Canadian COVID-19 host genetics cohort replicates known severity associations.

The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic contributors to severe COVID-19 (considering 3,499 hospitalized cases and 4,975 non-hospitalized after quality control). We investigated the evidence for replication of loci reported by the International Host Genetics Initiative (HGI); analyzed the X chromosome; conducted rare variant gene-based analysis and polygenic risk score testing. Population stratification was adjusted for using meta-analysis across ancestry groups. We replicated two loci identified by the HGI for COVID-19 severity: the LZTFL1/SLC6A20 locus on chromosome 3 and the FOXP4 locus on chromosome 6 (the latter with a variant significant at P < 5E-8). We found novel significant associations with MRAS and WDR89 in gene-based analyses, and constructed a polygenic risk score that explained 1.01% of the variance in severe COVID-19. This study provides independent evidence confirming the robustness of previously identified COVID-19 severity loci by the HGI and identifies novel genes for further investigation.

The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16176. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Characterization of direct and/or indirect genetic associations for multiple traits in longitudinal studies of disease progression.

When quantitative longitudinal traits are risk factors for disease progression and subject to random biological variation, joint model analysis of time-to-event and longitudinal traits can effectively identify direct and/or indirect genetic association of single nucleotide polymorphisms (SNPs) with time-to-event. We present a joint model that integrates: (1) a multivariate linear mixed model describing trajectories of multiple longitudinal traits as a function of time, SNP effects, and subject-specific random effects and (2) a frailty Cox survival model that depends on SNPs, longitudinal trajectory effects, and subject-specific frailty accounting for dependence among multiple time-to-event traits. Motivated by complex genetic architecture of type 1 diabetes complications (T1DC) observed in the Diabetes Control and Complications Trial (DCCT), we implement a 2-stage approach to inference with bootstrap joint covariance estimation and develop a hypothesis testing procedure to classify direct and/or indirect SNP association with each time-to-event trait. By realistic simulation study, we show that joint modeling of 2 time-to-T1DC (retinopathy and nephropathy) and 2 longitudinal risk factors (HbA1c and systolic blood pressure) reduces estimation bias in genetic effects and improves classification accuracy of direct and/or indirect SNP associations, compared to methods that ignore within-subject risk factor variability and dependence among longitudinal and time-to-event traits. Through DCCT data analysis, we demonstrate feasibility for candidate SNP modeling and quantify effects of sample size and Winner's curse bias on classification for 2 SNPs identified as having indirect associations with time-to-T1DC traits. Joint analysis of multiple longitudinal and multiple time-to-event traits provides insight into complex traits architecture.

Minimizing fall-related injuries in at-risk older adults: The falling safely training (FAST) study protocol.

Background: Falls are the leading cause of accidental injury among the elderly. Fall prevention is currently the main strategy to minimize fall-related injuries in at-risk older adults. However, the success of fall prevention programs in preventing accidental injury in elderly populations is inconsistent. An alternative novel approach to directly target fall-related injuries is teaching older adults movement patterns which reduce injury risk. The purpose of the current study will be to explore the feasibility and preliminary efficacy of teaching at-risk older adults safe-falling strategies to minimize the risk of injury. Methods/design: The Falling Safely Training (FAST) study will be a prospective, single-blinded randomized controlled trial. A total of 28 participants will be randomly assigned to four weeks of FAST or to an active control group with a 1:1 allocation. People aged ≥65 years, at-risk of injurious falls, and with normal hip bone density will be eligible. The FAST program will consist of a standardized progressive training of safe-falling movement strategies. The control group will consist of evidence-based balance training (modified Otago exercise program). Participants will undergo a series of experimentally induced falls in a laboratory setting at baseline, after the 4-week intervention, and three months after the intervention. Data on head and hip movement during the falls will be collected through motion capture. Discussion: The current study will provide data on the feasibility and preliminary efficacy of safe-falling training as a strategy to reduce fall impact and head motion, and potentially to reduce hip and head injuries in at-risk populations. Registration: The FAST study is registered at http://Clinicaltrials.gov (NCT05260034).

Penalized maximum likelihood inference under the mixture cure model in sparse data.

INTRODUCTION: When a study sample includes a large proportion of long-term survivors, mixture cure (MC) models that separately assess biomarker associations with long-term recurrence-free survival and time to disease recurrence are preferred to proportional-hazards models. However, in samples with few recurrences, standard maximum likelihood can be biased. OBJECTIVE AND METHODS: We extend Firth-type penalized likelihood (FT-PL) developed for bias reduction in the exponential family to the Weibull-logistic MC, using the Jeffreys invariant prior. Via simulation studies based on a motivating cohort study, we compare parameter estimates of the FT-PL method to those by ML, as well as type 1 error (T1E) and power obtained using likelihood ratio statistics. RESULTS: In samples with relatively few events, the Firth-type penalized likelihood estimates (FT-PLEs) have mean bias closer to zero and smaller mean squared error than maximum likelihood estimates (MLEs), and can be obtained in samples where the MLEs are infinite. Under similar T1E rates, FT-PL consistently exhibits higher statistical power than ML in samples with few events. In addition, we compare FT-PL estimation with two other penalization methods (a log-F prior method and a modified Firth-type method) based on the same simulations. DISCUSSION: Consistent with findings for logistic and Cox regressions, FT-PL under MC regression yields finite estimates under stringent conditions, and better bias-and-variance balance than the other two penalizations. The practicality and strength of FT-PL for MC analysis is illustrated in a cohort study of breast cancer prognosis with long-term follow-up for recurrence-free survival.

The SPEER: An interprofessional team behavior rubric to optimize geriatric clinical care.

Geriatric patients with complex health care needs can benefit from interprofessional (IP) care; however, a major gap in health professional education is determining how to prepare future providers for IP collaboration. Effective IP team behavior assessment tools are needed to teach, implement, and evaluate IP practice skills. After review of IP evaluation tools, the Standardized Patient Encounter Evaluation Rubric (SPEER) was created to evaluate team dynamics in IP practice sites.Independent sample t-tests between faculty and learner SPEER scores showed learners scored themselves 15 points higher than their faculty scores (p < .001). Cronbach's α showed high internal consistency (α = 0.91). Paired t-tests found that learners identified improvements in the team's ability to address the patient's education needs and to allow the patients to voice their expectations. Faculty identified improvements in the teams' ability to make recommendations. Faculty evaluations of learner teams showed improvements in raw ratings on all but two items. Qualitative data analysis for emergent themes showed learners desired team functioning feedback and how teamwork could improve to provide optimal IP care.In conclusion, the SPEER can help faculty and learners identify growth in their teams' ability to perform key IP skills in clinical sites.

Enhanced stability and clinical absorption of a form of encapsulated vitamin A for food fortification.

Food fortification is an effective strategy to address vitamin A (VitA) deficiency, which is the leading cause of childhood blindness and drastically increases mortality from severe infections. However, VitA food fortification remains challenging due to significant degradation during storage and cooking. We utilized an FDA-approved, thermostable, and pH-responsive basic methacrylate copolymer (BMC) to encapsulate and stabilize VitA in microparticles (MPs). Encapsulation of VitA in VitA-BMC MPs greatly improved stability during simulated cooking conditions and long-term storage. VitA absorption was nine times greater from cooked MPs than from cooked free VitA in rats. In a randomized controlled cross-over study in healthy premenopausal women, VitA was readily released from MPs after consumption and had a similar absorption profile to free VitA. This VitA encapsulation technology will enable global food fortification strategies toward eliminating VitA deficiency.

Microglia Phenotypes in Aging and Neurodegenerative Diseases.

Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development. This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimer's disease (AD), and Parkinson's disease (PD). The primary focus is translational research in preclinical animal models and bulk/single-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.

Phytohormone abscisic acid ameliorates neuropathic pain via regulating LANCL2 protein abundance and glial activation at the spinal cord.

Spinal neuroinflammation plays a critical role in the genesis of neuropathic pain. Accumulating data suggest that abscisic acid (ABA), a phytohormone, regulates inflammatory processes in mammals. In this study, we found that reduction of the LANCL2 receptor protein but not the agonist ABA in the spinal cord is associated with the genesis of neuropathic pain. Systemic or intrathecal administration of ABA ameliorates the development and pre-existence of mechanical allodynia and heat hyperalgesia in animals with partial sciatic nerve ligation (pSNL). LANCL2 is expressed only in microglia in the spinal dorsal horn. Pre-emptive treatment with ABA attenuates activation of microglia and astrocytes, ERK activity, and TNFα protein abundance in the dorsal horn in rats with pSNL. These are accompanied by restoration of spinal LANCL2 protein abundance. Spinal knockdown of LANCL2 gene with siRNA recapitulates the behavioral and spinal molecular changes induced by pSNL. Activation of spinal toll-like receptor 4 (TLR4) with lipopolysaccharide leads to activation of microglia, and over production of TNFα, which are concurrently accompanied by suppression of protein levels of LANCL2 and peroxisome proliferator activated-receptor γ. These changes are ameliorated when ABA is added with LPS. The anti-inflammatory effects induced by ABA do not requires Gi protein activity. Our study reveals that the ABA/LANCL2 system is a powerful endogenous system regulating spinal neuroinflammation and nociceptive processing, suggesting the potential utility of ABA as the management of neuropathic pain.

Right ventricular dysfunction in patients with COVID-19 pneumonitis whose lungs are mechanically ventilated: a multicentre prospective cohort study.

Cardiovascular complications due to COVID-19, such as right ventricular dysfunction, are common. The combination of acute respiratory distress syndrome, invasive mechanical ventilation, thromboembolic disease and direct myocardial injury creates conditions where right ventricular dysfunction is likely to occur. We undertook a prospective, multicentre cohort study in 10 Scottish intensive care units of patients with COVID-19 pneumonitis whose lungs were mechanically ventilated. Right ventricular dysfunction was defined as the presence of severe right ventricular dilation and interventricular septal flattening. To explore the role of myocardial injury, high-sensitivity troponin and N-terminal pro B-type natriuretic peptide plasma levels were measured in all patients. We recruited 121 patients and 118 (98%) underwent imaging. It was possible to determine the primary outcome in 112 (91%). Severe right ventricular dilation was present in 31 (28%), with interventricular septal flattening present in nine (8%). Right ventricular dysfunction (the combination of these two parameters) was present in seven (6%, 95%CI 3-13%). Thirty-day mortality was 86% in those with right ventricular dysfunction as compared with 45% in those without (p = 0.051). Patients with right ventricular dysfunction were more likely to have: pulmonary thromboembolism (p < 0.001); higher plateau airway pressure (p = 0.048); lower dynamic compliance (p = 0.031); higher plasma N-terminal pro B-type natriuretic peptide levels (p = 0.006); and raised plasma troponin levels (p = 0.048). Our results demonstrate a prevalence of right ventricular dysfunction of 6%, which was associated with increased mortality (86%). Associations were also observed between right ventricular dysfunction and aetiological domains of: acute respiratory distress syndrome; ventilation; thromboembolic disease; and direct myocardial injury, implying a complex multifactorial pathophysiology.

CCL5 production in lung cancer cells leads to an altered immune microenvironment and promotes tumor development.

Current immunotherapies for lung cancer are only effective in a subset of patients. Identifying tumor-derived factors that facilitate immunosuppression offers the opportunity to develop novel strategies to supplement and improve current therapeutics. We sought to determine whether expression of driver oncogenes in lung cancer cells affects cytokine secretion, alters the local immune environment, and influences lung tumor progression. We demonstrate that oncogenic EGFR and KRAS mutations, which are early events in lung tumourigenesis, can drive cytokine and chemokine production by cancer cells. One of the most prominent changes was in CCL5, which was rapidly induced by KRASG12V or EGFRL858R expression, through MAPK activation. Immunocompetent mice implanted with syngeneic KRAS-mutant lung cancer cells deficient in CCL5 have decreased regulatory T cells (Tregs), evidence of T cell exhaustion, and reduced lung tumor burden, indicating tumor-cell CCL5 production contributes to an immune suppressive environment in the lungs. Furthermore, high CCL5 expression correlates with poor prognosis, immunosuppressive regulatory T cells, and alteration to CD8 effector function in lung adenocarcinoma patients. Our data support targeting CCL5 or CCL5 receptors on immune suppressive cells to prevent formation of an immune suppressive tumor microenvironment that promotes lung cancer progression and immunotherapy insensitivity.

Linguistic aspects of stuttering: research updates on the language-fluency interface.

Purpose: Although commonly defined as a speech disorder, stuttering interacts with the language production system in important ways. Our purpose is to summarize research findings on linguistic variables that influence stuttering assessment and treatment. Method and Results: Numerous topics are summarized. First, we review research that has examined linguistic features that increase stuttering frequency and influence where it occurs. Second, we tackle the question of whether or not persons who stutter exhibit subtle language differences or deficits. Next, we explore language factors that appear to influence recovery from early stuttering in children. The final topic discusses the unique challenges inherent in differentially diagnosing stuttering in bilingual children. Clinical implications for each topic are discussed. Discussion: The article concludes with a discussion of the unique differences in the integration of language and speech demands by people who stutter, when compared to people who are typically fluent, and their clinical ramifications.

Novel model to teach health care delivery in geriatrics.

Introducing health policy to interprofessional graduate students, anchoring health policy to older adult health needs, while conveying how current policy issues will affect their individual careers is challenging, yet essential, for health profession education. This novel program integrated graduate level health profession learners from medicine, nurse practitioner, pharmacy, psychology, social work, physical therapy and occupational therapy disciplines. The aim was to embed health policy into an existing interprofessional (IP) geriatrics course at an academic medical center. Selection of disciplines was based on prior collaborative work and faculty interest. The objectives were to 1. Introduce current health policies that affect older adults; 2. Understand the effects of health policy and social determinants of health on the older adults in their future practice; 3. Challenge learners to apply their knowledge and develop health advocacy strategies for older adults; and 4) Teach the importance of teamwork in interprofessional practice within a geriatric population.The health policy curriculum impacted 487 learners for 12 sessions over three years. Four themes emerged with the sessions: health policy awareness, interprofessional appreciation, patient care "pearls," and pharmacological considerations in geriatrics. Each of the eight modules generated thoughtful recommendations by the learners, providing a glimpse into future workforce priorities.

Comparing evaluations of social situations for adults who do and do not stutter.

PURPOSE: Numerous research studies indicate that stuttering is associated with increased risk for social anxiety disorder (SAD). Interpretation bias is one of four cognitive biases thought to maintain symptoms associated with SAD. Interpretation bias occurs when one evaluates social situations as more negative than they actually are. The purpose of this study was to investigate if adults who do and do not stutter interpret positive, ambiguous, mildly negative, and profoundly negative social situations similarly, or-if like individuals with SAD-adults who stutter exhibit negative interpretation biases. METHOD: Forty-eight adults who stutter and 42 age-and gender-matched adults who do not stutter participated. Participants completed the Fear of Negative Evaluation (FNE) and were assigned to one of four groups: adults who stutter with high FNE (AWS-High), adults who stutter with low FNE (AWS-Low), adults who do not stutter with high FNE (AWNS-High), and adults who do not stutter with low FNE (AWNS-Low). All participants completed the trait scale of the State Trait Anxiety Inventory (STAI) and the Interpretation and Judgmental Questionnaire (IJQ). The IJQ contains descriptions of four types of social situations: positive, mildly negative, profoundly negative, and ambiguous. Within each situation type there are five different scenarios, for a total of 20 scenarios across the four situation types. Participants provided written responses to these 20 social scenarios. Qualitative analyses were used to understand how members of each group interpreted the different social scenarios. RESULTS: Thematic analysis revealed that each group responded in similar ways to each of the social scenarios, regardless of the type of situation. Adults who do and do not stutter with low and high FNE agreed on many themes related to the 20 social scenarios, and they agreed across all four types of social situations. Somewhat surprisingly, the theme "stuttering" was mentioned infrequently by the adults who stutter. CONCLUSIONS: Results suggested that adults who do and do not stutter with low and high FNE interpret social situations similarly, and that no group demonstrated a negative interpretation bias consistent with what is observed in adults with SAD. The interpretations provided by each group were appropriate to the specific scenarios being evaluated.

Pleiotropic effects of the COX-2/PGE2 axis in the glioblastoma tumor microenvironment.

Glioblastoma (GBM) is the most common and aggressive form of malignant glioma. The GBM tumor microenvironment (TME) is a complex ecosystem of heterogeneous cells and signaling factors. Glioma associated macrophages and microglia (GAMs) constitute a significant portion of the TME, suggesting that their functional attributes play a crucial role in cancer homeostasis. In GBM, an elevated GAM population is associated with poor prognosis and therapeutic resistance. Neoplastic cells recruit these myeloid populations through release of chemoattractant factors and dysregulate their induction of inflammatory programs. GAMs become protumoral advocates through production a variety of cytokines, inflammatory mediators, and growth factors that can drive cancer proliferation, invasion, immune evasion, and angiogenesis. Among these inflammatory factors, cyclooxygenase-2 (COX-2) and its downstream product, prostaglandin E2 (PGE2), are highly enriched in GBM and their overexpression is positively correlated with poor prognosis in patients. Both tumor cells and GAMs have the ability to signal through the COX-2 PGE2 axis and respond in an autocrine/paracrine manner. In the GBM TME, enhanced signaling through the COX-2/PGE2 axis leads to pleotropic effects that impact GAM dynamics and drive tumor progression.

Preparing a healthcare workforce for geriatrics care: an Interprofessional team based learning program.

BACKGROUND: Improving the care of older adults in our healthcare system involves teams working together. As the geriatrics population rises globally, health science learners need to be prepared to work collaboratively to recognize and treat common conditions in geriatrics. To enable workforce preparation, the Institute of Medicine and the National League for Nursing emphasize the need to implement interprofessional active learning activities for undergraduate healthcare learners at academic medical centers. METHODS: The Geriatrics Champions Program was a team-based learning activity created to meet this task. It was a 24-month program, repeated twice, that impacted 768 learners and 151 faculty from medicine, occupational therapy, physical therapy, nursing, social welfare, psychology, pharmacy and dietetics. Each class was intentionally divided into 20 interprofessional teams that met four times annually. Each session focused on one geriatrics domain. The objectives were centered around the specific geriatrics competencies for each health profession, divided into the eight domains written in the "American Geriatrics Society IM-FM Residency Competencies". Evaluation consisted of individual and team Readiness Assessment Tests (iRAT and tRAT). Surveys were also used to collect feedback using a Likert scale. Wilcoxon signed rank tests were used to compare iRAT and tRAT scores. Other analyses identified characteristics associated with tRAT performance group (Unpaired t-tests) and tRAT performance on the raw scale (Pearson correlation). Paired t-tests using a 7-level Likert Scale measured pre-post change in learner knowledge. RESULTS: Student tRAT scores were 30% higher than iRAT scores (p < 0.001). Teams were more likely to score 100% on the initial tRAT attempt if more team members attended the current session (p < 0.001), more health professions were represented by team members in attendance (p = 0.053), and the team had a better track record of past attendance (p < 0.01). In the post-program evaluation, learners felt this program was helpful for their career preparation in interprofessional geriatrics care. CONCLUSIONS: Learners understood that teams performed better than individuals in the care of older adults. Feedback from the learners and faculty was consistently positive and learners felt better prepared for geriatrics care. The program's benefits may extend beyond individual sessions.