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This study aimed to develop and evaluate the acceptability and feasibility of a web-based platform for parents to support preschoolers' development of physical literacy. Specifically, this intervention focused on children's motor and social-emotional skill development. Twenty parents (M[subscript age] = 35.7, SD = 4.2) of preschool-aged children (M[subscript age] = 4.1, SD = 0.6) were assigned three intervention modules and completed weekly usage and feedback questionnaires (1 = strongly disagree, 5 = strongly agree). Parents (n = 15) also completed a follow-up interview. Parents indicated the modules were useable (4.5/5), useful (4.5/5), feasible (4.4/5), enjoyable (4.5/5), and acceptable (4.5/5). Five themes underlying parental engagement were generated: (a) "activity organization and planning," (b) "(de)motivators," (c) "parent knowledge and skills," (d) "experience with the platform," and (e) "application to everyday routines." The online modules under investigation were deemed both acceptable and feasible by parents. However, factors such as time and knowledge may impact parental engagement at home. Future research is needed to better understand the antecedents to parent physical literacy support behaviors in the early years.

An external focus of attention and autonomy support are identified as key factors to optimize motor learning; however, research in children is limited. Moreover, research has failed to examine these factors in ecologically valid motor learning settings, like physical education. Therefore, the present study examined the effects of external focus of attention when delivered using autonomy-supportive or controlling instructional language on children's motor learning. Thirty-three novice participants (10.30 ± 0.52 years) practiced a land-based curling task under supportive (external-focus instructions delivered with supportive language), controlling (external-focus instructions delivered with controlling language), or neutral (external instructions embedded in the task aim) conditions before completing a retention and transfer test. The supportive group produced higher positive affect after practice and greater accuracy in the retention test compared with the other groups. The findings provide support for the OPTIMAL (optimizing performance through intrinsic motivation and attention for learning) theory of motor learning that combining an external focus and autonomy support conditions improves motor learning.

Abstract Background Adrenal tumours are associated with familial adenomatous polyposis (FAP). In the literature, most studies use the clinical definition of FAP (more than 100 adenomatous polyps found in endoscopic studies). However, not all patients that meet clinical criteria for FAP carry pathogenic mutations in the adenomatous polyposis coli (APC) gene, as there is genetic heterogeneity responsible for FAP with the polyposis sometimes explained by genetic and environmental factors other than pathogenic APC mutations. Reciprocally, not all the patients with pathogenic APC variants will fulfil the classic criteria of FAP. Objective This study aims to investigate the characteristics of adrenal tumours in patients with pathogenic or likely pathogenic APC variants and explore the hormonal function of these patients. Method This is a retrospective cohort study. Patients with pathogenic or likely pathogenic APC variants were recruited and their radiological assessments were reviewed. Patient demographic data, APC variants, adrenal mass characteristics and hormonal testing results were collected. Result The prevalence of adrenal mass was 26.7% (24/90) among patients with pathogenic or likely pathogenic APC variants. Using the classic definition, the prevalence was 32.4% (22/68). Four patients had adrenal hormone testing, two of which had Conn’s syndrome and two had nonspecific subclinical results. Conclusion In our cohort, the prevalence of adrenal tumours among patients with pathogenic and likely pathogenic APC mutations is at least twice to three times higher than the general population prevalence reported from international population-based studies. The hormonal functions of patients with pathogenic APC variants and adrenal tumours can be investigated with routine testing in further research.

Abstract Background Both length of hospital stay and discharge to a skilled nursing facility are key drivers of total knee arthroplasty (TKA)-associated spending. Identifying patients who require increased postoperative care may improve expectation setting, discharge planning, and cost reduction. Balance deficits affect patients undergoing TKA and are critical to recovery. We aimed to assess whether a device that measures preoperative balance predicts patients’ rehabilitation needs and outcomes after TKA. Methods 40 patients indicated for primary TKA were prospectively enrolled and followed for 12 months. Demographics, KOOS-JR, and PROMIS data were collected at baseline, 3-months, and 12-months. Single-leg balance and sway velocity were assessed preoperatively with a force plate (Sparta Science, Menlo Park, CA). The primary outcome was patients’ discharge facility (home versus skilled nursing facility). Secondary outcomes included length of hospital stay, KOOS-JR scores, and PROMIS scores. Results The mean preoperative sway velocity for the operative leg was 5.7 ± 2.7 cm/s, which did not differ from that of the non-operative leg (5.7 ± 2.6 cm/s, p = 1.00). Five patients (13%) were discharged to a skilled nursing facility and the mean length of hospital stay was 2.8 ± 1.5 days. Sway velocity was not associated with discharge to a skilled nursing facility (odds ratio, OR = 0.82, 95% CI = 0.27–2.11, p = 0.690) or longer length of hospital stay (b = -0.03, SE = 0.10, p = 0.738). An increased sway velocity was associated with change in PROMIS items from baseline to 3 months for global07 (“How would you rate your pain on average?” b = 1.17, SE = 0.46, p = 0.015) and pain21 (“What is your level of pain right now?” b = 0.39, SE = 0.17, p = 0.025) at 3-months. Conclusion Preoperative balance deficits were associated with postoperative improvements in pain and function after TKA, but a balance focused biometric that measured single-leg sway preoperatively did not predict discharge to a skilled nursing facility or length of hospital stay after TKA making their routine measurement cost-ineffective.

Abstract An acute loss of smell emerged as a striking symptom present in roughly half of the people infected with the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus in the early phases of the COVID‐19 pandemic. In most COVID‐19 patients, olfaction recovers over the course of a few weeks. However, a lasting partial or complete loss of smell, often associated with distorted olfactory perceptions termed parosmia, has emerged as a widespread problem impacting at least 5%–10% of those who experience anosmia due to COVID‐19. Our inability to offer effective therapies to this hyposmic or anosmic population, comprising millions of patients, highlights an enormous unmet need for the medical system. Here, we summarize the current understanding of the pathobiology causing acute olfactory loss due to SARS‐CoV‐2 infection, focusing on how the virus interacts with the peripheral olfactory system, a major site of viral infection. We also explore the problem of long‐COVID olfactory dysfunction, which may accompany other persistent systemic disorders collectively termed postacute sequelae of COVID‐19. Specifically, we discuss an emerging model focused on unresolved immune cell activity driving ongoing dysfunction. Finally, we review current and future therapeutic approaches aimed at restoring olfactory function.

Abstract Artificial intelligence-enabled electrocardiogram (ECG) algorithms are gaining prominence for the early detection of cardiovascular (CV) conditions, including those not traditionally associated with conventional ECG measures or expert interpretation. This study develops and validates such models for simultaneous prediction of 15 different common CV diagnoses at the population level. We conducted a retrospective study that included 1,605,268 ECGs of 244,077 adult patients presenting to 84 emergency departments or hospitals, who underwent at least one 12-lead ECG from February 2007 to April 2020 in Alberta, Canada, and considered 15 CV diagnoses, as identified by International Classification of Diseases, 10th revision (ICD-10) codes: atrial fibrillation (AF), supraventricular tachycardia (SVT), ventricular tachycardia (VT), cardiac arrest (CA), atrioventricular block (AVB), unstable angina (UA), ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), pulmonary embolism (PE), hypertrophic cardiomyopathy (HCM), aortic stenosis (AS), mitral valve prolapse (MVP), mitral valve stenosis (MS), pulmonary hypertension (PHTN), and heart failure (HF). We employed ResNet-based deep learning (DL) using ECG tracings and extreme gradient boosting (XGB) using ECG measurements. When evaluated on the first ECGs per episode of 97,631 holdout patients, the DL models had an area under the receiver operating characteristic curve (AUROC) of 90% for 4 diagnoses (AVB, HCM, MS, STEMI). DL models outperformed XGB models with about 5% higher AUROC on average. Overall, ECG-based prediction models demonstrated good-to-excellent prediction performance in diagnosing common CV conditions.

Abstract Background Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes. Materials and methods We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms. Results Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers. Conclusions Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.

Abstract Background A previous scoping review of legal-involved veterans’ health and healthcare (1947–2017) identified studies and their limitations. Given the influx of literature published recently, this study aimed to update the previous review and map articles to the Veterans-Sequential Intercept Model (V-SIM) – a conceptual model used by key partners, including Veterans Health Administration, veteran advocates, criminal justice practitioners, and local governments to identify intercept points in the criminal legal system where resources and programming can be provided. Developing an updated resource of literature is essential to inform current research, discover gaps, and highlight areas for future research. Methods A systematic search of 5 databases identified articles related to legal-involved veterans’ health and healthcare published between December 2017 through December 2022. The first and senior authors conducted abstract reviews, full-text reviews, and data extraction of study characteristics. Finally, each article was sorted by the various intercept points from the V-SIM. Results Of 903 potentially relevant articles, 107 peer-reviewed publications were included in this review, most related to mental health (66/107, 62%) and used an observational quantitative study design (95/107, 89%). Although most articles did not explicitly use the V-SIM to guide data collection, analyses, or interpretation, all could be mapped to this conceptual model. Half of the articles (54/107, 50%) collected data from intercept 5 (Community Corrections and Support Intercept) of the V-SIM. No articles gathered data from intercepts 0 (Community and Emergency Services Intercept), 1 (Law Enforcement Intercept), or 2 (Initial Detention and Court Hearings Intercept). Conclusions There were 107 articles published in the last five years compared to 190 articles published in 70 years covered in the last review, illustrating the growing interest in legal-involved veterans. The V-SIM is widely used by front-line providers and clinical leadership, but not by researchers to guide their work. By clearly tying their research to the V-SIM, researchers could generate results to help guide policy and practice at specific intercept points. Despite the large number of publications, research on prevention and early intervention for legal-involved veterans is lacking, indicating areas of great need for future studies.

IntroductionIn the setting of pediatric and adolescent young adult cancer, increased access to genomic profiling has enhanced the detection of genetic variation associated with cancer predisposition, including germline syndromic conditions. Noonan syndrome (NS) is associated with the germline RAS pathway activating alterations and increased risk of cancer. Herein, we describe our comprehensive molecular profiling approach, the association of NS with glioma and glioneuronal tumors, and the clinical and histopathologic characteristics associated with the disease.MethodsWithin an institutional pediatric cancer cohort (n = 314), molecular profiling comprised of paired somatic disease–germline comparator exome analysis, RNA sequencing, and tumor classification by DNA methylation analysis was performed.ResultsThrough the implementation of paired analysis, this study identified 4 of 314 (1.3%) individuals who harbored a germline PTPN11 variant associated with NS, of which 3 individuals were diagnosed with a glioma or glioneuronal tumor. Furthermore, we extend this study through collaboration with a peer institution to identify two additional individuals with NS and a glioma or glioneuronal tumor. Notably, in three of five (60%) individuals, paired genomic profiling led to a previously unrecognized diagnosis of Noonan syndrome despite an average age of cancer diagnosis of 16.8 years. The study of the disease-involved tissue identified signaling pathway dysregulation through somatic alteration of genes involved in cellular proliferation, survival, and differentiation.DiscussionComparative pathologic findings are presented to enable an in-depth examination of disease characteristics. This comprehensive analysis highlights the association of gliomas and glioneuronal tumors with RASopathies and the potential therapeutic challenges and importantly demonstrates the utility of genomic profiling for the identification of germline cancer predisposition.

Enteric pathogens navigate distinct regional microenvironments within the intestine that cue important adaptive behaviors. We investigated the response of Citrobacter rodentium, a model of human pathogenic Escherichia coli infection in mice, to regional gastrointestinal pH. We found that small intestinal pH (4.4-4.8) triggered virulence gene expression and altered cell morphology, supporting initial intestinal attachment, while higher pH, representative of C. rodentium's replicative niches further along the murine intestine, supported pathogen growth. Gastric pH, a key barrier to intestinal colonization, caused significant accumulation of intra-bacterial reactive oxygen species (ROS), inhibiting growth of C. rodentium and related human pathogens. Within-host adaptation increased gastric acid survival, which may be due to a robust acid tolerance response (ATR) induced at colonic pH. However, the intestinal environment changes throughout the course of infection. We found that murine gastric pH decreases postinfection, corresponding to increased serum gastrin levels and altered host expression of acid secretion-related genes. Similar responses following Salmonella infection may indicate a protective host response to limit further pathogen ingestion. Together, we highlight interlinked bacterial and host adaptive pH responses as an important component of host-pathogen coevolution.

ABSTRACT Introduction There is growing scientific and policy recognition that optimising health before a potential pregnancy (preconception health) improves reproductive outcomes and the lifelong health of future children. However, public awareness on this topic is low. We conducted a public consultation to develop language recommendations and identify and prioritise approaches to inform research and improve public awareness of preconception health. Methods A public consultation was undertaken with people of any gender aged 18–50 years living in the United Kingdom who were not currently expecting a child. Public contributors were recruited through patient and public involvement, community and support groups, an existing cohort study, and an LGBTQ+ charity. An initial round of online group discussions (February/March 2021) explored public contributors' knowledge of preconception health, their recommendations for appropriate language, and ideas about public health approaches. In a subsequent discussion round (May 2021), language recommendations were refined and suggested approaches prioritised. Discussions were summarised based on notes taken by two researchers. Results Fifty‐four people joined the initial discussion round (66% women, 21% men, 13% nonbinary or transgender; 55% aged 18–30 years, 30% 31–40 years, 15% 41–50 years). Of these, 36 people (67%) participated in the subsequent round. Very few had heard the term ‘preconception health’, understood what it means, or why and for whom it is important. They recommended avoiding unfamiliar terms without further explanation (e.g., preconception health, medical terms), using language that is positive, encouraging and gender‐sensitive where possible, and using messages that are specific, nonjudgmental and realistic. The phrases ‘health and well‐being during the childbearing years’, ‘health and well‐being before pregnancy and parenthood’ and ‘planning for parenthood’ resonated with most public contributors. School‐based education, social media campaigns and the National Health Service emerged as priority approaches/settings for raising awareness. Conclusion This public consultation produced recommendations from a diverse group of people of reproductive age in the United Kingdom to improve language and prioritise approaches that increase public understanding of preconception health in ways that are relevant and appropriate to them. This should begin in schools and will require adaptation of curricula, alongside co‐development of public awareness campaigns and guidance for healthcare professionals. Patient or Public Contribution This public consultation included a diverse group of members of the public. They were not involved in the original design of the project, but following the initial round of online group discussions, they contributed to the interpretation and refinement of the emerging concepts in a subsequent round of group meetings. After the consultation activity, public contributors formed a Public Advisory Group and have subsequently been involved in other studies on the same topic. Two public contributors (E.R. and F.F.) provided critical input in the preparation and revision of this manuscript and are co‐authors of the paper.

Summary: Eosinophils are involved in host protection against multicellular organisms. However, their recruitment to the mesenteric lymph node (mLN) during type 2 immunity is understudied. Our results demonstrate that eosinophil association with lymphoid stromal niches constructed by fibroblastic reticular cells (FRCs) and lymphatic endothelial cells is diminished in mice selectively lacking interleukin (IL)-4Rα or lymphotoxin-β (LTβ) expression on B cells. Furthermore, eosinophil survival, activation, and enhanced Il1rl1 receptor expression are driven by stromal cell and B cell dialogue. The ligation of lymphotoxin-β receptor (LTβR) on FRCs improves eosinophil survival and significantly augments IL-33 expression and eosinophil homing to the mLN, thus confirming the significance of lymphotoxin signaling for granulocyte recruitment. Eosinophil-deficient ΔdblGATA-1 mice show diminished mLN expansion, reduced interfollicular region (IFR) alarmin expression, and delayed helminth clearance, elucidating their importance in type 2 immunity. These findings provide insight into dialogue between stromal cells and B cells, which govern mLN eosinophilia, and the relevance of these mechanisms during type 2 immunity.

Right-sided subclavian artery aneurysms (SAAs) are exceedingly rare. The most common cause of intrathoracic SAAs is atherosclerosis; however, causes can also include infection, trauma, cystic medial degeneration, Marfan syndrome, and Takayasu arteritis. Symptoms present most commonly with compression of surrounding structures, although adverse events, including rupture, thrombosis, and embolization, can also occur. We present a case of a 30-year-old woman with an asymptomatic, 15-mm, right-sided SAA, which was successfully resected with subsequent end-to-end primary anastomosis.

Background There are insufficient in vitro bone models that accommodate long-term culture of osteoblasts and support their differentiation to osteocytes. The increased demand for effective therapies for bone diseases, and the ethical requirement to replace animals in research, warrants the development of such models. Here we present an in-depth protocol to prepare, create and maintain three-dimensional, in vitro, self-structuring bone models that support osteocytogenesis and long-term osteoblast survival (>1 year). Methods Osteoblastic cells are seeded on a fibrin hydrogel, cast between two beta-tricalcium phosphate anchors. Analytical methods optimised for these self-structuring bone model (SSBM) constructs, including RT-qPCR, immunofluorescence staining and XRF, are described in detail. Results Over time, the cells restructure and replace the initial matrix with a collagen-rich, mineralising one; and demonstrate differentiation towards osteocytes within 12 weeks of culture. Conclusions Whilst optimised using a secondary human cell line (hFOB 1.19), this protocol readily accommodates osteoblasts from other species (rat and mouse) and origins (primary and secondary). This simple, straightforward method creates reproducible in vitro bone models that are responsive to exogenous stimuli, offering a versatile platform for conducting preclinical translatable research studies.

With the global prevalence of allergic disease continuing to rise at an alarming rate, the need for effective and safe therapeutics is paramount. Given the critical role of the early-life microbiota on immune development, emerging research suggests the potential use of live biotherapeutic products (LBP) for the prevention and treatment of childhood allergy. However, findings are limited and inconsistent. Therefore, the present review critically evaluates the current animal and human data on the therapeutic value of LBPs in allergy, the underlying immunological mechanisms by which LBPs may mediate allergy susceptibility, limitations of the current research that need to be addressed, and future research directions. Accordingly, LBPs may protect against allergic disease through several immunological and physiological mechanisms during early-life, including regulation of Th1/Th2 balance, SCFA-induced activation of GPR41/43 and HDAC inhibition, and maturation of epithelial barrier integrity. Taken together, current findings indicate powerful immunomodulatory properties of LBPs on allergic immune response, with LBPs offering exciting potential as a novel therapeutic tool for childhood allergy. However, the efficacy of LBPs in allergy is complex and influenced by many population and methodological factors, resulting in varied therapeutic benefits. While research thus far has focused on traditional probiotic strains, greater investigation into microbial consortiums selected from the microbiota of non-allergic infants may provide greater promise as a therapeutic tool for allergic disease. Further investigation, particularly into long-term efficacy, strain-specific effects, optimal supplementation regimes, and use of multi-strain consortiums, is necessary before findings can be translated into clinical applications to tackle childhood allergic disease.

BackgroundThe application of nanomaterials (NMs) and nano-enabled products (NEPs) across many industries has been extensive and is still expanding decades after first being identified as an emerging technology. Additive manufacturing has been greatly impacted and has seen the benefits of integrating NMs within products. With the expansion of nanotechnology, there has been a need to develop more adaptive and responsive methods to ascertain risks and ensure technology is developed safely. The Safe(r)-by-Design (SbD) concept can be used to establish safe parameters and minimise risks during the materials’ lifecycle, including the early stages of the supply chain. Exposure monitoring has advanced in recent years with the creation of standardised protocols for occupational exposure assessment of nano-objects and their aggregates and agglomerates (NOAA).MethodsTo aid in the development of an online SbD-supporting platform by the EU-funded project SAbyNA, we adopt a Europe Standard for monitoring release of NOAA to identify if a greater release of NOAA is associated with incorporation of NMs within NEPs compared to a polymer matrix alone. Case studies included filaments of polypropylene (PP) with nano-Ag or polycarbonate (PC) with single-walled carbon nanotubes (SWCNTs). NMs were received in masterbatch, and therefore previously modified to align with SbD interventions. Results were collected in line with European Standard recommendations: monitoring particle concentrations using direct reading instruments (DRI), sampling for offline chemical and morphological analysis, and collecting contextual information.Results and discussionBased on the criteria described in the European standard (BS EN 17058), data from both case studies identified that inhalation exposure relating to NM was “unlikely”. Despite this, during the production of the SWCNT-PC filaments, some noteworthy observations were made, including several DRI activity measurements shown to be higher than background levels, and material morphologically similar to the reference SWCNT/polymeric masterbatch observed in offline analysis. The data collected during this campaign were used to discuss choices available for data interpretation and decision-making in the European Standard for monitoring release of NOAA and also to facilitate the development of SAbyNA’s user-friendly industry platform for the SbD of NMs and NEPs.

Aim: To investigate developmental trajectories in early childhood and predictors of class assignment. Methods: Data were available for Gen2 infants at 12 (n = 2275), 24 (n = 1845) and 36 (n = 2110) months of age in the Raine Study. Latent growth class analysis was used to identify developmental trajectories based on the Ages and Stages Questionnaire. Multivariate logistic regression analyses were used to estimate associations between foetal growth restriction, gestational age, child biological sex, breast feeding, parental age, socioeconomic factors and developmental trajectories. Results: Two groups of infants were identified, one typically performing and one poorer performing. Being born early-term, pre-term and male were associated with poorer development. Not exposed to breastfeeding was associated with the lower trajectories in the adaptive and personal-social domains. Conclusions: Developmental surveillance and advice for early-term infants should be considered. Findings highlight the continued need to support and promote breastfeeding as a protective mechanism for child development.