Sleep fragmentation despite intact rest-activity patterns in premanifest Huntington's disease: An actigraphy study.

OBJECTIVE: Sleep research in Huntington's disease (HD) has primarily focused on manifest HD, with significantly less attention given to premanifest HD (Pre-HD). Therefore, we investigated sleep and rest-activity patterns in people with Pre-HD versus healthy controls (HC). METHODS: We conducted a cross-sectional study including 36 Pre-HD and 48 HC participants. Pre-HD participants were stratified into three groups according to their proximity to estimated diagnosis, using a cytosine-adenine-guanine (CAG) and current age-based predictive model: NEAR (<9 years to diagnosis), MID (9-15 years to diagnosis) and FAR (>15 years to diagnosis). Sleep and rest-activity patterns were assessed using wrist-worn actigraphy, a sleep diary, and sleep questionnaires. RESULTS: NEAR and MID groups experienced higher fragmentation index than HC and FAR groups. NEAR and MID groups also exhibited greater WASO than the FAR group. NEAR and MID groups showed lower intra-daily variability (IV) than HC and FAR groups, with the NEAR group also being more active in the most active 10 h (M10). Groups did not differ on subjective sleep measures, inter-daily stability (IS), sleep regularity index, relative amplitude, or amount of activity in the least active 5 h (L5). Considering all Pre-HD participants, fewer years to diagnosis, higher CAG-age-product (CAP) scores (a measure of cumulative exposure to the HD-causing gene mutation) and larger CAG repeat lengths correlated with higher WASO, fragmentation index, L5, IS, and lower sleep efficiency and IV. Higher CAP score correlated with higher M10. CONCLUSIONS: Despite intact rest-activity patterns and similar subjective sleep quality to HC, greater sleep fragmentation is a prominent and early feature in Pre-HD. Therefore, reducing sleep fragmentation may be a potential target for sleep intervention in HD. Longitudinal studies using larger samples are needed to assess sleep across the disease spectrum and its impact on clinical outcomes, like cognition.

Placental Evolution: Innovating how to Feed Babies.

The evolution of the placenta was transformative. It changed how offspring are fed during gestation from depositing all the resources into an egg to continually supplying resources throughout gestation. Placental evolution is infinitely complex, with many moving parts, but at the core it is driven by a conflict over resources between the mother and the baby, which sets up a Red Queen race, fueling rapid diversification of morphological, cellular, and genetic forms. Placentas from even closely related species are highly divergent in form and function, and many cellular processes are distinct. If we could extract the entirety of genomic information for placentas across all species, including the many hundreds that have evolved in fish and reptiles, we could find their shared commonality, and that would tell us which of the many pieces really matter. We do not have this information, but we do have clues. Convergent evolution mechanisms were repeatedly used in the placenta, including the intense selective pressure to co-opt an envelope protein to build a multinucleated syncytium, the use of the same hormones and structural proteins in placentas derived from separate embryonic origins that arose hundreds of millions of years apart, and the co-option of endogenous retroviruses to form capsids as a way of transport and as mutagens to form new enhancers. As a result, the placental genome is the Wild West of biology, set up to rapidly change, adapt, and innovate. This ability to adapt facilitated the evolution of big babies with big brains and will continue to support offspring and their mothers in our ever-changing global environment.

Leveraging machine learning to study how temperament scores predict pre-term birth status.

Background: Preterm birth (birth at <37 completed weeks gestation) is a significant public heatlh concern worldwide. Important health, and developmental consequences of preterm birth include altered temperament development, with greater dysregulation and distress proneness. Aims: The present study leveraged advanced quantitative techniques, namely machine learning approaches, to discern the contribution of narrowly defined and broadband temperament dimensions to birth status classification (full-term vs. preterm). Along with contributing to the literature addressing temperament of infants born preterm, the present study serves as a methodological demonstration of these innovative statistical techniques. Study design: This study represents a metanalysis conducted with multiple samples (N = 19) including preterm (n = 201) children and (n = 402) born at term, with data combined across investigations to perform classification analyses. Subjects: Participants included infants born preterm and term-born comparison children, either matched on chronological age or age adjusted for prematurity. Outcome measures: Infant Behavior Questionnaire-Revised Very Short Form (IBQ-R VSF) was completed by mothers, with factor and item-level data considered herein. Results and conclusions: Accuracy estimates were generally similar regardless of the comparison groups. Results indicated a slightly higher accuracy and efficiency for IBQR-VSF item-based models vs. factor-level models. Divergent patterns of feature importance (i.e., the extent to which a factor/item contributed to classification) were observed for the two comparison groups (chronological age vs. adjusted age) using factor-level scores; however, itemized models indicated that the two most critical items were associated with effortful control and negative emotionality regardless of comparison group.

Assessing Methods to Ascertain Persistence and Adherence of Oral Anticoagulants in Patients with Atrial Fibrillation.

BACKGROUND: Persistence and adherence to oral anticoagulants (OACs) is crucial for its effectiveness in stroke prevention in atrial fibrillation (AF). We aimed to assess the impact of different ascertainment methods on estimated persistence rates. METHODS: We conducted a retrospective cohort study based on the Medicare claims data (01/01/2013-12/31/2019). We built an incident user cohort of OAC (apixaban, dabigatran, edoxaban, rivaroxaban, and warfarin) prescription filling. We measured OAC medication persistence and adherence using the following approaches: 1) treatment-anniversary based persistence: if there is an active prescription overlapping the 180th and 365th day with vs. without a 15-day buffer period (i.e., overlapping with 165th-195th and 350th-380th day); 2) dispensing-gap-based persistence: if there is OAC discontinuation defined as having gap between prescriptions more than a threshold (e.g., 5 to 60 days) and secondarily, 3) proportion of days covered (PDC) adherence: proportion of days in which patient had filled medication available over the 365-day interval. RESULTS: We identified 1,398,692 patients who initiated OACs during the study interval. With the treatment-anniversary based approach, only 51.2 to 65.4% of the patients persisted with the medication for either warfarin or DOACs at 180 days, and the number dropped to 43.4 to 60.7% at one year. Adding a 15-day buffer period increased the treatment-anniversary based persistence rates by 6.5 to 10.5%. When the allowable gap increased from 5 to 60 days, the persistence rates increased by 36.3 to 42.4% for all OACs. Apixaban users had the highest PDC (74 to 75%) over the 365 days, compared to other OACs (60 to 69%). CONCLUSIONS: We found that the estimated persistence rates are sensitive to the choice of ascertainment methods. When reporting and comparing persistence findings using the claims database, definitions of OAC discontinuation must be clearly delineated.

Rethinking the residual approach: Leveraging machine learning to operationalize cognitive resilience in Alzheimer's disease.

Cognitive resilience describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. We propose an alternative strategy which overcomes the standard approach's limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and construct to be measured and achieves better estimation accuracy on simulated ground-truth data.

Deciphering transcript architectural complexity in bacteria and archaea.

RNA transcripts are potential therapeutic targets, yet bacterial transcripts have uncharacterized biodiversity. We developed an algorithm for transcript prediction called tp.py using it to predict transcripts (mRNA and other RNAs) in Escherichia coli K12 and E2348/69 strains (Bacteria:gamma-Proteobacteria), Listeria monocytogenes strains Scott A and RO15 (Bacteria:Firmicute), Pseudomonas aeruginosa strains SG17M and NN2 strains (Bacteria:gamma-Proteobacteria), and Haloferax volcanii (Archaea:Halobacteria). From >5 million E. coli K12 and >3 million E. coli E2348/69 newly generated Oxford Nanopore Technologies direct RNA sequencing reads, 2,487 K12 mRNAs and 1,844 E2348/69 mRNAs were predicted, with the K12 mRNAs containing more than half of the predicted E. coli K12 proteins. While the number of predicted transcripts varied by strain based on the amount of sequence data used, across all strains examined, the predicted average size of the mRNAs was 1.6-1.7 kbp, while the median size of the 5'- and 3'-untranslated regions (UTRs) were 30-90 bp. Given the lack of bacterial and archaeal transcript annotation, most predictions were of novel transcripts, but we also predicted many previously characterized mRNAs and ncRNAs, including post-transcriptionally generated transcripts and small RNAs associated with pathogenesis in the E. coli E2348/69 LEE pathogenicity islands. We predicted small transcripts in the 100-200 bp range as well as >10 kbp transcripts for all strains, with the longest transcript for two of the seven strains being the nuo operon transcript, and for another two strains it was a phage/prophage transcript. This quick, easy, and reproducible method will facilitate the presentation of transcripts, and UTR predictions alongside coding sequences and protein predictions in bacterial genome annotation as important resources for the research community.IMPORTANCEOur understanding of bacterial and archaeal genes and genomes is largely focused on proteins since there have only been limited efforts to describe bacterial/archaeal RNA diversity. This contrasts with studies on the human genome, where transcripts were sequenced prior to the release of the human genome over two decades ago. We developed software for the quick, easy, and reproducible prediction of bacterial and archaeal transcripts from Oxford Nanopore Technologies direct RNA sequencing data. These predictions are urgently needed for more accurate studies examining bacterial/archaeal gene regulation, including regulation of virulence factors, and for the development of novel RNA-based therapeutics and diagnostics to combat bacterial pathogens, like those with extreme antimicrobial resistance.

Ultrasound-guided percutaneous thrombin injection for the management of upper extremity pseudoaneurysms: 20 years of tertiary care center experience.

PURPOSE: To evaluate the safety and efficacy of ultrasound-guided percutaneous thrombin injection for the treatment of upper extremity pseudoaneurysms. METHODS: An institutional database containing 8,316,467 radiology reports was searched for suitable cases over a 241-month period. Fourteen female and 10 male patients, average age of 69.7 years (range 29-93) underwent a total of 26 procedures for the management of upper extremity pseudoaneurysms, involving the radial (n = 9), brachial (n = 9) or other upper extremity arteries (n = 6). Baseline demographic and pseudoaneurysm characteristics were documented, together with primary and secondary success, failures, and complications. All procedures were performed with real-time ultrasound guidance. RESULTS: The mean pseudoaneurysm volume was 9.93 cm3 (range 0.06-111.62 cm3). Twelve cases were related to central line placement or arterial access. Primary success was obtained in 50% (n = 12) after a single ultrasound-guided thrombin injection, and secondary success was achieved in an additional six (for a total success of 75%). Success was highest for the treatment of brachial artery pseudoaneurysms (87.5%), and in those who were diagnosed within 7 days of the inciting event, findings that were statistically significant (p-value 0.046 and 0.002, respectively). CONCLUSIONS: Ultrasound-guided percutaneous thrombin injection is safe and effective for managing upper extremity pseudoaneurysms.

A critical assessment of time-to-antibiotics recommendations in pediatric sepsis.

The Pediatric Surviving Sepsis Campaign (SSC) Guidelines recommend delivery of antibiotics within one hour for children with septic shock and, for those without shock but with sepsis-related organ dysfunction, as soon as feasible within three hours. In this review, we summarize the available adult and pediatric literature supporting these recommendations. We also explore the implications of implementing time-to-antibiotic goals at the point of antibiotic initiation in clinical practice, as well as the potential downstream impacts of these goals on antibiotic de-escalation.

Comparison of the Analgesic Duration Using Ultrasound-guided Popliteal Sciatic Nerve Block between Diabetics with Neuropathy and Nondiabetics without Neuropathy.

INTRODUCTION: In India, the prevalence of diabetes mellitus neuropathy was reported to be as high as 30%. Eight percentage of the diabetic population suffer from foot ulceration and 1.8% have amputations. Popliteal nerve block can be potentially used for foot and ankle surgery with several advantages. AIM: To compare analgesic duration of an ultrasound (US)-guided popliteal sciatic nerve block between diabetics with neuropathy and nondiabetics without neuropathy. PATIENTS AND METHODS: Participants were allocated into two groups for popliteal sciatic nerve blocks under US guidance. The primary outcome was the duration to onset of sensory and motor blockade. The secondary outcome was the duration to rescue analgesic and the visual analog scale scoring within 24 h. Hemodynamic outcomes were also monitored along with the above variables. RESULTS: It was observed that the onset of sensory blockade was faster in participants with diabetes mellitus with peripheral neuropathy as compared to the nondiabetic participants and the duration for onset of motor blockade in dorsiflexion was faster in diabetic patients as compared to the nondiabetic patients (17.48 ± 3.21 min). However, there was no significant changes when comparing the onset of duration to loss of plantar flexion, in diabetics (17.86 ± 2.29 min) versus in nondiabetics (18.51 ± 3.32 min). The duration for rescue analgesics was found to be longer in diabetic participants (13.19 ± 2.14 h) as compared to the nondiabetic participants (11.44 ± 1.86 h). No differences were observed in the hemodynamic changes and the complications associated with local anesthetics in either group. CONCLUSION: Diabetic patients with neuropathy have faster onset of blockade when compared to nondiabetic patients without neuropathy which may be due to the degenerative condition of the peripheral nerves in them. The hemodynamic parameters do not play a role in defining the outcome of the block.

Résumé Introduction:En Inde, la prévalence de la neuropathie liée au diabète sucré atteignait 30 %. Huit pour cent de la population diabétique souffrent d'ulcères du pied et 1,8 % sont amputés. Le bloc du nerf poplité peut être potentiellement utilisé pour la chirurgie du pied et de la cheville avec plusieurs avantages.Objectif:Comparer la durée analgésique d'un bloc du nerf sciatique poplité guidé par échographie (É.-U.) entre des diabétiques atteints de neuropathie et des non diabétiques sans neuropathie.Patients et méthodes:Les participants ont été répartis en deux groupes pour les blocs du nerf sciatique poplité sous la direction des États-Unis. Le critère de jugement principal était la durée jusqu'à l'apparition du blocus sensoriel et moteur. Le résultat secondaire était la durée nécessaire pour sauver l'analgésique et l'échelle visuelle analogique après 24 h. Les résultats hémodynamiques ont également été surveillés avec les variables ci-dessus.Résultats:Il a été observé que l'apparition du blocage sensoriel était plus rapide chez les participants atteints de diabète sucré avec neuropathie périphérique que chez les participants non diabétiques et (la durée d'apparition du blocage moteur en dorsiflexion était plus rapide chez les patients diabétiques que chez les patients non diabétiques (Cependant, il n'y a eu aucun changement significatif en comparant le début de la durée à la perte de flexion plantaire, chez les diabétiques (17,86 ± 2,29 min) versus chez les non diabétiques (18,51 ± 3,32 min). La durée des analgésiques de secours a été trouvée être plus longue chez les participants diabétiques (13,19 ± 2,14 h) par rapport aux participants non diabétiques (11,44 ± 1,86 h). Aucune différence n'a été observée dans les changements hémodynamiques et les complications associées aux anesthésiques locaux dans les deux groupes.Conclusion:Patients diabétiques atteints de neuropathie ont un début de blocage plus rapide que les patients non diabétiques sans neuropathie, ce qui peut être dû à l'état dégénératif des nerfs périphériques chez eux. Les paramètres hémodynamiques ne jouent aucun rôle dans la définition de l'issue du bloc.

Key actors in neuropathophysiology: The role of γδ T cells.

The neuroimmune axis has been the focus of many studies, with special emphasis on the interactions between the central nervous system and the different immune cell subsets. T cells are namely recognized to play a critical role due to their interaction with nerves, by secreting cytokines and neurotrophins, which regulate the development, function, and survival of neurons. In this context, γδ T cells are particularly relevant, as they colonize specific tissues, namely the meninges, and have a wide variety of complex functions that balance physiological systems. Notably, γδ T cells are not only key components for maintaining brain homeostasis but are also responsible for triggering or preventing inflammatory responses in various pathologies, including neurodegenerative diseases as well as neuropsychiatric and developmental disorders. Here, we provide an overview of the current state of the art on the contribution of γδ T cells in neuropathophysiology and delve into the molecular mechanisms behind it. We aim to shed light on γδ T cell functions in the central nervous system while highlighting upcoming challenges in the field and providing new clues for potential therapeutic strategies.

Emotion-related Processes Between Parents and Adolescents: Evidence for Bidirectional Effects over Time.

Parent emotion socialization has long been studied in relation to children's socioemotional adjustment. Little attention has been paid to how parents' socialization responses are shaped by youth characteristics over time, such as emotional lability. The present study explored the mutual influence between parent emotion socialization and adolescent emotional lability. Participants were 87 adolescents (M = 14.23 years old, SD = .50; 50 girls) and their parents, who completed questionnaires at three time points from 8th grade through 10th grade. Hierarchical linear modeling demonstrated mutual influences between parent emotion socialization and adolescent emotional lability, with relations moderated by adolescent gender. Increases in parents' reward of negative emotion predicted decreased emotional lability in girls. Parents' increased magnification of negative emotions corresponded to decreased emotional lability in boys. Boys' increases in emotional lability predicted decreased parental magnification of negative emotions over time. Increases in parents' magnification of negative emotions predicted increased emotional lability in girls. Girls' increases in emotional lability corresponded to increased parental magnification over time. There were no longitudinal effects of adolescent emotional lability on parents' reward, override, and punishment of negative emotions. Future directions and clinical applications are discussed.

Diagnostic Validation of the Updated Pediatric Sepsis Biomarker Risk II for Acute Kidney Injury Prediction Model in Pediatric Septic Shock.

OBJECTIVES: We previously derived the updated Pediatric Sepsis Biomarker Risk for Acute Kidney Injury (PERSEVERE-II AKI) prediction model, which had robust diagnostic test characteristics for severe AKI on day 3 (D3 severe AKI) of septic shock. We now sought to validate this model in an independent cohort of children to the one in which the model was developed. DESIGN: A secondary analysis of a multicenter, prospective, observational study carried out from January 2019 to December 2022. SETTING: Ten PICUs in the United States. PATIENTS: Children with septic shock 1 week to 18 years old admitted to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Seventy-nine of 363 patients (22%) had D3 severe AKI, defined as Kidney Disease Improving Global Outcomes stage 2 or higher. Patients were assigned a probability of D3 severe AKI using the PERSEVERE-II AKI model. The model predicted D3 severe AKI with an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.85-0.93), sensitivity of 77% (95% CI, 66-86%), specificity of 88% (95% CI, 84-92%), positive predictive value of 65% (95% CI, 54-74%), and negative predictive value of 93% (95% CI, 89-96%). These data represent an increase in post-test probability of D3 severe AKI with a positive test from 22% to 65%, and a prevalence threshold of 28%. On multivariable regression, the PERSEVERE-II AKI prediction model demonstrated greater adjusted odds ratio (aOR) for D3 severe AKI (aOR, 11.2; 95% CI, 4.9-25.3) and lesser aOR for failure of D3 renal recovery from early AKI (aOR, 0.31; 95% CI, 0.13-0.69). CONCLUSIONS: The PERSEVERE-II AKI model demonstrates consistently robust performance for prediction of new or persistent D3 severe AKI in children with septic shock. A major limitation is that actual D3 severe AKI prevalence is below the prevalence threshold for the test, and thus future work should focus on evaluating use in enriched populations.

Adolescent Peer Relationship Difficulties, Prosociality, and Parental Emotion Socialization: Moderating Roles of Adolescent Gender.

The present study examined longitudinal, transactional associations between youth social adjustment (prosociality, peer relationship difficulties) and parental emotion socialization in early adolescence. Adolescent gender was considered as a potential moderator. Eighty-seven adolescent-parent dyads (50 girls, 37 boys) participated in 8th grade, with follow-up waves in 9th and 10th grade. Adolescents reported their experiences of peer victimization and their parents' emotion socialization responses, and parents reported youth prosocial behavior and peer relation problems. Hierarchical linear modeling results indicated transactional associations between parent supportive/unsupportive responses and adolescent peer relations and prosociality over time, some of which were moderated by adolescent gender. Increases in parental supportive emotion socialization corresponded to decreased experiences of peer victimization over time for girls, but not boys. When peer victimization increased over time, girls reported less parental supportive responses and all adolescents reported receiving more unsupportive responses from parents. For all adolescents, parents' increased supportive responses also corresponded to decreased peer problems and increased prosocial behavior. As prosocial behavior increased, so did parental supportive responses. Increases in parents' unsupportive responses related to decreased prosocial behavior, and increases in adolescent prosocial behavior related to decreases in parents' unsupportive responses. Results suggest that there is mutual influence between parent emotion socialization and adolescent social adjustment. Adolescent girls appear to uniquely benefit from parents' supportive emotional socialization in relation to their experiences of peer victimization. Potential mechanisms and implications are discussed.

Pseudoendocrine sarcoma: a rare new entity with unique radiologic and pathologic/molecular characteristics.

Pseudoendocrine sarcoma is a rare, recently described intermediate grade sarcoma of uncertain phenotype that most commonly affects the paraspinal location in older patients with a distinctive endocrine/paraganglioma-like morphology and unique CTNNB1 point mutation. While these tumors appear as epithelial or even benign endocrine tumors, these lack markers for such and are highlighted by nuclear expression of beta-catenin. This case is the first among the previously reported only twenty-five cases of this entity, including one original series and a few case reports, to correlate the radiologic imaging with the pathologic features. Furthermore, this case illustrates the oldest-to-date patient with this unique location as a palpable painful chest wall/paraspinal location, with new morphologic observations and, finally, this is only the second case to have this specific CTNNB1 hotspot point mutation for this rare entity.

Bioluminescent Assay for the Quantification of Cellular Glycogen Levels.

Glycogen is a large polymer of glucose that functions as an important means of storing energy and maintaining glucose homeostasis. Glycogen synthesis and degradation pathways are highly regulated and their dysregulation can contribute to disease. Glycogen storage diseases are a set of disorders that arise from improper glycogen metabolism. Glycogen storage disease II, known as Pompe disease, is caused by a genetic mutation that leads to increased glycogen storage in cells and tissues, resulting in progressive muscle atrophy and respiratory decline for patients. One approach for treating Pompe disease is to reduce glycogen levels by interfering with the glycogen synthesis pathway through glycogen synthase inhibitors. To facilitate the study of glycogen synthase inhibitors in biological samples, such as cultured cells, a high-throughput approach for measuring cellular glycogen was developed. A bioluminescent glycogen detection assay was automated and used to measure the glycogen content in cells grown in 384-well plates. The assay successfully quantified reduced glycogen stores in cells treated with a series of glycogen synthase 1 inhibitors, validating the utility of the assay for drug screening efforts and demonstrating its value for therapy development and glycogen metabolism research.

Small molecule inhibition of glycogen synthase I reduces muscle glycogen content and improves biomarkers in a mouse model of Pompe disease.

Pompe disease is a rare genetic disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). This enzyme is responsible for breaking down glycogen, leading to the abnormal accumulation of glycogen, which results in progressive muscle weakness and metabolic dysregulation. In this study, we investigated the hypothesis that the small molecule inhibition of glycogen synthase I (GYS1) may reduce muscle glycogen content and improve metabolic dysregulation in a mouse model of Pompe disease. To address this hypothesis, we studied four groups of male mice: a control group of wild-type B6129SF1/J mice fed either regular chow (WT) or a GYS1 inhibitor (MZ-101) diet (WT-GYS1), and Pompe model mice B6;129-Gaatm1Rabn/J fed either regular chow (GAA-KO) or MZ-101 diet (GAA-GYS1) for 7 days. Our findings revealed that GAA-KO mice exhibited abnormal glycogen accumulation in the gastrocnemius, heart, and diaphragm. In contrast, inhibiting GYS1 reduced glycogen levels in all tissues compared to GAA-KO mice. Furthermore, GAA-KO mice displayed reduced spontaneous activity during the dark cycle compared to WT mice, while GYS1 inhibition counteracted this effect. Compared to GAA-KO mice, GAA-GYS1 mice exhibited improved glucose tolerance and whole-body insulin sensitivity. These improvements in insulin sensitivity could be attributed to increased AMPK phosphorylation in the gastrocnemius of WT-GYS1 and GAA-GYS1 mice. Additionally, the GYS1 inhibitor led to a reduction in the phosphorylation of GSS641 and the LC3 autophagy marker. Together, our results suggest that targeting GYS1 could serve as a potential strategy for treating glycogen storage disorders and metabolic dysregulation.

MSK1 is required for the experience- and ampakine-dependent enhancement of spatial reference memory and reversal learning and for the induction of Arc and BDNF.

There is considerable interest in the development of nootropics, pharmacological agents that can improve cognition across a range of both cognitive modalities and cognitive disabilities. One class of cognitive enhancers, the ampakines, has attracted particular attention by virtue of improving cognition associated with animal models of neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as in age-related cognitive impairment. Ampakines elevate CNS levels of BDNF, and it is through this elevation that their beneficial actions are believed to occur. However, what transduces the elevation of BDNF into long-lasting cognitive enhancement is not known. We have previously shown that MSK1, by virtue of its ability to regulate gene transcription, converts the elevation of BDNF associated with environmental enrichment into molecular, synaptic, cognitive and genomic adaptations that underlie enrichment-induced enhanced synaptic plasticity and learning and memory, a property that MSK1 retains across the lifespan. To establish whether MSK1 similarly converts ampakine-induced elevations of BDNF into cognitive enhancement we tested an ampakine (CX929) in male WT mice and in male mice in which the kinase activity of MSK1 was inactivated. We found that MSK1 is required for the ampakine-dependent improvement in spatial reference memory and cognitive flexibility, and for the elevations of BDNF and the plasticity-related protein Arc associated with ampakines and experience. These observations implicate MSK1 as a key enabler of the beneficial effects of ampakines on cognitive function, and furthermore identify MSK1 as a hub for BDNF-elevating nootropic strategies.

Associations between sex, race/ethnicity, and age and the initiation of chronic high-risk medication in US older adults.

BACKGROUND: High-risk medication use is associated with an increased risk of adverse events, but little is known about its chronic utilization by key demographic groups. We aimed to study the associations between age, sex, and race/ethnicity with new chronic use of high-risk medications in older adults. METHODS: In this retrospective cohort study, we analyzed data from older adults aged ≥65 years enrolled in a national health insurer who started a high-risk medication between 2017 and 2022 across 16 high-risk medication classes. We used generalized estimating equations to estimate the associations between sociodemographic classifications and the onset of chronic high-risk medication use after initiation (≥90 days' supply across ≥2 fills within 180 days). We adjusted the analyses for sociodemographic and clinical patient characteristics and added three-way interaction terms for race/ethnicity, sex, and age to explore whether the outcome varied across different subgroups of race/ethnicity, age, and sex. RESULTS: Across 2,751,069 patients (mean age: 74 years [SD = 7], 72% White, 60% Female), 406,075 (15%) became new chronic users of ≥1 high-risk medication. Compared to White older adults, Asian (RR = 0.81, 95% CI: 0.79-0.84), Black (RR = 0.92, 95% CI: 0.90-0.94), and Hispanic (RR = 0.85, 95% CI: 0.83-0.86) older adults had a lower risk of becoming new chronic users. Men had a higher risk compared to women (RR = 1.09, 95% CI: 1.08-1.10). Age was not significantly associated with new chronic high-risk medication use (≥75 years: RR = 1.00, 95% CI: 1.00-1.01). We observed differences across some medication classes, like benzodiazepines, first-generation antihistamines, and antimuscarinics for which non-White older adults were at a higher risk. The joint presence of specific age, sex, and race/ethnicity characteristics decreased the risk of becoming a new chronic user (e.g., Hispanic/Female/65-74 years: RR = 0.96, 95% CI: 0.94-0.99). CONCLUSIONS: New chronic high-risk medication use varied across older adults by sociodemographic characteristics, suggesting the need to individualize medication optimization approaches and better understand how systematic barriers in access to health care may influence differences in high-risk medication use in older adults.

Modeling the interaction of vegetation and sea level rise on barrier island evolution.

Barrier islands provide a first line of defense against ocean flooding and storm surge. Biogeomorphic interactions are recognized as important in coastal system processes, but current barrier island models are primarily dominated by physical processes. Recent research has demonstrated different biogeomorphic states that influence response to sea level rise and other disturbance. Building on this understanding, we present a cellular model utilizing biotic and abiotic processes and their interactions for barrier island evolution. Using the literature and field derived parameters, we model barrier island evolution and compare to three decades of change for Smith Island, a Virginia Coast Reserve barrier island. We conduct simulations that show the impact of biogeomorphic states on island migration under different sea level rise scenarios. We find that migration is highest in areas with low topography and light vegetation cover (i.e. disturbance reinforcing) compared to areas with greater topographic complexity and high cover of woody vegetation i.e. disturbance resisting). This study demonstrates the importance of biogeomorphic interactions for barrier island evolution with sea level rise and will aid future predictions for these important ecosystems with climate change.