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eSports is a newly rising field with rapidly increasing cultural validity. Despite the wide array of similarities between eSports and traditional sports, behavioral skill acquisition interventions have yet to be applied to video game skills. Although video feedback has been established as effective for traditional sports, further research is needed to validate its efficacy as a standalone intervention. In this study, the effects of video feedback were analyzed with three participants in a nonconcurrent multiple baseline across subjects design. Participants performed a specific in‐game behavior (an anti‐air attack) in a controlled match against the researcher, then viewed recordings of their performance and received positive and corrective feedback from the researchers. The generalization of the skill improvement was evaluated through the rate of successful skill implementation in ranked online matches. Results showed that the video feedback intervention improved performance over baseline for all participants and generalized to online matches. [ABSTRACT FROM AUTHOR]

Introduction: Adolescent girls and young women (AGYW) who may benefit from HIV pre‐exposure prophylaxis (PrEP) face high levels of common mental disorders (e.g. depression, anxiety). Common mental disorders can reduce PrEP adherence and increase HIV risk, yet mental health interventions have not been well‐integrated into PrEP delivery. Methods: We conducted a four‐phase human‐centred design process, from December 2020 to April 2022, to understand mental health challenges among AGYW in Johannesburg, South Africa and barriers to integrated mental health and PrEP services. In the "Discover" phase, we conducted in‐depth interviews with AGYW and key informants (KIs) in Johannesburg. We conducted a rapid qualitative analysis, informed by the Consolidated Framework for Implementation Research (CFIR), to identify facilitators and barriers of integrated mental health and PrEP services and mapped barriers to potential implementation strategies. In the "Design" and "Build" phases, we conducted stakeholder workshops to iteratively adapt an evidence‐based mental health intervention, the Friendship Bench, and refine implementation strategies for South African PrEP delivery settings. In the "Test" phase, we piloted our adapted Friendship Bench package. Results: Interviews with 70 Discover phase participants (48 AGYW, 22 KIs) revealed the importance of integrated mental health and PrEP services for South African AGYW. Interviewees described barriers and implementation strategies for mental health and PrEP services around the CFIR domains: intervention characteristics (e.g. challenges with AGYW "opening up"); outer Johannesburg setting (e.g. community stigma); inner clinic setting (e.g. judgemental healthcare providers); characteristics of counsellors (e.g. training gaps); and the implementation process (e.g. need for demand creation). The Design and Build workshops included 13 AGYW and 15 KIs. Implementation barriers related to the quality and accessibility of public‐sector clinic services, lay counsellor training, and community education and demand creation activities were prioritized. This led to 12 key Friendship Bench adaptations and the specification of 10 implementation strategies that were acceptable and feasible in initial pilot testing with three AGYW. Conclusions: Using a human‐centred approach, we identified determinants and potential solutions for integrating mental health interventions within PrEP services for South African AGYW. This design process centred stakeholders' perspectives, enabling rapid development of an adapted Friendship Bench intervention implementation package. [ABSTRACT FROM AUTHOR]

Introduction: Advanced therapies offer unprecedented opportunities for treating rare neurological disorders (RNDs) in children. However, health literacy, perceptions and understanding of novel therapies need elucidation across the RND community. This study explored healthcare professionals' and carers' perspectives of advanced therapies in childhood‐onset RNDs. Methods: In this mixed‐methodology cross‐sectional study, 20 healthcare professionals (clinicians, genetic counsellors and scientists) and 20 carers completed qualitative semistructured interviews and custom‐designed surveys. Carers undertook validated psychosocial questionnaires. Thematic and quantitative data analysis followed. Results: Participants described high positive interest in advanced therapies, but low knowledge of, and access to, reliable information. The substantial 'therapeutic gap' and 'therapeutic odyssey' common to RNDs were recognised in five key themes: (i) unmet need and urgency for access; (ii) seeking information; (iii) access, equity and sustainability; (iv) a multidisciplinary and integrated approach to care and support and (v) difficult decision‐making. Participants were motivated to intensify RND clinical trial activity and access to advanced therapies; however, concerns around informed consent, first‐in‐human trials and clinical trial procedures were evident. There was high‐risk tolerance despite substantial uncertainties and knowledge gaps. RNDs with high mortality, increased functional burdens and no alternative therapies were consistently prioritised for the development of advanced therapies. However, little consensus existed on prioritisation to treatment access. Conclusions: This study highlights the need to increase clinician and health system readiness for the clinical translation of advanced therapeutics for RNDs. Co‐development and use of educational and psychosocial resources to support clinical decision‐making, set therapeutic expectations and promotion of equitable, effective and safe delivery of advanced therapies are essential. Patient or Public Contribution: Participant insights into the psychosocial burden and information need to enhance the delivery of care in this formative study are informing ongoing partnerships with families, including co‐production and dissemination of psychoeducational resources featuring their voices hosted on the Sydney Children's Hospitals Network website SCHN Brain-Aid Resources. [ABSTRACT FROM AUTHOR]

Kidney transplantation is the most successful kidney replacement therapy available, resulting in improved recipient survival and societal cost savings. Yet, nearly 70 years after the first successful kidney transplant, there are still numerous barriers and untapped opportunities that constrain the access to transplant. The literature describing these barriers is extensive, but the practices and processes to solve them are less clear. Solutions must be multidisciplinary and be the product of strong partnerships among patients, their networks, health care providers, and transplant programs. Transparency in the referral, evaluation, and listing process as well as organ selection are paramount to build such partnerships. Providing early culturally congruent and patient‐centered education as well as maximizing the use of local resources to facilitate the transplant work up should be prioritized. Every opportunity to facilitate pre‐emptive kidney transplantation and living donation must be taken. Promoting the use of telemedicine and kidney paired donation as standards of care can positively impact the work up completion and maximize the chances of a living donor kidney transplant. [ABSTRACT FROM AUTHOR]

Objective: The study objective was to investigate the effect of cold exposure on the plasma levels of five potential human brown adipokines (chemokine ligand 14 [CXCL14], growth differentiation factor 15 [GDF15], fibroblast growth factor 21 [FGF21], interleukin 6 [IL6], and bone morphogenic protein 8b [BMP8b]) and to study whether such cold‐induced effects are related to brown adipose tissue (BAT) volume, activity, or radiodensity in young humans. Methods: Plasma levels of brown adipokines were measured before and 1 h and 2 h after starting an individualized cold exposure in 30 young adults (60% women, 21.9 ± 2.3 y; 24.9 ± 5.1 kg/m2). BAT volume, 18F‐fluorodeoxyglucose uptake, and radiodensity were assessed by a static positron emission tomography‐computerized tomography scan after cold exposure. Results: Cold exposure increased the concentration of CXCL14 (Δ2h = 0.58 ± 0.98 ng/mL; p = 0.007), GDF15 (Δ2h = 19.63 ± 46.2 pg/mL; p = 0.013), FGF21 (Δ2h = 33.72 ± 55.13 pg/mL; p = 0.003), and IL6 (Δ1h = 1.98 ± 3.56 pg/mL; p = 0.048) and reduced BMP8b (Δ2h = −37.12 ± 83.53 pg/mL; p = 0.022). The cold‐induced increase in plasma FGF21 was positively associated with BAT volume (Δ2h: β = 0.456; R2 = 0.307; p = 0.001), but not with 18F‐fluorodeoxyglucose uptake or radiodensity. None of the changes in the other studied brown adipokines was related to BAT volume, activity, or radiodensity. Conclusions: Cold exposure modulates plasma levels of several potential brown adipokines in humans, whereas only cold‐induced changes in FGF21 levels are associated with BAT volume. These findings suggest that human BAT might contribute to the circulatory pool of FGF21. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a 64-year-old female kidney transplant recipient who developed a lung mass. The patient had received immunosuppressive medications and prophylactic antibiotics following the transplant. After presenting with weight loss, fever, and cough, the patient was diagnosed with Nocardia nova infection. Treatment with antibiotics led to significant improvement in the patient's condition. The article emphasizes the importance of considering Nocardia infection in immunocompromised patients and highlights the role of CT imaging in diagnosing and managing the condition. [Extracted from the article]

Introduction: Utilization of hepatitis C viremic (HCV+) deceased donor kidneys (DDKT) for aviremic recipients increases opportunities for transplantation with excellent short‐term outcomes. Our primary aim was to understand longer‐term outcomes, specifically assessing kidney and liver function in the first year posttransplant. Methods: This was a retrospective single‐center study of adult DDKT recipients of HCV+ kidneys (cases) matched 1:1 to recipients of HCV‐ kidneys (comparators). Between‐group outcomes were analyzed using comparisons of means and proportions, survival analysis methods, and multivariable mixed effects models. Results: Sixty‐five cases and 65 comparators had statistically comparable demographic and clinical characteristics. There were no between‐group differences in serum creatinine or estimated glomerular filtration rate at month 12 (p =.662) or in their trajectories over months 1–12 (p >.292). Within the first 60 days, rates of liver function values >3 times upper limit of normal among cases were comparable to comparators for aspartate aminotransferase (AST) (14% vs. 6%, p =.242) and higher for alanine transaminase (ALT) (23% vs. 6%, p =.011). AST declined during the first 8 weeks (p =.005) and stabilized for both groups (p =.406) during the following 10 months. ALT declined during the first 8 weeks (p <.001), continued to decline over months 3–12 (p =.016), and the trajectory was unrelated to antiviral therapy initiation among cases. Conclusions: Aviremic recipients of HCV+ kidneys had comparable kidney outcomes to matched recipients of HCV‐ kidneys. Despite more HCV+ recipients having an elevation in ALT within the first 60 days, ALT values normalized with no identified liver complications attributed to HCV. [ABSTRACT FROM AUTHOR]

Proteoglycans are core proteins associated with carbohydrate/sugar moieties that are highly variable in disaccharide composition, which dictates their function. These carbohydrates are named glycosaminoglycans, and they can be attached to proteoglycans or found free in tissues or on cell surfaces. Glycosaminoglycans such as hyaluronan, chondroitin sulfate, dermatan sulfate, keratan sulfate, and heparin/heparan sulfate have multiple functions including involvement in inflammation, immunity and connective tissue structure, and integrity. Heparan sulfate is a highly sulfated polysaccharide that is abundant in the periodontium including alveolar bone. Recent evidence supports the contention that heparan sulfate is an important player in modulating interactions between damage associated molecular patterns and inflammatory receptors expressed by various cell types. The structure of heparan sulfate is reported to dictate its function, thus, the utilization of a homogenous and structurally defined heparan sulfate polysaccharide for modulation of cell function offers therapeutic potential. Recently, a chemoenzymatic approach was developed to allow production of many structurally defined heparan sulfate carbohydrates. These oligosaccharides have been studied in various pathological inflammatory conditions to better understand their function and their potential application in promoting tissue homeostasis. We have observed that specific size and sulfation patterns can modulate inflammation and promote tissue maintenance including an anabolic effect in alveolar bone. Thus, new evidence provides a strong impetus to explore heparan sulfate as a potential novel therapeutic agent to treat periodontitis, support alveolar bone maintenance, and promote bone formation. [ABSTRACT FROM AUTHOR]

Hepatitis B remains a public health problem worldwide despite vaccine availability. Although the existing diagnostic tools help detect the infection, logistics support and limited resources and technologies affect their usefulness and reliability in developing countries. This systematic review evaluated the performance of dried blood spots (DBS) as a collection and storage tool for diagnosing an hepatitis B virus (HBV) infection. A comprehensive search using OVID, Scopus and CINAHL databases was performed to collate articles published up to April 2023 that detected Hepatitis B infections using DBS. Five reviewers independently performed identification, screening, quality assessment and data extraction. A qualitative synthesis of the included studies was conducted. Of the 402 articles, 78 met the inclusion criteria. The results show that most studies focused on populations with known HBV, HCV and/or HIV status. Approximately half (49%) of the included studies utilized the Whatman Protein Saver Card for DBS collection. The DBS samples were then predominantly stored in room temperature conditions. In line with this, storage conditions influenced the concentration and stability of the analyte from the DBS samples, affecting the accuracy of downstream diagnostic methods. ELISA methods, using hepatitis B surface antigen (HBsAg) as an HBV marker, were the most widely used diagnostic tool for detecting HBV infection in DBS samples. The simplicity and cost‐effectiveness of the ELISA technique highlight its potential to be used in low‐resource settings. In line with this, the detection of HBsAg using an ELISA immunoassay had higher sensitivity (85.6%–100%), and specificity (95%–100%) ranges as compared to other target molecules and methods. Although this review only performed a qualitative analysis, DBS offers a promising method for collecting and storing blood samples; however, the standardization of sampling, storing conditions and diagnostic techniques is required to ensure sustainable application. [ABSTRACT FROM AUTHOR]

Background: Cortical microinfarcts (CMI) are emerging biomarkers of vascular damage associated with cognitive decline and are frequent in sporadic AD (sAD) patients. However, no study assessed CMI in Down syndrome (DS), a genetically determined form of AD. Therefore, we aimed to assess CMI's frequency in adults with DS, sAD, and cognitively unimpaired euploid controls and its relationship with age, sex, clinical status, and APOE ε4 carriership. Method: Cross‐sectional study. We included 175 participants with 3T‐MRI: 64 with DS (39 asymptomatic [aDS], 11 prodromal AD [pDS], and 14 AD‐dementia [dDS]), 62 with sAD (41 prodromal AD, 21 AD dementia), and 49 controls. A neuroradiologist blind to participants' data visually analyzed the 3T‐MRI images following a validated protocol to detect CMI (Figure 1). We compared CMI's prevalence in the different clinical groups along the AD continuum in DS and sAD, in APOE ε4 carriers vs. non‐carriers, and males vs. females using Chi‐square, Mann‐Whitney, or Kruskal‐Wallis tests when appropriate. Result: CMI's prevalence was 7.8% in DS (5.1% in aDS, 21.4% in pDS, and 0% in dDS [p = 0.085]), 17.7% in sAD (22.0% in prodromal AD and 9.5% in AD dementia [p = 0.389]), and 10.2% in controls (p = 0.207). CMI frequency increased with age in DS, sAD, and controls (Table 1). Regarding sex, CMI's frequency was 10% in men and 5.9% in women with DS (p = 0.884), and 27.3% in men and 12.5% in women with sAD (p = 0.267). In controls, CMIs' frequency was 10% in men and 10.3% in women (p = 1.000). Regarding APOEε4 carriership, CMI's prevalence was 21.4% in APOEε4 carriers and 9.1% in non‐carriers in sAD (p = 0.428), 8.7% in carriers and 6.0% in non‐carriers in DS (p = 1.000), and 8.3% in carriers and 8.6% in non‐carriers controls (p = 1.000) (Table 2). Conclusion: CMI's prevalence increased with age, but was not different in DS, sporadic AD, and controls. Also, sex and APOEε4 carriership did not impact the prevalence of CMI in the three study groups. [ABSTRACT FROM AUTHOR]

Introduction: The COVID‐19 pandemic allowed for the rapid implementation of telemedicine for kidney transplant patients; however, widespread adoption may worsen existing health care inequities among vulnerable populations. This study aimed to characterize telemedicine utilization by kidney transplant patients during the early pandemic with particular attention to healthcare equity. Methods: A retrospective analysis of kidney transplant patients interacting with telemedicine was performed. Patient demographic data and distance to the transplant center were obtained. The National Center for Health Statistics (NCHS) Urban‐Rural Classification Scheme for Counties and Brokamp Neighborhood Deprivation Index (NDI) score were used to characterize patients' counties of residence. Multivariable logistic regression evaluated associations between patient and community characteristics and the likelihood of an encounter being telemedicine. Results: This study included 1033 patients who participated in 3727 encounters from March 11 through October 2020. Characteristics associated with decreased likelihood of telemedicine use were increased age (OR =.993; 95% CI =.986‐.999, P =.022), non‐White vs. White race (OR =.826, 95% CI =.697‐.979; P =.028), male vs. female sex (OR =.746, 95% CI =.632‐.880; P <.001), and a higher Brokamp Neighborhood Deprivation Index score (OR =.159; 95% CI =.029‐.873; P =.034). The effect of distance to the transplant center on the likelihood of a telemedicine encounter differed by NCHS Urban‐Rural designation (interaction P =.018), with its likelihood increasing by 2%–3% with each 10‐mile increment among persons residing in medium‐, small‐, and non‐metropolitan counties compared to those residing in the most rural counties. Conclusions: Telemedicine visits were less often completed by patients of older age, non‐white race, male sex, and those residing in counties having higher NDI scores. While telemedicine has the potential to improve healthcare access and decrease costs, proactive efforts need to be taken to mitigate disparities in vulnerable populations. [ABSTRACT FROM AUTHOR]

Background: Virtual reality (VR) technology has been increasingly used in the management of people living with dementia, serving as a novel and important non‐pharmacologic approach to address the complex behavioral and psychological symptoms. The objective of this phase 1 study was to develop an immersive gamification technology system (ImGTS), specifically, a VR application, and describe its acceptability, usability, and safety in a cohort of healthy adults. Method: The development of ImGTS included software and hardware designs appropriate for the local context and tested using two distinct set‐ups: head‐mounted display (HMD) and the Semi‐Cave automatic virtual environment (Semi‐CAVE). Qualitative and quantitative data questionnaires, with responses analyzed using thematic analysis and descriptive statistics were used to measure the sense of place, usability and safety of the two set‐ups. Result: Participants who used the HMD (n = 15) and the Semi‐CAVE (n = 15) had positive impressions and clear recollections of the VR experience. Incidence of VR sickness symptoms was low, and the mean total VR sickness scores decreased across sessions. Participants in both groups were able to perform key tasks in the VR experience, and the majority performed these actions with ease by the final testing session (n = 15 for the HMD, n = 13 for the Semi‐CAVE). The three main activities were given a 'neutral to positive' description in terms of satisfaction. Conclusion: The technology we developed had a considerable level of impact in eliciting important aspects of cognition and emotion. Through self‐reported measures and researcher observations, we found that the HMD and Semi‐CAVE VR setups were safe, acceptable and usable by healthy adult participants. [ABSTRACT FROM AUTHOR]

Summary: Shade tolerance is an ecological concept used in a wide range of disciplines, from plant physiology to landscaping or gardening. It refers to the strategy of some plants to persist and even thrive in environments with low light levels because of the shade produced by the vegetation proximity (e.g. in the understory). Shade tolerance influences the organization, structure, functioning, and dynamics of plant communities. However, little is known about its molecular and genetic basis. By contrast, there is a good understanding on how plants deal with the proximity of other plants, a divergent strategy used by most crops to respond to vegetation proximity. While generally shade‐avoiding species strongly elongate in response to the proximity of other plants, shade‐tolerant species do not. Here we review the molecular mechanisms that control the regulation of hypocotyl elongation in shade‐avoiding species as a reference framework to understand shade tolerance. Comparative studies indicate that shade tolerance is implemented by components also known to regulate hypocotyl elongation in shade‐avoiding species. These components, however, show differential molecular properties that explain how, in response to the same stimulus, shade‐avoiding species elongate while shade‐tolerant ones do not. [ABSTRACT FROM AUTHOR]

Summary: Inorganic phosphate (Pi) is a necessary macronutrient for basic biological processes. Plants modulate their root system architecture (RSA) and cellular processes to adapt to Pi deprivation albeit with a growth penalty. Excess application of Pi fertilizer, on the contrary, leads to eutrophication and has a negative environmental impact.We compared RSA, root hair elongation, acid phosphatase activity, metal ion accumulation, and brassinosteroid hormone levels of Solanum lycopersicum (tomato) and Solanum pennellii, which is a wild relative of tomato, under Pi sufficiency and deficiency conditions to understand the molecular mechanism of Pi deprivation response in tomato.We showed that S. pennellii is partially insensitive to phosphate deprivation. Furthermore, it mounts a constitutive response under phosphate sufficiency. We demonstrate that activated brassinosteroid signaling through a tomato BZR1 ortholog gives rise to the same constitutive phosphate deficiency response, which is dependent on zinc overaccumulation.Collectively, these results reveal an additional strategy by which plants can adapt to phosphate starvation. [ABSTRACT FROM AUTHOR]

Background: Atrophy of basal forebrain (BF) cholinergic neurons is an early event in Alzheimer's disease (AD) and is associated with cognitive impairment. Down syndrome (DS) is now recognized as a genetically determined form of AD. Therefore, people with DS represent a priority population to study biomarkers of AD pathology and neurodegeneration. Degeneration of BF neurons occurs both in sporadic AD and in DS brains with advanced AD pathology. However, the dynamics of BF atrophy and its changes with age and AT(N) biomarkers have not been studied in DS. Method: We included 246 adults with DS (mean age 43.2 ±11.0 years; 43% female). Volumes of antero‐medial and posterior areas of the BF (amBF and pBF, respectively) were extracted from T1‐weighted 3T MR images using voxel‐based morphometry in SPM12 in combination with a stereotactic atlas of BF functional subdivisions (Figure 1). Differences in amBF and pBF volume in each AD clinical stage (Asymptomatic, Prodromal and Demented) were assessed with Kruskall‐Wallis and pairwise Wilcoxon tests. The relationship of BF volumes with age and AT(N) biomarkers in the cerebrospinal fluid (CSF) (amyloid‐β 42/40 ratio [aβ ratio], phosphorylated Tau 181 [pTau], total Tau [tTau] and neurofilament light [NFL]) was assessed in a subset of subjects (n = 161 [aβ ratio, pTau and tTau] and n = 95 [NFL]) with locally estimated scatterplot smoothing (LOESS) and linear regression in R, respectively. Result: Volumes of amBF and pBF decreased significantly with age (Figure 2), with a steeper decline during the fifth decade of life. BF volumes also declined with AD clinical stage (Figure 3), and had significant correlations with CSF aβ ratio (p<0.001 r2 = 0.22), pTau (p<0.001 r2 = 0.20), tTau (p<0.001 r2 = 0.20) and NFL (p<0.001 r2 = 0.33) (Figure 4). Conclusion: In DS, BF volume decreases with age, AT(N) biomarkers and along the cognitive stages of the AD continuum. [ABSTRACT FROM AUTHOR]

Objective: This study evaluated the effectiveness of an automated prompt in the electronic medical record (EMR) to increase screening rates for metabolic conditions and referrals to health education and to improve BMI percentile among children with obesity. Methods: The intervention used an EMR reminder that provided a panel of lab orders (hemoglobin A1c, lipid panel, and alanine aminotransferase) during clinical encounters among pediatric patients ages 10 to 18 with BMI ≥ 95th percentile. Data on demographics, comorbid conditions, BMI, lab results, and health education referrals were analyzed. Cohorts during the year before (n = 3479) and after (n = 3439) workflow implementation were compared. Results: The distribution of race/ethnicity among children with obesity was 56% Hispanic, 19% White, 11% Filipino, 4% Pacific Islander, 3% Black, and 1% East/South Asian. Orders for metabolic lab tests increased from 2% in the pre‐workflow period to 52% in the post‐workflow period (p < 0.0001). Completed screening rates improved from 1% to 27% (p < 0.0001). Health education referrals increased from 0.4% to 7% (p < 0.0001). We observed a mean change in BMI percentile of −0.13% (p = 0.06). Conclusions: This study validates the use of an EMR‐based prompt to improve metabolic lab screening and health education referrals among children with obesity. During the limited period of follow‐up, we found no significant change in BMI percentile. [ABSTRACT FROM AUTHOR]

Organ procurement organizations (OPOs) play a central role in the recovery, preservation, and distribution of deceased donor kidneys for transplantation in the United States. We conducted a national survey to gather information on OPO practices and perceived barriers to efficient organ placement in the face of the new circle‐based allocation and asked for suggestions to overcome them. Of the 57 OPOs, 44 responded (77%). The majority of OPOs (61%) reported barriers to obtaining a kidney biopsy, including lack of an available pathologist. Most OPOs (55%) indicated barriers to pumping owing to a lack of available staff and transportation. Respondents agreed or strongly agreed that the new allocation system has worsened transportation challenges (85%), increased provisional acceptances of kidneys (66%), increased communication challenges with transplant centers (68%), and worsened the efficiency of organ allocation (83%). OPO‐suggested solutions include making transplant centers more accountable for inefficient selection practices, developing reliable transportation options, and removing the requirement for national sharing. These findings underscore the need to examine closely the trade‐offs of the new allocation system with respect to costs, organ ischemia, and discard. These findings may help inform practice and policy for overcoming transportation barriers and improving the efficiency of organ placement. [ABSTRACT FROM AUTHOR]

Summary: Plant tissues can be enriched in phytonutrients not only by stimulating their biosynthesis but also by providing appropriate sink structures for their sequestering and storage. In the case of carotenoids, they accumulate at high levels in chromoplasts naturally found in flowers and fruit. Chromoplasts can also be artificially differentiated from leaf chloroplasts by boosting carotenoid production with the bacterial protein crtB.Here we used electron and confocal microscopy together with subplastidial fractionation and transcript, protein and metabolite analyses to analyze the structural and biochemical changes occurring in crtB‐induced artificial chromoplasts and their impact on the accumulation of health‐related isoprenoids.We show that leaf chromoplasts develop plastoglobules (PG) harboring high levels of carotenoids (mainly phytoene and pro‐vitamin A β‐carotene) but also other nutritionally relevant isoprenoids, such as tocopherols (vitamin E) and phylloquinone (vitamin K1). Further promoting PG proliferation by exposure to intense (high) light resulted in a higher accumulation of these health‐related metabolites but also an acceleration of the chloroplast‐to‐chromoplast conversion. We further show that the production of reactive oxygen species (ROS) stimulates chromoplastogenesis.Our data suggest that carotenoid accumulation and ROS production are not just consequences but promoters of the chromoplast differentiation process. See also the Commentary on this article by Lundquist, 237: 1483–1485. [ABSTRACT FROM AUTHOR]

Background: Strong associations between age, Alzheimer's disease (AD), and vascular risk factors create challenges to delineate the specific relationships between white matter hyperintensities (WMH) and AD pathophysiology. Down syndrome (DS), a genetically determined form of AD, is not typically complicated by systematic vascular risk factors like hypertension and atherosclerosis and can therefore provide critical information in this regard. We aim to further characterize topography of WMH in DS along the AD continuum and define associations with demographic, genetic, fluid and other imaging biomarkers. Method: In this cross‐sectional study, adults with DS from Down‐Alzheimer Barcelona Neuroimaging Initiative (DABNI) underwent a 3T‐MRI protocol, including 3D‐T1 and 3D‐FLAIR acquisitions. Gray matter (GM) volumes were computed using the CAT12 Toolbox. WMH were segmented using the lesion prediction algorithm implemented in the Lesion Segmentation Toolbox for SPM12. Segmented maps were binarized (threshold of 0.5) and WMH volumes were extracted in each brain lobe, subregions of the corpus callosum, and periventricular versus deep regions (using the standard 10mm limit from the lateral ventricles). Non‐parametric statistical tests were used to assess effects of disease severity on WMH and define associations between WMH and demographic and genetic data, CSF AD biomarkers and GM volumes. Results: We included 116 individuals with DS (Table 1). WMH volume was higher in prodromal and demented groups for all brain regions (Fig 1). Moreover, WMH increased with disease severity such that the demented group demonstrated larger WMH volume than the prodromal group in periventricular regions, frontal and temporal lobes, and body and splenium subregions of the corpus callosum. Total WMH volume was associated with age but not sex, intellectual disability or APOE haplotype (Fig 2). Total WMH volume was negatively related to CSF Aβ42/40 ratio and positively related to CSF t‐tau and p‐tau‐181 concentrations (Fig 3). Associations with GM volumes were widespread, but strongest in parieto‐occipital‐temporal regions. Conclusion: WMH increases with AD pathology and the emergence of clinical symptoms in DS, a population with lower vascular risk factors. It also relates to neurodegeneration in typical AD regions at both asymptomatic and symptomatic stages. Altogether, this suggests that WMH might be intrinsically related to AD pathophysiological processes. [ABSTRACT FROM AUTHOR]

Introduction: Biomedical progress has facilitated breakthrough advanced neurotherapeutic interventions, whose potential to improve outcomes in rare neurological diseases has increased hope among people with lived experiences and their carers. Nevertheless, gene, somatic cell and other advanced neurotherapeutic interventions carry significant risks. Rare disease patient organizations (RDPOs) may enhance patient experiences, inform expectations and promote health literacy. However, their perspectives are understudied in paediatric neurology. If advanced neurotherapeutics is to optimize RDPO contributions, it demands further insights into their roles, interactions and support needs. Methods: We used a mixed‐methodology approach, interviewing 20 RDPO leaders representing paediatric rare neurological diseases and following them up with two online surveys featuring closed and open‐ended questions on advanced neurotherapeutics (19/20) and negative mood states (17/20). Qualitative and quantitative data were analysed using thematic discourse analysis and basic descriptive statistics, respectively. Results: Leaders perceived their roles to be targeted at educational provision (20/20), community preparation for advanced neurotherapeutic clinical trials (19/20), information simplification (19/20) and focused research pursuits (20/20). Although most leaders perceived the benefits of collaboration between stakeholders, some cited challenges around collaborative engagement under the following subthemes: conflicts of interest, competition and logistical difficulties. Regarding neurotherapeutics, RDPO leaders identified support needs centred on information provision, valuing access to clinician experts and highlighting a demand for co‐developed, centralized, high‐level and understandable, resources that may improve information exchange. Leaders perceived a need for psychosocial support within themselves and their communities, proposing that this would facilitate informed decision‐making, reduce associated psychological vulnerabilities and maintain hope throughout neurotherapeutic development. Conclusion: This study provides insights into RDPO research activities, interactions and resource needs. It reveals a demand for collaboration guidelines, central information resources and psychosocial supports that may address unmet needs and assist RDPOs in their advocacy. Patient or Public Contribution: In this study, RDPO leaders were interviewed and surveyed to examine their perspectives and roles in advanced neurotherapeutic development. Some participants sent researchers postinterview clarification emails regarding their responses to questions. [ABSTRACT FROM AUTHOR]

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Summary: Background: miRNA have been proposed as potential biomarkers of metabolic diseases. Objectives: To identify potential miRNA biomarkers of early metabolic‐associated fatty liver disease (MAFLD) and/or insulin resistance (IR) in preadolescent children. Methods: A total of 70 preadolescents, aged 8.5–12 years old participated in the study. Hepatic fat was assessed by magnetic resonance imaging. Fasting blood biochemical parameters were measured and HOMA‐IR calculated. Peripheral blood mononuclear cells (PBMC)‐derived miRNA profiles associated with MAFLD (≥5.5% hepatic fat) and IR (HOMA‐IR ≥2.5) were identified using untargeted high‐throughput miRNAs sequencing (RNA‐seq). Results: A total of 2123 PBMC‐derived miRNAs were identified in children with (21.4%) or without MAFLD. Among them, hsa‐miR‐143‐3p, hsa‐miR‐142‐5p and hsa‐miR‐660‐5p were up‐regulated, and p‐hsa‐miR‐247, hsa‐let‐7a‐5p and hsa‐miR‐6823‐3p down‐regulated. Importantly, children with MAFLD had consistently higher miR‐660‐5p expression levels than their peers without it (p < 0.01), regardless of weight status. A total of 2124 PBMC‐derived miRNA were identified in children with IR (28.6%) versus children without IR, where thirteen of them were dysregulated (p < 0.05) in children with IR. In addition, children with IR showed higher levels of miR‐374a‐5p and miR‐190a‐5p (p < 0.01) and lower levels of miR‐4284 and miR‐4791 (p < 005), than their peers without IR in both the whole sample and in those with overweight or obesity. Conclusions: Our study results suggest circulating miR‐660‐5p as a potential biomarker of the presence of MAFLD in preadolescent children while circulating miR‐320a, miR‐142‐3p, miR‐190a‐5p, miR‐374a‐5p and let‐7 family miRNAs could serve as potential biomarkers of IR in children. [ABSTRACT FROM AUTHOR]

Vertebral osteomyelitis is a rare clinical condition accounting for 1%–7% of all bone‐related infections. The increase in chronic diseases such as diabetes mellitus or those that lead to immunosuppression, the increase in spinal instrumentation including epidural catheters for pain management, and the continual increase in intravenous (IV) drug use are factors that have led to the rise in cases. The condition may present subtly without clinical signs and symptoms making early diagnosis difficult. Here, we present a rare case of spontaneous osteodiscitis of the cervical spine complicated by epidural abscess/phlegmon, burst fracture, and spinal cord injury due to methicillin‐resistant Staphylococcus aureus (MRSA) bacteremia in a patient with a history of intravenous drug use who presented with neck pain. The patient was treated with IV antibiotics and decompressive surgery and, however, was unable to regain the mobility of the lower extremities and regained only slight mobility in the upper extremities leading to an ultimate diagnosis of functional quadriplegia. [ABSTRACT FROM AUTHOR]

Background: Congenital conditions comprise a significant portion of the global burden of surgical conditions in children. In Somaliland, over 250,000 children do not receive required surgical care annually, although the estimated costs and benefits of scale-up of children's surgical services to address this disease burden is not known. Methods: We developed a Markov model using a decision tree template to project the costs and benefits of scale-up of surgical care for children across Somaliland. We used a proxy set of congenital anomalies across Somaliland to estimate scale-up costs using three different scale-up rates. The cost-effectiveness ratio and net societal monetary benefit were estimated using these models, supported by disability weights in existing literature. Results: Overall, we found that scale-up of surgical services at an aggressive rate (22.5%) over a 10-year time horizon is cost effective. Although the scale-up of surgical care for most conditions in the proxy set was cost effective, scale-up of hydrocephalus and spina bifida are not as cost effective as other conditions. Conclusions: Our analysis concludes that it is cost effective to scale-up surgical services for congenital anomalies for children in Somaliland. [ABSTRACT FROM AUTHOR]

Background: Bacterial contamination in platelets remain a major public health concern, which prompted the US Food and Drug Administration guidance for bacterial contamination mitigation. Pathogen reduction technology (PRT) is one mitigation strategy that has shown success in Europe over the last decade. Therefore, our center sought to transition from a dual system of bacterial culturing (BacT) and PRT to full PRT.Methods: A 1 month pilot study was conducted to simulate 100% PRT conditions. Our center also collected baseline data on key platelet production metrics in the 4 months prior to 100% PRT and compared it to the 4 months post-implementation.Results: The pilot study showed no statistical differences in split rate, proportion of low-yield products, or proportion of single, double, and triple collections. The only observed difference was an 11 min increase in the average duration of double collections. Our baseline versus post-implementation monitoring showed no difference in split rate, discard rate, percentage of low-yield units, and average yield of low yield units. Statistical differences were detected in the proportion of single, double, and triple collections, as well as the average yield of full dose products. Roughly 20% of our inventory consisted of low-yield products.Discussion: With suitable mitigation strategies, transitioning to a full PRT inventory may result in higher net margins while not adversely affecting overall platelet production. A pilot study is a good way to project potential effects of switching from a dual BacT and PRT inventory to full PRT, and can be adopted by other centers aiming to make the transition. [ABSTRACT FROM AUTHOR]

This study evaluated the effectiveness of behavioral skills training (BST) to teach peer‐trainers to implement video feedback (Study 1) and evaluated the effectiveness of peer‐implemented video feedback to increase proper deadlifting form across 3 participants (Study 2). A nonconcurrent, multiple baseline design across participants was employed to evaluate BST and peer implemented video feedback. Results demonstrate that BST was effective for teaching peer‐trainers to implement video feedback and video feedback led to improvement of deadlifting form across all participants. [ABSTRACT FROM AUTHOR]

Salinity is a major environmental constraint affecting rice production in both irrigated and non-irrigated areas and threatening global food security. Development of salt-tolerant rice varieties with desirable agronomic traits is a logical approach to maintain high yield in saline areas. Here, we report development of two multi-parent advanced generation introgression line (MAGIL) rice populations in two US cultivar backgrounds and their physiological and morphological evaluation under salinity stress at germination and seedling stages. From the initial screening of 180 MAGILs in sand culture, 36 tolerant-to-moderately salt-tolerant lines were selected and further confirmed in hydroponics experiment. The selected MAGILs showed lower root and shoot Na+/K+ ratio compared with the recurrent parents. The principal component and cluster-based analysis using 12 morphophysiological traits revealed grouping of the selected lines with tolerant donors. Genotyping results with 100 polymorphic SSR markers indicated a low level of genetic diversity among these lines. Clustering based on molecular marker data separated the MAGILs from the salt tolerance donors in both populations but were grouped with the recurrent parents, suggesting genetic similarity of MAGILs with recurrent parents. The salt-tolerant MAGILs identified in this study are useful resource for investigating molecular and physiological bases of salt-tolerant mechanisms as well as for evaluating their yield potential for release as salt-tolerant rice varieties. [ABSTRACT FROM AUTHOR]

Perfluorooctanoic acid is a synthetic compound mostly used in a wide range of consumer products with several adverse effects on somatic cells and gametes. It has been linked to hepatotoxic and carcinogenic effects, alterations in the immune system, endocrine, and reproductive alterations. In vivo studies show an increase in reactive oxygen species and DNA damage. However, the mechanisms by which this compound affects fertility, remain contradictory. Therefore, the aim of the present study was to evaluate the effect of perfluorooctanoic acid on oocyte viability and maturation, as well as the viability, generation of oxidative stress, and genotoxic damage in the cumulus cells exposed during in vitro maturation. This compound had a negative effect on oocyte viability (lethal concentration, LC50 = 269 μM) and maturation (inhibition maturation concentration IM50 = 75 μM), while in cumulus cells the LC50 was 158 μM. The generation of reactive oxygen species evaluated in cumulus cells, protein carbonylation, and DNA damage, was significantly increased at 40 μM perfluorooctanoic acid. This study provides evidence that perfluorooctanoic acid causes reactive oxygen species generation, protein oxidation, and DNA damage in cumulus cells, compromising the maturation and viability of porcine oocyte, which may affect fertility. [ABSTRACT FROM AUTHOR]

Solid organ transplant (SOT) recipients are at high risk for severe coronavirus disease 2019 (COVID‐19). Studies suggest that early intervention with monoclonal antibody (MAB) treatment directed against the SARS‐CoV‐2 spike protein may reduce the risk of emergency department visits or hospitalization for COVID‐19, especially in high‐risk patients. Herein, we describe our single‐center experience of 93 SOT (50 kidney, 17 liver, 11 lung, nine heart, and six dual‐organ) recipients with mild to moderate COVID‐19 who were treated with bamlanivimab or casirivimab‐imdevimab per emergency use authorization guidelines. Median age of recipients was 55 [(Interquartile range) 44–63] years, and 41% were diabetic. Median time from transplant to MAB was 64 (IQR 24–122) months and median time from the onset of COVID‐19 symptoms to the infusion was 6 (IQR 4–7) days. All patients had a minimum 30 days of study follow‐up. The 30‐day hospitalization rate for COVID‐19‐directed therapy was 8.7%. Infusion‐related adverse events were rare and generally mild. Biopsy‐proven organ rejection occurred in two patients, and there were no graft losses or deaths. A comparator group of 72 SOT recipients diagnosed with COVID‐19 who were eligible but did not receive MAB treatment had a higher 30‐day hospitalization rate for COVID‐19‐directed therapy (15.3%), although this difference was not statistically significant, after adjustment for age (Odds Ratio 0.49 [95% Confidence Interval 0.18–1.32], p = 0.16). Our experience suggests that MAB treatment, with respect to the available MAB formulations and circulating viral variants present during our study period, may provide favorable outcomes for mild to moderate COVID‐19 in SOT recipients. [ABSTRACT FROM AUTHOR]

Introduction: The Down syndrome population has a high prevalence for dementia, often showing their first clinical symptoms in their 40s. Methods: In a longitudinal cohort, we investigate whether amyloid deposition at time point 1 (TP1) could predict cortical thickness change at time point 2 (TP2). The association between tau burden and cortical thickness was also examined at time point 3 (TP3). Results: Between TP1 and TP2 there was pronounced cortical thinning in temporo‐parietal cortices and cortical thickening in the frontal cortex. Baseline amyloid burden was strongly associated to cortical thinning progression, especially in the temporo‐parietal regions. At TP3, tau deposition negatively correlated with cortical atrophy in regions where tau usually accumulates at later Braak stages. Discussion: A higher amount of amyloid accumulation triggers a cascade of changes of disease‐causing processes that eventually lead to dementia. As expected, we found that regions where tau usually accumulates were those also displaying high levels of cortical atrophy. [ABSTRACT FROM AUTHOR]

Introduction: Extracellular volume (ECV) predicts mortality in hemodialysis patients, but it is difficult to assess clinically. Peridialytic blood pressure (BP) measurements can help ECV assessment. Orthostatic BP is routinely measured clinically, but its association with ECV is unknown. Methods: In a cohort of hypertensive hemodialysis patients, we measured posthemodialysis ECV/weight with bioimpedance spectroscopy and analyzed its association with post‐HD orthostatic BP measurements obtained during routine care. Using linear and logistic regression, the primary outcomes were orthostatic BP change and orthostatic hypotension (OH) defined by systolic BP decrease of at least 20 mmHg or diastolic decrease of at least 10 mmHg. Model 1 controlled for sex, age, and diabetes. Model 2 additionally controlled for ultrafiltration rate and antihypertensive medications. We conducted sensitivity analysis using OH definition of systolic BP decrease of at least 30 mmHg. Findings: Among 57 participants, mean orthostatic systolic BP change was −7.30 (20) mmHg and mean ECV/weight was 0.24 (0.04) L/kg. Post‐HD ECV/weight was not associated with orthostatic systolic BP change (β = 8.2, p = 0.6). There were 16 participants with and 41 participants without OH. The ECV/weight did not differ between these groups (0.22 [0.04] vs. 0.24 [0.05] L/Kg, p = 0.09) and did not predict OH in logistic regression (OR 11, 4.04; 95% CI 0.2–671, 0.03–0.530 in the two models.) In a sensitivity analysis, ECV/weight was lower in the OH group (0.22 [0.03] vs. 0.25 [0.04] L/kg, p = 0.005), but this was accompanied by differences in sex and diabetes. Using logistic regression, there was no independent association between ECV/weight with OH. Discussion: Orthostatic systolic BP change after HD completion is not a reliable indicator of posthemodialysis ECV. When considering other factors associated with orthostatic BP, ECV/weight is not independently associated with OH. Although transient postdialytic differences in intravascular volume may be associated with OH, posthemodialysis OH does not necessarily indicate ECV depletion. [ABSTRACT FROM AUTHOR]

Summary: Metabolic resistance to 4‐hydroxyphenylpyruvate dioxygenase (HPPD)‐inhibiting herbicides is a threat in controlling waterhemp (Amaranthus tuberculatus) in the USA. We investigated resistance mechanisms to syncarpic acid‐3 (SA3), a nonselective, noncommercial HPPD‐inhibiting herbicide metabolically robust to Phase I oxidation, in multiple‐herbicide‐resistant (MHR) waterhemp populations (SIR and NEB) and HPPD inhibitor‐sensitive populations (ACR and SEN).Dose–response experiments with SA3 provided ED50‐based resistant : sensitive ratios of at least 18‐fold. Metabolism experiments quantifying parent SA3 remaining in excised leaves during a time course indicated MHR populations displayed faster rates of SA3 metabolism compared to HPPD inhibitor‐sensitive populations.SA3 metabolites were identified via LC‐MS‐based untargeted metabolomics in whole plants. A Phase I metabolite, likely generated by cytochrome P450‐mediated alkyl hydroxylation, was detected but was not associated with resistance. A Phase I metabolite consistent with ketone reduction followed by water elimination was detected, creating a putative α,β‐unsaturated carbonyl resembling a Michael acceptor site. A Phase II glutathione–SA3 conjugate was associated with resistance.Our results revealed a novel reduction–dehydration–GSH conjugation detoxification mechanism. SA3 metabolism in MHR waterhemp is thus atypical compared to commercial HPPD‐inhibiting herbicides. This previously uncharacterized detoxification mechanism presents a unique opportunity for future biorational design by blocking known sites of herbicide metabolism in weeds. [ABSTRACT FROM AUTHOR]

Kidney transplantation (KT) from hepatitis C virus infected (HCV+) donors to HCV negative recipients achieve excellent graft function but have relatively higher rates of post‐KT co‐infections presumably due to prolonged HCV viremia in transmission‐and‐treat approach. Ezetimibe acts as an antagonist of Niemann‐Pick C1‐Like 1 receptor required for HCV entry and theoretically can reduce HCV viremia. However, no data is available to examine the role of ezetimibe as a bridge therapy between KT surgery and direct acting antiviral (DAA) initiation. A retrospective cohort study including 70 HCV+ to HCV negative KT recipients from Methodist University Hospital and Vanderbilt University Medical Center was performed to determine the association between ezetimibe usage and HCV viremia. Twenty patients received ezetimibe daily while 50 patients did not. Primary outcome of study was mean HCV RNA level at 1–2 weeks post‐KT and before initiation of DAA. Median (IQR) viral load (VL) in log copies/ml was one log lower in ezetimibe group versus non‐ezetimibe group (4.1 [3.7–5.3] vs. 5.1 [4.4–5.5], P =.01), and highest VL was also lower in ezetimibe group (4.2 [3.7–5.4] vs. 5.4 [4.7–5.9], P =.006). We concluded that ezetimibe bridge therapy might be associated with reduction in HCV VL while waiting for DAA initiation in HCV+ to HCV negative KT recipients. [ABSTRACT FROM AUTHOR]

Background: Puerto Ricans, the second largest US Latino group, are underrepresented in genomic studies of Alzheimer disease (AD). We describe a multi‐source ascertainment approach, networking with community and governmental stakeholders, as part of the Puerto Rico (PR) Alzheimer Disease Initiative (PRADI) whose goal is to increase recruitment and retention of PR individuals in genomic research.The National Alzheimer's disease Action Plan 2015‐2025 served as a framework for PRADI group that aims to fill two of the goals of the plan: increase research and education. Method: We developed collaborative relationships with community and governmental organizations that serve the elderly and AD patients from 37/78 (47%) municipalities of PR to identify potential research participants. Trust and transparency were central to our interactions with community groups. We educated patients and caregivers about AD and their possible contribution to science. Bringing academia to the community encouraged participation. Additionally, we established relationships with multiple neurologists across PR caring for AD patients and their families. For recruitment and enrollment PRADI team members visited families in the homes, daycare facilities and clinics. All participants were assigned diagnoses by a clinical adjudication committee comprised of neurologists and neuropsychologists with expertise in AD and related dementias (ADRD) Result: Since 2016 we have enrolled 1, 281 individuals. Among these 752 are unrelated individuals (193 AD, 170 mild cognitive impairment (MCI), 306 cognitively unimpaired (CU) and 83 with other diagnoses (OD). 529 individuals (195 AD, 76 MCI, 178 CU and 80 OD) were part of 155 multiplex AD families. Most families are from Eastern and Northern PR regions, reflecting dense population areas with large cities. Longitudinal follow‐up of the first 167 participants for diagnostic updates is complete. 64 individuals were ascertained in the continental US (cUS). Of the 167 individuals in the longitudinal follow‐up (3‐5 years), 7.2% progressed from either CU to MCI or AD, or MCI to AD. Conclusion: The PRADI group multisource ascertainment approach enabled recruitment and retention of participants both in PR and the cUS. Longitudinal clinical data across the cohort further enriches the impact of genomic studies in a diverse population. [ABSTRACT FROM AUTHOR]

Background: Plasma concentrations of phosphorylated threonine‐181 of Tau (pTau181) and the ratio of amyloid beta isoforms Ab42/Ab40 are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). However, measurement of these biomarkers is mostly from individuals of non‐Hispanic, European ancestry. Given differences in AD risk, generalizability of these findings is not assured in individuals of diverse ancestry. This study evaluates the utility of plasma pTau181 and Ab42/Ab40 in discriminating clinically diagnosed AD from cognitively intact, age‐matched controls in ancestrally diverse, admixed cohorts. Method: We measured plasma pTau181 and Aβ42/Aβ40 with Simoa chemistry using the pTau181 AdvantageV2 and NEUROLOGY 3‐PLEX A assays, respectively. Our cohorts consisted of: 642 African Americans (162 AD and 480 cognitively intact (CI)), 906 Puerto Ricans (385 AD and 521 CI), 149 Peruvians (49 AD and 100 CI), 60 Cubans (26 AD and 34 CI), and 246 non‐Hispanic, European ancestry (22 AD and 224 CI). Linear mixed‐effect regression models adjusted for age, sex, population substructure and relatedness followed by Bonferroni correction was applied to identify differences across AD status. Diagnostic performance and construct receiver operator characteristic (ROC) curves were created from logistic regression models. Result: Plasma pTau181 concentrations were increased in individuals with AD compared to CI (p < 2×10−16) taking into account all individuals and in each cohort separately (African Americans, p = 1.2×10−9; Puerto Ricans, p = 7.6×10−9; Peruvians, p = 0.02), and European ancestry, p = 2.2×10−8) except for the Cubans where there was a trend. There was no significant difference in the plasma Aβ42/Aβ40 ratio, however there was a trend towards a decreasing concentration in AD. Using the area under the ROC, pTau181 was more accurate at predicting status than the Aβ42/Aβ40 ratio, but the classification improved when both biomarkers were combined. The accuracy varied widely over the individual cohorts with AUC from 0.845 for African Americans to 0.683 for Peruvians. Conclusion: These results suggest AD biomarkers are generalizable across ancestries, though the predictive value may differ depending on specific ancestral backgrounds. Ultimately, combining genomic and biomarker data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses in individuals of diverse ancestries. [ABSTRACT FROM AUTHOR]

Background: The variant G206A in Presenilin‐1 (PSEN1) gene has been identified almost exclusively in Alzheimer Disease (AD) Puerto Rican families. This variant represents a founder effect on the African background. The G206A variant associates with extreme variability in age of onset (AOO), ranging from 30 to 90 years. In contrast, other variants at the same amino acid of PSEN1 (G206N, G206S) have a tighter range of AOO (30‐35 years). We aim to identify the molecular mechanisms involved in the AOO variability between G206A carriers through functional analysis of induced pluripotent stem cells (iPSCs). Method: Genotyping data were phased using SHAPEIT to identify local ancestry and RFMix to estimate genetic ancestry. p‐Tau181 levels were tested from plasma using Simoa (Quanterix HD‐X). iPSCs of G206A carriers with different AOO were reprogrammed using non‐integrating Sendai virus. These clonal lines were assessed for pluripotency and chromosomal stability Isogenic construction of G206A iPSC lines is currently in progress. Result: We screened for G206A carriers using whole genome from 896 individuals (182 families) and identified 43 carriers (39 AD and 4 cognitively unimpaired <65 years) from 8 families and 3 isolated cases. 55% of AD G206A carriers had AOO <65. A single African haplotype was identified in all G206Acarriers. We observed higher pTau181 levels in AD G206A carriers with early age of onset, compared to those with late onset. Association analysis did not identify APOE4 or SYNJ1 polymorphisms as contributing to the differences in AOO within G206A carriers. To perform functional studies, we selected three with early (<65) and three with late (>65) AOO AD peripheral blood mononuclear cells (PBMCs)that were reprogrammed into iPSC lines. G‐band Karyotype, factor loss analyses, genetic finger printing, immunocytochemistry (ICC) and qRT‐PCR for intracellular and surface pluripotency markers was confirmed in the iPSC lines. Conclusion: The PSEN1 G206A variant, originating in African ancestry haplotype revealing a founder effect, is an important contributor to AD in an underserved population. Understanding the role of the G206A variant in AD pathogenesis and the factors that influence its effect on AOO will provide insight on AD pathogenesis, age of onset variation and identification of potential novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: The APOE4 genotype is the main contributor to the risk of developing Late Onset Alzheimer's Disease (LOAD), while the APOE3 genotype has no effect on LOAD risk. Previously our group has shown that Local Ancestry (LA) surrounding APOE4 regulates APOE expression in adult individuals. As LOAD pathology has been shown to develop decades before the onset of symptoms, we sought to explore if LA has similar or different effect in mitotic cells, and whether the APOE3 genotype modulates the effect of the LA. To answer this question, we generated APOEε3/3 and APOEε4/4 isogenic induced Pluripotent Stem Cells (iPSCs) lines from individuals with either European LA or African LA. Method: PBMCs were derived from APOEε4/4 carrying individuals with either African or European APOE LA. To generate APOE isogenic lines, we formed a ribonucleoprotein (RNP) complex using a previously published APOE sgRNA (Lin et al. 2018) and performed nucleofection using the 4D‐Nucleofector system (Lonza). Homozygous APOEε3/3 edited and APOEε4/4 unedited isogenic clones were selected, and confirmed to lack unwanted off‐target editing. Isogenic clone pluripotency was confirmed by immunocytochemistry (SOX2, NANOG and OCT4a staining). APOE expression in the isogenic clones was tested by quantitative Real‐Time PCR and significance was calculated by Student's T‐test. Result: Isogenic clones were similar in their pluripotency and growth characteristics. Preliminary APOE expression in the iPSC line carrying the African LA was higher (p = 0.0002) in each of the individual APOEε3/3 KI clones (n = 3) compared to each of the individual unedited APOEε4/4 clones (n = 2), showing consistency within each isogenic group. In contrast, the APOE expression in the iPSC line carrying the European LA was not significant in the APOEε3/3 KI clones (n = 2) compared to the parental line. Conclusion: Our data suggests that differences in local ancestry has a direct effect on the expression of APOE isoforms in iPSCs. This finding supports previous reports in frontal cortex suggesting that the regulation of APOE expression differs depending on ancestry. [ABSTRACT FROM AUTHOR]

Pressure injuries (PI) are infrequent in paediatric patients, prevalence estimates ranging from 1.4% to 8.2%, and reaching values as high as 43.1% in critical care areas. They can be associated with congenital neurological or metabolic disorders that cause reduced mobility or require the need for medical devices. In children, most pressure injuries heal spontaneously. However, a small percentage of ulcers that is refractory to conservative management or is too severe at presentation (Stage 3 or 4) will be candidates for surgery. We retrospectively reviewed the clinical history of paediatric patients affected by pressure injuries from four European Plastic Surgery Centres. Information was collected from clinical and radiology records, and laboratory reports. An accurate search of the literature revealed only two articles reporting on the surgical treatment of pressure injuries in children. After debridement, we performed surgical coverage of the pressure injuries. We report here our experience with 18 children aged 1–17 years, affected by pressure injury Stages 3 and 4. They were successfully treated with pedicled (17 patients) or free flaps (1 patient). The injuries involved the sacrum (6/18 patients), lower limb (3/18 patients), thoracic spine (2/18 patients), ischium (3/18 patients, bilateral in one patient), temporal area (3/18 patients), hypogastrium (1/18 patients) and were associated to medical devices in three cases. Flaps were followed for a minimum of 19 months and up to 13 years. Only two patients developed true recurrences that were treated again surgically. Pressure injuries are infrequent in children and rarely need surgical treatment. Pedicled flaps have a high success rate. Recurrences, contrary to what is reported in the literature, were rare. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to examine the Alzheimer's disease metabolite signature through magnetic resonance spectroscopy in adults with Down syndrome and its relation with Alzheimer's disease biomarkers and cortical thickness. Methods: We included 118 adults with Down syndrome from the Down Alzheimer Barcelona Imaging Initiative and 71 euploid healthy controls from the Sant Pau Initiative on Neurodegeneration cohort. We measured the levels of myo‐inositol (a marker of neuroinflammation) and N‐acetyl‐aspartate (a marker of neuronal integrity) in the precuneus using magnetic resonance spectroscopy. We investigated the changes with age and along the disease continuum (asymptomatic, prodromal Alzheimer's disease, and Alzheimer's disease dementia stages). We assessed the relationship between these metabolites and Aβ42/Aβ40 ratio, phosphorylated tau‐181, neurofilament light (NfL), and YKL‐40 cerebrospinal fluid levels as well as amyloid positron emission tomography uptake using Spearman correlations controlling for multiple comparisons. Finally, we computed the relationship between cortical thickness and metabolite levels using Freesurfer. Results: Asymptomatic adults with Down syndrome had a 27.5% increase in the levels of myo‐inositol, but equal levels of N‐acetyl‐aspartate compared to euploid healthy controls. With disease progression, myo‐inositol levels increased, whereas N‐acetyl‐aspartate levels decreased in symptomatic stages of the disease. Myo‐inositol was associated with amyloid, tau, and neurodegeneration markers, mainly at symptomatic stages of the disease, whereas N‐acetyl‐aspartate was related to neurodegeneration biomarkers in symptomatic stages. Both metabolites were significantly associated with cortical thinning, mainly in symptomatic participants. Interpretation: Magnetic resonance spectroscopy detects Alzheimer's disease related inflammation and neurodegeneration, and could be a good noninvasive disease‐stage biomarker in Down syndrome. ANN NEUROL 2021;90:407–416 [ABSTRACT FROM AUTHOR]

Objective: Few treatments exist for pediatric obesity. Metformin holds potential for pediatric weight loss. This large retrospective study examined the effect of metformin on weight, BMI, BMI z score, and cardiometabolic outcomes.Methods: The study included 7,068 patients aged 10 to 17 years with BMI at or above the 95th percentile and evidence of insulin resistance. The final cohort of 955 patients with BMI data at 0 to 24 months was categorized into three groups: metformin plus intensive lifestyle changes, intensive counseling alone, and routine counseling. In order to adjust for pubertal BMI changes, a subgroup analysis was conducted for adolescents aged 15 to 17 years.Results: At 6 and 12 months, metformin treatment produced significant reductions in weight (-3.5 kg and -5.3 kg, p < 0.0001), BMI (-1.06 kg/m² and -1.23 kg/m², p < 0.0001), and BMI z score (-0.05 and -0.07, p ≤ 0.002), which continued to decrease at 24 months (-0.05 and -0.08, p = 0.11 and 0.01), compared with control groups. Adolescents aged 15 to 17 years showed similar improvements. Systolic blood pressure and high-density lipoprotein cholesterol also improved in the metformin group.Conclusions: Metformin with lifestyle interventions significantly reduced weight, BMI, and BMI z score in pediatric patients with obesity and insulin resistance up to 24 months, compared with intensive and routine counseling alone. [ABSTRACT FROM AUTHOR]

Introduction: Numerous effective HIV prevention options exist, including behaviour change interventions, condom promotion and biomedical interventions, like voluntary medical male circumcision and pre‐exposure prophylaxis. However, populations at risk of HIV also face overlapping vulnerabilities to common mental disorders and severe mental illness. Mental health status can affect engagement in HIV risk behaviours and HIV prevention programmes. We conducted a narrative review of the literature on HIV prevention among key populations and other groups vulnerable to HIV infection to understand the relationship between mental health conditions and HIV prevention outcomes and summarize existing evidence on integrated approaches to HIV prevention and mental healthcare. Methods: We searched five databases for studies published from January 2015 to August 2020, focused on HIV prevention and mental health conditions among key populations and individuals with serious mental illness. Studies were included if they evaluated an HIV prevention intervention or assessed correlates of HIV risk reduction and included assessment of mental health conditions or a mental health intervention. Results and discussion: We identified 50 studies meeting our inclusion criteria, of which 26 were randomized controlled trials or other experimental designs of an HIV prevention intervention with or without a mental health component. Behaviour change interventions were the most common HIV prevention approach. A majority of studies recruited men who have sex with men and adolescents. Two studies provided distinct approaches to integrated HIV prevention and mental health service delivery. Overall, a majority of included studies showed that symptoms of mental disorder or distress are associated with HIV prevention outcomes (e.g. increased risky sexual behaviour, poor engagement in HIV prevention behaviours). In addition, several studies conducted among groups at high risk of poor mental health found that integrating a mental health component into a behaviour change intervention or linking mental health services to combination prevention activities significantly reduced risk behaviour and mental distress and improved access to mental healthcare. Conclusions: Evidence suggests that mental health conditions are associated with poorer HIV prevention outcomes, and tailored integrated approaches are urgently needed to address overlapping vulnerabilities among key populations and other individuals at risk. [ABSTRACT FROM AUTHOR]