Mitral Cell Dendritic Morphology in the Adult Zebrafish Olfactory Bulb following Growth, Injury and Recovery.

The role of afferent target interactions in dendritic plasticity within the adult brain remains poorly understood. There is a paucity of data regarding the effects of deafferentation and subsequent dendritic recovery in adult brain structures. Moreover, although adult zebrafish demonstrate ongoing growth, investigations into the impact of growth on mitral cell (MC) dendritic arbor structure and complexity are lacking. Leveraging the regenerative capabilities of the zebrafish olfactory system, we conducted a comprehensive study to address these gaps. Employing an eight-week reversible deafferentation injury model followed by retrograde labeling, we observed substantial morphological alterations in MC dendrites. Our hypothesis posited that cessation of injury would facilitate recovery of MC dendritic arbor structure and complexity, potentially influenced by growth dynamics. Statistical analyses revealed significant changes in MC dendritic morphology following growth and recovery periods, indicating that MC total dendritic branch length retained significance after 8 weeks of deafferentation injury when normalized to individual fish physical characteristics. This suggests that regeneration of branch length could potentially function relatively independently of growth-related changes. These findings underscore the remarkable plasticity of adult dendritic arbor structures in a sophisticated model organism and highlight the efficacy of zebrafish as a vital implement for studying neuroregenerative processes.

Diversity, Inclusion, and Health Equity in Academic Family Medicine.

BACKGROUND AND OBJECTIVES: Diversity, inclusion, and health equity (DIHE) are integral to the practice of family medicine. Academic family medicine has been grappling with these issues in recent years, particularly with a focus on racism and health inequity. We studied the current state of DIHE activities in academic family medicine departments and suggest a framework for departments to become more diverse, inclusive, antiracist, and focused on health equity and racial justice. METHODS: As part of a larger annual membership survey, family medicine department chairs were asked for their assessment of departmental DIHE and antioppression activities, and infrastructure and resources committed to increasing DIHE. RESULTS: More than 60% of family medicine department chairs participating in this study rate their departments highly in promoting DIHE and antioppression, and 66% of chairs report an institutional infrastructure that is working well. Just over half of departments or institutions have had a climate survey in the past 3 years, 47.3% of departments have a diversity officer, and 26% of departments provide protected time or resources for a diversity officer. CONCLUSIONS: The majority of family medicine department chairs rate their departments highly on DIHE. However, only 50% of departments have formally assessed climate in the past 3 years, fewer have diversity officers, and even fewer invest resources in their diversity officers. This disconnect should motivate academic family medicine departments to undertake formal self-assessment and implement a strategic plan that includes resource investment in DIHE, measurable outcomes, and sustainability.

COVID-19 Exposure Risk, Burnout, and Shifts in Family Medicine Faculty's Efforts: A National Survey.

BACKGROUND AND OBJECTIVES: In response to the COVID-19 pandemic, academic family physicians had to change their clinical, teaching, research, and administrative efforts, while simultaneously balancing their home environment demands. It is unclear how the changes in effort affected physicians' personal well-being, particularly burnout. This study sought to identify changes in faculty's clinical, teaching, research, and administrative efforts during the COVID-19 pandemic and how effort shifts were associated with burnout. We also examined associations with important demographics and burnout. METHODS: We took data from the 2020 Council of Academic Family Medicine's Educational Research Alliance survey of family medicine educators and practicing physicians during November 2020 through December 2020. We analyzed self-report measures of demographics, effort (clinical, teaching, research, and administrative) before and during the pandemic, COVID-19 exposure level, and rates of burnout (emotional exhaustion and depersonalization) using logistic regressions. RESULTS: Most participants reported no change in efforts. If changes were reported, clinical (21.6%) and administrative (24.8%) efforts tended to increase from before to during the pandemic, while teaching tended to decrease (27.7%). Increases in teaching and clinical efforts were associated with higher rates of emotional exhaustion. Higher depersonalization was associated with increased clinical efforts. Being older and working in a rural setting was associated with lower burnout, while being female was associated with higher burnout. CONCLUSIONS: Shifts in effort across academic family physicians' multiple roles were associated with emotional exhaustion and, to a lesser degree, depersonalization. The high rates of burnout demand additional attention from directors and administrators, especially among female physicians.

Infant, pediatric and adult well visit trends before and during the COVID-19 pandemic: a retrospective cohort study.

BACKGROUND: Adult well visits declined during COVID-19, but literature is inconsistent in regard to whether childhood well visits declined. We determined if the COVID-19 pandemic was associated with a change in well visits among infants, children, adolescents and adults before, compared to during the COVID-19 pandemic, including through the emergence of the Delta variant. METHODS: De-identified electronic health care data came from a multi-state Midwest health care system. Eligible patients (n = 798,571) had ≥ 1 well visit between 7/1/2018 and 6/30/2021. Trends in well visits per month for children (< 1, 1-4, 5-11, 12-17 years) and adults (18-39, 40-64, ≥ 65 years) over 3-years were assessed using Joinpoint regression models and monthly percent change (MPC). RESULTS: Well visits remained stable for infants (< 1 year of age) (MPC = -0.1; 95% CI = -0.3, 0.1). For children 1-4 years and all adults, visits were stable prior to 2020, decreased from 1/2020 to 4/2020 (MPC range -20 to -40), increased from 4/2020-7/2020 (MPC range 30 to 72), and remained stable after 7/2020. Children 5-17 had seasonal variation in visits where low points occurred in Jan/Feb 2019 and high points in Aug 2019 (start of school year); however, the low point in 2020 occurred in April 2020 and the seasonal variation normalized after this. CONCLUSIONS: In a large Mid-western health care system, infant well visits did not decline at the onset (3/1/2020) of the COVID-19 pandemic. Although well visits for all other ages decreased to a low point in 4/2020, a rapid return to pre-pandemic utilization rates occurred by 7/2020. The brief decrease in preventive care may have had little impact on health.

Faculty Engagement and Productivity During the COVID-19 Pandemic.

BACKGROUND AND OBJECTIVES: COVID-19 has had an unprecedented effect on faculty of academic family medicine departments. We sought to characterize faculty's self-reported changes in engagement and productivity in clinical, education, and scholarly efforts during the COVID-19 pandemic, and to correlate the changes with age, gender, and level of COVID-19 exposure. We also sought to determine if differences in faculty engagement and productivity were related to departmental efforts to create virtual community, manage conflict, foster engagement with colleagues, and support faculty emotional well-being. METHODS: We surveyed family medicine department faculty nationally on the effects of the COVID-19 pandemic on their engagement and productivity in clinical care, teaching and research, and on the effect of departmental efforts on well-being. RESULTS: Most respondents reported decreased engagement and productivity across clinical, teaching, and research domains. Older age and male gender were associated with higher clinical engagement. Most respondents were satisfied with their departments' virtual community but reported that social distancing had a negative impact on departmental ability to problem-solve and on personal emotional well-being. Higher engagement and productivity in all three domains of effort (clinical, teaching, and research) were associated with respondents' well-being and with positive perceptions of their department's efforts. CONCLUSIONS: Clinical, teaching, and research engagement and productivity for academic family physicians decreased during the COVID-19 pandemic. Faculty well-being and departmental interventions lessened the impact of diminished productivity and research engagement.

Lower dementia risk in patients vaccinated against herpes zoster.

Context: Herpes zoster (HZ) infection increases dementia risk but it is not known if HZ vaccination is associated with lower risk for dementia. Objective: Determine if patients with HZ vaccination vs. those who remain unvaccinated, have a lower risk for dementia in a cohort of Veterans Health Administration (VHA) patients. Replicate results in a private sector, medical claims patient cohort. Study Design: Retrospective cohort. Competing risk (VHA) and Cox proportional hazard (MarketScan) models estimated the association between HZ vaccination and incident dementia in all patients and in age (65-69, 70-74, ≥75) and race (White, Black, Other) sub-groups. Expanded models accounted for the effect of antivirals and HZ infection between index and end of follow-up. Sensitivity analysis measured the association between HZ vaccination and incident Alzheimer's dementia (AD). E-values computed to test for bias due to unmeasured confounding and selection bias. Setting/Data set: VHA cohort (10/1/2008 - 9/30/2019) with replication in MarketScan® commercial and Medicare claims (1/1/2009-12/31/2018). Population studied: Eligible patients (VHA n=136,016; MarketScan n=172,790) were ≥65 years of age and free of dementia for two years prior to baseline. All patients had 3 or more 'well visits' to control for confounding related to use of preventive health care services. Outcome measures: Incident dementia. Results: VHA patients were 75.6 (SD±7.5) years of age, 4% female, and 91.2% were white race. MarketScan patients were 69.8 (SD±5.6) years of age, on average and 65.4% were female. years of age on average, 65.0% were female. After controlling for confounding, HZ vaccination compared with no vaccination, was significantly associated with lower dementia risk (VHA HR= 0.69; 95%CI: 0.67-0.72; MarketScan HR=0.65; 95%CI:0.57-0.74). No difference in outcomes were observed by race and HZ vaccination was associated with lower AD risk. Results were stable after adjusting for antivirals and HZ infection. E-values indicated results are not explained by selection bias or unmeasured confounding. Conclusions: Among patients ≥65 years of age, HZ vaccination is associated with a 31-35% reduced risk of dementia. Confirmation in other study designs is warranted. Results may be explained by nonspecific neuroprotection and vaccination training the immune system to limit damaging inflammation. Results highlight the importance of HZ vaccination.

Comparison of rates of dementia among older adult recipients of two, one, or no vaccinations.

BACKGROUND: Multiple types of vaccinations are associated with lower risk for dementia, but it is not known if receiving more than one vaccination type is associated with a greater decrease in incident dementia as compared with receiving only one type. We determined if dementia risk is lowest in patients who receive both herpes zoster (HZ) and tetanus, diphtheria, pertussis (Tdap) vaccinations as compared with receipt of only one or the other type of vaccination. METHODS: Primary analysis in a Veterans Health Administration (VA) cohort was replicated in private sector medical claims data. Eligible patients were ≥65 years of age and free of dementia for 2 years prior to baseline (VHA n = 80,070; MarketScan n = 129,200). At index, patients either had both HZ and Tdap, only HZ, only Tdap, or neither vaccination. Confounding was controlled with generalized boosted propensity scores and inverse probability of treatment weighting. Competing risk (VHA) and Cox proportional hazard (MarketScan) models estimated the association between vaccination status and incident dementia. RESULTS: VHA patients' mean age was 76.8 ± 7.6 years, 4.4% were female and 90.9% were White, and MarketScan patients' mean age was 70.5 ± 5.9 and 65.4% were female. In both cohorts, having both HZ and Tdap vaccinations compared with no vaccination was significantly associated with lower dementia risk (VHA HR = 0.50; 95% CI: 0.43-0.59; MarketScan HR = 0.58; 95% CI: 0.38-0.89). In both cohorts, compared with neither vaccination, patients with only one or the other vaccination types had a significantly lower risk for dementia. Incident dementia was lower in patients with both vaccinations versus only one vaccination type. CONCLUSIONS AND RELEVANCE: Receiving two types of vaccinations versus one type was associated with lower dementia risk. Vaccinations may have non-specific associations with incident dementia. Low cost and accessible, common adult vaccinations may be an overlooked intervention for reducing dementia risk.

Impact of herpes zoster vaccination on incident dementia: A retrospective study in two patient cohorts.

BACKGROUND: Herpes zoster (HZ) infection increases dementia risk, but it is not known if herpes zoster vaccination is associated with lower risk for dementia. We determined if HZ vaccination, compared to no HZ vaccination, is associated with lower risk for incident dementia. METHODS AND FINDINGS: Data was obtained from Veterans Health Affairs (VHA) medical records (10/1/2008-9/30/2019) with replication in MarketScan® commercial and Medicare claims (1/1/2009-12/31/2018). Eligible patients were ≥65 years of age and free of dementia for two years prior to baseline (VHA n = 136,016; MarketScan n = 172,790). Two index periods (either start of 2011 or 2012) were defined, where patients either had or did not have a HZ vaccination. Confounding was controlled with propensity scores and inverse probability of treatment weighting. Competing risk (VHA) and Cox proportional hazard (MarketScan) models estimated the association between HZ vaccination and incident dementia in all patients and in age (65-69, 70-74, ≥75) and race (White, Black, Other) sub-groups. Sensitivity analysis measured the association between HZ vaccination and incident Alzheimer's dementia (AD). HZ vaccination at index versus no HZ vaccination throughout follow-up. VHA patients mean age was 75.7 (SD±7.4) years, 4.0% were female, 91.2% white and 20.2% had HZ vaccination. MarketScan patients mean age was 69.9 (SD±5.7) years, 65.0% were female and 14.2% had HZ vaccination. In both cohorts, HZ vaccination compared with no vaccination, was significantly associated with lower dementia risk (VHA HR = 0.69; 95%CI: 0.67-0.72; MarketScan HR = 0.65; 95%CI:0.57-0.74). HZ vaccination was not related to dementia risk in MarketScan patients aged 65-69 years. No difference in HZ vaccination to dementia effects were found by race. HZ vaccination was associated with lower risk for AD. CONCLUSIONS: HZ vaccination is associated with reduced risk of dementia. Vaccination may provide nonspecific neuroprotection by training the immune system to limit damaging inflammation, or specific neuroprotection that prevents viral cytopathic effects.

Dementia risk following influenza vaccination in a large veteran cohort.

BACKGROUND: Two Taiwan based studies indicated influenza vaccinations are associated with lower risk for dementia in patient cohorts with chronic disease. We determined if such associations exist in a large, nationally distributed sample of U.S. patients not selected for chronic disease. METHODS: Data was obtained from Veterans Health Administration medical records (9/1/2009 - 8/31/19). Eligible patients were ≥65 years of age and free of dementia for two years prior to enrollment through the end of the first influenza season (9/1/2009 to 3/1/2012). Competing risk models estimated the risk of dementia in those with influenza vaccination (n = 66,822) compared to those without vaccination (n = 56,925). Propensity scores and inverse probability of treatment weighting controlled for confounding. RESULTS: On average, patients were 75.5 (±7.3) years of age, 3.8% were female and 91.6% were white race. After controlling for confounding, patients with influenza vaccination were significantly less likely to develop dementia compared to patients without vaccination (HR = 0.86; 95 %CI:0.83-0.88). Patients with 1, 2 or 3-5 vaccines vs. none had similar risks for dementia and patients with ≥ 6 influenza vaccines vs. none had a significant lower risk for dementia (HR = 0.88, 95 %CI: 0.83-0.94). CONCLUSIONS: Repeated receipt of influenza vaccinations, compared to remaining unvaccinated, is associated with lower risk for dementia. This is consistent with the hypotheses that vaccinations may reduce risk of dementia by training the immune system and not by preventing specific infectious disease. If vaccines are identified as causative factors in reducing incident dementia, they offer an inexpensive, low-risk intervention with effects greater than any existing preventive measure.

Lower Risk for Dementia Following Adult Tetanus, Diphtheria, and Pertussis (Tdap) Vaccination.

BACKGROUND: Adult vaccinations may reduce risk for dementia. However, it has not been established whether tetanus, diphtheria, pertussis (Tdap) vaccination is associated with incident dementia. METHODS: Hypotheses were tested in a Veterans Health Affairs (VHA) cohort and replicated in a MarketScan medical claims cohort. Patients were at least 65 years of age and free of dementia for 2 years prior to index date. Patients either had or did not have a Tdap vaccination by the start of either of the 2 index periods (2011 or 2012). Follow-up continued through 2018. Controls had no Tdap vaccination for the duration of follow-up. Confounding was controlled using entropy balancing. Competing risk (VHA) and Cox proportional hazard (MarketScan) models estimated the association between Tdap vaccination and incident dementia in all patients and age subgroups (65-69, 70-74, and ≥75 years). RESULTS: VHA patients were, on average, 75.6 (SD ± 7.5) years of age, 4% female, and 91.2% were White. MarketScan patients were 69.8 (SD ± 5.6) years of age, on average and 65.4% were female. After controlling for confounding, patients with, compared to without, Tdap vaccination had a significantly lower risk for dementia in both cohorts (VHA: hazard ratio [HR] = 0.58; 95% confidence interval [CI]:0.54-0.63 and MarketScan: HR = 0.58; 95% CI:0.48-0.70). CONCLUSIONS: Tdap vaccination was associated with a 42% lower dementia risk in 2 cohorts with different clinical and sociodemographic characteristics. Several vaccine types are linked to decreased dementia risk, suggesting that these associations are due to nonspecific effects on inflammation rather than vaccine-induced pathogen-specific protective effects.

Diving into the streams and waves of constitutive and regenerative olfactory neurogenesis: insights from zebrafish.

The olfactory system is renowned for its functional and structural plasticity, with both peripheral and central structures displaying persistent neurogenesis throughout life and exhibiting remarkable capacity for regenerative neurogenesis after damage. In general, fish are known for their extensive neurogenic ability, and the zebrafish in particular presents an attractive model to study plasticity and adult neurogenesis in the olfactory system because of its conserved structure, relative simplicity, rapid cell turnover, and preponderance of neurogenic niches. In this review, we present an overview of the anatomy of zebrafish olfactory structures, with a focus on the neurogenic niches in the olfactory epithelium, olfactory bulb, and ventral telencephalon. Constitutive and regenerative neurogenesis in both the peripheral olfactory organ and central olfactory bulb of zebrafish is reviewed in detail, and a summary of current knowledge about the cellular origin and molecular signals involved in regulating these processes is presented. While some features of physiologic and injury-induced neurogenic responses are similar, there are differences that indicate that regeneration is not simply a reiteration of the constitutive proliferation process. We provide comparisons to mammalian neurogenesis that reveal similarities and differences between species. Finally, we present a number of open questions that remain to be answered.

Promotion of Clinical Educators: A Critical Need in Academic Family Medicine.

BACKGROUND AND OBJECTIVES: Academic family medicine departments have traditionally promoted faculty using research and scholarship criteria augmented by teaching, clinical care, and service. Clinic-focused faculty who spend significant time in direct patient care may not have enough time to meet promotion criteria, although they are critical for training future family physicians and for rebalancing the system of academic promotion. METHODS: We surveyed family medicine department chairs on the effects of protected time for scholarship, presence of promotion and tenure (P and T) committees, salary increase, and special promotion tracks on promotion of physician faculty. RESULTS: Promotion rates to both associate and full professor were higher for faculty with 25% time for scholarship than for clinic-focused faculty. For clinic-focused faculty, promotion rates to associate professor were higher than they were to full professor. No differences were found for promotion to associate professor and full professor for faculty with 25% protected time for scholarship. No differences were found in promotion rates for either rank between departments that had P and T committees and those that didn't, whether promotion came with a salary increase, or if departments had a special track for physician faculty whose job is patient care. CONCLUSIONS: Promotion rates are higher for faculty with protected time for scholarship than for clinic-focused faculty for promotion to both associate and full professor. Clinic demands on faculty may reduce the likelihood of engaging in scholarship or research that in many academic family medicine departments is necessary for promotion.

Role of Macrophages and Microglia in Zebrafish Regeneration.

Currently, there is no treatment for recovery of human nerve function after damage to the central nervous system (CNS), and there are limited regenerative capabilities in the peripheral nervous system. Since fish are known for their regenerative abilities, understanding how these species modulate inflammatory processes following injury has potential translational importance for recovery from damage and disease. Many diseases and injuries involve the activation of innate immune cells to clear damaged cells. The resident immune cells of the CNS are microglia, the primary cells that respond to infection and injury, and their peripheral counterparts, macrophages. These cells serve as key modulators of development and plasticity and have been shown to be important in the repair and regeneration of structure and function after injury. Zebrafish are an emerging model for studying macrophages in regeneration after injury and microglia in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. These fish possess a high degree of neuroanatomical, neurochemical, and emotional/social behavioral resemblance with humans, serving as an ideal simulator for many pathologies. This review explores literature on macrophage and microglial involvement in facilitating regeneration. Understanding innate immune cell behavior following damage may help to develop novel methods for treating toxic and chronic inflammatory processes that are seen in trauma and disease.

Zebrafish Astroglial Morphology in the Olfactory Bulb Is Altered With Repetitive Peripheral Damage.

Zebrafish do not possess the typical astrocytes that are found in mammalian systems. In some brain areas, this teleost has radial glia that appears to perform astrocyte-like functions, but these cells have not been described in the zebrafish olfactory bulb. Mammalian astrocytes facilitate neuroplasticity and undergo astrogliosis after insult. The role of these cells in the zebrafish olfactory system after the damage has been poorly explored. This is important to examine because zebrafish have a high degree of neuroplasticity and the olfactory bulb is a brain area renowned for plasticity. The goal of this study was to explore the potential role of zebrafish astrocytes in the olfactory bulb damage response, with a goal to exploit the high level of regeneration in this system. We found that anti-glial fibrillary acidic protein (GFAP) labels numerous processes in the zebrafish olfactory bulb that are concentrated in the nerve and glomerular layers (GL) and do not show radial glial-like morphology. We propose to term this astroglia, since their location and response to damage suggests that they are similar in function to the mammalian astrocyte. To induce repetitive peripheral damage to the olfactory organ, a wax plug was inserted into the nasal cavity of adult zebrafish every 12 h for up to 7 days; this crushes the olfactory organ and leads to degradation of olfactory sensory neuron axons that project to the olfactory bulb. After 1 day, we found a significant increase in astroglial labeling in the affected bulb when compared to the internal control bulb and astroglial branches appeared to increase in number and size. By the third day of plug insertions there was no significant difference in astroglial labeling between the affected bulb and the internal control bulb. These data lead us to believe that astrogliosis does occur in the presence of peripheral damage, but this process attenuates within 1 week and no glial scar is evident upon recovery from the damage. Further exploration of astrocytes in zebrafish, in particular this apparent attenuation of astrogliosis, has the potential to elucidate key differences in glial function between teleosts and mammals.

Prescribing Patterns and Use of Risk-Reduction Tools After Implementing an Opioid-Prescribing Protocol.

BACKGROUND: The literature on results from primary care-based opioid-prescribing protocols is small and results have been mixed. To advance this field, we evaluated whether opioid prescribing changed after a comprehensive protocol was implemented and whether change was associated with the number and type of risk reduction tools adopted. METHODS: Electronic medical record data were obtained for 2607 patients. Demographics, Patient Health Questionnaire-9 scores, body mass index, and utilization levels of protocol elements were measured for 24 months prior and 18 months post implementation of an opioid-prescribing protocol within a federally qualified health center. χ2 and t-tests were computed to estimate change in opioid prescribing, morphine-equivalent dose, comedication prescribing, and number and type of protocol elements utilized. RESULTS: The opioid protocol was associated with an increase in urine drug screens from 18.3% to 26.8% from pre to postimplementation (P < .0001). There was no significant increase in opioid treatment agreements. Tramadol (21.4% to 16.8%, P = .0006) and antidepressant (56.0% to 51.6%, P = .012) prescribing significantly decreased. Total opioid prescriptions and maximum morphine-equivalent doses were similar from pre to postimplementation. Protocol elements were more often used when patients had a higher opioid dose and were receiving benzodiazepines. CONCLUSIONS: Implementing a multi-faceted opioid-prescribing protocol was not associated with change in number or dose of opioid prescriptions but was associated with greater use of urine drug screens, and risk reduction tools were used more often in high-risk patients. Implementation research is needed to identify barriers to maximizing adherence to opioid protocols.

Microglial response patterns following damage to the zebrafish olfactory bulb.

The inherent plasticity of the zebrafish olfactory system serves as a useful model for examining immune cell responses after injury. Microglia are the resident immune cells of the CNS that respond to damage by migrating to the site of injury and phagocytizing neuronal debris. While the olfactory system is renowned for its ability to recover from damage, the specific mechanisms of microglial involvement in olfactory system plasticity are unknown. To approach the potentially time-dependent effects of microglial activation after injury, we performed a time course analysis of microglial response profiles and patterns following different forms of damage: deafferentation by cautery ablation of the olfactory organ, deafferentation by chemical ablation of the olfactory epithelium, and direct lesioning of the olfactory bulb. Our aim was to demonstrate that immunocytochemistry and microscopy methods in zebrafish can be used to determine the timing of distinct microglial response patterns following various forms of injury. We found that permanent and temporary forms of damage to the olfactory bulb resulted in different microglial response profiles from 1 to 72 h after injury, suggesting that there may be critical timepoints in which microglia are activated that contribute to tissue and neuronal repair with a regenerative outcome versus a degenerative outcome. These distinctions between the different forms of damage suggest temporal changes relative to the potential for regeneration, since cautery deafferentation is permanent and unrecoverable while chemical ablation deafferentation and direct lesioning is reversible and can be used to observe the microglial relationship in neural regeneration and functional recovery in future studies.