Modeling longitudinal oral health status and pneumonia risk: secondary data analyses of an integrated dental-medical cohort.

BACKGROUND: Mounting evidence indicates potential associations between poor oral health status (OHS) and increased pneumonia risk. Relative pneumonia risk was assessed in the context of longitudinally documented OHS. METHODS: Electronic medical/dental patient data captured from 2007 through 2019 were retrieved from the integrated health records of Marshfield Clinic Health Systems. Participant eligibility initiated with an assessment of OHS, stratified into the best, moderate, or worst OHS groups, with the additional criterion of 'no pneumonia diagnosis in the past 90 days'. Pneumonia incidence was longitudinally monitored for up to 1 year from each qualifying dental visit. Models were assessed, with and without adjustment for prior pneumonia incidence, adjusted for smoking and subjected to confounding mitigation attributable to known pneumonia risk factors by applying propensity score analysis. Time-to-event analysis and proportional hazard modeling were applied to investigate relative pneumonia risk over time among the OHS groups. RESULTS: Modeling identified associations between any incident pneumonia subtype and 'number of missing teeth' (p < 0.001) and 'clinically assessed periodontal status' (p < 0.01), which remained significant following adjustment for prior pneumonia incidence and smoking. The hazard ratio (HR) for 'any incident pneumonia' in the best OHS group for 'number of missing teeth' was 0.65, 95% confidence interval (CI) [0.54 - 0.79] (unadjusted) and 0.744, 95% CI [0.61 - 0.91] (adjusted). The HR for 'any incident pneumonia' in the best 'clinically assessed periodontal status' group was 0.72, 95% CI [0.58 - 0.90] (unadjusted) and 0.78, 95% CI [0.62 - 0.97] (adjusted). CONCLUSION/CLINICAL RELEVANCE: Poor OHS increased pneumonia risk. Proactive attention of medical providers to patient OHS and health literacy surrounding oral-systemic disease association is vital, especially in high-risk populations.

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake.

The organic anion transporting polypeptide family member (OATP) 1B3 is a hepatic uptake transporter that has a broad substrate recognition and plays a significant role in regulating elimination of endogenous biomolecules or xenobiotics. OATP1B3 works in tandem with OATP1B1, with which it shares approximately 80% sequence homology and a high degree of substrate overlap. Despite some substrates being recognized solely by OATP1B3, its ability to compensate for loss of OATP1B1-mediated elimination and recognition by regulatory agencies, little is known about OATP1B3 regulatory factors and how they are involved with drug-drug interaction. It was recently discovered that OATP1B1 function is mediated by the activity of a particular tyrosine kinase that is sensitive to a variety of tyrosine kinase inhibitors (TKIs). This study reports that OATP1B3 is similarly regulated, as at least 50% of its activity is reduced by 20 US Food and Drug Administration -approved TKIs. Nilotinib was assessed as the most potent OATP1B3 inhibitor among the investigated TKIs, which can occur at clinically relevant concentrations and acted predominantly through noncompetitive inhibition without impacting membrane expression. Finally, OATP1B3 function was determined to be sensitive to the knockdown of the Lck/Yes novel tyrosine kinase that is sensitive to nilotinib and has been previously implicated in mediating OATP1B1 activity. Collectively, our findings identify tyrosine kinase activity as a major regulator of OATP1B3 function which is sensitive to kinase inhibition. Given that OATP1B1 is similarly regulated, simultaneous disruption of these transporters can have drastic effects on systemic drug concentrations, which would promote adverse events. SIGNIFICANCE STATEMENT: The organic anion transporting polypeptide family member (OATP) 1B3 is a facilitator of hepatic drug elimination, although much is unknown of how OATP1B3 activity is mediated, or how such regulators contribute to drug-drug interactions. This study reports that OATP1B3 activity is dependent on the Lck/Yes novel tyrosine kinase, which is sensitive to numerous tyrosine kinase inhibitors. These findings provide insight into the occurrence of many clinical drug-drug interactions, and a rationale for future study of tyrosine kinases regulating drug disposition.

MOSCATO: a supervised approach for analyzing multi-Omic single-Cell data.

BACKGROUND: Advancements in genomic sequencing continually improve personalized medicine, and recent breakthroughs generate multimodal data on a cellular level. We introduce MOSCATO, a technique for selecting features across multimodal single-cell datasets that relate to clinical outcomes. We summarize the single-cell data using tensors and perform regularized tensor regression to return clinically-associated variable sets for each 'omic' type. RESULTS: Robustness was assessed over simulations based on available single-cell simulation methods, and applicability was assessed through an example using CITE-seq data to detect genes associated with leukemia. We find that MOSCATO performs favorably in selecting network features while also shown to be applicable to real multimodal single-cell data. CONCLUSIONS: MOSCATO is a useful analytical technique for supervised feature selection in multimodal single-cell data. The flexibility of our approach enables future extensions on distributional assumptions and covariate adjustments.

Gene-set integrative analysis of multi-omics data using tensor-based association test.

MOTIVATION: Facilitated by technological advances and the decrease in costs, it is feasible to gather subject data from several omics platforms. Each platform assesses different molecular events, and the challenge lies in efficiently analyzing these data to discover novel disease genes or mechanisms. A common strategy is to regress the outcomes on all omics variables in a gene set. However, this approach suffers from problems associated with high-dimensional inference. RESULTS: We introduce a tensor-based framework for variable-wise inference in multi-omics analysis. By accounting for the matrix structure of an individual's multi-omics data, the proposed tensor methods incorporate the relationship among omics effects, reduce the number of parameters, and boost the modeling efficiency. We derive the variable-specific tensor test and enhance computational efficiency of tensor modeling. Using simulations and data applications on the Cancer Cell Line Encyclopedia (CCLE), we demonstrate our method performs favorably over baseline methods and will be useful for gaining biological insights in multi-omics analysis. AVAILABILITY AND IMPLEMENTATION: R function and instruction are available from the authors' website: https://www4.stat.ncsu.edu/~jytzeng/Software/TR.omics/TRinstruction.pdf. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PodoSighter: A Cloud-Based Tool for Label-Free Podocyte Detection in Kidney Whole-Slide Images.

BACKGROUND: Podocyte depletion precedes progressive glomerular damage in several kidney diseases. However, the current standard of visual detection and quantification of podocyte nuclei from brightfield microscopy images is laborious and imprecise. METHODS: We have developed PodoSighter, an online cloud-based tool, to automatically identify and quantify podocyte nuclei from giga-pixel brightfield whole-slide images (WSIs) using deep learning. Ground-truth to train the tool used immunohistochemically or immunofluorescence-labeled images from a multi-institutional cohort of 122 histologic sections from mouse, rat, and human kidneys. To demonstrate the generalizability of our tool in investigating podocyte loss in clinically relevant samples, we tested it in rodent models of glomerular diseases, including diabetic kidney disease, crescentic GN, and dose-dependent direct podocyte toxicity and depletion, and in human biopsies from steroid-resistant nephrotic syndrome and from human autopsy tissues. RESULTS: The optimal model yielded high sensitivity/specificity of 0.80/0.80, 0.81/0.86, and 0.80/0.91, in mouse, rat, and human images, respectively, from periodic acid-Schiff-stained WSIs. Furthermore, the podocyte nuclear morphometrics extracted using PodoSighter were informative in identifying diseased glomeruli. We have made PodoSighter freely available to the general public as turnkey plugins in a cloud-based web application for end users. CONCLUSIONS: Our study demonstrates an automated computational approach to detect and quantify podocyte nuclei in standard histologically stained WSIs, facilitating podocyte research, and enabling possible future clinical applications.

Automated Computational Detection of Interstitial Fibrosis, Tubular Atrophy, and Glomerulosclerosis.

BACKGROUND: Interstitial fibrosis, tubular atrophy (IFTA), and glomerulosclerosis are indicators of irrecoverable kidney injury. Modern machine learning (ML) tools have enabled robust, automated identification of image structures that can be comparable with analysis by human experts. ML algorithms were developed and tested for the ability to replicate the detection and quantification of IFTA and glomerulosclerosis that renal pathologists perform. METHODS: A renal pathologist annotated renal biopsy specimens from 116 whole-slide images (WSIs) for IFTA and glomerulosclerosis. A total of 79 WSIs were used for training different configurations of a convolutional neural network (CNN), and 17 and 20 WSIs were used as internal and external testing cases, respectively. The best model was compared against the input of four renal pathologists on 20 new testing slides. Further, for 87 testing biopsy specimens, IFTA and glomerulosclerosis measurements made by pathologists and the CNN were correlated to patient outcome using classic statistical tools. RESULTS: The best average performance across all image classes came from a DeepLab version 2 network trained at 40× magnification. IFTA and glomerulosclerosis percentages derived from this CNN achieved high levels of agreement with four renal pathologists. The pathologist- and CNN-based analyses of IFTA and glomerulosclerosis showed statistically significant and equivalent correlation with all patient-outcome variables. CONCLUSIONS: ML algorithms can be trained to replicate the IFTA and glomerulosclerosis assessment performed by renal pathologists. This suggests computational methods may be able to provide a standardized approach to evaluate the extent of chronic kidney injury in situations in which renal-pathologist time is restricted or unavailable.

Identification of supervised and sparse functional genomic pathways.

Functional pathways involve a series of biological alterations that may result in the occurrence of many diseases including cancer. With the availability of various "omics" technologies it becomes feasible to integrate information from a hierarchy of biological layers to provide a more comprehensive understanding to the disease. In many diseases, it is believed that only a small number of networks, each relatively small in size, drive the disease. Our goal in this study is to develop methods to discover these functional networks across biological layers correlated with the phenotype. We derive a novel Network Summary Matrix (NSM) that highlights potential pathways conforming to least squares regression relationships. An algorithm called Decomposition of Network Summary Matrix via Instability (DNSMI) involving decomposition of NSM using instability regularization is proposed. Simulations and real data analysis from The Cancer Genome Atlas (TCGA) program will be shown to demonstrate the performance of the algorithm.

Symptoms upon postural change and orthostatic hypotension in adolescents with concussion.

Objective: Concussion is associated with dysautonomia, altered blood pressure (BP) control, and may cause Orthostatic Hypotension (OH). We measured prevalence of OH using the 1-minute supine-to-standing OH Test in adolescents with concussion and controls.Participants: Adolescents within 10 days of injury (Concussion Group, n = 297, 15.0 ± 1.7 years, 59% male) were compared with controls (Control Group, n = 214, 15.0 ± 1.5 years, 58% male).Methods: BP, heart rate (HR), and complaints of lightheadedness/dizziness were measured after 2-minute supine and 1-minute standing. Control Group was assessed once. Concussion Group was assessed twice; (1) initial visit (mean 6.0 ± 3 days-since-injury) and (2) after clinical recovery (mean 46.3 ± 42 days-since-injury).Results: Initial visit; Concussion Group reported feeling lightheaded/dizzy on postural change more often than the Control Group (37% vs 4%, p < .001) but did not differ in meeting standard OH criteria (3% vs 5%, p = .32). Experiencing symptoms did not correlate with meeting OH criteria, but correlated with abnormal vestibulo-ocular reflex. After clinical recovery; Concussion Group did not differ in experiencing lightheaded/dizziness on postural change than controls (4%, p = .65).Conclusion: Adolescents commonly experience orthostatic intolerance after concussion without meeting the standard criteria for OH.

Derivation of a Focused, Brief Concussion Physical Examination for Adolescents With Sport-Related Concussion.

OBJECTIVE: To describe the derivation of a brief but pertinent physical examination (PE) for adolescents who have sustained sport-related concussion (SRC). DESIGN: Prospective cohort. SETTING: University concussion management clinic. PARTICIPANTS: Acutely concussed (AC, n = 52, 15.5 ± 1.4 years, 4.4 ± 2 days since injury, 26.2 ± 38 days to recovery, 71% males) and healthy control (HC) adolescents (n = 30, 15.8 ± 1.4 years, 73% males). INTERVENTION: Acutely concussed had a PE on visit 1 and were retested at visit 2 (13.6 ± 1 day after visit 1). Acutely concussed were further characterized as normal recovery (NR, n = 41, 15.5 ± 1.5 years, recovery time 13.0 ± 7 days) and delayed recovery (DR, n = 11, 15.5 ± 1.2 years, recovery time 75.4 ± 63 days). MAIN OUTCOME MEASURE: Physical examination findings, including cervical, vestibular, and oculomotor systems. RESULTS: Visit 1 abnormal PE signs were significantly greater in AC versus HC (2.79 ± 2.13 vs 0.07 ± 0.37, P < 0.0001) but not in NR versus DR (2.61 ± 2.2 vs 3.45 ± 1.8, P = 0.246). Visit 2 abnormal PE signs differentiated NR versus DR (0.17 ± 0.7 vs 2.45 ± 2.1, P < 0.0001). CONCLUSIONS: A brief focused PE can help to diagnose SRC, establish recovery, and may have prognostic value.

A Preliminary Study of Early-Onset Dementia of Former Professional Football and Hockey Players.

OBJECTIVE: To provide an overview of 3 studies of the same population of retired professional contact sport athletes compared with age-matched noncontact sport athlete controls on cognition, executive function, behavior, and advanced brain imaging. SETTING: University Concussion Management Clinic. PARTICIPANTS: Twenty-two retired professional hockey and football athletes (average age 56 years) and 21 age-matched noncontact sport athlete controls. DESIGN: Case control. MAIN MEASURES: Participants were assessed on a broad range of neuropsychological measures that are associated with identification of mild cognitive impairment and executive function. Athletes were also assessed using self-report measures of executive function and personality. Advanced structural and functional imaging techniques were utilized as well. RESULTS: The former National Football League and National Hockey League athletes perceived themselves to have impaired executive function, but this was not confirmed by objective neurocognitive assessment. No significant differences were found when comparing contact-sport athletes with controls on the presence of mild cognitive impairment or brain structural and functional tissue injury. Contact sport athletes were more anxious and more likely to report unusual beliefs and experiences. CONCLUSION: None of the retired contact sport athletes qualified as having early-onset dementia consistent with chronic traumatic encephalopathy. There were no remarkable differences in imaging, cognition, behavior, or executive function from noncontact sport athletes. The results underscore an apparent disconnect between public perceptions and evidence-based conclusions about the inevitability of chronic traumatic encephalopathy and the potential neurodegenerative effect on former athletes from contact sports.

A systematic review of criteria used to define recovery from sport-related concussion in youth athletes.

OBJECTIVE: The Concussion in Sport Group guidelines recommend a multifaceted approach to help clinicians make return to sport decisions. The purpose of this study was to identify the most common multifaceted measures used to define clinical recovery from sport-related concussion in young athletes (high school and/or college level) and to summarise existing knowledge of criteria used to make return to sport decisions. DESIGN: Systematic review. DATA SOURCES: The PubMed (MEDLINE), SPORTDiscus and Embase electronic databases were searched from 1 January 2000 to 1 March 2017 by three independent reviewers. ELIGIBILITY CRITERIA: Inclusion criteria: elementary, high school and college age groups, and a specific definition of clinical recovery that required two or more measures. EXCLUSION CRITERIA: review articles, articles using the same sample population, case studies, non-English language and those that used one measure only or did not specify the recovery measures used. STUDY QUALITY: Study quality was assessed using the Downs and Black Criteria. RESULTS: Of 2023 publications, 43 met inclusion criteria. Included articles reported the following measures of recovery: somatic symptom resolution or return to baseline (100%), cognitive recovery or return to baseline (86%), no exacerbation of symptoms on physical exertion (49%), normalisation of balance (30%), normal special physical examination (12%), successful return to school (5%), no exacerbation of symptoms with cognitive exertion (2%) and normalisation of cerebral blood flow (2%). Follow-up to validate the return to sport decision was reported in eight (19%) articles. Most studies were case-control or cohort (level of evidence 4) and had significant risk of bias. CONCLUSION: All studies of sport-related concussion use symptom reports to define recovery. A minority of studies used multiple measures of outcome or had clearly defined recovery criteria, the most common being a combination of a self-reported symptom checklist and a computerised neurocognitive test. Future studies ideally should define recovery a priori using objective physiological measures in addition to symptom reports.

Safety and Prognostic Utility of Provocative Exercise Testing in Acutely Concussed Adolescents: A Randomized Trial.

OBJECTIVE: To evaluate (1) systematic assessment of exercise tolerance in adolescents shortly after sport-related concussion (SRC) and (2) the prognostic utility of such assessment. DESIGN: Prospective randomized controlled trial. SETTING: University and community sports medicine centers. PARTICIPANTS: Adolescents with SRC (1-9 days from injury). Sixty-five were randomized and 54 completed the study (mean age 15 years, 4 days after injury). INTERVENTIONS: Buffalo Concussion Treadmill Test (BCTT, n = 27) or not (controls, n = 27) on visit day #1. Heart rate threshold (HRt) at symptom exacerbation represented level of exercise tolerance. Participants reported symptoms daily for 14 days and then had follow-up BCTT (n = 54). Recovery was defined as returning to normal level of symptoms and exercise tolerance, verified by independent physician examination. MAIN OUTCOME MEASURES: Days to recovery and typical (≤21 days) versus prolonged recovery (>21 days). Mixed effects linear models and linear regression techniques examined symptom reports and time to recovery. Linear regression assessed the association of HRt with recovery time. RESULTS: Days to recovery (P = 0.7060) and typical versus prolonged recovery (P = 0.1195) were not significantly different between groups. Symptom severity scores decreased in both groups over 14 days (P < 0.0001), were similar (P = 0.2984), and did not significantly increase the day after the BCTT (P = 0.1960). Lower HRt on visit day #1 was strongly associated with prolonged recovery time (P = 0.0032). CONCLUSIONS: Systematic evaluation of exercise tolerance using the BCTT within 1 week after SRC did not affect recovery. The degree of early exercise intolerance after SRC was important for prognosis. This has implications for school academic and team preparation.

Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression: An NRG Oncology/Gynecologic Oncology Group study.

OBJECTIVE: Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. METHODS: Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. RESULTS: Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. CONCLUSIONS: Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.

High stathmin expression is a marker for poor clinical outcome in endometrial cancer: An NRG oncology group/gynecologic oncology group study.

OBJECTIVE: Gynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin. METHODS: We analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer. RESULTS: We first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin. CONCLUSIONS: Our findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases.

Identification of consistent functional genetic modules.

It is often of scientific interest to find a set of genes that may represent an independent functional module or network, such as a functional gene expression module causing a biological response, a transcription regulatory network, or a constellation of mutations jointly causing a disease. In this paper we are specifically interested in identifying modules that control a particular outcome variable such as a disease biomarker. We discuss the statistical properties that functional networks should possess and introduce the concept of network consistency which should be satisfied by real functional networks of cooperating genes, and directly use the concept in the pathway discovery method we present. Our method gives superior performance for all but the simplest functional networks.

Dynamics of the Streptococcus gordonii Transcriptome in Response to Medium, Salivary α-Amylase, and Starch.

Streptococcus gordonii, a primary colonizer of the tooth surface, interacts with salivary α-amylase via amylase-binding protein A (AbpA). This enzyme hydrolyzes starch to glucose, maltose, and maltodextrins that can be utilized by various oral bacteria for nutrition. Microarray studies demonstrated that AbpA modulates gene expression in response to amylase, suggesting that the amylase-streptococcal interaction may function in ways other than nutrition. The goal of this study was to explore the role of AbpA in gene regulation through comparative transcriptional profiling of wild-type KS1 and AbpA(-) mutant KS1ΩabpA under various environmental conditions. A portion of the total RNA isolated from mid-log-phase cells grown in 5% CO2 in (i) complex medium with or without amylase, (ii) defined medium (DM) containing 0.8% glucose with/without amylase, and (iii) DM containing 0.2% glucose and amylase with or without starch was reverse transcribed to cDNA and the rest used for RNA sequencing. Changes in the expression of selected genes were validated by quantitative reverse transcription-PCR. Maltodextrin-associated genes, fatty acid synthesis genes and competence genes were differentially expressed in a medium-dependent manner. Genes in another cluster containing a putative histidine kinase/response regulator, peptide methionine sulfoxide reductase, thioredoxin protein, lipoprotein, and cytochrome c-type protein were downregulated in KS1ΩabpA under all of the environmental conditions tested. Thus, AbpA appears to modulate genes associated with maltodextrin utilization/transport and fatty acid synthesis. Importantly, in all growth conditions AbpA was associated with increased expression of a potential two-component signaling system associated with genes involved in reducing oxidative stress, suggesting a role in signal transduction and stress tolerance.

A novel characterization of the generalized family wise error rate using empirical null distributions.

We present a novel characterization of the generalized family wise error rate: kFWER. The interpretation allows researchers to view kFWER as a function of the test statistics rather than current methods based on p-values. Using this interpretation we present several theorems and methods (parametric and non-parametric) for estimating kFWER in various data settings. With this version of kFWER, researchers will have an estimate of kFWER in addition to knowing what tests are significant at the estimated kFWER. Additionally, we present methods that use empirical null distributions in place of parametric distributions in standard p-value kFWER controlling schemes. These advancements represent an improvement over common kFWER methods which are based on parametric assumptions and merely report the tests that are significant under a given value for kFWER.

Evaluation of the Zurich Guidelines and exercise testing for return to play in adolescents following concussion.

OBJECTIVE: To evaluate return to play (RTP) and return to classroom outcomes when the Zurich guidelines are combined with a standardized exercise treadmill test [Buffalo Concussion Treadmill Test (BCTT)] and computerized neuropsychological (cNP) testing in adolescent athletes after concussion. DESIGN: Retrospective chart review and follow-up. SETTING: University Sports Medicine Concussion Clinic. PARTICIPANTS: One hundred seventeen athletes (75% male) with sport concussion ages 13 to 19 years and telephone follow-up of 91 (77.8%) athletes and their parents. INTERVENTIONS: Concussed athletes who were asymptomatic at rest completed Automated Neuropsychological Assessment Metrics or Immediate Post-concussion Assessment and Cognitive Test cNP testing followed by the BCTT on the same day. Athletes then followed the Zurich consensus guidelines for RTP. MAIN OUTCOME MEASURES: The primary outcome measure was the degree of success in RTP, that is, RTP with or without return of concussive symptoms. Secondary outcome measure was return to school with or without symptoms. RESULTS: All athletes returned to sport without exacerbation of symptoms. Telephone follow-up revealed that 38.5% experienced new issues upon return to the classroom. Forty-eight percent of athletes had 1 or more cNP subtests below average (

TLR7 activation of age-associated B cells mediates disease in a mouse model of primary Sjögren's disease.

Primary Sjögren's disease (pSD) (also referred to as Sjögren's syndrome) is an autoimmune disease that primarily occurs in women. In addition to exocrine gland dysfunction, pSD patients exhibit B cell hyperactivity. B cell-intrinsic TLR7 activation is integral to the pathogenesis of systemic lupus erythematosus, a disease that shares similarities with pSD. The role of TLR7-mediated B cell activation in pSD, however, remains poorly understood. We hypothesized that age-associated B cells (ABCs) were expanded in pSD and that TLR7-stimulated ABCs exhibited pathogenic features characteristic of disease. Our data revealed that ABC expansion and TLR7 expression were enhanced in a pSD mouse model in a Myd88-dependent manner. Splenocytes from pSD mice showed enhanced sensitivity to TLR7 agonism as compared with those derived from control animals. Sort-purified marginal zone B cells and ABCs from pSD mice showed enhanced inflammatory cytokine secretion and were enriched for antinuclear autoantibodies following TLR7 agonism. Finally, IgG from pSD patient sera showed elevated antinuclear autoantibodies, many of which were secreted preferentially by TLR7-stimulated murine marginal zone B cells and ABCs. These data indicate that pSD B cells are hyperresponsive to TLR7 agonism and that TLR7-activated B cells contribute to pSD through cytokine and autoantibody production. Thus, therapeutics that target TLR7 signaling cascades in B cells may have utility in pSD patients.

Parents of 5-to-12-year-old children with food allergies report more frequent use of structure-based food parenting practices.

Objectives: Food parenting practices (FPP) can have effects on children's eating behaviors. Over 8 million children in the US have food allergies, however, little is known about FPP for those who have children with food allergies. The objective of this study was to describe FPP among children with food allergies. Methods: Recruited across the United States using ResearchMatch in February and March 2021, parents of children ages 5-12 years (n = 346; n = 77 with food allergies) completed a single, online survey which measured health history, demographics, and FPP. Linear regressions were used to examine associations between FPP of children with and without food allergies, and associations between food allergy factors and FPP. Results: Parents of children with food allergies reported greater use of limit exposure than parents of children without food allergies (B = 0.131; [CI], 0.021-0.293; P = 0.024), with no differences in other types of FPP. Conclusions: Parents of children with food allergies reported more frequent structure-based FPP than parents of children without food allergies. More work is needed to explore mechanisms that promote positive food parenting among this population.