Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome

Purpose: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data. Methods: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes’ rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants. Results: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic. Conclusion: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care

Identification of a BET Family Bromodomain/Casein Kinase II/TAF-Containing Complex as a Regulator of Mitotic Condensin Function

SummaryCondensin is a central regulator of mitotic genome structure with mutants showing poorly condensed chromosomes and profound segregation defects. Here, we identify NCT, a complex comprising the Nrc1 BET-family tandem bromodomain protein (SPAC631.02), casein kinase II (CKII), and several TAFs, as a regulator of condensin function. We show that NCT and condensin bind similar genomic regions but only briefly colocalize during the periods of chromosome condensation and decondensation. This pattern of NCT binding at the core centromere, the region of maximal condensin enrichment, tracks the abundance of acetylated histone H4, as regulated by the Hat1-Mis16 acetyltransferase complex and recognized by the first Nrc1 bromodomain. Strikingly, mutants in NCT or Hat1-Mis16 restore the formation of segregation-competent chromosomes in cells containing defective condensin. These results are consistent with a model where NCT targets CKII to chromatin in a cell-cycle-directed manner in order to modulate the activity of condensin during chromosome condensation and decondensation

Adaptations Made to Pediatric Consultation-Liaison Psychiatry Service Delivery During the Early Months of the COVID-19 Pandemic: A North American Multisite Survey.

BackgroundThe COVID-19 pandemic led to rapid changes in clinical service delivery across hospital systems nationally. Local realities and resources were key driving factors impacting workflow changes, including for pediatric consultation-liaison psychiatry service (PCLPS) providers.ObjectiveThis study aims to describe the early changes implemented by 22 PCLPSs from the United States and Canada during the COVID-19 pandemic. Understanding similarities and differences in adaptations made to PCLPS care delivery can inform best practices and future models of care.MethodsA 20-point survey relating to PCLPS changes during the COVID-19 pandemic was sent to professional listservs. Baseline hospital demographics, hospital and PCLPS workflow changes, and PCLPS experience were collected from March 20 to April 28, 2020, and from August 18 to September 10, 2020. Qualitative data were collected from responding sites. An exploratory thematic analysis approach was used to analyze the qualitative data that were not dependent on predetermined coding themes. Descriptive statistics were calculated using Microsoft Excel.ResultsTwenty-two academic hospitals in the United States and Canada responded to the survey, with an average of 303 beds/hospital. Most respondents (18/22) were children's hospitals. Despite differences in regional impact of COVID-19 and resource availability, there was significant overlap in respondent experiences. Restricted visitation to one caregiver, use of virtual rounding, ongoing trainee involvement, and an overall low number of COVID-positive pediatric patients were common. While there was variability in PCLPS care delivery occurring virtually versus in person, all respondents maintained some level of on-site presence. Technological limitations and pediatric provider preference led to increased on-site presence.ConclusionsTo our knowledge, this is the first multicenter study exploring pandemic-related PCLPS changes in North America. Findings of this study demonstrate that PCLPSs rapidly adapted to COVID-19 realities. Common themes emerged that may serve as a model for future practice. However, important gaps in understanding their effectiveness and acceptability need to be addressed. This multisite survey highlights the importance of establishing consensus through national professional organizations to inform provider and hospital practices

‘Orientalism is a partisan book’: applying Edward Said's insights to early modern travel writing

Since its publication in 1978, Edward Said's Orientalism has had a significant impact on postcolonial studies in a range of fields. This paper assesses his impact on the historiography of Anglophone travel writing concerning Ottoman Empire during the early modern period. Said's analysis of the relationship between representational power and colonial authority remains relevant to our understanding of early modern travel texts. Said's epistemology raises significant issues for historians of early modern intercultural encounters. This article summarises recent debates surrounding early modern travel narratives. It contrasts doctrinaire applications of Said's theory with more recent, particularistic studies. It provides a much-needed survey of travel writing historiography that considers the continuing impact of Said's postcolonial thought on the study of early modern travel narratives relating to the Ottoman Middle East. In so doing, it explores the lack of fit between early modern travel narratives and Said's methodology. I explore the methodological problems thrown up by conventional applications of Said's epistemology to precolonial travellers' texts. Based on a wide-ranging survey of Said's oeuvre, the article demonstrates that, more than 30 years on, Said's work remains relevant to the historiographical challenges presented by early modern English travel writing about Islam

Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer’s Disease

Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA-induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM)

A Knowledge Synthesis of Cross-Cultural Psychotherapy Research: A Critical Review

This article presents a current knowledge synthesis of empirical studies on cross-cultural psychotherapy since 1980. Guided by a critical review framework, our search in seven relevant databases generated 80 studies published in English. Main themes are organized into (1) therapists’ cultural competence (n = 46); (2) therapy process in cross-cultural dyads (n = 22); and (3) cross-cultural differences in gender, sexual orientation, or social class (n = 12). Compared to previous reviews on cross-cultural psychotherapy, the findings of this review highlight a broad range of methodological rigor in both quantitative and qualitative studies. Most studies examined actual therapy participants rather than participants in analog studies, thus emulating more therapy-near experiences in cross-cultural psychotherapy research. Also, several studies explored cross-cultural compositions beyond racial and ethnic majority therapist-minority client dyads, and included therapists of color as the participants, exploring reverse power dynamics in therapy and giving voices to foreign-born therapists. The therapy process research provides rich and full descriptions around the dynamic and interactional therapy process in cross-cultural dyads, which can be used to foster cultural sensitivities among therapists in their practice and training. We discuss the limitations of the studies included in the review and its implications for psychotherapy practice, training, and future research.This research was funded by the Royal Bank Fellowship of Canada (PI: Eunjung Lee, Fellow: Andrea Greenblatt)

Development, delivery and evaluation of a social work elective offered in a hospital setting

Abstract: This paper describes a qualitative study about a Master’s level elective course offered on-site at a Canadian pediatric hospital and delivered by frontline hospital social workers. Ten social workers and four students participated in the study which captured their experiences in the course. A grounded theory approach guided this study. Social workers discussed an enhanced sense of professional self, impact on their daily roles and various opportunities resulting from participation. Students discussed diversity, development of a realistic understanding of the social work role and the unique format of the course. Implications for future course development and university-agency partnerships are discussed.Keywords: social work; education; pediatrics; hospital; teachin

The Impact of the COVID-19 Pandemic on Social Workers at the Frontline: A Survey of Canadian Social Workers

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Social workers are facing increasingly complex client needs during the coronavirus disease of 2019 (COVID-19) pandemic. Because of the social distancing requirements of the pandemic, social workers have undergone transformative changes in practice with the rapid uptake of virtual technologies. The objective of our study was to understand the experiences of social workers during the first-wave of the COVID-19 pandemic. We conducted a cross-sectional, web-based survey, comprised of close-ended and open-ended questions. Survey participants included social workers who were the members of a provincial social work association in Ontario, Canada. With n = 2,470 participants, the response rate was close to 40 per cent. Descriptive statistics were conducted on the close-ended questions. Two open-ended questions were coded using the thematic analysis. Nine themes were identified on the impact to social worker’s employment status: increased work-load; loss of employment; redeployment to new settings; early retirement; concern for personal health and safety; social workers in private practice seeing fewer clients; personal caregiving responsibilities; limiting recent graduates’ employment potential and social workers experiencing new opportunities. There were five themes on the impact on social work practice: clients with increasing complexities; challenges with transition to virtual care; benefits with transition to virtual care; adapting in-person services and personal well-being.This study was financially supported by the OASWs