Evaluating fall event definitions relative to lower limb prosthesis users' lived experiences.

PURPOSE: Evaluate specific elements of previously proposed fall and near-fall definitions to determine whether they fully capture lower limb prosthesis (LLP) users' lived experiences. METHODS: Semi-structured interviews were conducted with 24 LLP users. Interview transcripts were reviewed, coded, and analyzed using deductive thematic analysis to identify shared experiences and inform revisions to previously reported definitions. RESULTS: Four major themes emerged: a fall can be initiated by more than just a loss of balance, loss of balance and losing balance are considered similar, falls are not limited to landing on the ground or floor, and catching yourself and recovering your balance are distinct responses to a loss of balance. CONCLUSIONS: Two revisions were made to previous definitions to better align with LLP users' experiences and historically overlooked fall circumstances. A fall is defined as a loss of balance or sudden loss of support where your body lands on the ground, floor, or another object. A near-fall was defined as a loss of balance where you caught yourself or recovered your balance without landing on the ground, floor, or another object. Implementation of these new definitions will aid the collection of accurate, consistent, and meaningful fall data, enhancing aggregation and comparison across studies.

Falls are a top health concern for lower limb prosthesis users.Understanding how lower limb prosthesis users experience falls helps build meaningful fall definitions.Standardized definitions allow clinicians to document fall events with greater consistency and justify fall prevention interventions.

White adipocytes in subcutaneous fat depots require KLF15 for maintenance in preclinical models.

Healthy adipose tissue is essential for normal physiology. There are 2 broad types of adipose tissue depots: brown adipose tissue (BAT), which contains adipocytes poised to burn energy through thermogenesis, and white adipose tissue (WAT), which contains adipocytes that store lipids. However, within those types of adipose, adipocytes possess depot and cell-specific properties that have important implications. For example, the subcutaneous and visceral WAT confers divergent risk for metabolic disease. Further, within a depot, different adipocytes can have distinct properties; subcutaneous WAT can contain adipocytes with either white or brown-like (beige) adipocyte properties. However, the pathways that regulate and maintain this cell and depot-specificity are incompletely understood. Here, we found that the transcription factor KLF15 is required for maintaining white adipocyte properties selectively within the subcutaneous WAT. We revealed that deletion of Klf15 is sufficient to induce beige adipocyte properties and that KLF15's direct regulation of Adrb1 is a critical molecular mechanism for this process. We uncovered that this activity is cell autonomous but has systemic implications in mouse models and is conserved in primary human adipose cells. Our results elucidate a pathway for depot-specific maintenance of white adipocyte properties that could enable the development of therapies for obesity and associated diseases.

Lipidomics of homeoviscous adaptation to low temperatures in Staphylococcus aureus utilizing exogenous straight-chain unsaturated fatty acids.

It is well established that Staphylococcus aureus can incorporate exogenous straight-chain unsaturated fatty acids (SCUFAs) into membrane phospho- and glyco-lipids from various sources in supplemented culture media and when growing in vivo during infection. Given the enhancement of membrane fluidity when oleic acid (C18:1Δ9) is incorporated into lipids, we were prompted to examine the effect of medium supplementation with C18:1Δ9 on growth at low temperatures. C18:1Δ9 supported the growth of a cold-sensitive, branched-chain fatty acid (BCFA)-deficient mutant at 12°C. Interestingly, we found similar results in the BCFA-sufficient parental strain, supported by the fact that the incorporation of C18:1Δ9 into the membrane increased membrane fluidity in both strains. We show that the incorporation of C18:1Δ9 and its elongation product C20:1Δ11 into membrane lipids was required for growth stimulation and relied on a functional FakAB incorporation system. Lipidomics analysis of the phosphatidylglycerol and diglycosyldiacylglycerol lipid classes revealed major impacts of C18:1Δ9 and temperature on lipid species. Growth at 12°C in the presence of C18:1Δ9 also led to increased production of the carotenoid pigment staphyloxanthin. The enhancement of growth by C18:1Δ9 is an example of homeoviscous adaptation to low temperatures utilizing an exogenous fatty acid. This may be significant in the growth of S. aureus at low temperatures in foods that commonly contain C18:1Δ9 and other SCUFAs in various forms. IMPORTANCE: We show that Staphylococcus aureus can use its known ability to incorporate exogenous fatty acids to enhance its growth at low temperatures. Individual species of phosphatidylglycerols and diglycosyldiacylglycerols bearing one or two degrees of unsaturation derived from the incorporation of C18:1Δ9 at 12°C are described for the first time. In addition, enhanced production of the carotenoid staphyloxanthin occurs at low temperatures. The studies describe a biochemical reality underlying membrane biophysics. This is an example of homeoviscous adaptation to low temperatures utilizing exogenous fatty acids over the regulation of the biosynthesis of endogenous fatty acids. The studies have likely relevance to food safety in that unsaturated fatty acids may enhance the growth of S. aureus in the food environment.

A dual-center analysis of conservative versus liberal glycoprotein IIb-IIIa antagonist strategies in the treatment of ST-elevation myocardial infarction.

While the efficacy of GpIIb-IIIa-inhibitors during primary PCI (pPCI) for ST-elevated myocardial infarction (STEMI) has previously been demonstrated, its ongoing role and safety in combination with newer P2Y12-inhibitors is unclear. We therefore sought to compare outcomes between two centers with divergent approaches to the use of GpIIbIIIa antagonists in pPCI. We performed a retrospective chart review of all-comer STEMI patients treated with pPCI at two high-volume Montreal academic tertiary care centers. One center tended to use GpIIb-IIIa-inhibitors up-front in a large proportion of patients (liberal strategy) and the other preferring a bail-out approach (conservative strategy). Baseline patient characteristics and procedural data were compared between the two groups. The main efficacy outcome was rate of no-reflow/slow-reflow and the main safety outcome was BARC ≥ 2 bleeding events. A total of 459 patients were included, of whom 167 (36.5%) were exposed to a GpIIb-IIIa-antagonist. There was a significant overall difference in use of GpIIb-IIIa-antagonist between the two centers (60.5% vs. 16.1%, p < 0.01). Rate of no-reflow/slow-reflow was similar between groups (2.6% vs. 1.4%, p = 0.22). In-hospital rates of unplanned revascularization, stroke and death were also not different between groups. Use of a liberal GpIIb--IIIa-antagonist strategy was however associated with a higher risk of bleeding (OR 3.16, 95% CI 1.57-6.37, p < 0.01), which persisted after adjustment for covariables (adjusted OR 2.85, 95% CI 1.40-5.81, p < 0.01). In this contemporary retrospective cohort, a conservative, bail-out only GpIIb--IIIa-antagonist strategy was associated with a lower incidence of clinically relevant bleeding without any signal for an increase in no-reflow/slow-reflow or ischemic clinical events.

Trees have overlapping potential niches that extend beyond their realized niches.

Tree species appear to prefer distinct climatic conditions, but the true nature of these preferences is obscured by species interactions and dispersal, which limit species' ranges. We quantified realized and potential thermal niches of 188 North American tree species to conduct a continental-scale test of the architecture of niches. We found strong and consistent evidence that species occurring at thermal extremes occupy less than three-quarters of their potential niches, and species' potential niches overlap at a mean annual temperature of ~12°C. These results clarify the breadth of thermal tolerances of temperate tree species and support the centrifugal organization of thermal niches. Accounting for the nonrealized components of ecological niches will advance theory and prediction in global change ecology.

CCAR1 promotes DNA repair via alternative splicing.

DNA repair is directly performed by hundreds of core factors and indirectly regulated by thousands of others. We massively expanded a CRISPR inhibition and Cas9-editing screening system to discover factors indirectly modulating homology-directed repair (HDR) in the context of ∼18,000 individual gene knockdowns. We focused on CCAR1, a poorly understood gene that we found the depletion of reduced both HDR and interstrand crosslink repair, phenocopying the loss of the Fanconi anemia pathway. CCAR1 loss abrogated FANCA protein without substantial reduction in the level of its mRNA or that of other FA genes. We instead found that CCAR1 prevents inclusion of a poison exon in FANCA. Transcriptomic analysis revealed that the CCAR1 splicing modulatory activity is not limited to FANCA, and it instead regulates widespread changes in alternative splicing that would damage coding sequences in mouse and human cells. CCAR1 therefore has an unanticipated function as a splicing fidelity factor.

Effects of Harmful Algal Blooms on Amphibians and Reptiles are Under-Reported and Under-Represented.

Harmful algal blooms (HABs) are a persistent and increasing problem globally, yet we still have limited knowledge about how they affect wildlife. Although semi-aquatic and aquatic amphibians and reptiles have experienced large declines and occupy environments where HABs are increasingly problematic, their vulnerability to HABs remains unclear. To inform monitoring, management, and future research, we conducted a literature review, synthesized the studies, and report on the mortality events describing effects of cyanotoxins from HABs on freshwater herpetofauna. Our review identified 37 unique studies and 71 endpoints (no-observed-effect and lowest-observed-effect concentrations) involving 11 amphibian and 3 reptile species worldwide. Responses varied widely among studies, species, and exposure concentrations used in experiments. Concentrations causing lethal and sublethal effects in laboratory experiments were generally 1 to 100 µg/L, which contains the mean value of reported HAB events but is 70 times less than the maximum cyanotoxin concentrations reported in the environment. However, one species of amphibian was tolerant to concentrations of 10,000 µg/L, demonstrating potentially immense differences in sensitivities. Most studies focused on microcystin-LR (MC-LR), which can increase systemic inflammation and harm the digestive system, reproductive organs, liver, kidneys, and development. The few studies on other cyanotoxins illustrated that effects resembled those of MC-LR at similar concentrations, but more research is needed to describe effects of other cyanotoxins and mixtures of cyanotoxins that commonly occur in the environment. All experimental studies were on larval and adult amphibians; there were no such studies on reptiles. Experimental work with reptiles and adult amphibians is needed to clarify thresholds of tolerance. Only nine mortality events were reported, mostly for reptiles. Given that amphibians likely decay faster than reptiles, which have tissues that resist decomposition, mass amphibian mortality events from HABs have likely been under-reported. We propose that future efforts should be focused on seven major areas, to enhance our understanding of effects and monitoring of HABs on herpetofauna that fill important roles in freshwater and terrestrial environments. Environ Toxicol Chem 2024;00:1-14. Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Relevance of learning health systems to physiatrists and its synergy with implementation science: A commentary.

As health care attempts to bridge the gap between evidence and practice, the concept of the learning health system (LHS) is becoming increasingly relevant. LHS integrates evidence with health systems data, driving health care quality and outcomes through updates in policy, practice, and care delivery. In addition, LHS research is becoming critically important as there are several initiatives underway to increase research capacity, expertise, and implementation, including attempts to stimulate increasing numbers of LHS researchers. Physical Medicine & Rehabilitation (PM&R) physicians (physiatrists), nurses, therapists (physical therapists, occupational therapists, speech therapists, clinical psychologists), and scientists are affiliated with LHSs. As LHS research expands in health care systems, better awareness and understanding of LHSs and LHS research competencies are key for rehabilitation professionals including physiatrists. To address this need, the Agency of Healthcare Research and Quality (AHRQ) identified 33 core competencies, grouped into eight domains, for training LHS researchers. The domains are: (1) Systems Science; (2) Research Questions and Standards of Scientific Evidence; (3) Research Methods; (4) Informatics; (5) Ethics of Research and Implementation in Health Systems; (6) Improvement and Implementation Science; (7) Engagement, Leadership, and Research Management; and the recently added (8) Health and Healthcare Equity and Justice. The purpose of this commentary is to define LHS and its relevance to physiatrists, present the role of implementation science (IS) in LHSs and application of IS principles to design LHSs, illustrate current LHS research in rehabilitation, and discuss potential solutions to improve awareness and to stimulate interest in LHS research and IS among physiatrists in LHSs.

The prognostic effect of mechanical, ultrastructural, and ECM signatures in glioblastoma core and rim.

Glioblastoma (GBM) is a highly invasive, aggressive brain cancer that carries a median survival of 15 months and is resistant to standard therapeutics. Recent studies have demonstrated that intratumoral heterogeneity plays a critical role in promoting resistance by mediating tumor adaptation through microenvironmental cues. GBM can be separated into two distinct regions-a core and a rim, which are thought to drive specific aspects of tumor evolution. These differences in tumor progression are regulated by the diverse biomolecular and biophysical signals in these regions, but the acellular biophysical characteristics remain poorly described. This study investigates the mechanical and ultrastructural characteristics of the tumor extracellular matrix (ECM) in patient-matched GBM core and rim tissues. Seven patient-matched tumor core and rim samples and one non-neoplastic control were analyzed using atomic force microscopy, scanning electron microscopy, and immunofluorescence imaging to quantify mechanical, ultrastructural, and ECM composition changes. The results reveal significant differences in biophysical parameters between GBM core, rim, and non-neoplastic tissues. The GBM core is stiffer, denser, and is rich in ECM proteins hyaluronic acid and tenascin-C when compared to tumor rim and non-neoplastic tissues. These alterations are intimately related and have prognostic effect with stiff, dense tissue correlating with longer progression-free survival. These findings reveal new insights into the spatial heterogeneity of biophysical parameters in the GBM tumor microenvironment and identify a set of characteristics that may correlate with patient prognosis. In the long term, these characteristics may aid in the development of strategies to combat therapeutic resistance.

Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML.

While intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), data from older patients shows that hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remissions among patients with NPM1 mutations. Whether IC or HMA/VEN is superior in patients ≥60 years-old with NPM1-mutant AML is unknown. To compare IC and HMA/VEN, we performed an international, multicenter retrospective cohort study of patients with newly diagnosed, NPM1-mutant AML.We included 221 patients (147 IC, 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR; defined as CR + CR with incomplete count recovery [CRi]) rate was similar for IC and HMA/VEN (cCR: 85% vs. 74%; p=0.067). While OS was favorable with IC in unselected patients compared to HMA/VEN (24-month OS 59% [95% CI: 52-69%] vs. 38% [95% CI 27-55%]; p=0.013), it was not statistically different among patients 60-75 years-old (60% [95% CI 52-70%] vs. 44% [95% CI 29-66%]; p=0.069) and patients who received an allogeneic stem cell transplant (70% [95% CI: 58-85%] vs. 66% [95% CI: 44-100%]; p=0.56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS with IC 65% [95% 56-74%] vs. 40% [95% CI: 26-60%] with HMA/VEN; p=0.009) and without FLT3-ITD mutations might benefit from IC compared with HMA/VEN (24-month OS: 68% [95% CI: 59-79%] vs. 43% [95% CI: 29-63%]; p=0.008). In multivariable analysis, OS was not statistically different for patients treated with IC and HMA/VEN (hazard ratio for death HMA/VEN vs. IC: 0.71; 95% CI: 0.40-1.27; p=0.25).

Characterization of adverse events in injured patients at risk of hemorrhagic shock: a secondary analysis of three harmonized prehospital randomized clinical trials.

Background: The reporting of adverse events (AEs) is required and well defined in the execution of clinical trials, but is poorly characterized particularly in prehospital trials focusing on traumatic injury. In the setting of prehospital traumatic injury trials, no literature currently exists analyzing the clinical implications of AEs and their associations with mortality and morbidity. We sought to analyze AEs from three prehospital hemorrhagic shock trials and characterize their time course, incidence, severity, associated clinical outcomes, and relatedness. Methods: We performed a secondary analysis of three prehospital randomized clinical trials. We analyzed AEs at both the patient level as well as the individual AE level. We categorized patients who had no AEs, a single documented AE and those with multiple events (>1 AE). We characterized AE timing, severity, relatedness and attributable mortality outcomes. Results: We included 1490 patients from the three harmonized clinical trials, with 299 (20.1%) individual patients having at least a single AE documented with 529 AEs documented overall as a proportion of patients had multiple events. Over 44% of patients had a death-related misclassified AE. Patients with at least a single documented AE had a significantly higher 28-day mortality (log-rank χ2=81.27, p<0.001) compared with those without an AE documented. Patients with a single AE had a significant higher mortality than those with multiple AEs, potentially due to survival bias (log-rank χ2=11.80, p=0.006). When relatedness of each individual AE was characterized, over 97% of AEs were classified as 'definitely not related' or 'probably not related' to the intervention. Conclusions: AEs in hemorrhagic shock trials are common, occur early and are associated with mortality and survival bias. The potential for inaccurate reporting exists, and education and training remain essential for appropriate treatment arm comparison. The current results have important relevance to injury-related clinical trials. Trial registration numbers: NCT01818427, NCT02086500 and NCT03477006. Level of evidence: II.

A Joint Trauma System Clinical Practice Guideline: Traumatic Brain Injury Management and Basic Neurosurgery in the Deployed Environment.

Management of the patient with moderate to severe brain injury in any environment can be time consuming and resource intensive. These challenges are magnified while forward deployed in austere or hostile environments. This Joint Trauma System Clinical Practice Guideline provides recommendations for the treatment and medical management of casualties with moderate to severe head injuries in an environment where personnel, resources, and follow-on care are limited. These guidelines have been developed by acknowledging commonly recognized recommendations for neurosurgical and neuro-critical care patients and augmenting those evaluations and interventions based on the experience of neurosurgeons, trauma surgeons, and intensivists who have delivered care during recent coalition conflicts.

Synthesis and properties of anhydrous rare-earth phosphates, monazite and xenotime: a review.

The synthesis methods, crystal structures, and properties of anhydrous monazite and xenotime (REPO4) crystalline materials are summarized within this review. For both monazite and xenotime, currently available Inorganic Crystal Structure Database data were used to study the effects of incorporating different RE cations on the unit cell parameters, cell volumes, densities, and bond lengths. Domains of monazite-type and xenotime-type structures and other AXO4 compounds (A = RE; X = P, As, V) are discussed with respect to cation sizes. Reported chemical and radiation durabilities are summarized. Different synthesis conditions and chemicals used for single crystals and polycrystalline powders, as well as first-principles calculations of the structures and thermophysical properties of these minerals are also provided.

Ligand-based design of [18F]OXD-2314 for PET imaging in non-Alzheimer's disease tauopathies.

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [3H]OXD-2115, and in silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.

Uncovering multi-level mental healthcare barriers for migrants: a qualitative analysis across China, Germany, Netherlands, Romania, and South Africa.

BACKGROUND: Forced displacement is a significant issue globally, and it affected 112 million people in 2022. Many of these people have found refuge in low- and middle-income countries. Migrants and refugees face complex and specialized health challenges, particularly in the area of mental health. This study aims to provide an in-depth qualitative assessment of the multi-level barriers that migrants face in accessing mental health services in Germany, Macao (Special Administrative Region of China), the Netherlands, Romania, and South Africa. The ultimate objective is to inform tailored health policy and management practices for this vulnerable population. METHODS: Adhering to a qualitative research paradigm, the study centers on stakeholders' perspectives spanning microsystems, mesosystems, and macrosystems of healthcare. Utilizing a purposive sampling methodology, key informants from the aforementioned geographical locations were engaged in semi-structured interviews. Data underwent thematic content analysis guided by a deductive-inductive approach. RESULTS: The study unveiled three pivotal thematic barriers: language and communication obstacles, cultural impediments, and systemic constraints. The unavailability of professional interpreters universally exacerbated language barriers across all countries. Cultural barriers, stigmatization, and discrimination, specifically within the mental health sector, were found to limit access to healthcare further. Systemic barriers encompassed bureaucratic intricacies and a conspicuous lack of resources, including a failure to recognize the urgency of mental healthcare needs for migrants. CONCLUSIONS: This research elucidates the multifaceted, systemic challenges hindering equitable mental healthcare provision for migrants. It posits that sweeping policy reforms are imperative, advocating for the implementation of strategies, such as increasing the availability of language services, enhancing healthcare providers' capacity, and legal framework and policy change to be more inclusive. The findings substantially contribute to scholarly discourse by providing an interdisciplinary and international lens on the barriers to mental healthcare access for displaced populations.

Structure and transcription of integrated HPV DNA in vulvar carcinomas.

HPV infections are associated with a fraction of vulvar cancers. Through hybridization capture and DNA sequencing, HPV DNA was detected in five of thirteen vulvar cancers. HPV16 DNA was integrated into human DNA in three of the five. The insertions were in introns of human NCKAP1, C5orf67, and LRP1B. Integrations in NCKAP1 and C5orf67 were flanked by short direct repeats in the human DNA, consistent with HPV DNA insertions at sites of abortive, staggered, endonucleolytic incisions. The insertion in C5orf67 was present as a 36 kbp, human-HPV-hetero-catemeric DNA as either an extrachromosomal circle or a tandem repeat within the human genome. The human circularization/repeat junction was defined at single nucleotide resolution. The integrated viral DNA segments all retained an intact upstream regulatory region and the adjacent viral E6 and E7 oncogenes. RNA sequencing revealed that the only HPV genes consistently transcribed from the integrated viral DNAs were E7 and E6*I. The other two HPV DNA+ tumors had coinfections, but no evidence for integration. HPV-positive and HPV-negative vulvar cancers exhibited contrasting human, global gene expression patterns partially overlapping with previously observed differences between HPV-positive and HPV-negative cervical and oropharyngeal cancers. A substantial fraction of the differentially expressed genes involved immune system function. Thus, transcription and HPV DNA integration in vulvar cancers resemble those in other HPV-positive cancers. This study emphasizes the power of hybridization capture coupled with DNA and RNA sequencing to identify a broad spectrum of HPV types, determine human genome integration status of viral DNAs, and elucidate their structures.

Anterior Cruciate Ligament Repair Leads to Improved Patient-Reported Outcomes Compared to Anterior Cruciate Ligament Reconstruction.

Introduction Anterior cruciate ligament (ACL) tears occur frequently in young athletes, and ligament repair and reconstruction are surgical treatments. Although there are suggested benefits for both approaches, there is a lack of direct comparisons between ACL repair and reconstruction.This study aims to compare the mid-term functional outcomes and quality of life measures between patients that have undergone ACL repair versus reconstruction. Methods A retrospective review was conducted for demographic and operative report data of patients who underwent an ACL repair or reconstruction between 2012 and 2018. Patients were contacted over the phone and underwent a Patient-Reported Outcomes Measurement Information System (PROMIS) survey evaluating pain interference, mobility, and function. Patients were excluded from the study if there was an incomplete operative note, missing contact information, or failure to answer phone calls. Results A total of 74 eligible patients were included, with n = 54 in the ACL reconstruction group (73.0%) and n = 20 in the ACL repair group (27.0%). Reconstruction patients had a PROMIS (median (IQR)) physical function score of 22.50 (16.00-59.00), as compared to repair patients' physical function score of 60.00 (21.50-60.00). There was a significant difference favoring repair (p = 0.040). In addition, ACL reconstruction patients had a significantly higher rate of additional procedures, with 63.0% of reconstruction patients receiving an additional operation as compared to 30.0% of repair patients (p = 0.017). The surgery type did not show a significant effect on physical function scores, while additional procedures remained significant in the linear regression analysis. Conclusion Although ACL repair is associated with improved physical function scores as compared to reconstruction in the univariate analysis, surgery type did not show significance when controlling for other variables. Further studies are necessary to compare patients with similar injuries to account for differences in additional procedures, but the results remain promising in assisting with patient-driven treatment decisions.

Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in THY1+ ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration.