Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.

By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors.

Molecular and anatomical characterization of parabrachial neurons and their axonal projections.

The parabrachial nucleus (PBN) is a major hub that receives sensory information from both internal and external environments. Specific populations of PBN neurons are involved in behaviors including food and water intake, nociceptive responses, breathing regulation, as well as learning and responding appropriately to threatening stimuli. However, it is unclear how many PBN neuron populations exist and how different behaviors may be encoded by unique signaling molecules or receptors.

The prediction capability of a cataract surgery risk stratification model based on a large electronic medical record dataset.

Purpose: The aim of this study was to develop a risk stratification system that predicts visual outcomes (uncorrected corrected visual acuity at one week and five weeks postoperative) in patients undergoing cataract surgery.

Methods: This was a retrospective analysis in a multitier ophthalmology network. Data from all patients who underwent phacoemulsification or manual small-incision cataract surgery between January 2018 and December 2019 were retrieved from an electronic medical record system.

Investigating recovery from problem substance use using digital photovoice.

This study investigates the complex process of recovery from problem substance use using a visual research method known as 'Photovoice'. Seven service users from a harm reduction drug service were given digital cameras and asked to photograph 'people, places, and things' meaningful to them in their recovery. These photographs were then used as a catalyst for discussion during two in-depth interviews.

Assessing the effects of alternative plant-based meats . animal meats on biomarkers of inflammation: a secondary analysis of the SWAP-MEAT randomized crossover trial.

Alternative plant-based meats have grown in popularity with consumers recently and researchers are examining the potential health effects, or risks, from consuming these products. Because there have been no studies to date that have specifically assessed the health effects of plant-based meats on biomarkers of inflammation, the purpose of this work was to conduct a secondary analysis of the Study With Appetizing Plantfood - Meat Eating Alternatives Trial (SWAP-MEAT). SWAP-MEAT was a randomised crossover trial that involved generally healthy adults eating 2 or more servings of plant-based meats per day for 8 weeks (i.

CIITA promoter polymorphism impairs monocytes HLA-DR expression in patients with septic shock.

Low monocyte (m)HLA-DR expression is associated with mortality in sepsis. G-286A∗rs3087456 polymorphism in promoter III of HLA class II transactivator (), the master regulator of HLA, has been associated with autoimmune diseases but its role in sepsis has never been demonstrated. In 203 patients in septic shock, GG genotype was associated with 28-day mortality and mHLA-DR remained low whereas it increased in patients with AA or AG genotype.

The GPR88 agonist RTI-13951-33 reduces alcohol drinking and seeking in mice.

GPR88 is an orphan G-protein-coupled receptor that is considered a potential target to treat neuropsychiatric disorders, including addiction. Most knowledge about GPR88 function stems from knockout mouse studies, and in vivo pharmacology is still scarce. Here we examine the effects of the novel brain-penetrant agonist RTI-13951-33 on several alcohol-related behaviours in the mouse.

Forecasting Institutional LINAC Utilization in Response to Varying Workload.

Pandemics, natural disasters, and other unforeseen circumstances can cause short-term variation in radiotherapy utilization. In this study, we aim to develop a model to forecast linear accelerator (LINAC) utilization during periods of varying workloads. Using computed tomography (CT)-simulation data and the rate of new LINAC appointment bookings in the preceding week as input parameters, a multiple linear regression model to forecast LINAC utilization over a 15-working day horizon was developed and tested on institutional data.

Diversity, Equity, and Inclusion: A Decade of Progress?

The concepts of diversity, equity, and inclusion are fundamental and more recently heavily discussed within medicine, research, and the larger society. There is increasing awareness that diversity of thoughts, perspectives, and backgrounds yields stronger teams and more effective results. There is also increasing awareness that stark inequities from systemic, institutional, and individual levels exist that limit the baseline opportunities for many populations.

The imperative of professional dementia care.

Despite negative effects on their health and social lives, many informal carers of people living with dementia claim to be acting in accordance with a moral obligation. Indeed, feelings of failure and shame are commonly reported by those who later give up their caring responsibilities, suggesting a widespread belief that professional dementia care, whether delivered in the person's own home or in an institutional setting, ought always to be a last resort. In this paper, however, I suggest that this common intuition gets things the wrong way around.

Assessment of Canadian perinatal mental health services from the provider perspective: Where can we improve?

Purpose: Perinatal mental health disorders are common, and rates have increased during the COVID-19 pandemic. It is unclear where providers may improve perinatal mental health care, particularly in countries lacking national guidelines, such as Canada.

Methods: A cross-sectional survey of perinatal health providers was conducted to describe the landscape of perinatal mental health knowledge, screening, and treatment practices across Canada.

A is for Airway: An Interprofessional Simulation Event to Re-Establish the Importance of Communication.

Establishing an airway in the operating room is an interdisciplinary activity that requires focus of all participants. An interprofessional simulation event was designed to reestablish the importance of this OR event for student registered nurse anesthetists and registered nurse first assists.

Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms.

Serum tryptase is a biomarker used to aid in the identification of certain myeloid neoplasms, most notably systemic mastocytosis, where basal serum tryptase (BST) levels >20 ng/mL are a minor criterion for diagnosis. Although clonal myeloid neoplasms are rare, the common cause for elevated BST levels is the genetic trait hereditary α-tryptasemia (HαT) caused by increased germline TPSAB1 copy number. To date, the precise structural variation and mechanism(s) underlying elevated BST in HαT and the general clinical utility of tryptase genotyping, remain undefined.

Exercising choice over feedback schedules during practice is not advantageous for motor learning.

The idea that there is a self-controlled learning advantage, where individuals demonstrate improved motor learning after exercising choice over an aspect of practice compared to no-choice groups, has different causal explanations according to the OPTIMAL theory or an information-processing perspective. Within OPTIMAL theory, giving learners choice is considered an autonomy-supportive manipulation that enhances expectations for success and intrinsic motivation. In the information-processing view, choice allows learners to engage in performance-dependent strategies that reduce uncertainty about task outcomes.

Stimuli-Responsive Polymer Coatings for the Rapid and Tunable Contact Transfer of Plasmid DNA to Soft Surfaces.

We report the design and characterization of thin polymer-based coatings that promote the contact transfer of DNA to soft surfaces under mild and physiologically relevant conditions. Past studies reveal polymer multilayers fabricated using linear poly(ethylene imine) (LPEI), poly(acrylic acid) (PAA), and plasmid DNA promote contact transfer of DNA to vascular tissue. Here, we demonstrate that changes in the structure of the polyamine building blocks of these materials can have substantial impacts on rates and extents of contact transfer.

Readmission and Resource Utilization in Patients From Socioeconomically Distressed Communities Following Lumbar Fusion.

Study Design: Retrospective cohort study.

Objective: To determine whether: (1) patients from communities of socioeconomic distress have higher readmission rates or postoperative healthcare resource utilization and (2) there are differences in patient-reported outcome measures (PROMs) based on socioeconomic distress.

Summary Of Background Data: Socioeconomic disparities affect health outcomes, but little evidence exists demonstrating the impact of socioeconomic distress on postoperative resource utilization or PROMs.

Effect of the of 10-valent pneumococcal conjugate vaccine in Nepal 4 years after introduction: an observational cohort study.

Background: In Nepal, Streptococcus pneumoniae (pneumococcus) is a common cause of bacterial pneumonia in children, and is a major health concern. There are few data on the effect of vaccination on the disease or colonisation with pneumococci in the nasopharynx of children in this setting. The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced into the routine infant immunisation schedule in Nepal in 2015.

A high-throughput 384-well CometChip platform reveals a role for 3-methyladenine in the cellular response to etoposide-induced DNA damage.

The Comet or single-cell gel electrophoresis assay is a highly sensitive method to measure cellular, nuclear genome damage. However, low throughput can limit its application for large-scale studies. To overcome these limitations, a 96-well CometChip platform was recently developed that increases throughput and reduces variation due to simultaneous processing and automated analysis of 96 samples.

Reliability of the Critical Thinking in Communication Science and Disorders: A Content-Specific Critical Thinking Assessment.

Introduction: Students and professionals in communication sciences and disorders (CSD) need to exhibit good critical thinking (CT) skills when engaged in clinical tasks. CSD clinicians must make decisions that are free from biases and support their claim with facts. Thus, CSD clinicians need to be trained to question their clinical practices and to skeptically evaluate new practices that develop.

Aberrant protein expression of Appl1, Sortilin and Syndecan-1 during the biological progression of prostate cancer.

Diagnosis and assessment of patients with prostate cancer is dependent on accurate interpretation and grading of histopathology. However, morphology does not necessarily reflect the complex biological changes occurring in prostate cancer disease progression, and current biomarkers have demonstrated limited clinical utility in patient assessment. This study aimed to develop biomarkers that accurately define prostate cancer biology by distinguishing specific pathological features that enable reliable interpretation of pathology for accurate Gleason grading of patients.

Lower Risk of Revision Surgery After Arthroscopic Versus Open Irrigation and Débridement for Shoulder Septic Arthritis.

Background: In the treatment of native shoulder septic arthritis, the optimal irrigation and débridement modality-arthroscopic versus open-is a matter of controversy. We aim to compare revision-free survival (RFS), complications, and resource utilization between these approaches.

Methods: The National Readmission Database was queried from 2016 to 2019 to identify patients using International Classification of Diseases, 10th revision, diagnostic and procedure codes.

RB1-deficient squamous cell carcinoma: the proposed source of combined Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine (NE) carcinoma arising from integration of Merkel cell polyomavirus (MCPyV) DNA into a host cell or from ultraviolet light-induced genetic damage (proportions vary geographically). Tumors in the latter group include those with "pure" NE phenotype and those "combined" with other elements, most often squamous cell carcinoma (SCC). We performed comprehensive genomic profiling (CGP) of MCPyV+ and MCPyV- (pure and combined) tumors, to better understand their mutational profiles and shed light on their pathogenesis.

Risk factors associated with mortality in hospitalized patients with laboratory confirmed SARS-CoV-2 infection during the period of omicron (B.1.1.529) variant predominance.

Background: SARS-CoV-2 Omicron variant has a high transmission rate. In December 2021, Omicron became the dominant variant and quickly accounted for majority of infections in the United States. Drug shortages have led to prioritization of patients for COVID-19 treatment based on risk factors for severe disease.

A Multicenter, Randomized, Controlled, Clinical Trial Evaluating Dehydrated Human Amniotic Membrane in the Treatment of Venous Leg Ulcers.

Background: This randomized controlled trial evaluated the safety and effectiveness of weekly and biweekly applications of dehydrated human amnion and chorion allograft (dHACA) plus standard of care compared to standard of care alone on chronic venous leg ulcers.

Methods: This open-label randomized controlled trial included patients with chronic venous leg ulcers at eight wound care centers across the United States. The primary endpoint was the proportion of healed ulcers at 12 weeks.