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The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA, and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinsons disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1741 participants had SAA data and of these 1030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD, and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively. We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary.

BACKGROUND: Molecular-based approaches to understanding concussion pathophysiology provide complex biological information that can advance concussion research and identify potential diagnostic and/or prognostic biomarkers of injury. OBJECTIVE: The aim of this study was to identify gene expression changes in peripheral blood that are initiated following concussion and are relevant to concussion response and recovery. METHODS: We analyzed whole blood transcriptomes in a large cohort of concussed and control collegiate athletes who were participating in the multicenter prospective cohort Concussion Assessment, Research, and Education (CARE) Consortium study. Blood samples were collected from collegiate athletes at preseason (baseline), within 6 h of concussion injury, and at four additional prescribed time points spanning 24 h to 6 months post-injury. RNA sequencing was performed on samples from 230 concussed, 130 contact control, and 102 non-contact control athletes. Differential gene expression and deconvolution analysis were performed at each time point relative to baseline. RESULTS: Cytokine and immune response signaling pathways were activated immediately after concussion, but at later time points these pathways appeared to be suppressed relative to the contact control group. We also found that the proportion of neutrophils increased and natural killer cells decreased in the blood following concussion. CONCLUSIONS: Transcriptome signatures in the blood reflect the known pathophysiology of concussion and may be useful for defining the immediate biological response and the time course for recovery. In addition, the identified immune response pathways and changes in immune cell type proportions following a concussion may inform future treatment strategies.

IntroductionAlthough dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete.MethodsWe applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43.ResultsFinal included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility.DiscussionA novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies.HighlightsLatent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

Ron Shavit,1 Talma Kushnir,2,3 Yaniv Nudelman,4,5 Shmuel Springer1 1The Neuromuscular & Human Performance Laboratory, Department of Physical Therapy, Faculty of Health Sciences, Ariel University, Ariel, Israel; 2Department of Psychology, Ariel University, Ariel, Israel; 3Adelson School of Medicine, Ariel University, Ariel, Israel; 4Department of Physical Therapy, Ariel University, Ariel, Israel; 5Maccabi Healthcare Services, Tel-Aviv, IsraelCorrespondence: Shmuel Springer, The Neuromuscular & Human Performance Laboratory, Department of Physical Therapy, Ariel University, Ariel University, Ariel, Israel, Tel +972-584572869, Email Shmuels@ariel.ac.ilPurpose: Direct access to physical therapy (PT) requires PTs to act as primary care providers, making differential diagnosis a critical component of patient assessment. We investigated how participation in postgraduate training in differential diagnosis and medical screening influences PTs’ confidence, self-efficacy, attitudes and beliefs about treating patients with low back pain (LBP).Patients and Methods: This prospective, two-arm study involved 49 PTs in an intervention group and 70 in a control group. The intervention included 40-hours of training on medical screening and differential diagnosis, focusing on red flags, clinical reasoning and referral pathways, while the control group received no intervention. Clinical confidence, self-efficacy, attitudes and beliefs were measured before, immediately after, and 6-months after training. Outcomes included the Primary Care Confidence Scale (PCCS), which assesses confidence in primary care practice, detection of serious pathology, and medical screening; the Physiotherapy Self-Efficacy (PSE) questionnaire, evaluating clinical self-efficacy in assessing and treating patients with LBP; and the Attitudes to Back Pain Scale for Musculoskeletal Practitioners (ABS-mp), which measures clinicians’ attitudes and beliefs about LBP.Results: The intervention group showed significant immediate improvements in PCCS scores (40.26 ± 5.23 to 45.24 ± 4.20, Cohen’s d = 1.08, p < 0.001) and PSE scores (51.06 ± 6.46 to 54.65 ± 5.78, Cohen’s d = 0.6, p < 0.001). At six-month, significant interaction effects were observed for PCCS (F = 17.49, Partial η² = 0.131, p < 0.001) and PSE scores (F = 5.87, Partial η² = 0.06, p < 0.05) and PSE scores (55.32 ± 6.09, p < 0.05), with the intervention group maintaining improvements while the control group showed no significant changes. No significant changes were observed in ABS-mp scores.Conclusion: This study highlights the positive impact of training in medical screening and differential diagnosis on reducing concerns and increasing clinical confidence and self-efficacy.Keywords: primary care, confidence, self-efficacy

The effects of music exposure on vocal performers remain relatively unknown. This study aimed to assess the immediate and long-term effects of music and singing practice on the peripheral auditory system of vocal performers using otoscopy, pure-tone audiometry, and noise dosimetry. The hearing status, sound pressure levels (SPLs), and sound doses of 12 vocal performers with normal hearing at the study’s onset were evaluated. Pre- and post-study questionnaires regarding the participants’ otologic health and music-making activities, as well as repeated hearing evaluations, were implemented. Additionally, noise dosimetry was conducted on each participant’s most vocally active day of the week. Audiometric assessments generally revealed normal hearing thresholds, with some exceptions. Half of the participants exhibited elevated low-frequency thresholds and over half of the participants displayed emerging audiometric “notches” at 6000 Hz. Noise dosimetry measurements indicated that most of the participants were consistently exposed to SPLs during music-making activities that exceeded recommended limits. Questionnaire responses highlighted that the participants often engaged in extra-curricular music-making activities, frequently with piano accompaniment, and with little to no use of hearing protection devices. A few of the participants reported histories of otologic issues and potential hearing problems.

IntroductionWe aimed to describe baseline amyloid-beta (Aβ) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD).MethodsWe analyzed baseline [18F]Florbetaben (Aβ) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged

IntroductionThe Rey Auditory Verbal Learning Test (RAVLT) is a useful neuropsychological test for describing episodic memory impairment in dementia. However, there is limited research on its utility in early-onset Alzheimer's disease (EOAD). We assess the influence of amyloid and diagnostic syndrome on several memory scores in EOAD.MethodsWe transcribed RAVLT recordings from 303 subjects in the Longitudinal Early-Onset Alzheimer's Disease Study. Subjects were grouped by amyloid status and syndrome. Primacy, recency, J-curve, duration, stopping time, and speed score were calculated and entered into linear mixed effects models as dependent variables.ResultsCompared with amyloid negative subjects, positive subjects exhibited effects on raw score, primacy, recency, and stopping time. Inter-syndromic differences were noted with raw score, primacy, recency, J-curve, and stopping time.DiscussionRAVLT measures are sensitive to the effects of amyloid and syndrome in EOAD. Future work is needed to quantify the predictive value of these scores.HighlightsRAVLT patterns characterize various presentations of EOAD and EOnonAD Amyloid impacts raw score, primacy, recency, and stopping time Timing-based scores add value over traditional count-based scores.

IntroductionWe used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD).MethodsWe included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden.ResultsEOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers.DiscussionThe effects of sex and APOE ε4 must be considered when studying these populations.HighlightsNovel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE ε4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

IntroductionMagnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker.MethodsWe analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment.ResultsThe EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment.DiscussionThe EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD.HighlightsWe developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

IntroductionOne goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD).MethodsCerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated.ResultsBiomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure.DiscussionThis study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

ObjectiveInvestigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without β-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses.HighlightsLearning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.

IntroductionWe examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS).MethodsBaseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70).ResultsAffective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD.DiscussionOverall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD.

ObjectiveThe Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset

IntroductionOne goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants.MethodsLEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study.ResultsPreviously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases.DiscussionResults suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases.HighlightsSequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.

IntroductionWe compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloid-negative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study.MethodsWe investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden.ResultsEOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group.DiscussionEOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD.HighlightsThis study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early-onset amyloid-negative cognitively impaired (EOnonAD) groups across all brain regions.

Nuclear pore complexes (NPCs) direct the nucleocytoplasmic transport of macromolecules. Here, we provide a composite multiscale structure of the yeast NPC, based on improved 3D density maps from cryogenic electron microscopy and AlphaFold2 models. Key features of the inner and outer rings were integrated into a comprehensive model. We resolved flexible connectors that tie together the core scaffold, along with equatorial transmembrane complexes and a lumenal ring that anchor this channel within the pore membrane. The organization of the nuclear double outer ring reveals an architecture that may be shared with ancestral NPCs. Additional connections between the core scaffold and the central transporter suggest that under certain conditions, a degree of local organization is present at the periphery of the transport machinery. These connectors may couple conformational changes in the scaffold to the central transporter to modulate transport. Collectively, this analysis provides insights into assembly, transport, and NPC evolution.

ObjectivesTo determine whether implementation of an Emergency Critical Care Program (ECCP) is associated with improved survival and early downgrade of critically ill medical patients in the emergency department (ED).DesignSingle-center, retrospective cohort study using ED-visit data between 2015 and 2019.SettingTertiary academic medical center.PatientsAdult medical patients presenting to the ED with a critical care admission order within 12 hours of arrival.InterventionsDedicated bedside critical care for medical ICU patients by an ED-based intensivist following initial resuscitation by the ED team.Measurements and main resultsPrimary outcomes were inhospital mortality and the proportion of patients downgraded to non-ICU status while in the ED within 6 hours of the critical care admission order (ED downgrade

Summary: Host response to environmental exposures such as pathogens and chemicals can include modifications to the epigenome and transcriptome. Improved signature discovery, including the identification of the agent and timing of exposure, has been enabled by advancements in assaying techniques to detect RNA expression, DNA base modifications, histone modifications, and chromatin accessibility. The interrogation of the epigenome and transcriptome cascade requires analyzing disparate datasets from multiple assay types, often at single-cell resolution, derived from the same biospecimen. However, there remains a paucity of rigorous quality control standards of those datasets that reflect quality assurance of the underlying assay. This guide outlines a comprehensive suite of metrics that can be used to ensure quality from 11 different epigenetics and transcriptomics assays. Recommended mitigative actions to address failed metrics are provided. The workflow presented aims to improve benchwork protocols and dataset quality to enable accurate discovery of exposure signatures.

IntroductionThe relevance of biodegradable implants has gained more importance in modern clinical practice. The study aimed to evaluate the effects and outcomes of ankle fracture treatment with absorbable implants compared to metal screws. These implants are made from poly l-lactic-co-glycolic acid (PLGA), however, there are several other materials available on the market.MethodsIn a retrospective review, a total of 128 patients were under observation, with distal tibial fracture types ranging from Salter-Harris II-IV. In the absorbable group, patients were treated with the implants (n = 76). The metal group included patients treated with titanium or steel screws (n = 52). The extremities were placed in a cast for six weeks after surgery and were utilized for another 6–8 weeks. Patients were followed up for 12–30 months and were evaluated accordingly. The authors examined several aspects such as age, gender, open or closed repair, mechanism of injury, length of hospitalization, type of fracture, time of recovery, and complications.ResultsThere were no statistically significant differences between the groups regarding demographic qualities, such as age, type of fracture, side of injury, and length of cast application (p > 0.05 in all cases). Out of 76 patients in the PLGA group, only two presented with complications, so reoperation took place. The rest healed without complications or refractures. Two of those treated with metal screws (n = 52) had minor, and four had major complications with reoperation.DiscussionIn pediatric cases, PLGA implants may present excellent results for treating ankle fractures. They do not disturb the growth plate and do not require reoperation. For this reason, they reduce the burden on the patient and the healthcare provider while simultaneously decreasing the risk of complications, such as infections or problems due to general anesthesia.

INTRODUCTION: Open fractures are potentially devastating injuries for the professional athlete. We sought to compare return to sports (RTS) and performance in National Football League (NFL) athletes sustaining open versus closed fractures. METHODS: NFL athletes with surgically treated open and closed fractures of the forearm, tibial shaft, and ankle from 2009-2018 were identified through publicly available reports and records. Data including demographics, RTS, career duration, and the approximate value performance metric before and after injury were collected. Statistical analyses were performed comparing open to closed injuries. Continuous variables were compared using Mann-Whitney U or two sample t- tests while categorical variables were compared using Fishers exact test. RESULTS: Ninety-five athletes met inclusion criteria (10 open and 85 closed fractures). Overall, 90% (n = 9) returned to sport after an open injury and 83.5% (n = 71) returned after closed injury with a median time missed of 48.9 (range 35.1 - 117.4) weeks and 43.0 (range 2.4 - 108.0) weeks, respectively. Athletes undergoing forearm surgery were able to return sooner, at around 20.8 weeks, and ankle fractures conferred the lowest return rate at 80% (n = 48). There were no significant differences in career duration and post-injury performance between open or closed fracture cohorts. CONCLUSIONS: Although open fractures are relatively uncommon injuries seen in NFL athletes, our study suggests RTS for these players is high. Athletes undergoing surgical treatment for open fractures had similar RTS rates, performance metrics, and career durations compared to those with comparable closed fractures. This information can provide guidance for providers counseling elite athletes on postoperative expectations.

Study design: retrospective case series. Objective: the presenting clinical symptoms of spinal infections are often nonspecific and a delay in diagnosis can lead to adverse patient outcomes. The morbidity and mortality of patients with multifocal spinal infections is significantly higher compared to unifocal infections. The purpose of the current study was to analyse the risk factors for multifocal spinal infections. Methods: we conducted a retrospective review of all pyogenic non-tuberculous spinal infections treated surgically at a single tertiary care medical center from 2006-2020. The medical records, imaging studies, and laboratory data of 43 patients during this time period were reviewed and analysed after receiving Institutional Review Board approval. Univariate and multivariate analyses were performed to identify factors associated with a multifocal spinal infection. Results: 15 patients (35 %) had multifocal infections. In univariate analysis, there was a significant association with chronic kidney disease ( p = 0.040 ), gender ( p = 0.003 ), a white blood cell count ( p = 0.011 ), and cervical ( p < 0.001 ) or thoracic ( p < 0 .001) involvement. In multivariate analysis, both cervical and thoracic involvement remained statistically significant ( p = 0.001 and p < 0.001 , respectively). Conclusions: patients with infections in the thoracic or cervical region are more likely to have a multifocal infection. Multifocal pyogenic spinal infections remain a common entity and a total spine MRI should be performed to aid in prompt diagnosis.

We quantified concentrations of three isoforms of the endolysosomal lipid, bis(monoacylglycerol) phosphate (BMP) in the urine of deeply phenotyped cohorts in the Parkinson's Progression Markers Initiative: LRRK2 G2019S PD (N = 134) and non-manifesting carriers (NMC) (G2019S+ NMC; N = 182), LRRK2 R1441G PD (N = 15) and R1441G+ NMC (N = 15), GBA1 N409S PD (N = 76) and N409S+ NMC (N = 178), sporadic PD (sPD, N = 379) and healthy controls (HC) (N = 190). The effects of each mutation and disease status were analyzed using nonparametric methods. Longitudinal changes in BMP levels were analyzed using linear mixed models. At baseline, all LRRK2 carriers had 3-7× higher BMP levels compared to HC, irrespective of the disease status. GBA1 N409S carriers also showed significant, albeit smaller, elevation (~30-40%) in BMP levels compared to HC. In LRRK2 G2019S PD, urinary BMP levels remained stable over two years. Furthermore, baseline BMP levels did not predict disease progression as measured by striatal DaT imaging, MDS-UPDRS III Off, or MoCA in any of the cohorts. These data support the utility of BMP as a target modulation biomarker in therapeutic trials of genetic and sPD but not as a prognostic or disease progression biomarker.

La infancia como constructo social de la modernidad constituye un objeto de estudio de distintos campos de las Ciencias Sociales, pero también un objeto de intervención político-pedagógica. Este artículo tiene como propósito elaborar cruces interdisciplinarios en torno a la relación educación, escuela e infancias. Desde sus inicios la institución educativa se ocupó de la modelación de las sensibilidades y del disciplinamiento de los cuerpos de niños y niñas, contribuyendo a la construcción de un sujeto-infante hegemónico. En la actualidad los procesos de transformación cultural caracterizado por la economía del consumo, el auge desmedido de las nuevas tecnologías, los medios de comunicación y la desigualdad creciente producen nuevas subjetividades, así como diversas representaciones y discursos sobre estos sujetos. Esta reconstrucción teórica se realiza en el marco de una investigación socioeducativa que tiene como propósito comprender las experiencias emocionales que construyen niños y niñas en escuelas primarias situadas en contextos de vulnerabilidad social en Misiones, Argentina.

Background: Longer duration of deferred cord clamping (DCC), at least 120 s, is associated with the highest reduction in mortality compared to shorter durations of DCC or immediate cord clamping in preterm infants. We compared the neonatal outcomes of very preterm infants who received at least 60 s to those who received at least 120 s of DCC. Methods: This is a retrospective single-center study including preterm infants born n = 139) and 120 to 180 s in Period 2 (July 2016 to December 2019, n = 155). We compared the demographics, delivery room measures, and neonatal outcomes between the two periods as intent-to-treat analysis and per protocol analysis. Results: The intended duration of DCC was completed in 75% of infants in Period 1 (n = 106) and 76% of infants in Period 2 (n = 114). There was an increase in survival without major morbidities in the infants that received at least 120 s of DCC, which remained significant after adjusting for GA and erythropoietin use (Odds ratio 8.6, 95% CI 1.6 to 45.7). Conclusions: Longer duration of DCC is associated with improved survival without major morbidities in preterm infants

We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson's Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as

AbstractThis Glossary contains definitions, explanatory notes, and sources for terms used in physical organic chemistry. Its aim is to provide guidance on the terminology of physical organic chemistry, with a view to achieving a consensus on the meaning and applicability of useful terms and the abandonment of unsatisfactory ones. Owing to the substantial progress in the field, this 2021 revision of the Glossary is much expanded relative to the previous edition, and it includes terms from cognate fields.

(1) Background: This report aims to illustrate the development, progression, diagnosis, and treatment of chronically present articular surface lesions. (2) Methods: In this report, two patients are described from the point of the initial presentation of symptoms to surgical consultation based on radiologic findings. These patients underwent corrective surgery in the form of mosaicplasty to repair lesions present on the articular surface and the underlying subchondral bone. (3) Discussion: Diagnosing juvenile OCD remains challenging due to its variable clinical presentation and minute radiologic discoveries. X-rays are useful; however, the gold standard remains arthroscopy, which can be both diagnostic and therapeutic. Future prospects include the use of novel sonographic methods and the use of artificial intelligence within the given modalities. (4) Conclusions: The detailed imaging provided by MRI, combined with the insights from X-rays and potentially other modalities, allows for a nuanced understanding of this disease. This comprehensive approach ensures that treatment decisions are well-informed, optimising outcomes for young patients with this condition.

Nuclear pore complexes (NPCs) mediate the nucleocytoplasmic transport of macromolecules. Here we provide a structure of the isolated yeast NPC in which the inner ring is resolved by cryo-EM at sub-nanometer resolution to show how flexible connectors tie together different structural and functional layers. These connectors may be targets for phosphorylation and regulated disassembly in cells with an open mitosis. Moreover, some nucleoporin pairs and transport factors have similar interaction motifs, which suggests an evolutionary and mechanistic link between assembly and transport. We provide evidence for three major NPC variants that may foreshadow functional specializations at the nuclear periphery. Cryo-electron tomography extended these studies, providing a model of the in situ NPC with a radially expanded inner ring. Our comprehensive model reveals features of the nuclear basket and central transporter, suggests a role for the lumenal Pom152 ring in restricting dilation, and highlights structural plasticity that may be required for transport.

Following the outbreak of the COVID-19 pandemic, the U.S. government declared a state of emergency and many applied behavior analysis clinics temporarily closed. The current study described a pilot of an existing manualized caregiver behavior skills training, the Online and Applied System of Intervention Skills (OASIS), to promote telehealth caregiver training during the pandemic and facilitate the start of early intervention for families on waitlists. The OASIS telehealth curriculum trains caregivers to use applied behavior analysis with their children with autism spectrum disorder. Pre/post measures suggest that OASIS modestly improved parent knowledge, improved perceived quality of life, decreased stress, improved caregiver self-efficacy, and was viewed positively by participating families.

Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aβ)-positive EOAD, 200 Aβ-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18 F]Florbetaben and [18 F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.

ABSTRACT A female newborn presented with respiratory distress at birth and was diagnosed with congenital tracheal stenosis. The stenosis was positioned at the distal trachea and compromised the carina and the right and left bronchi. She underwent surgical treatment using circulatory life support with veno-arterial peripheral extracorporeal membrane oxygenation, and the airway was reconstructed using the slide tracheoplasty technique to build a neocarina. The patient had an excellent postoperative course, was successfully weaned from extracorporeal membrane oxygenation and invasive ventilation, and was discharged.

ObjectiveTo investigate maternal immunoglobulins' (IgM, IgG) response to SARS-CoV-2 infection during pregnancy and IgG transplacental transfer, to characterise neonatal antibody response to SARS-CoV-2 infection, and to longitudinally follow actively and passively acquired antibodies in infants.DesignA prospective observational study.SettingPublic healthcare system in Santa Clara County (California, USA).ParticipantsWomen with symptomatic or asymptomatic SARS-CoV-2 infection during pregnancy and their infants were enrolled between 15 April 2020 and 31 March 2021.OutcomesSARS-CoV-2 serology analyses in the cord and maternal blood at delivery and longitudinally in infant blood between birth and 28 weeks of life.ResultsOf 145 mothers who tested positive for SARS-CoV-2 during pregnancy, 86 had symptomatic infections: 78 with mild-moderate symptoms, and 8 with severe-critical symptoms. The seropositivity rates of the mothers at delivery was 65% (95% CI 0.56% to 0.73%) and the cord blood was 58% (95% CI 0.49% to 0.66%). IgG levels significantly correlated between the maternal and cord blood (Rs=0.93, p