Antibodies in neurological diseases: Established, emerging, explorative.

Within a few years, autoantibodies targeting the nervous system resulted in a novel disease classification. For several of them, which we termed 'established', direct pathogenicity has been proven and now guides diagnostic pathways and early immunotherapy. For a rapidly growing number of further anti-neuronal autoantibodies, the role in disease is less clear. Increasing evidence suggests that they could contribute to disease, by playing a modulating role on brain function. We therefore suggest a three-level classification of neurological autoantibodies according to the degree of experimentally proven pathogenicity and strength of clinical association: established, emerging, explorative. This may facilitate focusing on clinical constellations in which autoantibody-mediated mechanisms have not been assumed previously, including autoimmune psychosis and dementia, cognitive impairment in cancer, and neurodegenerative diseases. Based on recent data reviewed here, humoral autoimmunity may represent an additional "super-system" for brain health. The "brain antibody-ome", that is, the composition of thousands of anti-neuronal autoantibodies, may shape neuronal function not only in disease, but even in healthy aging. Towards this novel concept, extensive research will have to elucidate pathogenicity from the atomic to the clinical level, autoantibody by autoantibody. Such profiling can uncover novel biomarkers, enhance our understanding of underlying mechanisms, and identify selective therapies.

Sniffing can be initiated by dopamine's actions on ventral striatum neurons.

Sniffing is a motivated behavior displayed by nearly all terrestrial vertebrates. While sniffing is associated with acquiring and processing odors, sniffing is also intertwined with affective and motivated states. The neuromodulatory systems which influence the display of sniffing are unclear. Here, we report that dopamine release into the ventral striatum is coupled with bouts of sniffing and that stimulation of dopaminergic terminals in these regions drives increases in respiratory rate to initiate sniffing whereas inhibition of these terminals reduces respiratory rate. Both the firing of individual neurons and the activity of post-synaptic D1 and D2 receptor-expressing neurons in the ventral striatum are also coupled with sniffing and local antagonism of D1 and D2 receptors squelches sniffing. Together, these results support a model whereby sniffing can be initiated by dopamine's actions upon ventral striatum neurons. The nature of sniffing being integral to both olfaction and motivated behaviors implicates this circuit in a wide array of functions.

Demographic, co-intoxicants and other characteristics of citalopram-involved overdose deaths.

Selective serotonin reuptake inhibitors (SSRIs) including citalopram are commonly used antidepressants that can be involved in drug-related deaths along with opioids and other substances. This study characterized citalopram involvement in West Virginia (WV) drug-related deaths compared to other SSRI and non-SSRI-related deaths. All 2005-2021 WV drug-related deaths were analyzed in this retrospective study. Demographics, other substances involved, and comorbidities in cases in which citalopram was listed on the death certificate were compared to other SSRI-related and total non-SSRI deaths. Citalopram concentrations and the association between citalopram presence with predicted fentanyl concentrations were determined. Citalopram was the most common antidepressant present in the deaths (4.5% of 14,363 total), with most (81%) unintentional. Male: female ratios in citalopram cases (0.9:1) were significantly lower than in non-SSRI deaths (2.3:1). Almost two-thirds of citalopram deaths had ≥ 4 substances involved compared to 26% of non-SSRI deaths. Overall, oxycodone was most frequently identified in citalopram deaths (fentanyl more commonly in recent years), followed by alprazolam and diazepam. Cardiovascular comorbidity was significantly more common in citalopram than non-SSRI deaths. No association was found between citalopram presence and predicted fentanyl concentrations. Most citalopram-related deaths were unintentional and involved proportionately more females, with larger numbers of concurrent substances present and more cardiovascular comorbidity compared to non-SSRI deaths. Citalopram is widely used and less toxic than many antidepressants. The extent to which it contributed to overdose deaths can be difficult to ascertain given the multiple substances usually present.

Enteric glial cell diversification is influenced by spatiotemporal factors and source of neural progenitors in mice.

Previously focused primarily on enteric neurons, studies of the enteric nervous system (ENS) in both health and disease are now broadening to recognize the equally significant role played by enteric glial cells (EGCs). Commensurate to the vast array of gastrointestinal functions they influence, EGCs exhibit considerable diversity in terms of location, morphology, molecular profiles, and functional attributes. However, the mechanisms underlying this diversification of EGCs remain largely unexplored. To begin unraveling the mechanistic complexities of EGC diversity, the current study aimed to examine its spatiotemporal aspects in greater detail, and to assess whether the various sources of enteric neural progenitors contribute differentially to this diversity. Based on established topo-morphological criteria for categorizing EGCs into four main subtypes, our detailed immunofluorescence analyses first revealed that these subtypes emerge sequentially during early postnatal development, in a coordinated manner with the structural changes that occur in the ENS. When combined with genetic cell lineage tracing experiments, our analyses then uncovered a strongly biased contribution by Schwann cell-derived enteric neural progenitors to particular topo-morphological subtypes of EGCs. Taken together, these findings provide a robust foundation for further investigations into the molecular and cellular mechanisms governing EGC diversity.

Evaluation and Management of Kidney Dysfunction in Advanced Heart Failure: A Scientific Statement From the American Heart Association.

Early identification of kidney dysfunction in patients with advanced heart failure is crucial for timely interventions. In addition to elevations in serum creatinine, kidney dysfunction encompasses inadequate maintenance of sodium and volume homeostasis, retention of uremic solutes, and disrupted endocrine functions. Hemodynamic derangements and maladaptive neurohormonal upregulations contribute to fluctuations in kidney indices and electrolytes that may recover with guideline-directed medical therapy. Quantifying the extent of underlying irreversible intrinsic kidney disease is crucial in predicting whether optimization of congestion and guideline-directed medical therapy can stabilize kidney function. This scientific statement focuses on clinical management of patients experiencing kidney dysfunction through the trajectory of advanced heart failure, with specific focus on (1) the conceptual framework for appropriate evaluation of kidney dysfunction within the context of clinical trajectories in advanced heart failure, including in the consideration of advanced heart failure therapies; (2) preoperative, perioperative, and postoperative approaches to evaluation and management of kidney disease for advanced surgical therapies (durable left ventricular assist device/heart transplantation) and kidney replacement therapies; and (3) the key concepts in palliative care and decision-making processes unique to individuals with concomitant advanced heart failure and kidney disease.

Impact of proton pump inhibitors on pathologic response rates following fluoropyrimidine-based neoadjuvant chemotherapy in pancreatic cancer patients.

BACKGROUND: Proton pump inhibitors (PPIs) negatively impact fluoropyrimidine-based chemotherapy efficacy in colorectal cancer. This study assessed PPI impact on major pathologic response (mPR) rates of pancreatic adenocarcinoma (PDAC) patients receiving fluoropyrimidine-based chemotherapy. METHODS: An institutional retrospective review of resected PDAC patients receiving neoadjuvant fluoropyrimidine-based chemotherapy (98% FOLFIRINOX) from 2011 to 2021 was conducted. Outcomes were stratified by use or nonuse of PPIs within 6 months of neoadjuvant chemotherapy initiation. Primary outcome was mPR defined as complete or near complete response. RESULTS: Among 540 patients included, the median age was 64 (IQR: 60-70) years, 297 (55%) were male, and 202 (37%) were PPI users. 170 (31%) patients had mPR with similar rates among PPI users and nonusers (29% vs. 33%, p = 0.38). No difference in mPR was seen between PPI users and nonusers receiving chemoradiation (35% vs. 36%, p = 0.89) or ≥8 cycles of NAC (33% vs. 36%, p = 0.55). Median OS for PPI users was 30.9 versus 31.7 months for nonusers (p = 0.62). On multivariable analysis, PPI therapy was not associated with decreased survival. CONCLUSION: PPI usage did not significantly influence mPR or OS following neoadjuvant fluoropyrimidine-based chemotherapy in resected PDAC patients. Further analysis of all patients, not just those who underwent resection, is required.

Male Predominance in West Virginia Unintentional Overdose Deaths is Influenced by Alcohol and Co-Intoxicants.

BACKGROUND: To examine sex differences in overdose (OD) mortality based upon substances involved. METHODS: A retrospective database analysis of West Virginia OD decedents (12,666 unintentional OD deaths, 2005-early 2023). Exposures were substances judged to contribute to death. The main outcome measure was determination of male to female death ratios with varying co-intoxicant involvement, particularly related to alcohol and fentanyl. Secondary outcomes included associations of fentanyl concentrations with alcohol concentrations and male sex, including fentanyl (F) and inactive metabolite norfentanyl (N) concentration variability between sexes. RESULTS: Alcohol co-intoxication in OD deaths was associated with higher male:female death ratios, from 2.0 (alcohol absent) to 3.3 (alcohol present). There was a greater increase over time in alcohol involvement in recent deaths involving females compared to males (relative increases of 52% vs. 6%, respectively). Male:female ratios with alcohol and fentanyl co-involvement ranged from 5.9:1 (only two drugs involved) to 2.4:1 (= 5 substances), with females significantly more likely to have multiple substances contributing to death. Overall, males had statistically significantly larger fentanyl (F) to norfentanyl (N) median concentration ratios compared to females (8.8 vs. 6.9, respectively). Multivariable analyses found alcohol presence was associated with a statistically significant 22% reduction in predicted fentanyl concentrations. CONCLUSIONS: Male:female ratios in unintentional OD deaths were higher with greater alcohol involvement and lower with fewer co-intoxicants. Fentanyl and norfentanyl concentration differences by sex were observed. It is important to determine possible contributors to sex differences in OD death rates to better target prevention and treatment initiatives.

A Novel Mouse Home Cage Lickometer System Reveals Sex- and Housing-Based Influences on Alcohol Drinking.

Alcohol use disorder (AUD) is a significant global health issue. Despite historically higher rates among men, AUD prevalence and negative alcohol-related outcomes in women are rising. Loneliness in humans has been associated with increased alcohol use, and traditional rodent drinking models involve single housing, presenting challenges for studying social enrichment. We developed LIQ PARTI (Lick Instance Quantifier with Poly-Animal RFID Tracking Integration), an open-source tool to examine home cage continuous access two-bottle choice drinking behavior in a group-housed setting, investigating the influence of sex and social isolation on ethanol consumption and bout microstructure in C57Bl/6J mice. LIQ PARTI, based on our previously developed single-housed LIQ HD system, accurately tracks drinking behavior using capacitive-based sensors and RFID technology. Group-housed female mice exhibited higher ethanol preference than males, while males displayed a unique undulating pattern of ethanol preference linked to cage changes, suggesting a potential stress or novelty-related response. Chronic ethanol intake distinctly altered bout microstructure between male and female mice, highlighting sex and social environmental influences on drinking behavior. Social isolation with the LIQ HD system amplified fluid intake and ethanol preference in both sexes, accompanied by sex- and fluid-dependent changes in bout microstructure. However, these effects largely reversed upon resocialization, indicating the plasticity of these behaviors in response to social context. Utilizing a novel group-housed home cage lickometer device, our findings illustrate the critical interplay of sex and housing conditions in voluntary alcohol drinking behaviors in C57Bl/6J mice, facilitating nuanced insights into the potential contributions to AUD etiology.

Sentiment Analysis of Twitter Posts Related to a COVID-19 Test & Trace Program in NYC.

As part of a program evaluation of the New York City Test & Trace program (T2)-one of the largest such programs in the USA-we conducted a study to assess how implementing organizations (NYC Health + Hospitals, government agencies, CBOs) communicated information about the T2 program on Twitter. Study aims were as follows: (1) quantify user engagement of posts ("tweets") about T2 by NYC organizations on Twitter and (2) examine the emotional tone of social media users' T2-related tweets in our sample of 1987 T2-related tweets. Celebrities and CBOs generated more user engagement (0.26% and 0.07%, respectively) compared to government agencies (e.g., Mayor's Office, 0.0019%), reinforcing the value of collaborating with celebrities and CBOs in social media public health campaigns. Sentiment analysis revealed that positive tweets (46.5%) had higher user engagement than negative tweets (number of likes: R2 = .095, p < .01), underscoring the importance of positively framing messages for effective public health campaigns.

High-quality peptide evidence for annotating non-canonical open reading frames as human proteins.

A major scientific drive is to characterize the protein-coding genome as it provides the primary basis for the study of human health. But the fundamental question remains: what has been missed in prior genomic analyses? Over the past decade, the translation of non-canonical open reading frames (ncORFs) has been observed across human cell types and disease states, with major implications for proteomics, genomics, and clinical science. However, the impact of ncORFs has been limited by the absence of a large-scale understanding of their contribution to the human proteome. Here, we report the collaborative efforts of stakeholders in proteomics, immunopeptidomics, Ribo-seq ORF discovery, and gene annotation, to produce a consensus landscape of protein-level evidence for ncORFs. We show that at least 25% of a set of 7,264 ncORFs give rise to translated gene products, yielding over 3,000 peptides in a pan-proteome analysis encompassing 3.8 billion mass spectra from 95,520 experiments. With these data, we developed an annotation framework for ncORFs and created public tools for researchers through GENCODE and PeptideAtlas. This work will provide a platform to advance ncORF-derived proteins in biomedical discovery and, beyond humans, diverse animals and plants where ncORFs are similarly observed.

Operant ethanol self-administration behaviors do not predict sex differences in continuous access home cage drinking.

Understanding sex differences in disease prevalence is critical to public health, particularly in the context of alcohol use disorder (AUD). The goal of this study was to understand sex differences in ethanol drinking behavior and define the precise conditions under which sex differences emerge. Consistent with prior work, C57BL/6J females drank more than males under continuous access two-bottle choice conditions. However, using ethanol self-administration - where an operant response results in access to an ethanol sipper for a fixed time period - we found no sex differences in operant response rates or ethanol consumption (volume per body weight consumed, as well as lick behavior). This remained true across a wide range of parameters including acquisition, when the ethanol sipper access period was manipulated, and when the concentration of the ethanol available was scaled. The only sex differences observed were in total ethanol consumption, which was explained by differences in body weight between males and females, rather than by sex differences in motivation to drink. Using dimensionality reduction approaches, we found that drinking behavior in the operant context did not cluster by sex, but rather clustered by high and low drinking phenotypes. Interestingly, these high and low drinking phenotypes in the operant context showed no correlation with those same categorizations in the home cage context within the same animals. These data underscore the complexity of sex differences in ethanol consumption, highlighting the important role that drinking conditions/context plays in the expression of these differences.

Sex-Related Differences and Influence of Pregnancy in Transposition of Great Arteries With Systemic Right Ventricle.

Background: There is a paucity of data regarding sex-related differences on cardiac outcomes in the context of transposition of the great arteries (TGA) with a systemic right ventricle and biventricular physiology (sRV-biV). Moreover, the long-term impact of pregnancy on cardiac outcomes remains unknown. Objectives: The purpose of this study was to identify sex-related differences and the influence of pregnancy on cardiac outcomes in TGA sRV-biV population. Methods: A retrospective cohort study was conducted on 213 adults with TGA sRV-biV, 82 (38.4%) women, age 42.6 ± 12.8 years, with a median follow-up of 16 years. Cardiac events, interventions, last follow-up sRV-biV dysfunction, and heart failure (HF) medications were compared between men vs women, and women with vs without pregnancies resulting in live births. Results: Women had a lower incidence of nonsustained ventricular tachycardia (HR: 1.80; 95% CI: 1.04-3.09, P = 0.035) and nonsignificantly fewer HF-related hospitalizations than men (HR: 2.10; 95% CI: 0.95-4.67, P = 0.069) in univariable analysis. At the last follow-up, women had a lower prevalence of moderate to severe sRV-biV dysfunction than men (P < 0.001) and were less frequently prescribed HF therapy. Women had fewer implantable cardioverter-defibrillators for primary prevention than men (P = 0.016), with no difference for secondary prevention. Women who had pregnancies resulting in live births (N = 47), had a high prevalence of cardiac events in the 15 (IQR: 9-28) years following pregnancy with no significant differences with those without (N = 32) pregnancies. Conclusions: Women with a sRV-biV have fewer adverse cardiovascular events than men. Due to sRV-biV, pregnancy remains with high maternal risk but is not associated with worse long-term cardiac outcomes under rigorous multidisciplinary cardio-obstetrical care.

Rationale and design of the BeyeOMARKER study: prospective evaluation of blood- and eye-based biomarkers for early detection of Alzheimer's disease pathology in the eye clinic.

BACKGROUND: Alzheimer's disease (AD) is a common, complex and multifactorial disease that may require screening across multiple routes of referral to enable early detection and subsequent future implementation of tailored interventions. Blood- and eye-based biomarkers show promise as low-cost, scalable and patient-friendly tools for early AD detection given their ability to provide information on AD pathophysiological changes and manifestations in the retina, respectively. Eye clinics provide an intriguing real-world proof-of-concept setting to evaluate the performance of these potential AD screening tools given the intricate connections between the eye and brain, presumed enrichment for AD pathology in the aging population with eye disorders, and the potential for an accelerated diagnostic pathway for under-recognized patient groups. METHODS: The BeyeOMARKER study is a prospective, observational, longitudinal cohort study aiming to include individuals visiting an eye-clinic. Inclusion criteria entail being ≥ 50 years old and having no prior dementia diagnosis. Excluded eye-conditions include traumatic insults, superficial inflammation, and conditions in surrounding structures of the eye that are not engaged in vision. The BeyeOMARKER cohort (n = 700) will undergo blood collection to assess plasma p-tau217 levels and a brief cognitive screening at the eye clinic. All participants will subsequently be invited for annual longitudinal follow-up including remotely administered cognitive screening and questionnaires. The BeyeOMARKER + cohort (n = 150), consisting of 100 plasma p-tau217 positive participants and 50 matched negative controls selected from the BeyeOMARKER cohort, will additionally undergo Aß-PET and tau-PET, MRI, retinal imaging including hyperspectral imaging (primary), widefield imaging, optical coherence tomography (OCT) and OCT-Angiography (secondary), and cognitive and cortical vision assessments. RESULTS: We aim to implement the current protocol between April 2024 until March 2027. Primary outcomes include the performance of plasma p-tau217 and hyperspectral retinal imaging to detect AD pathology (using Aß- and tau-PET visual read as reference standard) and to detect cognitive decline. Initial follow-up is ~ 2 years but may be extended with additional funding. CONCLUSIONS: We envision that the BeyeOMARKER study will demonstrate the feasibility of early AD detection based on blood- and eye-based biomarkers in alternative screening settings, and will improve our understanding of the eye-brain connection. TRIAL REGISTRATION: The BeyeOMARKER study (Eudamed CIV ID: CIV-NL-23-09-044086; registration date: 19th of March 2024) is approved by the ethical review board of the Amsterdam UMC.

A General Neurologist's Practical Diagnostic Algorithm for Atypical Parkinsonian Disorders: A Consensus Statement.

Purpose of Review: The most common four neurodegenerative atypical parkinsonian disorders (APDs) are progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB). Their formal diagnostic criteria often require subspecialty experience to implement as designed and all require excluding competing diagnoses without clearly specifying how to do that. Validated diagnostic criteria are not available at all for many of the other common APDs, including normal pressure hydrocephalus (NPH), vascular parkinsonism (VP), or drug-induced parkinsonism (DIP). APDs also include conditions of structural, genetic, vascular, toxic/metabolic, infectious, and autoimmune origin. Their differential diagnosis can be challenging early in the course, if the presentation is atypical, or if a rare or non-neurodegenerative condition is present. This review equips community general neurologists to make an early provisional diagnosis before, or in place of, referral to a tertiary center. Early diagnosis would allay diagnostic uncertainty, allow prompt symptomatic management, provide disease-specific information and support resources, avoid further pointless testing and treatments, and create the possibility of trial referral. Recent Findings: We address 64 APDs using one over-arching flow diagram and a series of detailed tables. Most instances of APDs can be diagnosed with a careful history and neurological exam, along with a non-contrast brain MRI. Additional diagnostic tests are rarely needed but are delineated where applicable. Our diagnostic algorithm encourages referral to a tertiary center whenever the general neurologist feels it would be in the patient's best interest. Our algorithm emphasizes that the diagnosis of APDs is an iterative process, refined with the appearance of new diagnostic features, availability of new technology, and advances in scientific understanding of the disorders. Clinicians' proposals for all diagnostic tests for the APDs, including repeat visits, should be discussed with patients and their families to ensure that the potential information to be gained aligns with their larger clinical goals. Summary: We designed this differential diagnostic algorithm for the APDs to enhance general neurologists' diagnostic skills and confidence and to help them address the less common or more ambiguous cases.

Clusters of emerging multidrug-resistant organisms in US health care facilities during the initial months of the SARS-CoV-2 pandemic.

BACKGROUND: Outbreaks of emerging multidrug-resistant organisms (eMDROs), including carbapenem-resistant Enterobacterales, carbapenem-resistant Acinetobacter baumannii, and Candida auris, have been reported among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients. We describe eMDRO clusters in SARS-CoV-2 units and associated infection control (IC) practices early in the SARS-CoV-2 pandemic. METHODS: We conducted a retrospective survey of a convenience sample of health departments in 11 states to describe clusters of eMDROs that began before November 1, 2020 and involved SARS-CoV-2 units. Cluster characteristics and IC practices during the cluster period were assessed using a standardized outbreak report form, and descriptive analyses were performed. RESULTS: Overall, 18 eMDRO clusters (10 carbapenem-resistant Enterobacterales, 6 C auris, 1 carbapenem-resistant Pseudomonas aeruginosa, and 1 carbapenem-resistant A baumannii) in 18 health care facilities involving 397 patients were reported from 10 states. During the cluster period, 60% of facilities reported a shortage of isolation gowns, 69% extended use of gowns, and 67% reported difficulty obtaining preferred disinfectants. Reduced frequency of hand hygiene audits was reported in 85% of acute care hospitals during the cluster period compared with before the pandemic. CONCLUSIONS: Changes in IC practices and supply shortages were identified in facilities with eMDRO outbreaks during the SARS-CoV-2 pandemic and might have contributed to eMDRO transmission.

The safety of recombinant human hyaluronidase PH20 in nonclinical models: An overview of toxicology, pharmacology, and impact of anti-PH20 antibodies.

Hyaluronan (HA) is a glycosaminoglycan that forms a gel-like barrier in the subcutaneous (SC) space, limiting bulk fluid flow and the dispersion of SC-administered therapeutics. Recombinant human hyaluronidase PH20 (rHuPH20) facilitates the rapid delivery of co-administered therapeutics by depolymerizing HA in the SC space. Administration of rHuPH20 can induce the formation of anti-rHuPH20 antibodies, or anti-drug antibodies (ADAs), with the potential to bind endogenous PH20 hyaluronidase in the adult testes and epididymis. Using a variety of relevant animal models and multiple dose regimens of rHuPH20 across the full spectrum of animal development, we demonstrated that rHuPH20 administration resulted in the formation of ADAs. Although these ADAs can bind both the recombinant rHuPH20 enzyme and recombinant versions of animal model-specific hyaluronidases, they had no impact on fertility parameters (as measured by sperm concentration and motility, litter size, and litter viability) or fetal development. We present the result of our nonclinical studies in order of the developmental lifecycle, beginning with adults. Toxicology studies that extend beyond the standard package are also presented. These studies demonstrate the favorable safety profile of rHuPH20 and ADAs in nonclinical models. Additionally, we identified substantial safety margins for clinically relevant doses of rHuPH20.

Genotype-First Approach Identifies an Association between rs28374544/FOG2S657G and Liver Disease through Alterations in mTORC1 Signaling.

Metabolic dysfunction-associated Fatty Liver Disease (MAFLD) has emerged as one of the leading cardiometabolic diseases. Friend of GATA2 (FOG2) is a transcriptional co-regulator that has been shown to regulate hepatic lipid metabolism and accumulation. Using meta-analysis from several different biobank datasets, we identified a coding variant of FOG2 (rs28374544, A1969G, S657G) predominantly found in individuals of African ancestry (minor allele frequency~20%), which is associated with liver failure/cirrhosis phenotype and liver injury. To gain insight into potential pathways associated with this variant, we interrogated a previously published genomics dataset of 38 human induced pluripotent stem cell (iPSCs) lines differentiated into hepatocytes (iHeps). Using Differential Gene Expression Analysis and Gene Set Enrichment Analysis, we identified the mTORC1 pathway as differentially regulated between iHeps from individuals with and without the variant. Transient lipid-based transfections were performed on the human hepatoma cell line (Huh7) using wild-type FOG2 and FOG2S657G and demonstrated that FOG2S657G increased mTORC1 signaling, de novo lipogenesis, and cellular triglyceride synthesis and mass. In addition, we observed a significant downregulation of oxidative phosphorylation in FOG2S657G cells in fatty acid-loaded cells but not untreated cells, suggesting that FOG2S657G may also reduce fatty acid to promote lipid accumulation. Taken together, our multi-pronged approach suggests a model whereby the FOG2S657G may promote MAFLD through mTORC1 activation, increased de novo lipogenesis, and lipid accumulation. Our results provide insights into the molecular mechanisms by which FOG2S657G may affect the complex molecular landscape underlying MAFLD.

BNST GluN2D-containing NMDARs contribute to ethanol intake but not negative affective behaviors in female mice.

BACKGROUND: Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST) and Crh+ neurons in this region play a key role in chronic ethanol-induced increases in volitional intake, hypothesized to be driven by emergent negative affective behaviors. Excitatory N-methyl-d-aspartate receptors (NMDARs) are a major target of ethanol, and chronic ethanol exposure has been shown to regulate NMDAR function and expression. Specifically, GluN2D subunit-containing NMDARs have emerged as a target of interest due to their limited distribution and potential roles in affective behavior. METHODS: Male and female mice underwent a home cage chronic drinking forced abstinence model (CDFA) to assess the impact of 1 day or 2 weeks of ethanol abstinence on BNST synaptic transmission and BNST Grin gene expression. Constitutive and conditional BNST GluN2D knockout mice were used to assess the impact of GluN2D deletion on continuous access ethanol intake as well as negative affect behaviors, using the open field, elevated zero maze, and forced swim tasks. RESULTS: We report here that excitatory transmission undergoes time-dependent upregulation in BNST Crh+ cells. Further, knockdown of dorsal BNST (dBNST) GluN2D expression significantly decreases ethanol intake in female, but not male, mice. While BNST Grin2b expression was significantly increased in protracted abstinence following CDFA, no differences in Grin2d expression were observed in the dBNST or dBNST Crh+ neurons. Finally, we find that deletion of GluN2D fails to alter negative affect in ethanol-naïve female mice. CONCLUSIONS: These data suggest a role for BNST GluN2D-containing NMDARs in ethanol drinking but not ethanol abstinence, highlighting sex differences and behavioral specificity. Overall, these data further suggest roles for BNST synaptic signaling in volitional ethanol intake that are partially independent of actions on affective behavior.

Identifying priority challenges of older adults with COPD: A multiphase intervention refinement study.

BACKGROUND: Identifying priority challenges of older adults with chronic obstructive pulmonary disease (COPD) is critical to designing interventions aimed at improving their well-being and independence. OBJECTIVE: To prioritize challenges of older adults with COPD and those who care for them to guide refinement of a telephonic nurse coach intervention for patients with COPD and their family caregivers (EPIC: Empowering People to Independence in COPD). DESIGN: Multiphase study guided by Baltes Theory of Successful Aging and the 5Ms Framework: Phase 1: Nominal group technique (NGT), a structured process of prioritizing responses to a question through group consensus. Phase 2: Rapid qualitative analysis. Phase 3: Intervention mapping and refinement. SETTING: Ambulatory, virtual. PARTICIPANTS: Older adults with COPD, family caregivers, clinic staff (nurses, respiratory therapists), clinicians (physicians, nurse practitioners), and health system leaders. RESULTS: NGT sessions were conducted by constituency group with 37 participants (n = 7 patients, n = 6 family caregivers, n = 8 clinic staff, n = 9 clinicians, n = 7 health system leaders) (Phase 1). Participants generated 92 statements across five themes (Phase 2): (1) "Barriers to care", (2) "Family caregiver needs", (3) "Functional status and mobility issues", (4) "Illness understanding", and (5) "COPD care complexities". Supplemental oxygen challenges emerged as a critical problem, and prioritized challenges differed by group. Patients and clinic staff prioritized "Functional status and mobility issues", family caregivers prioritized "Family caregiver needs", and clinicians and health system leaders prioritized "COPD care complexities". Intervention mapping (Phase 3) guided EPIC refinement focused on meeting patient priorities of independence and mobility but accounting for all priorities. CONCLUSIONS: Diverse constituency groups identified priority challenges for older adults with COPD. Functional status and mobility issues, particularly related to supplemental oxygen, emerged as patient prioritized challenges. IMPLICATIONS: Patient-centered interventions for older adults with COPD must account for their prioritized functional and supplemental oxygen needs and explore diverse constituent perspectives to facilitate intervention enrichment.