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Abstract Activation-induced cytidine deaminase (AID) is a B cell-specific mutator required for antibody diversification. However, it is also implicated in the etiology of several B cell malignancies. Evaluating the AID-induced mutation load in patients at-risk for certain blood cancers is critical in assessing disease severity and treatment options. We have developed a digital PCR (dPCR) assay that allows us to quantify mutations resulting from AID modification or DNA double-strand break (DSB) formation and repair at sites known to be prone to DSBs. Implementation of this assay shows that increased AID levels in immature B cells increase genome instability at loci linked to chromosomal translocation formation. This includes the CRLF2 locus that is often involved in translocations associated with a subtype of acute lymphoblastic leukemia (ALL) that disproportionately affects Hispanics, particularly those with Latin American ancestry. Using dPCR, we characterize the CRLF2 locus in B cell-derived genomic DNA from both Hispanic ALL patients and healthy Hispanic donors and found increased mutations in both, suggesting that vulnerability to DNA damage at CRLF2 may be driving this health disparity. Our ability to detect and quantify these mutations will potentiate future risk identification, early detection of cancers, and reduction of associated cancer health disparities.

Assessment is a key driver for engagement and a widely criticised aspect of the tertiary student experience. In regard to assessment, in particular, feedback, rubrics and peer review have been major focuses for researchers in recent years. This research utilised an innovative peer review process in a triad structure to evaluate and improve assessment rubrics in a business course at a regional university in Australia. Data from interviews with academics and students was analysed using a recognised 10 question framework to evaluate the quality of the rubrics used in the course. The results indicated the 10 question framework was a useful tool to evaluate the quality of the rubrics. In addition, the process of peer review of assessment artefacts, in a triad structure improved assessment literacies of the participating academics, improved accountability evidence, and led to greater staff and student satisfaction due to improved assessment experiences. This research contributes to new knowledge due to its focuses on assessment rubrics, the efficacy of the 10 question framework as a reviewing mechanism and the use of academic triads to review assessment and not teaching performance.

Research questionTalent transfer, an accelerated sport pathway to expertise, holds considerable appeal for sports organisations. As an emerging area of academic research across a range of sport disciplines, there is opportunity for to advance knowledge and practice. This review aimed to (a) explore how talent transfer has been defined, to develop a synthesised definition; (b) systematically identify the factors that influence talent transfer; and (c) investigate how theory underpins and enhances understanding of talent transfer.Research methodsA systematic review was conducted of 12 peer-reviewed journal articles on talent transfer using the PRISMA approach.Results and findingsAiming for a comprehensive, multidisciplinary perspective, the results: introduce a clear, synthesised conceptualisation of talent transfer as an accelerated sport pathway in which a highly trained athlete in one sport (donor sport), transitions to a new sport (recipient sport) with the potential of achieving high-performance success; systematically map influencing factors; and outline considered theories. Factors influencing talent transfer span individual, task-related, and environmental constraints. The review exposes a scarcity of theoretical foundation in current research, suggesting ecological dynamics as a promising approach to advance research and practice.ImplicationsPractical and theoretical implications arise, emphasising the usefulness of a synthesised definition and a multifactorial approach for designing, implementing, evaluating, and researching talent transfer pathways. This benefits sports administrators, managers, and researchers.

Background: Patients living with chronic obstructive pulmonary disease (COPD) are at risk for lower respiratory tract infections caused by respiratory syncytial virus (RSV). The first RSV vaccines were approved in 2023 for adults ages 60 years and older. The safety and efficacy of the RSV vaccines and their clinical implications in patients living with COPD, apart from composite comorbidity results, are under-reported. Methods: This rapid review aimed to collect and report data pertaining to RSV vaccine safety and efficacy in patients living with COPD. Resources searched included Ovid MEDLINE, EMBASE, International Pharmaceutical Abstracts, published peer-reviewed abstracts, ClinicalTrials.gov, and the United States Food and Drug Administration (FDA) website. Results: Seven records were included: five research manuscripts and two ongoing clinical trials. Patients living with COPD were included in RSV vaccine clinical trials, but outcomes of RSV vaccine safety and efficacy in patients living with COPD were grossly unreported. Conclusions: Future clinical trials of patients living with COPD and subgroup analyses of patients living with COPD within existing studies evaluating RSV vaccine safety and efficacy are necessary to substantiate outcomes in this population.

Abstract Glycemic variability remains frequent in patients with type 1 diabetes treated with insulin pumps. Heterogeneous spreads of insulin infused by pump in the subcutaneous (SC) tissue are suspected but were barely studied. We propose a new real-time ex-vivo method built by combining high-precision imaging with simultaneous pressure measurements, to obtain a real-time follow-up of insulin subcutaneous propagation. Human skin explants from post-bariatric surgery are imaged in a micro-computed tomography scanner, with optimised parameters to reach one 3D image every 5 min during 3 h of 1UI/h infusion. Pressure inside the tubing is recorded. A new index of dispersion (IoD) is introduced and computed upon the segmented 3D insulin depot per time-step. Infusions were hypodermal in 58.3% among 24 assays, others being intradermal or extradermal. Several minor bubbles and one occlusion were observed. IoD increases with time for all injections. Inter-assay variability is the smallest for hypodermal infusions. Pressure elevations were observed, synchronised with air bubbles arrivals in the tissue. Results encourage the use of this method to compare infusion parameters such as pump model, basal rate, catheter characteristics, infusion site characteristics or patient phenotype.

Vincent Q Pham,1 Hannah M Miller,2 Elise O Fernandez,3 Daniel de Marchi,4 Hongtu Zhu,4 David Fleischman2 1Northeast Ohio Medical University, Rootstown, OH, USA; 2Department of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA; 3School of Medicine, University of North Carolina, Chapel Hill, NC, USA; 4Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USACorrespondence: David Fleischman, Department of Ophthalmology, University of North Carolina, 5126 Bioinformatics Bldg #7040, Chapel Hill, NC, 27599-7040, USA, Tel +1 919 966-5296, Fax +1 919 966-1908, Email david8fleischman@gmail.comPurpose: Falls are associated with ocular trauma in the elderly. However, it is unlikely for a fall to cause ocular injury unless there is a disruption in the protective maneuvers that shield the face. We suspect ocular injury may be an early indicator of systemic or neurologic degeneration. This study investigates the 5-year incidence of cardiovascular and neurodegenerative diseases in older patients who sustained ocular or periorbital injuries.Patients and Methods: This was a retrospective cohort study. The study population included 141 patients over the age of 65 who sustained trauma to the eye, orbit, or eyelid between April 2011 and June 2016. The control population included 141 patients with a similar range of comorbidities who received cataract surgery during the same period. The study measured new diagnoses of various disorders during the 5-year period following presentation.Results: There were a total of 180 females and 102 males in the study. The mean ages of the control and subject group were 76 and 81.8, respectively. Of our twelve tested comorbidity types, patients that suffered a periocular trauma were more likely to develop heart failure (p=0.00244), dementia (p=0.00002), Alzheimer’s disease (p=0.00087), and vascular disease (p=0.00037).Conclusion: Geriatric patients who sustained ocular and periocular injuries had a greater incidence of heart failure, dementia, Alzheimer’s disease, and atherosclerosis diagnoses in the 5-year period following injury. The findings of this study suggest that periocular trauma may be an early indicator of underlying degenerative or systemic disease. Ophthalmologists should ensure proper primary care follow-up in conjunction with recovery from injury.Keywords: ocular injury, comorbidities, eye injury, degenerative disease

Abstract Purpose: This study aimed to evaluate the effect of intraoperative positioning and ocular immobility on the amount of cerebrospinal fluid around the optic nerve in patients undergoing prone spinal surgery by measuring the optic nerve sheath diameter (ONSD) using ultrasound. Methods: Consecutive participants (n = 15 patients, 30 eyes) were scanned preoperatively, intraoperatively approximately 20 minutes before the end of the surgery, and postoperatively in the post-anesthesia care unit at least 10 min after the completion of the surgery at one academic hospital. Results: On average, patients who underwent prone spinal surgery had a 21% increase in ONSD intraoperatively, with a positive time-dependent relationship with the overall length of surgery (P < 0.001). ONSDs postoperatively returned to baseline and were not significantly different from preoperative measurements. Conclusion: Our findings suggest pooling and inadequate clearance of perioptic cerebrospinal fluid during prone spinal surgery that improves following termination of the procedure and return of the patient to an upright position.

Talent transfer has enabled elite athletes to be successful in another sport, with great potential in para-sport. Previous research suggests that similarities between donor and recipient sports may facilitate talent transfer; however, this remains unclear in para-sport. This study investigated patterns between donor and recipient sports' characteristics, identifying the impact on talent transfer in para-sport. An Australian case study utilizing secondary data of 38 Australian Paralympians who competed at the Paralympic Games from 2000 through 2020 was analyzed. Results demonstrated that similarities between sports were not significantly associated with successful talent transfers between Paralympic sports. Understanding patterns associated with successful Paralympic talent transfers offers a foundation of knowledge for designing and developing future talent-transfer pathways and research. Based on this study, it is recommended that sport administrators and practitioners explore greater opportunity for talent transfer in para-sport, rather than limiting talent-transfer opportunities based on athletes' donor sports. [ABSTRACT FROM AUTHOR]

Purpose: To present a novel characterization of a lens condition termed macrophakia which includes large or proportionally large lenses with shallow anterior chamber dimensions that are statistically deviant of a normal population. Observations: We identified five eyes from three cases to have significantly large lens parameters and small anterior chamber depths. In all five eyes, the anterior chamber depth was less than 2 mm and the anterior chamber depth to lens thickness ratio was two standard deviations outside the normative range of lens and chamber measurements. These large lenses were all observed in the absence of typical pathology and other biometric abnormalities. Conclusions and importance: A novel lens characterization termed macrophakia is proposed to describe large or proportionately large lenses. Naming this condition is clinically relevant and will enhance cataract evaluations and patient education.

Abstract Here we show that striated muscle preferentially expressed protein kinase α (Spegα) maintains cardiac function in hearts with Spegβ deficiency. Speg is required for stability of excitation-contraction coupling (ECC) complexes and interacts with esterase D (Esd), Cardiomyopathy-Associated Protein 5 (Cmya5), and Fibronectin Type III and SPRY Domain Containing 2 (Fsd2) in cardiac and skeletal muscle. Mice with a sequence encoding a V5/HA tag inserted into the first exon of the Speg gene (HA-Speg mice) display a >90% decrease in Spegβ but Spegα is expressed at ~50% of normal levels. Mice deficient in both Spegα and Speg β (Speg KO mice) develop a severe dilated cardiomyopathy and muscle weakness and atrophy, but HA-Speg mice display mild muscle weakness with no cardiac involvement. Spegα in HA-Speg mice suppresses Ca2+ leak, proteolytic cleavage of Jph2, and disruption of transverse tubules. Despite it’s low levels, HA-Spegβ immunoprecipitation identified Esd, Cmya5 and Fsd2 as Spegβ binding partners that localize to triads and dyads to stabilize ECC complexes. This study suggests that Spegα and Spegβ display functional redundancy, identifies Esd, Cmya5 and Fsd2 as components of both cardiac dyads and skeletal muscle triads and lays the groundwork for the identification of new therapeutic targets for centronuclear myopathy.

BackgroundThis study will pilot-test an innovative just-in-time adaptive intervention to reduce severe respiratory illness among children with severe cerebral palsy (CP). Our intervention program, Respiratory Exacerbation–Plans for Action and Care Transitions (RE-PACT), delivers timely customized action planning and rapid clinical response when hospitalization risk is elevated. ObjectiveThis study aims to establish RE-PACT’s feasibility, acceptability, and fidelity in up to 90 children with severe CP. An additional aim is to preliminarily estimate RE-PACT’s effect size. MethodsThe study will recruit up to 90 caregivers of children with severe CP aged 0 to 17 years who are cared for by a respiratory specialist or are receiving daily respiratory treatments. Participants will be recruited from pediatric complex care programs at the University of Wisconsin–Madison (UW) and the University of California, Los Angeles (UCLA). Study participants will be randomly assigned to receive usual care through the complex care clinical program at UW or UCLA or the study intervention, RE-PACT. The intervention involves action planning, rapid clinical response to prevent and manage respiratory illness, and weekly SMS text messaging surveillance of caregiver confidence for their child to avoid hospitalization. RE-PACT will be run through 3 successively larger 6-month trial waves, allowing ongoing protocol refinement according to prespecified definitions of success for measures of feasibility, acceptability, and fidelity. The feasibility measures include recruitment and intervention time. The acceptability measures include recruitment and completion rates as well as intervention satisfaction. The fidelity measures include observed versus expected rates of intervention and data collection activities. The primary clinical outcome is a severe respiratory illness, defined as a respiratory diagnosis requiring hospitalization. The secondary clinical outcomes include hospital days and emergency department visits, systemic steroid courses, systemic antibiotic courses, and death from severe respiratory illness. ResultsThe recruitment of the first wave began on April 27, 2022. To date, we have enrolled 30 (33%) out of 90 participants, as projected. The final wave of recruitment will end by October 31, 2023, and the final participant will complete the study by April 30, 2024. We will start analyzing the complete responses by April 30, 2024, and the publication of results is expected at the end of 2024. ConclusionsThis pilot intervention, using adaptive just-in-time strategies, represents a novel approach to reducing the incidence of significant respiratory illness for children with severe CP. This protocol may be helpful to other researchers and health care providers caring for patients at high risk for acute severe illness exacerbations. Trial RegistrationClinicalTrials.gov NCT05292365; https://clinicaltrials.gov/study/NCT05292365 International Registered Report Identifier (IRRID)DERR1-10.2196/49705

The STABILISE (stent-assisted balloon-induced intimal disruption and relamination in aortic dissection repair) technique has shown promising results for treating type B aortic dissections, but the potential exists for fatal adverse effects. We present a case of infrarenal aortic rupture while using a compliant balloon to balloon mold the true lumen inside previously placed bare metal stents during the STABILISE technique. Caution is advised for providers who wish to perform the STABILISE technique, and we recommend using a semi-compliant balloon sized to the smallest total aortic diameter to mitigate the risk of rupture.

ABSTRACTMyeloproliferative neoplasms (MPNs) are a class of rare hematological malignancies that result in the overproduction of myeloid lineage cells. These malignancies result in increased cytokine production and inflammation, which correlate with worsened symptom burden and prognosis. Other than bone marrow transplantation, there is no cure for myeloproliferative neoplasms. As such, treatments focus on reducing thrombotic risk, inflammation, and symptom burden. Because current pharmacological treatments carry significant side effects, there is a need to explore low-risk therapies that may modulate inflammation and alleviate symptom burden. One potential way to achieve this is adherence to a Mediterranean (MED) diet, which is rich in anti-inflammatory foods, reduces inflammatory biomarkers, and beneficially alters the gut microbiome. We performed a 15-week clinical trial of 28 individuals with MPN who were randomized to dietary counseling based on either a Mediterranean diet or standard U.S. Guidelines for Americans. Our primary objective was to determine whether MPN patients could adopt a Mediterranean eating pattern when supported with dietician counseling. As exploratory endpoints, we investigated the impact of diet and inflammation on the gut microbiome. Using shotgun metagenomic sequencing, we found that microbiome diversity and composition were stable throughout the study duration in both cohorts. Furthermore, we discovered significant differences in the microbiomes between MPN subtypes, such as increased beta-dispersion in subjects with myelofibrosis. Lastly, we found several significant correlations between the abundance of multiple bacterial taxa and cytokine levels. Together, this study provides insight into the interaction between diet, inflammation, and the gut microbiome.IMPORTANCEThe gut microbiome serves as an interface between the host and the diet. Diet and the gut microbiome both play important roles in managing inflammation, which is a key aspect of myeloproliferative neoplasm (MPN). Studies have shown that a Mediterranean (MED) diet can reduce inflammation. Therefore, we longitudinally characterized the gut microbiomes of MPN patients in response to Mediterranean or standard 2020 US Guidelines for Americans dietary counseling to determine whether there were microbiome-associated changes in inflammation. We did not find significant changes in the gut microbiome associated with diet, but we did find several associations with inflammation. This research paves the way for future studies by identifying potential mechanistic targets implicated in inflammation within the MPN gut microbiome.

Subclavian artery coverage is frequently required to achieve an adequate proximal seal during thoracic endovascular aortic repair. The thoracic branch endoprosthesis (TBE; W.L. Gore & Associates) is the first U.S. Food and Drug Administration–approved branched device for thoracic endovascular aortic repair, designed for left subclavian artery incorporation. However, anatomic suitability of the TBE has been shown to be limited. In the present report, we describe a novel technique using the TBE in a sandwich periscope configuration to allow for emergent repair of a ruptured thoracic aortic aneurysm with a highly angulated proximal seal zone and aberrant right subclavian artery.

Abstract In vitro ovarian follicle culture is a new frontier in assisted reproductive technology with tremendous potential, especially for fertility preservation. Folliculogenesis within the ovary is a complex process requiring interaction between somatic cell components and the oocyte. Conventional two-dimensional culture on tissue culture substrata impedes spherical growth and preservation of the spatial arrangements between oocyte and surrounding granulosa cells. Granulosa cell attachment and migration can leave the oocyte naked and unable to complete the maturation process. Recognition of the importance of spatial arrangements between cells has spurred research in to three-dimensional culture system. Such systems may be vital when dealing with human primordial follicles that may require as long as three months in culture. In the present work we review pertinent aspects of in vitro follicle maturation, with an emphasis on tissue-engineering solutions for maintaining the follicular unit during the culture interval. We focus primarily on presenting the various 3-dimensional culture systems that have been applied for in vitro maturation of follicle:oocyte complexes. We also try to present an overview of outcomes with various biomaterials and animal models and also the limitations of the existing systems.

Abstract Body-worn sensors (BWS) could provide valuable information in the management of Parkinson’s disease and support therapeutic decisions based on objective monitoring. To study this pivotal step and better understand how relevant information is extracted from BWS results and translated into treatment adaptation, eight neurologists examined eight virtual cases composed of basic patient profiles and their BWS monitoring results. Sixty-four interpretations of monitoring results and the subsequent therapeutic decisions were collected. Relationship between interrater agreements in the BWS reading and the severity of symptoms were analyzed via correlation studies. Logistic regression was used to identify associations between the BWS parameters and suggested treatment modifications. Interrater agreements were high and significantly associated with the BWS scores. Summarized BWS scores reflecting bradykinesia, dyskinesia, and tremor predicted the direction of treatment modifications. Our results suggest that monitoring information is robustly linked to treatment adaptation and pave the way to loop systems able to automatically propose treatment modifications from BWS recordings information.

Abstract Non-compliance to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy can result in increased disease activity in neovascular age-related macular degeneration (nAMD). Our study aims to determine effects of unplanned delay in anti-VEGF injection treatment for nAMD. This retrospective observational study included patients with delays in receiving intravitreal injections for nAMD treatment from March to May 2020 by at least 21 days. Baseline demographic and clinical characteristics, visual acuity (VA), central macular thickness (CMT) measured on optical coherence tomography (OCT), and duration of delayed treatment were analyzed for 3 time points, the pre-delay visit (v1) and post-delay visits (v2 and v3). Data were compared to age-matched controls treated for nAMD in 2019 without delay. Demographic characteristics were compared using two-sample t-tests for continuous variables and Pearson’s chi-square tests for categorical variables. For the two primary outcomes of interest, VA and CMT, means and standard deviations were reported for each combination of group and time. Each outcome was modeled using a linear mixed model with the group, time and group-time interaction as fixed effects. A total of 69 patients (99 eyes) in the treatment delay group and 44 patients (69 eyes) in the control group were identified. Statistically significant differences between control and delayed groups were detected for VA (difference in mean logMAR = 0.16; 95% CI 0.06, 0.27; p = 0.002) and CMT (difference in mean CMT = 29; 95% CI 12, 47; p = 0.001) at v2. No differences were detected for v1 and v3 time points for both outcomes. An unplanned delay in intravitreal injection treatment for nAMD resulted in an increase in CMT and worsening of VA compared to controls observed at v2. At v3, CMT and VA recovered to near v1 levels. This study demonstrates that a one-time, brief interruption in treatment for nAMD results in reversible, temporary worsening.

In recent years, governments and international organizations have initiated numerous large-scale tree planting projects with the dual goals of restoring landscapes and supporting rural livelihoods. However, there remains a need for greater knowledge of drivers and conditions that enable positive social and environmental outcomes over the long term. In this study, we used interpretable machine learning (IML) to explore win–win and win–lose outcomes between livelihood benefits and forest cover using four decades of tree plantation data from northern India. Our results indicated that, in areas with a larger population of socioeconomically marginalized groups, moderate levels of education, and existing histories of community collective action, there is a higher probability of achieving joint positive outcomes. We also found that joint positive outcomes are more common within a consolidated local institutional space, suggesting that decentralized governance structures with cross-sectoral duties and functions may be better equipped to mediate conflicts between intersecting forest and land use challenges. Finally, our findings showed that non-forestry and anti-poverty interventions such as universal labor generation programs and universal education are associated with improved forest cover alongside livelihood benefits from plantations. Whereas contemporary policy discussions have given substantial attention to tree plantation schemes, our work suggests that effective restoration requires much more than planting alone. A broad mixture of socioeconomic, institutional, and policy interventions is needed to create favorable conditions for long-term success. In particular, anti-poverty programs may serve as important indirect policy pathways for ensuring restoration gains.

Objective: Cardiorespiratory fitness (CRF) is tightly linked with health and longevity and is implicated in metabolic flexibility and substrate metabolism. The high capacity runner (HCR) and low capacity runner (LCR) rat lines are a genetically heterogeneous rat model selected and bred for CRF that reflect CRF in humans by exhibiting differences in nutrient handling. This study aims to differentiate the intrinsic substrate preference of the HCR compared to LCR rats to better understand the intersection of mitochondrial respiration and intrinsic CRF. Methods: We performed bulk skeletal muscle RNA-Sequencing on male and female HCR and LCR rats and assessed the effect of rat line on mitochondrial gene expression pathways using the MitoCarta3.0 database. In a separate cohort of rats, mitochondria were isolated from skeletal and cardiac muscle and maximal oxidation rates were measured using an Oroboros O2k when provided either pyruvate or fatty acid substrates. Results: The expression of mitochondrial genes are significantly upregulated in HCR skeletal muscle in both male and female rats. In respirometry experiments, fatty acid oxidative capacities were greater in HCR compared to LCR, and male compared to female rats, as a function of both mitochondrial quality and mitochondrial density. This effect was greater in the skeletal muscle than in the heart. Pyruvate oxidation did not differ significantly between lines. Conclusions: The capacity for increased fatty acid oxidation in the HCR rat is a result of selection for running capacity and is likely a key contributor to the healthy metabolic phenotype of individuals with high CRF.