report, we evaluated successfully the expression levels of VHR protein in 62 hysterectomy or conization specimens showing the various (pre) neoplastic cervical epithelial lesions and 35 additional cases of hysterectomy performed for non-cervical pathologies, from patients under 50 years of age. We used a tissue microarray and IHC technique to evaluate the expression of the VHR phosphatase. Immunofluorescence staining under confocal microscopy, Western blotting and RT-PCR methods were used to investigate the localization and expression levels of VHR. RESULTS: We report that VHR is upregulated in (pre) neoplastic lesions (squamous intraepithelial lesions; SILs) of the uterine cervix mainly in high grade SIL (H-SIL) compared to normal exocervix. In the invasive cancer, VHR is also highly expressed with nuclear localization in the majority of cells compared to normal tissue where VHR is always in the cytoplasm. We also report that this phosphatase is highly expressed in several cervix cancer cell lines such as HeLa, SiHa, CaSki, C33 and HT3 compared to primary keratinocytes. The immunofluorescence technique under confocal microscopy shows that VHR has a cytoplasmic localization in primary keratinocytes, while it localizes in both cytoplasm and nucleus of the cancer cell lines investigated. We report that the up-regulation of this phosphatase is mainly due to its post-translational stabilization in the cancer cell lines compared to primary keratinocytes rather than increases in the transcription of DUSP3 locus. CONCLUSION: These results together suggest that VHR can be considered as a new marker for cancer progression in cervix carcinoma and potential new target for anticancer therapy

The common FTO variant rs9939609 is not associated with BMI in a longitudinal study on a cohort of Swedish men born 1920-1924

<p>Abstract</p> <p>Background</p> <p>Common FTO (fat mass and obesity associated) gene variants have recently been strongly associated with body mass index and obesity in several large studies. Here we set out to examine the association of the <it>FTO </it>variant rs9939609 with BMI in a 32 year follow up study of men born 1920-1924. Moreover, we analyzed the effect of physical activity on the different genotypes.</p> <p>Methods</p> <p>The <it>FTO </it>rs9936609 was genotyped using an Illumina golden gate assay. BMI was calculated using standard methods and body fat was estimated by measuring skinfold thickness using a Harpenden caliper. Physical activity was assessed using a four question medical questionnaire.</p> <p>Results</p> <p><it>FTO </it>rs9939609 was genotyped in 1153 elderly Swedish men taking part of a population-based cohort study, the ULSAM cohort. The risk of obesity and differences in BMI according to genotype at the ages of 50, 60, 70, 77 and 82 were investigated. We found no increased risk of obesity and no association with BMI at any age with the <it>FTO </it>rs9939609 variant. We found however interaction between physical activity at the age of 50 years and genotype on BMI levels (p = 0.039) and there was a clear trend towards larger BMI differences between the TT and AA carriers as well as between AT and AA carriers in the less physically active subjects.</p> <p>Conclusion</p> <p>Here we found that the well established obesity risk allele for a common variant in <it>FTO </it>does not associate with increased BMI levels in a Swedish population of adult men which reached adulthood before the appearance of today's obesogenic enviroment. There is an interaction between physical activity and the effect of the FTO genotype on BMI levels suggesting that lack of physical activity is a requirement for an association of FTO gene variants to obesity.</p

Polygenic risk for obesity and its interaction with lifestyle and sociodemographic factors in European children and adolescents

Background Childhood obesity is a complex multifaceted condition, which is influenced by genetics, environmental factors, and their interaction. However, these interactions have mainly been studied in twin studies and evidence from population-based cohorts is limited. Here, we analyze the interaction of an obesity-related genome-wide polygenic risk score (PRS) with sociodemographic and lifestyle factors for BMI and waist circumference (WC) in European children and adolescents. Methods The analyses are based on 8609 repeated observations from 3098 participants aged 2-16 years from the IDEFICS/I.Family cohort. A genome-wide polygenic risk score (PRS) was calculated using summary statistics from independent genome-wide association studies of BMI. Associations were estimated using generalized linear mixed models adjusted for sex, age, region of residence, parental education, dietary intake, relatedness, and population stratification. Results The PRS was associated with BMI (beta estimate [95% confidence interval (95%-CI)] = 0.33 [0.30, 0.37], r(2) = 0.11, p value = 7.9 x 10(-81)) and WC (beta [95%-CI] = 0.36 [0.32, 0.40], r(2) = 0.09, p value = 1.8 x 10(-71)). We observed significant interactions with demographic and lifestyle factors for BMI as well as WC. Children from Southern Europe showed increased genetic liability to obesity (BMI: beta [95%-CI] = 0.40 [0.34, 0.45]) in comparison to children from central Europe (beta [95%-CI] = 0.29 [0.23, 0.34]), p-interaction = 0.0066). Children of parents with a low level of education showed an increased genetic liability to obesity (BMI: beta [95%-CI] = 0.48 [0.38, 0.59]) in comparison to children of parents with a high level of education (beta [95%-CI] = 0.30 [0.26, 0.34]), p-interaction = 0.0012). Furthermore, the genetic liability to obesity was attenuated by a higher intake of fiber (BMI: beta [95%-CI] interaction = -0.02 [-0.04,-0.01]) and shorter screen times (beta [95%-CI] interaction = 0.02 [0.00, 0.03]). Conclusions Our results highlight that a healthy childhood environment might partly offset a genetic predisposition to obesity during childhood and adolescence.Peer reviewe

Risk of eating disorders in immigrant populations

Objective: The risk of certain psychiatric disorders is elevated among immigrants. To date, no population studies on immigrant health have addressed eating disorders. We examined whether risk of eating disorders in first- and second-generation immigrants differ from native-born Danes and Swedes. Method: All individuals born 1984-2002 (Danish cohort) and 1989-1999 (Swedish cohort) and residing in the respective country on their 10th birthday were included. They were followed up for the development of eating disorders based on outpatient and inpatient data. Results: The risks of all eating disorder types were lower among first-generation immigrants compared to the native populations: Incidence-rate ratio (95% confidence interval) 0.39 (0.29, 0.51) for anorexia nervosa, 0.60 (0.42, 0.83) for bulimia nervosa, and 0.62 (0.47, 0.79) for other eating disorders in Denmark and 0.27 (0.21, 0.34) for anorexia nervosa, 0.30 (0.18, 0.51) for bulimia nervosa, and 0.39 (0.32, 0.47) for other eating disorders in Sweden. Likewise, second-generation immigrants by both parents were at lower risk, whereas those with only one foreign-born parent were not. Conclusion: The decreased risk of eating disorders among immigrants is opposite to what has been observed for other psychiatric disorders, particularly schizophrenia. Possible explanations include buffering socio-cultural factors and underdetection in healthcare.NoneAccepte

Peroxiredoxin II Regulates Effector and Secondary Memory CD8+ T cell Responses

Reactive oxygen intermediates (ROI) generated in response to receptor stimulation play an important role in cellular responses. However, the effect of increased H2O2on an antigen-specific CD8+ T cell response was unknown. Following T cell receptor (TCR) stimulation, the expression and oxidation of peroxiredoxin II (PrdxII), a critical antioxidant enzyme, increased in CD8+ T cells. Deletion of PrdxII increased ROI, S phase entry, division, and death during in vitro division. During primary acute viral and bacterial infection, the number of effector CD8+ T cells in PrdxII-deficient mice was increased, while the number of memory cells were similar to those of the wild-type cells. Adoptive transfer of P14 TCR transgenic cells demonstrated that the increased expansion of effector cells was T cell autonomous. After rechallenge, effector CD8+ T cells in mutant animals were more skewed to memory phenotype than cells from wild-type mice, resulting in a larger secondary memory CD8+ T cell pool. During chronic viral infection, increased antigen-specific CD8+ T cells accumulated in the spleens of PrdxII mutant mice, causing mortality. These results demonstrate that PrdxII controls effector CD8+ T cell expansion, secondary memory generation, and immunopathology

Physical Activity Attenuates the Genetic Predisposition to Obesity in 20,000 Men and Women from EPIC-Norfolk Prospective Population Study

Shengxu Li and colleagues use data from a large prospective observational cohort to examine the extent to which a genetic predisposition toward obesity may be modified by living a physically active lifestyle

Circulating metabolites and the risk of type 2 diabetes: a prospective study of 11,896 young adults from four Finnish cohorts

Aims/hypothesis Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case−control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. Methods NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24–45 years). Associations between baseline metabolites and risk of developing diabetes during 8–15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. Results Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59–1.50; p< 0.0009). Among the strongest biomarkers of diabetes risk were branched-chain and aromatic amino acids (OR 1.31–1.33) and triacylglycerol within VLDL particles (OR 1.33–1.50), as well as linoleic n-6 fatty acid (OR 0.75) and non-esterified cholesterol in large HDL particles (OR 0.59). The metabolic biomarkers were more strongly associated with deterioration in post-load glucose and insulin resistance than with future fasting hyperglycaemia. A multi-metabolite score comprised of phenylalanine, non-esterified cholesterol in large HDL and the ratio of cholesteryl ester to total lipid in large VLDL was associated with future diabetes risk (OR 10.1 comparing individuals in upper vs lower fifth of the multi-metabolite score) in one of the cohorts (mean age 31 years). Conclusions/interpretation Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk