α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies.

Aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Evidence exists for aSyn "strains" - conformations with distinct biological properties. However, biomarkers for PD vs. DLB, including potential aSyn strain differences, are lacking. Here, we used two monoclonal antibodies selective for different in vitro aSyn species - termed Strain A and B - to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma. Surprisingly, levels of Strain A and B aSyn species differed in plasma from individuals with PD vs. DLB in two independent cohorts. Lower plasma aSyn Strain A species also predicted subsequent PD cognitive decline. Strain A and Strain B aSyn species were undetectable in CSF, but plasma aSyn species could template aSyn fibrillization, particularly in PD. Our findings suggest that aSyn strains may impact LBD clinical presentation and originate outside the brain.

Mixed-field ABO front typing as an early sign of disease recurrence in ABO-matched stem cell transplantation.

ABO group testing is critical for allogeneic stem cell transplantation because mismatches can cause both transfusion and engraftment challenges. Even with ABO-matched donor-recipient pairs, ABO group determination may provide valuable insight into allograft status. Herein, we report a case of a 76-year-old female patient with myeloid neoplasm who underwent ABO-matched stem cell transplantation and in whom mixed-field ABO antigen expression during routine follow-up testing post-transplantation was the first sign of a change in transplant graft status; the mixed-field findings pre-dated changes in formal chimerism testing. This case underscores the potential of mixed-field ABO typing as an early indicator of disease recurrence in ABO-matched stem cell transplants and suggests that, in such cases, more sensitive forms of chimerism testing and/or closer monitoring for disease recurrence, particularly in the clinical setting of myeloid neoplasms, may be warranted.

Utilizing Relative Citation Ratio to Compare Academic Productivity by Gender in Plastic Surgery.

INTRODUCTION: The relative citation ratio (RCR) is a bibliometric index utilized to assess research productivity. Mean relative citation ratio (m-RCR) and weighted relative citation ratio (w-RCR) can be utilized to assess individual research quality as well as career-long productivity, respectively. We sought to determine differences in academic productivity between genders and identify demographic variables associated with increased academic productivity. METHODS: A list of Plastic and Reconstructive Surgery residency programs was compiled utilizing the American Council of Academic Plastic Surgeons website. Each program department's website was utilized to generate a list of practicing surgeons and respective demographic information. Both mean and weighted RCR were obtained using the iCite, a National Institutes of Health bibliometric tool. Surgeons were excluded if any demographic or RCR data was not accessible. Chi-squared test, Mann-Whitney U test, Kruskal-Wallis test, and multivariable linear regressions were performed. RESULTS: A total of 785 academic plastic surgeons met the criteria and were included in the analysis, 186 of whom were women and 599 men. Both academic rank and model of residency training were significantly associated with gender in chi-squared analysis (P < 0.05). Mean relative citation ratio was higher among men in departments. Mean w-RCR was higher among men of assistant professor status, chief/chairperson status, integrated model of residency training, faculty size ≥six and in departments and divisions. Academic rank and faculty size were associated with higher w-RCR upon multivariable linear regression. CONCLUSIONS: Although differences exist in mean w-RCR between men and women in plastic surgery, gender is not a predictor of increased academic productivity. RCR is an accurate means of assessing gender differences in academic productivity as it comprehensively considers both quality and quantity of research and may be superior to other, older bibliometric indices.

An international study presenting a federated learning AI platform for pediatric brain tumors.

While multiple factors impact disease, artificial intelligence (AI) studies in medicine often use small, non-diverse patient cohorts due to data sharing and privacy issues. Federated learning (FL) has emerged as a solution, enabling training across hospitals without direct data sharing. Here, we present FL-PedBrain, an FL platform for pediatric posterior fossa brain tumors, and evaluate its performance on a diverse, realistic, multi-center cohort. Pediatric brain tumors were targeted due to the scarcity of such datasets, even in tertiary care hospitals. Our platform orchestrates federated training for joint tumor classification and segmentation across 19 international sites. FL-PedBrain exhibits less than a 1.5% decrease in classification and a 3% reduction in segmentation performance compared to centralized data training. FL boosts segmentation performance by 20 to 30% on three external, out-of-network sites. Finally, we explore the sources of data heterogeneity and examine FL robustness in real-world scenarios with data imbalances.

Association of quantitative histopathology measurements with antemortem medial temporal lobe cortical thickness in the Alzheimer's disease continuum.

The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer's disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies.

Treatment of Brachial Plexus Injuries following Gunshot Injuries: A Systematic Review.

Introduction: Brachial plexus injuries (BPI) from gunshot injuries are uncommon but usually severe and can cause chronic pain, loss of function, and permanent nerve damage. Multiple surgical techniques including neurolysis, end-to-end suture repair, and graft repair have been described for the treatment of these injuries. However, surgical indication, timing, and technique for these injuries remain controversial. This systematic review aims to investigate the treatment modalities for patients with BPI due to gunshot-related injuries. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) methodology was employed for this review. PubMed, Cochrane Reviews, Embase, and CINAHL databases were included. The following keywords constituted our search criteria: gun-shot-wounds, brachial plexus, traum∗, and management. Results: A total of 90 studies were imported for screening, from which 9 papers met our final inclusion/exclusion criteria. The most common studies utilized in this review were retrospective chart reviews followed by case series. In total, there were 628 patients that suffered from gunshot wounds to the brachial plexus. Most patients underwent some form of delayed nerve repair consisting of neurolysis, end-to-end epineural repair, or graft repair with a sural or antebrachial cutaneous nerve graft. Several patients suffered from complications, with neuroma being the most common long-term complication that required reoperation. Conclusion: The optimal timing for surgeries involving BPIs should be determined after examining the level of nerve damage, associated injuries, operative risks, and electrophysiological workup for indications of spontaneous regeneration. Early surgical interventions were indicated for patients presenting with associated vascular or thoracic injuries, compressive masses, and nerve transection by sharp instruments in most selected papers.

Mechanisms of manipulation: a systematic review of the literature on immediate anatomical structural or positional changes in response to manually delivered high-velocity, low-amplitude spinal manipulation.

BACKGROUND: Spinal manipulation (SM) has been claimed to change anatomy, either in structure or position, and that these changes may be the cause of clinical improvements. The aim of this systematic review was to evaluate and synthesise the peer-reviewed literature on the current evidence of anatomical changes in response to SM. METHODS: The review was registered with PROSPERO (CRD42022304971) and reporting was guided by the standards of the PRISMA Statement. We searched Medline, Embase, CINAHL, AMED, Cochrane Library all databases, PEDro, and the Index to Chiropractic Literature from inception to 11 March 2022 and updated on 06 June 2023. Search terms included manipulation, adjustment, chiropractic, osteopathy, spine and spine-related structures. We included primary research studies that compared outcomes with and without SM regardless of study design. Manipulation was defined as high-velocity, low-amplitude thrust delivered by hand to the spine or directly related joints. Included studies objectively measured a potential change in an anatomical structure or in position. We developed a novel list of methodological quality items in addition to a short, customized list of risk of bias (RoB) items. We used quality and RoB items together to determine whether an article was credible or not credible. We sought differences in outcomes between SM and control groups for randomised controlled trials and crossover studies, and between pre- and post-SM outcomes for other study designs. We reported, in narrative form, whether there was a change or not. RESULTS: The search retrieved 19,572 articles and 20 of those were included for review. Study topics included vertebral position (n = 3) facet joint space (n = 5), spinal stiffness (n = 3), resting muscle thickness (n = 6), intervertebral disc pressure (n = 1), myofascial hysteresis (n = 1), and further damage to already damaged arteries (n = 1). Eight articles were considered credible. The credible articles indicated that lumbar facet joint space increased and spinal stiffness decreased but that the resting muscle thickness did not change. CONCLUSION: We found few studies on this topic. However, there are two promising areas for future study: facet joint space and spinal stiffness. A research strategy should be developed with funding for high quality research centres.

Beyond the Rainbow: Advancing 2S/LGBTQ+ Health Equity at a Time of Political Volatility.

Two-Spirit, lesbian, gay, bisexual, transgender, queer and other sexual and gender minority (2S/LGBTQ+) populations continue to experience profound health disparities. In this article, we prioritize five issues in 2S/LGBTQ+ health equity and discuss policy interventions to address disparities in each area: (1) poverty in 2S/LGBTQ+ communities; (2) Two-Spirit mental health; (3) health equity issues in migrant and racialized LGBTQ+ populations; (4) challenges in implementing bans on conversion therapy; and (5) the evolving context of gender-affirming care. Multi-level policy interventions, including those in healthcare-adjacent contexts such as housing and immigration, will be critical to address the structural undercurrents driving health inequities for 2S/LGBTQ+ populations. Recognizing growing complexity and political volatility in the lives of 2S/LGBTQ+ people across Canada, we challenge healthcare policy actors to recognize the breadth of structural barriers to 2S/LGBTQ+ health equity issues and act with urgency in this area.

Achieving 2S/LGBTQ+ Health Equity Requires Grappling With the Structural Drivers of Poor Health in Sexual and Gender Minorities.

While the need for research, policy and practice addressing the health equity issues of Two-Spirit, lesbian, gay, bisexual, transgender, queer and other sexual and gender minority (2S/LGBTQ+) populations is increasingly recognized, we acknowledge that significant gaps remain in this area. As authors in this themed issue have consistently pointed out, interventions that grapple with the intersectionally varied structural drivers of 2S/LGBTQ+ health remain lacking and, in particular, warrant urgent consideration. This is especially the case during a time when structural threats to the well-being of 2S/LGBTQ+ populations are on the rise, both in Canada and in other geopolitical contexts.

Clinician Perspective on Once-Daily Zanubrutinib Dosing for B-Cell Malignancies at a Single Center.

Zanubrutinib, a next-generation, irreversible, highly potent, and selective Bruton tyrosine kinase inhibitor, is approved by the U.S. Food and Drug Administration to treat patients with B-cell malignancies in 2 dose regimens: 160 mg twice daily (BID) and 320 mg once daily (QD). Although the 160 mg BID regimen was the recommended phase 2 dose and more widely used in clinical trials, both regimens have yielded similar efficacy and safety. Currently, there is a lack of reported clinician experience on zanubrutinib QD versus BID practice patterns. This article provides perspectives on zanubrutinib dosing through interviews with 2 clinical care professionals at the Maryland Oncology Hematology Center, based on their experiences treating patients with Waldenström macroglobulinemia (WM) or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Zanubrutinib QD is the preferred regimen for some physicians and pharmacists, as it may improve treatment adherence within weeks after initiation compared with BID dosing. According to the clinician interviews provided in this report, patients have reported positive experiences with QD dosing, including a reduced administration burden in those with complicated polypharmacy. Thus, observations from this single center indicate that the zanubrutinib QD regimen may offer benefits to both patients with WM or CLL/SLL and their clinical care teams and should be considered in patients receiving zanubrutinib.

Automated deep learning segmentation of high-resolution 7 Tesla postmortem MRI for quantitative analysis of structure-pathology correlations in neurodegenerative diseases.

Postmortem MRI allows brain anatomy to be examined at high resolution and to link pathology measures with morphometric measurements. However, automated segmentation methods for brain mapping in postmortem MRI are not well developed, primarily due to limited availability of labeled datasets, and heterogeneity in scanner hardware and acquisition protocols. In this work, we present a high-resolution dataset of 135 postmortem human brain tissue specimens imaged at 0.3 mm3 isotropic using a T2w sequence on a 7T whole-body MRI scanner. We developed a deep learning pipeline to segment the cortical mantle by benchmarking the performance of nine deep neural architectures, followed by post-hoc topological correction. We evaluate the reliability of this pipeline via overlap metrics with manual segmentation in 6 specimens, and intra-class correlation between cortical thickness measures extracted from the automatic segmentation and expert-generated reference measures in 36 specimens. We also segment four subcortical structures (caudate, putamen, globus pallidus, and thalamus), white matter hyperintensities, and the normal appearing white matter, providing a limited evaluation of accuracy. We show generalizing capabilities across whole-brain hemispheres in different specimens, and also on unseen images acquired at 0.28 mm3 and 0.16 mm3 isotropic T2*w fast low angle shot (FLASH) sequence at 7T. We report associations between localized cortical thickness and volumetric measurements across key regions, and semi-quantitative neuropathological ratings in a subset of 82 individuals with Alzheimer's disease (AD) continuum diagnoses. Our code, Jupyter notebooks, and the containerized executables are publicly available at the project webpage (https://pulkit-khandelwal.github.io/exvivo-brain-upenn/).

The ADNI4 Digital Study: A novel approach to recruitment, screening, and assessment of participants for AD clinical research.

INTRODUCTION: We evaluated preliminary feasibility of a digital, culturally-informed approach to recruit and screen participants for the Alzheimer's Disease Neuroimaging Initiative (ADNI4). METHODS: Participants were recruited using digital advertising and completed digital surveys (e.g., demographics, medical exclusion criteria, 12-item Everyday Cognition Scale [ECog-12]), Novoic Storyteller speech-based cognitive test). Completion rates and assessment performance were compared between underrepresented populations (URPs: individuals from ethnoculturally minoritized or low education backgrounds) and non-URPs. RESULTS: Of 3099 participants who provided contact information, 654 enrolled in the cohort, and 595 completed at least one assessment. Two hundred forty-seven participants were from URPs. Of those enrolled, 465 met ADNI4 inclusion criteria and 237 evidenced possible cognitive impairment from ECog-12 or Storyteller performance. URPs had lower ECog and Storyteller completion rates. Scores varied by ethnocultural group and educational level. DISCUSSION: Preliminary results demonstrate digital recruitment and screening assessment of an older diverse cohort, including those with possible cognitive impairment, are feasible. Improving engagement and achieving educational diversity are key challenges. HIGHLIGHTS: A total of 654 participants enrolled in a digital cohort to facilitate ADNI4 recruitment. Culturally-informed digital ads aided enrollment of underrepresented populations. From those enrolled, 42% were from underrepresented ethnocultural and educational groups. Digital screening tools indicate > 50% of participants likely cognitively impaired. Completion rates and assessment performance vary by ethnocultural group and education.

Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics.

The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNA-seq and ATAC-seq in Alzheimer's disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), analyzing 41 participants and ∼1 million cells (RNA + ATAC) from three brain regions varying in vulnerability and pathological burden. We identify 32 shared, disease-associated cell types and 14 that are disease specific. Disease-specific cell states represent glial-immune mechanisms and selective neuronal vulnerability impacting layer 5 intratelencephalic neurons in AD, layer 2/3 intratelencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We identify disease-associated gene regulatory networks and cells impacted by causal genetic risk, which differ by disorder. These data illustrate the heterogeneous spectrum of glial and neuronal compositional and gene expression alterations in different dementias and identify therapeutic targets by revealing shared and disease-specific cell states.

Vitrectomy as an Adjunct to Treat-and-Extend Anti-VEGF Injections for Diabetic Macular Edema: The Vitrectomy in Diabetic Macular Oedema (VIDEO) Randomized Clinical Trial.

Importance: There are reported benefits from vitrectomy for diabetic macular edema (DME); however, data precede anti-vascular endothelial growth therapy (VEGF) therapy, supporting a need to assess the current role of vitrectomy. Objective: To determine rates of recruitment and efficacy outcomes of vitrectomy plus internal limiting membrane (ILM) peeling adjunctive to treat-and-extend (T&E) anti-VEGF injections for diabetic macular edema (DME). Design, Setting, and Participants: This was a single-masked, multicenter randomized clinical trial at 21 sites in the United Kingdom from June 2018 to January 2021, evaluating single eyes of treatment-naive patients with symptomatic vision loss from DME for less than 1 year. Inclusion criteria were best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score greater than 35 (approximate Snellen equivalent, 20/200 or better) and central subfield thickness (CST) greater than 350 µm after 3 monthly intravitreal injections of ranibizumab or aflibercept. Data analysis was performed in July 2023. Interventions: Patients were randomized 1:1 into vitrectomy plus standard care or standard care alone and further stratified into groups with vs without vitreomacular interface abnormality. Both groups received a T&E anti-VEGF injection regimen with aflibercept, 2 mg, or ranibizumab, 0.5 mg. The vitrectomy group additionally underwent pars plana vitrectomy with epiretinal membrane or ILM peel within 1 month of randomization. Main Outcomes and Measures: Rate of recruitment and distance BCVA. Secondary outcome measures were CST, change in BCVA and CST, number of injections, rate of completed follow-up, and withdrawal rate. Results: Over 32 months, 47 of a planned 100 patients were enrolled; 42 (89%; mean [SD] age, 63 [11] years; 26 [62%] male) completed 12-month follow-up visits. Baseline characteristics appeared comparable between the control (n = 23; mean [SD] age, 66 [10] years) and vitrectomy (n = 24; mean [SD] age, 62 [12] years) groups. No difference in 12-month BCVA was noted between groups, with a 12-month median (IQR) BCVA letter score of 73 (65-77) letters (Snellen equivalent, 20/40) in the control group vs 77 (67-81) letters (Snellen equivalent, 20/32) in the vitrectomy group (difference, 4 letters; 95% CI, -8 to 2; P = .24). There was no difference in BCVA change from baseline (median [IQR], -1 [-3 to 2] letters for the control group vs -2 [-8 to 2] letters for the vitrectomy group; difference, 1 letter; 95% CI, -5 to 7; P = .85). No difference was found in CST changes (median [IQR], -94 [-122 to 9] µm for the control group vs -32 [-48 to 25] µm for the vitrectomy group; difference, 62 µm; 95% CI, -110 to 11; P = .11). Conclusions and Relevance: Enrollment goals could not be attained. However, with 47 participants, evidence did not support a clinical benefit of vitrectomy plus ILM peeling as an adjunct to a T&E regimen of anti-VEGF therapy for DME. Trial Registration: isrctn.org Identifier: ISRCTN59902040.

Is #Gender Affirmation Surgery Trending? An Analysis of Plastic Surgery Residency Social Media Content.

Purpose: Given rising demand for gender affirmation surgery (GAS), lesbian, gay, bisexual, transgender, queer, and others' (LGBTQ+) patient care, and sexual and gender minority (SGM) representation in plastic surgery, we sought to analyze integrated residency programs' posts for LGBTQ+ content. Methods: Programs were identified from the American Council of Academic Plastic Surgeons website. Accounts were searched for on Instagram, Facebook, and Twitter. Posts uploaded through June 24, 2021 were analyzed. Mann-Whitney U- and Kruskal-Wallis tests were used to compare content between programs. Results: Of 82 programs, 76 (92.7%), 31 (37.8%), and 30 (36.6%) have Instagram, Facebook, and Twitter accounts, respectively. Two hundred eighty-one (1.3%) posts displayed LGBTQ+ content, including educational (29.9%), research (17.4%), news (11.0%), resident interests (10.7%), pride/diversity (9.6%), posts to attract applicants/patients (7.5%), operative/clinic cases (6.8%), faculty spotlights (6.4%), and patient testimonials (1.1%). One hundred eighty-one (64.4%) posts described GAS overall, 42 (23.2%) described top, 32 (17.7%) described genital, and 32 (17.7%) described facial surgery. Instagram and Facebook have more LGBTQ+ content than Twitter (p≤0.037). Newly accredited programs have significantly more LGBTQ+ content on Facebook (p=0.036). Programs in the West, having more perceived prestige, or GAS fellowships tended to have more LGBTQ+ content. Conclusion: Despite growing demand for GAS and thus training, 1% of content on plastic surgery residency social media accounts is LGBTQ+ related. Reasons for lack of representation require further investigation but may include (1) limited GAS and LGBTQ+ patient exposure during training or (2) lack of SGM inclusivity for residents, faculty, and patients.

Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). METHOD: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. RESULTS: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP. CONCLUSIONS: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.