Multisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges.

Modulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures and are practical for chronic daily home use are desirable for a variety of therapeutic applications. Repetitive audio-visual stimulation, or sensory flicker, is an accessible approach that modulates hippocampus in mice, but its effects in humans are poorly defined. We therefore quantified the neurophysiological effects of flicker with high spatiotemporal resolution in patients with focal epilepsy who underwent intracranial seizure monitoring. In this interventional trial (NCT04188834) with a cross-over design, subjects underwent different frequencies of flicker stimulation in the same recording session with the effect of sensory flicker exposure on local field potential (LFP) power and interictal epileptiform discharges (IEDs) as primary and secondary outcomes, respectively. Flicker focally modulated local field potentials in expected canonical sensory cortices but also in the medial temporal lobe and prefrontal cortex, likely via resonance of stimulated long-range circuits. Moreover, flicker decreased interictal epileptiform discharges, a pathological biomarker of epilepsy and degenerative diseases, most strongly in regions where potentials were flicker-modulated, especially the visual cortex and medial temporal lobe. This trial met the scientific goal and is now closed. Our findings reveal how multi-sensory stimulation may modulate cortical structures to mitigate pathological activity in humans.

State Department of Motor Vehicles Reporting Mandates of Dementia Diagnoses and Dementia Underdiagnosis.

Importance: With older drivers representing the fastest growing segment of the driver population and dementia prevalence increasing with age, policymakers face the challenge of balancing road safety and mobility of older adults. In states that require reporting a dementia diagnosis to the Department of Motor Vehicles (DMV), individuals with dementia may be reluctant to disclose symptoms of cognitive decline, and clinicians may be reluctant to probe for those symptoms, which may be associated with missed or delayed diagnoses. Objective: To assess whether DMV reporting policies for drivers with dementia are associated with primary care clinicians' underdiagnosing dementia. Design, Setting, and Participants: This cross-sectional study used data from the 100% Medicare fee-for-service program and the Medicare Advantage plans from 2017 to 2019 on 223 036 primary care clinicians with at least 25 Medicare patients. Statistical analysis was performed from July to October 2023. Exposures: State DMV reporting policies for drivers with dementia. Main Outcomes and Measures: The main outcome was a binary variable indicating whether the clinician underdiagnosed dementia or not. Each clinician's expected number of dementia cases was estimated using a predictive model based on patient characteristics. Comparing the estimation with observed dementia diagnoses identified clinicians who underdiagnosed dementia vs those who did not, after accounting for sampling errors. Results: Four states have clinician reporting mandates, 14 have mandates requiring drivers to self-report dementia diagnoses, and 32 states and the District of Columbia do not have explicit requirements. Among primary care clinicians in states with clinician reporting mandates (n = 35 620), 51.4% were female, 91.9% worked in a metropolitan area, and 19.9% of the patient panel were beneficiaries dually eligible for Medicare and Medicaid. Among primary care clinicians in states with patient self-reporting mandates (n = 57 548), 55.7% were female, 83.1% worked in a metropolitan area, and 15.4% of the patient panel were dually eligible for Medicare and Medicaid. Among clinicians in states without mandates, 55.7% were female, 83.0% worked in a metropolitan area, and 14.6% of the patient panel were dually eligible for Medicare and Medicaid. Clinicians in states with clinician reporting mandates had an adjusted 12.4% (95% CI, 10.5%-14.2%) probability of underdiagnosing dementia compared with 7.8% (95% CI, 6.9%-8.7%) in states with self-reporting and 7.7% (95% CI, 6.9%-8.4%) in states with no mandates, an approximately 4-percentage point difference (P < .001). Conclusions and Relevance: Results of this cross-sectional study of primary care clinicians suggest that mandatory DMV policies for clinicians to report patients with dementia may be associated with a higher risk of missed or delayed dementia diagnoses. Future research is needed to better understand the unintended consequences and the risk-benefit tradeoffs of these policies.

Chronic exercise improves hepatic acylcarnitine handling.

Exercise mediates tissue metabolic function through direct and indirect adaptations to acylcarnitine (AC) metabolism, but the exact mechanisms are unclear. We found that circulating medium-chain acylcarnitines (AC) (C12-C16) are lower in active/endurance trained human subjects compared to sedentary controls, and this is correlated with elevated cardiorespiratory fitness and reduced adiposity. In mice, exercise reduced serum AC and increased liver AC, and this was accompanied by a marked increase in expression of genes involved in hepatic AC metabolism and mitochondrial ß-oxidation. Primary hepatocytes from high-fat fed, exercise trained mice had increased basal respiration compared to hepatocytes from high-fat fed sedentary mice, which may be attributed to increased Ca2+ cycling and lipid uptake into mitochondria. The addition of specific medium- and long-chain AC to sedentary hepatocytes increased mitochondrial respiration, mirroring the exercise phenotype. These data indicate that AC redistribution is an exercise-induced mechanism to improve hepatic function and metabolism.

Advance Care Planning Among Sexual Minority Men: Sociodemographic, Health Care, and Health Status Predictors.

Objectives: Advance care planning (ACP) specifies decision-making surrogates and preferences for serious illness or end-of-life medical care. ACP research has largely neglected sexual minority men (SMM), a population that experiences disparities in health care and health status. Methods: We examined formal and informal ACP among SMM ages 40+ in the Multicenter AIDS Cohort Study (N = 1,071). Results: For informal ACP (50%), younger SMM and men with past cardiovascular events had greater odds of planning; single men had lower odds of planning. For formal ACP (39%), SMM with greater socioeconomic status had greater odds of planning; SMM who were younger, of racial/ethnic minority identities, who were single or in a relationship without legal protections, and who lacked a primary care home had lower odds of planning. Discussion: Findings warrant further exploration of both informal and formal planning. More equitable, culturally-humble engagement of SMM may facilitate access, uptake, and person-centered planning.

Left-Hemisphere Cortical Language Regions Respond Equally to Observed Dialogue and Monologue.

Much of the language we encounter in our everyday lives comes in the form of conversation, yet the majority of research on the neural basis of language comprehension has used input from only one speaker at a time. Twenty adults were scanned while passively observing audiovisual conversations using functional magnetic resonance imaging. In a block-design task, participants watched 20 s videos of puppets speaking either to another puppet (the dialogue condition) or directly to the viewer (the monologue condition), while the audio was either comprehensible (played forward) or incomprehensible (played backward). Individually functionally localized left-hemisphere language regions responded more to comprehensible than incomprehensible speech but did not respond differently to dialogue than monologue. In a second task, participants watched videos (1-3 min each) of two puppets conversing with each other, in which one puppet was comprehensible while the other's speech was reversed. All participants saw the same visual input but were randomly assigned which character's speech was comprehensible. In left-hemisphere cortical language regions, the time course of activity was correlated only among participants who heard the same character speaking comprehensibly, despite identical visual input across all participants. For comparison, some individually localized theory of mind regions and right-hemisphere homologues of language regions responded more to dialogue than monologue in the first task, and in the second task, activity in some regions was correlated across all participants regardless of which character was speaking comprehensibly. Together, these results suggest that canonical left-hemisphere cortical language regions are not sensitive to differences between observed dialogue and monologue.

Pharmacological inhibition of CLK2 activates YAP by promoting alternative splicing of AMOTL2.

Yes-associated protein (YAP), the downstream effector of the evolutionarily conserved Hippo pathway, promotes cellular proliferation and coordinates certain regenerative responses in mammals. Small molecule activators of YAP may, therefore, display therapeutic utility in treating disease states involving insufficient proliferative repair. From a high-throughput chemical screen of the comprehensive drug repurposing library ReFRAME, here we report the identification of SM04690, a clinical stage inhibitor of CLK2, as a potent activator of YAP-driven transcriptional activity in cells. CLK2 inhibition promotes alternative splicing of the Hippo pathway protein AMOTL2, producing an exon-skipped gene product that can no longer associate with membrane-bound proteins, resulting in decreased phosphorylation and membrane localization of YAP. This study reveals a novel mechanism by which pharmacological perturbation of alternative splicing inactivates the Hippo pathway and promotes YAP-dependent cellular growth.

A comparison of the outcomes of pulmonary versus extrapulmonary extensive-stage small cell carcinoma.

BACKGROUND: Extrapulmonary small cell carcinomas (EPSCCs) are rare cancers, comprising 0.1-0.4% of all cancers. The scarcity of EPSCC studies has led current treatment strategies to be extrapolated from small cell lung cancer (SCLC), justified by analogous histological and clinical features. AIMS: We conducted a retrospective cohort study comparing the outcomes of extensive-stage (ES) SCLC and EPSCC. METHODS: Patients diagnosed with ES SCLC or EPSCC between 2010 and 2020 from four hospitals in Sydney were identified. Patients who received active treatment and best supportive care were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and overall response rates (ORRs). RESULTS: Three hundred and eighty-four patients were included (43 EPSCC vs. 340 SCLC). EPSCC were of genitourinary (n = 15), unknown primary (n = 13) and gastrointestinal (n = 12) origin. Treatment modalities for EPSCC compared to SCLC included palliative chemotherapy (56% vs 73%), palliative radiotherapy (47% vs 59%) and consolidation chest radiotherapy (10% of SCLC). Overall, median OS was 6.4 versus 7 months for EPSCC versus SCLC respectively, but highest in prostate EPSCC (25.6 months). Of those who received chemotherapy (22 EPSCC vs 233 SCLC), median OS was 10.4 versus 8.4 months (HR OS 0.81, 95% confidence interval (CI): 0.5-1.31, P = 0.38); PFS was 5.4 versus 5.5 months (HR PFS 0.93, 95% CI: 0.58-1.46, P = 0.74) and ORR were 73% versus 68%. CONCLUSIONS: EPSCC and SCLC appeared to have comparable OS and treatment outcomes. However, the wide range of OS in EPSCC highlights the need for an improved understanding of its genomics to explore alternative therapeutics.

Reported changes in romantic and sexual behavior among college and graduate students during COVID-19.

Objective: To understand changes in romantic and sexual behavior among college and graduate students in North Carolina during COVID-19. Participants: Participants were between 18-30 years old and enrolled in a two- or four-year college or graduate program in North Carolina (n = 926). Methods: A cross-sectional web-based survey was administered to college and graduate students to assess romantic and sexual behavioral changes during COVID-19. Results: Participants continued to engage in in-person sexual intercourse during COVID-19 and reported an increase in online and virtual dating. Although the majority of participants reported following COVID-19 guidelines, they did not frequently use risk mitigation strategies such as declining kissing or sex due to COVID-19 concerns, inquiring about recent COVID-19 tests, or having sexual contact without kissing. Conclusion: Study findings suggest a need for colleges and universities to help students manage COVID-19 prevention in intimate relationships.

A covalent inhibitor of the YAP-TEAD transcriptional complex identified by high-throughput screening.

Yes-associated protein (YAP), the master transcriptional effector downstream of the Hippo pathway, regulates essential cell growth and regenerative processes in animals. However, the activation of YAP observed in cancers drives cellular proliferation, metastasis, chemoresistance, and immune suppression, making it of key interest in developing precision therapeutics for oncology. As such, pharmacological inhibition of YAP by targeting its essential co-regulators, TEA domain transcription factors (TEADs) would likely promote tumor clearance in sensitive tumor types. From a fluorescence polarization-based high throughput screen of over 800 000 diverse small molecules, here we report the identification of a pyrazolopyrimidine-based scaffold that inhibits association of YAP and TEADs. Medicinal chemistry-based optimization identified mCMY020, a potent, covalent inhibitor of TEAD transcriptional activity that occupies a conserved, central palmitoylation site on TEADs.

How does Twitter account moderation work? Dynamics of account creation and suspension on Twitter during major geopolitical events.

Social media moderation policies are often at the center of public debate, and their implementation and enactment are sometimes surrounded by a veil of mystery. Unsurprisingly, due to limited platform transparency and data access, relatively little research has been devoted to characterizing moderation dynamics, especially in the context of controversial events and the platform activity associated with them. Here, we study the dynamics of account creation and suspension on Twitter during two global political events: Russia's invasion of Ukraine and the 2022 French Presidential election. Leveraging a large-scale dataset of 270M tweets shared by 16M users in multiple languages over several months, we identify peaks of suspicious account creation and suspension, and we characterize behaviors that more frequently lead to account suspension. We show how large numbers of accounts get suspended within days of their creation. Suspended accounts tend to mostly interact with legitimate users, as opposed to other suspicious accounts, making unwarranted and excessive use of reply and mention features, and sharing large amounts of spam and harmful content. While we are only able to speculate about the specific causes leading to a given account suspension, our findings contribute to shedding light on patterns of platform abuse and subsequent moderation during major events.

Patient Perspectives on Transitions from Acute to Community-Based Physiotherapy Care Following Total Knee Replacement Surgery Within the Context of a Bundled Care Model.

Purpose: Research on fiscal implications of the bundled care (BC) model exist; however, patient-perceived experiences are less well known. As BC expands in Ontario, this study aims to examine these experiences with physiotherapy care within the total knee replacement (TKR) BC programme. Methods: Qualitative cross-sectional study design. Semi-structured one-on-one telephone interviews were conducted with eight patients four to six weeks post-TKR. Thematic analysis was used. Results: This exploratory study identified three themes across the care journey that patients perceived as influencing their physiotherapy experiences: timely access to physiotherapy care, quality of physiotherapy care, and patient outcomes. Communication, clinical support, and social support were sub-themes. Conclusions: Patients' overall experiences with BC physiotherapy were positive. Areas for improvement included coordination of postoperative physiotherapy and return-to-work support. Patients valued group settings and were interested in meeting previous TKR patients. Health system planners are advised to consider incorporating patient experiences when evaluating and developing BC programmes to achieve patient-centred outcomes.

Objectif : il existe des recherches sur les conséquences budgétaires du modèle des faisceaux de soins (FS), mais les expériences perçues par les patients sont moins connues. Puisque le FS se généralise en Ontario, la présente étude vise à examiner ces expériences dans le contexte des soins physiothérapiques au sein du programme de FS de l'arthroplastie totale du genou (ATG). Méthodologie : étude transversale qualitative. Les chercheurs ont effectué des entrevues téléphoniques individuelles semi-structurées auprès de huit patients, de quatre à six semaines après une ATG. Ils ont utilisé une analyse thématique. Résultats : cette étude exploratoire a permis de faire ressortir trois thèmes dans le parcours des soins que les patients perçoivent comme influents sur leurs expériences de la physiothérapie : l'accès rapide aux soins de physiothérapie, la qualité de ces soins et l'issue des patients. Les sous-thèmes de la communication, du soutien clinique et du soutien social ont également été dégagés. Conclusions : les expériences globales des patients à l'égard de la physiothérapie des FS étaient positives. Les secteurs à améliorer incluaient la coordination de la physiothérapie postopératoire et le soutien au retour au travail. Les patients aimaient les contextes de groupe et s'intéressaient à rencontrer des patients qui avaient déjà subi une ATG. Les planificateurs du système de santé sont invités à envisager d'intégrer les expériences des patients lorsqu'ils évaluent et développent des programmes de FS pour obtenir des résultats axés sur les patients.

Current Discoveries and Future Implications of Eating Disorders.

Eating disorders (EDs) are characterized by severe disturbances in eating behaviors and can sometimes be fatal. Eating disorders are also associated with distressing thoughts and emotions. They can be severe conditions affecting physical, psychological, and social functions. Preoccupation with food, body weight, and shape may also play an important role in the regulation of eating disorders. Common eating disorders have three major types: anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). In some cases, EDs can have serious consequences for an individual's physical and mental health. These disorders often develop during adolescence or early adulthood and affect both males and females, although they are more commonly diagnosed in young adult females. Treatment for EDs typically involves a combination of therapy, nutrition counseling, and medical care. In this narrative review, the authors summarized what is known of EDs and discussed the future directions that may be worth exploring in this emerging area.

Expected and diagnosed rates of mild cognitive impairment and dementia in the U.S. Medicare population: observational analysis.

BACKGROUND: With the emergence of disease-modifying Alzheimer's treatments, timely detection of early-stage disease is more important than ever, as the treatment will not be indicated for later stages. Contemporary population-level data for detection rates of mild cognitive impairment (MCI), the stage at which treatment would ideally start, are lacking, and detection rates for dementia are only available for subsets of the Medicare population. We sought to compare documented diagnosis rates of MCI and dementia in the full Medicare population with expected rates based on a predictive model. METHODS: We performed an observational analysis of Medicare beneficiaries aged 65 and older with a near-continuous enrollment over a 3-year observation window or until death using 100% of the Medicare fee-for-service or Medicare Advantage Plans beneficiaries from 2015 to 2019. Actual diagnoses for MCI and dementia were derived from ICD-10 codes documented in those data. We used the 2000-2016 data of the Health and Retirement Study to develop a prediction model for expected diagnoses for the included population. The ratios between actually diagnosed cases of MCI and dementia over number of cases expected, the observed over expected ratio, reflects the detection rate. RESULTS: Although detection rates for MCI cases increased from 2015 to 2019 (0.062 to 0.079), the results mean that 7.4 of 8 million (92%) expected MCI cases remained undiagnosed. The detection rate for MCI was 0.039 and 0.048 in Black and Hispanic beneficiaries, respectively, compared with 0.098 in non-Hispanic White beneficiaries. Individuals dually eligible for Medicare and Medicaid had lower estimated detection rates than their Medicare-only counterparts for MCI (0.056 vs 0.085). Dementia was diagnosed more frequently than expected (1.086 to 1.104) from 2015 to 2019, mostly in non-Hispanic White beneficiaries (1.367) compared with 0.696 in Black beneficiaries and 0.758 in Hispanic beneficiaries. CONCLUSIONS: These results highlight the need to increase the overall detection rates of MCI and of dementia particularly in socioeconomically disadvantaged groups.

Mechanistic Investigation of Ni-Catalyzed Reductive Cross-Coupling of Alkenyl and Benzyl Electrophiles.

Mechanistic investigations of the Ni-catalyzed asymmetric reductive alkenylation of N-hydroxyphthalimide (NHP) esters and benzylic chlorides are reported. Investigations of the redox properties of the Ni-bis(oxazoline) catalyst, the reaction kinetics, and mode of electrophile activation show divergent mechanisms for these two related transformations. Notably, the mechanism of C(sp3) activation changes from a Ni-mediated process when benzyl chlorides and Mn0 are used to a reductant-mediated process that is gated by a Lewis acid when NHP esters and tetrakis(dimethylamino)ethylene is used. Kinetic experiments show that changing the identity of the Lewis acid can be used to tune the rate of NHP ester reduction. Spectroscopic studies support a NiII-alkenyl oxidative addition complex as the catalyst resting state. DFT calculations suggest an enantiodetermining radical capture step and elucidate the origin of enantioinduction for this Ni-BOX catalyst.

Pharmacological inhibition of CLK2 activates YAP by promoting alternative splicing of AMOTL2.

Yes-associated protein (YAP), the downstream effector of the evolutionarily conserved Hippo pathway, promotes cellular proliferation and coordinates certain regenerative responses in mammals. Small molecule activators of YAP may therefore display therapeutic utility in treating disease states involving insufficient proliferative repair. From a high-throughput chemical screen of the comprehensive drug repurposing library ReFRAME, here we report the identification of SM04690, a clinical stage inhibitor of CLK2, as a potent activator of YAP driven transcriptional activity in cells. CLK2 inhibition promotes alternative splicing of the Hippo pathway protein AMOTL2, producing an exon-skipped gene product that can no longer associate with membrane-bound proteins, resulting in decreased phosphorylation and membrane localization of YAP. This study reveals a novel mechanism by which pharmacological perturbation of alternative splicing inactivates the Hippo pathway and promotes YAP dependent cellular growth.

Report of a Rare Case of Intracranial Extramedullary Hematopoiesis Mimicking a Brain Tumor.

Failure of the bone marrow to maintain adequate blood cell production to match blood metabolic demand incites the production of cell lines outside the bone marrow, which is known as extramedullary hematopoiesis. Herein, we are reporting an 80-year-old male patient who presented with two weeks of worsening headaches and behavioral changes. Labs showed thrombocytosis and imaging showed a large right-sided hemorrhagic brain mass. No evidence of malignancy was seen elsewhere. Brain mass biopsy showed intracranial extramedullary hematopoiesis (IEMH) and bone marrow biopsy confirmed the diagnosis of essential thrombocythemia (ET)/myelofibrosis. This case adds to a few reported cases of IEMH, and to the best of our knowledge, this is the first reported case of IEMH in association with ET. It helps remind clinicians to keep IEMH in the differential diagnosis of those presenting with signs and symptoms of elevated intracranial pressure (ICP) and a newly found brain mass on the background of previously diagnosed or suspected myeloproliferative neoplasms.

Mapping N- to C-terminal allosteric coupling through disruption of a putative CD74 activation site in D-dopachrome tautomerase.

The macrophage migration inhibitory factor (MIF) protein family consists of MIF and D-dopachrome tautomerase (also known as MIF-2). These homologs share 34% sequence identity while maintaining nearly indistinguishable tertiary and quaternary structure, which is likely a major contributor to their overlapping functions, including the binding and activation of the cluster of differentiation 74 (CD74) receptor to mediate inflammation. Previously, we investigated a novel allosteric site, Tyr99, that modulated N-terminal catalytic activity in MIF through a "pathway" of dynamically coupled residues. In a comparative study, we revealed an analogous allosteric pathway in MIF-2 despite its unique primary sequence. Disruptions of the MIF and MIF-2 N termini also diminished CD74 activation at the C terminus, though the receptor activation site is not fully defined in MIF-2. In this study, we use site-directed mutagenesis, NMR spectroscopy, molecular simulations, in vitro and in vivo biochemistry to explore the putative CD74 activation region of MIF-2 based on homology to MIF. We also confirm its reciprocal structural coupling to the MIF-2 allosteric site and N-terminal enzymatic site. Thus, we provide further insight into the CD74 activation site of MIF-2 and its allosteric coupling for immunoregulation.

Ex Situ Reconstruction-Shaped Ir/CoO/Perovskite Heterojunction for Boosted Water Oxidation Reaction.

The oxygen evolution reaction (OER) is the performance-limiting step in the process of water splitting. In situ electrochemical conditioning could induce surface reconstruction of various OER electrocatalysts, forming reactive sites dynamically but at the expense of fast cation leaching. Therefore, achieving simultaneous improvement in catalytic activity and stability remains a significant challenge. Herein, we used a scalable cation deficiency-driven exsolution approach to ex situ reconstruct a homogeneous-doped cobaltate precursor into an Ir/CoO/perovskite heterojunction (SCI-350), which served as an active and stable OER electrode. The SCI-350 catalyst exhibited a low overpotential of 240 mV at 10 mA cm-2 in 1 M KOH and superior durability in practical electrolysis for over 150 h. The outstanding activity is preliminarily attributed to the exponentially enlarged electrochemical surface area for charge accumulation, increasing from 3.3 to 175.5 mF cm-2. Moreover, density functional theory calculations combined with advanced spectroscopy and 18O isotope-labeling experiments evidenced the tripled oxygen exchange kinetics, strengthened metal-oxygen hybridization, and engaged lattice oxygen oxidation for O-O coupling on SCI-350. This work presents a promising and feasible strategy for constructing highly active oxide OER electrocatalysts without sacrificing durability.