Development of a parent-reported screening tool for avoidant/restrictive food intake disorder (ARFID): Initial validation and prevalence in 4-7-year-old Japanese children The prevalence of avoidant/restrictive food intake disorder (ARFID) in the general child population is still largely unknown and validated screening instruments are lacking. The aims of this study were to investigate the prevalence of children screening positive for ARFID in a Japanese birth cohort using a newly developed parent-reported screening tool, to estimate the prevalence of children with ARFID experiencing physical versus psychosocial consequences of their eating pattern, and to provide preliminary evidence for the validity of the new screening tool. Data were collected from 3,728 4-7-year-old children born in Kochi prefecture (response rate was 56.5%), Japan, between 2011 and 2014; a sub-sample of the Japan Environment and Childrens Study (JECS). Parents completed a questionnaire including the ARFID screener and several other measures to assess convergent validity. The point prevalence of children screening positive for ARFID was 1.3%; half of them met criteria for ARFID based on psychosocial impairment alone, while the other half met diagnostic criteria relating to physical impairment (and additional psychosocial impairment in many cases). Sensory sensitivity to food characteristics (63%) and/or lack of interest in eating (51%) were the most prevalent drivers of food avoidance. Children screening positive for ARFID were lighter in weight and shorter in height, they showed more problem behaviors related to mealtimes and nutritional intake, and they were more often selective eaters and more responsive to satiety, providing preliminary support for the validity of the new screening tool. This is the largest screening study to date of ARFID in children up to 7 years. Future studies should examine the diagnostic validity of the new ARFID screener using clinically ascertained cases. Further research on ARFID prevalence in the general population is needed.
One Year of Evidence on Mental Health Disorders in China during the COVID-19 Crisis - A Systematic Review and Meta-Analysis This paper provides a systematic review and meta-analysis on the prevalence rate of mental health issues of general population, general and frontline healthcare workers (HCWs) in China over one year of the COVID-19 crisis. We systematically searched PubMed, Embase, Web of Science, and Medrxiv at November 16th, 2020, pooled data using random-effects meta-analyses to estimate the prevalence rates, and ran meta-regression to tease out the heterogeneity. The meta-regression results uncovered several predictors of the prevalence rates, including severity, type of mental issues, population, sampling location, and study quality. Pooled prevalence rates are significantly different from, yet largely between, the findings of previous meta-analyses, suggesting the results of our larger study are consistent with yet more accurate than the findings of the smaller, previous meta-analyses. The prevalence rates of distress and insomnia and those of frontline HCWs are higher suggest future research and interventions should pay more attention to those mental outcomes and populations. Our findings suggest a need to examine the prevalence rates at varying levels of severity. The one-year cumulative evidence on sampling locations (Wuhan vs. non-Wuhan) corroborates the typhoon eye effect theory.

Trial registrationCRD4202022059
Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

MethodsA literature-based substance use risk algorithm identified 696 ABCD Study(R) participants for hair sample collections between baseline and 2-year follow-up (spanning ages 9-13) for laboratory analysis. Chi-square and t-tests assessed differences between participants demographics, positive and negative hair tests, risk algorithm scores, and self-reported substance use.

ResultsHair testing confirmed that 17% of at-risk 9-13 year-olds had evidence of past 3-month use of one (n=99), two (n=17), three (n=3), or four (n=2) drug classes. After considering prescribed medication use, 11% had a positive test incongruent with self- or parent-report. No participant with a positive result self-reported substance use consistent with their toxicology results. Participants with positive tests under-reported use (p<.001), reported less sipping of alcohol (p<.001), and scored higher on the risk algorithm (p<.001) than those with negative hair toxicology.

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth. Effectiveness of a short term induction regimen of a biosimilar Adalimumab in the long term management of symptomatic Ankylosing Spondylitis Symptomatic Ankylosing Spondylitis: A Community Based Proof of Concept Observational Study IntroductionCost and drug toxicity often deter prolonged therapeutic use of anti-TNF agents in ankylosing spondylitis (AS). A planned study was completed to endorse our clinic based observation of long term relief following short-term administration of anti-TNF agent.

Methods50 consenting patients with symptomatic active chronic AS under rheumatology care in a community clinic were enrolled. They had no past history of anti-TNF use. 40 mg standard biosimilar adalimumab (BS-ADA, Exemptia trade name)was injected subcutaneously every fortnight for six injections (10 weeks). Patients were monitored at several time points. Improvement was assessed at regular interval as per protocol which included standard indices (Bath and Assessment Spondyloarthritis International Society /ASAS). An intention to treat analysis with significant p<0.05 was carried out.

ResultsPatients showed early and substantial significant improvement in pain, NSAID requirement, function and in several indices (ASAS 20 & 40, ASAS partial remission, BASDAI, BASFI, ASDAS) which persisted after stopping injections. 84% and 52 % of patients respectively showed ASAS 20 improvement at week 12 and 48: corresponding ASAS partial remission 34% and 24%. Over 50% patients maintained prolonged improvement and provided proof of concept (defined a-priori). Serum Interleukin-6 assay showed a sharp reduction at 24 weeks. None developed TB or serious drug toxicity. 11 patients withdrew (mostly inadequate response). Absence of control was a limitation.

ConclusionA ten-week administration of biosimilar adalimumab in difficult to treat AS showed early substantial improvement which often persisted for 24 weeks. This unconventional strategy was socioeconomically appealing. It merits further validation and acceptance especially in resource strained settings. An observational study of the association between COVID-19 vaccination rates and entry into the "Million Dollar Vax" competition ObjectivesAre financial incentives from entry in a vaccine lottery associated with a higher probability of vaccination for COVID-19?

DesignA cross-sectional study with adjustment for covariates using logistic regression

SettingOctober and November 2021, Australia.

Participants2,375 respondents of the Taking the Pulse of the Nation Survey

InterventionsParticipation in the Million Dollar Vaccination Lottery

Primary and secondary outcome measuresThe proportion of respondents who had any vaccination, a first dose only, or second dose compared to all other respondents

ResultsThose who participated in the lottery were 2.27 times more likely to be vaccinated after the lottery opened on October 1st than those who did not. This was driven by those receiving second doses. Lottery participants were 1.38 times more likely to receive their first dose after October 1st and 2.31 times more likely to receive their second dose after October 1st.

ConclusionsLottery participation is associated with a higher vaccination rate, with this effect dominated by a higher rate of second doses. There is a smaller insignificant difference for those receiving a first dose, suggesting lotteries may not be as effective at reducing vaccine hesitancy, compared to  nudging people to get their second dose more quickly.

Strengths and limitations of this studyO_LIWe use a nationally representative sample of individuals.
C_LIO_LIWe distinguish between the association between lottery participation and first and second doses.
C_LIO_LIWe adjust for a rich set of individual characteristics associated with vaccination status
C_LIO_LIThe strong association for second dose vaccinations may reflect some individuals who had already had scheduled their second dose after the lottery opened, potentially leading to an overestimate of the association.
C_LI

Ethics statementThis study was approved by the University of Melbourne Faculty of Business and Economics & Melbourne Business School Human Ethics Advisory Group (Ref: 2056754.1). "If somebody had told me I'd feel like I do now, I wouldn't have believed them"    Older adults' experiences of the BELL trial: a qualitative study ObjectivesThis study examined older adults experiences of participating in the BELL trial, involving 12-weeks of group-based hardstyle kettlebell training.

MethodsIn the BELL trial, 28 insufficiently active older adults (15 women, 13 men, 59-79 years) completed 6 weeks of face-to-face group training, and 6 weeks of home-based training. In-depth semi-structured interviews were audio recorded and transcribed, inductively coded, with themes constructed thematically from patterns of shared meaning.

ResultsFour higher-order themes were developed that reflect older adults experiences participating in a group-exercise program of hardstyle kettlebell training. These included: (1) "Its one of the best things weve done" - enjoying the physical and psychosocial benefits, (2) "Its improved it tremendously!" - change in a long-term health condition, (3) "It put me on a better course" - overcoming challenges, (4) "I wasnt just a number" - feeling part of a group/community.

DiscussionFindings highlight the perceived physical and psychological benefits of participating in hardstyle group kettlebell training, the value attributed to being part of an age-matched community of like-minded people engaged in group-exercise, as well as the challenges participants faced, and the sense of achievement in overcoming them. Implications for program design and delivery, and future research are discussed. NeuroEPO improves cognition in Parkinson's disease. Preliminary report. BackgroundCognitive impairment is a feature of Parkinsons Disease (PD) from the early stages, but currently, no treatment for cognitive deficits in PD is available. Erythropoietin (EPO) has been studied for its potential neuroprotective properties in neurologic disorders with a beneficial action on cognition.

ObjectiveTo evaluate if NeuroEPO, a new formulation of EPO with low content of sialic acid, improves the cognitive function in PD patients.

MethodsA double-blind, randomized, placebo-controlled physician lead trial was conducted. The sample was composed of 26 PD patients (HY stages I-II), where 15 received intranasal NeuroEPO for 5 weeks, and another age and gender-matched 11 patients were randomly assigned to the Placebo. All the samples received 9 months of intensive NeuroEPO treatment during a post-trial. The cognitive functions were assessed using a comprehensive neuropsychological battery before, one week, and 6 months after the first intervention and one week after a 9months post-trial. The effects of NeuroEPO were evaluated using a multivariate linear mixed-effects model using a latent variable for cognition instead of the raw neuropsychological scores.

ResultsA significant and direct effect of the Dose of NeuroEPO (p=0.00003) was found on cognitive performance with a strong positive influence of educational level (p=0.0032) and negative impact of age (p=0.0063).

ConclusionsThese preliminary results showed a positive effect of NeuroEPO on cognition in PD patients with better benefit for younger and higher educated patients. Airway management, procedural data, and mortality records of patients undergoing surgery for mucormycosis associated with coronavirus disease (COVID-19) In India, the second wave of coronavirus disease (COVID -19) was associated with a distinct surge in cases of invasive fungal infection with mucormycosis. This disease was seen typically in the sinonasal form in COVID-19 patients. Uncontrolled diabetes, steroid use in COVID-19 treatment, etc. were some of the postulated risk factors for the association of COVID 19 and Mucormycosis. The management plan of these cases included surgical debridement, systemic antifungal therapy, sugar control, and management of antifungal related systemic adverse effects. In this retrospective case record review, we aimed to evaluate the airway management plan, demographics, and overall outcomes in patients undergoing surgical resection for COVID-19 associated mucormycosis. Forty-one (71.9 %) patients had a diagnosis of sino-nasal mucormycosis, fourteen (24.6%) had a diagnosis of rhino-orbital mucormycosis, and 2 patients (3.5%) were diagnosed with palatal mucormycosis. Total 44 (77.19 %) patients had co-morbidities. The most common co-morbidity was Diabetes Mellitus 42 (73.6%), followed by hypertension 21 (36.84%) and Acute kidney injury 14 (28.07%). We used the intubation difficulty scale score to assess intubating conditions. Intubation was easy to slightly difficult in 53 out of 57 patients. In our study, mortality occurred in 7 (12.28 %) patients. The median mortality time was 60 (range, 27-74) days. The median time to hospital discharge was 53.5 (range,10-85) days. Managing COVID-19 on its own is challenging and additional mucormycosis can lead to increased morbidity and mortality. Despite challenges and risks, timely and meticulous interventions can reduce complications. Culture and understanding the role of feedback for health professions students: Realist synthesis protocol. IntroductionClinical education has moved to a "competency-based" model with an emphasis on workplace-based learning and assessment which, in turn, depends on feedback to be effective. Further, the understanding of feedback has changed from information about a performance directed to the learner performing the task, to a dialogue, which enables the learner to act and develop.

In health professional education, feedback is a complex interaction between trainee, supervisor, and the healthcare system. Most published research on feedback in health professional education originates in Europe and North America. Our interest is on the impact of Culture on this process, particularly in the context of Asian cultures.

The (scientific) realist approach of Pawson and Tilley provides a means to examine complex interventions in social situations, and thus is an appropriate lens to use for this study. This is a protocol for a realist synthesis which asks how, why and in what circumstances do Asian Cultures influence health professional trainees to seek, respond to and use feedback given in the clinical environment, if at all.

Methods and analysisAn initial search was performed to help define the scope of the review question and develop our initial program theory. The formal electronic search was carried out in February 2020 and included: CINAHL, ERIC, MEDLINE, and PsycInfo, and repeated in October 2020.

Retrieved articles were imported into Covidence for screening and data extraction, after which components of the Context - Mechanisms - Outcomes configurations will be sought to refine the initial program theory.

Ethics and DisseminationAs this study is a literature review, ethics approval is not required.

The findings will be documented in line with the RAMESES publications standards for Realist syntheses,[41] and we plan to disseminate the findings by means of a peer-reviewed journal article and conference presentation(s).

Strengths and limitations of this studyO_LIThe synthesis aims to identify the how and why Asian Cultures may influence feedback seeking and provision to health professional trainees, if at all.
C_LIO_LITo our knowledge, there are few studies of feedback seeking and provision to health professional trainees in Asia.
C_LIO_LIA Realist approach has the potential to help explain the complex nature of Cultures impact on feedback.
C_LIO_LIOnly studies published in the English language will be included, so transferability of our findings to non-English speaking environments may be lacking.
C_LIO_LIIn addition to formal literature database searches, we will need to conduct citation mining to locate other relevant resources.
C_LI CD19+IgD+CD27- naive B Cells as predictors of humoral response to COVID 19 mRNA vaccination in immunocompromised patients Immunocompromised patients are considered high-risk and prioritized for vaccination against COVID-19. We aimed to analyze B-cell subsets in these patients to identify potential predictors of humoral vaccination response. Patients (n=120) suffering from hematologic malignancies or other causes of immunodeficiency and healthy controls (n=79) received a full vaccination series with an mRNA vaccine. B-cell subsets were analyzed prior to vaccination. Two independent anti-SARS-CoV-2 immunoassays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed three to four weeks after the second vaccination. Seroconversion occurred in 100% of healthy controls, in contrast to 67% (RBD) and 82% (TSP) of immunocompromised patients, while only 32% (RBD) and 22% (TSP) achieved antibody levels comparable to those of healthy controls. The number of circulating CD19+IgD+CD27- naive B cells was strongly associated with antibody levels ({rho}=0.761, P<0.001) and the only independent predictor for achieving antibody levels comparable to healthy controls (OR 1.07 per 10-{micro}l increase, 95%CI 1.02-1.12, P=0.009). Receiver operating characteristic analysis identified a cut-off at [&ge;]61 naive B cells per {micro}l to discriminate between patients with and without an optimal antibody response. Consequently, measuring naive B cells in immunocompromised hematologic patients could be useful in predicting their humoral vaccination response. A Randomised Trial of a Wearable UV dosimeter for Skin Cancer Prevention BackgroundNon-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States, affecting 5 million people and costing $8.1 billion per year. Despite well-defined guidelines on ultraviolet radiation (UVR) avoidance, it remains difficult for people to assess their individual exposure, as UVR is invisible and the onset of symptoms due to UVR damage are delayed.

MethodsIn a prospective, randomized-controlled trial, 97 patients with a history of actinic keratoses were enrolled from March 2018 to July 2018 and followed over 6 months. 50 patients were given a wearable device that measured UV exposure and a smartphone application that provided both real-time and cumulative UV exposure information, and 47 patients were provided with UV protection counseling by a dermatologist.

ResultsWe observed a significant decrease in the incidence rate of NMSC in the intervention group compared to the control group over 3 months (p = 0.02). We did not observe a significant decrease in the incidence rate of actinic keratoses (AK) in the intervention group compared to the control group. The observed clinical benefit was not accompanied by psychological side effects such as anxiety and depression.

ConclusionsThis study suggests that providing real-time UV exposure data using a wearable UV dosimeter is a safe and effective behavioral change strategy to prevent NMSC. (Funded by the National Cancer Institute, contract HHSN261201700005C; ClinicalTrials.gov number NCT03315286.) The effect of stimulus duration on preferences for gain adjustments when listening to speech ObjectivesIn the personalisation of hearing aid fittings, gain is often adjusted to suit patient preferences using live speech. When using brief sentences as stimuli, the minimum gain adjustments necessary to elicit consistent preferences ( preference thresholds) were previously found to be much greater than typical adjustments in current practice. The current study examined the role of duration on preference thresholds.

DesignParticipants heard 2, 4 and 6-s segments of a continuous monologue presented successively in pairs. The first segment of each pair was presented at each individuals real-ear or prescribed gain. The second segment was presented with a {+/-}0-12 dB gain adjustment in one of three frequency bands. Participants judged whether the second was "better", "worse" or "no different" from the first.

Study SampleTwenty-nine adults, all with hearing-aid experience.

ResultsThe minimum gain adjustments needed to elicit "better" or "worse" judgments decreased with increasing duration for most adjustments. Inter-participant agreement and intra-participant reliability increased with increasing duration up to 4 s, then remained stable.

ConclusionsProviding longer stimuli improves the likelihood of patients providing reliable judgments of hearing-aid gain adjustments, but the effect is limited, and alternative fitting methods may be more viable for effective hearing-aid personalisation. Global reports of takotsubo (stress) cardiomyopathy following COVID-19 vaccination: a systematic review and meta-analysis Background and aimsConcerns have been raised recently about takotsubo cardiomyopathy after receiving COVID-19 vaccines, particularly the messenger RNA (mRNA) vaccines. The goal of this study was to compile case reports in order to provide a comprehensive overview of takotsubo cardiomyopathy associated with COVID-19 vaccines.

MethodsFrom inception until March 10, 2022, a systematic literature search was conducted in PubMed and Google Scholar. The study included individuals who developed cardiac takotsubo cardiomyopathy as a result of receiving COVID-19 vaccinations, regardless of the type of vaccine or dose.

ResultsEight studies, including 8 cases, participated in the current systematic review. The median age was 61.6 years; 87.5% were female, while 12.5% were male. 75% of the patients received the mRNA COVID-19 vaccines, while 25% received other types. In addition, takotsubo cardiomyopathy occurred in 62.5% of patients after receiving the first dose and another 25% after the second dose of COVID-19 vaccines. Moreover, the mean number of days to the onset of symptoms was 2.62 days. All cases had an elevated troponin test and abnormal ECG findings. The left ventricular ejection fraction (LVEF) was above 50% among all cases. In terms of the average length of stay in the hospital, 62.5% stayed for 10.2 days, and all cases recovered from their symptoms.

ConclusionTakotsubo (stress) cardiomyopathy complications that are associated with COVID-19 vaccination are rare, they can be life-threatening. Chest pain should be considered an alarming symptom, especially in those who had received a second dose of the vaccine in the last 3 days. For diagnosis, CK-MB and troponin are better biomarkers to confirm myocarditis than CRP, ESR, and NT-proBNP. All of cases completely recovered. A User Preference Analysis Of Commercial Breath Ketone Sensors To Inform The Development Of Portable Breath Ketone Sensors For Diabetes Management In Young People BackgroundPortable breath ketone sensors may help people with Type 1 Diabetes Mellitus (T1DM) avoid episodes of diabetic ketoacidosis; however the design features preferred by users have not been studied. We aimed to elucidate breath analysis and design preferences associated with commercial breath ketone devices among young people with T1DM aged 12-16 years and their parents in order to inform the development of a breath ketone sensor prototype for diabetes management.

Research Designs and MethodsTwo commercially available breath ketone sensors, designed for ketogenic diet monitoring, were explored over one week by ten young people with T1DM to get an insight into breath measurements. Participants interacted with the devices at least twice daily for five days, taking breath ketone, blood ketone and blood glucose measurements. Semi-structured interviews were conducted post-testing with the young participants and their caregivers to elicit preferences related to breath analysis and to inform the co-design of a diabetes breath ketone sensor prototype. To validate the results from a professional healthcare perspective, we interviewed two diabetes educators working in pediatric care about their perspective of young people using breath ketone sensors.

ResultsParticipants acknowledged the non-invasiveness of breath sensors as compared to blood testing. Affordability, reliability and accuracy were identified as prerequisites for breath ketone sensors used for diabetes management. Design features valued by young people included portability, ease of use, sustainability, readability and suitability for use in public. The time required to use breath sensors was similar to that for blood testing. The requirement to maintain a 10-second breath exhalation posed a challenge for users. Diabetes educators highlighted the ease of use of breath devices especially for young people with insufficient blood ketone testing.

ConclusionsBreath ketone sensors for diabetes management bear potential to facilitate ketone testing in young people. Our study affirms features for young people that drive usability of breath sensors among this population, and provides a model of user preference assessment.

Highlights/new findingsO_LIPortable breath ketone sensors potentially offer a non-invasive alternative to blood ketone testing in diabetes management, especially for young people with diabetes.
C_LIO_LIA user preference assessment of portable non-medical breath ketone devices among young people with Type 1 Diabetes Mellitus demonstrates the key values associated with breath ketone devices for diabetes management.
C_LIO_LIThe time to test for breath ketones was similar to that of blood ketone testing.
C_LIO_LIYoung people can and should be engaged in co-creation of medical devices that they will use.
C_LI Subpopulation-specific Machine Learning Prognosis for Underrepresented Patients with Double Prioritized Bias Correction Many clinical datasets are intrinsically imbalanced, dominated by overwhelming majority groups. Off-the-shelf machine learning models that optimize the prognosis of majority patient types (e.g., healthy class) may cause substantial errors on the minority prediction class (e.g., disease class) and demographic subgroups (e.g., Black or young patients). For example, our work found that missed death cases are 3.14 times higher than missed survival cases in a mortality prediction model. In the typical one-machine-learning-model-fits-all paradigm, racial and age disparities are likely to exist, but unreported. What makes it worse is the deceptive nature of widely used whole-population metrics, such as AUC-ROC. We show that some metrics fail to reflect serious prediction deficiencies. To mitigate representational biases, we design a double prioritized (DP) bias correction technique. Our method trains customized models for specific ethnicity or age groups, a substantial departure from the one-model-predicts-all convention. We report our findings on four prognosis tasks over two imbalanced clinical datasets. DP reduces relative disparities among race and age groups, 5.6% to 86.8% better than the 8 existing sampling solutions being compared, in terms of the minority class' recall. GARD is a pan-cancer predictor of radiation therapy benefit BackgroundDespite advances in cancer genomics, radiation therapy (RT) is still prescribed based on an empiric one-size-fits-all paradigm. Previously, we proposed a novel algorithm using the genomic adjusted radiation dose (GARD) to personalize RT prescription dose based on the biological effect of a given physical RT dose, calculated using individual tumor genomics. We hypothesize that GARD will reveal interpatient heterogeneity associated with opportunities to improve outcomes compared to physical RT dose alone. To test this hypothesis, and the GARD-based RT dosing paradigm, we performed a pooled pan-cancer analysis in 11 separate clinical cohorts of 1,615 unique patients with 7 different cancer types that represent all available cohorts with the data required to calculate GARD, together with clinical outcome.

MethodsUsing 11 previously-published datasets of cancers including breast, head and neck, non-small cell lung, pancreas, endometrium, melanoma and glioma, we defined two clinical endpoints: (i) time to first recurrence and (ii) overall survival, comprising 1,298 (982 +RT, 316 -RT) and 677 patients (424 +RT, 253 -RT), respectively. We used Cox regression stratified by cohort to test association between GARD and outcome with separate models using RT dose and sham-GARD for comparison. Interaction tests between GARD and treatment (+/- RT) were performed using the Wald statistic.

ResultsPooled analysis of all available data reveal that GARD as a continuous variable is associated with recurrence (HR = 0.982, CI [0.970, 0.994], p = 0.002) and survival (HR = 0.970, CI [0.953, 0.988], p = 0.001). The interaction test revealed the effect of GARD on survival depends on whether or not that patient received RT (Wald statistic: p=0.011). Physical RT dose and sham-GARD were not significantly associated with either outcome.

ConclusionsThe biologic effect of radiation therapy, as quantified by GARD, is significantly associated with recurrence and survival for those patients treated with radiation: it is predictive of RT benefit; and physical RT dose is not. We propose integration of genomics into radiation dosing decisions, using a GARD-based framework, as the new paradigm for personalizing RT prescription dose. How Informative Were Early SARS-CoV-2 Treatment and Prevention Trials? A longitudinal cohort analysis of trials registered on clinicaltrials.gov BackgroundEarly in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic.

MethodsWe created a cohort of SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We evaluated trials on 3 criteria of informativeness: potential redundancy, design quality and feasibility of patient-participant recruitment. The study protocol was prospectively registered with the Open Science Framework (https://osf.io/fp726/).

ResultsWe included 500 trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.0% (95% Confidence Interval 23.7 - 36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%.

ConclusionsLess than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic. Caffeine and Methylliberine: A Human Pharmacokinetic Interaction Study Methylliberine and theacrine are methylurates found in the leaves of various Coffea species and Camellia assamica var. kucha, respectively. We previously demonstrated that the methylxanthine caffeine increased theacrines oral bioavailability in humans. Consequently, we conducted a double-blind, placebo-controlled study pharmacokinetic study in humans administered methylliberine, theacrine, and caffeine to determine methylliberines pharmacokinetic interaction potential with either caffeine or theacrine. Subjects (n = 12) received an oral dose of either methylliberine (25 or 100 mg), caffeine (150 mg), methylliberine (100 mg) plus caffeine (150 mg), or methylliberine (100 mg) plus theacrine (50 mg) using a randomized, double-blind, crossover design. Blood samples were collected over 24 hours and analyzed for methylliberine, theacrine, and caffeine using UPLC-MS/MS. Methylliberine exhibited linear pharmacokinetics that were unaffected by co-administration of either caffeine or theacrine. However, methylliberine co-administration resulted in decreased oral clearance (41.9 {+/-} 19.5 vs. 17.1 {+/-} 7.80 L/hr) and increased half-life (7.2 {+/-} 5.6 versus 15 {+/-} 5.8 hrs) of caffeine. Methylliberine had no impact on caffeines maximum concentration (440 {+/-} 140 vs. 458 {+/-} 93.5 ng/mL) or oral volume of distribution (351 {+/-} 148 vs. 316 {+/-} 76.4 L). We previously demonstrated theacrine bioavailability was enhanced by caffeine, however, caffeine pharmacokinetics were unaffected by theacrine. Herein, we found that methylliberine altered caffeine pharmacokinetics without a reciprocal interaction, which suggests caffeine may interact uniquely with different methylurates. Understanding the mechanism(s) of interaction between methylxanthines and methylurates is of critical importance in light of the recent advent of dietary supplements containing both purine alkaloid classes. The effect of hypersensitivity pneumonitis guideline on pathologic diagnosis of interstitial pneumonia Hypersensitivity pneumonitis (HP) and interstitial pneumonia (IP) have several overlapping characteristics, and a high diagnostic concordance rate of HP is rarely obtained. New guideline, highly influenced by pathology, were devised for its diagnosis. We recently reported that the 2020 HP guideline may result in a possible overdiagnosis of fibrotic HP (fHP) through multidisciplinary discussion. Here, we attempted to investigate the impact of the 2020 HP guideline on the pathological diagnosis of cases previously diagnosed as IP. We classified 247 cases with fibrotic IP diagnoses sourced from 2014-2019 into three categories according to the 2020 HP guideline: typical, probable, and indeterminate HP. The original pathological diagnosis and categorization based on the 2020 HP guideline were compared. The clinical data including serum data and pulmonary function tests were compared among groups. The number of cases that changed to HP from an original diagnosis other than HP based on the guideline was 56 (23%). The clinical data of these cases bore a greater resemblance to cases diagnosed as indeterminate for HP than those diagnosed as typical or probable. The ratio of typical and probable HP to the total cases was significantly lower when using a transbronchial lung cryobiopsy (TBLC). Based on the new guideline, the pathological diagnosis of HP efficiently excluded HP cases but increased the rate of HP diagnosis for cases with fibrotic IP that may not suit an HP diagnosis. Thus, a TBLC may not be useful when imparting findings for fibrotic HP diagnosis using the new criteria.

Key messagesO_LIWhat is the key question? >
Does the 2020 HP Guideline improve pathological diagnosis?
C_LIO_LIWhat is the bottom line? >
By applying the new guideline, about 1/4 of the pathological diagnoses were changed from not chronic HP to probable or typical fHP, but most of the changed cases showed a clinical picture closer to not chronic HP.
C_LIO_LIWhy read on? >
To understand that simple application of the pathological criteria of the HP guideline may cause a misleading diagnosis.
C_LI Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

AimsDetermine factors affecting RTW status and time in patients treated with aRCR under state-based compensation schemes, compared to those outside such schemes.

MethodsPatients undergoing aRCR by one surgeon with minimum 1-year follow-up were grouped into those under (CP) or outside (non-CP) workers or vehicle accident compensation schemes, matched by age and gender. RTW status and time were assessed using chi-square analysis and multivariable linear regression.

ResultsOf 1054 available patients, 90 CP patients were identified with 29 consented and matched to non-CP (N=29). A higher proportion of CP patients (17.2 vs 0%, P<0.001) never returned to work and a lower proportion resumed pre-injury duties at first RTW (3 vs 52%, P<0.01). Median time to first RTW did not differ between CP and non-CP groups (5.1 vs 4.4, P=0.86). Smoking (P=0.007) and post-injury activity level (P=0.004) were significantly associated with longer time to first RTW, whereas compensation status was not.

ConclusionsCP patients undergoing aRCR in NSW are at risk of not returning to work. For those that return, there is no significant difference compared to non-CP in time to first RTW. Particularly, patient and management factors associated with extended time to first RTW have been identified. Interventions aimed at modifiable factors such as smoking cessation and increasing preoperative activity may improve future outcomes.

What is already known about this subjectO_LIWork-related injury and disease present a significant financial burden to the Australian economy ($AUD61.8billion per annum), with shoulder conditions due to body stressing accounting for 7% of this total cost (>$AUD4.2billion)
C_LIO_LIPatients receiving compensation appear to have poorer outcomes and take longer to return to work than their non-compensated counterparts, but the degree to which this occurs is variably reported in the literature
C_LIO_LIThe effect of modifiable factors on return to work status and time remain unclear, and have not previously been reported for the Australian population under the New South Wales workers compensation scheme
C_LI

What this study addsO_LIPatients receiving arthroscopic rotator cuff repair under a compensable scheme in New South Wales are at increased risk of not returning to work compared to patients presenting outside of a compensable scheme and patients in equivalent schemes internationally
C_LIO_LIPatients reporting a longer duration of symptoms and smokers are at increased risk of extended time to first return to work
C_LI

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI Using explainable machine learning to identifypatients at risk of reattendance at discharge from emergency departments Short-term reattendances to emergency departments are a key quality of care indicator. Identifying patients at increased risk of early reattendance could help reduce the number of missed critical illnesses and could reduce avoidable utilization of emergency departments by enabling targeted post-discharge intervention. In this manuscript we present a retrospective, single-centre study where we created and evaluated an extreme gradient boosted decision tree model trained to identify patients at risk of reattendance within 72 hours of discharge from an emergency department (University Hospitals Southampton Foundation Trust, UK). Our model was trained using 35,447 attendances by 28,945 patients and evaluated on a hold-out test set featuring 8,847 attendances by 7,237 patients. The set of attendances from a given patient appeared exclusively in either the training or the test set. Our model was trained using both visit level variables (e.g., vital signs, arrival mode, and chief complaint) and a set of variables available in a patients electronic patient record, such as age and any recorded medical conditions. On the hold-out test set, our highest performing model obtained an AUROC of 0.747 (95% CI : 0.722-0.773) and an average precision of 0.233 (95% CI : 0.194-0.277). These results demonstrate that machine-learning models can be used to classify patients, with moderate performance, into low and high-risk groups for reattendance. We explained our models predictions using SHAP values, a concept developed from coalitional game theory, capable of explaining predictions at an attendance level. We demonstrated how clustering techniques can be used to investigate the different sub-groups of explanations present in our patient cohort. Early prediction of preeclampsia in pregnancy with circulating cell-free RNA Liquid biopsies that measure circulating cell-free RNA (cfRNA) offer an unprecedented opportunity to noninvasively study the development of pregnancy-related complications and to bridge gaps in clinical care. Here, we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia (PE), a multi-organ syndrome which is the second largest cause of maternal death globally. We find that changes in cfRNA gene expression between normotensive (NT) and preeclamptic mothers are striking and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial, and immune cell types and tissues that reflect important aspects of PE physiology and suggest new hypotheses for disease progression. This enabled identification and independent validation of a panel of 18 genes whose measurement between 5-16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of PE well before the clinical symptoms manifest themselves. Finally, we demonstrate that cfRNA changes reflect the multifactorial nature of PE and provide a means to non-invasively monitor maternal organ health. Tests based on these observations could help predict and manage who is at risk for PE, an important and until now unachieved objective for obstetric care. Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function. BackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.

Material & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.

ResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.

ConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities. The effect of D-cycloserine on brain processing of breathlessness over pulmonary rehabilitation - an experimental medicine study BackgroundPulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial NMDA-receptor agonist, D-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials.

Methods72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ID: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250mg D-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between D-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions.

ResultsNo difference between D-cycloserine and placebo groups was observed across the primary or secondary outcome measures. Questionnaire and measures of respiratory function showed no group difference.

ConclusionsThis is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of D-cycloserine would not be worthwhile.

Key MessagesO_ST_ABSWhat is the key question?C_ST_ABSDoes the partial NMDA-receptor agonist, D-cycloserine, augment the effects of pulmonary rehabilitation on breathlessness related brain activity?

What is the bottom line?Rigorous trial methodology and validated surrogate end-points revealed no effect of D-cycloserine on breathlessness related brain activity across pulmonary rehabilitation.

Why read on?This study highlights both the value of functional magnetic resonance imaging in "de-risking" expensive clinical trials and provides detailed investigation of brain-targeted points for pharmacological treatments of breathlessness. COVID-19 mRNA Vaccination in Lactation: Assessment of adverse events and vaccine related antibodies in mother-infant dyads BackgroundData regarding adverse events observed in the lactating mother-infant dyad and their immune response to COVID-19 mRNA vaccination during lactation are needed to inform vaccination guidelines.

MethodsFrom a prospective cohort of 50 lactating individuals who received mRNA-based vaccines for COVID-19 (mRNA-1273 and BNT162b2), blood and milk samples were collected prior to first vaccination dose, immediately prior to 2nd dose, and 4-10 weeks after 2nd dose. Symptoms in mother and infant were assessed by detailed questionnaires. Anti-SARS-CoV-2 antibody levels in blood and milk were measured by Pylon 3D automated immunoassay and ELISA. In addition, vaccine-related PEGylated proteins in milk were measured by ELISA. Blood samples were collected from a subset of infants whose mothers received the vaccine during lactation (4-15 weeks after mothers 2nd dose).

ResultsNo severe maternal or infant adverse events were reported in this cohort. Two mothers and two infants were diagnosed with COVID-19 during the study period. PEGylated proteins, were not found at significant levels in milk after vaccination. After vaccination, levels of anti-SARS-CoV-2 IgG and IgM significantly increased in maternal plasma and there was significant transfer of anti-SARS-CoV-2-Receptor Binding Domain (anti-RBD) IgA and IgG antibodies to milk. Milk IgA levels after the 2nd dose were negatively associated with infant age. Anti-SARS-CoV-2 IgG antibodies were not detected in the plasma of infants whose mothers were vaccinated during lactation.

ConclusionsCOVID-19 mRNA vaccines generate robust immune responses in plasma and milk of lactating individuals without severe adverse events reported.