CTCF is essential for proper mitotic spindle structure and anaphase segregation.

Mitosis is an essential process in which the duplicated genome is segregated equally into two daughter cells. CTCF has been reported to be present in mitosis and has a role in localizing CENP-E, but its importance for mitotic fidelity remains to be determined. To evaluate the importance of CTCF in mitosis, we tracked mitotic behaviors in wild-type and two different CTCF CRISPR-based genetic knockdowns. We find that knockdown of CTCF results in prolonged mitoses and failed anaphase segregation via time-lapse imaging of SiR-DNA. CTCF knockdown did not alter cell cycling or the mitotic checkpoint, which was activated upon nocodazole treatment. Immunofluorescence imaging of the mitotic spindle in CTCF knockdowns revealed disorganization via tri/tetrapolar spindles and chromosomes behind the spindle pole. Imaging of interphase nuclei showed that nuclear size increased drastically, consistent with failure to divide the duplicated genome in anaphase. Long-term inhibition of CNEP-E via GSK923295 recapitulates CTCF knockdown abnormal mitotic spindles with polar chromosomes and increased nuclear sizes. Population measurements of nuclear shape in CTCF knockdowns do not display decreased circularity or increased nuclear blebbing relative to wild-type. However, failed mitoses do display abnormal nuclear morphologies relative to successful mitoses, suggesting that population images do not capture individual behaviors. Thus, CTCF is important for both proper metaphase organization and anaphase segregation which impacts the size and shape of the interphase nucleus likely through its known role in recruiting CENP-E.

Senior Residents' Perceived Competence in Evidence-Based Treatments for Major Depressive Disorder.

OBJECTIVE: The current study aims to assess the self-reported competence of graduating psychiatry residents in Canada to provide pharmacotherapy and psychotherapy for major depressive disorder as recommended in national practice guidelines. METHODS: Canadian psychiatry residents who participated in an optional national review course to prepare for licensing were anonymously surveyed regarding their experience and competence in providing treatments recommended by the 2016 Canadian Network for Mood and Anxiety Treatments guidelines. RESULTS: The majority (89%, 130/146) reported competence in ≥ 5 medication monotherapies (e.g., selective serotonin/norepinephrine reuptake inhibitors, bupropion, mirtazapine) and ≥ 3 adjuncts (e.g., mirtazapine, second-generation antipsychotics). While 76% expressed interest in practicing multiple psychotherapeutic modalities, only 47% reported self-assessed competence in delivering multiple modalities. Only 42% reported pharmacological competence (≥ 5 monotherapies, ≥ 3 adjuncts) and competence in ≥ 2 psychotherapies. Only 9% reported competence in offering medication, psychotherapy, and electroconvulsive therapy. Less than two-thirds endorsed sufficient didactic teaching (58%) or supervision in pharmacotherapy (50%) for treatment-resistant depression. CONCLUSIONS: Canadian psychiatry residents report competence in prescribing many first-line medications. However, only a minority report competence in prescribing medications and competence in psychotherapies and/or electroconvulsive therapy. Given known biases in assessments by self-report, real-world competence may be even lower. This study identifies gaps between national practice guidelines and the comfort of the emerging psychiatric workforce in delivering recommended treatments. These gaps in resident competence may lead to under-use of effective treatments for depression. Residency programs should consider how to improve resident competence in providing the full range of evidence-based treatments for depression.

CTCF is essential for proper mitotic spindle structure and anaphase segregation.

Mitosis is an essential process in which the duplicated genome is segregated equally into two daughter cells. CTCF has been reported to be present in mitosis but its importance for mitotic fidelity remains to be determined. To evaluate the importance of CTCF in mitosis, we tracked mitotic behaviors in wild type and two different CTCF CRISPR-based genetic knockdowns. We find that knockdown of CTCF results in prolonged mitoses and failed anaphase segregation via time lapse imaging of SiR-DNA. CTCF knockdown did not alter cell cycling or the mitotic checkpoint, which was activated upon nocodazole treatment. Immunofluorescence imaging of the mitotic spindle in CTCF knockdowns revealed disorganization via tri/tetrapolar spindles and chromosomes behind the spindle pole. Imaging of interphase nuclei showed that nuclear size increased drastically, consistent with failure to divide the duplicated genome in anaphase. Population measurements of nuclear shape in CTCF knockdowns do not display decreased circularity or increased nuclear blebbing relative to wild type. However, failed mitoses do display abnormal nuclear morphologies relative to successful mitoses, suggesting population images do not capture individual behaviors. Thus, CTCF is important for both proper metaphase organization and anaphase segregation which impacts the size and shape of the interphase nucleus.

Alteplase or tenecteplase for thrombolysis in ischemic stroke: An illustrated review.

Intravenous thrombolysis is a standard of care treatment for patients with acute ischemic stroke. Tissue plasminogen activator (tPA) has been the main thrombolytic agent used since the publication of the seminal National Institutes of Neurological Disorders and Stroke trial in 1995. There is now mounting evidence to support the routine use of Tenecteplase (TNK) to treat acute ischemic stroke. TNK is a genetically modified tPA with higher fibrin specificity, longer half-life, and reduced systemic coagulopathy. In this illustrated review, we compare the indications, doses, mechanisms of action, efficacy and safety of TNK and tPA. We provide an overview of published clinical trials studying TNK in acute ischemic stroke, including dose-escalation studies and head-to-head comparisons with tPA. Finally, we summarize current acute stroke guideline recommendations and suggest treatment algorithms to manage the two main complications of intravenous thrombolysis: symptomatic intracerebral hemorrhage and angioedema.

Challenges in conducting research on collaborative mental health care: a qualitative study.

BACKGROUND: We sought to understand poor uptake of the Primary Care Assessment and Research of a Telephone Intervention for Neuropsychiatric Conditions with Education and Resources study (PARTNERs), a pragmatic randomized controlled trial of a collaborative care intervention for people experiencing depression, anxiety or at-risk drinking. We explored primary care providers' experience with PARTNERs, and preferences regarding collaborative care models and trials. METHODS: In this qualitative study, we interviewed primary care providers across Ontario who had participated in PARTNERs, using stratified sampling to reach high-, low- and nonreferring providers in urban and rural settings. We audio-recorded, transcribed and thematically analyzed the interviews between May and December 2017, collecting and analyzing data concurrently until achieving saturation. RESULTS: We interviewed 23 primary care providers. They valued the unique availability of telephone-based coaching for patients but desired greater integration of the coach into their practice. They appreciated expert psychiatric recommendations but rarely changed their practices. Sites varied in organizational adoption and implementation of the study, including whether they designated a local champion, proactively identified eligible patients, integrated the study into existing workflows and reflected on (and revised) practices. These behaviours affected continuing awareness of the study and referral rates. INTERPRETATION: Study uptake was influenced by the limited relationship between PARTNERs coaches and primary care providers, and variable attention to leadership, training and quality improvement as vital elements of collaborative care. Study designs focusing on implementation could promote reach and penetration of novel interventions in the practice setting and more successfully advance collaborative care implementation.