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Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case–control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10–13) and African ancestries (rs2066702; P = 2.2 × 10–9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit–hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

Background: PLK1 is a serine/threonine kinase master regulator of the cell cycle, overexpressed in AML blasts. Onvansertib (ONV) is an oral, highly selective next-generation PLK1 inhibitor that demonstrated anti-tumor activity in AML preclinical models. The safety and efficacy of ONV in combination with decitabine (DAC) in patients with R/R AML is under study in an ongoing phase 1b/2 clinical trial (NCT03303339). Here we report results of correlative studies to identify molecular predictors of response to the ONV-DAC combination. Methods: R/R AML patients were treated for 5 days with ONV (orally) and DAC (20 mg/m 2 IV qd x 5d) in 21- or 28-day cycles. Patients who completed at least 1 cycle of treatment were considered evaluable for efficacy. At baseline, bone marrow (BM) samples were collected for targeted next-generation sequencing (Myeloid VariantPlex, Archer) and blood samples for RNA-sequencing. Results: As of July 7, 2021, 23 patients were treated with ONV (12 - 90 mg/m 2) + DAC in Phase 1b and 32 patients with ONV 60 mg/m 2 + DAC in Phase 2. Nine (20%) of the 46 patients that were evaluable for efficacy achieved a complete remission with or without complete hematologic recovery (CR/CRi) as their best response (7 CR and 2 CRi). Another 6 patients had ≥50% BM blast decrease from baseline at one point on trial therapy. Those 6 patients plus the 9 patients who achieved CR/CRi are referred to as BM responders (n=15). RNA-seq was performed on blood collected from 32 patients, including 12 BM responders. Differential gene expression, gene-set, and machine learning analyses of BM responders versus non-responders identified a gene expression signature predictive of response to the ONV-DAC combination. No association between the ONV-DAC signature and DAC response was observed after applying the ONV-DAC signature to gene expression profiles from patients treated with DAC as a single agent in a multicenter Phase 2 study (NCT00866073), indicating that the gene signature is specific to the combination. The ONV-DAC signature was also applied to the BeatAML cohort (n=399) and identified 241 predicted responders. Mutation analysis of the BeatAML cohort revealed a positive association between predicted ONV-DAC response and mutations in splicing factors (SF) such as SRSF2, suggesting that SF mutations may serve as a response biomarker for the ONV-DAC combination. Indeed, genomic analysis of baseline BM samples from patients evaluable for efficacy in our Phase 1b/2 (n=46), showed a significant increase in clinical responses in patients with SRSF2 and SF3B1 mutations versus patients with other alterations (Figure 1 and Table 1). In addition, biomarkers reported to be positively correlated with DAC responses (TP53 and TET2 mutations, high fetal hemoglobin expression) were not associated with ONV-DAC clinical responses (Figure 1). Conclusion: We identified a gene expression signature associated with clinical response to the ONV-DAC combination, that did not predict response to DAC single agent. The ONV-DAC predictive signature was found to be correlated with SF mutations in the BeatAML cohort. In our cohort, we confirmed the association between clinical response to ONV-DAC and SF mutations. These analyses support further investigation of the ONV-DAC combination in R/R AML patients with SF mutations and the potential use of ONV-DAC for other hematological diseases with high prevalence of SF mutations such as myelodysplastic syndrome and chronic myelomonocytic leukemia. Figure 1 Figure 1. Disclosures Zeidan: Janssen: Consultancy; Astellas: Consultancy; Astex: Research Funding; Genentech: Consultancy; Daiichi Sankyo: Consultancy; Aprea: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Epizyme: Consultancy; BeyondSpring: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Pfizer: Other: Travel support, Research Funding; BioCryst: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Geron: Other: Clinical Trial Committees; Kura: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Incyte: Consultancy, Research Funding; AstraZeneca: Consultancy; Jasper: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Jazz: Consultancy; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Ridinger: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Croucher: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Samuëlsz: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Erlander: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Ruffner: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company; ALX Oncology: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company; Anthem INC: Current equity holder in publicly-traded company; Cardinal Health: Current equity holder in publicly-traded company; Change Healthcare: Current equity holder in publicly-traded company; CVS Health Corp: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Organon: Current equity holder in publicly-traded company. Wang: GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

Some people feel they are invincible to the novel coronavirus SARS-CoV-2 (COVID-19). They believe that being infected with COVID-19 would not be a serious threat to their health. While these people may or may not be correct in their personal risk assessment, we find that such perceived invincibility may undermine community efforts to achieve herd immunity. Multi-level analysis of survey respondents across 51 countries finds that perceived invincibility from COVID-19 is negatively associated with believing there is a need to prevent the spread of COVID-19 in one’s community (n= 218,956) and one’s willingness to inoculate against the disease (n= 71,148). These effects are most pronounced among individuals from countries lower in cultural collectivism (e.g., USA, UK, Canada) and highlight the need to consider the interplay of individual and cultural factors in our efforts to understand, predict, and promote preventative health behavior during a pandemic.

Simple Summary Preclinical analyses identified APR-246 as a potent treatment option for neuroblastoma. However, a specific mode of action, sufficient biomarkers and promising combination partners are still missing. Here, we analyze the susceptibilities of different entities and relate them to gene expression profiles and previously described biomarkers. We propose a gene signature, consisting of 13 genes, as a novel predictive biomarker. Furthermore, we provide evidence that APR-246 directly targets metabolic weaknesses in neuroblastoma cell lines, thus hampering ROS detoxification. This makes APR-246 suitable to be combined with ROS-inducing HDAC inhibitors, a treatment combination that has not been described for neuroblastoma thus far. Abstract APR-246 (Eprenetapopt/PRIMA-1Met) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800 cancer cell lines (50 entities; Cancer Therapeutics Response Portal, CTRP) to APR-246 treatment. In particular, neuroblastoma, lymphoma and acute lymphocytic leukemia cells were highly responsive. With gene expression data from the Cancer Cell Line Encyclopedia (CCLE; n = 883) and patient samples (n = 1643) from the INFORM registry study, we confirmed that these entities express low levels of SLC7A11, a previously described predictive biomarker for APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding APR-246 with approved HDAC-inhibitors, known to elevate ROS, substantially increased APR-246 sensitivity in cell cultures and in vivo in two zebrafish neuroblastoma xenograft models. These data provide evidence that APR-246, in combination with HDAC-inhibitors, displays a novel potent targeted treatment option for neuroblastoma patients.

Advocacy for open recognition and equality by Jewish LGBT people, both in their social communities and within temples and synagogues of each branch of contemporary Judaism, began in the 1970s with the founding of openly gay and lesbian congregations in England and the United States. This article traces the evolution of the arguments for and against inclusion over the last forty years through diverse publications from organizational and denomination documents and reports, periodical articles from the social sciences, personal accounts by LGBT Jews (both lay and members of the rabbinate), dissertations, and monographs.

Garden of Broken Statues: Exploring Censorship in RussiaOn the Burning of BooksWhich Side Are You On? Seven Social Responsibility Debates in American Librarianship, 1990–2015

Resume L’imagerie est desormais un outil pivot pour la prise en charge des patients en cancerologie solide. Elle permet d’apprecier, le plus objectivement possible, l’efficacite du traitement. Du fait du developpement et de la generalisation des TEP couplees au TDM, il semblait important de refaire le point sur les differents outils accessibles, morphologiques et metaboliques, pour la pratique quotidienne en medecine nucleaire cancerologique. Les criteres morphologiques les plus utilises aujourd’hui en cancerologie generale sont les criteres RECIST 1.1, bases sur une evaluation par TDM. Mais ceux-ci ont certaines limites. D’autres criteres ont donc ete developpes comme les criteres d’Immune-Related Response Criteria pour les immunotherapies. Concernant l’evaluation metabolique, des criteres d’interpretation sont egalement disponibles depuis 1999 (criteres EORTC) et 2009 (criteres PERCIST), avec leurs methodologies propres. Enfin, des criteres specifiques sont utilises pour le cancer de la prostate, bases sur la scintigraphie osseuse. Cet article permet de refaire le point sur ces differents outils et leurs complementarites.

Background and Objectives There is inconsistent evidence about the potential influence of smoking on recovery from alcohol dependence. Our study aimed at assessing the impact of smoking-behavior on relapse during a 12 months follow-up period following a detoxification in patients with Alcohol Use Disorder (AUD). Methods Three hundred Patients with AUD (74.9% smoking) were recruited from two inpatient detoxification units in psychiatric hospitals in Germany and their alcohol consumption was prospectively followed for 1 year. Data on different indicators of smoking behavior was gathered. Cox regression model was used to evaluate potential risk factors on time to relapse of alcohol consumption. Two hundred seventy-nine participants (n = 279) were included in the final analysis. Results Smoking increased the risk for alcohol relapse (hazard ratio = 3.962, 95% CI 1.582–9.921). However, this increased risk is slightly reduced with higher numbers of daily consumed cigarettes (hazard ratio per cigarette = .986, 95% CI .976–.995). Conclusion Smoking reduced the probability of maintaining alcohol abstinence significantly, whereas higher number of cigarettes smoked daily diminished the increased risk of alcohol relapse in alcohol-dependent patients. Scientific Significance Coordinated psychiatric and substance abuse interventions for different subgroups of patients with AUD in the post-acute treatment phase are necessary. Individualized treatment planning is especially important in smoking patients with AUD who are vulnerable for a relapse to alcohol drinking and for somatic complications. Our findings might support individualized treatment plans. (Am J Addict 2017;26:366–373)

Kap. 4 beschreibt den prinzipiellen Unterrichtsverlauf einer Unterrichtseinheit zum Thema: „Grundelemente von Algorithmen“ unter Verwendung der MicroBerry-Lernumgebung. Neben der Vorbereitung werden verschiedene Phasen der Durchfuhrung der Unterrichtseinheit, wie zum Beispiel Einstiegsmoglichkeiten, Themenvorstellung und der prinzipielle Aufbau der Arbeitsblatter beschrieben. Auserdem werden ein moglicher Aufbau und wichtige Aspekte bei der Durchfuhrung der Projektphase erlautert.

In diesem Theorieteil gehen wir der Frage nach, welchen Anforderungen eine Lernumgebung fur den Anfangsunterricht der Informatik genugen sollte. Da in den „Grundsatzen eines guten Informatikunterrichts“ (GI 2008), auf den Konstruktivismus verwiesen wird, nahern wir uns dieser Frage, indem wir zunachst auf konstruktivistische Lehr-Lern-Theorien eingehen. Anschliesend stellen wir das Konzept des problemorientierten Lernens nach Hense et al. (2001) vor. Dieses Konzept erweist sich als kompatibel zu den Anforderungen einer konstruktivistischen Lernumgebung und bietet sich, auch aufgrund der Problemorientierung, gut fur den Informatikunterricht an. Neben der Problemorientierung, als wichtige Komponente des Informatikunterrichts, wird die Bedeutung von Interesse und Motivation im schulischen Kontext erortert und daraus weitere wesentliche Anforderungen an Lernumgebungen abgeleitet. Erlautert werden dabei das Konzept der Interessenentwicklung nach Krapp (1998) und die Selbstbestimmungstheorie nach Deci und Ryan (2002). Aus diesen Theorien heraus begrunden wir die Sinnhaftigkeit des fachubergreifenden Lernens und nehmen Bezug zum Technikunterricht und zur Methode des Projektunterrichts. Diese verschiedenen Aspekte fuhren zur begrundeten Konzeption der MicroBerry-Lernumgebung, die abschliesend dargestellt wird.

Background: The American Medical Association has defined the field of health systems sciences (HSS), viewed as a “third pillar” of medical education, alongside the basic and clinical sciences. Because a shared competency framework is lacking between undergraduate (UME) and graduate medical education (GME), entering residents are unprepared to implement HSS concepts in the workplace. The UME-GME transition is a critical timeframe to prepare trainees with skills for safe and effective care and foster a dedication to improving the health care system. This study investigates GME faculty observations of knowledge, attitudes and behaviors that define successful practice within HSS. Design and Methods: This study is an inductive-deductive qualitative study of phone interviews of Vanderbilt residency program directors, associate program directors and core faculty representing programs that train year-one residents. Interview questions were piloted and revised. Interviews were performed by a trained qualitative researcher, audio-recorded and transcribed. An initial codebook was developed, and de-identified transcripts were independently analyzed by two qualitative researchers using inductive and deductive approaches to identify themes and subthemes. All codes were discussed and reconciled for agreement. Results: Seventeen interviews were completed (17/39, 45%), representing a variety of specialties. Faculty described a developmental framework involving inputs, core workforce skills, HSS-related skills, and outputs. Inputs represent pre-curricular preparatory experiences common to well-prepared residents (ex. professional degrees, work experience, extracurricular involvement, medical school exposure). Successful residents exhibit core workforce characteristics and behaviors, for example, a growth mindset, curiosity, initiative, and desire to learn the system. While GME faculty often feel unprepared to teach or assess HSS concepts, they describe specific HSS-related skills unique to specific learning environments that characterize successful practice among entering residents. “Systems thinking” involves integrating skills across multiple domains and results in high-quality, person-centered care and systems improvements. Discussion: Faculty observations of the behaviors, knowledge and attitudes that define successful practice within HSS has highlighted the importance of pre-curricular experience including medical school curricula; core workforce characteristics and behaviors; and describes entry level skills within each of the HSS domains that characterize successful practice. This study provides an initial description of successful practice within HSS for entering residents.

In diesem Kapitel wird die MicroBerry-Lernumgebung detailliert beschrieben. Zunachst werden die Rahmenbedingungen und die einzelnen Hardwarekomponenten der Lernumgebung erlautert. Dazu zahlen der mogliche Aufbau des Klassenraums, die verwendeten Sortimentskasten sowie die Beschreibung des Raspberry Pi und der verwendeten Zusatzplatine Explorer HAT Pro, bis hin zum Hardwareaufbau eines Netzwerks. Im Weiteren wird die verwendete Software beschrieben. Man erfahrt dabei viele Details uber die Installation und Konfiguration des Betriebssystems, der Erstellung und Verwendung einer Image-Datei, sowie des Einrichtens eines Kommunikationsnetzwerkes uber VNC. Auserdem werden wichtige Grundlagen zu den Programmiersprachen Scratch und Python dargestellt und erlautert. Auch das Programm „Dia“, das wir zur Erstellung von Flussdiagrammen nutzen, wird beschrieben.

In diesem Kapitel wird das Projektskript beschrieben, das wir den Schulerinnen und Schulern zur Unterstutzung der Projektphase zur Verfugung stellen. Dieses Skript dient als Ideensammlung und Nachschlagewerk. Hier findet man beispielsweise die Beschreibungen und Beschaltungen der gangigsten Bauteile, mit dem Ziel, in der Projektphase auf zeitaufwendige Internetrecherchen verzichten zu konnen.