Alternative models to support weight loss in chronic musculoskeletal conditions: effectiveness of a physiotherapist-delivered intensive diet programme for knee osteoarthritis, the POWER randomised controlled trial.

OBJECTIVES: To determine if physiotherapists can deliver a clinically effective very low energy diet (VLED) supplementary to exercise in people with knee osteoarthritis (OA) and overweight or obesity. METHODS: 88 participants with knee OA and body mass index (BMI) >27 kg/m2 were randomised to either intervention (n=42: VLED including two daily meal replacement products supplementary to control) or control (n=46: exercise). Both interventions were delivered by unblinded physiotherapists via six videoconference sessions over 6 months. The primary outcome was the percentage change in body weight at 6 months, measured by a blinded assessor. Secondary outcomes included BMI, waist circumference, waist-to-hip ratio, self-reported measures of pain, function, satisfaction and perceived global change, and physical performance tests. RESULTS: The intervention group lost a mean (SD) of 8.1% (5.2) body weight compared with 1.0% (3.2) in the control group (mean (95% CI) between-group difference 7.2% (95% CI 5.1 to 9.3), p<0.001), with significantly lower BMI and waist circumference compared with control group at follow-up. 76% of participants in the intervention group achieved ≥5% body weight loss and 37% acheived ≥10%, compared with 12% and 0%, respectively, in the control group. More participants in the intervention group (27/38 (71.1%)) reported global knee improvement than in the control group (20/42 (47.6%)) (p=0.02). There were no between-group differences in any other secondary outcomes. No serious adverse events were reported. CONCLUSION: A VLED delivered by physiotherapists achieved clinically relevant weight loss and was safe for people with knee OA who were overweight or obese. The results have potential implications for future service models of care for OA and obesity. TRIAL REGISTRATION NUMBER: NIH, US National Library of Medicine, Clinicaltrials.gov NCT04733053 (1 February 2021).

Clinical Outcomes of Human Rhinovirus/Enterovirus Infection in Pediatric Hemopoietic Cell Transplant Patients.

BACKGROUND: Respiratory viral infections are common among pediatric transplant patients, with human rhinovirus (HRV) being the most frequent. In pediatric patients undergoing hemopoietic cell transplant (HCT), infection with HRV has been associated with progression to lower respiratory tract infection (LRTI) and adverse outcomes. We describe the clinical presentation and outcomes of HRV infection in children undergoing HCT. METHODS: Single-center retrospective study. HCT recipients who were positive for HRV/EV (HRV+) or negative for any respiratory virus (VN) by BioFire® FilmArray® panel between October 2014 and December 2017, were included. Primary outcomes were progression to LRTI, ICU admission, all-cause mortality at 3 and 6 months, and respiratory event-related mortality at 6 months. RESULTS: 227 patients (160 allogeneic HCT) were included. Of all patients, 108/227 (47.6%) were HRV+. From all HRV+, 95/108 (88%) were symptomatic and 68/107 (63.6%) of the diagnosis were made pretransplant. The median age of HRV+ was significantly lower than VN patients (5 vs 10 years). Cough and rhinorrhea were more frequently observed in HRV+ (53.7 and 60% vs 19.8 and 22.8%, respectively). No differences were found between both groups pretransplant and overall in rates progression to LRTI, ICU admission, mechanical ventilation, all-cause within 3 and 6 months, and mortality related with respiratory failure. No significant association was found between the severity of respiratory disease and the type of conditioning, type of transplant, or absolute lymphocyte count. CONCLUSIONS: HRV infection is frequently detected in HCT recipients but is not associated with severity of respiratory disease, need for intensive care unit or mortality, including those diagnosed before transplant, suggesting that delaying HCT in this scenario may not be needed. Multicenter larger studies are required to confirm these findings.

Digital PCR to Measure SARS-CoV-2 RNA, Variants, and Outcomes in Youth.

BACKGROUND: The role of SARS-CoV-2 viral load in predicting contagiousness, disease severity, transmissibility, and clinical decision-making continues to be an area of great interest. However, most studies have been in adults and have evaluated SARS-CoV-2 loads using cycle thresholds (Ct) values, which are not standardized preventing consistent interpretation critical to understanding clinical impact and utility. Here, a quantitative SARS-CoV-2 reverse-transcription digital PCR (RT-dPCR) assay normalized to WHO International Units was applied to children at risk of severe disease diagnosed with COVID-19 at St. Jude Children's Research Hospital between March 28, 2020, and January 31, 2022. METHODS: Demographic and clinical information from children, adolescents, and young adults treated at St. Jude Children's Research Hospital were abstracted from medical records. Respiratory samples underwent SARS-CoV-2 RNA quantitation by RT-dPCR targeting N1 and N2 genes, with sequencing to determine the genetic lineage of infecting virus. RESULTS: Four hundred and sixty-two patients aged 0-24 years (median 11 years old) were included during the study period. Most patients were infected by the omicron variant (43.72%), followed by ancestral strain (22.29%), delta (13.20%), and alpha (2.16%). Viral load at presentation ranged from 2.49 to 9.14 log10 IU/mL, and higher viral RNA loads were associated with symptoms (OR 1.32; CI 95% 1.16-1.49) and respiratory disease (OR 1.23; CI 95% 1.07-1.41). Viral load did not differ by SARS-CoV-2 variant, vaccination status, age, or baseline diagnosis. CONCLUSIONS: SARS-CoV-2 RNA loads predict the presence of symptomatic and respiratory diseases. The use of standardized, quantitative methods is feasible, allows for replication, and comparisons across institutions, and has the potential to facilitate consensus quantitative thresholds for risk stratification and treatment.

Prediction of attributable mortality in pediatric patients with cancer admitted to the intensive care unit for suspected infection: A comprehensive evaluation of risk scores.

OBJECTIVE: To evaluate the performance of existing sepsis scores for prediction of adverse outcomes in children with cancer admitted to the ICU with suspected sepsis. DESIGN: Retrospective chart review using data available at 1, 6, 12, and 24 h after ICU admission to calculate the Pediatric Risk of Mortality 3 (PRISM-3), Pediatric Sequential Organ Failure Assessment (pSOFA), Paediatric Logistic Organ Dysfunction 2 (PELOD-2), and Quick Pediatric Sequential Organ Failure Assessment (qSOFA) scores. Area under the receiver operator characteristic curve (AUROC) was used to evaluate performance for prediction of attributable mortality. Sensitivity analyses included recalculation of scores using worst preceding values for each variable, excluding hematologic parameters, and prediction of alternative outcomes. SETTING: St. Jude Children's Research Hospital, a pediatric comprehensive cancer center in the USA. PATIENTS: Pediatric patients (<25 years of age) receiving conventional therapy for cancer admitted to the ICU with suspected sepsis between 2013 and 2019. RESULTS: Of 207 included episodes of suspected sepsis, attributable mortality was 16 (7.7%) and all evaluated sepsis scores performed poorly (maximal AUROC of 0.73 for qSOFA at 1 and 24 h). Sensitivity analyses did not identify an alternative approach that significantly improved prediction. CONCLUSIONS: Currently available sepsis scores perform poorly for prediction of attributable mortality in children with cancer who present to ICU with suspected sepsis. More research is needed to identify reliable predictors of adverse outcomes in this population.

Lessons learnt from a nationally funded training and mentoring programme for early-mid career musculoskeletal researchers in Australia.

INTRODUCTION: Quality training and mentoring are crucial components of successful career development for early mid career researchers (EMCRs). This paper describes the overarching framework of novel ongoing national Training and Mentoring Programme Melbourne University Sydney Queensland:Impact (MUSQ:Impact) for musculoskeletal researchers, including a description of how it was set up and established, and lessons learned from its implementation. RESULTS: The MUSQ:Impact programme spans four multidisciplinary musculoskeletal research teams across three universities in Australia, comprising 40-60 EMCR members. It was established to provide EMCRs with a unique learning environment and opportunities to gain exposure to, and network with, other national musculoskeletal research teams. Specific goals are to focus on core research competencies (e.g. writing skills, managing grant budgets, public speaking and media engagement, research translation), provide career mentoring, fund development activities (e.g. conference attendance, laboratory visits, skill development courses), and share training resources (e.g. data dictionaries, project summaries). A Steering Committee of 10-12 EMCR members, co-chaired by a senior researcher and one EMCR, is responsible for overseeing MUSQ:Impact and organising regular activities, including a monthly webinar series, a mentor/mentee scheme, annual group research retreats, annual infographic competition, and funding awards. An evaluation survey found that most participants perceived each activity to be beneficial and of value to their research career and development. CONCLUSION: This paper presents the structure of national training and mentoring programme that serves as a potential template for other research teams to adapt within their own contexts.

'I saw it as a marriage-You can't have one without the other': A qualitative study of patient and physiotherapist experiences with a therapeutic combined strength and aerobic physical activity exercise programme for hip osteoarthritis.

INTRODUCTION: To explore physiotherapist and patient experiences with, and acceptability of, a 12-week physiotherapist-guided combined strength and aerobic physical activity exercise programme for hip osteoarthritis (OA). METHODS: A qualitative study using semi-structured interviews with 13 people with hip OA and four physiotherapists. Patients underwent a 12-week home exercise programme customised by weekly visits with one of the four physiotherapists. The programme aimed for patients to participate in 150 min of moderate-intensity aerobic physical activity, and 20-30 min of strengthening exercise 2-3 times per week in concordance with American College of Sports Medicine (ACSM) dosage guidelines. Following the programme, patients and physiotherapists participated in individual semi-structured interviews to explore the acceptability of the exercise programme and barriers and facilitators to participation. Data were audio-recorded, transcribed and analysed using a thematic approach. RESULTS: Five over-arching themes (supporting subthemes) were identified from both patient and physiotherapist interviews: (i) positive outcomes (functional improvements, pain relief, empowerment through experience, commitment to continue); (ii) combined benefits of aerobic and strength exercises (complimentary effects, strengthening exercises key); (iii) valuing support from the physiotherapist (personalised care, skill performance feedback, coach effect, accountability); (iv) motivation and opportunity for exercise (positive symptom loop, integration into daily routine, prior exercise experience, Fitbit motivation); and (v) time-consuming commitment (physiotherapy visit frequency, travel inconvenience, time for exercise). CONCLUSIONS: Experiences of participants in this study indicate that, although time-consuming, a combined aerobic physical activity and strengthening programme prescribed at ACSM dosage guidelines is acceptable and confers positive outcomes in individuals with hip OA.

Microbiota Predict Infections and Acute Graft-Versus-Host Disease After Pediatric Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Despite preventive measures, infections continue to pose significant risks to pediatric allogeneic hematopoietic cell transplantation (allo-HCT) recipients. The gut microbiota has been linked to clinical outcomes following adult allo-HCT. This study evaluated whether similar disruptions or differing microbiota patterns were associated with infection risk in pediatric allo-HCT. METHODS: In a prospective observational study, fecal samples were obtained from 74 children before conditioning and upon neutrophil recovery. Microbiome signatures identified through sequencing were examined for their associations with infections or acute graft-versus-host disease (aGVHD) in the first-year post-HCT using Cox proportional hazards analysis. RESULTS: Microbiome disruption in adults, did not predict infection risk in pediatric allo-HCT. Unique microbiota signatures were associated with different infections or aGVHD. A ratio of strict and facultative anaerobes (eg, Lachnoclostridium, Parabacteroides) prior to conditioning predicted bacteremia risk (Cox hazard ratio [HR], 3.89). A distinct ratio of oral (eg, Rothia, Veillonella) to intestinal anaerobes (eg, Anaerobutyricum, Romboutsia) at neutrophil recovery predicted likelihood of bacterial infections (Cox HR, 1.81) and viral enterocolitis (Cox HR, 1.96). CONCLUSIONS: Interactions between medical interventions, pediatric hosts, and microbial communities contribute to microbiota signatures that predict infections. Further multicenter study is necessary to validate the generalizability of these ratios as biomarkers.

Clinical Correlation of Adenoviral Load in the Respiratory Tract Measured by Digital PCR in Immunocompromised Children.

Immunocompromised patients can have life-threatening adenoviral infection. Viral load in blood and stool is commonly used to guide antiviral therapy. We developed and evaluated a digital polymerase chain reaction assay to quantify human adenovirus in the respiratory tract and showed that higher peak load correlates with disseminated infection, mechanical ventilation, and death.

Effects of an Online Education Program on Physical Therapists' Confidence in Weight Management for People With Osteoarthritis: A Randomized Controlled Trial.

OBJECTIVE: To evaluate effects of an online education program about weight management for osteoarthritis on physical therapists' self-reported confidence in knowledge and skills in weight management and attitudes toward obesity. METHODS: In a 2-group randomized controlled trial, 80 physical therapists (58 female physical therapists) were randomized to education or control groups. The theoretically informed and evidence-informed online self-directed training program covered biopsychosocial elements of obesity and weight management. The primary outcome was self-reported confidence in knowledge in weight management using a customized validated tool (scale 14-70, higher scores indicating higher confidence) assessed at baseline and 6 weeks. Secondary measures included confidence in nutrition care, clinical skills in weight management, and weight stigma. Process measures evaluated participant experience. Differences in change between groups were compared using linear regression models adjusted for baseline scores and stratifying variables (clinical setting; confidence in weight management). Moderation analysis was performed using an interaction approach in a linear regression model and multivariable fractional polynomial interaction approach. RESULTS: A total of 79 participants (99%) completed outcome measures at 6 weeks. The education group demonstrated greater improvement in confidence in knowledge than the control group (adjusted mean difference 22.6 units, 95% confidence interval 19.6, 25.5). Greater improvement in knowledge was associated with lower baseline values (interaction P = 0.002). Secondary outcomes showed greater improvements in confidence in skills and nutrition care and in weight stigma domains favoring the education group. Over 90% of participants would recommend the program to peers. CONCLUSION: An online education program improves physical therapists' short-term confidence in knowledge and skills in weight management for people with osteoarthritis and reduces weight-stigmatized attitudes.

Acceptability of Dance PREEMIE (a Dance PaRticipation intervention for Extremely prEterm children with Motor Impairment at prEschool age) from the perspectives of families and dancer teachers: a reflexive thematic analysis.

BACKGROUND: Physical activity (PA) participation is important for children born extremely preterm or extremely low birthweight as it provides opportunities to improve motor skills and cardiovascular fitness; however there is little evidence on interventions promoting PA participation for this group, particularly at preschool age. OBJECTIVE: This study aims to explore the acceptability, a critical component of intervention feasibility, of a novel dance participation intervention. METHODS: Semi-structured interviews explored the acceptability of Dance PREEMIE, a Dance PaRticipation intervention for Extremely prEterm children with Motor Impairment at prEschool age (trial registration ACTRN12619001266156), from the perspectives of dance teachers delivering the intervention (n = 6), and parents of participating children (n = 6). Data were analyzed using reflexive thematic analysis. RESULTS: Five themes were developed: 1) placing the child center-stage: a shared motivation to promote child wellbeing and development; 2) Dance PREEMIE as a catalyst for participation; 3) child development takes time, practice and exposure; 4) the value of being informed; and 5) dance teachers as architects of the learning environment. CONCLUSION: Dance PREEMIE was acceptable to both parents of participating children and dance teachers. Findings from this study may inform future interventions aiming to improve PA participation for children with motor impairment at preschool age.

Prediction of Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection by Quantitative Digital Polymerase Chain Reaction Normalized to International Units.

Although numerous studies have evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using cycle threshold (Ct) values as a surrogate of viral ribonucleic acid (RNA) load, few studies have used standardized, quantitative methods. We validated a quantitative SARS-CoV-2 digital polymerase chain reaction assay normalized to World Health Organization International Units and correlated viral RNA load with symptoms and disease severity.

Effectiveness of a telehealth physiotherapist-delivered intensive dietary weight loss program combined with exercise in people with knee osteoarthritis and overweight or obesity: study protocol for the POWER randomized controlled trial.

BACKGROUND: Obesity is associated with knee osteoarthritis (OA). Weight loss, alongside exercise, is a recommended treatment for individuals with knee OA and overweight/obesity. However, many patients cannot access weight loss specialists such as dietitians. Innovative care models expanding roles of other clinicians may increase access to weight loss support for people with knee OA. Physiotherapists may be well placed to deliver such support. This two-group parallel, superiority randomized controlled trial aims to compare a physiotherapist-delivered diet and exercise program to an exercise program alone, over 6 months. The primary hypothesis is that the physiotherapist-delivered diet plus exercise program will lead to greater weight loss than the exercise program. METHODS: 88 participants with painful knee OA and body mass index (BMI) > 27 kg/m2 will be recruited from the community. Following baseline assessment, participants will be randomised to either exercise alone or diet plus exercise groups. Participants in the exercise group will have 6 consultations (20-30 min) via videoconference with a physiotherapist over 6 months for a strengthening exercise program, physical activity plan and educational/exercise resources. Participants in the diet plus exercise group will have 6 consultations (50-75 min) via videoconference with a physiotherapist prescribing a ketogenic very low-calorie diet with meal replacements and educational resources to support weight loss and healthy eating, plus the intervention of the exercise only group. Outcomes are measured at baseline and 6 months. The primary outcome is percentage change in body weight measured by a blinded assessor. Secondary outcomes include self-reported knee pain, physical function, global change in knee problems, quality of life, physical activity levels, and internalised weight stigma, as well as BMI, waist circumference, waist-to-hip ratio, physical performance measures and quadriceps strength, measured by a blinded assessor. Additional measures include adherence, adverse events, fidelity and process measures. DISCUSSION: This trial will determine whether a physiotherapist-delivered diet plus exercise program is more effective for weight loss than an exercise only program. Findings will inform the development and implementation of innovative health service models addressing weight management and exercise for patients with knee OA and overweight/obesity. TRIAL REGISTRATION: NIH US National Library of Medicine, Clinicaltrials.gov NCT04733053 (Feb 1 2021).

Effects of adding aerobic physical activity to strengthening exercise on hip osteoarthritis symptoms: protocol for the PHOENIX randomised controlled trial.

BACKGROUND: Hip osteoarthritis (OA) is a leading cause of musculoskeletal pain. Exercise is a core recommended treatment. Most evidence is based on muscle-strengthening exercise, but aerobic physical activity has potential to enhance clinical benefits. The primary aim of this study is to test the hypothesis that adding aerobic physical activity to a muscle strengthening exercise leads to significantly greater reduction in hip pain and improvements in physical function, compared to a lower-limb muscle strengthening exercise program alone at 3 months. METHODS: This is a superiority, 2-group, parallel randomised controlled trial including 196 people with symptomatic hip OA from the community. Following baseline assessment, participants are randomly allocated to receive either i) aerobic physical activity and muscle strengthening exercise or; ii) muscle strengthening exercise only. Participants in both groups receive 9 consultations with a physiotherapist over 3 months. Both groups receive a progressive muscle strengthening exercise program in addition to advice about OA management. The aerobic physical activity plan includes a prescription of moderate intensity aerobic physical activity with a goal of attaining 150 min per week. Primary outcomes are self-reported hip pain assessed on an 11-point numeric rating scale (0 = 'no pain' and 10 = 'worst pain possible') and self-reported physical function (Western Ontario and McMaster Universities Osteoarthritis Index physical function subscale) at 3 months. Secondary outcomes include other measures of self-reported pain (assessed at 0, 3, 9 months), self-reported physical function (assessed at 0, 3, 9 months), performance-based physical function (assessed at 0, 3 months), joint stiffness (assessed at 0, 3, 9 months), quality of life (assessed at 0, 3, 9 months), muscle strength (assessed at 0, 3 months), and cardiorespiratory fitness (assessed at 0, 3 months). Other measures include adverse events, co-interventions, and adherence. Measures of body composition, serum inflammatory biomarkers, quantitative sensory measures, anxiety, depression, fear of movement and self-efficacy are included to explore causal mechanisms. DISCUSSION: Findings will assist to provide an evidence-based recommendation regarding the additional effect of aerobic physical activity to lower-limb muscle strengthening on hip OA pain and physical function. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry reference: ACTRN 12619001297112. Registered 20th September 2019.

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8+ T cells.

Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7-CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell antigen receptor (TCR) sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.

Pre-existing humoral immunity to human common cold coronaviruses negatively impacts the protective SARS-CoV-2 antibody response.

SARS-CoV-2 infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death. A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoVs) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination. Therefore, we analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. We found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity. However, a case-control study indicates that baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity. Additionally, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes the generation of SARS-CoV-2-neutralizing antibodies in mice. Together, these data suggest that pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants.

Challenges With Strengthening Exercises for Individuals With Knee Osteoarthritis and Comorbid Obesity: A Qualitative Study With Patients and Physical Therapists.

OBJECTIVE: To explore challenges associated with implementing a home-based strengthening exercise program for individuals with knee osteoarthritis and comorbid obesity. METHODS: This is a qualitative study embedded within a randomized controlled trial comparing 2 home-based strengthening programs (weight-bearing functional exercise versus non-weight-bearing quadriceps strengthening exercise) for individuals with knee osteoarthritis and comorbid obesity. Patients in both exercise programs attended 5 consultations with a physical therapist and undertook a home-based exercise program for 12 weeks. After trial completion, semistructured individual telephone interviews were conducted with 22 patients and all 7 physical therapists who delivered trial interventions. Interviews were recorded, transcribed verbatim, and thematically analyzed using an inductive approach. RESULTS: Three themes arose: 1) psychological challenges (false assumptions about exercise; fear of pain; disliking exercise; mental effort of the weight-bearing functional program; underestimating capability); 2) physical challenges (complexity of the weight-bearing functional program; cuff weights and straight leg raise being problematic in non-weight-bearing quadriceps program; other health conditions); and 3) overcoming challenges (incentives to exercise; accountability; education and reassurance; tailoring the exercise program). CONCLUSION: Patients and physical therapists experienced numerous psychological and physical challenges to exercise, including a fear of pain, having false assumptions about exercise, difficulties with exercise performance, application of cuff weights, and adverse impacts of other health conditions.

SARS-CoV-2 antigen exposure history shapes phenotypes and specificity of memory CD8 T cells.

Although mRNA vaccine efficacy against severe COVID-19 remains high, variant emergence and breakthrough infections have changed vaccine policy to include booster immunizations. However, the effect of diverse and repeated antigen exposures on SARS-CoV-2 memory T cells is poorly understood. Here, we utilize DNA-barcoded MHC-multimers combined with scRNAseq and scTCRseq to capture the ex vivo profile of SARS-CoV-2-responsive T cells within a cohort of individuals with one, two, or three antigen exposures, including vaccination, primary infection, and breakthrough infection. We found that the order of exposure determined the relative distribution between spike- and non-spike-specific responses, with vaccination after infection leading to further expansion of spike-specific T cells and differentiation to a CCR7-CD45RA+ effector phenotype. In contrast, individuals experiencing a breakthrough infection mount vigorous non-spike-specific responses. In-depth analysis of over 4,000 epitope-specific T cell receptor sequences demonstrates that all types of exposures elicit diverse repertoires characterized by shared, dominant TCR motifs, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and that current vaccination protocols continue to expand and differentiate spike-specific memory responses.

Host Predictors of Broadly Cross-Reactive Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants of Concern Differ Between Infection and Vaccination.

BACKGROUND: Following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination there is significant variability between individuals in protective antibody levels against SARS-CoV-2, and within individuals against different virus variants. However, host demographic or clinical characteristics that predict variability in cross-reactive antibody levels are not well-described. These data could inform clinicians, researchers, and policymakers on the populations most likely to require vaccine booster shots. METHODS: In an institutional review board-approved prospective observational cohort study of staff at St. Jude Children's Research Hospital, we identified participants with plasma samples collected after SARS-CoV-2 infection, after mRNA vaccination, and after vaccination following infection, and quantitated immunoglobulin G (IgG) levels by enzyme-linked immunosorbent assay to the spike receptor binding domain (RBD) from 5 important SARS-CoV-2 variants (Wuhan Hu-1, B.1.1.7, B.1.351, P.1, and B.1.617.2). We used regression models to identify factors that contributed to cross-reactive IgG against 1 or multiple viral variants. RESULTS: Following infection, a minority of the cohort generated cross-reactive antibodies, IgG antibodies that bound all tested variants. Those who did had increased disease severity, poor metabolic health, and were of a particular ancestry. Vaccination increased the levels of cross-reactive IgG levels in all populations, including immunocompromised, elderly, and persons with poor metabolic health. Younger people with a healthy weight mounted the highest responses. CONCLUSIONS: Our findings provide important new information on individual antibody responses to infection/vaccination that could inform clinicians on populations that may require follow-on immunization.

Feasibility of a Dance PaRticipation intervention for Extremely prEterm children with Motor Impairment at prEschool age (Dance PREEMIE).

BACKGROUND: Physical activity (PA) participation provides opportunities for preschool-age children to improve motor skills. This is especially important for children born extremely preterm (EP) or extremely low birthweight (ELBW) who are at greater risk of motor impairment, and are participating less frequently in PA, compared with children born at term. There is limited evidence on improving PA participation for this population. METHODS: This case series design study evaluated the feasibility of a Dance PaRticipation intervention for Extremely prEterm children with Motor Impairment at prEschool age (Dance PREEMIE), a community-based dance class intervention aiming to improve PA participation. Children born EP/ELBW with motor impairment were recruited at 3 years' corrected age. Dance teachers were recruited from community dance schools and provided with study-specific training. Intervention feasibility was assessed using; recruitment capability, class attendance, child involvement and enjoyment, teacher self-efficacy, and implementation fidelity. RESULTS: Ten children and seven dance teachers were recruited. Most children (n = 7) attended >75% of classes. Children enjoyed the classes and were mostly 'somewhat-very' or 'very' involved. Teachers reported improved self-efficacy for teaching dance to children with motor impairment after attending the training day. CONCLUSION: Further research is warranted to evaluate the efficacy of Dance PREEMIE in larger samples.

An Assessment of Serological Assays for SARS-CoV-2 as Surrogates for Authentic Virus Neutralization.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and has since caused a global pandemic resulting in millions of cases and deaths. Diagnostic tools and serological assays are critical for controlling the outbreak, especially assays designed to quantitate neutralizing antibody levels, considered the best correlate of protection. As vaccines become increasingly available, it is important to identify reliable methods for measuring neutralizing antibody responses that correlate with authentic virus neutralization but can be performed outside biosafety level 3 (BSL3) laboratories. While many neutralizing assays using pseudotyped virus have been developed, there have been few studies comparing the different assays to each other as surrogates for authentic virus neutralization. Here, we characterized three enzyme-linked immunosorbent assays (ELISAs) and three pseudotyped vesicular stomatitis virus (VSV) neutralization assays and assessed their concordance with authentic virus neutralization. The most accurate assays for predicting authentic virus neutralization were luciferase- and secreted embryonic alkaline phosphatase (SEAP)-expressing pseudotyped virus neutralizations, followed by green fluorescent protein (GFP)-expressing pseudotyped virus neutralization, and then the ELISAs. IMPORTANCE The ongoing COVID-19 pandemic is caused by infection with severe acute respiratory syndrome virus 2 (SARS-CoV-2). Prior infection or vaccination can be detected by the presence of antibodies in the blood. Antibodies in the blood are also considered to be protective against future infections from the same virus. The "gold standard" assay for detecting protective antibodies against SARS-CoV-2 is neutralization of authentic SARS-CoV-2 virus. However, this assay can only be performed under highly restrictive biocontainment conditions. We therefore characterized six antibody-detecting assays for their correlation with authentic virus neutralization. The significance of our research is in outlining the advantages and disadvantages of the different assays and identifying the optimal surrogate assay for authentic virus neutralization. This will allow for more accurate assessments of protective immunity against SARS-CoV-2 following infection and vaccination.