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Abstract Background Dysferlinopathies are a clinically heterogeneous group of muscular dystrophies caused by gene mutations resulting in deficiency of the membrane-associated protein dysferlin. They manifest post-growth and are characterised by muscle wasting (primarily in the limb and limb-gridle muscles), inflammation, and replacement of myofibres with adipose tissue. The precise pathomechanism for dysferlinopathy is currently unclear; as such there are no treatments currently available. Glucocorticoids (GCs) are widely used to reduce inflammation and treat muscular dystrophies, but when administered to patients with dysferlinopathy, they have unexpected adverse effects, with accelerated loss of muscle strength. Methods To investigate the mechanistic basis for the adverse effects of GCs in dysferlinopathy, the potent GC dexamethasone (Dex) was administered for 4–5 weeks (0.5–0.75 µg/mL in drinking water) to dysferlin-deficient BLA/J and normal wild-type (WT) male mice, sampled at 5 (Study 1) or 10 months (Study 2) of age. A wide range of analyses were conducted. Metabolism- and immune-related gene expression was assessed in psoas muscles at both ages and in quadriceps at 10 months of age. For the 10-month-old mice, quadriceps and psoas muscle histology was assessed. Additionally, we investigated the impact of Dex on the predominantly slow and fast-twitch soleus and extensor digitorum longus (EDL) muscles (respectively) in terms of contractile function, myofibre-type composition, and levels of proteins related to contractile function and metabolism, plus glycogen. Results At both ages, many complement-related genes were highly expressed in BLA/J muscles, and WT mice were generally more responsive to Dex than BLA/J. The effects of Dex on BLA/J mice included (i) increased expression of inflammasome-related genes in muscles (at 5 months) and (ii) exacerbated histopathology of quadriceps and psoas muscles at 10 months. A novel observation was pronounced staining for glycogen in many myofibres of the damaged quadriceps muscles, with large pale vacuolated myofibres, suggesting possible myofibre death by oncosis. Conclusion These pilot studies provide a new focus for further investigation into the adverse effects of GCs on dysferlinopathic muscles.

Abstract Objective This study evaluated the diagnostic performance of a widely available cognitive screener, the Montreal cognitive assessment (MoCA), to detect cognitive impairment in older patients (age ≥ 55) with epilepsy residing in the US, using the International Classification of Cognitive Disorders in Epilepsy (IC‐CoDE) as the gold standard. Methods Fifty older adults with focal epilepsy completed the MoCA and neuropsychological measures of memory, language, executive function, and processing speed/attention. The IC‐CoDE taxonomy divided participants into IC‐CoDE Impaired and Intact groups. Sensitivity and specificity across several MoCA cutoffs were examined. Spearman correlations examined relationships between the MoCA total score and clinical and demographic variables and MoCA domain scores and individual neuropsychological tests. Results IC‐CoDE impaired patients demonstrated significantly lower scores on the MoCA total, visuospatial/executive, naming, language, delayed recall, and orientation domain scores (Cohen's d range: 0.336–2.77). The recommended MoCA cutoff score

Abstract Introduction Given the prevalence and staggering cost of neurological disorders, there is dire need for effective early detection and intervention tools. Emerging evidence suggests that multidisciplinary lifestyle interventions (MLI) may mitigate the risk and progression of neurological disorders. The objectives of this protocol are (1) to test the impact of MLI on the progression of neurological disorders and (2) to identify multi-omic biomarkers for early stages of neurological disease and the impact of MLIs on these biomarkers. Methods and analysis We present the Multidisciplinary lifestyle Interventions for Neurological Disorders during the Silent phase (MINDS) protocol, a randomized controlled trial of MLI in neurologically healthy older adults (≥ 50 years old) exhibiting elevated risk for common neurological disorders: stroke, epilepsy, Parkinson’s Disease, or Alzheimer’s disease and related dementias. Participants will be randomly assigned to intervention (n = 100) or control (n = 100) groups. The intervention group will receive 3 months of weekly 2-hour sessions on diet education, yoga, music therapy, and cognitive skills training. The participants’ neurological health and engagement in relevant lifestyle practices will be assessed at regular intervals for 12 months. Neuroimaging and samples for multi-omic analyses will be collected at baseline, and at 3 months and 12 months after enrollment. Primary outcomes will be signs of progression of the neurological disorder risk that qualified them for study enrollment or a clinical diagnosis of the disorder. Secondary and exploratory outcomes will be based on self-reported health and multi-omic data. Data analysis will include between-group and longitudinal within-group analyses. Perspectives The MINDS protocol and trial aims to clarify the impact of MLI on the progression of neurological disorder risk or diagnosis in older adults and to identify biomarkers that can be used to confirm MLI efficacy. The ability to validate the impact of MLI on neurological disorder progression based on biomarker data allows the identification of individuals most likely to benefit from such therapies in the early stages of neurological disease. Trial registration The trial is registered on the National Institutes of Health (NIH) ClinicalTrials.gov (NCT05984056) site. It was registered on August 2nd, 2023. The trial has full approval of the Cleveland Clinic Internal Review Board.

Abstract Human papillomavirus (HPV) is the cause of almost all cases of cervical cancer, a disease that kills some 340,000 women per year. The timeline from initial infection with HPV to the onset of invasive cervical cancer spans decades, and observational studies of this process are limited to settings in which treatment of precancerous lesions was withheld or inadequate. Such studies have been critical for understanding the natural history of HPV. Modeling can shed additional insight on the natural history of HPV, especially across geographical settings with varying prevalence of factors known to affect the host-side immune response to HPV, such as HIV and tobacco use. In this study, we create models for the 30 most populous countries in Sub-Saharan Africa, each with country-specific demographic, and behavioral inputs. We found that it was not possible to fit the data if we assumed that the natural history parameters were exactly identical for all countries, even after accounting for demographic and behavioral differences, but that we could achieve a good fit with the addition of a single immunocompetence parameter for each country. Our results indicate that variation in host immune responses may play a role in explaining the differences in the burden of cervical cancer between countries, which in turn implies a greater need for more geographically diverse data collection to understand the natural history of HPV.

Abstract Background Tissue non-specific alkaline phosphatase (TNSALP; encoded by the ALPL gene) has a critical role in the postnatal regulation of phosphate homeostasis, yet how TNSALP activity and expression are regulated during pregnancy remain largely unknown. This study tested the hypothesis that progesterone (P4) and/or interferon tau (IFNT) regulate TNSALP activity during pregnancy in sheep. Methods In Exp. 1, ewes were bred and received daily intramuscular injections of either corn oil vehicle (CO) or 25 mg progesterone in CO (P4) for the first 8 days of pregnancy and were hysterectomized on either Day 9, 12, or 125 of gestation. In Exp. 2, ewes were fitted with intrauterine catheters on Day 7 of the estrous cycle and received daily intramuscular injections of 50 mg P4 in CO and/or 75 mg progesterone receptor antagonist (RU486) in CO from Days 8 to 15, and twice daily intrauterine injections of either control proteins (CX) or IFNT (25 µg/uterine horn/d) from Days 11 to 15 (treatment groups: P4 + CX; P4 + IFNT; RU486 + P4 + CX; and RU486 + P4 + IFNT) and were hysterectomized on Day 16. Results In Exp. 1, endometria from ewes administered P4 had greater expression of ALPL mRNA than ewes administered CO on Day 12. TNSALP activity appeared greater in the epithelia, stratum compactum stroma, and endothelium of the blood vessels in the endometrium and myometrium from ewes administered P4 than ewes administered CO on Day 12. On Day 125, TNSALP activity localized to uterine epithelial and endothelial cells, independent of P4 treatment. TNSALP activity in placentomes appeared greater in P4 treated ewes and was detected in endothelial cells and caruncular tissue in P4 treated but not CO treated ewes. In Exp. 2, endometrial homogenates from ewes administered RU486 + P4 + CX had lower TNSALP activity those for P4 + CX and P4 + IFNT ewes. Immunoreactive TNSALP protein appeared greater in the mid- and deep-glandular epithelia in RU486 + P4 + CX treated ewes as compared to the other treatment groups. Enzymatic activity appeared greater on the apical surface of the deep glandular epithelia in endometria from ewes treated with RU486 + P4 + CX compared to the other treatment groups. Conclusions These results suggest that P4, but not IFNT, regulates the expression and activity of TNSALP in utero-placental tissues and has the potential to contribute to the regulation of phosphate availability that is critical for conceptus development during pregnancy.

In 2020, the WHO launched its first global strategy to accelerate the elimination of cervical cancer, outlining an ambitious set of targets for countries to achieve over the next decade. At the same time, new tools, technologies, and strategies are in the pipeline that may improve screening performance, expand the reach of prophylactic vaccines, and prevent the acquisition, persistence and progression of oncogenic HPV. Detailed mechanistic modelling can help identify the combinations of current and future strategies to combat cervical cancer. Open-source modelling tools are needed to shift the capacity for such evaluations in-country. Here, we introduce the Human papillomavirus simulator (HPVsim), a new open-source software package for creating flexible agent-based models parameterised with country-specific vital dynamics, structured sexual networks, and co-transmitting HPV genotypes. HPVsim includes a novel methodology for modelling cervical disease progression, designed to be readily adaptable to new forms of screening. The software itself is implemented in Python, has built-in tools for simulating commonly-used interventions, includes a comprehensive set of tests and documentation, and runs quickly (seconds to minutes) on a laptop. Performance is greatly enhanced by HPVsim's multiscale modelling functionality. HPVsim is open source under the MIT License and available via both the Python Package Index (via pip install) and GitHub (hpvsim.org).

Abstract Background Physical activity levels are low in people with Parkinson’s disease (PD) and have proved difficult to increase with exercise programs alone. Intervention approaches that address both the capacity to engage in physical activity and self-management strategies to change and maintain exercise behaviours are needed to address this intractable issue. Methods This will be an assessor-blinded, randomized controlled trial performed in Brisbane, Australia. Ninety-two people with mild-moderate PD will be randomly allocated to two groups: usual care, and a physiotherapy-led group exercise program combined with self-management strategies. In the intervention group, twelve, 80-min sessions will be conducted over 4 weeks in groups of up to 4 participants. The intervention will consist of circuit training including treadmill walking to target aerobic fitness, and activities targeting strength, balance, and gait performance. In addition, each session will also incorporate strategies focusing on self-management and behaviour change, augmented by the provision of a fitness activity tracker. Outcome measures will be collected at baseline (T1), immediately post intervention (T2) and at 6 months follow-up (T3). The primary outcome measure is free-living physical activity (average daily step count over 7 days) at pre (T1) and post (T2) intervention measured using an activPAL™ device. Secondary outcome measures captured at all time points include time spent walking, sedentary and in moderate intensity exercise over 7 days; spatiotemporal gait performance (step length, gait speed, endurance); health-related quality of life; and outcome expectations and self-efficacy for exercise. Discussion Sustainability of gains in physical activity following exercise interventions is a challenge for most populations. Our incorporation of a chronic disease self-management approach into the exercise program including fitness tracking extends previous trials and has potential to significantly improve free-living physical activity in people with PD. Trial registration This study has been prospectively registered in Australian and New Zealand Clinical Trial Registry (ACTRN12617001057370), registered on 19/07/2017. Available from www.anzctr.org.au/ACTRN12617001057370.aspx .

Movement research has typically been performed using three-dimensional (3D) marker-based motion capture, which is considered the “gold-standard” for biomechanical assessment. However, limitations exist due to the lack of portability, extensive preparation for data collection, marker placement training, error due to marker movement, and possible skin irritation due to marker adhesives. There is inherent error due to motion artifact stemming from skin movement and differences in marker placement between testers. Markerless motion capture systems are emerging as a new method of kinematic assessment. These methods require little preparation and there is no need to alter participant clothing. Markerless motion capture has also been validated for the lower extremity in healthy older adults during gait. However, it has not been validated for other populations or for the assessment of upper extremity (UE) motion. Therefore, the purpose of this study was to examine differences in calculated UE kinematics between marker-based and a markerless motion capture system. Participants attended two data collection sessions. Marker-based and markerless motion capture data was collected simultaneously while participants completed the Box and Blocks test (BBT). Kinematic and spatiotemporal data from both systems was exported using identical time series to ensure the same conditions for comparisons. Intraclass Correlation Coefficients (ICCs) were calculated to determine between session reliability for both systems on range of motion and peak joint angular data to ensure movement variability was not affecting measurement consistency. ICCs and Bland Altman statistics were also calculated between the systems. Root mean square deviation (RMSD) values were determined between demeaned UE joint angles for the two systems to examine movement pattern differences. The resulting between-session ICCs for each system showed that the markerless system shared similar reliability during this task as the marker-based system, further supporting the effect of variability on between-session reliability. Between-system ICCs resulted in good (0.70.9) agreement. Bland Altman results confirmed the existence of measurement bias between the systems. RMSD values for all UE joint angles were found to be less than 6°. Overall, the results from this study support the use of markerless motion capture in clinical settings to examine upper extremity biomechanics in children.

ABSTRACTDuring HIV infection of CD4+ T cells, ubiquitin pathways are essential to viral replication and host innate immune response; however, the role of specific E3 ubiquitin ligases is not well understood. Proteomics analyses identified 116 single-subunit E3 ubiquitin ligases expressed in activated primary human CD4+ T cells. Using a CRISPR-based arrayed spreading infectivity assay, we systematically knocked out 116 E3s from activated primary CD4+ T cells and infected them with NL4-3 GFP reporter HIV-1. We found 10 E3s significantly positively or negatively affected HIV infection in activated primary CD4+ T cells, including UHRF1 (pro-viral) and TRAF2 (anti-viral). Furthermore, deletion of either TRAF2 or UHRF1 in three JLat models of latency spontaneously increased HIV transcription. To verify this effect, we developed a CRISPR-compatible resting primary human CD4+ T cell model of latency. Using this system, we found that deletion of TRAF2 or UHRF1 initiated latency reactivation and increased virus production from primary human resting CD4+ T cells, suggesting these two E3s represent promising targets for future HIV latency reversal strategies.IMPORTANCEHIV, the virus that causes AIDS, heavily relies on the machinery of human cells to infect and replicate. Our study focuses on the host cell’s ubiquitination system which is crucial for numerous cellular processes. Many pathogens, including HIV, exploit this system to enhance their own replication and survival. E3 proteins are part of the ubiquitination pathway that are useful drug targets for host-directed therapies. We interrogated the 116 E3s found in human immune cells known as CD4+ T cells, since these are the target cells infected by HIV. Using CRISPR, a gene-editing tool, we individually removed each of these enzymes and observed the impact on HIV infection in human CD4+ T cells isolated from healthy donors. We discovered that 10 of the E3 enzymes had a significant effect on HIV infection. Two of them, TRAF2 and UHRF1, modulated HIV activity within the cells and triggered an increased release of HIV from previously dormant or “latent” cells in a new primary T cell assay. This finding could guide strategies to perturb hidden HIV reservoirs, a major hurdle to curing HIV. Our study offers insights into HIV-host interactions, identifies new factors that influence HIV infection in immune cells, and introduces a novel methodology for studying HIV infection and latency in human immune cells.

Abstract Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

We report 2 cases of pharyngeal monkeypox virus and group A Streptococcus co-infection in the United States. No rash was observed when pharyngitis symptoms began. One patient required intubation before mpox was diagnosed. Healthcare providers should be aware of oropharyngeal mpox manifestations and possible co-infections; early treatment might prevent serious complications.

Abstract While 9-valent human papillomavirus (HPV) vaccination is approved by the US Food and Drug Administration for use in adolescents as young as age 9, providers typically recommend it at ages 11–12. Studies suggest that recommending HPV vaccination at 9 or 10 years of age could increase up-to-date vaccination by age 13, which could especially benefit rural populations with reduced access to primary health care and lower HPV vaccination coverage than urban areas. This study aimed to assess the feasibility of the age-9 recommendation of HPV vaccination in rural clinics. We conducted in-depth interviews with providers and staff from two primary care clinics in central North Carolina to understand attitudes toward recommending HPV vaccination to 9- and 10-year-olds. All interviewees agreed that HPV vaccination was important for cancer prevention and should be recommended before the onset of sexual activity, agreeing that HPV vaccination could be initiated before age 11 to improve timeliness and completion of the vaccination series. However, opinions were mixed on whether HPV vaccination should be initiated as young as 9 years old. Two key informants recruited from two university-affiliated clinics described their experiences recommending HPV vaccination to 9- and 10-year-olds, including a modified vaccination schedule that promotes HPV vaccination during routine well-child visits, prior to pubertal onset, and alongside other recommended adolescent vaccines. Age-9 recommendation and administration of HPV vaccination is possible with minimal changes to current clinical practices and could increase the convenience and acceptability of HPV vaccination in under-vaccinated settings.

Abstract Honey bee colony management is critical to mitigating the negative effects of biotic and abiotic stressors. However, there is significant variation in the practices implemented by beekeepers, which results in varying management systems. This longitudinal study incorporated a systems approach to experimentally test the role of three representative beekeeping management systems (conventional, organic, and chemical-free) on the health and productivity of stationary honey-producing colonies over 3 years. We found that the survival rates for colonies in the conventional and organic management systems were equivalent, but around 2.8 times greater than the survival under chemical-free management. Honey production was also similar, with 102% and 119% more honey produced in conventional and organic management systems, respectively, than in the chemical-free management system. We also report significant differences in biomarkers of health including pathogen levels (DWV, IAPV, Vairimorpha apis, Vairimorpha ceranae) and gene expression (def-1, hym, nkd, vg). Our results experimentally demonstrate that beekeeping management practices are key drivers of survival and productivity of managed honey bee colonies. More importantly, we found that the organic management system—which uses organic-approved chemicals for mite control—supports healthy and productive colonies, and can be incorporated as a sustainable approach for stationary honey-producing beekeeping operations.

Category: Midfoot/Forefoot; Other Introduction/Purpose: The first tarsometatarsal (TMT) joint plays a crucial role in maintaining the stability of the midfoot and medial column. Disorders of this joint are associated with hallux valgus, hallux rigidus, flatfoot, Lisfranc injury and arthritis, and many others. It has been proven that there is a high variability in the morphology of the joint which may be related to joint stability thereby leading to certain deformities. Understanding the morphology of the articular surfaces comprising the joint is necessary. While prior studies have used XR and CT to analyze the joint[1], we present our work using 3D surface mapping to evaluate the cartilaginous articulation of the1st TMT joint. Methods: 22 fresh-frozen cadaveric feet without trauma nor surgery or significant deformities were dissected to expose the medial cuneiform (MeC) and 1st metatarsal (MT) bones, and the articular surfaces of the 1st TMT joint. Surface mapping of the articular surfaces and the two bones was completed using an Artec Space Spider 3D scanner and Mmics. Further digital analysis was completed using GeoMagic Studio 10. Results: Means and Standard Deviations (SDs) of the articular surface and the bone length were summarized in Table 1. The average articular area of the 1st TMT joint was 337.26 (±63.43) mm 2 on MeC, and 337.94 (±66.16) mm 2 on the 1st MT, with the length of the bones measured 25.50 (±2.56) mm for MeC and 63.93 (±4.22) mm for the 1st MT. There were statistically significant linear correlation between the articular-area and the length of the bone on both sides. 1 mm bone length increase was correlated with 11.48 mm 2 articular-area increase on MeC; and 10.33 mm 2 articular-area increase on 1st MT. (Figure 1,2) There were three types of morphologies of the 1st TMT joint (Type 1, with 2 facets linked to each other; Type 2, with 2 facets separated; Type 3, 1 large dorsal facet and two separate smaller facets inferiorly). The facet pattern is more obvious on the 1st MT than the MeC side. (Figure 3) Conclusion: Previous studies of the 1st TMT morphology were done using either direct manual measurements with descriptive reporting which does not reflect the exact contour of the joint, or XR/WBCT which cannot demonstrate the cartilaginous articulation. This study used a novel technique of surface mapping which overcame the above issues. The remodeled cartilaginous articular surfaces provide foundations for further comparison study, as well as integration of 3D surface mapping with weight- bearing CT analysis, which is currently under investigation by our research group. This will provide important information for diagnosis, surgical planning, and follow-up treatment for relevant disorders.

Category: Hindfoot; Ankle Introduction/Purpose: Recent studies have highlighted the important role of peritalar joint congruence in maintaining the alignment of the hindfoot. Peritalar subluxation is associated with a variety of pathological deformities including flatfoot, cavovarus foot, clubfoot, as well as foot and ankle stress fractures. To date, studies of peritalar joint congruence have all been performed using either XR, WBCT based direct measurements, or 3D segmentation and analysis. However, none of these techniques can demonstrate the cartilage location nor disruption, nor the exact location of the articulation on the bone surface. Data bias caused by the limitations of these study methodologies is therefore inevitable. This study used 3D surface mapping to assess morphometrics of the cartilage surfaces of the peritalar joints. Methods: 11 fresh-frozen cadaveric feet without trauma nor surgery or significant deformities were dissected to expose the calcaneus, cuboid, talus, and navicular bones, and the articular surfaces. Surface mapping of the articular surfaces and the two bones was completed using an Artec Space Spider 3D scanner and Mmics. Further digital analysis was completed using GeoMagic Studio 10. T-test was used for statistical comparisons, with p< 0.05 as statistically significantly different. Results: Detailed information of the articular surfaces is summarized in Table 1. The average articular area on both sides of the joint matched each other well in the posterior facet of the subtalar joint (4% difference), and calcaneocuboid joint (3% difference) without significant statistical difference, but not in the anterior & middle facets of the subtalar joint, nor the talonavicular joint. In the anterior & middle facets of the subtalar joint, the cartilage articular area on the talar side was 124% of that on the calcaneus (p < 0.05), and in the talonavicular joint the cartilage articular area on the navicular was 138% of that on the talus (p < 0.05). Conclusion: The cartilage articular surfaces in certain peritalar joints do not match its opposing surface in size. In the talonavicular joint, it is easy to understand since area of the socket must be much smaller than that of the ball in order for the joint to glide and rotate. There must be functional reasons for this phenomenon to happen in the anterior and middle facets of the subtalar joint, which need further investigation. This study shows that the extent of subluxation of the peritalar joints may be physiological and should not necessarily be considered as pathological.

Over the last two decades there has been a focus on teaching science using an enquiry approach where students are actively engaged in investigations that capture their interest, encourage them to ask questions, and investigate potential solutions to the problems they are confronting. The purpose of this case-study was to investigate how one Year 5 science teacher introduced his students to a unit of science on Matter, used different discourses to capture students’ interest in the enquiry-based tasks, and provided hands-on activities to enable them to test-out their ideas and develop explanations for what they found. The case-study highlights how the teacher used a range of authoritative and dialogic interactions to not only capture students’ interest in the tasks but also to encourage and challenge them to share their ideas with others. It was interesting to note how the students became more adept at expressing their opinions and providing explanations and justifications for the ‘scientific’ understandings they had developed during their enquiry-based science lessons.

Abstract Background This study explored the specialty preferences of China-educated international medical students (IMSs), who are mainly from low- and middle-income countries (LMICs) and constitute a potential medical workforce both for their home countries and foreign countries, and the influence of migration intentions on their specialty preferences. Methods A cross-sectional, questionnaire-based survey was conducted at 5 universities in China. The questionnaire link was distributed electronically among the IMSs at the 5 universities via emails. The questionnaire enquired IMSs’ demographic information, migration intentions and their specialty preferences. The Chi-square test was applied to determine the influence of the respondent’s gender, intention to practise in the home country and intention to practise in a high-income country on their specialty choices. The Chi-square test was also applied to determine the influence of the respondent’s gender, year of study and country of origin on their preferences for generalist-orientated or non-generalist orientated specialties. Results Altogether, 452 IMSs returned their responses, yielding a response rate of 64.1%. Approximately half of the IMSs planned to not return to their home country. The most selected specialty was general surgery and the least selected specialty was physical medicine and rehabilitation. No significant differences were evident in most specialty preferences between those who intended to return home and those who intended to stay abroad. Among the IMSs having intentions of returning to their home country, male students tended to choose a generalist-orientated specialty, while female students tended to choose a non-generalist-orientated specialty. Conclusion China-educated IMSs could play important roles in the primary care services as well as other shortage specialties both for their home countries or foreign countries. Therefore, it is recommended that governments in these countries plan migration and recruitment policies that cater for these studying-abroad medical students from LMICs, especially in this challenging time during the COVID-19 pandemic.

Sun exposure carries both harms and benefits. Exposing the skin to the sun is the main modifiable cause of skin cancers, which exert a considerable health and economic burden in Australia. The most well-established benefit of exposure to ultraviolet (UV) radiation is vitamin D production. Australia has the highest incidence of skin cancer in the world but, despite the high ambient UV radiation, approximately one quarter of the population is estimated to be vitamin D deficient. Balancing the risks and benefits is challenging and requires effective communication. We sought to provide a snapshot of public knowledge and attitudes regarding sun exposure and vitamin D and to examine the associations between these factors and sun protective behaviors. In 2020 we administered an online survey; 4824 participants with self-reported fair or medium skin color were included in this analysis. Only 25% and 34% of participants were able to identify the amount of time outdoors needed to maintain adequate vitamin D status in summer and winter, respectively and 25% were concerned that sunscreen use inhibits vitamin D synthesis. This lack of knowledge was associated with suboptimal sun protection practices. Public education is warranted to prevent over-exposure, while supporting natural vitamin D production.

Abstract Between June and August 2020, an agent-based model was used to project rates of COVID-19 infection incidence and cases diagnosed as positive from 15 September to 31 October 2020 for 72 geographic settings. Five scenarios were modelled: a baseline scenario where no future changes were made to existing restrictions, and four scenarios representing small or moderate changes in restrictions at two intervals. Post hoc, upper and lower bounds for number of diagnosed Covid-19 cases were compared with actual data collected during the prediction window. A regression analysis with 17 covariates was performed to determine correlates of accurate projections. It was found that the actual data fell within the lower and upper bounds in 27 settings and out of bounds in 45 settings. The only statistically significant predictor of actual data within the predicted bounds was correct assumptions about future policy changes (OR 15.04; 95% CI 2.20–208.70; p = 0.016). Frequent changes in restrictions implemented by governments, which the modelling team was not always able to predict, in part explains why the majority of model projections were inaccurate compared with actual outcomes and supports revision of projections when policies are changed as well as the importance of modelling teams collaborating with policy experts.

Abstract Background Individuals with PTEN hamartoma tumor syndrome (PHTS) demonstrate a distinct neurobehavioral profile suggesting primary disruption of frontal lobe symptoms, with more severe cognitive deficits in those with associated autism spectrum disorder (ASD) that extend to other areas of neurobehavioral function as well (e.g., adaptive behavior, sensory deficits). The current study sought to characterize longitudinal neurobehavioral profiles in individuals with PHTS who completed serial assessments (2–3 evaluations) over a 2-year time period. Methods Comprehensive neurobehavioral evaluations were conducted on 92 participants (age range 6–21) with PHTS and/or ASD. Spaghetti plots and linear mixed effects models were used to visualize the individual patient profiles and group trends and examine the group differences in cognitive/behavioral test scores over time. Practice-adjusted reliable change indices (RCIs) and standardized regression-based change scores (SRBs) were calculated for those measures in the battery with adequate sample sizes and test–retest reliabilities for future use in assessing neurobehavioral change in children and young adults with PHTS. Results Wide individual differences were observed at baseline across all measures. Encouragingly, baseline differences between patient groups persisted at the same magnitude over a 2-year time period with no differences in longitudinal neurobehavioral profiles within any one group. Test–retest reliabilities were generally high, ranging from 0.62 to 0.97, and group mean change from baseline to 12 months was small (range − 3.8 to 3.7). A Microsoft Excel calculator was created that clinicians and researchers can use to automatically calculate RCI and SRB thresholds at both 80% and 90% confidence intervals using test scores from a given child or young adult with PHTS. Conclusions Our results suggest that the neurobehavioral phenotypes observed in individuals with PHTS remain relatively stable over time, even in those with ASD. The RCIs and SRBs provided can be used in future research to examine patient outcomes at the individual level as well as to detect negative deviations from the expected trajectory that can be used to inform intervention strategies.

Abstract Background Recent evidence suggests important roles for progesterone (P4) and interferon tau in the regulation of calcium, phosphate, and vitamin D signaling in the uteri of pregnant sheep. However, the effects of P4 and estradiol (E2), with respect to the expression of their receptors PGR and ESR1, respectively, in uterine epithelia on mineral signaling during the estrous cycle has not been investigated. Estrous cycles of mature Suffolk ewes were synchronized, prostaglandin F2α was administered, and ewes were observed for estrus (designated as Day 0) in the presence of vasectomized rams. On Days 1, 9, or 14 of the estrous cycle, hysterectomies were performed. Results 25-hydroxyvitamin D was more abundant in plasma from ewes on Day 14 than Day 1 (P

Abstract Memory dysfunction is prevalent in temporal lobe epilepsy (TLE), but little is known about the underlying molecular etiologies. Single-nucleus RNA sequencing technology was used to examine differences in cellular heterogeneity among left (language-dominant) temporal neocortical tissues from patients with TLE with (n = 4) or without (n = 2) impairment in verbal episodic memory. We observed marked cell heterogeneity between memory phenotypes and identified numerous differentially expressed genes across all brain cell types. The most notable differences were observed in glutamatergic (excitatory) and GABAergic (inhibitory) neurons with an overrepresentation of genes associated with long-term potentiation, long-term depression, and MAPK signaling, processes known to be essential for episodic memory formation.

Summary: Much of the world’s population had already been infected with COVID-19 by the time the Omicron variant emerged at the end of 2021, but the scale of the Omicron wave was larger than any that had come before or has happened since, and it left a global imprinting of immunity that changed the COVID-19 landscape. In this study, we simulate a South African population and demonstrate how population-level vaccine effectiveness and efficiency changed over the course of the first 2 years of the pandemic. We then introduce three hypothetical variants and evaluate the impact of vaccines with different properties. We find that variant-chasing vaccines have a narrow window of dominating pre-existing vaccines but that a variant-chasing vaccine strategy may have global utility, depending on the rate of spread from setting to setting. Next-generation vaccines might be able to overcome uncertainty in pace and degree of viral evolution.

Much attention over the last two decades has been given to inquiry-based learning in science as a way of capturing students’ interest and participation in learning. However, while the research on inquiry-based learning consistently demonstrates that students do attain higher learning outcomes than peers who are taught by traditional transmission approaches, little research has been attached to researching the key elements of this approach that contribute to its success. This review focuses on the role of inquiry-based learning where students work in cooperative groups to investigate topics that challenge their curiosity, encouraging them to ask questions to clarify their understandings, evaluate evidence that may help to explain phenomena, and predict potential solutions to the problems at hand. The key role teachers play in inducting students into ways of thinking and reasoning and providing opportunities for them to work with others in the context of inquiry-based learning will also be discussed.

Cooperative learning is more effective in a well-managed classroom with diverse ethnic, linguistic, and religious backgrounds. To that end, this study examined the state of applications of cooperative learning and student diversity in polytechnic colleges in southwest Ethiopia. A qualitative research methodology, specifically grounded theory design was employed to achieve the research purpose. The empirical data was gathered from 20 educational officials through in-depth interviews at sample polytechnic colleges. Student diversity found to have a significant influence on how cooperative learning is implemented. It has also been found that the perception of department heads towards diversity has a significant influence on the application of cooperative learning. The study’s findings also showed that managing diversity among students and interacting with peers within groups and from other groups has a positive influence on cooperative learning. In conclusion, the application of cooperative learning is affected by perceptional and structural factors of student diversity. Thus, this research recommends further study to be conducted on the relationship between diversity management and cooperative learning.

Abstract We used an agent-based model Covasim to assess the risk of sustained community transmission of SARSCoV-2/COVID-19 in Queensland (Australia) in the presence of high-transmission variants of the virus. The model was calibrated using the demographics, policies, and interventions implemented in the state. Then, using the calibrated model, we simulated possible epidemic trajectories that could eventuate due to leakage of infected cases with high-transmission variants, during a period without recorded cases of locally acquired infections, known in Australian settings as “zero community transmission”. We also examined how the threat of new variants reduces given a range of vaccination levels. Specifically, the model calibration covered the first-wave period from early March 2020 to May 2020. Predicted epidemic trajectories were simulated from early February 2021 to late March 2021. Our simulations showed that one infected agent with the ancestral (A.2.2) variant has a 14% chance of crossing a threshold of sustained community transmission (SCT) (i.e., > 5 infections per day, more than 3 days in a row), assuming no change in the prevailing preventative and counteracting policies. However, one agent carrying the alpha (B.1.1.7) variant has a 43% chance of crossing the same threshold; a threefold increase with respect to the ancestral strain; while, one agent carrying the delta (B.1.617.2) variant has a 60% chance of the same threshold, a fourfold increase with respect to the ancestral strain. The delta variant is 50% more likely to trigger SCT than the alpha variant. Doubling the average number of daily tests from ∼ 6,000 to 12,000 results in a decrease of this SCT probability from 43 to 33% for the alpha variant. However, if the delta variant is circulating we would need an average of 100,000 daily tests to achieve a similar decrease in SCT risk. Further, achieving a full-vaccination coverage of 70% of the adult population, with a vaccine with 70% effectiveness against infection, would decrease the probability of SCT from a single seed of alpha from 43 to 20%, on par with the ancestral strain in a naive population. In contrast, for the same vaccine coverage and same effectiveness, the probability of SCT from a single seed of delta would decrease from 62 to 48%, a risk slightly above the alpha variant in a naive population. Our results demonstrate that the introduction of even a small number of people infected with high-transmission variants dramatically increases the probability of sustained community transmission in Queensland. Until very high vaccine coverage is achieved, a swift implementation of policies and interventions, together with high quarantine adherence rates, will be required to minimise the probability of sustained community transmission.

[This corrects the article DOI: 10.1371/journal.pone.0214908.].

Abstract Background In settings with zero community transmission, any new SARS-CoV-2 outbreaks are likely to be the result of random incursions. The level of restrictions in place at the time of the incursion is likely to considerably affect possible outbreak trajectories, but the probability that a large outbreak eventuates is not known. Methods We used an agent-based model to investigate the relationship between ongoing restrictions and behavioural factors, and the probability of an incursion causing an outbreak and the resulting growth rate. We applied our model to the state of Victoria, Australia, which has reached zero community transmission as of November 2020. Results We found that a future incursion has a 45% probability of causing an outbreak (defined as a 7-day average of > 5 new cases per day within 60 days) if no restrictions were in place, decreasing to 23% with a mandatory masks policy, density restrictions on venues such as restaurants, and if employees worked from home where possible. A drop in community symptomatic testing rates was associated with up to a 10-percentage point increase in outbreak probability, highlighting the importance of maintaining high testing rates as part of a suppression strategy. Conclusions Because the chance of an incursion occurring is closely related to border controls, outbreak risk management strategies require an integrated approaching spanning border controls, ongoing restrictions, and plans for response. Each individual restriction or control strategy reduces the risk of an outbreak. They can be traded off against each other, but if too many are removed there is a danger of accumulating an unsafe level of risk. The outbreak probabilities estimated in this study are of particular relevance in assessing the downstream risks associated with increased international travel.

Abstract Objective: This study aimed to describe the vitamin D status of pregnant women in Western Australia and identify predictors of deficiency in pregnancy. Methods: A cross‐sectional study was conducted using linked data from statewide administrative data collections. Participants included pregnant women aged 18–44 years who gave birth between 2012 and 2014. Results: The mean 25‐hydroxyvitamin D (25[OH]D) concentration was 70.7 nmol L−1 (SD 25.7; range 5–255 nmol L−1). Approximately one‐fifth of the pregnant women were vitamin D deficient (

Category: Hindfoot; Ankle; Other Introduction/Purpose: Recently joint congruence has been given a lot of focus in studies evaluating foot and ankle deformities. XR and WBCT scans are the commonly used techniques, however, neither can accurately reflect articular surfaces particularly in joints where only partial bone surfaces are covered by articular cartilage. This study introduced a novel technique using 3D surface mapping and CT bone segmentation to assess articular morphology and congruence of the calcaneocuboid (CC) joint. Methods: A CT scan of a fresh frozen cadaveric foot without trauma history nor deformity was taken and then the calcaneus and cuboid bones were dissected free with all soft tissue removed. Segmentation and reconstruction of the calcaneus and cuboid from the CT scan was performed using Materialise Mimics. Surface mapping and digital reconstructions of the calcaneus and cuboid bones as well as the calcaneocuboid articular surfaces were then obtained using an Artec Space Spider 3D scanner. Both the CT and surface mapping reconstructions were imported into Geomagic Studio 10 where the reconstructed calcaneus via CT was merged with the reconstructed calcaneus via surface mapping. The same procedures were performed with the reconstructions of the cuboid. Then cartilage surfaces from the calcaneocuboid joint of the surface mapping reconstruction were outlined on and compared to the bone surfaces underneath. Results: The articular surfaces of the calcaneocuboid joint were shaped according to the bone contour noting however that on both sides, the articular surface did not fully match the bone surface. On the calcaneal side, the dimension of the bone surface was 357.72 mm 2 , while the articular surface was 300.92 mm 2 (percentage of bone covered by cartilage: 84.12%). On the Cuboid side, the dimension of the bone surface was 372.41 mm 2 while the articular surface was 302.60 mm 2 (percentage of bone covered by cartilage: 81.25%). When restoring the articulation of the reconstructed calcaneus and cuboid, there was incongruence of the two bone surfaces with the dorsolateral corner of the calcaneus and the plantarmedial corner of the cuboid uncovered by its contralateral bone. The same applied to the articular surfaces but at a smaller uncovering level (Figure 1). Conclusion: Even with 3D CT segmentation and reconstruction of articulating bones, one has no knowledge of the precise articular surface of a joint. 3D surface scanning is a reliable method to study morphology of the cartilage surface of a joint. 3D CT reconstruction combined with 3D surface mapping is a useful tool for studying both the bony surface and the cartilage surface of a joint. This study has implications for treatment of any joint in the foot which appears subluxated on XR or CT scans and where this may represent the normal bone morphology but not true subluxation. Articular congruence study under weightbearing condition is currently under investigation by our research group.

Abstract Population-level ecological studies show type 1 diabetes incidence is inversely correlated with ambient ultraviolet radiation (UVR) levels. We conducted a nested case–control study using administrative datasets to test this association at the individual level. Cases (n = 1819) were children born in Western Australia (WA) from 1980–2014, diagnosed with type 1 diabetes at ≤ 16 years. Controls (n = 27,259) were randomly selected from all live births in WA, matched to cases by sex and date of birth. Total ambient erythemal ultraviolet radiation (UVR) doses for each trimester of pregnancy and first year of life were estimated for each individual, using daily NASA satellite data that were date- and geographically-specific. Conditional logistic regression tested the association between UVR dose and case–control status. Type 1 diabetes risk was 42% lower in boys of mothers with third-trimester UVR dose in the highest (compared to the lowest) quartile (p = 0.04). Higher UVR in the first year of life was associated with lower type 1 diabetes risk among boys (p = 0.01). UVR dose was not associated with type 1 diabetes risk in girls. Higher UVR in late pregnancy and early life appear to interact with sex-specific factors to lower type 1 diabetes risk among boys in Western Australia.

Ecological attributes of a species can vary as resource requirements and social interactions change in response to the annual reproductive cycle. We examined variation in home range size, home range overlap, activity (2005–2006), and food item selection (2006–2007) of island foxes (Urocyon littoralis) on San Nicolas Island relative to reproduction-related events. Home ranges, particularly for males, were larger during the mating period compared with the post-mating, pup-rearing, and non-reproduction periods. Home range overlap with non-mate neighbors also increased during the mating period. The greater home range size and overlap during the mating season is consistent with foxes, particularly males, traveling into the ranges of neighboring pairs in an attempt to secure extra-pair copulations. Daily activity patterns did not vary among the reproductive periods. Use of vertebrate prey items increased during the period when adults would have been provisioning weaning young. These items (e.g., mice, birds, lizards) are protein-rich and easier to transport compared with smaller items (e.g., fruits, snails, insects) that also are commonly consumed by island foxes. Variation in ecological attributes among island foxes across the different seasons defined by reproductive events likely represents efforts to maximize mating opportunities, particularly among adult males, and to secure optimal resources for provisioning growing young. These patterns are consistent with those observed among other small canid species.

ObjectiveSeizure outcomes after brain surgery for drug-resistant epilepsy (DRE) are very heterogeneous and difficult to predict with models utilizing the current clinical, imaging, and electrophysiological variables. In this pilot study, we investigated whether genetic and molecular biomarkers (e.g., genomic, transcriptomic) can provide additional insight into differential response to surgery.MethodsPost-operative seizure-outcomes were collected at last follow-up (>6 months) for 201 adult patients with DRE who underwent surgery between 2004 and 2020. Resected tissue was sent for miRNA sequencing (n = 132) and mRNA sequencing (n = 135). Following the selection of 10 genes (SCN1A, NBEA, PTEN, GABRA1, LGL1, DEPDC5, IL1A, ABCB1, C3, CALHM1), we investigated SNPs in those 10 genes from previously acquired exome sequencing data (n = 106). Logistic regression was performed to test for associations between individual features (mRNAs, miRNAs, and SNPs) and post-operative seizure-outcome with an exploratory FDR P < 0.25 as the threshold for significance. Post-operative time-to-seizure analyses were performed for each SNP using a Cox proportional hazards model.ResultsThe majority of patients (83%) had temporal lobe epilepsy. Mean age at surgery was 38.3 years, and 56% were female. Three SNPs (rs10276036, rs11975994, rs1128503) in multi-drug resistance gene, ABCB1, were associated with post-operative seizure outcomes. Patients with alternate alleles in ABCB1 were more likely to be seizure-free at last follow-up (52–56% reduction in seizure recurrence; FDR P = 0.24). All three SNPs were in linkage disequilibrium and highly correlated with each other. Median post-operative time-to-seizure was 63 months for patients with 2 alternate alleles, 24–33 months with 1 alternate allele, and 10–11 months with 0 alternate alleles. These SNPs improved outcome prediction beyond MRI and sex alone. No independent miRNAs or mRNAs were significantly associated with seizure-outcome (P > 0.05). However, pathway analysis identified “cancer drug resistance by drug efflux” (mir-154 and mir-379) as enriched (P = 0.02), supporting the role of drug response genes in post-operative seizure recurrence.SignificanceABCB1 may have a role in epileptogenesis and surgery outcomes independent of its drug efflux activity necessitating further investigation. SNPs in ABCB1 may serve as independent predictors of post-operative outcome.

Calpain-3 (CAPN3) is a muscle-specific member of the calpain family of Ca2+-dependent proteases. It has been reported that CAPN3 can also be autolytically activated by Na+ ions in the absence of Ca2+, although this was only shown under non-physiological ionic conditions. Here we confirm that CAPN3 does undergo autolysis in the presence of high [Na+], but this only occurred if all K+ normally present in a muscle cell was absent, and it did not occur even in 36 mM Na+, higher than what would ever be reached in exercising muscle if normal [K+] was present. CAPN3 in human muscle homogenates was autolytically activated by Ca2+, with ~50% CAPN3 autolysing in 60 min in the presence of 2 µM Ca2+. In comparison, autolytic activation of CAPN1 required about 5-fold higher [Ca2+] in the same conditions and tissue. After it was autolysed, CAPN3 unbound from its tight binding on titin and became diffusible, but only if the autolysis led to complete removal of the IS1 inhibitory peptide within CAPN3, reducing the C-terminal fragment to 55 kDa. Contrary to a previous report, activation of CAPN3, either by raised [Ca2+] or Na+ treatment, did not cause proteolysis of the skeletal muscle Ca2+ release channel-ryanodine receptor, RyR1, in physiological ionic conditions. Treatment of human muscle homogenates with high [Ca2+] caused autolytic activation of CAPN1, accompanied by proteolysis of some titin and complete proteolysis of junctophilin (JP1, full length ~95 kDa), generating an equimolar amount of a diffusible ~75 kDa N-terminal JP1 fragment, but without any proteolysis of RyR1.

Abstract This paper addresses the absence of an international diagnostic taxonomy for cognitive disorders in patients with epilepsy. Initiated through the 2020 Memorandum of Understanding between the International League Against Epilepsy and the International Neuropsychological Society, neuropsychological representatives from both organizations met to address the problem and consequences of the absence of an international diagnostic taxonomy for cognitive disorders in epilepsy, overview potential solutions, and propose specific solutions going forward. The group concluded that a classification of cognitive disorders in epilepsy, including an overall taxonomy and associated operational criteria, was clearly lacking and sorely needed. This paper reviews the advantages and shortcomings of four existing cognitive diagnostic approaches, including taxonomies derived from the US National Neuropsychology Network, DSM‐V Neurocognitive Disorders, the Mild Cognitive Impairment classification from the aging/preclinical dementia literature, and the Research Domain Criteria Initiative. We propose a framework to develop a consensus‐based classification system for cognitive disorders in epilepsy that will be international in scope and be applicable for clinical practice and research globally and introduce the International Classification of Cognitive Disorders in Epilepsy (IC‐CODE) project.

Abstract Background Patients with Philadelphia-negative Myeloproliferative Neoplasms (MPN) suffer from numerous symptoms and decreased quality of life. Smoking is associated with an increased symptom burden in several malignancies. The aim of this study was to analyze the association between smoking and MPN-related symptom burden and explore MPN patients’ opinions on smoking. Methods A total of 435 patients with MPN participated in a cross-sectional internet-based survey developed by the Mayo Clinic and the Myeloproliferative Neoplasm Quality of Life Group. Patients reported their demographics, disease characteristics, tobacco use, and opinions on tobacco use. In addition, MPN-related symptoms were reported via the validated 10-item version of the Myeloproliferative Neoplasms Symptom Assessment Form. Results Current/former smokers reported worse fatigue (mean severity 5.6 vs. 5.0, p = 0.02) and inactivity (mean severity 4.0 vs. 3.4, p = 0.03) than never smokers. Moreover, current/former smokers more frequently experienced early satiety (68.5% vs. 58.3%, p = 0.03), inactivity (79.9% vs. 71.1%, p = 0.04), and concentration difficulties (82.1% vs. 73.1%, p = 0.04). Although not significant, a higher total symptom burden was observed for current/former smokers (mean 30.4 vs. 27.0, p = 0.07). Accordingly, overall quality of life was significantly better among never smokers than current/former smokers (mean 3.5 vs. 3.9, p = 0.03). Only 43.2% of the current/former smokers reported having discussed tobacco use with their physician, and 17.5% did not believe smoking increased the risk of thrombosis. Conclusion The current study suggests that smoking may be associated with increased prevalence and severity of MPN symptoms and underscores the need to enhance patient education and address tobacco use in the care of MPN patients.

Abstract Background Despite policies and programmes aimed at housing people who are homeless, there are still people who live and sleep rough. This project used the skills and knowledge of people in this situation to identify a strategy to mitigate some of the risks. Objective To describe the development and conduct of a co‐design project involving people who are homeless. Setting/Group Members A Working Group of 11 was formed following a careful recruitment process from people who had volunteered after consultation by the project team. The co‐design approach was guided by a set of principles. Methods Eight members of the Working Group were interviewed by an external researcher (RM). The approach was primarily deductive, with the principles adopted by the project team used as a framework for data collection and analysis. The co‐design process was captured by the project leaders (BK, PC) supplemented with documentation review and team discussions. Results The group met weekly for 12 weeks, with 8‐10 members present on average. They reviewed information from the survey, contributed ideas for solutions and ultimately decided to provide information via print, a website and an event. Important factors in on‐going involvement were carefully selecting group members and making participation rewarding for them. Discussion/Conclusions Vulnerable people such as those experiencing homelessness can be excluded from decision‐making processes affecting them, as they can be perceived as hard to reach and unable to make a meaningful contribution. This project demonstrated that a carefully managed project, with sufficient resources and commitment, it was possible to involve people who are homeless and maintain involvement over an extended time period. Public Contribution The Working Group reviewed survey findings and developed an intervention to minimize the health, social and legal harms of sleeping rough. Several members reviewe this paper.

Initial COVID-19 containment in the United States focused on limiting mobility, including school and workplace closures, with enormous societal and economic costs. Here, the authors demonstrate the feasibility of a test-trace-quarantine strategy using an agent-based model and detailed data on the Seattle region.

Recent research has established a connection between hearing aid (HA) users’ cognition and speech recognition performance with short and long compression release times (RT). Contradictive findings prevent researchers from using cognition to predict RT prescription. We hypothesized that the linguistic context of speech recognition test materials was one of the factors that accounted for the inconsistency. The present study was designed to examine the relationship between HA users’ cognition and their aided speech recognition performance with short and long RTs using materials with various linguistic contexts. Thirty-four older HA users’ cognitive abilities were quantified using a reading span test. They were fitted with behind-the-ear style HAs with adjustable RT settings. Three speech recognition tests were used: the word-in-noise (WIN) test, the American four alternative auditory feature (AFAAF) test, and the Bamford-Kowal-Bench speech-in-noise (BKB-SIN) test. The results showed that HA users with high cognitive abilities performed better on the AFAAF and the BKB-SIN than those with low cognitive abilities when using short RT. None of the speech recognition tests produced significantly different performance between the two RTs for either cognitive group. These findings did not support our hypothesis. The results suggest that cognition might not be important in prescribing RT.

Abstract Background Administration of progesterone (P4) to ewes during the first 9 to 12 days of pregnancy accelerates blastocyst development by day 12 of pregnancy, likely due to P4-induced up-regulation of key genes in uterine epithelia responsible for secretion and transport of components of histotroph into the uterine lumen. This study determined if acceleration of blastocyst development induced by exogenous P4 during the pre-implantation period affects fetal-placental development on day 125 of pregnancy. Suffolk ewes (n = 35) were mated to fertile rams and assigned randomly to receive daily intramuscular injections of either corn oil vehicle (CO, n = 18) or 25 mg progesterone in CO (P4, n = 17) for the first 8 days of pregnancy. All ewes were hysterectomized on day 125 of pregnancy and: 1) fetal and placental weights and measurements were recorded; 2) endometrial and placental tissues were analyzed for the expression of candidate mRNAs involved in nutrient transport and arginine metabolism; and 3) maternal plasma, fetal plasma, allantoic fluid, and amniotic fluid were analyzed for amino acids, agmatine, polyamines, glucose, and fructose. Results Treatment of ewes with exogenous P4 did not alter fetal or placental growth, but increased amounts of aspartate and arginine in allantoic fluid and amniotic fluid, respectively. Ewes that received exogenous P4 had greater expression of mRNAs for SLC7A1, SLC7A2, SLC2A1, AGMAT, and ODC1 in endometria, as well as SLC1A4, SLC2A5, SLC2A8 and ODC1 in placentomes. In addition, AZIN2 protein was immunolocalized to uterine luminal and glandular epithelia in P4-treated ewes, whereas AZIN2 localized only to uterine luminal epithelia in CO-treated ewes. Conclusions This study revealed that exogenous P4 administered in early pregnancy influenced expression of selected genes for nutrient transporters and the expression of a protein involved in polyamine synthesis on day 125 of pregnancy, suggesting a ‘programming’ effect of P4 on gene expression that affected the composition of nutrients in fetal-placental fluids.

BackgroundThe evidence associating consumption of dairy products and risk of MS is contradictory and inconclusive.ObjectiveTo test associations between dairy consumption and the likelihood of a first clinical diagnosis of central nervous system demyelination (FCD), a common precursor to MS.MethodsWe used data from the 2003–2006 Ausimmune Study, a population-based Australian, multicentre, matched case-control study (272 cases, 519 controls). Total dairy consumption (servings/day) was calculated by summing consumption of milk, cheese and yogurt. Covariate-adjusted treatment effects using augmented inverse probability weighting was used to test for associations with FCD. We conducted sensitivity analyses in the subset of participants who had had a classic first demyelinating event (FDE), defined as a single, first episode of symptoms suggestive of CNS demyelination.ResultsThere were no statistically significant associations between total dairy consumption (per one serving/day) and FCD (adjusted OR 1.00; 95% CI 0.93, 1.07; p = 0.979). However, yogurt consumption (vs. no yogurt consumption) was associated with an 11% decreased likelihood of FDE (adjusted OR 0.89; 95% CI 0.89, 0.79; p = 0.046).ConclusionWhile total dairy consumption was not associated with FCD in this Australian case-control study, yogurt consumption was associated with reduced likelihood of FDE.

Abstract Background Administration of exogenous progesterone (P4) to ewes during the pre-implantation period advances conceptus development and implantation. This study determined effects of exogenous P4 on transport of select nutrients and pathways that enhance conceptus development. Pregnant ewes (n = 38) were treated with either 25 mg P4 in 1 mL corn oil (P4, n = 18) or 1 mL corn oil alone (CO, n = 20) from day 1.5 through day 8 of pregnancy and hysterectomized on either day 9 or day 12 of pregnancy. Endometrial expression of genes encoding enzymes for synthesis of polyamines, transporters of glucose, arginine, and glycine, as well as progestamedins was determined by RT-qPCR. Results On day 12 of pregnancy, conceptuses from P4-treated ewes had elongated while those from CO-treated ewes were spherical. The mRNA expression of AZIN2, an arginine decarboxylase, was lower in endometria of P4-treated than CO-treated ewes on day 9 of pregnancy. Expression of FGF10, a progestamedin, was greater in endometria of CO and P4-treated ewes on day 12 of gestation in addition to P4-treated ewes necropsied on day 9 of gestation. Treatment with P4 down-regulated endometrial expression of amino acid transporter SLC1A4 on day 12 of pregnancy. Conclusions Results indicated that administration of exogenous P4 during the pre-implantation period advanced the expression of FGF10, which may accelerate proliferation of trophectoderm cells, but also was correlated with decreased expression of glycine and serine transporters and polyamine synthesis enzyme AZIN2. Further research with increased sample sizes may determine how differential expression affects endometrial functions and potentially embryonic loss.

Abstract Myopia (near-sightedness) is an important public health issue. Spending more time outdoors can prevent myopia but the long-term association between this exposure and myopia has not been well characterised. We investigated the relationship between time spent outdoors in childhood, adolescence and young adulthood and risk of myopia in young adulthood. The Kidskin Young Adult Myopia Study (KYAMS) was a follow-up of the Kidskin Study, a sun exposure-intervention study of 1776 children aged 6–12 years. Myopia status was assessed in 303 (17.6%) KYAMS participants (aged 25–30 years) and several subjective and objective measures of time spent outdoors were collected in childhood (8–12 years) and adulthood. Index measures of total, childhood and recent time spent outdoors were developed using confirmatory factor analysis. Logistic regression was used to assess the association between a 0.1-unit change in the time outdoor indices and risk of myopia after adjusting for sex, education, outdoor occupation, parental myopia, parental education, ancestry and Kidskin Study intervention group. Spending more time outdoors during childhood was associated with reduced risk of myopia in young adulthood (multivariable odds ratio [OR] 0.82, 95% confidence interval [CI] 0.69, 0.98). Spending more time outdoors in later adolescence and young adulthood was associated with reduced risk of late-onset myopia (≥ 15 years of age, multivariable OR 0.79, 95% CI 0.64, 0.98). Spending more time outdoors in both childhood and adolescence was associated with less myopia in young adulthood.

Abstract Background PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort. Methods Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model. Results Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status. Limitations Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments. Conclusions Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures. Trial registration ClinicalTrials.gov Identifier NCT02461446

BackgroundA balanced approach toward sun exposure and protection is needed by young people. Excessive sun exposure increases their risk for skin cancers such as melanoma, whereas some exposure is necessary for vitamin D and healthy bones. We have developed a new iOS smartphone app—Sun Safe—through a co-design process, which aims to support healthy and balanced decision-making by young teenagers (aged 12-13 years). ObjectiveThe aim of this study was to test the capacity of Sun Safe to improve sun health knowledge and behaviors of young teenagers in 3 pilot intervention studies completed in 2020. MethodsYoung teenagers (aged 12-13 years; N=57) were recruited through the web or through a local school via an open-access website and given access to Sun Safe (29/57, 51%) or a placebo (SunDial) app (28/57, 49%). Participants completed sun health questionnaires and knowledge quizzes before and after the 6-week intervention (either on the web or in class) and rated the quality of the app they used via a survey. ResultsOf the 57 participants, 51 (89%) participants (26, 51% for placebo arm and 25, 49% for the Sun Safe arm) completed these studies, with most (>50%) reporting that they used a smartphone to access their designated app either “once a fortnight” or “once/twice in total.” Improved sun health knowledge—particularly about the UV Index—was observed in participants who were given access to Sun Safe compared with those who used the placebo (−6.2 [percentage correct] difference in predicted means, 95% CI –12.4 to –0.03; P=.049; 2-way ANOVA). Unexpectedly, there were significantly more sunburn events in the Sun Safe group (relative risk 1.7, 95% CI 1.1-1.8; P=.02; Fisher exact test), although no differences in time spent outdoors or sun-protective behaviors were reported. COVID-19 pandemic–related community-wide shutdowns during April 2020 (when schools were closed) reduced the time spent outdoors by >100 minutes per day (–105 minutes per day difference in predicted means, 95% CI –150 to –59 minutes per day; P=.002; paired 2-tailed Student t test). Sun Safe was well-rated by participants, particularly for information (mean 4.2, SD 0.6 out of 5). ConclusionsAccess to the Sun Safe app increased sun health knowledge among young teenagers in these pilot intervention studies. Further investigations with larger sample sizes are required to confirm these observations and further test the effects of Sun Safe on sun-protective behaviors.

We present a healthy adolescent male with no past surgical history who presented with acute onset abdominal pain. Cross-sectional imaging was concerning for possible ileocecal intussusception, and repeat imaging demonstrated an internal hernia. The patient was taken to the operating room for exploration. He was discovered to have an ileocecal intussusception with a large cecal mass, as well as a left paraduodenal hernia. Closure of the mesenteric defect and ileocecectomy with primary anastomosis were performed. Pathology of the mass was consistent with colonic lipoma. Postoperatively, he had slow return of bowel function, but his recovery was otherwise uncomplicated. This case reports a rare presentation of concomitant ileocecal intussusception due to a cecal lipoma and congenital internal hernia. Intussusception in the pediatric population is typically idiopathic, and intussusception with a pathologic lead point is far more common in adults. Gastrointestinal lipomas are also uncommon in pediatric patients, and when discovered are generally small and asymptomatic. Internal hernias most commonly are due to acquired mesenteric defects or adhesive disease, though may present congenitally as seen in this patient. This case is unique because of the simultaneous occurrence of two separate surgical problems, both with atypical etiologies based on patient history and demographics.

Abstract Objective To determine whether serum neurofilament light chain (sNfL) levels are suppressed in patients with the clinically isolated syndrome (CIS) following narrowband ultraviolet B phototherapy (UVB‐PT). Methods sNfL levels were measured using a sensitive single‐molecule array assay at baseline and up to 12 months in 17 patients with CIS, 10 of whom received UVB‐PT, and were compared with healthy control (HC) and early relapsing remitting multiple sclerosis (RRMS) group. sNfL levels were correlated with magnetic resonance imaging total lesion volume (LV) determined using icobrain version 4.4.1 and with clinical outcomes. Results Baseline median sNfL levels were significantly higher in the CIS (20.6 pg/mL, interquartile range [IQR] 13.7–161.4) and RRMS groups (36.6 pg/ml [IQR] 16.2–212.2) than in HC (10.7 pg/ml [IQR] 4.9–21.5) (p = .012 and p = .0002, respectively), and were strongly correlated with T2 and T1 LV at 12 months (r = .800; p = .014 and r = .833; p = .008, respectively) in the CIS group. Analysis of changes in sNfL levels over time in the CIS group showed a significant cumulative suppressive effect of UVB‐PT in the first 3 months (UVB‐PT −10.6% vs non‐UVB‐PT +58.3%; p = .04) following which the levels in the two groups converged and continued to fall. Conclusions Our findings provide the basis for further studies to determine the utility of sNfL levels as a marker of neuro‐axonal damage in CIS and early MS and for assessing the efficacy of new therapeutic interventions such as UVB‐PT.

Background: In its severest form, non-accidental injury (NAI) in children is fatal. South Africa has been reported to have double the global average of child homicides. Autopsy is the main investigation in fatal NAI with post-mortem skeletal surveys (PMSS) playing an adjunctive role. Whilst fracture patterns associated with NAI in living patients have been established, this has not been investigated in PMSS in South Africa. Objectives: To determine the incidence and characteristics of fractures in suspected fatal NAI cases. To calculate the incidence of fractures according to high-, moderate- and low-specificity fracture locations for NAI. Methods: A retrospective review of all PMSS performed between 01 January 2012 and 03 December 2018 was conducted at the Charlotte Maxeke Johannesburg Academic Hospital. Results: Of the 73 PMSS, 33 (45.2%) demonstrated fractures. No statistical significance in sex was found: 38 (52.1%) were male and 35 (47.9%) were female (p 0.05). The mean age of those who sustained fractures was 28 months (standard deviation [s.d.]: 21 months). A total of 115 fractures were sustained, of that the top five bones fractured were the ribs 37 (32.2%), parietal bone 13 (11.3%), ulna 13 (11.3%), femur 13 (11.3%), and radius 11 (9.6%). High-specificity fracture locations accounted for 40/133 (30.1%). Conclusion: The fracture types in PMSS were similar to those in live skeletal surveys. Our study’s fracture rate was higher in comparison to international studies. The PMSS is a valuable adjunct to autopsy in detecting occult fractures of the limbs. We recommend that PMSS be performed in suspected fatal NAI cases at least in children up to 24 months of age.