Screening Strategies for Sleep-Disordered Breathing in Patients With Spinal Cord Injury in a Tertiary Care Rehabilitation Center.

BACKGROUND: Sleep-disordered breathing (SDB) is frequent in patients with spinal-cord injury (SCI). However, SDB is frequently underdiagnosed due to limited access to diagnostic testing and knowledge about the condition. Moreover, SDB heterogeneity (sleep apnea, obstructive sleep apnea or central sleep apnea and nocturnal alveolar hypoventilation) implies complex evaluation of both nocturnal respiratory effort and hypercapnia. The aim of this study was to compare different screening strategies for an SDB diagnosis in patients with SCI. METHODS: This was a retrospective analysis of data from subjects with SCI followed up in a tertiary-care rehabilitation center with a specialized sleep unit. Subjective (questionnaires) and objective data (polysomnography [PSG]), SpO2 extracted from the PSG, morning blood gases, and nocturnal transcutaneous CO2 (PtcCO2 ) were collected and analyzed. A retrospective comparison of different strategies for SDB screening was carried out. Each strategy was compared (alone and in combination) with the standard of care for sleep apnea (PSG) and nocturnal alveolar hypoventilation (PtcCO2 ) diagnosis. The performance of the usual cutoff and visual analysis was studied. RESULTS: Among 190 subjects with SCI who underwent a full night's PSG, data were available for 104 questionnaires and 162 with oximetry. Nocturnal alveolar hypoventilation was screened by PtcCO2 and blood gases in 52 subjects with SCI. Questionnaires (the modified Screening for Obstructive Sleep Apnea in Tetraplegia and the Epworth Sleepiness Scale) had poor performance for identifying sleep apnea and did not identify nocturnal alveolar hypoventilation. SpO2 (oxygen desaturation index score ≥ 13) and visual analysis of SpO2 were good at identifying sleep apnea but insufficient to identify nocturnal alveolar hypoventilation. Diurnal blood gases were poor predictors of nocturnal alveolar hypoventilation. CONCLUSIONS: Questionnaires were of limited use in subjects with SCI, but the oxygen desaturation index derived from oximetry performed well for sleep apnea screening. Both diurnal blood gases and oximetry visual analysis were insufficient for nocturnal alveolar hypoventilation screening. PtcCO2 monitoring should be mandatory and ideally combined with PSG given the heterogeneity of SDB phenotypes and associated sleep comorbidities of patients with SCI.

Concomitant Botulinum Toxin Injections for Neurogenic Detrusor Overactivity and Spasticity-A Retrospective Analysis of Practice and Safety.

As multiple indications for botulinum toxin injections (BTIs) can coexist for neurological patients, there are to date no description of concomitant injections (CIs) to treat both spasticity and neurogenic detrusor overactivity incontinence (NDOI) in patients with spinal cord injuries (SCIs) and multiple sclerosis (MS). We therefore identified patients followed at our institution by health data hub digging, using a specific procedure coding system in use in France, who have been treated at least once with detrusor and skeletal muscle BTIs within the same 1-month period, over the past 5 years (2017-2021). We analyzed 72 patients representing 319 CIs. Fifty (69%) were male, and the patients were mostly SCI (76%) and MS (18%) patients and were treated by a mean number of CIs of 4.4 ± 3.6 [1-14]. The mean cumulative dose was 442.1 ± 98.8 U, and 95% of CIs were performed within a 72 h timeframe. Among all CIs, five patients had symptoms evocative of distant spread but only one had a confirmed pathological jitter in single-fiber EMG. Eleven discontinued CIs for surgical alternatives: enterocystoplasty (five), tenotomy (three), intrathecal baclofen (two) and neurotomy (one). Concomitant BTIs for treating both spasticity and NDOI at the same time appeared safe when performed within a short delay and in compliance with actual knowledge for maximum doses.

The expanding clinical and genetic spectrum of DYNC1H1-related disorders.

Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy-chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging, and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.

Development and evaluation of two educational sessions on take-home lead exposure prevention for construction workers and their families.

Take-home exposures occur when workers accidentally bring workplace contaminants home. Regular job responsibilities may expose construction workers to lead, which extends to their households via the take-home pathway. The present study aimed to develop and evaluate 2 educational sessions addressing take-home lead exposure tailored to construction workers and their families. Educational materials on take-home lead exposure and prevention strategies were designed following guidance from US government institutions and experts on construction work, lead exposure, and educational interventions. The educational materials were pilot-tested with construction workers and their family members during in-person or online sessions in English or Spanish. Changes in knowledge of take-home lead exposure were assessed through pre- and post-testing and open-ended feedback was collected from both participants and session facilitators. The study sample comprised 44 participants, including 33 workers and 11 family members. Among all participants, 81% were male, 46% were Hispanic or Latino, and the average age was 29 years. Post-test scores (µ = 93%, SD = 10%) were higher than pre-test scores (µ = 82%, SD = 19%), and younger participants (<30 years) were more likely to have a lower pre-test score compared to older participants (≥30 years). Overall, feedback from participants and facilitators was positive, indicating appropriate duration, appealing visuals, and ease of engagement through the training activities. Effective public health education for lead-exposed construction workers and their families is needed to reduce lead exposure disparities, especially among children of workers. Interventions must recognize that take-home exposures are not isolated to occupational or home environments.

Variations in the Anatomic Morphology of the Scapular Spine and Implications on Fracture After Reverse Shoulder Arthroplasty.

INTRODUCTION: This study evaluates the role of anatomic scapular morphology in acromion and scapular spine fracture (SSAF) risk after reverse shoulder arthroplasty (RSA). METHODS: Twelve scapular measurements were captured based on pilot study data, including scapular width measurements at the acromion (Z1), middle of the scapular spine (Z2), and medial to the first major angulation (Z3). Measurements were applied to 3D-CT scans from patients who sustained SSAF after RSA (SSAF group) and compared with those who did not (control group). Measurements were done by four investigators, and the intraclass correlation coefficient was calculated. Regression analysis determined trends in fracture incidence. RESULTS: One hundred forty-nine patients from two separate surgeons (J.L., A.M.) were matched by age and surgical indication of whom 51 sustained SSAF after reverse shoulder arthroplasty. Average ages for the SSAF and control cohorts were 78.6 and 72.1 years, respectively. Among the SSAF group, 15 were Levy type I, 26 Levy type II, and 10 Levy type 3 fractures. The intraclass correlation coefficient of Z1, Z2, and Z3 measurements was excellent (0.92, 0.92, and 0.94, respectively). Zone 1 and 3 measurements for the control group were 18.6 ± 3.7 mm and 3.2 ± 1.0 mm, respectively, compared with 22.5 ± 5.9 mm and 2.0 ± 0.70 mm in the SSAF group, respectively. The fracture group trended toward larger Z1 and smaller Z3 measurements. The average scapular spine proportion (SSP), Z1/Z3, was significantly greater in the control 6.20 ± 1.80 versus (12.60 ± 6.30; P < 0.05). Regression analysis showed a scapular spine proportion of ≤5 was associated with a fracture risk <5%, whereas an SSP of 9.2 correlated with a 50% fracture risk. DISCUSSION: Patients with a thicker acromions (Z1) and thinner medial scapular spines (Z3) have increased fracture risk. Understanding anatomic scapular morphology may allow for better identification of high-risk patients preoperatively.

Correlation Between Patient-Reported and Clinician-Measured Shoulder Range of Motion in Patients Undergoing Shoulder Surgery.

INTRODUCTION: There has been increasing interest in remote measures of patients' health, both in the clinical and research settings. This study sought to evaluate correlations between patient-reported and clinician-measured (CM) shoulder range of motion (ROM). METHODS: ROM measures including elevation, abduction, and internal rotation were recorded by a patient-reported picture-based survey and clinician measurement during each patient visit. A total of 13,842 visits over a 16-year period met inclusion criteria. Spearman correlation was performed to determine the correlation between patient-reported and CM elevation, abduction, and internal rotation. A subgroup analysis was conducted to evaluate motion in patients who underwent arthroplasty and arthroscopy. RESULTS: Patients were 52.4% male with a median age of 67 years (range, 18 to 96). PR and CM shoulder ROM were gathered at 13,842 patient visits. Strong correlations between PR and CM elevation (r = 0.70) and internal rotation (r = 0.66) were found, as well as a moderate correlation between PR and CM abduction (r = 0.59). Strong correlations were found between all three PR and CM measures of motion in the arthroplasty subgroup (elevation r = 0.74, abduction r = 0.63, and internal rotation r = 0.64). CONCLUSIONS: There is a strong correlation between patient-reported and CM shoulder elevation and internal rotation, as well as a moderate correlation between PR and CM abduction. This allows for a method of assessing patient motion without requiring an in-person visit. LEVEL OF EVIDENCE: Level III Retrospective Cohort Study.

Multiple Prenatal Exposures and Acute Care Clinical Encounters for Asthma among Children Born to Mothers Living near a Superfund Site.

Prenatal exposures are associated with childhood asthma, and risk may increase with simultaneous exposures. Pregnant women living in lower-income communities tend to have elevated exposures to a range of potential asthma risk factors, which may interact in complex ways. We examined the association between prenatal exposures and the risk of childhood asthma acute care clinical encounters (hospitalization, emergency department visit, observational stay) using conditional logistic regression with a multivariable smooth to model the interaction between continuous variables, adjusted for maternal characteristics, and stratified by sex. All births near the New Bedford Harbor (NBH) Superfund site (2000-2006) were followed through 2011 using the Massachusetts Pregnancy to Early Life Longitudinal data system to identify children ages 5-11 with asthma acute care clinical encounters (265 cases among 7,787 with follow-up). Hazard ratios (HRs) were higher for children living closer to the NBH with higher cord blood Pb levels than children living further away from the NBH with lower Pb levels (P<0.001). HRs were highest for girls (HR=4.17, 95% CI: 3.60, 4.82) compared to boys (HR=1.72, 95% CI: 1.46, 2.02). Our results suggest that prenatal Pb exposure in combination with residential proximity to the NBH is associated with childhood asthma acute care clinical encounters.

Neural alignment during outgroup intervention predicts future change of affect towards outgroup.

While social psychology studies have shown that paradoxical thinking intervention has a moderating effect on negative attitudes toward members from rival social groups (i.e. outgroup), the neural underpinnings of the intervention have not been studied. Here, we investigate this by examining neural alignment across individuals at different phases during the intervention regarding Covid-19 vaccine-supporters' attitudes against vaccine-opposers. We raise two questions: Whether neural alignment varies during the intervention, and whether it predicts a change in outgroup attitudes measured via a survey 2 days after the intervention and compared to baseline. We test the neural alignment using magnetoencephalography-recorded neural oscillations and multiset canonical correlation analysis. We find a build-up of neural alignment which emerges at the final phase of the paradoxical thinking intervention in the precuneus-a hub of mentalizing; there was no such effect in the control conditions. In parallel, we find a behavioral build-up of dissent to the interventional stimuli. These neural and behavioral patterns predict a prosocial future change in affect and actions toward the outgroup. Together, these findings reveal a new operational pattern of mentalizing on the outgroup, which can change the way individuals may feel and behave toward members of that outgroup.

Post-translational modification-centric base editor screens to assess phosphorylation site functionality in high throughput.

Signaling pathways that drive gene expression are typically depicted as having a dozen or so landmark phosphorylation and transcriptional events. In reality, thousands of dynamic post-translational modifications (PTMs) orchestrate nearly every cellular function, and we lack technologies to find causal links between these vast biochemical pathways and genetic circuits at scale. Here we describe the high-throughput, functional assessment of phosphorylation sites through the development of PTM-centric base editing coupled to phenotypic screens, directed by temporally resolved phosphoproteomics. Using T cell activation as a model, we observe hundreds of unstudied phosphorylation sites that modulate NFAT transcriptional activity. We identify the phosphorylation-mediated nuclear localization of PHLPP1, which promotes NFAT but inhibits NFκB activity. We also find that specific phosphosite mutants can alter gene expression in subtle yet distinct patterns, demonstrating the potential for fine-tuning transcriptional responses. Overall, base editor screening of PTM sites provides a powerful platform to dissect PTM function within signaling pathways.

Aircraft noise exposure and body mass index among female participants in two Nurses' Health Study prospective cohorts living around 90 airports in the United States.

OBJECTIVE: Aircraft noise exposure is linked to cardiovascular disease risk. One understudied candidate pathway is obesity. This study investigates the association between aircraft noise and obesity among female participants in two prospective Nurses' Health Study (NHS and NHSII) cohorts. METHODS: Aircraft day-night average sound levels (DNL) were estimated at participant residential addresses from modeled 1 dB (dB) noise contours above 44 dB for 90 United States (U.S.) airports in 5-year intervals 1995-2010. Biennial surveys (1994-2017) provided information on body mass index (BMI; dichotomized, categorical) and other individual characteristics. Change in BMI from age 18 (BMI18; tertiles) was also calculated. Aircraft noise exposures were dichotomized (45, 55 dB), categorized (<45, 45-54, ≥55 dB) or continuous for exposure ≥45 dB. Multivariable multinomial logistic regression using generalized estimating equations were adjusted for individual characteristics and neighborhood socioeconomic status, greenness, population density, and environmental noise. Effect modification was assessed by U.S. Census region, climate boundary, airline hub type, hearing loss, and smoking status. RESULTS: At baseline, the 74,848 female participants averaged 50.1 years old, with 83.0%, 14.8%, and 2.2% exposed to <45, 45-54, and ≥55 dB of aircraft noise, respectively. In fully adjusted models, exposure ≥55 dB was associated with 11% higher odds (95% confidence interval [95%CI]: -1%, 24%) of BMIs ≥30.0, and 15% higher odds (95%CI: 3%, 29%) of membership in the highest tertile of BMI18 (ΔBMI 6.7 to 71.6). Less-pronounced associations were observed for the 2nd tertile of BMI18 (ΔBMI 2.9 to 6.6) and BMI 25.0-29.9 as well as exposures ≥45 versus <45 dB. There was evidence of DNL-BMI trends (ptrends ≤ 0.02). Stronger associations were observed among participants living in the West, arid climate areas, and among former smokers. DISCUSSION: In two nationwide cohorts of female nurses, higher aircraft noise exposure was associated with higher BMI, adding evidence to an aircraft noise-obesity-disease pathway.

It's not you (well, it is a bit you), it's me: Self- versus social image in warm-glow giving.

Attempts by charities to motivate giving tend to focus on potential donors' altruistic tendencies. However, prior research suggests that approximately 50% of individuals are to some extent motivated by warm glow, the satisfaction received from the act of giving. The satisfaction derives from looking good to themselves (self-image) and/or to others (social image). We conduct an online experiment on MTurk participants (n = 960) with a more realistic simulation of being watched to determine the importance of self- and social image to warm-glow giving. We find evidence that suggests that social image concerns do not increase the likelihood that someone will give but they do increase the amount given; average giving is significantly higher in the treatments when feelings of being watched are stimulated. Our results suggest that charities looking to increase their donor bases might effectively do so by focusing on self-image concerns. Charities wishing to increase the amount donated might effectively do so by focusing on the social image concerns of the donor.

Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study.

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.

The association of maternal-infant interactive behavior, dyadic frontal alpha asymmetry, and maternal anxiety in a smartphone-adapted still face paradigm.

Mother-infant interactions form a strong basis for emotion regulation development in infants. These interactions can be affected by various factors, including maternal postnatal anxiety. Electroencephalography (EEG) hyperscanning allows for simultaneous assessment of mother-infant brain-to-behavior association during stressful events, such as the still-face paradigm (SFP). This study aimed at investigating dyadic interactive behavior and brain-to-behavior association across SFP and identifying neural correlates of mother-infant interactions in the context of maternal postnatal anxiety. We measured frontal alpha asymmetry (FAA), a physiological correlate of emotion regulation and a potential marker of risk for psychopathology. To emulate real-life interactions, EEG and behavioral data were collected from 38 mother-infant dyads during a smartphone-adapted dual-SFP. Although the behavioral data showed a clear still-face effect for the smartphone-adapted SFP, this was not reflected in the infant or maternal FAA. Brain-to-behavior data showed higher infant negative affect being associated with more infant leftward FAA during the still-face episodes. Finally, mothers with higher postnatal anxiety showed more right FAA during the first still-face episode, suggesting negative affectivity and a need to withdraw from the situation. Our results form a baseline for further research assessing the effects of maternal postnatal anxiety on infants' FAA and dyadic interactive behavior.

Generation WhatsApp: inter-brain synchrony during face-to-face and texting communication.

Texting has become one of the most prevalent ways to interact socially, particularly among youth; however, the effects of text messaging on social brain functioning are unknown. Guided by the biobehavioral synchrony frame, this pre-registered study utilized hyperscanning EEG to evaluate interbrain synchrony during face-to-face versus texting interactions. Participants included 65 mother-adolescent dyads observed during face-to-face conversation compared to texting from different rooms. Results indicate that both face-to-face and texting communication elicit significant neural synchrony compared to surrogate data, demonstrating for the first time brain-to-brain synchrony during texting. Direct comparison between the two interactions highlighted 8 fronto-temporal interbrain links that were significantly stronger in the face-to-face interaction compared to texting. Our findings suggest that partners co-create a fronto-temporal network of inter-brain connections during live social exchanges. The degree of improvement in the partners' right-frontal-right-frontal connectivity from texting to the live social interaction correlated with greater behavioral synchrony, suggesting that this well-researched neural connection may be specific to face-to-face communication. Our findings suggest that while technology-based communication allows humans to synchronize from afar, face-to-face interactions remain the superior mode of communication for interpersonal connection. We conclude by discussing the potential benefits and drawbacks of the pervasive use of texting, particularly among youth.

Functional and radiographic results of anatomic total shoulder arthroplasty in the setting of subscapularis dysfunction: 5-year outcomes analysis.

BACKGROUND: Subscapularis management is a critical component to the success of anatomic total shoulder arthroplasty (TSA). Failure to heal the subscapularis can result in pain, weakness, loss of function, and revision. However, not all patients have poor outcomes. The purpose of this study is to compare patients with normal and dysfunctional subscapularis function following TSA in regard to (1) patient-reported outcome measures (PROMs); (2) range of motion (ROM) and strength; (3) achievement of minimal clinically important differences (MCIDs); and (4) specific functional internal rotation tasks. METHODS: A retrospective review of patients treated with TSA for osteoarthritis with a minimum 2-year follow-up was performed to identify patients with subscapularis dysfunction. Subscapularis dysfunction was diagnosed when any degree of weakness in internal rotation was detected on physical examination (positive belly press sign). These patients were case controlled matched on a 1:3 ratio to patients with normal subscapularis function based on age and sex. PROMs, measured active motion, revision rates, patient satisfaction, and postoperative radiographic findings were compared. Population-specific institutional anchor-based MCID values were used to compare the improvement in PROM. RESULTS: Of the 668 patients included, 34 patients (5.1%) demonstrated evidence of subscapularis dysfunction. Mean follow-up for the normal subscapularis function cohort was 63.4 ± 29.7 and 58.7 ± 26.8 for the dysfunctional subscapularis cohort. Patients with subscapularis dysfunction demonstrated significantly worse postoperative Simple Shoulder Test, Single Assessment Numerical Evaluation, visual analog scale (VAS) function, VAS pain, and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores with higher rates of unsatisfactory results when compared to patients with normal subscapularis function. Abduction, elevation, internal rotation ROM, along with supraspinatus and external rotation strength were also significantly worse in the dysfunctional group. Similarly, these patients were more likely to have decreased ability to perform functional internal rotation tasks, with only 47% of the patients being able to reach the small of their back compared to 85% with normal subscapularis function. Radiographically, the dysfunctional cohort demonstrated higher rates of anterior subluxation (56% vs. 7%; P < .001) and glenoid loosening (24% vs. 5%; P = .004). Similarly, revision rates were significantly higher for patients with subscapularis dysfunction (8 patients, 23.5%). Nonetheless, the dysfunctional subscapularis cohort demonstrated improvements in VAS pain (4.0 ± 3.7) and ASES (46.4 ± 35.9) scores that exceeded MCID thresholds. CONCLUSION: Patients who develop subscapularis dysfunction after TSA have significantly worse PROMs, ROM, functional tasks of internal rotation, and radiographic outcomes, as well as increased rates of revision. Although patients show worse outcomes and high revision rates compared with their normal-functioning counterparts, these patients maintained improvement above MCID thresholds for pain and function at a mean 5-year follow-up.

Efficient prime editing in mouse brain, liver and heart with dual AAVs.

Realizing the promise of prime editing for the study and treatment of genetic disorders requires efficient methods for delivering prime editors (PEs) in vivo. Here we describe the identification of bottlenecks limiting adeno-associated virus (AAV)-mediated prime editing in vivo and the development of AAV-PE vectors with increased PE expression, prime editing guide RNA stability and modulation of DNA repair. The resulting dual-AAV systems, v1em and v3em PE-AAV, enable therapeutically relevant prime editing in mouse brain (up to 42% efficiency in cortex), liver (up to 46%) and heart (up to 11%). We apply these systems to install putative protective mutations in vivo for Alzheimer's disease in astrocytes and for coronary artery disease in hepatocytes. In vivo prime editing with v3em PE-AAV caused no detectable off-target effects or significant changes in liver enzymes or histology. Optimized PE-AAV systems support the highest unenriched levels of in vivo prime editing reported to date, facilitating the study and potential treatment of diseases with a genetic component.

Clinico-biological refinement of BCL11B-related disorder and identification of an episignature: A series of 20 unreported individuals.

PURPOSE: BCL11B-related disorder (BCL11B-RD) arises from rare genetic variants within the BCL11B gene, resulting in a distinctive clinical spectrum encompassing syndromic neurodevelopmental disorder, with or without intellectual disability, associated with facial features and impaired immune function. This study presents an in-depth clinico-biological analysis of 20 newly reported individuals with BCL11B-RD, coupled with a characterization of genome-wide DNA methylation patterns of this genetic condition. METHODS: Through an international collaboration, clinical and molecular data from 20 individuals were systematically gathered, and a comparative analysis was conducted between this series and existing literature. We further scrutinized peripheral blood DNA methylation profile of individuals with BCL11B-RD, contrasting them with healthy controls and other neurodevelopmental disorders marked by established episignature. RESULTS: Our findings unveil rarely documented clinical manifestations, notably including Rubinstein-Taybi-like facial features, craniosynostosis, and autoimmune disorders, all manifesting within the realm of BCL11B-RD. We refine the intricacies of T cell compartment alterations of BCL11B-RD, revealing decreased levels naive CD4+ T cells and recent thymic emigrants while concurrently observing an elevated proportion of effector-memory expressing CD45RA CD8+ T cells (TEMRA). Finally, a distinct DNA methylation episignature exclusive to BCL11B-RD is unveiled. CONCLUSION: This study serves to enrich our comprehension of the clinico-biological landscape of BCL11B-RD, potentially furnishing a more precise framework for diagnosis and follow-up of individuals carrying pathogenic BCL11B variant. Moreover, the identification of a unique DNA methylation episignature offers a valuable diagnosis tool for BCL11B-RD, thereby facilitating routine clinical practice by empowering physicians to reevaluate variants of uncertain significance within the BCL11B gene.

Acromion fractures after reverse shoulder arthroplasty occur in predictable clusters.

BACKGROUND: Acromion and scapular spine fractures (ASFs) following reverse total shoulder arthroplasty (RSA) have been reported at a rate of 3.9%. The location of the fracture has been shown to be an important factor in determining the outcomes of nonoperative treatment, with medial fractures having worse outcomes than lateral fractures. As the debate between operative and nonoperative treatment continues, a more precise understanding of the location of the fracture is necessary for effective management. The purpose of this study was to use 3-dimensional computed tomography (CT) reconstruction to characterize the exact location of ASFs after RSA. METHODS: A retrospective review of 2 separate institutional shoulder and elbow repositories was performed. Patients with post-RSA ASFs documented by post-fracture CT scans were included. The query identified 48 patients who sustained postoperative ASFs after RSA between July 2008 and September 2021. CT scans of patients with ASFs were segmented using Mimics software. Eight patients were excluded because of poor image quality. Each bone model was manipulated using 3-Matic Medical software to align the individual scapula with an idealized bone model to create a view of scapular fracture locations on a normalized bone model. This model was used to classify the fractures using the modified Levy classification. RESULTS: The study cohort consisted of 40 patients with a diagnosis of postoperative ASF after RSA. The median age at the time of surgery was 76 years (interquartile range, 73-79 years). The cohort comprised 32 women (80%) and 8 men (20%), with a median body mass index of 27.8. Only 10 patients (25%) had a previous diagnosis of osteoporosis and 6 (13%) had a diagnosis of inflammatory arthritis; 53% of patients underwent RSA owing to rotator cuff tear arthropathy. The distribution of fracture locations was similar within the cohort. However, lateral fractures were slightly more prevalent. The most common fracture location was the type I zone, with 12 fracture lines (29%). There were 11 fracture lines (26%) in the type IIa zone, 10 (23%) in the type IIb zone, 0 in the type IIc zone, and 9 (21%) in the type III zone. CONCLUSION: ASFs after RSA occur in 4 predictable clusters. No fractures appeared to distinctly cluster in the type IIc zone, which may not represent a true fracture zone. Understanding the distribution of these fractures will help to enable the future design of implants and devices to stabilize the fractures that require fixation.

MyPathway Human Epidermal Growth Factor Receptor 2 Basket Study: Pertuzumab + Trastuzumab Treatment of a Tissue-Agnostic Cohort of Patients With Human Epidermal Growth Factor Receptor 2-Altered Advanced Solid Tumors.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The MyPathway multiple-basket study (ClinicalTrials.gov identifier: NCT02091141) is evaluating targeted therapies in nonindicated tumors with relevant molecular alterations. We assessed pertuzumab + trastuzumab in a tissue-agnostic cohort of adult patients with human epidermal growth factor receptor 2 (HER2)-amplified and/or -overexpressed and/or -mutated solid tumors. The primary end point was objective response rate (ORR); secondary end points included survival and safety. At data cutoff (March 2022), 346 patients with HER2 amplification and/or overexpression with/without HER2 mutations (n = 263), or HER2 mutations alone (n = 83) had been treated. Patients with HER2 amplification and/or overexpression had an ORR of 25.9% (68/263, 95% CI, 20.7 to 31.6), including five complete responses (urothelial [n = 2], salivary gland [n = 2], and colon [n = 1] cancers). Activity was higher in those with wild-type (ORR, 28.1%) versus mutated KRAS (ORR, 7.1%). Among patients with HER2 amplification, ORR was numerically higher in patients with immunohistochemistry (IHC) 3+ (41.0%; 32/78) or 2+ (21.9%; 7/32), versus 1+ (8.3%; 1/12) or no expression (0%; 0/20). In patients with HER2 mutations alone, ORR was 6.0% (5/83, 95% CI, 2.0 to 13.5). Pertuzumab + trastuzumab showed activity in various HER2-amplified and/or -overexpressed tumors with wild-type KRAS, with the range of activity dependent on tumor type, but had limited activity in the context of KRAS mutations, HER2 mutations alone, or 0-1+ HER2 expression.