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Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Despite the negative health consequences associated with smoking, most smokers find it difficult to quit. This is especially true for smokers with elevated social anxiety. One factor that may play a role in maintaining smoking with elevated anxiety is false safety behavior (FSB), behaviors geared toward decreasing anxiety short-term but that maintain or increase anxiety long-term. The present study tested whether FSB explained the relation of social anxiety severity with smoking among 71 current smokers. Avoidance-related FSB was the only type of FSB related to cigarettes smoked per day (CPD) and it was robustly related to more CPD. Further, social anxiety was related to CPD indirectly via FSB-Avoidance. Findings suggest that more frequent use of avoidance behaviors to manage anxiety may maintain smoking and may partially explain the high rates of smoking among those with elevated social anxiety. Thus, FSB may be a promising target in smoking cessation interventions, especially among those with elevated social anxiety.

The Coronavirus disease 2019 (COVID-19) pandemic has contributed to over 500,000 deaths, and hospitalization of thousands of individuals worldwide. Cross-sectional data indicate that anxiety and depression levels are greater during the pandemic, yet no known prospective studies have tested this assertion. Further, individuals with elevated trait anxiety prior to a global pandemic may theoretically be more apt to experience greater pandemic-related anxiety and/or impairment. The current study tested whether anxiety and depression increased from the month before the state's Stay-At-Home order to the period of the Stay-At-Home order among 120 young adults in Louisiana, a state with especially high rates of COVID-19 related infections and deaths. We also tested whether pre-pandemic social anxiety was related to greater pandemic related anxiety, depression, and COVID-related worry and impairment. Depression but not anxiety increased during the Stay-At-Home order. Further, pre-pandemic trait anxiety, social anxiety, and depression were statistically significant predictors of anxiety and depression during the Stay-At-Home order, although only social anxiety was robustly related to COVID-related worry and impairment. Emotional distress increased during the COVID-19 pandemic Stay-At-Home order and this is especially the case among individuals with pre-pandemic elevations in trait anxiety (especially social anxiety) and depression.

High grade gliomas/diffuse midline gliomas (HGG/DMG) historically have a poor prognosis with an overall survival of less than 20% at 5 years. The pathophysiology is under close investigation across the world in efforts to understand this tumor type with aims of increasing effective treatment options. We present our results on the feasibility and outcomes of patients treated on our Molecular Guided Therapy study. Tumor samples were analyzed with whole exome (DNA) and RNA sequencing. Three drug matching algorithms were utilized to generate a report that was reviewed at a multi-institutional tumor board meeting, culminating in a proposed treatment protocol. Eleven patients enrolled, but one did not complete cycle 1 of therapy due to progression of disease, thus ten patients (6-HGG, 4-DMG) were evaluable and received at least 2 cycles of therapy. Time to reports generated and tumor board assembly was (median) 18 and 24 days, respectively. Secondary goals included evaluation of efficacy. Responses showed 50% of patients with stable disease or better at 2 cycles of therapy, but these were temporary with median time to progression of 81 days. In conclusion, we determined that it is feasible to collect individual biological DNA and RNA sequencing information to offer patients individualized treatment plans for this devastating group of diseases. Though data is not statistically significant, we show that there is a suggestion of efficacy in this approach to treatment for patients, indicating a need to expand on this treatment approach with individualized medicine.

The properties of thin supported polymer films can be dramatically impacted by the substrate upon which it resides. A simple way to alter the properties of the substrate (chemistry, rigidity, dynamics) is by coating it with an immiscible polymer. Here we describe how ultrathin (ca. 2 nm) hydrophilic polymer layers of poly(acrylic acid), PAA, and poly(styrenesulfonate), PSS, impact the aging behavior and the residual stress in thin films of poly(butylnorbornene-ran-hydroxyhexafluoroisopropyl norbornene), BuNB-r-HFANB. The aging rate decreases as the film thickness (h) is decreased, but the extent of this change depends on the adjacent layer. Even for the thickest films (h>500 nm), there is a decrease in the aging rate at 100 °C when BuNB-r-HFANB is in contact with PSS. In an effort to understand the origins of these differences in the aging behavior, the elastic modulus and residual stress (σ(R)) in the films were determined by wrinkling as a function of aging time. The change in the elastic modulus during aging does not appear to be directly correlated with the densification or expansion of the films, but the aging rates appear to roughly scale as hσ(R)(1/3). These results illustrate that the physical aging of thin polymer films can be altered by adjacent polymers.

Cannabis use disorder (CUD) is the most common illicit substance use disorder and individuals with CUD have high rates of comorbid anxiety disorders. Comorbidity between CUD and anxiety disorders is of public health relevance given that although motivation enhancement therapy (MET) combined with cognitive-behavioral therapy (CBT) is an efficacious intervention for CUD, outcomes are worse for patients with elevated anxiety. The current study tested the acceptability and efficacy of the integration of a transdiagnostic anxiety CBT (i.e., treatment of patients with any anxiety disorder) with MET-CBT (integrated cannabis and anxiety reduction treatment, or ICART) for CUD compared to MET-CBT alone. Treatment-seeking cannabis users (56.4% male, Mage = 23.2, 63.3% non-Hispanic White) with CUD and at least one comorbid anxiety disorder were randomly assigned to ICART (n = 27) or MET-CBT (n = 28). Patients in the ICART condition attended significantly more treatment sessions than those in the MET-CBT condition. Patients in the ICART condition were more likely to be abstinent post-treatment than those in MET-CBT. Further, treatment produced decreases in cannabis use and related problems. Notably, therapy type did not moderate the impact of treatment on frequency of use and related problems. Together, these data suggest that ICART may be at least as efficacious as a gold-standard psychosocial CUD treatment, MET-CBT, for a difficult-to-treat subpopulation of cannabis users.

Background Refugees from Burma who consume fish caught from local waterbodies have increased risk of exposure to environmental contaminants. We used respondent driven sampling (RDS) to sample this hard-to-reach population for the first Biomonitoring of Great Lakes Populations program. In the current study, we examined the interview data and assessed the effectiveness of RDS to sample the unique population. Methods In 2013, we used RDS to sample 205 Burmese refugees and immigrants residing in Buffalo, New York who consumed fish caught from Great Lakes waters. RDS-adjusted population estimates of sociodemographic characteristics, residential history, fish consumption related behaviors, and awareness of fish advisories were obtained. We also examined sample homophily and equilibrium to assess how well the RDS assumptions were met in the study. Results Our sample was diverse with respect to sex, age, years residing in Buffalo, years lived in a refugee camp, education, employment, and fish consumption behaviors, and each of these variables reached equilibrium by the end of recruitment. Burmese refugees in Buffalo consumed Great Lakes fish throughout the year; a majority of them consumed the fish more than two times per week during summer, and about one third ate local fish more than once per week in winter. An estimated 60% of Burmese refugees in Buffalo had heard about local fish advisories. Conclusions RDS has the potential to be an effective methodology for sampling refugees and immigrants in conducting biomonitoring and environmental exposure assessment. Due to high fish consumption and limited awareness and knowledge of fish advisories, some refugee and immigrant populations are more susceptible to environmental contaminants. Increased awareness on local fish advisories is needed among these populations.

SummaryExome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.Video Abstract

The evidence-based use of resources for cancer care at end of life (EOL) has the potential to relieve suffering, reduce health care costs, and extend life. Internal benchmarks need to be established within communities to achieve these goals. The purpose for this study was to evaluate data within our community to determine our EOL cancer practices.A random sample of 390 patients was obtained from the 942 cancer deaths in Wicomico County, Maryland, for calendar years 2004 to 2008. General demographic, clinical event, and survival data were obtained from that sample using cancer registry and hospice databases as well as manual medical record reviews. In addition, the intensity of EOL cancer care was assessed using previously proposed indicator benchmarks. The significance of potential relationships between variables was explored using χ(2) analyses.Mean age at death was 70 years; 52% of patients were male; 34% died as a result of lung cancer. Median survival from diagnosis to death was 8.4 months with hospice admission and 5.8 months without hospice (P = .11). Four of eight intensity-of-care indicators (ie, intensive care unit [ICU] admission within last month of life,one hospitalization within last month of life, hospital death, and hospice referral3 days before death) all significantly exceeded the referenced benchmarks. Hospice versus nonhospice admissions were associated (P.001) with ICU admissions (2% v 13%) and hospital deaths (2% v 54%).These data suggest opportunities to improve community cancer center EOL care.

International audience; This chapter uses John Gagnon and William Simon's sexual script theory in order to make sense of gay men's relation to barebacking fantasies. Bracketing moral panics, it proposes an interpretative sociology of how gay men who enjoy watching barebacking pornography account for the relation between their pornographic fantasies and their sexual realities. Barebacking pornography is a controversial entertainment that relies on an eroticized focus on condomless " raw " and " juicy " anal penetration. It emerged in the US in the late 1990s and mainstreamed over the decade of the 2000s in France, while HIV were remaining high among gay men. Based on the analysis of sixteen in-depth interviews, this chapter analyzes how the sexual subjectivities of HIV-positive and HIV-negative gay men have been differently fragmented by moral panics regarding the carnal appeal of barebacking fantasies.