A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure.

Leptin inhibition of bone mass accrual requires the integrity of specific hypothalamic neurons but not expression of its receptor on these neurons. The same is true for its regulation of appetite and energy expenditure. This suggests that leptin acts elsewhere in the brain to achieve these three functions. We show here that brainstem-derived serotonin (BDS) favors bone mass accrual following its binding to Htr2c receptors on ventromedial hypothalamic neurons and appetite via Htr1a and 2b receptors on arcuate neurons. Leptin inhibits these functions and increases energy expenditure because it reduces serotonin synthesis and firing of serotonergic neurons. Accordingly, while abrogating BDS synthesis corrects the bone, appetite and energy expenditure phenotypes caused by leptin deficiency, inactivation of the leptin receptor in serotonergic neurons recapitulates them fully. This study modifies the map of leptin signaling in the brain and identifies a molecular basis for the common regulation of bone and energy metabolisms. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

Measuring continuity in primary care: how it is done and why it matters.

Continuity of care (COC) is a foundational element of primary care and is associated with improved patient satisfaction and health outcomes and decreased total cost of care. The patient-physician relationship is highly valued by both parties and is often the reason providers choose to specialize in primary care. In some settings, such as outpatient residency clinics, however, patients may only see their primary care provider (PCP) 50% or less of the time. Considering the many benefits of COC for patients and providers, there is a clear need for us in primary care to understand how to compare different COC measures across studies and how to choose the best COC measure when conducting quality improvement efforts. However, at least 32 different measures have been used to evaluate COC. The manifold variations for measuring COC arise from data source restrictions, purpose (research or clinical use), perspective (patient or provider), and patient visit frequency/type. Key factors distinguishing common COC formulas are data source (e.g. claims data or electronic medical records), and whether a PCP is identifiable. There is no "right" formula, so understanding the nuances of COC measurement is essential for primary care research and clinical quality improvement. While the full complexity of COC cannot be captured by formulas and indices, they provide an important measure of how consistently patients are interacting with the same provider.

The pathophysiology of repetitive concussive traumatic brain injury in experimental models; new developments and open questions.

In recent years, there has been an increasing interest in the pathophysiology of repetitive concussive traumatic brain injury (rcTBI) in large part due to the association with dramatic cases of progressive neurological deterioration in professional athletes, military personnel, and others. However, our understanding of the pathophysiology of rcTBI is less advanced than for more severe brain injuries. Most prominently, the mechanisms underlying traumatic axonal injury, microglial activation, amyloid-beta accumulation, and progressive tau pathology are not yet known. In addition, the role of injury to dendritic spine cytoskeletal structures, vascular reactivity impairments, and microthrombi are intriguing and subjects of ongoing inquiry. Methods for quantitative analysis of axonal injury, dendritic injury, and synaptic loss need to be refined for the field to move forward in a rigorous fashion. We and others are attempting to develop translational approaches to assess these specific pathophysiological events in both animals and humans to facilitate clinically relevant pharmacodynamic assessments of candidate therapeutics. In this article, we review and discuss several of the recent experimental results from our lab and others. We include new initial data describing the difficulty in modeling progressive tau pathology in experimental rcTBI, and results demonstrating that sertraline can alleviate social interaction deficits and depressive-like behaviors following experimental rcTBI plus foot shock stress. Furthermore, we propose a discrete set of open, experimentally tractable questions that may serve as a framework for future investigations. In addition, we also raise several important questions that are less experimentally tractable at this time, in hopes that they may stimulate future methodological developments to address them. This article is part of a Special Issue entitled "Traumatic Brain Injury".

Effect of Virtual Versus In Person Interpreting on Diabetes Outcomes in Non-English Language Preference Patients: A Pilot Study.

OBJECTIVE: The objective of this pilot study was to explore the impact of interpreter format (virtual vs in person) on clinical outcomes in patients with non-English language preference (NELP) and type 2 diabetes mellitus (T2DM) in a primary care setting. We hypothesized that NELP patients utilizing in person interpreters would have improved HbA1c values, better follow-up rate, and more complex care plans compared to patients utilizing virtual interpreters. METHODS: We completed a retrospective chart review of 137 NELP patients with T2DM who required a medical interpreter (February to June 2021). We calculated univariate and bivariate statistics to characterize the sample and assess the extent to which measures of continuity (follow-up visit rate and time to follow-up visit), quality (change in HbA1c), and complexity (medication intervention complexity) were associated with interpreter type. RESULTS: There was no statistically significant difference in follow-up rate or average days to follow-up visit for NELP patients with in person as opposed to virtual interpreters. Patients with virtual interpreters demonstrated a non-statistically significant decrease in HbA1c compared to those with in person interpreters. Finally, there was no statistically significant association between interpreter format and intervention complexity. CONCLUSIONS: Quality medical interpretation contributes to optimal health outcomes in NELP patients with diabetes. Our study suggests that both in person and virtual interpreters can be effective in providing care for NELP patients, especially for chronic disease management in the context of a primary care relationship. It also highlights the importance of pursuing additional qualitative and mixed method studies to better understand the benefits of various interpreter formats across different visit types.

Current Procedural Practices of Family Medicine Teaching Physicians.

BACKGROUND AND OBJECTIVES: Proficiency in procedural care achieved during residency is a major driver of family physician scope of practice. To date, no inventory exists of the advanced procedures and clinical skills performed by teaching family physicians. This study comprises the first such survey and assesses the attitude of respondents toward the importance of family physicians performing procedures. METHODS: We sent a clinical skills inventory to a convenience sample of teaching family physicians employed at 18 medical school-affiliated, community, and military residency programs across the United States. RESULTS: The overall response rate was 46% (N=337). Respondents performed a median of 12 advanced procedures and clinical skills (IQR: 8-18). Endorsed procedures ranged from skin biopsy (n=316, 93.8%) and joint injection (n=279, 82.8%) to colonoscopy (n=21, 6.2%) and cesarean delivery (n=23, 6.8%), and reported skills ranged from medication-assisted treatment (n=181, 53.7%) to highly active antiretrovial therapy (n=35, 10.4%). Gender and career stage were associated with statistically significant differences in endorsement of specific procedures. For example, fracture management was more likely to be performed by late- versus early-career faculty (54.1% vs 24.2%, P<.001) and by male versus female respondents (54.9% vs 24.2%, P<.001). Most respondents (84.3%) agreed that future family physicians should learn procedures and advanced clinical skills. CONCLUSIONS: Family medicine teaching faculty perform a wide array of procedures and advanced skills. Apparent differences by career stage and gender identity in the performance of some of the procedural and skill areas may portend a shift in the procedural training of future family physicians.

A descriptive examination of international family/shared meals: Prevalence, meal types, media at meals, and emotional well-being.

INTRODUCTION: Studies in the United States have shown associations between family/shared meal frequency and child health and well-being. Less is known about family/shared meal characteristics (e.g., frequency, meal type, meal activities) in adults and international samples and whether there are protective associations between family/shared meal frequency and emotional well-being. Also unknown, is whether family meals provide protective associations for other family members in the household. METHOD: In a 2022 cross-sectional study, an online survey was administered in the United States, Italy, and Germany. One adult respondent (49.5% female; Mage = 45.6) from each household (n = 1,983) reported on family/shared meals and well-being. A second family member (e.g., partner, child) responded in a subset of households (n = 1,915). Descriptive statistics by country, Spearman correlations between meal frequency and well-being, and Kruskal-Wallis comparisons of mood indicators across countries were run. RESULTS: The majority of adults across countries engaged in six or more family/shared meals per week, with more meals on weekends. Breakfast, lunch, and dinner family/shared meals were more common on weekends, and European countries reported engaging in a higher prevalence of all meal types. Higher frequency of family/shared meals was significantly correlated with fewer depressive symptoms, more connectedness, and higher levels of happiness in adults across countries and in a second household member. DISCUSSION: Family/shared meals were beneficial across an international sample and may provide protective spillover effects for multiple household members. Clinicians and researchers who work with families may want to consider assessing for and intervening on family meal frequency. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Impact of Set-Day Clinic on Physician Continuity in a Family Medicine Residency Clinic.

BACKGROUND AND OBJECTIVES: Continuity of care between patients and their primary care providers is associated with improved patient outcomes and experience, decreased health care costs, and improved provider well-being. Strategies to enhance continuity of care in residency programs involve electronic health record, scheduling, and panel management methods. Our study compared physician-patient continuity rates (pre and post) for one family medicine residency's implementation of a set-day clinic (SDC) scheduling model. METHODS: In July 2019, Bethesda Clinic switched from a rotation-driven scheduling (RDS) model to SDC. Physicians were divided into two scheduling groups: Monday, Thursday, or Friday; or Tuesday, Wednesday, or Friday. We used visit data from two 6-month periods, October 2018 to March 2019 (RDS) and October 2021 to March 2022 (SDC), to calculate continuity using the continuity for physician formula. We used t tests to compare mean continuity rates between the RDS and SDC periods. In June 2022, faculty and residents were emailed a nine-question survey about SDC. RESULTS: Adherence to the SDC model ranged from 65% to 76%. Postgraduate year (PGY) 3 residents' continuity increased significantly (P<.001) from 44% (RDS) to 56% (SDC), while PGY2 residents' continuity increased, nonsignificantly, from 38% to 43%. Among those that completed the survey, 94% of residents and 78% of faculty were in favor of SDC. CONCLUSIONS: We demonstrated that SDC is feasible and well received by residents and faculty alike. Continuity was highest for PGY2 and PGY3 residents during the SDC period. Predictable clinic schedules have the potential to improve continuity in family medicine residency clinics and may improve physician well-being.

Krüppel-like factor 9 is necessary for late-phase neuronal maturation in the developing dentate gyrus and during adult hippocampal neurogenesis.

The dentate gyrus (DG) is modified throughout life by integration of new adult-born neurons. Similarities in neuronal maturation during DG development and adult hippocampal neurogenesis suggest that genetically encoded intrinsic regulatory mechanisms underlying these temporally distinct processes are conserved and reused. Here, we identify a novel transcriptional regulator of dentate granule neuron maturation, Krüppel-like factor 9 (Klf-9). We show that Klf-9 expression is induced by neuronal activity and as dentate granule neurons functionally integrate in the developing and adult DG. During development, dentate granule neurons lacking Klf-9 show delayed maturation as reflected by altered expression of early-phase markers, dendritic spine formation, and electrophysiological properties. Adult Klf-9-null mice exhibit normal stem cell proliferation and cell fate specification in the DG but show impaired differentiation of adult-born neurons and decreased neurogenesis-dependent synaptic plasticity. Behavioral analysis of Klf-9-null mice revealed a subtle increase in anxiety-like behavior and an impairment in contextual fear discrimination learning. Thus, Klf-9 is necessary for late-phase maturation of dentate granule neurons both in DG development and during adult hippocampal neurogenesis. Klf-9-dependent neuronal maturation may therefore represent a candidate regulatory mechanism underlying these temporally distinct processes.

Individual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces.

Responses to threat-related stimuli are influenced by conscious and unconscious processes, but the neural systems underlying these processes and their relationship to anxiety have not been clearly delineated. Using fMRI, we investigated the neural responses associated with the conscious and unconscious (backwardly masked) perception of fearful faces in healthy volunteers who varied in threat sensitivity (Spielberger trait anxiety scale). Unconscious processing modulated activity only in the basolateral subregion of the amygdala, while conscious processing modulated activity only in the dorsal amygdala (containing the central nucleus). Whereas activation of the dorsal amygdala by conscious stimuli was consistent across subjects and independent of trait anxiety, activity in the basolateral amygdala to unconscious stimuli, and subjects' reaction times, were predicted by individual differences in trait anxiety. These findings provide a biological basis for the unconscious emotional vigilance characteristic of anxiety and a means for investigating the mechanisms and efficacy of treatments for anxiety.

Increased fear response to contextual cues in mice lacking the 5-HT1A receptor.

Serotonin 1A receptor knockout (5-HT1AR KO) mice exhibit increased behavioral inhibition in conflict tests. To gain further insight into their anxiety-related phenotype, we subjected these mice to additional behavioral tests. First, we considered whether behavioral inhibition in these knockout mice is a consequence of reduced exploratory motivation. The knockout mice engage in normal exploration during a light-dark test and normal exploration of a novel object in a familiar environment, suggesting that the anxiety-related phenotype is not due to reduced exploratory drive. Second, we tested whether these mice exhibit increased behavioral inhibition in response to any aversive cues, or whether this response depends on cue modality. Knockout mice respond normally to discrete aversive cues in the Vogel lick-suppression test, arguing that their phenotype is restricted to conflict tests based on complex or spatial aversive cues. Third, to probe the processing of spatial aversive cues, we assessed fear conditioning to contextual cues. After contextual fear conditioning, knockout and wild-type (WT) mice express freezing responses when exposed to the training environment. However, when placed in an ambiguous environment containing both conditioned and novel cues, the freezing response of knockout mice does not significantly decrease as it does in WT mice, suggesting that the knockout fear response is biased toward threatening cues. We hypothesize that this inappropriate generalization of fearful behavior to a context containing both fearful and neutral stimuli, a phenomenon that occurs in a subset of human anxiety disorders such as panic disorder and post-traumatic stress disorder, underlies the anxiety phenotype of 5-HT1AR KO mice.

Repetitive concussive traumatic brain injury interacts with post-injury foot shock stress to worsen social and depression-like behavior in mice.

The debilitating effects of repetitive concussive traumatic brain injury (rcTBI) have been increasingly recognized in both military and civilian populations. rcTBI may result in significant neurological, cognitive, and affective sequelae, and is often followed by physical and/or psychological post-injury stressors that may exacerbate the effects of the injury and prolong the recovery period for injured patients. However, the consequences of post-injury stressors and their subsequent effects on social and emotional behavior in the context of rcTBI have been relatively little studied in animal models. Here, we use a mouse model of rcTBI with two closed-skull blunt impacts 24 hours apart and social and emotional behavior testing to examine the consequences of a stressor (foot shock fear conditioning) following brain injury (rcTBI). rcTBI alone did not affect cued or contextual fear conditioning or extinction compared to uninjured sham animals. In the sucrose preference test, rcTBI animals had decreased preference for sucrose, an anhedonia-like behavior, regardless of whether they experienced foot shock stress or were non-shocked controls. However, rcTBI and post-injury foot shock stress had synergistic effects in tests of social recognition and depression-like behavior. In the social recognition test, animals with both injury and shock were more impaired than either non-shocked injured mice or shocked but uninjured mice. In the tail suspension test, injured mice had increased depression-like behavior compared with uninjured mice, and shock stress worsened the depression-like behavior only in the injured mice with no effect in the uninjured mice. These results provide a model of subtle emotional behavioral deficits after combined concussive brain injury and stress, and may provide a platform for testing treatment and prevention strategies for social behavior deficits and mood disorders that are tailored to patients with traumatic brain injury.

Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders.

Although an influence of adult neurogenesis in mediating some of the effects of antidepressants has received considerable attention in recent years, much less is known about how alterations in this form of plasticity may contribute to psychiatric disorders such as anxiety and depression. One way to begin to address this question is to link the functions of adult-born hippocampal neurons with specific endophenotypes of these disorders. Recent studies have implicated adult-born hippocampal neurons in pattern separation, a process by which similar experiences or events are transformed into discrete, non-overlapping representations. Here we propose that impaired pattern separation underlies the overgeneralization often seen in anxiety disorders, specifically post-traumatic stress disorder and panic disorder, and therefore represents an endophenotype for these disorders. The development of new, pro-neurogenic compounds may therefore have therapeutic potential for patients who display pattern separation deficits.