GeneMatch: A novel recruitment registry using at‐home APOE genotyping to enhance referrals to Alzheimer’s prevention studies

IntroductionRecruitment for Alzheimer’s disease (AD) prevention research studies is challenging because of lack of awareness among cognitively healthy adults coupled with the high screen fail rate due to participants not having a genetic risk factor or biomarker evidence of the disease. Participant recruitment registries offer one solution for efficiently and effectively identifying, characterizing, and connecting potential eligible volunteers to studies.MethodsIndividuals aged 55‐75 years who live in the United States and self‐report not having a diagnosis of cognitive impairment such as MCI or dementia are eligible to join GeneMatch. Participants enroll online and are provided a cheek swab kit for DNA extraction and apolipoprotein E (APOE) genotyping. Participants are not told their APOE results, although the results may be used in part to help match participants to AD prevention studies.ResultsAs of August 2018, 75,351 participants had joined GeneMatch. Nearly 30% of participants have one APOE4 allele, and approximately 3% have two APOE4 alleles. The percentages of APOE4 heterozygotes and homozygotes are inversely associated with age (P < .001).DiscussionGeneMatch, the first trial‐independent research enrollment program designed to recruit and refer cognitively healthy adults to AD prevention studies based in part on APOE test results, provides a novel mechanism to accelerate prescreening and enrollment for AD prevention trials.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152681/1/alzjjalz201812007.pd

Misperceptions About β-Blockers and Diuretics

Based on a series of clinical trials showing no difference in the effectiveness or tolerability of most major classes of antihypertensive medications, the Joint National Commission on High Blood Pressure Treatment recommends that physicians prescribe β-blockers or diuretics as initial hypertensive therapy unless there are compelling indications for another type of medication. Nevertheless, many physicians continue to favor more expensive medications like angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers as first line agents. The persistent use of these agents raises questions as to whether physicians perceive ACE inhibitors and calcium channel blockers to be better than β-blockers and diuretics. METHODS:  We surveyed 1,200 primary care physicians in 1997, and another 500 primary care physicians in 2000, and asked them to estimate the relative effectiveness and side effects of 4 classes of medication in treating a hypothetical patient with uncomplicated hypertension: ACE inhibitors, β-blockers, calcium channel blockers, and diuretics. In addition, we asked them to indicate whether they ever provided free samples of hypertension medications to their patients. RESULTS:  Perceptions of the relative effectiveness and side effects of the 4 classes of hypertension medications did not significantly change over the 3 years, nor did prescription recommendations. Physicians perceive that diuretics are less effective at lowering blood pressure than the other 3 classes ( P  < .001). They also perceive that β-blockers are less tolerated than the other 3 classes ( P  < .001). In a multivariate model, perceptions of effectiveness and tolerability displayed significant associations with prescription preference independent of background variables. The only other variable to contribute significantly to the model was provision of free medication samples to patients. CONCLUSIONS:  Despite numerous clinical trials showing no difference in the effectiveness or side-effect profiles of these 4 classes of drugs, most physicians believed that diuretics were less effective and β-blockers were less tolerated than other medications. Moreover, their prescription practices were associated with their provision of free samples provided by pharmaceutical representatives, even after adjusting for other demographic characteristics. Efforts to increase physicians’ prescribing of β-blockers and diuretics may need to be directed at overcoming misunderstandings about the effectiveness and tolerability of these medicines. J GEN INTERN MED 2003;18:977–983.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75385/1/j.1525-1497.2003.20414.x.pd

The Atacama Cosmology Telescope: Sunyaev Zel'dovich Selected Galaxy Clusters at 148 GHz in the 2008 Survey

We report on twenty-three clusters detected blindly as Sunyaev-Zel'dovich (SZ) decrements in a 148 GHz, 455 square-degree map of the southern sky made with data from the Atacama Cosmology Telescope 2008 observing season. All SZ detections announced in this work have confirmed optical counterparts. Ten of the clusters are new discoveries. One newly discovered cluster, ACT-CL J0102-4915, with a redshift of 0.75 (photometric), has an SZ decrement comparable to the most massive systems at lower redshifts. Simulations of the cluster recovery method reproduce the sample purity measured by optical follow-up. In particular, for clusters detected with a signal-to-noise ratio greater than six, simulations are consistent with optical follow-up that demonstrated this subsample is 100% pure. The simulations further imply that the total sample is 80% complete for clusters with mass in excess of 6x10^14 solar masses referenced to the cluster volume characterized by five hundred times the critical density. The Compton y -- X-ray luminosity mass comparison for the eleven best detected clusters visually agrees with both self-similar and non-adiabatic, simulation-derived scaling laws.Comment: 13 pages, 7 figures, Accepted for publication in Ap

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings.

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.The European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (EU-GEI)

The limits of fiction: politics and absent scenes in Susumu Hani’s Bad Boys (Furyōshōnen, 1960). A film re-reading through its script

This text proposes an updated analysis of Susumu Hani’s Bad Boys (1960) through the director’s theoretical contribution and the re-reading of his script. This film, made within the limits of reality and fiction, was instrumental in the cinematic language of the sixties in Japan. Hani implemented herein a style that he developed during his earlier decade as a documentary maker for Iwanami Eiga studios. Hani based his filmmaking method on a philosophical pragmatism extracted from the practices of an amateur writing called seikatsu kiroku (life document) that appeared in the early 1950s. In fact, Bad Boys is a loose adaptation of Tobenai Tsubasa (Wings that Cannot Fly) an example of seikatsu kiroku consisting of a compilation of experiences written by inmates from the Kurihama reformatory. Hani responded to the demands for a new realism of the time with this film, which he made collectively with the former inmates of that reformatory. Additionally, a close analysis of the script reveals significant ‘absent scenes’ of student demonstrations, which are similar to those Oshima and Yoshida used in 1960. This fact evidences Hani’s shared concern with other filmmakers of the time about the necessities of bringing cinema closer to topical issues

Clinical differences between younger and older adults with HIV/AIDS starting antiretroviral therapy in Uganda and Zimbabwe: a secondary analysis of the DART trial

Clinical and immunological data about HIV in older adults from low and middle income countries is scarce. We aimed to describe differences between younger and older adults with HIV starting antiretroviral therapy in two low-income African countries