An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors.

Analysis of the human hematopoietic progenitor compartment is being transformed by single-cell multimodal approaches. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) enables coupled surface protein and transcriptome profiling, thereby revealing genomic programs underlying progenitor states. To perform CITE-seq systematically on primary human bone marrow cells, we used titrations with 266 CITE-seq antibodies (antibody-derived tags) and machine learning to optimize a panel of 132 antibodies. Multimodal analysis resolved >80 stem, progenitor, immune, stromal and transitional cells defined by distinctive surface markers and transcriptomes. This dataset enables flow cytometry solutions for in silico-predicted cell states and identifies dozens of cell surface markers consistently detected across donors spanning race and sex. Finally, aligning annotations from this atlas, we nominate normal marrow equivalents for acute myeloid leukemia stem cell populations that differ in clinical response. This atlas serves as an advanced digital resource for hematopoietic progenitor analyses in human health and disease.

Transmembrane Pickets Connect Cyto- and Pericellular Skeletons Forming Barriers to Receptor Engagement.

Phagocytic receptors must diffuse laterally to become activated upon clustering by multivalent targets. Receptor diffusion, however, can be obstructed by transmembrane proteins ("pickets") that are immobilized by interacting with the cortical cytoskeleton. The molecular identity of these pickets and their role in phagocytosis have not been defined. We used single-molecule tracking to study the interaction between Fcγ receptors and CD44, an abundant transmembrane protein capable of indirect association with F-actin, hence likely to serve as a picket. CD44 tethers reversibly to formin-induced actin filaments, curtailing receptor diffusion. Such linear filaments predominate in the trailing end of polarized macrophages, where receptor mobility was minimal. Conversely, receptors were most mobile at the leading edge, where Arp2/3-driven actin branching predominates. CD44 binds hyaluronan, anchoring a pericellular coat that also limits receptor displacement and obstructs access to phagocytic targets. Force must be applied to traverse the pericellular barrier, enabling receptors to engage their targets.

EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics.

Epidermal growth factor receptor (EGFR) regulates many crucial cellular programs, with seven different activating ligands shaping cell signaling in distinct ways. Using crystallography and other approaches, we show how the EGFR ligands epiregulin (EREG) and epigen (EPGN) stabilize different dimeric conformations of the EGFR extracellular region. As a consequence, EREG or EPGN induce less stable EGFR dimers than EGF-making them partial agonists of EGFR dimerization. Unexpectedly, this weakened dimerization elicits more sustained EGFR signaling than seen with EGF, provoking responses in breast cancer cells associated with differentiation rather than proliferation. Our results reveal how responses to different EGFR ligands are defined by receptor dimerization strength and signaling dynamics. These findings have broad implications for understanding receptor tyrosine kinase (RTK) signaling specificity. Our results also suggest parallels between partial and/or biased agonism in RTKs and G-protein-coupled receptors, as well as new therapeutic opportunities for correcting RTK signaling output.

Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance.

Laboratory mice, while paramount for understanding basic biological phenomena, are limited in modeling complex diseases of humans and other free-living mammals. Because the microbiome is a major factor in mammalian physiology, we aimed to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide, we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart and was transferred to and maintained in laboratory mice over several generations. Laboratory mice reconstituted with natural microbiota exhibited reduced inflammation and increased survival following influenza virus infection and improved resistance against mutagen/inflammation-induced colorectal tumorigenesis. By demonstrating the host fitness-promoting traits of natural microbiota, our findings should enable the discovery of protective mechanisms relevant in the natural world and improve the modeling of complex diseases of free-living mammals. VIDEO ABSTRACT.

Nonstochastic reprogramming from a privileged somatic cell state.

Reprogramming somatic cells to induced pluripotency by Yamanaka factors is usually slow and inefficient and is thought to be a stochastic process. We identified a privileged somatic cell state, from which acquisition of pluripotency could occur in a nonstochastic manner. Subsets of murine hematopoietic progenitors are privileged whose progeny cells predominantly adopt the pluripotent fate with activation of endogenous Oct4 locus after four to five divisions in reprogramming conditions. Privileged cells display an ultrafast cell cycle of ∼8 hr. In fibroblasts, a subpopulation cycling at a similar ultrafast speed is observed after 6 days of factor expression and is increased by p53 knockdown. This ultrafast cycling population accounts for >99% of the bulk reprogramming activity in wild-type or p53 knockdown fibroblasts. Our data demonstrate that the stochastic nature of reprogramming can be overcome in a privileged somatic cell state and suggest that cell-cycle acceleration toward a critical threshold is an important bottleneck for reprogramming. PAPERCLIP:

Single-cell analysis reveals transcriptional dynamics in healthy primary parathyroid tissue.

Studies on human parathyroids are generally limited to hyperfunctioning glands owing to the difficulty in obtaining normal human tissue. We therefore obtained non-human primate (NHP) parathyroids to provide a suitable alternative for sequencing that would bear a close semblance to human organs. Single-cell RNA expression analysis of parathyroids from four healthy adult M. mulatta reveals a continuous trajectory of epithelial cell states. Pseudotime analysis based on transcriptomic signatures suggests a progression from GCM2 hi progenitors to mature parathyroid hormone (PTH)-expressing epithelial cells with increasing core mitochondrial transcript abundance along pseudotime. We sequenced, as a comparator, four histologically characterized hyperfunctioning human parathyroids with varying oxyphil and chief cell abundance and leveraged advanced computational techniques to highlight similarities and differences from non-human primate parathyroid expression dynamics. Predicted cell-cell communication analysis reveals abundant endothelial cell interactions in the parathyroid cell microenvironment in both human and NHP parathyroid glands. We show abundant RARRES2 transcripts in both human adenoma and normal primate parathyroid cells and use coimmunostaining to reveal high levels of RARRES2 protein (also known as chemerin) in PTH-expressing cells, which could indicate that RARRES2 plays an unrecognized role in parathyroid endocrine function. The data obtained are the first single-cell RNA transcriptome to characterize nondiseased parathyroid cell signatures and to show a transcriptomic progression of cell states within normal parathyroid glands, which can be used to better understand parathyroid cell biology.

Simultaneous multicolor fluorescence imaging using PSF splitting.

We present a way to encode more information in fluorescence imaging by splitting the original point spread function (PSF), which offers broadband operation and compatibility with other PSF engineering modalities and existing analysis tools. We demonstrate the approach using the 'Circulator', an add-on that encodes the fluorophore emission band into the PSF, enabling simultaneous multicolor super-resolution and single-molecule microscopy using essentially the full field of view.

Dysregulation of alternative splicing in spinocerebellar ataxia type 1.

Spinocerebellar ataxia type 1 is caused by an expansion of the polyglutamine tract in ATAXIN-1. Ataxin-1 is broadly expressed throughout the brain and is involved in regulating gene expression. However, it is not yet known if mutant ataxin-1 can impact the regulation of alternative splicing events. We performed RNA sequencing in mouse models of spinocerebellar ataxia type 1 and identified that mutant ataxin-1 expression abnormally leads to diverse splicing events in the mouse cerebellum of spinocerebellar ataxia type 1. We found that the diverse splicing events occurred in a predominantly cell autonomous manner. A majority of the transcripts with misregulated alternative splicing events were previously unknown, thus allowing us to identify overall new biological pathways that are distinctive to those affected by differential gene expression in spinocerebellar ataxia type 1. We also provide evidence that the splicing factor Rbfox1 mediates the effect of mutant ataxin-1 on misregulated alternative splicing and that genetic manipulation of Rbfox1 expression modifies neurodegenerative phenotypes in a Drosophila model of spinocerebellar ataxia type 1 in vivo. Together, this study provides novel molecular mechanistic insight into the pathogenesis of spinocerebellar ataxia type 1 and identifies potential therapeutic strategies for spinocerebellar ataxia type 1.

CDK9 phosphorylates RUNX1 to promote megakaryocytic fate in megakaryocytic-erythroid progenitors.

The specification of megakaryocytic (Mk) or erythroid (E) lineages from primary human megakaryocytic-erythroid progenitors (MEP) is crucial for hematopoietic homeostasis, yet the underlying mechanisms regulating fate specification remain elusive. In this study, we identify RUNX1 as a key modulator of gene expression during MEP fate specification. Overexpression of RUNX1 in primary human MEP promotes Mk specification, while pan-RUNX inhibition favors E specification. Although total RUNX1 levels do not differ between Mk progenitors (MkP) and E progenitors (ErP), there are higher levels of serine-phosphorylated RUNX1 in MkP than ErP, and mutant RUNX1 with phospho-serine/threonine mimetic mutations (RUNX1-4D) significantly enhances the functional efficacy of RUNX1. To model the effects of RUNX1 variants, we employ human erythroleukemia (HEL) cell lines expressing wild-type (WT), phosphomimetic (RUNX1-4D), and non-phosphorylatable (RUNX1-4A) mutants showing that the three forms of RUNX1 differentially regulate expression of 2,625 genes. Both WT and RUNX1-4D variants increase expression in 40%, and decrease expression in another 40%, with lesser effects of RUNX1-4A. We find a significant overlap between the upregulated genes in WT and RUNX1-4D-expressing HEL cells and those upregulated in primary human MkP versus MEP. While inhibition of known RUNX1 serine/threonine kinases does not affect phosphoserine RUNX1 levels in primary MEP, specific inhibition of CDK9 in MEP leads to both decreased RUNX1 phosphorylation and increased erythroid commitment. Collectively, our findings show that serine/threonine phosphorylation of RUNX1 promotes Mk fate specification and introduce a novel kinase for RUNX1 linking the fundamental transcriptional machinery with activation of a cell-type specific transcription factor.

Gastrulation: making and shaping germ layers.

Gastrulation is a fundamental phase of animal embryogenesis during which germ layers are specified, rearranged, and shaped into a body plan with organ rudiments. Gastrulation involves four evolutionarily conserved morphogenetic movements, each of which results in a specific morphologic transformation. During emboly, mesodermal and endodermal cells become internalized beneath the ectoderm. Epibolic movements spread and thin germ layers. Convergence movements narrow germ layers dorsoventrally, while concurrent extension movements elongate them anteroposteriorly. Each gastrulation movement can be achieved by single or multiple motile cell behaviors, including cell shape changes, directed migration, planar and radial intercalations, and cell divisions. Recent studies delineate cyclical and ratchet-like behaviors of the actomyosin cytoskeleton as a common mechanism underlying various gastrulation cell behaviors. Gastrulation movements are guided by differential cell adhesion, chemotaxis, chemokinesis, and planar polarity. Coordination of gastrulation movements with embryonic polarity involves regulation by anteroposterior and dorsoventral patterning systems of planar polarity signaling, expression of chemokines, and cell adhesion molecules.

Prevalence of and Annual Conversion Rates to Mild Cognitive Impairment and Dementia: Prospective, Longitudinal Study of an Essential Tremor Cohort.

OBJECTIVE: Despite recent attention to cognitive impairment in essential tremor, few studies examine rates of conversion to diagnoses of mild cognitive impairment and dementia. Development of dementia in essential tremor is associated with loss of functional ability and a doubling of mortality rate. This prospective, longitudinal study comprehensively reports the prevalence and incidence of, and the annual rates of conversion to, mild cognitive impairment and dementia in an essential tremor cohort. METHODS: Patients underwent detailed cognitive assessments and were assigned diagnoses of normal cognition, mild cognitive impairment, or dementia. There were 222 patients at baseline (mean age = 79.3 ± 9.7 years), and 177 patients participated in follow-up evaluations at 18, 36, 54, and 72 months (mean years of observation = 5.1 ± 1.7). Data were compared to those of historical controls and Parkinson disease patients. RESULTS: The cumulative prevalence of dementia and average annual conversion rate of mild cognitive impairment to dementia were 18.5% and 12.2%, nearly three times higher than rates in the general population, and approximately one half the magnitude of those reported for Parkinson disease patients. The cumulative prevalence of mild cognitive impairment (26.6%) was almost double that of the general population, but less than that in Parkinson disease populations. INTERPRETATION: We present the most complete exposition of the longitudinal trajectory of cognitive impairment in an essential tremor cohort yet presented. The prevalence of and conversion rates to dementia in essential tremor fall between those associated with the natural course of aging and the more pronounced rates observed in Parkinson disease. ANN NEUROL 2024;95:1193-1204.

The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation.

Exposure to a plethora of environmental challenges commonly triggers pathological type 2 cell-mediated inflammation. Here we report the pathological role of the Wnt antagonist Dickkopf-1 (Dkk-1) upon allergen challenge or non-healing parasitic infection. The increased circulating amounts of Dkk-1 polarized T cells to T helper 2 (Th2) cells, stimulating a marked simultaneous induction of the transcription factors c-Maf and Gata-3, mediated by the kinases p38 MAPK and SGK-1, resulting in Th2 cell cytokine production. Circulating Dkk-1 was primarily from platelets, and the increase of Dkk-1 resulted in formation of leukocyte-platelet aggregates (LPA) that facilitated leukocyte infiltration to the affected tissue. Functional inhibition of Dkk-1 impaired Th2 cell cytokine production and leukocyte infiltration, protecting mice from house dust mite (HDM)-induced asthma or Leishmania major infection. These results highlight that Dkk-1 from thrombocytes is an important regulator of leukocyte infiltration and polarization of immune responses in pathological type 2 cell-mediated inflammation.

Genomic investigation and clinical correlates of the in vitro ß-lactam: NaHCO3 responsiveness phenotype among methicillin-resistant Staphylococcus aureus isolates from a randomized clinical trial.

NaHCO3 responsiveness is a novel phenotype where some methicillin-resistant Staphylococcus aureus (MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO3. NaHCO3 responsiveness correlated with treatment response to ß-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO3-responsive strains with ß-lactams was associated with faster clearance of bacteremia. The CAMERA2 trial (Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus) randomly assigned participants with MRSA bloodstream infections to standard therapy, or to standard therapy plus an anti-staphylococcal ß-lactam (combination therapy). For 117 CAMERA2 MRSA isolates, we determined by broth microdilution the MIC of cefazolin and oxacillin, with and without 44 mM of NaHCO3. Isolates exhibiting ≥4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO3 were considered "NaHCO3-responsive" to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO3-responsive and non-responsive strains, and that were assigned to combination treatment with a ß-lactam. Thirty-one percent (36/117) and 25% (21/85) of MRSA isolates were NaHCO3-responsive to cefazolin and oxacillin, respectively. The NaHCO3-responsive phenotype was significantly associated with sequence type 93, SCCmec type IVa, and mecA alleles with substitutions in positions -7 and -38 in the regulatory region. Among participants treated with a ß-lactam, there was no association between the NaHCO3-responsive phenotype and persistent bacteremia (cefazolin, P = 0.82; oxacillin, P = 0.81). In patients from a randomized clinical trial with MRSA bloodstream infection, isolates with an in vitro ß-lactam-NaHCO3-responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a ß-lactam.

Heterochiral modifications enhance robustness and function of DNA in living human cells.

Oligonucleotide therapeutics are becoming increasingly important as more are approved by the FDA, both for treatment and vaccination. Similarly, dynamic DNA nanotechnology is a promising technique that can be used to sense exogenous input molecules or endogenous biomarkers and integrate the results of multiple sensing reactions in situ via a programmed cascade of reactions. The combination of these two technologies could be highly impactful in biomedicine by enabling smart oligonucleotide therapeutics that can autonomously sense and respond to a disease state. A particular challenge, however, is the limited lifetime of standard nucleic acid components in living cells and organisms due to degradation by endogenous nucleases. In this work, we address this challenge by incorporating mirror-image, ʟ-DNA nucleotides to produce heterochiral "gapmers". We use dynamic DNA nanotechnology to show that these modifications keep the oligonucleotide intact in living human cells for longer than an unmodified strand. To this end, we used a sequential transfection protocol for delivering multiple nucleic acids into living human cells while providing enhanced confidence that subsequent interactions are actually occurring within the cells. Taken together, this work advances the state of the art of ʟ-nucleic acid protection of oligonucleotides and DNA circuitry for applications in vivo.

Trophic cascades within and across ecosystems: The role of anti-predatory defences, predator type and detritus quality.

Species in one ecosystem can indirectly affect multiple biodiversity components and ecosystem functions of adjacent ecosystems. The magnitude of these cross-ecosystem effects depends on the attributes of the organisms involved in the interactions, including traits of the predator, prey and basal resource. However, it is unclear how predators with cross-ecosystem habitat interact with predators with single-ecosystem habitat to affect their shared ecosystem. Also, unknown is how such complex top-down effects may be mediated by the anti-predatory traits of prey and quality of the basal resource. We used the aquatic invertebrate food webs in tank bromeliads as a model system to investigate these questions. We manipulated the presence of a strictly aquatic predator (damselfly larvae) and a predator with both terrestrial and aquatic habitats (spider), and examined effects on survival of prey (detritivores grouped by anti-predator defence), detrital decomposition (of two plant species differing in litter quality), nitrogen flux and host plant growth. To evaluate the direct and indirect effects each predator type on multiple detritivore groups and ultimately on multiple ecosystem processes, we used piecewise structural equation models. For each response variable, we isolated the contribution of different detritivore groups to overall effects by comparing alternate model formulations. Alone, damselfly larvae and spiders each directly decreased survival of detritivores and caused multiple indirect negative effects on detritus decomposition, nutrient cycling and host plant growth. However, when predators co-occurred, the spider caused a negative non-consumptive effect on the damselfly larva, diminishing the net direct and indirect top-down effects on the aquatic detritivore community and ecosystem functioning. Both detritivore traits and detritus quality modulated the strength and mechanism of these trophic cascades. Predator interference was mediated by undefended or partially defended detritivores as detritivores with anti-predatory defences evaded consumption by damselfly larvae but not spiders. Predators and detritivores affected ecosystem decomposition and nutrient cycling only in the presence of high-quality detritus, as the low-quality detritus was consumed more by microbes than invertebrates. The complex responses of this system to predators from both recipient and adjacent ecosystems highlight the critical role of maintaining biodiversity components across multiple ecosystems.

As espécies em um ecossistema podem afetar indiretamente múltiplos componentes da biodiversidade e funções ecossistêmicas em ecossistemas adjacentes. A magnitude destes efeitos entre ecossistemas depende dos atributos dos organismos envolvidos nas interações, incluindo características do predador, da presa e do recurso basal. No entanto, não está claro como os predadores com habitat em múltiplos ecossistemas interagem com predadores de um ecossistema único, e como isso afeta o ecossistema partilhado entre eles. Além disso, não se sabe como esses efeitos complexos do tipo top­down podem ser mediados pelas características antipredatórias da presa e pela qualidade do recurso basal. Usamos as teias alimentares de invertebrados aquáticos de bromélias­tanque como um sistema modelo para investigar essas questões. Nós manipulamos a presença de um predador estritamente aquático (larvas de zigópteros) e um predador com habitats terrestre e aquático (aranha), e examinamos os efeitos na sobrevivência de presas (grupos de detritívoros com diferentes estratégias de defesa antipredatória), decomposição de detritos foliares (de duas espécies de plantas diferindo na qualidade foliar), fluxo de nitrogênio e crescimento da planta hospedeira. Para avaliar os efeitos diretos e indiretos de cada tipo de predador em múltiplos grupos de detritívoros e, finalmente, em múltiplos processos ecossistêmicos, utilizamos modelos de equações estruturais por partes (piecewiseSEM). Para cada variável resposta, isolamos a contribuição de diferentes grupos de detritívoros bem como seus efeitos globais, comparando modelos alternativos. Larvas de zigópteros e aranhas diminuíram diretamente a sobrevivência dos detritívoros e causaram múltiplos efeitos negativos indiretos na decomposição de detritos, na ciclagem de nutrientes e no crescimento da planta hospedeira. No entanto, quando os predadores coocorreram, a aranha causou um efeito negativo não consumível na larva de zigóptero, diminuindo os efeitos líquidos, diretos e indiretos, do tipo top­down na comunidade de detritívoros aquáticos e no funcionamento do ecossistema. Tanto os atributos antipredatórios dos detritívoros quanto a qualidade dos detritos modularam a força e o mecanismo dessas cascatas tróficas. A interferência do predador foi mediada por detritívoros indefesos ou com defesa parcial. Entretanto, os detritívoros com defesas antipredatórias escaparam do consumo por larvas de zigópteros, mas não por aranhas. Predadores e detritívoros afetaram a decomposição do ecossistema e a ciclagem de nutrientes apenas na presença de detritos de alta qualidade, uma vez que os detritos de baixa qualidade foram consumidos mais por micróbios do que por invertebrados. As respostas complexas deste sistema aos predadores tanto de ecossistemas receptores quanto adjacentes destacam o papel crítico da manutenção dos componentes da biodiversidade em múltiplos ecossistemas.

Dermatology's role in the fight against human trafficking: A report from the AAD Ad Hoc Task Force and call to action.

While the majority of American Academy of Dermatology members have some broad awareness of human trafficking, most are not aware of it in their communities or of the skin signs that could prompt identification of those being exploited, and have requested educational resources to assist patients affected by trafficking. The American Academy of Dermatology Ad Hoc Task Force on Dermatologic Resources for the Intervention and Prevention of Human Trafficking has been working to develop relevant resources, including an online toolkit on the American Academy of Dermatology website: https://www.aad.org/member/clinical-quality/clinical-care/human-trafficking.

Temporal development of the gut microbiome in early childhood from the TEDDY study.

The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial-immune crosstalk during this time thought to be involved in the pathobiology of later life diseases1-9 such as persistent islet autoimmunity and type 1 diabetes10-12. However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n = 12,005) and metagenomic sequencing (n = 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3-14), a transitional phase (months 15-30), and a stable phase (months 31-46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacterium species (B. breve and B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case-control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial-immune crosstalk for long-term health.

Subjective Sleep Disturbance and Lewy Pathology: Data from a Cohort of Essential Tremor Brain Donors.

INTRODUCTION: Sleep disturbances have been associated with essential tremor (ET). However, their pathophysiological underpinnings remain unknown. In this exploratory study, we examined the association between subjective sleep disturbances and the presence of Lewy pathology (LP) on postmortem brain examination in ET cases. METHODS: Fifty-two ET cases enrolled in a prospective, longitudinal study were assessed over an average period of 42 months. Cases completed the Pittsburgh Sleep Quality Index (PSQI), which yields seven component scores (e.g., sleep quality, sleep latency). For each component score, we calculated the difference between the last score and the baseline score. Brains were harvested at death. Each had a complete neuropathological assessment, including extensive α-synuclein immunostaining. We examined the associations between baseline PSQI scores and the change in PSQI scores (last - first), and LP on postmortem brain examination. RESULTS: ET cases had a mean baseline age of 87.1 ± 4.8 years. LP was observed in 12 (23.1%) of 52 cases; in 7 of these 12, LP was observed in the locus coeruleus (LC). Change in time needed to fall asleep (last - first sleep latency component score) was associated with presence of LP on postmortem brain examination - greater increase in sleep latency was associated with higher odds of LP (odds ratio = 2.98, p = 0.02). The greatest increase in sleep latency was observed in cases with LP in the LC (p = 0.04). CONCLUSION: In ET cases, increases in sleep latency over time could be a marker of underlying LP, especially in the LC.

Baseline Depressive Symptoms as a Predictor of Incident Dementia in a Prospectively Followed Cohort of Elders with Essential Tremor.

INTRODUCTION: Essential tremor (ET) patients may exhibit a variety of non-motor features, including cognitive decline and depressive symptoms. Studies of several neurodegenerative diseases link depression to cognitive decline, suggesting depression is an early marker of dementia. We examined whether baseline depressive symptoms predict incident dementia in elders with ET. METHODS: Hundred and forty-one ET cases aged 70 years or older at baseline, enrolled in a prospective study of cognitive performance, took part in evaluations at baseline and at 18, 36, 54, and 72 months. Participants completed the Geriatric Depression Scale (GDS), a 30-item self-report measure of depressive symptoms, and a battery of neuropsychological tests and functional assessments, from which we derived cognitive diagnoses at each evaluation. Cox proportional hazards regression equations determined incident dementia risk based on participants' baseline depression scores. RESULTS: Mean baseline age was 81.5 ± 6.7 years. Higher baseline GDS scores were associated with increased risk of dementia in an unadjusted model (hazards ratio [HR] = 1.11, 95% confidence interval [CI] = 1.02-1.20, p = 0.01) and after controlling for baseline age, education, number of medications, and tremor onset age (HR = 1.13, 95% CI = 1.02-1.25, p = 0.02). CONCLUSION: Baseline depression scores predicted incident dementia in elders with ET. With each one-point increase in baseline depression score, there was a 13% increase in incident dementia risk. Given the published data that reported depression may be twice as high in elders with ET compared to controls, this association is particularly worrisome in the ET population.

Motivation and accessing care among drug treatment court involved women: A sequential, mixed-methods approach.

Drug treatment courts (DTC) address substance use disorders (SUD) but not cooccurrencing HIV or hepatitis C virus (HCV). This pilot explored feasibility and preliminary outcomes of the Women's Initiative Supporting Health (WISH) intervention and health-related motivation, both based in self-determination theory (SDT) regarding HIV/HCV and SUD treatment. WISH feasibility study: 79 DTC women completed a one-time survey regarding motivation and willingness to engage in future interventions. WISH intervention: 22 women from DTC with SUD and HIV or HCV received a 6-session, peer motivational enhancement health behavior-oriented interventions. Recruitment strategies were feasible. SDT-based measures demonstrated internal consistency in this under-studied population, with perceived competence/autonomy associationed with motivation to reduce HIV/HCV/SUD risk. Women DTC participants indicated acceptance and showed internally consistent results in SDT-based motivation measures These WISH feasibility and intervention pilot studies lay a foundation for future studies addressing motivation to access healthcare among women DTC participants.