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Contains fulltext : 289359.pdf (Publisher’s version ) (Closed access) Functional movement disorder (FMD) is a common manifestation of functional neurological disorder presenting with diverse phenotypes such as tremor, weakness and gait disorder. Our current understanding of the basic epidemiological features of this condition is unclear. We aimed to describe and examine the relationship between age at onset, phenotype and gender in FMD in a large meta-analysis of published and unpublished individual patient cases. An electronic search of PubMed was conducted for studies from 1968 to 2019 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Individual patient data were collected through a research network. We described the distribution of age of onset and how this varied by gender and motor phenotype. A one-stage meta-analysis was performed using multilevel mixed-effects linear regression, including random intercepts for country and data source. A total of 4905 individual cases were analysed (72.6% woman). The mean age at onset was 39.6 years (SD 16.1). Women had a significantly earlier age of onset than men (39.1 years vs 41.0 years). Mixed FMD (23.1%), tremor (21.6%) and weakness (18.1%) were the most common phenotypes. Compared with tremor (40.7 years), the mean ages at onset of dystonia (34.5 years) and weakness (36.4 years) were significantly younger, while gait disorders (43.2 years) had a significantly later age at onset. The interaction between gender and phenotype was not significant. FMD peaks in midlife with varying effects of gender on age at onset and phenotype. The data gives some support to ‘lumping’ FMD as a unitary disorder but also highlights the value in ‘splitting’ into individual phenotypes where relevant.Data are available upon reasonable request. 8 p.

Introduction Hypertonicity of the pelvic floor (PFH) is a disabling condition with urological, gynecological and gastrointestinal symptoms, sexual problems and chronic pelvic pain, impacting quality of life. Pelvic floor physical therapy (PFPT) is a first-line intervention, yet no systematic review on the efficacy of PFPT for the treatment of PFH has been conducted. Objectives To systematically appraise the current literature on efficacy of PFPT modalities related to PFH. Methods PubMed, Embase, Emcare, Web of Science, and Cochrane databases were searched from inception until February 2020. A manual search from reference lists of included articles was performed. Ongoing trials were reviewed using clinicaltrial.gov. Randomized controlled trials (RCTs), prospective - and retrospective cohorts and case-study analyses were included. Outcome measures were pelvic floor muscle tone and function, pain reports, sexual function, pelvic floor symptom scores, quality of life and patients’ perceived effect. Results The literature search resulted in 10 eligible studies including 4 RCTs, 5 prospective studies, and 1 case study published between 2000 and 2019. Most studies had a high risk of bias associated with the lack of a comparison group, insufficient sample sizes and non-standardized interventions. Six studies were of low and 4 of medium quality. All studies were narratively reviewed. Three of 4 RCTs found positive effects of PFPT compared to controls on five out of 6 outcome measures. The prospective studies found significant improvements in all outcome measures that were assessed. PFPT seems to be efficacious in patients with chronic prostatitis, chronic pelvic pain syndrome, vulvodynia, and dyspareunia. Smallest effects were seen in patients with interstitial cystitis and painful bladder syndrome. Conclusion The findings of this systematic review suggest that PFPT can be beneficial in patients with PFH. Further high-quality RCTs should be performed to confirm the effectiveness of PFPT in the treatment of PFH. van Reijn-Baggen DA, Han-Geurts IJM, Voorham-van der Zalm PJ, et al. Pelvic Floor Physical Therapy for Pelvic Floor Hypertonicity: A Systematic Review of Treatment Efficacy. Sex Med Rev 2021;XX:1–22.

OBJECTIVE: A substantial number of sexual assault victims report experiencing some form of peritraumatic tonic immobility (TI). A self-report questionnaire that is widely used to assess TI retrospectively is the Tonic Immobility Scale (TIS). This study explored the factor structure of the TIS in a clinical sample of adolescent and young adults.METHOD: The sample comprised 131 female rape victims, aged 13-25, who were referred for specialized trauma-focused treatment. An exploratory factor analysis (EFA) was performed.RESULTS: The EFA showed support for a three-factor model, with factors TI, Fear, and Detachment. Item correlations ranged from .32 to .57 for TI, from .14 to .35 for Fear, and .29 for the two Detachment items.CONCLUSIONS: We found support for a three-factor solution distinguishing TI, fear, and detachment, suggesting the need to further develop the TIS with different subscales in varying age groups and clinical samples. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The prospective, multicenter TESTBREAST study was initiated with the aim of identifying a novel panel of blood-based protein biomarkers to enable early breast cancer detection for moderate-to-high-risk women. Serum samples were collected every (half) year up until diagnosis. Protein levels were longitudinally measured to determine intrapatient and interpatient variabilities. To this end, protein cluster patterns were evaluated to form a conceptual basis for further clinical analyses. Using a mass spectrometry-based bottom-up proteomics strategy, the protein abundance of 30 samples was analyzed: five sequential serum samples from six high-risk women; three who developed a breast malignancy (cases) and three who did not (controls). Serum samples were chromatographically fractionated and an in-depth serum proteome was acquired. Cluster analyses were applied to indicate differences between and within protein levels in serum samples of individuals. Statistical analyses were performed using ANOVA to select proteins with a high level of clustering. Cluster analyses on 30 serum samples revealed unique patterns of protein clustering for each patient, indicating a greater interpatient than intrapatient variability in protein levels of the longitudinally acquired samples. Moreover, the most distinctive proteins in the cluster analysis were identified. Strong clustering patterns within longitudinal intrapatient samples have demonstrated the importance of identifying small changes in protein levels for individuals over time. This underlines the significance of longitudinal serum measurements, that patients can serve as their own controls, and the relevance of the current study set-up for early detection. The TESTBREAST study will continue its pursuit toward establishing a protein panel for early breast cancer detection.

This research has been conducted using the UK Biobank resource under application number 9072. Copyright © The Author(s) 2021. Higher adiposity is an established risk factor for psychiatric diseases including depression and anxiety. The associations between adiposity and depression may be explained by the metabolic consequences and/or by the psychosocial impact of higher adiposity. We performed one-and two-sample Mendelian randomization (MR) in up to 145 668 European participants from the UK Biobank to test for a causal effect of higher adiposity on 10 well-validated mental health and well-being outcomes derived using the Mental Health Questionnaire (MHQ). We used three sets of adiposity genetic instruments: (a) a set of 72 BMI genetic variants, (b) a set of 36 favourable adiposity variants and (c) a set of 38 unfavourable adiposity variants. We additionally tested causal relationships (1) in men and women separately, (2) in a subset of individuals not taking antidepressants and (3) in non-linear MR models. Two-sample MR provided evidence that a genetically determined one standard deviation (1-SD) higher BMI (4.6 kg/m2) was associated with higher odds of current depression [OR: 1.50, 95%CI: 1.15, 1.95] and lower well-being [ß:-0.15, 95%CI:-0.26,-0.04]. Findings were similar when using the metabolically favourable and unfavourable adiposity variants, with higher adiposity associated with higher odds of depression and lower well-being scores. Our study provides further evidence that higher BMI causes higher odds of depression and lowers well-being. Using genetics to separate out metabolic and psychosocial effects, our study suggests that in the absence of adverse metabolic effects higher adiposity remains causal to depression and lowers well-being. Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK (SBF004\1079 to J.O., F.C. and J.T.); Wellcome Senior Research Fellowship (WT220390 to R.M.F.). Diabetes UK RD Lawrence fellowship (17/0005594 to H.Y.).

The tumor‐stroma ratio (TSR) has proven to be a strong prognostic factor in breast cancer, demonstrating better survival for patients with stroma‐low tumors. Since the role of the TSR as a predictive marker for neoadjuvant chemotherapy outcome is yet unknown, this association was evaluated for HER2‐negative breast cancer in the prospective DIRECT and NEOZOTAC trials. The TSR was assessed on 375 hematoxylin and eosin‐stained sections of pre‐treatment biopsies. Associations between the TSR and chemotherapy response according to the Miller‐Payne (MP) grading system, and between the TSR and pathological response were examined using Pearson's chi‐square, Cochran‐Armitage test for trend and regression analyses. A stroma‐low tumor prior to neoadjuvant chemotherapy was significantly associated with a higher MP score (P = .005). This relationship remained significant in the estrogen receptor (ER)‐negative subgroup (P = .047). The univariable odds ratio (OR) of a stroma‐low tumor on pathological complete response (pCR) was 2.46 (95% CI 1.34‐4.51, P = .004), which attenuated to 1.90 (95% CI 0.85‐4.25, P = .119) after adjustment for relevant prognostic factors. Subgroup analyses revealed an OR of 5.91 in univariable analyses for ER‐negativity (95% CI 1.19‐29.48, P = .030) and 1.48 for ER‐positivity (95% CI 0.73‐3.01, P = .281). In conclusion, a low amount of stroma on pre‐treatment biopsies is associated with a higher MP score and pCR rate. Therefore, the TSR is a promising biomarker in predicting neoadjuvant treatment outcome. Incorporating this parameter in routine pathological diagnostics could be worthwhile to prevent overtreatment and undertreatment.

Highlights • Living with a spouse or partner was associated with reduced odds of lifetime depression. • No evidence of an association between having two children and lifetime depression. • Having three or more children was associated with higher odds of lifetime depression. • Associations were similar across age groups, the sexes, neighbourhood deprivation and genetic predisposition. • Mendelian randomisation analyses indicate a causal effect of number of children on depression., Background We examined associations between family status (living with a spouse or partner and number of children) and lifetime depression. Methods We used data from the UK Biobank, a large prospective study of middle-aged and older adults. Lifetime depression was assessed as part of a follow-up mental health questionnaire. Logistic regression was used to estimate associations between family status and depression. We included extensive adjustment for social, demographic and other potential confounders, including depression polygenic risk scores. Results 52,078 participants (mean age = 63.6, SD = 7.6; 52% female) were included in our analyses. Living with a spouse or partner was associated with substantially lower odds of lifetime depression (OR = 0.67, 95% CI 0.62-0.74). Compared to individuals without children, we found higher odds of lifetime depression for parents of one child (OR = 1.17, 95% CI 1.07-1.27) and parents of three (OR = 1.11, 95% CI 1.03-1.20) or four or more children (OR = 1.27, 95% CI 1.14-1.42). Amongst those not cohabiting, having any number of children was associated with higher odds of lifetime depression. Our results were consistent across age groups, the sexes, neighbourhood deprivation and genetic risk for depression. Exploratory Mendelian randomisation analyses suggested a causal effect of number of children on lifetime depression. Limitations Our data did not allow distinguishing between non-marital and marital cohabitation. Results may not generalise to all ages or populations. Conclusions Living with a spouse or partner was strongly associated with reduced odds of depression. Having one or three or more children was associated with increased odds of depression, especially in individuals not living with a spouse or partner.

Purpose The tumor-stroma ratio (TSR) has repeatedly proven to be correlated with patient outcomes in breast cancer using large retrospective cohorts. However, studies validating the TSR often show variability in methodology, thereby hampering comparisons and uniform outcomes. Method This paper provides a detailed description of a simple and uniform TSR scoring method using Hematoxylin and Eosin (H&E)-stained core biopsies and resection tissue, specifically focused on breast cancer. Possible histological challenges that can be encountered during scoring including suggestions to overcome them are reported. Moreover, the procedure for TSR estimation in lymph nodes, scoring on digital images and the automatic assessment of the TSR using artificial intelligence are described. Conclusion Digitized scoring of tumor biopsies and resection material offers interesting future perspectives to determine patient prognosis and response to therapy. The fact that the TSR method is relatively easy, quick, and cheap, offers great potential for its implementation in routine diagnostics, but this requires high quality validation studies.

Objectives Initial trauma care could potentially be improved when conventional imaging and selective CT scanning is omitted and replaced by immediate total-body CT (iTBCT) scanning. Because of the potentially increased radiation exposure by this diagnostic approach, proper selection of the severely injured patients is mandatory. Methods In the REACT-2 trial, severe trauma patients were randomized to iTBCT or conventional imaging and selective CT based on predefined criteria regarding compromised vital parameters, clinical suspicion of severe injuries, or high-risk trauma mechanisms in five trauma centers. By logistic regression analysis with backward selection on the 15 study inclusion criteria, a revised set of criteria was derived and subsequently tested for prediction of severe injury and shifts in radiation exposure. Results In total, 1083 patients were enrolled with median ISS of 20 (IQR 9–29) and median GCS of 13 (IQR 3–15). Backward logistic regression resulted in a revised set consisting of nine original and one adjusted criteria. Positive predictive value improved from 76% (95% CI 74–79%) to 82% (95% CI 80–85%). Sensitivity decreased by 9% (95% CI 7–11%). The area under the receiver operating characteristics curve remained equal and was 0.80 (95% CI 0.77–0.83), original set 0.80 (95% CI 0.77–0.83). The revised set retains 8.78 mSv (95% CI 6.01–11.56) for 36% of the non-severely injured patients. Conclusions Selection criteria for iTBCT can be reduced from 15 to 10 clinically criteria. This improves the positive predictive value for severe injury and reduces radiation exposure for less severely injured patients. Key Points • Selection criteria for iTBCT can be reduced to 10 clinically useful criteria. • This reduces radiation exposure in 36% of less severely injured patients. • Overall discriminative capacity for selection of severely injured patients remained equal.

Transforming growth factor-β (TGF-β) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-β signaling by binding to the inhibitory SMAD7 and inducing its proteasomal degradation. How RNF12 activity is regulated and its exact role in cancer is incompletely understood. Here we report that RNF12 was overexpressed in invasive breast cancers and its high expression correlated with poor prognosis. RNF12 promoted breast cancer cell migration, invasion, and experimental metastasis in zebrafish and murine xenograft models. RNF12 levels were positively associated with the phosphorylated AKT/protein kinase B (PKB) levels, and both displayed significant higher levels in the basal-like subtype compared with the levels in luminal-like subtype of breast cancer cells. Mechanistically, AKT-mediated phosphorylation induced the nuclear localization of RNF12, maintained its stability, and accelerated the degradation of SMAD7 mediated by RNF12. Furthermore, we demonstrated that RNF12 and AKT cooperated functionally in breast cancer cell migration. Notably, RNF12 expression strongly correlated with both phosphorylated AKT and phosphorylated SMAD2 levels in breast cancer tissues. Thus, our results uncovered RNF12 as an important determinant in the crosstalk between the TGF-β and AKT signaling pathways during breast cancer progression.

Purpose Distal radius fractures are very common and account for approximately 17% of all fractures treated. Multiple treatment methods are available to treat these fractures, both operative and nonoperative. This study aimed at evaluating the functional and clinical outcomes after treatment of distal radius fractures with the IlluminOss® System in adult patients. Methods A retrospective case series was performed in a single-level two-trauma center. All consecutive adult patients with a distal radius fracture, treated with the IlluminOss® System between 01 August 2012 and 15 August 2015, were included in this study. Baseline patient characteristics and clinical data were retrospectively extracted from the medical records. Radial inclination, volar/dorsal tilt, ulnar variance, and radial length were measured on the latest available standard radiographs. In addition, patients were prospectively subjected to physical examination and were asked to complete the Disabilities of the Arm, Shoulder, and Hand, Patient-Rated Wrist Evaluation, and Short Form-36 questionnaires. Results Twenty-six patients with 31 distal radius fractures were included. The median age at time of trauma was 77 years and 96% were females. Five patients developed a total of seven complications. Due to persisting pain one reoperation was performed, removing a small prominent part of the implant. Both patient-reported outcome scores and radiographic results were good to excellent. Conclusions The IlluminOss® System is a feasible option to treat distal radius fractures with seemingly good clinical and functional outcome. One out of seven complications required surgical intervention. These outcomes justify more detailed prospective research.

The authors investigated the pathways (genetic, environmental, lifestyle, medical) leading to inflammation in major depressive disorder using C-reactive protein (CRP), genetic, and phenotypic data from the UK Biobank.This was a case-control study of 26,894 participants with a lifetime diagnosis of major depressive disorder from the Composite International Diagnostic Interview and 59,001 control subjects who reported no mental disorder and had not reported taking any antidepressant medication. Linear regression models of log CRP level were fitted to regress out the effects of age, sex, body mass index (BMI), and smoking and to test whether the polygenic risk score (PRS) for major depression was associated with log CRP level and whether the association between log CRP level and major depression remained after adjusting for early-life trauma, socioeconomic status, and self-reported health status.CRP levels were significantly higher in patients with depression relative to control subjects (2.4 mg/L compared with 2.1 mg/L, respectively), and more case than control subjects had CRP levels3 mg/L (21.2% compared with 16.8%, respectively), indicating low-grade inflammation. The PRS for depression was positively and significantly associated with log CRP levels, but this association was no longer significant after adjustment for BMI and smoking. The association between depression and increased log CRP level was substantially reduced, but still remained significant, after adjustment for the aforementioned clinical and sociodemographic factors.The data indicate that the "genetic" contribution to increased inflammation in depression is due to regulation of eating and smoking habits rather than an "autoimmune" genetic predisposition. Moreover, the association between depression and increased inflammation even after full adjustment indicates either the presence of yet unknown or unmeasured psychosocial and clinical confounding factors or that a core biological association between depression and increased inflammation exists independently from confounders.

Background The effect of immediate total-body CT (iTBCT) on health economic aspects in patients with severe trauma is an underreported issue. This study determined the cost-effectiveness of iTBCT compared with conventional radiological imaging with selective CT (standard work-up (STWU)) during the initial trauma evaluation. Methods In this multicentre RCT, adult patients with a high suspicion of severe injury were randomized in-hospital to iTBCT or STWU. Hospital healthcare costs were determined for the first 6 months after the injury. The probability of iTBCT being cost-effective was calculated for various levels of willingness-to-pay per extra patient alive. Results A total of 928 Dutch patients with complete clinical follow-up were included. Mean costs of hospital care were €25 809 (95 per cent bias-corrected and accelerated (bca) c.i. €22 617 to €29 137) for the iTBCT group and €26 155 (€23 050 to €29 344) for the STWU group, a difference per patient in favour of iTBCT of €346 (€4987 to €4328) (P = 0.876). Proportions of patients alive at 6 months were not different. The proportion of patients alive without serious morbidity was 61.6 per cent in the iTBCT group versus 66.7 per cent in the STWU group (difference −5.1 per cent; P = 0.104). The probability of iTBCT being cost-effective in keeping patients alive remained below 0.56 for the whole group, but was higher in patients with multiple trauma (0.8–0.9) and in those with traumatic brain injury (more than 0.9). Conclusion Economically, from a hospital healthcare provider perspective, iTBCT should be the diagnostic strategy of first choice in patients with multiple trauma or traumatic brain injury.

Women identified with an increased risk of breast cancer due to mutations in cancer susceptibility genes or a familial history of breast cancer undergo tailored screening with the goal of detecting tumors earlier, when potential curative interventions are still possible. Ideally, screening would identify signs of carcinogenesis even before a tumor is detectable by imaging. This could be achieved by timely signaling of altered biomarker levels for precancerous processes in liquid biopsies. Currently, the Nipple Aspirate Fluid (NAF) and the Trial Early Serum Test BREAST cancer (TESTBREAST), both ongoing, prospective, multicenter studies, are investigating biomarkers in liquid biopsies to improve breast cancer screening in high-risk women. The NAF study focuses on changes over time in miRNA expression levels both in blood and NAF samples, whereas the TESTBREAST study analyzes changes in protein levels in blood samples at sequential interval timepoints. These within-subject changes are studied in relation to later occurrence of breast cancer using a nested case–control design. These longitudinal studies face their own challenges in execution, such as hindrances in logistics and in sample processing that were difficult to anticipate. This article offers insight into those challenges and concurrently aims to provide useful strategies for the set-up of similar studies. See related commentary by Sauter, p. 429

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p=2.5x10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials. White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

Background Identifying causal risk factors for self-harm is essential to inform preventive interventions. Epidemiological studies have identified risk factors associated with self-harm, but these associations can be subject to confounding. By implementing genetically informed methods to better account for confounding, this study aimed to better identify plausible causal risk factors for self-harm. Methods and findings Using summary statistics from 24 genome-wide association studies (GWASs) comprising 16,067 to 322,154 individuals, polygenic scores (PSs) were generated to index 24 possible individual risk factors for self-harm (i.e., mental health vulnerabilities, substance use, cognitive traits, personality traits, and physical traits) among a subset of UK Biobank participants (N = 125,925, 56.2% female) who completed an online mental health questionnaire in the period from 13 July 2016 to 27 July 2017. In total, 5,520 (4.4%) of these participants reported having self-harmed in their lifetime. In binomial regression models, PSs indexing 6 risk factors (major depressive disorder [MDD], attention deficit/hyperactivity disorder [ADHD], bipolar disorder, schizophrenia, alcohol dependence disorder, and lifetime cannabis use) predicted self-harm, with effect sizes ranging from odds ratio (OR) = 1.05 (95% CI 1.02 to 1.07, q = 0.008) for lifetime cannabis use to OR = 1.20 (95% CI 1.16 to 1.23, q = 1.33 × 10−35) for MDD. No systematic differences emerged between suicidal and non-suicidal self-harm. To further probe causal relationships, two-sample Mendelian randomisation (MR) analyses were conducted, with MDD, ADHD, and schizophrenia emerging as the most plausible causal risk factors for self-harm. The genetic liabilities for MDD and schizophrenia were associated with self-harm independently of diagnosis and medication. Main limitations include the lack of representativeness of the UK Biobank sample, that self-harm was self-reported, and the limited power of some of the included GWASs, potentially leading to possible type II error. Conclusions In addition to confirming the role of MDD, we demonstrate that ADHD and schizophrenia likely play a role in the aetiology of self-harm using multivariate genetic designs for causal inference. Among the many individual risk factors we simultaneously considered, our findings suggest that systematic detection and treatment of core psychiatric symptoms, including psychotic and impulsivity symptoms, may be beneficial among people at risk for self-harm., Kai Xiang Lim and co-workers use genetic instruments to investigate risk factors associated with self-harm., Author summary Why was this study done? Self-harm is an act of self-injury or self-poisoning carried out by an individual and can be subdivided into suicidal and non-suicidal self-harm. Self-harm has been found to be associated with a range of risk factors, but these associations can be subject to confounding. Using genetic information to help strengthen causal inference can help to identify plausibly causal risk factors for self-harm. What did the researchers do and find? We used data from UK Biobank participants, who provided their genetic information and answered questions about their engagement in self-harming. We investigated 24 potential individual risk factors for self-harm. Out of these 24 risk factors, major depressive disorder, attention-deficit hyperactivity disorder and schizophrenia appeared to be the most plausible causal risk factors for self-harm. No difference emerged between risk factors for non-suicidal and suicidal self-harm. What do these findings mean? Using a different design, with different sets of assumptions, than epidemiological studies that are not genetically informed, we showed that psychiatric symptoms related to major depressive disorder, attention deficit/hyperactivity disorder, and schizophrenia plausibly play a role as individual risk factors leading to an increased risk of self-harm. Detecting and treating psychiatric symptoms, such as impulsivity and psychotic symptoms, may be helpful for people at risk for self-harm.

BACKGROUND AND OBJECTIVES: Imagery rescripting is an effective treatment strategy for trauma related disorders, but its underlying mechanisms are still largely unknown. The aim of the present study was to test whether a) imagery (versus writing) is essential in the process of rescripting, and b) rescripting affects emotional memories on an implicit level.METHODS: Healthy participants were subjected to an experimental trauma ('trauma film'), and randomly allocated to four conditions: recall of film + Imagery Rescripting (ImRs), recall of film + Writing Rescripting (WRs), recall only (ImRE), or no recall + no manipulation (NM). Next, participants recorded intrusion frequency and distress during one week, after which they executed a visual interference task (VIT) including neutral and trauma film stills, to access implicit emotional memory.RESULTS: Main findings were that ImRs and WRs resulted in fewer intrusions than NM, with no differences between both rescripting conditions. We did not find an effect on intrusion distress and the VIT.LIMITATIONS: Stills in the VIT were distracted from all four film scenes, whereas rescripting was done on one scene only, possibly obscuring the effect. Also, an analogue sample was used, which may limit generalizability to clinical samples.CONCLUSIONS: We replicated previous effects of ImRs on intrusion development. Furthermore, no superior effect of imagery as key modality for rescripting was found; writing seems a viable alternative. Measures for implicit emotional memory such as the VIT may have to be applied relatively soon after the experimental session (e.g., same day as the experimental session).

Purpose Flail chest was traditionally treated non-operatively using mechanical ventilation and pain control. In order to reduce the occurrence of ventilation-associated complications and long-term disability, operative rib fixation is becoming a proven standard therapy for these patients. However, the consequences of the surgical complications may influence success rates negatively. The aim of this study was to compare the outcome of flail chest treatment by surgical rib fixation with non-operative treatment, with special focus on the impact of surgical complications. Methods A retrospective case series of operatively treated flail chest patients was compared with non-operatively treated patients. Patients’ injury and treatment characteristics and outcome parameters (e.g., duration of mechanical ventilation, length of Intensive Care stay (ICLOS) and hospital length of stay (HLOS), mortality, surgery-related complications and pneumonia) were collected from the patients’ medical files. Crude and matched-pairs analyses were performed in SPSS. Results Twenty-three operatively and 47 non-operatively treated patients were enrolled. Operatively treated patients required significantly shorter mechanical ventilation; median 4 days versus 12 days for the non-operative group (p = 0.011). The matched-pairs analysis also showed a lower pneumonia rate (35% versus 80%; p = 0.035) and a shorter HLOS (median 21 versus 23 days; p = 0.028) in the operative group. No significant differences in duration of ICLOS, and occurrence of other injury-related adverse events were found between both groups. Seven surgery-related complications occurred, of which three required invasive solutions. Conclusions Operative fixation of a flail chest in trauma patients results in a lower rate of pneumonia, less mechanical ventilation days and shorter hospital stay, compared with non-operative treatment, but at the cost of surgery-related complications requiring invasive solutions in some cases.

Background The peri-traumatic stress response is a strong predictor of symptom development after trauma exposure. Regarding witnessing trauma, the stress response might depend on the susceptibility to others' emotions (emotional contagion, EC). This study investigated whether EC moderates the immediate stress response using a trauma film paradigm. Methods Ninety-five healthy participants were randomly exposed to a trauma or a neutral film. Perceived stressfulness of the film and pre-to post-film changes in self-reported anxiety, heart rate and saliva cortisol levels were assessed. EC towards negative and positive emotions was measured using the emotional contagion scale and its emotion-specific subscales. Results Overall, the trauma film was perceived as distressing and elicited an increase in self-reported anxiety, heart rate and saliva cortisol levels relative to the neutral film. EC towards negative emotions was positively related to the perceived stressfulness of the film, increased anxiety and increased heart rate. The association with saliva cortisol levels was also in the expected direction, but not statistically significant. These associations were not found for EC towards positive emotions. Discussion EC towards negative emotions may be an important predictor of trauma exposure outcomes. Further research should clarify its specific contribution in witnessing and undergoing trauma.

Insufficient hemodynamics during agonal phase-i.e. the period between withdrawal of life-sustaining treatment and circulatory arrest-in Maastricht category III circulatory-death donors (DCD) potentially exacerbate ischemia/reperfusion injury. We included 409 Dutch adult recipients of DCD donor kidneys transplanted between 2006 and 2014. Peripheral oxygen saturation (SpO2-with pulse oximetry at the fingertip) and systolic blood pressure (SBP-with arterial catheter) were measured during agonal phase, and were dichotomized into minutes of SpO2>60% or SpO2 80 mmHg or SBP

Intelligence, or general cognitive function, is phenotypically and genetically correlated with many traits, including a wide range of physical, and mental health variables. Education is strongly genetically correlated with intelligence (rg = 0.70). We used these findings as foundations for our use of a novel approach—multi-trait analysis of genome-wide association studies (MTAG; Turley et al. 2017)—to combine two large genome-wide association studies (GWASs) of education and intelligence, increasing statistical power and resulting in the largest GWAS of intelligence yet reported. Our study had four goals: first, to facilitate the discovery of new genetic loci associated with intelligence; second, to add to our understanding of the biology of intelligence differences; third, to examine whether combining genetically correlated traits in this way produces results consistent with the primary phenotype of intelligence; and, finally, to test how well this new meta-analytic data sample on intelligence predicts phenotypic intelligence in an independent sample. By combining datasets using MTAG, our functional sample size increased from 199,242 participants to 248,482. We found 187 independent loci associated with intelligence, implicating 538 genes, using both SNP-based and gene-based GWAS. We found evidence that neurogenesis and myelination—as well as genes expressed in the synapse, and those involved in the regulation of the nervous system—may explain some of the biological differences in intelligence. The results of our combined analysis demonstrated the same pattern of genetic correlations as those from previous GWASs of intelligence, providing support for the meta-analysis of these genetically-related phenotypes.

The authors declare no competing financial interests except for the following. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; O.H.F. received grants from Metagenics (on women’s health and epigenetics) and from Nestle (on child health); L.J.B. is listed as an inventor on Issued U.S. Patent 8,080,371,“Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction; P.S. has received research awards from Pfizer Inc., is a consultant for Mundipharma Co. (Cambridge, UK), is a patent holder with Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor; Patent number: 20120263794), and has a patent application with University of Heidelberg (Heidelberg, Germany) (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; Europäische Patentanmeldung 15 000 771.4); P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative (IMI) project; M.A.N.’s participation is supported by a consulting contract between Data Tecnica Internation and the National Institute on Aging (NIH, Bethesda, MD, USA), and he also consults for Illumina, Inc., the Michael J. Fox Foundation, and University of California Healthcare among others; and M.J.C. is Chief Scientist for Genomics England, a UK government company.; International audience; Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined approximately 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

Publisher's version (útgefin grein)., Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension., The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Contains fulltext : 191289.pdf (Publisher’s version ) (Open Access) Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 x 10(-21)), left fusiform gyrus (d=-0.288; P=8.25 x 10(-21)) and left rostral middle frontal cortex (d=-0.276; P=2.99 x 10(-19)). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Background and Objectives Neuraxial blockade using a midline approach can be challenging. Part of this challenge lies in finding the optimal approach of the needle to its target. The present study aimed at finding (1) the optimal point of insertion of the needle between the tips of 2 adjacent spinous processes and (2) the optimal angle relative to the skin at which the needle should approach the epidural or subarachnoid space. Methods A computer algorithm systematically analyzed computed tomography scans of vertebral columns of a cohort of 52 patients. On midsagittal sections, the possible points of insertion of a virtual needle and the corresponding angles through which the epidural or subarachnoid space can be reached were calculated. Results The point chosen to introduce the needle between 2 adjacent spinous processes determines the range of angles through which the epidural or subarachnoid space can be reached. At the thoracic interspaces 1-2 through 3-4, thoracic interspaces 5-6 through 9-10, and at the lumbar vertebral interspaces 2-3 through 4-5, the optimal point of insertion is slightly inferior to the point halfway between the tips of the spinous processes. For thoracic interspace 4-5, the optimal point of insertion is slightly superior to the point halfway between the tips of the spinous processes. For the other interspaces, the optimal point of insertion is approximately halfway between the tips of the spinous processes. The optimal angle to direct the needle varies from 9 degrees at the thoracolumbar junction and at the lumbar interspaces 3-4 and 4-5, to 53 degrees at the thoracic interspace 7-8. Conclusions Our study has resulted in practical suggestions-based on accurate, reproducible measurements in patients-As to where to insert the needle and how to angulate the needle when performing neuraxial anesthesia using a midline approach.

INTRODUCTION: It’s imperative to understand the specific and shared aetiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. METHODS: Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic aetiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in eleven data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. RESULTS: All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. CONCLUSIONS: The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic aetiology irrespective of the age depression first presents.

Background: Living in livestock-dense areas has been associated with health effects, suggesting airborne exposures to livestock farm emissions to be relevant for public health. Livestock farm emissions involve complex mixtures of various gases and particles. Endotoxin, a pro-inflammatory agent of microbial origin, is a constituent of livestock farm emitted particulate matter (PM) that is potentially related to the observed health effects. Quantification of livestock associated endotoxin exposure at residential addresses in relation to health outcomes has not been performed earlier. Objectives: We aimed to assess exposure-response relations for a range of respiratory endpoints and atopic sensitization in relation to livestock farm associated PM10 and endotoxin levels. Methods: Self-reported respiratory symptoms of 12,117 persons participating in a population-based cross-sectional study were analyzed. For 2494 persons, data on lung function (spirometry) and serologically assessed atopic sensitization was additionally available. Annual-average PM10 and endotoxin concentrations at home addresses were predicted by dispersion modelling and land-use regression (LUR) modelling. Exposure-response relations were analyzed with generalized additive models. Results: Health outcomes were generally more strongly associated with exposure to livestock farm emitted endotoxin compared to PM10. An inverse association was observed for dispersion modelled exposure with atopic sensitization (endotoxin: p = .004, PM10: p = .07) and asthma (endotoxin: p = .029, PM10: p = .022). Prevalence of respiratory symptoms decreased with increasing endotoxin concentration at the lower range, while at the higher range prevalence increased with increasing concentration (p .05). Conclusions: Exposure to livestock farm emitted particulate matter is associated with respiratory health effects and atopic sensitization in non-farming residents. Results indicate endotoxin to be a potentially plausible etiologic agent, suggesting non-infectious aspects of microbial emissions from livestock farms to be important with respect to public health. Keywords: Livestock farming, Emissions, Air pollution, Public health, Spatial modelling, Endotoxin

People’s differences in cognitive functions are partly heritable and are associated with important life outcomes. Previous genome-wide association (GWA) studies of cognitive functions have found evidence for polygenic effects yet, to date, there are few replicated genetic associations. Here we use data from the UK Biobank sample to investigate the genetic contributions to variation in tests of three cognitive functions and in educational attainment. GWA analyses were performed for verbal–numerical reasoning (N=36 035), memory (N=112 067), reaction time (N=111 483) and for the attainment of a college or a university degree (N=111 114). We report genome-wide significant single-nucleotide polymorphism (SNP)-based associations in 20 genomic regions, and significant gene-based findings in 46 regions. These include findings in the ATXN2, CYP2DG, APBA1 and CADM2 genes. We report replication of these hits in published GWA studies of cognitive function, educational attainment and childhood intelligence. There is also replication, in UK Biobank, of SNP hits reported previously in GWA studies of educational attainment and cognitive function. GCTA-GREML analyses, using common SNPs (minor allele frequency>0.01), indicated significant SNP-based heritabilities of 31% (s.e.m.=1.8%) for verbal–numerical reasoning, 5% (s.e.m.=0.6%) for memory, 11% (s.e.m.=0.6%) for reaction time and 21% (s.e.m.=0.6%) for educational attainment. Polygenic score analyses indicate that up to 5% of the variance in cognitive test scores can be predicted in an independent cohort. The genomic regions identified include several novel loci, some of which have been associated with intracranial volume, neurodegeneration, Alzheimer’s disease and schizophrenia.

Introduction: Prospective studies reporting associations between cognitive performance and subsequent incident dementia have been subject to attrition bias. Furthermore, the extent to which established risk factors account for such associations requires further elucidation. Methods: We used UK Biobank baseline cognitive data (n ≤ 488,130) and electronically linked hospital inpatient and death records during three‐ to eight‐year follow‐up, to estimate risk of total dementia (n = 1051), Alzheimer's disease (n = 352), and vascular dementia (n = 169) according to four brief cognitive tasks, with/without adjustment for constitutional and modifiable risk factors. Results: We found associations of cognitive task performance with all‐cause and cause‐specific dementia (P < .01); these were not accounted for by established risk factors. Cognitive data added up to 5% to the discriminative accuracy of receiver operating characteristic curve models; areas under the curve ranged from 82% to 86%. Discussion: This study offers robust evidence that brief cognitive testing could be a valuable addition to dementia prediction models.

Tonic immobility (TI; state of motor inhibition during threat) has been implicated in the onset of intrusive trauma memories, while controllability was associated with reduced anxiety. The present study investigated the interaction between TI and control in the development of intrusive memories of an analogue trauma. Sixty-four participants watched negative pictures while being allowed to close their eyes (InControl) or not (NoControl). They completed measures for spontaneous TI afterwards and recorded intrusive memories of the pictures in a diary in the subsequent week. Bayesian analyses were used to test informative hypotheses. Spontaneous TI during picture viewing was positively associated with increased intrusion frequency. Intrusion frequency did not differ for InControl versus NoControl. Moderation (control x TI) and non-moderation (main effect of TI only) were both adequate models, with no preference. Our results confirm the importance of TI in PTSD development. Implications of the findings regarding control merit more research.

Higher health literacy is associated with higher cognitive function and better health. Despite its wide use in medical research, no study has investigated the genetic contributions to health literacy. Using 5783 English Longitudinal Study of Ageing (ELSA) participants (mean age = 65.49, SD = 9.55) who had genotyping data and had completed a health literacy test at wave 2 (2004–2005), we carried out a genome-wide association study (GWAS) of health literacy. We estimated the proportion of variance in health literacy explained by all common single nucleotide polymorphisms (SNPs). Polygenic profile scores were calculated using summary statistics from GWAS of 21 cognitive and health measures. Logistic regression was used to test whether polygenic scores for cognitive and health-related traits were associated with having adequate, compared to limited, health literacy. No SNPs achieved genome-wide significance for association with health literacy. The proportion of variance in health literacy accounted for by common SNPs was 8.5% (SE = 7.2%). Greater odds of having adequate health literacy were associated with a 1 standard deviation higher polygenic score for general cognitive ability [OR = 1.34, 95% CI (1.26, 1.42)], verbal-numerical reasoning [OR = 1.30, 95% CI (1.23, 1.39)], and years of schooling [OR = 1.29, 95% CI (1.21, 1.36)]. Reduced odds of having adequate health literacy were associated with higher polygenic profiles for poorer self-rated health [OR = 0.92, 95% CI (0.87, 0.98)] and schizophrenia [OR = 0.91, 95% CI (0.85, 0.96)). The well-documented associations between health literacy, cognitive function and health may partly be due to shared genetic etiology. Larger studies are required to obtain accurate estimates of SNP-based heritability and to discover specific health literacy-associated genetic variants.

In the Netherlands, an association was found between the prevalence of pneumonia and living near goat and poultry farms in 2007-2013. This association then led to regulatory decisions to restrict the building of new goat farms and to reduce emissions of poultry farms. Confirmation of these results, however, is required because the period of previous analyses overlapped a Q-fever epidemic in 2007-2010. To confirm the association, we performed a population-based study during 2014-2016 based on general practitioner (GP) data. Electronic medical records of 90,183 persons were used to analyze the association between pneumonia and the population living in the proximity (within 500-2000 m distance) of goat and poultry farms. Data were analyzed with three types of logistic regression (with and without GP practice as a random intercept and with stratified analyses per GP practice) and a kernel model to discern the influence of different statistical methods on the outcomes. In all regression analyses involving adults, a statistically significant association between pneumonia and residence within 500 meters of goat farms was found (odds ratio [OR] range over all analyses types: 1.33-1.60), with a decreasing OR for increasing distances. In kernel analyses (including all ages), a population-attributable risk between 6.0 and 7.8% was found for a distance of 2000 meters in 2014-2016. The associations were consistent across all years and robust for mutual adjustment for proximity to other animals and for several other sensitivity analyses. However, associations with proximity to poultry farms are not supported by the present study. As the causes of the elevated pneumonia incidence in persons living close to goat farms remain unknown, further research into potential mechanisms is required for adequate prevention.

We examined associations between self-reported sleep measures and cognitive level and change (age 70–76 years) in a longitudinal, same-year-of-birth cohort study (baseline N = 1091; longitudinal N = 664). We also leveraged GWAS summary data to ascertain whether polygenic scores (PGS) of chronotype and sleep duration related to self-reported sleep, and to cognitive level and change. Shorter sleep latency was associated with significantly higher levels of visuospatial ability, processing speed, and verbal memory (β ≥ |0.184|, SE ≤ 0.075, p ≤ 0.003). Longer daytime sleep duration was significantly associated slower processing speed (β = −0.085, SE = 0.027, p = 0.001), and with steeper 6-year decline in visuospatial reasoning (β = −0.009, SE = 0.003, p = 0.008), and processing speed (β = −0.009, SE = 0.002, p < 0.001). Only longitudinal associations between longer daytime sleeping and steeper cognitive declines survived correction for important health covariates and false discovery rate (FDR). PGS of chronotype and sleep duration were nominally associated with specific self-reported sleep characteristics for most SNP thresholds (standardized β range = |0.123 to 0.082|, p range = 0.003 to 0.046), but neither PGS predicted cognitive level or change following FDR. Daytime sleep duration is a potentially important correlate of cognitive decline in visuospatial reasoning and processing speed in older age, whereas cross-sectional associations are partially confounded by important health factors. A genetic propensity toward morningness and sleep duration were weakly, but consistently, related to self-reported sleep characteristics, and did not relate to cognitive level or change.

Major depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

Evidence suggests that lifestyle factors, e.g. physical activity, moderate the manifestation of genetic susceptibility to obesity. The present study uses UK Biobank data to investigate interaction between polygenic scores (PGS) for two obesity indicators, and lifestyle and psychosocial factors in the prediction of the two indicators, with attention to sex-specific effects. Analyses were of 112 151 participants (58 914 females; 40 to 73 years) whose genetic data passed quality control. Moderation effects were analysed in linear regression models predicting body mass index (BMI) and waist-to-hip ratio (WHR), including interaction terms for PGS and each exposure. Greater physical activity, more education, higher income, moderate vs low alcohol consumption, and low material deprivation were each associated with a relatively lower risk for manifestation of genetic susceptibility to obesity (p

T-cell immunity in the liver is tightly regulated to prevent chronic liver inflammation in response to antigens and toxins derived from food and intestinal bacterial flora. Since the main sites of T cell activation in response to foreign components entering solid tissues are the draining lymph nodes (LN), we aimed to study whether Antigen-Presenting Cell (APC) subsets in human liver lymph-draining LN show features that may contribute to the immunologically tolerant liver environment. Healthy liver LN, iliac LN, spleen and liver perfusates were obtained from multi-organ donors, while diseased liver LN were collected from explanted patient livers. Inguinal LN were obtained from kidney transplant recipients. Mononuclear cells were isolated from fresh tissues, and immunophenotypic and functional characteristics of APC subsets were studied using flowcytometry and in ex vivo cultures. Healthy liver-draining LN contained significantly lower relative numbers of CD1c+ conventional dendritic cells (cDC2), plasmacytoid DC (PDC), and CD14+CD163+DC-SIGN+ macrophages (MF) compared to inguinal LN. Compared to spleen, both types of LN contained low relative numbers of CD141hi cDC1. Both cDC subsets in liver LN showed a more activated/mature immunophenotype than those in inguinal LN, iliacal LN, spleen and liver tissue. Despite their more mature status, cDC2 isolated from hepatic LN displayed similar cytokine production capacity (IL-10, IL-12, and IL-6) and allogeneic T cell stimulatory capacity as their counterparts from spleen. Liver LN from patients with inflammatory liver diseases showed a further reduction of cDC1, but had increased relative numbers of PDC and MF. In steady state conditions human liver LN contain relatively low numbers of cDC2, PDC, and macrophages, and relative numbers of cDC1 in liver LN decline during liver inflammation. The paucity of cDC in liver LN may contribute to immune tolerance in the liver environment.

Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total n deaths = 79,702) and ∼2.4% lower risk for fathers (total n deaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity. Marioni RE, Ritchie SJ, Joshi PK, Hagenaars SP, Okbay A, Fischer K, Adams MJ, Hill WD, Davies G, Social Science Genetic Association Consortium, Nagy R, Amador C, Läll K, Metspalu A, Liewald DC, Campbell A, Wilson JF, Hayward C, Esko T, Porteous DJ, Proceedings of the National Academy of Sciences of the United States of America, 2016, vol. 113, no. 47, pp. 13366-13371, 2016 Refereed/Peer-reviewed

Quantifying the microstructural properties of the human brain's connections is necessary for understanding normal ageing and disease. Here we examine brain white matter magnetic resonance imaging (MRI) data in 3,513 generally healthy people aged 44.64–77.12 years from the UK Biobank. Using conventional water diffusion measures and newer, rarely studied indices from neurite orientation dispersion and density imaging, we document large age associations with white matter microstructure. Mean diffusivity is the most age-sensitive measure, with negative age associations strongest in the thalamic radiation and association fibres. White matter microstructure across brain tracts becomes increasingly correlated in older age. This may reflect an age-related aggregation of systemic detrimental effects. We report several other novel results, including age associations with hemisphere and sex, and comparative volumetric MRI analyses. Results from this unusually large, single-scanner sample provide one of the most extensive characterizations of age associations with major white matter tracts in the human brain., Part of understanding ageing involves knowing how the brain's connecting pathways change in healthy aging. Here, authors provide a detailed characterisation of data from 3513 UK Biobank participants, and show that the microstructure of these pathways becomes more similar with age.

Summary Individuals with lower socio-economic status (SES) are at increased risk of physical and mental illnesses and tend to die at an earlier age [1, 2, 3]. Explanations for the association between SES and health typically focus on factors that are environmental in origin [4]. However, common SNPs have been found collectively to explain around 18% of the phenotypic variance of an area-based social deprivation measure of SES [5]. Molecular genetic studies have also shown that common physical and psychiatric diseases are partly heritable [6]. It is possible that phenotypic associations between SES and health arise partly due to a shared genetic etiology. We conducted a genome-wide association study (GWAS) on social deprivation and on household income using 112,151 participants of UK Biobank. We find that common SNPs explain 21% of the variation in social deprivation and 11% of household income. Two independent loci attained genome-wide significance for household income, with the most significant SNP in each of these loci being rs187848990 on chromosome 2 and rs8100891 on chromosome 19. Genes in the regions of these SNPs have been associated with intellectual disabilities, schizophrenia, and synaptic plasticity. Extensive genetic correlations were found between both measures of SES and illnesses, anthropometric variables, psychiatric disorders, and cognitive ability. These findings suggest that some SNPs associated with SES are involved in the brain and central nervous system. The genetic associations with SES obviously do not reflect direct causal effects and are probably mediated via other partly heritable variables, including cognitive ability, personality, and health., Highlights • Common SNPs explain 21% of social deprivation and 11% of household income • Two loci attained genome-wide significance for household income • Genes in these loci have been linked to synaptic plasticity • Genetic correlations were found between both measures of SES and many other traits, Individuals with lower socio-economic status (SES) are at increased risk of physical and mental illnesses. Hill et al. find extensive genetic correlations between SES and health, psychiatric, and cognitive traits. This suggests that the link between SES and health is driven, in part, by a shared genetic association.

Contains fulltext : 172623.pdf (Publisher’s version ) (Closed access) Coxiella burnetii, the causative agent of Q fever, is recognized by TLR2. TLR10 can act as an inhibitory receptor on TLR2-derived immune responses. Therefore, we investigated the role of TLR10 on C. burnetii-induced cytokine production and assessed whether genetic polymorphisms in TLR10 influences the development of chronic Q fever. HEK293 cells, transfected with TLR2, TLR10 or TLR2/TLR10, and human peripheral blood mononuclear cells (PBMCs) in the presence of anti-TLR10, were stimulated with C. burnetii. In both assays, the absence of TLR10 resulted in increased cytokine responses after C. burnetii stimulation. In addition, the effect of single nucleotide polymorphisms (SNPs) in TLR10 was examined in healthy volunteers whose PBMCs were stimulated with C. burnetii Nine Mile or the Dutch outbreak isolate C. burnetii 3262. Individuals bearing SNPs in TLR10 displayed increased cytokine production upon C. burnetii 3262 stimulation. Furthermore, 139 chronic Q fever patients and 220 controls were genotyped for TLR10 N241H, I775V and I369L. None of these polymorphisms were associated with increased susceptibility to chronic Q fever. In conclusion, TLR10 has an inhibitory effect on in vitro cytokine production by C. burnetii, but the presence of TLR10 polymorphisms does not lead to an increased risk of developing chronic Q fever.

Background Preclinical data suggest that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial.Methods In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks ' gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevoflurane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratified by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov, number NCT00756600.Findings Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98.6 (14.2) in the awake-regional group and 98.2 (14.7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0.169, 95% CI-2.30 to 2.64). The median duration of anaesthesia in the general anaesthesia group was 54 min.Interpretation For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia.Funding Australia National Health and Medical Research Council (NHMRC), Health Technologies Assessment-National Institute for Health Research UK, National Institutes of Health, Food and Drug Administration, Australian and New Zealand College of Anaesthetists, Murdoch Childrens Research Institute, Canadian Institute of Health Research, Canadian Anesthesiologists ' Society, Pfizer Canada, Italian Ministry of Heath, Fonds NutsOhra, and UK Clinical Research Network (UKCRN).

Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximalN= 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes

Exposure-based treatment for anxiety disorders is effective for many patients, but relapse is not uncommon. One predictor of the return of fear is the negative valence of fear-relevant stimuli. The aim of the current experiments was to examine whether counterconditioning with positive film clips reduces this negative stimulus valence as well as the return of fear, compared to standard extinction training and to an extinction training with non-contingent exposure to the positive film clips. Participants were 87 students in Experiment 1 (three-day paradigm), and 90 students in Experiment 2 (one-day paradigm). They first underwent a differential acquisition phase, in which one of three pictures was paired with an electric shock. They were then randomly allocated to one of the three intervention groups. Afterwards, they underwent a test phase in which pictures were presented without shock (to measure spontaneous recovery of fear), which was followed by unsignaled shocks to induce reinstatement of extinguished fear. Outcome variables were self-reported stimulus valence, shock expectancy, skin conductance, and fear-potentiated startle. In both experiments, counterconditioning decreased negative stimulus valence, relative to the other interventions, but it did not reduce spontaneous fear recovery or fear reinstatement. Overall, our findings do not support the notion that counterconditioning reduces return of fear.

Frontal EEG theta/beta ratio (TBR; negatively associated with attentional control, or AC) was previously reported to moderate threat‐level dependent attentional bias in a pictorial dot‐probe task, interacting with trait anxiety. Unexpectedly, this was independent from processing stage (using cue‐target delays of 200 and 500 ms) and also not observed for self‐reported trait AC. We therefore aimed to replicate these effects of TBR and trait anxiety and to test if effects of early versus late processing stages are evident for shorter cue‐target delays. This study also revisited the hypothesis that TBR and self‐reported trait AC show similar effects. Fifty‐three participants provided measurements of frontal TBR, self‐reported trait AC, trait anxiety, and dot‐probe task bias for mild and high threat pictures using the same dot‐probe task, but this time with 80‐ and 200‐ms cue‐target delays. Results indicated that higher TBR predicted more attention to mild than high threat, but this was independent from trait anxiety or delay. Lower self‐reported trait AC predicted more attention to mild than high threat, only after 200 ms (also independent of trait anxiety). We conclude that the moderating effect of TBR on threat‐level dependent dot‐probe task bias was replicated, but not the role of trait anxiety, and this study partially confirms that effects of trait AC are more dominant in later processing.

Polygenic scores can be used to distil the knowledge gained in genome-wide association studies for prediction of health, lifestyle, and psychological factors in independent samples. In this preregistered study, we used fourteen polygenic scores to predict variation in cognitive ability level at age 70, and cognitive change from age 70 to age 79, in the longitudinal Lothian Birth Cohort 1936 study. The polygenic scores were created for phenotypes that have been suggested as risk or protective factors for cognitive ageing. Cognitive abilities within older age were indexed using a latent general factor estimated from thirteen varied cognitive tests taken at four waves, each three years apart (initial n = 1091 age 70; final n = 550 age 79). The general factor indexed over two-thirds of the variance in longitudinal cognitive change. We ran additional analyses using an age-11 intelligence test to index cognitive change from age 11 to age 70. Several polygenic scores were associated with the level of cognitive ability at age-70 baseline (range of standardized β-values = -0.178 to 0.302), and the polygenic score for education was associated with cognitive change from childhood to age 70 (standardized β = 0.100). No polygenic scores were statistically significantly associated with variation in cognitive change between ages 70 and 79, and effect sizes were small. However, APOE e4 status made a significant prediction of the rate of cognitive decline from age 70 to 79 (standardized β = -0.319 for carriers vs. non-carriers). The results suggest that the predictive validity for cognitive ageing of polygenic scores derived from genome-wide association study summary statistics is not yet on a par with APOE e4, a better-established predictor.