Phenome-wide identification of therapeutic genetic targets, leveraging knowledge graphs, graph neural networks, and UK Biobank data.

The ongoing expansion of human genomic datasets propels therapeutic target identification; however, extracting gene-disease associations from gene annotations remains challenging. Here, we introduce Mantis-ML 2.0, a framework integrating AstraZeneca's Biological Insights Knowledge Graph and numerous tabular datasets, to assess gene-disease probabilities throughout the phenome. We use graph neural networks, capturing the graph's holistic structure, and train them on hundreds of balanced datasets via a robust semi-supervised learning framework to provide gene-disease probabilities across the human exome. Mantis-ML 2.0 incorporates natural language processing to automate disease-relevant feature selection for thousands of diseases. The enhanced models demonstrate a 6.9% average classification power boost, achieving a median receiver operating characteristic (ROC) area under curve (AUC) score of 0.90 across 5220 diseases from Human Phenotype Ontology, OpenTargets, and Genomics England. Notably, Mantis-ML 2.0 prioritizes associations from an independent UK Biobank phenome-wide association study (PheWAS), providing a stronger form of triaging and mitigating against underpowered PheWAS associations. Results are exposed through an interactive web resource.

Outcomes from 871,441 Consecutive Surgical Procedures without Overlap or with Maximally Permissible Non-Concurrent Overlap.

OBJECTIVE: To isolate the impact of subsumed surgery (a shorter procedure completed entirely during overlapping non-critical portions of a longer antecedent procedure) on patient outcomes. SUMMARY BACKGROUND DATA: The American College of Surgeons recently recommended the elimination of "concurrent surgery" with overlap during a procedure's critical portions. Guidelines for non-concurrent overlap have been established, but the safety of subsumed surgery remains to be examined. METHODS: All consecutive procedures from 2013 to 2021 within a multihospital academic medical center were included (n=871,441). Simple logistic regression was performed to compare postoperative events between patients undergoing non-overlap surgery (n=533,032) and completely subsumed surgery (n=11,319). Thereafter, coarsened exact matching was used to match patients with non-overlap and subsumed surgery 1:1 on CPT code, 18 demographic features, baseline health characteristics, and procedural variables (n=7,146). Exact-matched cases were subsequently limited to pairs performed by the same surgeon (n=5,028). Primary outcomes included 30-day readmission, ED visits, and reoperations. RESULTS: Univariate analysis suggested that subsumed surgery had a higher 30-day risk of readmission (OR 1.55, P<0.0001), ED evaluation (OR 1.19, P<0.0001), and reoperation (OR 1.98, P<0.0001). When comparison was limited to the exact same procedure and patients were matched on demographics and health characteristics, there were no outcome differences between patients with subsumed surgery and non-overlapping surgery, even when limiting analyses to the same surgeon. CONCLUSIONS: Similar surgeries for similar patients result in similar outcomes whether there is completely subsumed or no overlap. Individual surgeons performing a specific procedure have no outcome differences with subsumed and non-overlapping cases.

Multifidus atrophy and/or dysfunction following lumbar radiofrequency ablation: A systematic review.

BACKGROUND: Lumbar medial branch nerve radiofrequency ablation (LRFA) is an interventional procedure used to treat chronic lumbar facet joint pain. Because the medial branch nerves also innervate the multifidus muscle, it has been proposed that LRFA may pose a risk of multifidus atrophy and/or dysfunction. However, the quality and level of evidence to answer this clinical question have not been established. Therefore, this review aimed to systematically appraise the literature to discern whether the prevailing evidence substantiates the hypothesis in question. METHODS: A systematic review compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed to evaluate the quality and level of evidence of studies reporting functional and/or structural changes in the multifidus muscle following LRFA. RESULTS: Only five cohort studies met inclusion criteria. Two studies assessed changes in multifidus function following LRFA with confirmed denervation at electromyography and significant reduction in multifidus shear modulus with ultrasound shear wave elastography. Of the four studies that evaluated changes in multifidus structure with magnetic resonance imaging following LRFA, two demonstrated a decrease in cross-sectional area or an increase in fat infiltration, one demonstrated no change, and one revealed an apparent increase. Given the destructive nature attributed to LRFA, some degree of multifidus atrophy and/or dysfunction may be plausible, albeit with a very low certainty that relies on a restricted body of literature of modest quality and with a presence of high bias. CONCLUSION: There is a paucity of studies discussing the potential association between LRFA and multifidus atrophy and/or dysfunction. In light of the shortage of high-quality studies and the absence of standardized protocols to assess both changes in the structure and function of the multifidus subsequent to LRFA, there is a pressing need for more prospective studies with a high methodological rigor to comprehensively address and answer this enduring debate in clinical practice.

Lower vascular conductance responses to handgrip exercise are improved following acute antioxidant supplementation in young individuals with post-traumatic stress disorder.

Young individuals with post-traumatic stress disorder (PTSD) display peripheral vascular and autonomic nervous system dysfunction, two factors potentially stemming from a redox imbalance. It is currently unclear if these aforementioned factors, observed at rest, alter peripheral haemodynamic responses to exercise in this population. This study examined haemodynamic responses to handgrip exercise in young individuals with PTSD following acute antioxidant (AO) supplementation. Thirteen young individuals with PTSD (age 23 ± 3 years), and 13 age- and sex-matched controls (CTRL) participated in the study. Exercise-induced changes to arm blood flow (BF), mean arterial pressure (MAP) and vascular conductance (VC) were evaluated across two workloads of rhythmic handgrip exercise (3 and 6 kg). The PTSD group participated in two visits, consuming either a placebo (PL) or AO prior to their visits. The PTSD group demonstrated significantly lower VC (P = 0.04) across all exercise workloads (vs. CTRL), which was significantly improved following AO supplementation. In the PTSD group, AO supplementation improved VC in participants possessing the lowest VC responses to handgrip exercise, with AO supplementation significantly improving VC responses (3 and 6 kg: P < 0.01) by blunting elevated exercise-induced MAP responses (3 kg: P = 0.01; 6 kg: P < 0.01). Lower VC responses during handgrip exercise were improved following AO supplementation in young individuals with PTSD. AO supplementation was associated with a blunting of exercise-induced MAP responses in individuals with PTSD displaying elevated MAP responses. This study revealed that young individuals with PTSD exhibit abnormal, peripherally mediated exercise responses that may be linked to a redox imbalance.

American Society of Pain and Neuroscience Best Practice (ASPN) Guideline for the Treatment of Sacroiliac Disorders.

Clinical management of sacroiliac disease has proven challenging from both diagnostic and therapeutic perspectives. Although it is widely regarded as a common source of low back pain, little consensus exists on the appropriate clinical management of sacroiliac joint pain and dysfunction. Understanding the biomechanics, innervation, and function of this complex load bearing joint is critical to formulating appropriate treatment algorithms for SI joint disorders. ASPN has developed this comprehensive practice guideline to serve as a foundational reference on the appropriate management of SI joint disorders utilizing the best available evidence and serve as a foundational guide for the treatment of adult patients in the United States and globally.

Overcome the Limitation of Phenome-Wide Association Studies (PheWAS): Extension of PheWAS to Efficient and Robust Large-Scale ICD Codes Analysis.

The Phenome-wide association studies (PheWAS) have become widely used for efficient, high-throughput evaluation of relationship between a genetic factor and a large number of disease phenotypes, typically extracted from a DNA biobank linked with electronic medical records (EMR). Phecodes, billing code-derived disease case-control status, are usually used as outcome variables in PheWAS and logistic regression has been the standard choice of analysis method. Since the clinical diagnoses in EMR are often inaccurate with errors which can lead to biases in the odds ratio estimates, much effort has been put to accurately define the cases and controls to ensure an accurate analysis. Specifically in order to correctly classify controls in the population, an exclusion criteria list for each Phecode was manually compiled to obtain unbiased odds ratios. However, the accuracy of the list cannot be guaranteed without extensive data curation process. The costly curation process limits the efficiency of large-scale analyses that take full advantage of all structured phenotypic information available in EMR. Here, we proposed to estimate relative risks (RR) instead. We first demonstrated the desired nature of RR that overcomes the inaccuracy in the controls via theoretical formula. With simulation and real data application, we further confirmed that RR is unbiased without compiling exclusion criteria lists. With RR as estimates, we are able to efficiently extend PheWAS to a larger-scale, phenome construction agnostic analysis of phenotypes, using ICD 9/10 codes, which preserve much more disease-related clinical information than Phecodes.

Mind over Microplastics: Exploring Microplastic-Induced Gut Disruption and Gut-Brain-Axis Consequences.

As environmental plastic waste degrades, it creates an abundance of diverse microplastic particles. Consequently, microplastics contaminate drinking water and many staple food products, meaning the oral ingestion of microplastics is an important exposure route for the human population. Microplastics have long been considered inert, however their ability to promote microbial dysbiosis as well as gut inflammation and dysfunction suggests they are more noxious than first thought. More alarmingly, there is evidence for microplastics permeating from the gut throughout the body, with adverse effects on the immune and nervous systems. Coupled with the now-accepted role of the gut-brain axis in neurodegeneration, these findings support the hypothesis that this ubiquitous environmental pollutant is contributing to the rising incidence of neurodegenerative diseases, like Alzheimer's disease and Parkinson's disease. This comprehensive narrative review explores the consequences of oral microplastic exposure on the gut-brain-axis by considering current evidence for gastrointestinal uptake and disruption, immune activation, translocation throughout the body, and neurological effects. As microplastics are now a permanent feature of the global environment, understanding their effects on the gut, brain, and whole body will facilitate critical further research and inform policy changes aimed at reducing any adverse consequences.

The lethal and sublethal impacts of two tire rubber-derived chemicals on brook trout (Salvelinus fontinalis) fry and fingerlings.

Recent toxicity studies of stormwater runoff implicated N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-quinone) as the contaminant responsible for the mass mortality of coho salmon (Oncorhynchus kisutch). In the wake of this discovery, 6PPD-quinone has been measured in waterways around urban centers, along with other tire wear leachates like hexamethoxymethylmelamine (HMMM). The limited data available for 6PPD-quinone have shown toxicity can vary depending on the species. In this study we compared the acute toxicity of 6PPD-quinone and HMMM to Brook trout (Salvelinus fontinalis) fry and fingerlings. Our results show that fry are ∼3 times more sensitive to 6PPD-quinone than fingerlings. Exposure to HMMM ≤6.6 mg/L had no impact on fry survival. These results highlight the importance of conducting toxicity tests on multiple life stages of fish species, and that relying on fingerling life stages for species-based risk assessment may underestimate the impacts of exposure. 6PPD-quinone also had many sublethal effects on Brook trout fingerlings, such as increased interlamellar cell mass (ILCM) size, hematocrit, blood glucose, total CO2, and decreased blood sodium and chloride concentrations. Linear relationships between ILCM size and select blood parameters support the conclusion that 6PPD-quinone toxicity is an outcome of osmorespiratory challenges imposed by gill impairment.

Associations of meeting 24-hour movement behavior guidelines with social and emotional function in youth with ASD/ADHD.

BACKGROUND: The 24-hour movement behavior (24-HMB) guidelines recommend that children and adolescents (youth) should limit screen time (ST), get an adequate amount of sleep (SL), and engage in sufficient physical activity (PA) to ensure health and healthy development. Meeting 24-HMB guidelines is associated with positive mental health outcomes (e.g., social and emotional function) in the general population. However, it is unclear whether such findings extend to youth with Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). Thus, we examined associations of meeting 24-HMB guidelines with social and emotional function in youth with comorbid ASD/ADHD. METHODS: Data from the 2020-2021 National Survey of Children's Health - a U.S. national, population-based, cross-sectional study - were used. We extracted and analyzed data on youth (aged between 6 and 17 years) diagnosed with comorbidity of ASD/ADHD. Data on movement behaviors (PA, ST, and SL) and specific outcome variables (social function and emotional function) were collected through caregiver-proxy reports. Logistic regressions were performed to examine the associations between meeting 24-HMB guidelines and social and emotional outcomes adjusting for covariates (e.g., age, sex, ethnicity, weight status, birth status, socio-economic status, and receiving medication/behavioral treatment). RESULTS: Among 979 children and adolescents with comorbid ASD/ADHD, only 3.8 % met all three 24-HMB guidelines. In total, 45.0 % of participants met at least one guideline, and 25.5 % of those met at least two guidelines. Compared to those who did not meet any 24-HMB guidelines, meeting SL + ST guidelines was significantly associated with lower odds of poorer social function (being bullied: OR = 0.3, 95%CI [0.1-0.7]; arguing: OR = 0.2, 95%CI[0.1-0.4]). Furthermore, meeting PA + ST + SL guidelines was associated with lower odds of poorer emotional function (depression: OR = 0.5, 95%CI[0.3-0.7]). CONCLUSION: Meeting 24-HMB guidelines was associated with better social and emotional function in U.S. youth with comorbid ASD/ADHD; however, currently very few with comorbid ASD/ADHD meet all 24-HMB guidelines. These results emphasize the importance of promoting adherence to the 24-HMB guidelines among youth facing the challenges of comorbid ASD/ADHD. These cross-sectional findings point to the need for further empirical evidence from longitudinal studies to support our conclusions.

Prediction of Recurrent Lateral Ankle Sprain and Ankle Pain Using Applied Care Strategies and Patient-Reported Outcomes.

CONTEXT: Lateral ankle sprain (LAS) patients often have deficient patient-reported outcomes (PROs) at return-to-activity (RTA), potentially increasing risk for recurrent LAS and ankle pain. Additionally, applied care strategies are known to correct impairments, but their ability to mitigate risk for long-term consequences remains unknown. OBJECTIVE: To determine if applied care strategies and PRO scores at RTA and 6-months post-RTA predict recurrent LAS and ankle pain 12 months after an acute LAS. DESIGN: Prospective cohort study. SETTING: Online survey. PATIENTS OR OTHER PARTICIPANTS: We enrolled 63 individuals within one week of sustaining an acute LAS. MAIN OUTCOME MEASURES: Participants completed online surveys about their health history and recent LAS. At RTA and 6 months post-RTA, participants completed online surveys regarding demographics, applied care strategies, and patient reported outcomes (PROs): Foot and Ankle Disability Index, Identification of Functional Ankle Instability, Godin Leisure-Time Exercise Questionnaire, Short Form-8. At 12 months post-RTA, we asked participants if they sustained recurrent LAS. Chi-squares determined if recurrent LAS and ankle pain at 12-months were related to applied care strategies or ankle pain at RTA. Independent t-tests compared demographics and PROs at RTA and 6-months between participants with and without a recurrent LAS or ankle pain at 12-months. Logistic regression and area under the receiver operating characteristic (AUROC) analyses determined if demographics, applied care strategies, ankle pain at RTA, and PRO scores at RTA and 6-months predicted recurrent LAS and ankle pain at 12-months. RESULTS: Participants with a recurrent LAS had a lower walking boot use (P=0.05) and were taller than those without (P=0.03). Increased height and lack of walking boot use were predictive of recurrent LAS (P<0.01, R2=0.33, AUROC=0.81[0.68, 0.95]). CONCLUSIONS: LAS patients who are taller and do not use a walking boot might have greater risk for a recurrent LAS withing 12 months of RTA.

Ultrapotent Broadly Neutralizing Human-llama Bispecific Antibodies against HIV-1.

Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV-1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion-stabilized HIV-1 envelope (Env) trimer, BG505 DS-SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4-binding site (CD4bs) of vulnerability. Two of the vaccine-elicited CD4bs-targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a-hinge region and human IgG1-constant region (G36×3-IgG2a and R27×3-IgG2a), neutralized 96% of a multiclade 208-strain panel at geometric mean IC80s of 0.314 and 0.033 µg mL-1, respectively. Cryo-EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV-1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2-apex-targeting broadly neutralizing antibody, CAP256V2LS. The resultant human-llama bispecific antibody CAP256L-R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV-1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn-Fc mice similar to the parent CAP256V2LS. Vaccine-elicited llama nanobodies, when combined with V2-apex broadly neutralizing antibodies, may therefore be able to fulfill anti-HIV-1 therapeutic and prophylactic clinical goals.

Interdependence of cellular and network properties in respiratory rhythm generation.

How breathing is generated by the preBötzinger complex (preBötC) remains divided between two ideological frameworks, and a persistent sodium current (INaP) lies at the heart of this debate. Although INaP is widely expressed, the pacemaker hypothesis considers it essential because it endows a small subset of neurons with intrinsic bursting or "pacemaker" activity. In contrast, burstlet theory considers INaP dispensable because rhythm emerges from "preinspiratory" spiking activity driven by feed-forward network interactions. Using computational modeling, we find that small changes in spike shape can dissociate INaP from intrinsic bursting. Consistent with many experimental benchmarks, conditional effects on spike shape during simulated changes in oxygenation, development, extracellular potassium, and temperature alter the prevalence of intrinsic bursting and preinspiratory spiking without altering the role of INaP. Our results support a unifying hypothesis where INaP and excitatory network interactions, but not intrinsic bursting or preinspiratory spiking, are critical interdependent features of preBötC rhythmogenesis.

Implementation and evaluation of a learner-driven leadership initiative for pharmacy students and pharmacy residents.

Introduction: Leadership training is a crucial component of the pharmacy education curriculum. The Accreditation Council for Pharmacy Education (ACPE) emphasizes and encourages the use of different leadership initiatives, and universities employ tactics with varying levels of success to implement these initiatives. "Leadership theory" debates if leadership can be learned or if it is a natural-born skill. This article explores learned leadership and describes a small study deployed to different levels of pharmacy learners to foster leadership confidence and self-awareness. Educational Context and Methods: Second- and third-year didactic students in a leadership elective, voluntary fourth-year Advanced Pharmacy Practice Experience (APPE) students on an ambulatory care rotation, and first postgraduate year (PGY1) pharmacy residents were included in this initiative. Each cohort facilitated a leadership book club discussion and completed professional development activities over the course of their experience. Learners' perspectives on leadership were surveyed utilizing a pre-post survey study, administered prior to beginning the initiative and after completing the initiative. Findings and Discussion: Results demonstrated learners' perceived confidence and self-awareness in their leadership skills increased from pre-survey to post-survey. Evaluation of qualitative responses exhibited that participants found value in adding more leadership development to their pharmacy training. Most participants noted leadership book discussion facilitation as the most valuable part of the initiative and posited they would utilize skills gained through these discussions nearly every day in their careers. Results suggest PGY1 pharmacy residents showed the most significant increase in their scores from pre- to post-study, while didactic students showed the least significant increase. Implications: Our findings suggest learner-driven leadership initiatives, specifically learner-facilitated book club discussions, are beneficial to incorporate into both didactic and experiential coursework. Implementation of these discussions could be applied in many aspects of the curriculum with minimal resources and a reasonable expectation of perceived benefit to student leadership development.

A comparison of endoscopic endonasal versus open approaches for skull base chordoma: a comprehensive National Cancer Database analysis.

OBJECTIVE: The authors of this study aimed to investigate independent prognostic factors of survival with a particular focus on comparing the safety and efficacy of endoscopic endonasal versus open approaches in the surgical management of skull base chordoma. METHODS: A retrospective National Cancer Database review of skull base chordoma patients was performed to capture resection cases from 2010 to 2020, evaluating overall survival (OS), early postoperative mortality, readmission rates, and hospital length of stay (LOS) between surgical approaches and the independent prognostication of death utilizing Cox multivariate regression analysis. RESULTS: Among the 736 patients included in the cohort, 456 patients (62.0%) and 280 patients (38.0%) underwent endoscopic endonasal and open resection, respectively. These values represent a rate of change over the study period of +4.1 versus -0.14 cases per year, respectively. Gross-total resection was achieved in 32.5% of cases. A positive margin status was found in 51.8% of cases. There was no association between extent of resection and surgical approach (p = 0.257). There was no difference in OS (p = 0.562), 30- and 90-day mortality (p = 0.209 and 0.126, respectively), and 30-day readmission (p = 0.438) between the two surgical groups. The mean LOS was reduced by 2.1 days in the endoscopic cohort (p = 0.013) compared with the open approach cohort. Finally, multivariate analysis revealed a tumor size ≥ 4 cm (HR 4.03, p = 0.005) and public insurance (HR 2.76, p = 0.004) as negative predictors of survival and treatment at an academic center (HR 0.36, p = 0.043) as a positive prognosticator of survival. CONCLUSIONS: The endoscopic endonasal approach has been increasingly utilized over time and touts noninferiority with respect to safety and efficacy with a marked improvement in LOS, which carries substantial implications for both healthcare costs and enhanced patient recovery. Future prospective studies are necessary to further delineate trends and surgical outcomes for skull base chordoma.

Durable lymph-node expansion is associated with the efficacy of therapeutic vaccination.

Following immunization, lymph nodes dynamically expand and contract. The mechanical and cellular changes enabling the early-stage expansion of lymph nodes have been characterized, yet the durability of such responses and their implications for adaptive immunity and vaccine efficacy are unknown. Here, by leveraging high-frequency ultrasound imaging of the lymph nodes of mice, we report more potent and persistent lymph-node expansion for animals immunized with a mesoporous silica vaccine incorporating a model antigen than for animals given bolus immunization or standard vaccine formulations such as alum, and that durable and robust lymph-node expansion was associated with vaccine efficacy and adaptive immunity for 100 days post-vaccination in a mouse model of melanoma. Immunization altered the mechanical and extracellular-matrix properties of the lymph nodes, drove antigen-dependent proliferation of immune and stromal cells, and altered the transcriptional features of dendritic cells and inflammatory monocytes. Strategies that robustly maintain lymph-node expansion may result in enhanced vaccination outcomes.

Academic vs Community Retinal Surgery for Primary Retinal Detachment- Characteristics, Duration, and Value Analysis of Teaching Modifier.

PURPOSE: To compare operative time and case characteristics of primary rhegmatogenous retinal detachment (RRD) repairs between academic and community vitreoretinal surgeons. DESIGN: A retrospective, observational clinical study. SUBJECTS: Patients who underwent primary RRD repair surgeries at Massachusetts Eye and Ear between 2019-2021. METHODS: A random sample of 20 vitreoretinal surgeons distributed evenly among the "academic" or "community" setting was selected. Fifteen consecutive cases of primary RRD repair surgeries were included from each surgeon. A cost analysis was performed for the teaching modifier for the physician fee and for hospital costs. MAIN OUTCOME MEASURES: Length of surgery. RESULTS: Of 300 primary RRD repairs, fellows were present in 75%, which comprised all academic surgeon cases and 50% of community surgeon cases, p<0.001. Mean operation length was shorter for non-fellow community surgeon cases (55.0±24.1) than either academic (73.0±30.8) or community surgeon cases with fellows (75.7±32.5) (p<0.001). There was a higher percentage of macula-off RRDs in academic versus community surgeon cases (52.7% vs 38.0%, p=0.002) and higher rates of combined scleral buckle (SB)/PPV repairs (14% vs. 3%, p<0.001). When excluding combined SB/PPV cases, there was no difference in operative time between academic and community surgeon cases. Among RRDs repaired by PPV only, there was a 31.4% (16.6 minutes) greater procedure duration in cases with fellows compared to cases without fellows (p<0.001). Covariates associated with greater surgery time: addition of a scleral buckle (ß=32.6), membrane peel (ß=18.5), presence of a fellow (ß=14.5), proliferative vitreoretinopathy (ß=12.8), and greater number of retinal breaks (ß=2.4). The teaching modifier adds 16% extra reimbursement ($184.16) to the physician fee which is 50.9% of what is necessary to cover the percentage increase in surgeon time (31.4%). Using a time-driven activity-based costing for hospital costs, the extra 16.6 minutes leads to an additional $1038.00, which is 5.6 times more than the reimbursement for the modifier. CONCLUSIONS: Retinal detachment repair cases performed by academic surgeons are more likely to be macula-off and include the addition of a scleral buckle, which drive longer operative times. Medicare's reimbursement of the assistant modifier in a teaching facility significantly under compensates the time-driven activity-based costing of trainee participation.

Defining the balance between optimal immunity and immunopathology in influenza virus infection.

Influenza A viruses remain a global threat to human health, with continued pandemic potential. In this Review, we discuss our current understanding of the optimal immune responses that drive recovery from influenza virus infection, highlighting the fine balance between protective immune mechanisms and detrimental immunopathology. We describe the contribution of innate and adaptive immune cells, inflammatory modulators and antibodies to influenza virus-specific immunity, inflammation and immunopathology. We highlight recent human influenza virus challenge studies that advance our understanding of susceptibility to influenza and determinants of symptomatic disease. We also describe studies of influenza virus-specific immunity in high-risk groups following infection and vaccination that inform the design of future vaccines to promote optimal antiviral immunity, particularly in vulnerable populations. Finally, we draw on lessons from the COVID-19 pandemic to refocus our attention to the ever-changing, highly mutable influenza A virus, predicted to cause future global pandemics.

Utilization of Face-to-Face Vestibular Support Groups: A Comparison to Online Group Participation.

OBJECTIVE: This study compared the utilization and outcomes of face-to-face (F2F) vestibular support groups and online support communities (OSC) for individuals with vestibular disorders. METHODS: We distributed a 31-question anonymous electronic survey through the Vestibular Disorders Association (VeDA) to F2F participants, categorizing user involvement in F2F, OSCs, or both and assessed impact on medical decision-making, psychosocial benefits, and goals achieved. RESULTS: The F2F cohort consisted of 97 individuals comprising primarily of non-Hispanic White women (mean age = 57 years, SD ± 14 years) with diagnoses including persistent postural-perceptual dizziness (19%), Meniere's disease (15%), and vestibular neuritis (13%). Most participants were diagnosed by an otolaryngologist (65%) and attended F2F meetings monthly or less frequently (78%). The OSC group comprised of 551 individuals, primarily of non-Hispanic White women, but was younger in age (mean age = 50 years, SD ± 13 years). OSC participants notably engaged more, with 36% participating on a daily basis and 32% multiple times a week. F2F participants were older (mean age 57 years vs 50 years, P < .001) and more commonly referred by medical professionals (22% F2F vs 6% OSC, P < .001). Both groups had similar achieved goals, including hearing from others with the same diagnosis (84% vs 89%, P > .05) and similar impact on medical decision-making (75% vs 78%, P > .05). More F2F participants reported increased development of coping skills (79% F2F vs 69% OSC, P = .037). OSC participants typically found the group via an online search (75%), compared to 51% for F2F. OSC participants had higher daily engagement (36%) compared to F2F (1%). CONCLUSION: F2F users are older and more commonly referred by medical professionals. Despite less frequent engagement, F2F participants reported similar influences on achieved goals, medical decision-making, and impact on psychosocial benefits. These findings highlight the importance of both F2F and OSC support groups for individuals with vestibular disorders.