Widespread correction of brain pathology in feline alpha-mannosidosis by dose escalation of intracisternal AAV vector injection.

Alpha-mannosidosis is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Enzyme replacement therapy is available but is not approved for treating the CNS, since the enzyme does not penetrate the blood-brain barrier. However, intellectual disability is a major manifestation of the disease; thus, a complimentary treatment is needed. While enzyme replacement therapy into the brain is technically feasible, it requires ports and frequent administration over time that are difficult to manage medically. Infusion of adeno-associated viral vectors into the cerebrospinal fluid is an attractive route for broadly targeting brain cells. We demonstrate here the widespread post-symptomatic correction of the globally distributed storage lesions by infusion of a high dose of AAV1-feline alpha-mannosidase (fMANB) into the CSF via the cisterna magna in the gyrencephalic alpha-mannosidosis cat brain. Significant improvements in clinical parameters occurred, and widespread global correction was documented pre-mortem by non-invasive magnetic resonance imaging. Postmortem analysis demonstrated high levels of MANB activity and reversal of lysosomal storage lesions throughout the brain. Thus, CSF treatment by adeno-associated viral vector gene therapy appears to be a suitable complement to systemic enzyme replacement therapy to potentially treat the whole patient.

Synthetic Roadmap to a Large Library of Colloidal High-Entropy Rare Earth Oxyhalide Nanoparticles Containing up to Thirteen Metals.

Nanoparticles of high-entropy materials that incorporate five or more elements randomized on a crystalline lattice often exhibit synergistic properties that can be influenced by both the identity and number of elements combined. These considerations are especially important for structurally and compositionally complex materials such as multimetal multianion compounds, where cation and anion mixing can influence properties in competitive and contradictory ways. Here, we demonstrate the synthesis of a large library of colloidal high-entropy rare earth oxyhalide (REOX) nanoparticles. We begin with the synthesis of (LaCePrNdSmEuGdDyHoErYbScY)OCl, which homogeneously incorporates 13 distinct rare earth elements. Through time point studies, we find that (LaNdSmGdDy)OCl, a 5-metal analogue, forms through in situ generation of compositionally segregated core@shell@shell intermediates that convert to homogeneously mixed products through apparent core-shell interdiffusion. Assuming that all possible combinations of 5 through 13 rare earth metals are synthetically accessible, we propose the existence of a 7099-member REOCl nanoparticle library, of which we synthesize and characterize 40 distinct members. We experimentally validate the incorporation of a large number of rare earth elements using energy dispersive X-ray spectra, despite closely spaced and overlapping X-ray energy lines, using several fingerprint matching strategies to uniquely correlate experimental and simulated spectra. We confirm homogeneous mixing by analyzing elemental distributions in high-entropy nanoparticles versus physical mixtures of their constituent compounds. Finally, we characterize the band gaps of the 5- and 13-metal REOCl nanoparticles and find a significantly narrowed band gap, relative to the constituent REOCl phases, in (LaCePrNdSmEuGdDyHoErYbScY)OCl but not in (LaNdSmGdDy)OCl.

Electroconvulsive Therapy Changes Immunological Markers in Patients With Major Depressive Disorder: A Scoping Review.

ABSTRACT: Major depressive disorder (MDD) is a highly prevalent and disabling condition. As such, understanding the causes of and treatment options for MDD is critical. Electroconvulsive therapy (ECT) remains the gold standard depression treatment, but the molecular mechanisms that underlie its effects are still largely unknown. One such explanation hinges on the immuno-inflammatory correlates of ECT treatment, given mounting evidence supporting the inflammatory hypothesis of depression. This review aims to provide an overview of the suggested immunomodulatory effects of ECT and the predictive value of immune biomarkers in relation to treatment outcomes and side effects. We conducted a preregistered, systematic literature search utilizing MEDLINE (PubMed), Embase (Elsevier), and PsycINFO (EBSCO) databases. We employed keywords related to MDD, ECT, gut microbiome, and the immune system. We only included human subjects research published between 1985 and January 13, 2021. Twenty-six unique studies were included in our analyses. Findings indicate a proinflammatory profile associated with MDD, with immune biomarkers exhibiting acute and chronic changes following ECT. Consistently, lower baseline interleukin 6 levels and higher C-reactive protein levels are correlated with a greater reduction in depressive symptoms following ECT. Furthermore, included studies emphasize the predictive value of peripheral immune changes, specifically interleukin 6 and tumor necrosis factor α, on cognitive outcomes following ECT. Given these results, further exploration of the potential roles of immunomodulatory effects on ECT treatment outcomes, as well as adverse cognitive side effects, is indicated.

Gephyrin promotes autonomous assembly and synaptic localization of GABAergic postsynaptic components without presynaptic GABA release.

Synapses containing γ-aminobutyric acid (GABA) constitute the primary centers for inhibitory neurotransmission in our nervous system. It is unclear how these synaptic structures form and align their postsynaptic machineries with presynaptic terminals. Here, we monitored the cellular distribution of several GABAergic postsynaptic proteins in a purely glutamatergic neuronal culture derived from human stem cells, which virtually lacks any vesicular GABA release. We found that several GABAA receptor (GABAAR) subunits, postsynaptic scaffolds, and major cell-adhesion molecules can reliably coaggregate and colocalize at even GABA-deficient subsynaptic domains, but remain physically segregated from glutamatergic counterparts. Genetic deletions of both Gephyrin and a Gephyrin-associated guanosine di- or triphosphate (GDP/GTP) exchange factor Collybistin severely disrupted the coassembly of these postsynaptic compositions and their proper apposition with presynaptic inputs. Gephyrin-GABAAR clusters, developed in the absence of GABA transmission, could be subsequently activated and even potentiated by delayed supply of vesicular GABA. Thus, molecular organization of GABAergic postsynapses can initiate via a GABA-independent but Gephyrin-dependent intrinsic mechanism.

Decoding Early Psychoses: Unraveling Stable Microstructural Features Associated with Psychopathology Across Independent Cohorts.

BACKGROUND: Early Psychosis patients (EP, within 3 years after psychosis onset) show significant variability, making outcome predictions challenging. Currently, little evidence exists for stable relationships between neural microstructural properties and symptom profiles across EP diagnoses, limiting the development of early interventions. METHODS: A data-driven approach, Partial Least Squares (PLS) correlation, was used across two independent datasets to examine multivariate relationships between white matter (WM) properties and symptomatology, to identify stable and generalizable signatures in EP. The primary cohort included EP patients from the Human Connectome Project-Early Psychosis (n=124). The replication cohort included EP patients from the Feinstein Institute for Medical Research (n=78). Both samples included individuals with schizophrenia, schizoaffective disorder, and psychotic mood disorders. RESULTS: In both cohorts, a significant latent component (LC) corresponded to a symptom profile combining negative symptoms, primarily diminished expression, with specific somatic symptoms. Both LCs captured comprehensive features of WM disruption, primarily a combination of subcortical and frontal association fibers. Strikingly, the PLS model trained on the primary cohort accurately predicted microstructural features and symptoms in the replication cohort. Findings were not driven by diagnosis, medication, or substance use. CONCLUSIONS: This data-driven transdiagnostic approach revealed a stable and replicable neurobiological signature of microstructural WM alterations in EP, across diagnoses and datasets, showing a strong covariance of these alterations with a unique profile of negative and somatic symptoms. This finding suggests the clinical utility of applying data-driven approaches to reveal symptom domains that share neurobiological underpinnings.

Disease progression modelling reveals heterogeneity in trajectories of Lewy-type α-synuclein pathology.

Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer's disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.

Accuracy of Phantomless Calibration of Routine Computed Tomography Scans for Opportunistic Osteoporosis Screening in the Spine Clinic.

STUDY DESIGN: Diagnostic accuracy study. OBJECTIVE: To establish a simple method of phantomless bone mineral density (BMD) measurement by using preoperative lumbar Computed Tomography (CT) scans, and compare the accuracy of reference tissue combinations to diagnose low BMD against uncalibrated Hounsfield units (HUs). SUMMARY OF BACKGROUND DATA: HUs are used as a measure of BMD; however, associations between HU and T-scores vary widely. Quantitative CT (qCT) scans are more accurate, but they require density calibration with an object of known density (phantom), which limits feasibility. As an emerging technique, phantomless (internal) calibration of routine CT scans may provide a good opportunity for screening. METHODS: Patients who were scheduled to undergo lumbar surgery, with a preoperative CT scan, and a dual-energy x-ray absorptiometry (DXA) scan within six months were included. Four tissues were selected for calibration: subcutaneous adipose (A), erector spinae (ES), psoas (P) and aortic blood (AB). The HUs of these tissues were used in linear regression against ground-truth values. Calibrations were performed by using two different internal tissues at a time to maintain simplicity and in-office applicability.Volumetric bone mineral densities (vBMD) derived from internally calibrated CT scans were analyzed for new threshold values for low bone density. Areas under the curve (AUC) were calculated with 95% confidence intervals (CI). RESULTS: 45 patients were included (M/F=10/35, mean age:63.3). Calibrated vBMDs had stronger correlations with DXA T-scores when compared with HUs, with L2 exhibiting the highest coefficients. Calibration by using A and ES with the threshold of 162 mg/cm3 had a sensitivity of 90% in detecting low BMD (AUC=0.671). CONCLUSIONS: This novel method allows simple, in-office calibration of routine preoperative CT scans without the use of a phantom. Calibration using adipose and erector spinae with a threshold of 162 mg/cm3 is proposed for low bone density screening with high sensitivity (90%). LEVEL OF EVIDENCE: Level III.

Electronic Vapor Products: Alarming Trends in United States Adolescents.

Background: The use of electronic vapor products (EVPs) increases the risks of nicotine addiction, drug-seeking behavior, mood disorders, and avoidable premature morbidities and mortality. We explored temporal trends in EVP use among US adolescents. Methods: We used data from the Youth Risk Behavior Survey for school grades 9 through 12 from 2015 (earliest available data) to 2021 (the most recently available data) from the US Centers for Disease Control and Prevention (n=57,006). Results: Daily use of EVPs increased from 2.0% in 2015 to 7.2% in 2019, a greater than 3.5-fold increase. Although the percentage decreased to 5.0% in 2021, it was still a >2.5-fold increase since 2015. In 2015, the percentage of EVP use was significantly higher in boys (2.8%) than girls (1.1%). By 2021, the percentage of EVP use was higher in girls (5.6%) than boys (4.5%), a 1.24-fold increase. In addition, the percentage of EVP use in 2021 was higher in White youth (6.5%) vs Black (3.1%), Asian (1.2%), and Hispanic/Latino (3.4%) youth compared to 2015, but White and Black adolescents had the highest increases of approximately 3.0-fold between 2015 and 2021. Adolescents in grade 12 had the highest percentages of EVP use at all periods. Conclusion: These data show alarming statistically significant and clinically important increases in EVP use in US adolescents in school grades 9 through 12. The magnitude of the increases may have been blunted by coronavirus disease 2019, a hypothesis that requires direct testing in analytic studies. These trends create clinical and public health challenges that require targeted interventions such as mass media campaigns and peer interventions to combat the influences of social norms that promote the adoption of risky health behaviors during adolescence.

Predictors of Physical Activity One Year After Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: To identify predictors of moderate to vigorous physical activity (MVPA) at 12-months post-moderate-severe traumatic brain injury (TBI). Setting: Four inpatient rehabilitation centers. PARTICIPANTS: Individuals enrolled in the TBI Model Systems with moderate to severe TBI, admitted to inpatient rehabilitation, and able to ambulate without physical assistance from another person. DESIGN: Prospective longitudinal cohort study. MVPA was measured by having participants wear an ActiGraph GT3X on their wrist for 7 consecutive days. MAIN ANALYSES: We used multivariate regression to predict minutes per week of MVPA at 12 months after TBI. Three classes of predictors were entered hierarchically-demographic and clinical variables (age, sex, body mass index, education, TBI severity, neighborhood walkability score, and self-reported preinjury physical activity [PA] level), baseline TBI-related comorbid conditions (eg, measures of sleep, pain, mood, fatigue, and cognition), and intention to exercise and exercise self-efficacy assessed approximately 1 week after discharge from inpatient rehabilitation. RESULTS: 180 participants (ages 17.7-90.3 years) were enrolled, and 102 provided at least 5 days of valid accelerometer data at 12 months. At 12 months, participants recorded an average of 703 (587) minutes per week of MVPA. In univariate and multivariate analyses, age was the only significant predictor of 12-month MVPA (r = -0.52). A sharp decline in MVPA was observed in the tertile of participants who were over the age of 61. CONCLUSIONS: Older adults with TBI are at elevated risk of being physically inactive. Assuming PA may enhance health after TBI, older adults are a logical target for prevention or early intervention studies. Studies with longer outcomes are needed to understand the trajectory of PA levels after TBI.

An alternative to the igneous crust fluid + sediment melt paradigm for arc lava geochemistry.

A long-standing paradigm of arc geochemistry is that the trace element compositions of arc lavas arise from two compositionally distinct slab components: an aqueous dehydration fluid from the subducting igneous ocean crust that transports "fluid-mobile" elements, such as barium (Ba), and a sediment melt that supplies thorium (Th) and the light rare earth elements. This two-component framework has been widely called upon to explain global geochemical trends as well as geochemical variations within individual arcs, such as the Marianas. Here, we show that this paradigm is inconsistent with mass balance, due to the low Ba contents of igneous ocean crust, and with experimental data, which show that aqueous fluids from the igneous oceanic crust would be too dilute to substantially affect arc compositions. Observations previously attributed to the sediment melt/igneous-crust-fluid hypothesis are better explained by diverse subducting sediment compositions coupled with ambient mantle wedge heterogeneity, both globally and for the Marianas.

The HIV Environmental Riskscape: The Roles of HIV Sexual Risk and Resilience Factors among Black Men Who Have Sex with Men: Findings from the Real Talk Project.

Black and African American men who have sex with men (Black MSM) experience the greatest proportion of new HIV infections in the United States. To address this challenge, a better understanding of the HIV environment riskscape including both risk and resilience factors is warranted among Black MSM. Research indicates that stress is associated with increased HIV sexual risk behaviors. Further, behavioral factors such as serosorting and community level factors including social support and community connection are resilience factors that protect against risk behaviors. The present study examines whether everyday stress is associated with HIV sexual risk behavior, as well as the role of risk and resilience factors among 125 Black MSM recruited in the Real Talk study. The Real Talk project examined the relationships between resilience, HIV risk behaviors, and HIV prevention strategy among a sample of Black MSM. Using generalized estimating equations, our results indicate a positive association between everyday stress and engaging in condomless anal intercourse only after adjusting for risk, resilience, and correlate variables. Similarly, having multiple sex partners and using substances during sex also show positive associations with condomless anal intercourse. Resilience factors of engaging in serosorting and being connected to both the Black and gay communities were negatively associated with condomless anal intercourse. Future prevention research and programming should focus on both risk and resilience factors to mitigate new HIV infections among Black MSM.

AI Efficacy as a Function of Trainee Interpreter Proficiency: Lessons from a Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Recently, AI tools have been deployed with increasing speed in educational and clinical settings. However, the use of AI by trainees across different levels of experience has not been well studied. This study investigates the impact of AI assistance on diagnostic accuracy for intracranial hemorrhage (ICH) and large vessel occlusion (LVO) by medical students (MS) and resident trainees (RT). MATERIALS AND METHODS: This prospective study was conducted between March 2023 and October 2023. MS and RT were asked to identify ICH and LVO in 100 non-contrast head CTs and 100 head CTAs, respectively. One group received diagnostic aid simulating AI for ICH only (n = 26), the other for LVO only (n = 28). Primary outcomes included accuracy, sensitivity, and specificity for ICH / LVO detection without and with aid. Study interpretation time was a secondary outcome. Individual responses were pooled and analyzed with chi-square; differences in continuous variables were assessed with ANOVA. RESULTS: 48 participants completed the study, generating 10,779 ICH or LVO interpretations. With diagnostic aid, MS accuracy improved 11.0 points (P < .001) and RT accuracy showed no significant change. ICH interpretation time increased with diagnostic aid for both groups (P < .001) while LVO interpretation time decreased for MS (P < .001). Despite worse performance in detection of the smallest vs. the largest hemorrhages at baseline, MS were not more likely to accept a true positive AI result for these more difficult tasks. Both groups were considerably less accurate when disagreeing with the AI or when supplied with an incorrect AI result. CONCLUSIONS: This study demonstrated greater improvement in diagnostic accuracy with AI for MS compared to RT. However, MS were less likely than RT to overrule incorrect AI interpretations and were less accurate, even with diagnostic aid, than the AI was by itself. ABBREVIATIONS: ICH = intracranial hemorrhage; LVO = large vessel occlusion; MS = medical students; RT = resident trainees.

Unequal distributions of crowdsourced weather data in England and Wales.

Personal weather stations (PWS) can provide useful data on urban climates by densifying the number of weather measurements across major cities. They do so at a lower cost than official weather stations by national meteorological services. Despite the increasing use of PWS data, little attention has yet been paid to the underlying socio-economic and environmental inequalities in PWS coverage. Using social deprivation, demographic, and environmental indicators in England and Wales, we characterize existing inequalities in the current coverage of PWS. We find that there are fewer PWS in more deprived areas which also observe higher proportions of ethnic minorities, lower vegetation coverage, higher building height and building surface fraction, and lower proportions of inhabitants under 65 years old. This implies that data on urban climate may be less reliable or more uncertain in particular areas, which may limit the potential for climate adaptation and empowerment in those communities.

Decoding Early Psychoses: Unraveling Stable Microstructural Features Associated with Psychopathology Across Independent Cohorts.

Background: Early Psychosis patients (EP, within 3 years after psychosis onset) show significant variability, making outcome predictions challenging. Currently, little evidence exists for stable relationships between neural microstructural properties and symptom profiles across EP diagnoses, limiting the development of early interventions. Methods: A data-driven approach, Partial Least Squares (PLS) correlation, was used across two independent datasets to examine multivariate relationships between white matter (WM) properties and symptomatology, to identify stable and generalizable signatures in EP. The primary cohort included EP patients from the Human Connectome Project-Early Psychosis (n=124). The replication cohort included EP patients from the Feinstein Institute for Medical Research (n=78). Both samples included individuals with schizophrenia, schizoaffective disorder, and psychotic mood disorders. Results: In both cohorts, a significant latent component (LC) corresponded to a symptom profile combining negative symptoms, primarily diminished expression, with specific somatic symptoms. Both LCs captured comprehensive features of WM disruption, primarily a combination of subcortical and frontal association fibers. Strikingly, the PLS model trained on the primary cohort accurately predicted microstructural features and symptoms in the replication cohort. Findings were not driven by diagnosis, medication, or substance use. Conclusions: This data-driven transdiagnostic approach revealed a stable and replicable neurobiological signature of microstructural WM alterations in EP, across diagnoses and datasets, showing a strong covariance of these alterations with a unique profile of negative and somatic symptoms. This finding suggests the clinical utility of applying data-driven approaches to reveal symptom domains that share neurobiological underpinnings.

Predictive biomarkers and initial analysis of maternal immune alterations in postpartum preeclampsia reveal an immune-driven pathology.

Introduction: Postpartum preeclampsia (PPPE) is an under-diagnosed condition, developing within 48 hours to 6 weeks following an uncomplicated pregnancy. The etiology of PPPE is still unknown, leaving patients vulnerable and making the identification and treatment of patients requiring postpartum care an unmet need. We aimed to understand the immune contribution to PPPE at the time of diagnosis, as well as uncover the predictive potential of perinatal biomarkers for the early postnatal identification of high-risk patients. Methods: Placentas were collected at delivery from uncomplicated pregnancies (CTL) and PPPE patients for immunohistochemistry analysis. In this initial study, blood samples in PPPE patients were collected at the time of PPPE diagnosis (48h-25 days postpartum; mean 7.4 days) and compared to CTL blood samples taken 24h after delivery. Single-cell transcriptomics, flow cytometry, intracellular cytokine staining, and the circulating levels of inflammatory mediators were evaluated in the blood. Results: Placental CD163+ cells and 1st trimester blood pressures can be valuable non-invasive and predictive biomarkers of PPPE with strong clinical application prospects. Furthermore, changes in immune cell populations, as well as cytokine production by CD14+, CD4+, and CD8+ cells, suggested a dampened response with an exhausted phenotype including decreased IL1ß, IL12, and IFNγ as well as elevated IL10. Discussion: Understanding maternal immune changes at the time of diagnosis and prenatally within the placenta in our sizable cohort will serve as groundwork for pre-clinical and clinical research, as well as guiding clinical practice for example in the development of immune-targeted therapies, and early postnatal identification of patients who would benefit from more thorough follow-ups and risk education in the weeks following an uncomplicated pregnancy.

Parkinson's Disease Associated with G2019S LRRK2 Mutations without Lewy Body Pathology.

BACKGROUND: The G2019S leucine-rich repeat kinase 2 (LRRK2) gene mutation is an important and commonly found genetic determinant of Parkinson's disease (PD). The neuropathological findings associated with this mutation have thus far been varied but are most often associated with Lewy body (LB) pathology. OBJECTIVE: Describe a case of clinical Parkinson's disease with levodopa responsiveness found to have LRRK2 mutations and the absence of Lewy bodies. METHOD: We present an 89-year-old man with a 10-year history of slowly progressive parkinsonism suspected to be secondary to Parkinson's disease. RESULTS: Neuropathological evaluation revealed nigral degeneration without Lewy bodies or Lewy neurites, but there were frequent tau-immunopositive neurites and astrocytes in the putamen and substantia nigra, neocortical glial tau positive astrocytes associated with aging-related tau astrogliopathy (ARTAG), as well as neurofibrillary tangles, beta amyloid plaques, and amyloid angiopathy typical of advanced Alzheimer's disease. G2019S LRRK2 homozygous mutations were found. CONCLUSION: This case illustrates that levodopa-responsive clinical PD caused by G2019S LRRK2 mutations can occur without Lewy bodies.

The Benefits of Acute Exercise for Children's Cognition are Associated with Trait Anxiety.

INTRODUCTION: Children's anxiety is associated with decreased cognitive performance. One well-established behavioral intervention to transiently improve cognitive performance in children is acute aerobic exercise (AAE). Thus far, however, it is unclear whether the benefits of AAE on cognition vary based on individual differences in children's anxiety level. Therefore, we investigated whether trait anxiety levels mediate the effects of AAE on cognitive outcomes in preadolescent children. METHODS: Ninety-five preadolescent children (9-11 years, 41 females) underwent two experimental interventions in a random, crossover, and counterbalanced design: an exercise protocol (20 minutes of walking at 65-75% of HRpeak) and a non-exercise control (seated rest). Behavioral indices of cognitive performance (accuracy, reaction times, response time variability) were assessed before and after each intervention using a modified flanker task. The effects of each intervention on cognitive performance were calculated as pre- to post-intervention differences (effect scores). These scores were first correlated with children's personal characteristics: anxiety (STAIC), sex, age, BMI, IQ, and aerobic fitness. Significant correlations guided subsequent hierarchical regression models, which specifically tested for associations between the effects scores and anxiety levels while controlling for remaining relevant covariates. RESULTS: Regression analysis revealed that anxiety was a significant predictor of the effects that AAE and rest had on cognitive performance. Specifically, higher anxiety scores were associated with greater exercise-induced cognitive benefits (increased accuracy, decreased response time variability; p's < 0.05) and greater rest-induced cognitive impairments (decreased accuracy, increased response time variability; p's < 0.01). CONCLUSIONS: These findings suggest that children reporting higher trait anxiety might experience greater cognitive benefits from a single bout of AAE.

Associations Between Motor Competence and Executive Functions in Children and Adolescents: A Systematic Review and Meta-analysis.

BACKGROUND: Motor competence and executive functions co-develop throughout childhood and adolescence, and there is emerging evidence that improvements in motor competence may have cognitive benefits in these populations. There is a need to provide a quantitative synthesis of the cross-sectional, longitudinal and experimental studies that have examined the association between motor competence and executive functions in school-aged youth. OBJECTIVES: The primary aim of our systematic review was to synthesise evidence of the association between motor competence and executive functions in school-aged children and adolescents (5-18 years). Our secondary aim was to examine key moderators of this association. METHODS: We searched the PubMed, PsycINFO, Scopus, Ovid MEDLINE, SPORTDiscus and EMBASE databases from inception up to 27 June 2023. We included cross-sectional, longitudinal and experimental studies that assessed the association between motor competence (e.g., general motor competence, locomotor skills, object control skills and stability skills) and executive functions (e.g., general executive functions, inhibition, working memory and cognitive flexibility) in children and adolescents aged 5-18 years. RESULTS: In total, 12,117 records were screened for eligibility, and 44 studies were included. From the 44 included studies, we meta-analysed 37 studies with 251 effect sizes using a structural equation modelling approach in the statistical program R. We found a small positive association (r = 0.18, [95% confidence interval (CI) 0.13-0.22]) between motor competence and executive functions. The positive associations were observed in cross-sectional (r = 0.17, [95% CI 0.13-0.22]), longitudinal (r = 0.15, [95% CI 0.03-0.28]) and experimental studies (r = 0.25, [95% CI 0.01-0.45]). We also found that general motor competence (r = 0.25, [95% CI 0.18-0.33]), locomotor (r = 0.15, [95% CI 0.09-0.21]), object control (r = 0.14, [95% CI 0.08-0.20]) and stability (r = 0.14, [95% CI 0.08-0.20]) skills were associated with executive functions. We did not find any moderating effects for participants' age on the associations between motor competence and executive functions. CONCLUSIONS: Our findings suggest a small-to-moderate positive association between motor competence and executive functions in children and adolescents. The small number of experimental studies included in this review support the assertion that interventions targeting children's motor competence may be a promising strategy to improve their executive functions; however, more research is needed to confirm these findings. Future studies should explore the underlying mechanisms linking motor competence and executive functions as their comprehension may be used to optimise future intervention design and delivery. PROSPERO REGISTRATION: CRD42021285134.

Immediate Postoperative Change in the Upper Instrumented Screw-Vertebra Angle Is a Predictor for Proximal Junctional Kyphosis and Failure.

STUDY DESIGN: Retrospective review. OBJECTIVES: To determine if change in position of upper instrumented vertebral (UIV) screw between intraoperative prone and immediate postoperative standing radiographs is a predictor for proximal junctional kyphosis or failure (PJK/PJF). SUMMARY OF BACKGROUND DATA: Cranially directed UIV screws on post-operative radiographs have been found to be associated with PJK. Change in the screw position between intraoperative and immediate postoperative radiographs has not been studied. METHODS: Patients with posterior fusion ≥3 levels and UIV at or distal to T8, and minimum 2-year follow-up were identified from a single center database. Primary outcomes were radiographic PJK/PJF or revision for PJK/PJF. Demographic, surgical and radiographic variables, including intraoperative screw-vertebra (S-V) angle, change in S-V angle, direction of UIV screw (cranial-neutral-caudal) and rod-vertebra (R-V) angle were collected. RESULTS: 143 cases from 110 patients were included with a mean age of 62.9 years and a follow-up of 3.5 years. 54 (38%) cases developed PJK/PJF, of whom 30 required a revision. Mean S-V angle was -0.9°±5.5° intraoperative and -2.8°±5.5° postoperative. The group with PJK/PJF had a mean S-V angle change of -2.5°±2.4 while the rest had a change of -1.0°±1.6 (P=0.010). When the change in S-V angle was <5°, 33% developed PJK, this increased to 80% when it was ≥5° (P=0.001). Revision for PJK/PJF increased from 16% to 60% when S-V angle changed ≥5° (P=0.001). Regression analysis showed S-V angle change as a significant risk factor for PJK/PJF (P=0.047, OR=1.58) and for revision due to PJK/PJF (P=0.009, OR=2.21). CONCLUSIONS: Change in the S-V angle from intraop prone to immediate postop standing radiograph is a strong predictor for PJK/PJF and for revision. For each degree of S-V angle change, odds of revision for PJK/PJF increases by 2.2x. A change of 5° should alert the surgeon to the likely development of PJK/PJF requiring revision.