Regionally distinct GFAP promoter expression plays a role in off-target neuron expression following AAV5 transduction.

Astrocyte to neuron reprogramming has been performed using viral delivery of neurogenic transcription factors in GFAP expressing cells. Recent reports of off-target expression in cortical neurons following adeno-associated virus (AAV) transduction to deliver the neurogenic factors have confounded our understanding of the efficacy of direct cellular reprogramming. To shed light on potential mechanisms that may underlie the neuronal off-target expression of GFAP promoter driven expression of neurogenic factors in neurons, two regionally distinct cortices were compared-the motor cortex (MC) and medial prefrontal cortex (mPFC)-and investigated: (1) the regional tropism and astrocyte transduction with an AAV5-GFAP vector, (2) the expression of Gfap in MC and mPFC neurons; and (3) material transfer between astrocytes and neurons.

Molecular correlates for HPV-negative head and neck cancer engraftment prognosticate patient outcomes.

There is a pressing need to improve risk stratification and treatment selection for HPV-negative head and neck squamous cell carcinoma (HNSCC) due to the adverse side effects of treatment. One of the most important prognostic features is lymph nodes involvement. Previously, we demonstrated that tumor formation in patient-derived xenografts (i.

Systematic surveillance of SARS-CoV-2 reveals dynamics of variant mutagenesis and transmission in a large urban population.

Highly mutable pathogens generate viral diversity that impacts virulence, transmissibility, treatment, and thwarts acquired immunity. We previously described C19-SPAR-Seq, a high-throughput, next-generation sequencing platform to detect SARS-CoV-2 that we here deployed to systematically profile variant dynamics of SARS-CoV-2 for over 3 years in a large, North American urban environment (Toronto, Canada). Sequencing of the ACE2 receptor binding motif and polybasic furin cleavage site of the Spike gene in over 70,000 patients revealed that population sweeps of canonical variants of concern (VOCs) occurred in repeating wavelets.

Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.

Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discover that hippocampal and spinal cord motor neurons of mouse and human origin localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress.

Photodynamic therapy of cancer-associated infections.

Pathogens can be involved in tumor initiation, promotion, and progression through different mechanisms, and their treatment can prevent new cancer cases, improve outcomes, and revert poor-prognostic phenotypes. Photodynamic therapy (PDT) successfully treats different types of cancers and infections and, therefore, has a unique potential to address their combination. However, we believe this potential has been underutilized, and few researchers have investigated the impacts of PDT of both infection-related and cancer-related outcomes at once.

Central Taxa Are Keystone Microbes During Early Succession.

Microorganisms underpin numerous ecosystem processes and support biodiversity globally. Yet, we understand surprisingly little about what structures environmental microbiomes, including how to efficiently identify key players. Microbiome network theory predicts that highly connected hubs act as keystones, but this has never been empirically tested in nature.

Clinical presentations and complications of lichen sclerosus: A systematic review.

Lichen sclerosus (LS) is a chronic, inflammatory dermatosis most commonly characterized by changes in skin pigmentation and pruritus, with associated dyspareunia and genital architectural changes. There are a variety of complications associated with LS, which further worsen a patient's health-related quality of life. A systematic review was conducted to summarize the literature regarding clinical features of LS, as well as LS-associated complications.

Efficacy and Safety of Ultrasound-Guided Pulsed Radiofrequency Therapy of Stellate Ganglion on Refractory Painful Diabetic Peripheral Neuropathy.

Background: The best tool for the management of pain associated with distal symmetric peripheral neuropathy (DSPN) is a matter of debate. Therefore, the study aimed to explore whether ultrasound-guided pulsed radiofrequency (PRF) therapy of the stellate ganglion (SG) in type 2 diabetes mellitus (T2DM) patients with painful DSPN could decrease pain severity and the need for analgesics.

Methods: Fifty-six T2DM patients with refractory painful DSPN were enrolled in this study, who then received bilateral ultrasound-guided PRF therapy of SG.

Durvalumab and tremelimumab in patients with advanced rare cancer: a multi-centre, non-blinded, open-label phase II basket trial.

Background: Dual inhibition of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) has been shown to be an effective treatment strategy in many cancers. We sought to determine the objective response rate of combination durvalumab (D) plus tremelimumab (TM) in parallel cohorts of patients with carefully selected rare cancer types in which these agents had not previously been evaluated in phase II trials and for which there was clinical or biological rationale for dual immune checkpoint inhibitor therapy to be active.

Methods: We designed a multi-centre, non-blinded, open-label phase II basket trial with each of the following 8 rare cancers considered a separate phase II trial: salivary carcinoma, carcinoma of unknown primary (CUP) with tumour infiltrating lymphocytes and/or expressing PD-L1, mucosal melanoma, acral melanoma, osteosarcoma, undifferentiated pleomorphic sarcoma, clear cell carcinoma of the ovary (CCCO) or squamous cell carcinoma of the anal canal (SCCA).

Addressing Known hypertensive disOrders of pregnancy in woMen of African descent in Canada (AKOMA): protocol for a mixed method study.

Background: Hypertensive disorders of pregnancy (HDP) predispose a woman to maternity-related cardiovascular morbidity and mortality. However, there is limited literature on HDP among women of African descent in Canada.

Methods And Design: A convergent mixed-method study will be used to investigate the intersection of self-reported HDP risks in women of African descent in Canada with a history of a HDP (quantitative, cross-sectional survey) and explore the perception and experiences of women of African descent living in Canada with a history of a HDP in relation to the intersection of risk factors (critical qualitative inquiry, interviews).

Sex-differences in the risk of carpal tunnel syndrome: results from a large Ontario, Canada worker cohort.

Background: Carpal tunnel syndrome (CTS) is a prevalent cumulative strain injury associated with occupational risk factors such as vibration, repetitive and forceful wrist movements, and awkward wrist postures. This study aimed to identify Ontario workers at elevated risk for CTS and to explore sex differences in CTS risk among workers.

Methods: The Occupational Disease Surveillance System (ODSS) links accepted lost time compensation claims to health administrative databases.

Facilitators' experiences with virtual simulation and their impact on learning.

Background: Increasingly, virtual simulations are being integrated into higher education. A successful experience goes far beyond simply offering learners access to a virtual simulation; it requires a facilitator who understands the learners' needs and course objectives, choses the right virtual simulation for the learner, creates a welcoming space that promotes learning, and evaluates the experience.

Methods: Facilitators from three different healthcare programs and six educational institutions and students from two different healthcare programs were included in this exploratory qualitative research study.

Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation (the PROMIZING study): update to the statistical analysis plan for a randomized controlled trial.

Background: We previously published the protocol and statistical analysis plan for a randomized controlled trial of Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation: the PROMIZING study in Trials ( https://doi.org/10.1186/s13063-023-07163-w ).

Promoting trans patient autonomy in surgical preparation for phalloplasty and metoidioplasty: results from a community-based cross-sectional survey and implications for preoperative assessments.

Background: Some transgender and nonbinary people undergo phalloplasty and/or metoidioplasty as part of their medical transition process. Across surgical disciplines, a variety of resources are used to assist patients who are preparing for surgeries, including educational materials, workshops, peer support, and lifestyle changes. For gender-affirming surgeries, patients undergoing assessments to discern whether they are ready to undergo the surgery, and to assist them in achieving preparedness when needed.

Antisemitism in Medicine: An International Perspective.

Throughout history, Jewish people have long been recognized for their achievements in the world of medical science. For example, prior to the Holocaust, many outstanding physicians in Germany were Jewish. However, even in the 1930s, refugee European Jewish doctors faced significant barriers when they tried to escape and practice elsewhere because of long-standing prejudices and anti-Jewish quotas in medical schools and hospitals around the world.

Using Implementation Science to Evaluate the Implementation of Patient-Reported Outcome Measures (PROMs) in a Clinical Heart Failure Care Setting.

Background: Patients with heart failure (HF) can experience a poor quality-of-life (QOL), recurring hospitalizations, and progressive disease symptoms. Patient-reported outcome measures (PROMs) integrate patients' voices into clinical care, by assessing patient symptoms, function, and QOL. In 2022, PROMs were incorporated into the electronic health record system (Epic) at a large academic hospital in Toronto, Ontario, Canada.

Transfabric Leaks After Percutaneous Left Atrial Appendage Occlusion Procedures with the WATCHMAN FLX Device.

Background: Cardiac computed tomography imaging with contrast is being used increasingly to image left atrial appendage occlusion (LAAO) devices. Contrast flow across a device, also known as a transfabric leak (TFL), may indicate a lack of complete LAAO-device endothelialization. The data on the rate, predictors, and clinical events associated with TFL are limited.

Bringing Care Close to Home: Remote Management of Heart Failure In Partnership with Indigenous Communities In Northern Ontario, Canada.

Background: The Weeneebayko Area Health Authority (WAHA) is a regional, community-based Indigenous health authority in Northern Ontario, Canada. From September 2022 to March 2023, the WAHA and University Health Network engaged in a partnership that designed a collaborative model of care to address inequities in cardiology specialist access in Northern Ontario. This model implemented a digital therapeutic for heart failure, (the Medly program) and in-person cardiology clinics in the region.

Thrombus on Mitral Annular Calcification: A Systematic Review of Management and Outcomes.

Background: Mitral annular calcification (MAC) is a common chronic degenerative process of the mitral valve. Thrombus formation on MAC is a rare complication that likely contributes to the increased risk of thromboembolic events. Outcomes and management strategies for this condition are unknown.

Quantitative Characterization of Partitioning Stringency in SELEX.

Maintaining stringent conditions in SELEX (Systematic Evolution of Ligands by EXponential enrichment) is crucial for obtaining high-affinity aptamers. However, excessive stringency greatly increases the risk of SELEX failure. Controlling stringency has remained a technical challenge, largely dependent on intuition, due to the absence of a clear, quantitative measure of stringency.

Differences in smoking cessation behaviors and vaping status among adult daily smokers with and without depression, anxiety, and alcohol use: Findings from the 2018 and 2020 International Tobacco Control Four Country Smoking and Vaping (ITC 4CV) Surveys.

This study examined differences in quit attempts, 1-month quit success, and vaping status at follow-up among a cohort of 3709 daily smokers with and without depression, anxiety, and regular alcohol use who participated in both the 2018 and 2020 International Tobacco Control Four Country Smoking and Vaping (ITC 4CV) Surveys. At baseline, a survey with validated screening tools was used to classify respondents as having no, or one or more of the following: 1) depression, 2) anxiety, and 3) regular alcohol use. Multivariable adjusted regression analyses were used to examine whether baseline (2018) self-report conditions were associated with quit attempts; quit success; and vaping status by follow-up (2020).

Canadian Highly Sensitized Patient Program Report: A 1000 Kidney Transplants Story.

Purpose: Highly sensitized patients (HSPs) with kidney failure have limited access to kidney transplantation and poorer post-transplant outcomes. Prioritizing HSPs in kidney allocation systems and expanding the pool of deceased donors available to them has helped to reduce their wait times for transplant and enhanced post-transplant outcomes. The Canadian HSP Program was established by Canadian Blood Services in collaboration with provincial organ donation and transplantation programs throughout the country to increase transplant opportunities for transplant candidates needing very specific matches from deceased kidney donors.