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Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations. GBA1 is a gene of high clinical and therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher disease and monoallelic variants confer risk for PD and dementia with Lewy bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the African ancestry-specific GBA1 risk variant is a noncoding variant, suggesting a different mechanism of action. Using full-length RNA transcript sequencing, we identified partial intron 8 expression in risk variant carriers (G) but not in nonvariant carriers (T). Antibodies targeting the N terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting that the disease mechanism is RNA based. Clustered regularly interspaced short palindromic repeats editing of the reported index variant ( rs3115534 ) revealed that this is the sequence alteration responsible for driving the production of these transcripts containing intron 8. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and, therefore, has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity, we identified a dose-dependent reduction in risk variant carriers. Overall, we report the functional effect of a GBA1 noncoding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes.

IntroductionVariants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization.MethodsWe described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling.ResultsANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways.DiscussionThis study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity.HighlightsANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.

Effective conservation of wildlife requires current and accurate range maps of a species' distribution. While maintaining these resources can be challenging, especially for poorly documented species, the map is important for scientists, land managers, and decision makers alike. The International Union for the Conservation of Nature (IUCN) Red List of Threatened Species is a leading information source on the global extinction risk status of flora and fauna and provides current range maps for use in wildlife conservation and listing decisions. Chuck-wills-widow (Antrostomus carolinensis), a declining aerial insectivore whose contemporary range includes North and South America, is a near-threatened species according to IUCN, but its range map excludes areas known to support breeding populations. Here we compiled occurrence of Chuck-wills-widow within the state of Illinois across 6 data sources over a 65+ year period to highlight the occurrence of the species throughout the region. Although excluded from the current IUCN range map, we documented 947 occurrences of the species within Illinois since 1957. Through the use of minimum convex polygons (MCP), we report consistent and stable occurrence of Chuck-wills-widow, with the composite MCP ranging across the southern half of the state. Our results suggest that Chuck-wills-widow distribution within Illinois is not a result of recent colonization nor a climatic-induced shift in the species' distribution, but rather likely an underreporting of the species. This research illustrates how nocturnal or otherwise difficult to detect species may be widely underrepresented in public biodiversity databases and, as a result, have several gaps in their IUCN range maps. In addition to eBird and GBIF, we therefore encourage the inclusion of researchers and land managers along the range boundaries in the development of IUCN range maps, as local knowledge may be needed to fully describe the distribution of declining and underrepresented species. Received 22 August 2023. Accepted 17 June 2024. Key words: conservation mapping, extent of occurrence, geographic range, nightjars, species distribution, threatened species. (Spanish)--La conservacion efectiva de la vida silvestre requiere de mapas de rangos de distribucion de especies actuales y precisos. Aunque el mantenimiento de estos recursos puede ser un reto, especialmente para especies poco documentadas, el mapa es importante tanto para cientificos como para administradores de tierras y tomadores de decisiones. La Lista Roja de Especies Amenazadas de la Union Internacional para la Conservacion de la Naturaleza (IUCN) es una fuente de informacion de avanzada en el riesgo global de estatus de riesgo de extincion global de flora y fauna y proporciona mapas de rangos actuales para uso en conservacion de vida silvestre y toma de decisiones en listados. El chotacabras Antrostomus carolinensis, una especie aerea insectivora en declive cuyo rango contemporaneo incluye Norte y Sudamerica, es una especie casi amenazada segun la IUCN pero su mapa de rango de distribucion excluye areas conocidas por tener poblaciones reproductivas. Aqui compilamos registros de presencia de chotacabras Antrostomus carolinensis dentro del estado de Illinois usando 6 fuentes de datos en un periodo de tiempo de mas de 65 anos para resaltar los registros de presencia de la especie en la region. Aunque excluida del mapa de rango actual de la IUCN, documentamos 947 registros de la especie en Illinois desde 1957. A traves del uso de poligonos minimos convexos (MCP), reportamos presencia consistente y estable de chotacabras Antrostomus carolinensis, con el rango compuesto de MCP que cubre la mitad surena del estado. Nuestros resultados sugieren que la distribucion de chotacabras Antrostomus carolinensis en Illinois no es el resultado de colonizacion reciente ni de cambio de distribucion inducido por el cambio climatico, sino que se debe posiblemente a un subreporte de la especie. Esta investigacion ilustra como especies nocturnas o dificiles de detectar por otras razones pueden estar subrepresentadas en bases de datos publicas de biodiversidad y, como resultado, tener faltantes serios en sus mapas de rangos de la IUCN. Ademas de eBird y GBF, instamos a incluir a investigadores y adminostradores de tierras cercanas a los limites de rangos en el desarrollo de los mapas de rango de la IUCN, ya que el conocimiento local puede ser necesario para describir completamente la distribucion de especies en declive o subrepresentadas. Palabras clave: amplitud de presencia, chotacabras, distribucion de especies, especies amenazadas, mapeo de conservacion, rango geografico., Documenting the current range of a species is essential for effective wildlife conservation and management (Franklin 2010, Guisan et al. 2013). This information is vital for scientists, decision makers, and [...]

Introduction: The United States Veterans Health Administration is a leader in the use of telemental health (TMH) to enhance access to mental healthcare amidst a nationwide shortage of mental health professionals. The Tennessee Valley Veterans Affairs (VA) Health System piloted TMH in its emergency department (ED) and urgent care clinic (UCC) in 2019, with full 24/7 availability beginning March 1, 2020. Following implementation, preliminary data demonstrated that veterans ≥65 years old were less likely to receive TMH than younger patients. We sought to examine factors associated with older veterans receiving TMH consultations in acute, unscheduled, outpatient settings to identify limitations in the current process.Methods: This was a retrospective cohort study conducted within the Tennessee Valley VA Health System. We included veterans ≥55 years who received a mental health consultation in the ED or UCC from April 1, 2020–September 30, 2022. Telemental health was administered by a mental health clinician (attending physician, resident physician, nurse practitioner, or physician assistant) via iPad, whereas in-person evaluations were performed in the ED. We examined the influence of patient demographics, visit timing, chief complaint, and psychiatric history on TMH, using multivariable logistic regression.Results: Of the 254 patients included in this analysis, 177 (69.7%) received TMH. Veterans with high-risk chief complaints (suicidal ideation, homicidal ideation, or agitation) were less likely to receive TMH consultation (adjusted odds ratio [AOR]: 0.47, 95% confidence interval [CI] 0.24–0.95). Compared to attending physicians, nurse practitioners and physician assistants were associated with increased TMH use (AOR 4.81, 95% CI 2.04–11.36), whereas consultation by resident physicians was associated with decreased TMH use (AOR 0.04, 95% CI 0.00–0.59). The UCC used TMH for all but one encounter. Patient characteristics including their visit timing, gender, additional medical complaints, comorbidity burden, and number of psychoactive medications did not influence use of TMH.Conclusion: High-risk chief complaints, location, and type of mental health clinician may be key determinants of telemental health use in older adults. This may help expand mental healthcare access to areas with a shortage of mental health professionals and prevent potentially avoidable transfers in low-acuity situations. Further studies and interventions may optimize TMH for older patients to ensure safe, equitable mental health care. [West J Emerg Med. 2024;25(2)1–8.]

BACKGROUND: Timely reperfusion is necessary to reduce morbidity and mortality in patients with ST-elevation myocardial infarction (STEMI). Initial care by facilities with percutaneous coronary intervention (PCI) capabilities reduces time to reperfusion. We sought to examine whether insurance status was associated with initial care at emergency departments (EDs) with PCI capabilities among adult patients with STEMI. METHODS: We conducted a retrospective cross-sectional study using Department of Healthcare Access and Information, a nonpublic statewide database reporting ED visits and hospitalizations in California. We included adults initially arriving at EDs with STEMI by diagnostic code (International Classification of Diseases Ninth Revision or 10th Revision) from 2011 to 2019. Multivariable logistic regression modeling included initial care by PCI capable facility as the primary outcome and insurance status (none vs. any) as the primary exposure. Covariates included patient, facility, and temporal factors and we conducted multiple robustness checks. RESULTS: We analyzed 135,358 eligible visits with STEMI included. In our multivariable model, the odds of uninsured patients being initially treated at a PCI-capable facility were significantly lower than those of insured patients (adjusted odds ratio 0.62, 95% CI 0.54-0.72, p