Estimated Effectiveness of the BNT162b2 XBB Vaccine Against COVID-19.

Importance: Data describing the early additional protection afforded by the recently recommended BNT162b2 XBB vaccine (Pfizer-BioNTech; 2023-2024 formulation) are limited. Objective: To estimate the association between receipt of the BNT162b2 XBB vaccine and medically attended COVID-19 outcomes among US adults 18 years and older. Design, Setting, and Participants: This test-negative case-control study was performed to estimate the effectiveness of the BNT162b2 XBB vaccine against COVID-19-associated hospitalization and emergency department (ED) or urgent care (UC) encounters among adults in the Kaiser Permanente Southern California health system between October 10, 2023, and December 10, 2023. Cases were those presenting with an acute respiratory illness and who had a positive SARS-CoV-2 polymerase chain reaction test; controls had an acute respiratory illness but tested negative for SARS-CoV-2. Exposure: The primary exposure was receipt of the BNT162b2 XBB vaccine compared with not receiving an XBB vaccine of any kind, regardless of prior COVID-19 vaccination or SARS-CoV-2 infection history. Receipt of prior (non-XBB) versions of COVID-19 vaccines was also compared with being unvaccinated to estimate remaining protection from older vaccines. Main Outcomes and Measures: Analyses for cases and controls were conducted separately for COVID-19 hospital admissions and ED/UC encounters. Adjusted odds ratios and 95% CIs were estimated from multivariable logistic regression models that were adjusted for patient demographic and clinical characteristics. Estimation of vaccine effectiveness was calculated as 1 - odds ratio × 100%. Results: Among 2854 cases and 15 345 controls (median [IQR] age, 56 [37-72] years; 10 658 [58.6%] female), adjusted estimation of effectiveness of the BNT162b2 XBB vaccine received a median of 34 days prior vs not having received an XBB vaccine of any kind was 62% (95% CI, 32%-79%) against COVID-19 hospitalization and 58% (95% CI, 48%-67%) for ED/UC visits. Compared with being unvaccinated, those who had received only older versions of COVID-19 vaccines did not show statistically significant reduced risk of COVID-19 outcomes, including hospital admission. Conclusions and Relevance: Findings of this case-control study reaffirm current recommendations for broad age-based use of annually updated COVID-19 vaccines given that (1) the BNT162b2 XBB vaccine provided statistically significant additional protection against a range of COVID-19 outcomes and (2) older versions of COVID-19 vaccines offered little, if any, long-term protection, including against hospital admission, regardless of the number or type of prior doses received.

Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior.

Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI injury during late adolescence (at ~8 weeks old). Here we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior, and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. We show that mTBI increases LHb spontaneous tonic activity in female mice similar to what we previously observed in male mice as well as promoting LHb neuronal hyperexcitability and hyperpolarization-induced LHb bursting in both male and female mice. Interestingly, mTBI only increases LHb intrinsic excitability in male mice coincident with higher levels of the hyperpolarization-activated cation currents (HCN/Ih) and reduces levels of the M-type potassium currents while potentiating M-currents without altering intrinsic excitability in LHb neurons of female mice. Since persistent dysregulation of brain CRF systems is suggested to contribute to chronic psychiatric morbidities and that LHb neurons are highly responsive to CRF, we then tested whether LHb CRF subsystem becomes engaged following mTBI. We found that in vitro inhibition of CRF receptor type 1 (CRFR1) within the LHb reverses mTBI-induced enhancement of LHb tonic activity and hyperexcitability in both sexes, suggesting that an augmented intra-LHb CRF-CRFR1-mediated signaling contributes to the overall LHb hyperactivity following mTBI. Behaviorally, mTBI diminishes motivation for self-care grooming in female mice as in male mice. mTBI also alters defensive behaviors in the looming shadow task by shifting the innate defensive behaviors towards more passive action-locking rather than escape behaviors in response to an aerial threat in both male and female mice as well as prolonging the latency to escape responses in female mice. While, this model of mTBI reduces social preference in male mice, it induces higher social novelty seeking during the novel social encounters in both male and female mice. Overall, our study provides further translational validity for the use of this preclinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially affect young males and females when exposed to this type of mTBI injury during late adolescence.

Dysregulation of Kappa Opioid Receptor Neuromodulation of Lateral Habenula Synaptic Function following a Repetitive Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) increases the risk of cognitive deficits, affective disorders, anxiety and substance use disorder in affected individuals. Substantial evidence suggests a critical role for the lateral habenula (LHb) in pathophysiology of psychiatric disorders. Recently, we demonstrated a causal link between persistent mTBI-induced LHb hyperactivity due to synaptic excitation/inhibition (E/I) imbalance and motivational deficits in self-care grooming behavior in young adult male mice using a repetitive closed head injury mTBI model. One of the major neuromodulatory systems that is responsive to traumatic brain and spinal cord injuries, influences affective states and also modulates LHb activity is the dynorphin/kappa opioid receptor (Dyn/KOR) system. However, the effects of mTBI on KOR neuromodulation of LHb function is unknown. To address this, we first used retrograde tracing to anatomically verify that the mouse LHb indeed receives Dyn/KOR expressing projections. We identified several major KOR-expressing and Dyn-expressing synaptic inputs projecting to the mouse LHb. We then functionally evaluated the effects of in vitro KOR modulation of spontaneous synaptic activity within the LHb of male and female sham and mTBI mice at 4week post-injury using the repetitive closed head injury mTBI model. Similar to what we previously reported in the LHb of male mTBI mice, mTBI presynaptically diminished spontaneous synaptic activity onto LHb neurons, while shifting synaptic E/I toward excitation in female mouse LHb. Furthermore, KOR activation in either mouse male/female LHb generally suppressed spontaneous glutamatergic transmission without altering GABAergic transmission, resulting in a significant reduction in E/I ratios and decreased excitatory synaptic drive to LHb neurons of male and female sham mice. Interestingly following mTBI, while responses to KOR activation at LHb glutamatergic synapses were observed comparable to those of sham, LHb GABAergic synapses acquired an additional sensitivity to KOR-mediated inhibition. Thus, in contrast to sham LHb, we observed a reduction in GABA release probability in response to KOR stimulation in mTBI LHb, resulting in a chronic loss of KOR-mediated net synaptic inhibition within the LHb. Overall, our findings uncovered the previously unknown sources of major Dyn/KOR-expressing synaptic inputs projecting to the mouse LHb. Further, we demonstrate that an engagement of intra-LHb Dyn/KOR signaling provides a global suppression of excitatory synaptic drive to the mouse LHb which could act as an inhibitory braking mechanism to prevent LHb hyperexcitability. The additional engagement of KOR-mediated modulatory action on LHb GABAergic transmission by mTBI could contribute to the E/I imbalance after mTBI, with Dyn/KOR signaling serving as a disinhibitory mechanism for LHb neurons in male and female mTBI mice.

Intensive Aerobic Cycling Is Feasible and Elicits Improvements in Gait Velocity in Individuals With Multiple Sclerosis: A Preliminary Study.

BACKGROUND: Aerobic exercise (AEx) has many potential benefits; however, it is unknown whether individuals with multiple sclerosis (MS) can attain the optimal intensity and duration to harness its effects. Forced-rate exercise (FE) is a novel paradigm in which the voluntary pedaling rate during cycling is supplemented to achieve a higher exercise intensity. The aim of this pilot trial was to investigate the feasibility and initial efficacy of a 12-week FE or voluntary exercise (VE) cycling intervention for individuals with MS. METHODS: Twenty-two participants with MS (Expanded Disability Severity Scale [EDSS] 2.0-6.5) were randomly assigned to FE (n = 12) or VE (n = 10), each with twice weekly 45-minute sessions at a prescribed intensity of 60% to 80% of maximum heart rate (HR). RESULTS: Eighteen individuals (FE = 11; VE = 7) completed the intervention, however, adaptations were required in both groups to overcome barriers to cycling. Overall, participants exercised for an average of 42.2 ± 2.3 minutes at an aerobic intensity of 65% ± 7% of maximum HR and a pedaling cadence of 67.3 ± 13.3 RPM. Cycling led to improved treadmill walking speed (0.61 to 0.68 m/sec, P = .010), with somewhat greater improvement with FE compared to VE (increase of 0.09 vs 0.03 m/s, respectively, P = .17) post intervention. Notably, the participant with the highest disability level (EDSS 6.5) tolerated FE but not VE. CONCLUSIONS: Aerobic exercise is feasible for individuals with MS, although those with increased disability may require novel paradigms such as FE to achieve targeted intensity. Further trials are warranted to investigate the effects of FE across the MS disability spectrum.

Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior.

Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI injury during late adolescence (at ~8 weeks old). Here we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior, and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. We show that mTBI increases LHb spontaneous tonic activity in female mice similar to what we previously observed in male mice as well as promoting LHb neuronal hyperexcitability and hyperpolarization-induced LHb bursting in both male and female mice. Interestingly, mTBI only increases LHb intrinsic excitability in male mice coincident with higher levels of the hyperpolarization-activated cation currents (HCN/Ih) and reduces levels of the M-type potassium currents while potentiating M-currents without altering intrinsic excitability in LHb neurons of female mice. Since persistent dysregulation of brain CRF systems is suggested to contribute to chronic psychiatric morbidities and that LHb neurons are highly responsive to CRF, we then tested whether LHb CRF subsystem becomes engaged following mTBI. We found that in vitro inhibition of CRF receptor type 1 (CRFR1) within the LHb normalizes mTBI-induced enhancement of LHb tonic activity and hyperexcitability in both sexes, suggesting that an augmented intra-LHb CRF-CRFR1-mediated signaling contributes to the overall LHb hyperactivity following mTBI. Behaviorally, mTBI diminishes motivation for self-care grooming in female mice as in male mice. mTBI also alters defensive behaviors in the looming shadow task by shifting the innate defensive behaviors towards more passive action-locking rather than escape behaviors in response to an aerial threat in both male and female mice as well as prolonging the latency to escape responses in female mice. While, this model of mTBI reduces social preference in male mice, it induces higher social novelty seeking during the novel social encounters in both male and female mice. Overall, our study provides further translational validity for the use of this preclinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially affect young males and females when exposed to this type of mTBI injury during late adolescence.

AKAP150-anchored PKA regulates synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the mouse lateral habenula.

The scaffolding A-kinase anchoring protein 150 (AKAP150) is critically involved in kinase and phosphatase regulation of synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a key role in brain's processing of rewarding/aversive experiences, however its role in the lateral habenula (LHb, as an important brain reward circuitry) is completely unknown. Using whole cell patch clamp recordings in LHb of male wildtype and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), here we show that the genetic disruption of PKA anchoring to AKAP150 significantly reduces AMPA receptor-mediated glutamatergic transmission and prevents the induction of presynaptic endocannabinoid-mediated long-term depression in LHb neurons. Moreover, ΔPKA mutation potentiates GABAA receptor-mediated inhibitory transmission while increasing LHb intrinsic excitability through suppression of medium afterhyperpolarizations. ΔPKA mutation-induced suppression of medium afterhyperpolarizations also blunts the synaptic and neuroexcitatory actions of the stress neuromodulator, corticotropin releasing factor (CRF), in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPA and GABAA receptor synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPA receptor and potassium channel trafficking and endocannabinoid signaling within the LHb.

Pilot Implementation of a Nutrition-Focused Community-Health-Worker Intervention among Formerly Chronically Homeless Adults in Permanent Supportive Housing.

Food insecurity is a known health equity threat for formerly chronically homeless populations even after they transition into permanent housing. This project utilized a human-centered design methodology to plan and implement a nutrition-focused community-health-worker (CHW) intervention in permanent supportive housing (PSH). The project aimed to increase access to healthy foods, improve nutritional literacy, healthy cooking/eating practices, and build community/social connectedness among 140 PSH residents. Validated food-security screening conducted by CHWs identified low or very low food security among 64% of 83 residents who completed the baseline survey, which is similar to rates found in a previous study among formerly homeless populations placed in PSH. Major themes identified through an analysis of resident feedback include (1) lack of needed kitchenware/appliances for food preparation, (2) knowledge gaps on how to purchase and prepare healthier food, (3) positive perceptions of healthy food options, (4) expanded preferences for healthy, easy-to-prepare foods, (5) regaining cooking skills lost during homelessness, (6) positive experiences participating in group activities, (7) community re-entry, and (8) resident ownership. Preliminary findings suggest the use of a human-centered design methodology for planning and implementing this multi-level CHW intervention helped reduce food insecurity, engaged participants in learning and adopting healthy and safe cooking and eating practices, and fostered social connectedness and feelings of community among formerly chronically homeless PSH residents.

Aerobic cycling reduces fatigue and improves pain in persons with multiple sclerosis: A preliminary study.

Fatigue and pain are prevalent in persons with multiple sclerosis (PwMS), negatively impacting quality of life (QoL). Clinical management is challenging due to their multiple underlying causes. Aerobic exercise elicits central and peripheral effects, which may effectively manage MS-related symptoms. Our aim was to determine the effects of an aerobic cycling intervention on symptoms impacting QoL. Eighteen participants completed a 12-week moderate- to high-intensity aerobic cycling intervention. Participants reported significant improvements in physical fatigue, overall fatigue, pain intensity, and pain interference. Aerobic exercise should be considered as part of a multi-faceted approach to improve fatigue and pain in PwMS.

Effectiveness of BNT162b2 BA.4/5 bivalent mRNA vaccine against a range of COVID-19 outcomes in a large health system in the USA: a test-negative case-control study.

BACKGROUND: XBB-related omicron sublineages have recently replaced BA.4/5 as the predominant omicron sublineages in the USA and other regions globally. Despite preliminary signs of immune evasion of XBB sublineages, few data exist describing the real-world effectiveness of bivalent COVID-19 vaccines, especially against XBB-related illness. We aimed to investigate the effectiveness of the Pfizer--BioNTech BNT162b2 BA.4/5 bivalent vaccine against both BA.4/5-related and XBB-related disease in adults aged 18 years or older. METHODS: In this test-negative case-control study, we estimated the effectiveness of the BNT162b2 BA.4/5 bivalent vaccine using data from electronic health records of Kaiser Permanente Southern California health system members aged 18 years or older who received at least two doses of the wild-type COVID-19 mRNA vaccines. Participants sought care for acute respiratory infection between Aug 31, 2022, and April 15, 2023, and were tested for SARS-CoV-2 via PCR tests. Relative vaccine effectiveness (≥2 doses of wild-type mRNA vaccine plus a BNT162b2 BA.4/5 bivalent booster vs ≥2 doses of a wild-type mRNA vaccine alone) and absolute vaccine effectiveness (vs unvaccinated individuals) was estimated against critical illness related to acute respiratory infection (intensive care unit [ICU] admission, mechanical ventilation, or inpatient death), hospital admission, emergency department or urgent care visits, and in-person outpatient encounters with odds ratios from logistic regression models adjusted for demographic and clinical factors. We stratified vaccine effectiveness estimates for hospital admission, emergency department or urgent care visits, and outpatient encounters by omicron sublineage (ie, likely BA.4/5-related vs likely XBB-related), time since bivalent booster receipt, age group, number of wild-type doses received, and immunocompromised status. This study is registered with ClinicalTrials.gov (NCT04848584). FINDINGS: Analyses were conducted for 123 419 encounters (24 246 COVID-19 cases and 99 173 test-negative controls), including 4131 episode of critical illness (a subset of hospital admissions), 14 529 hospital admissions, 63 566 emergency department or urgent care visits, and 45 324 outpatient visits. 20 555 infections were BA.4/5 related and 3691 were XBB related. In adjusted analyses, relative vaccine effectiveness for those who received the BNT162b2 BA.4/5 bivalent booster compared with those who received at least two doses of a wild-type mRNA vaccine alone was an additional 50% (95% CI 23-68) against critical illness, an additional 39% (28-49) against hospital admission, an additional 35% (30-40) against emergency department or urgent care visits, and an additional 28% (22-33) against outpatient encounters. Waning of the bivalent booster from 0-3 months to 4-7 months after vaccination was evident for outpatient outcomes but was not detected for critical illness, hospital admission, and emergency department or urgent care outcomes. The relative effectiveness of the BNT162b2 BA.4/5 bivalent booster for XBB-related infections compared with BA.4/5-related infections was 56% (95% CI 12-78) versus 40% (27-50) for hospital admission; 34% (21-45) versus 36% (30-41) against emergency department or urgent care visits; and 29% (19-38) versus 27% (20-33) for outpatient encounters. INTERPRETATION: By mid-April, 2023, individuals previously vaccinated only with wild-type vaccines had little protection against COVID-19-including hospital admission. A BNT162b2 BA.4/5 bivalent booster restored protection against a range of COVID-19 outcomes, including against XBB-related sublineages, with the most substantial protection observed against hospital admission and critical illness. FUNDING: Pfizer.

An miRNA with a major impact on stress.

miRNAs regulate mRNAs, including those important for synapse function in the brain. Mucha and colleagues recently identified a novel miRNA-mRNA interaction in the basolateral amygdala that acts as a homeostatic counter to stress-induced anxiety and synaptic changes, suggesting miRNAs as potential avenues for therapeutic intervention in anxiety disorders.

Post-licensure safety study of new-onset immune-mediated diseases, herpes zoster, and anaphylaxis in adult recipients of HepB-CpG vaccine versus HepB-alum vaccine.

BACKGROUND: HepB-CpG (Heplisav-B) is a licensed hepatitis B vaccine with a novel adjuvant that requires 2 doses (0, 1 month) compared to HepB-alum (Engerix-B) which requires 3 doses (0, 1, 6 months). Monitoring safety outcomes following receipt of vaccines with novel adjuvants outside trial settings is important. Hence, as part of a post-marketing commitment, we compared the incidence of new-onset immune-mediated diseases, herpes zoster (HZ), and anaphylaxis among recipients of HepB-CpG versus HepB-alum. METHODS: This cohort study included adults not on dialysis who received ≥1 dose of hepatitis B vaccine from 8/7/2018 to 10/31/2019, during which HepB-CpG was routinely administered in 7 of 15 Kaiser Permanente Southern California medical centers while HepB-alum was administered in the other 8 centers. Recipients of HepB-CpG or HepB-alum were followed through electronic health records for 13 months for occurrence of pre-specified new-onset immune-mediated diseases, HZ, and anaphylaxis identified using diagnosis codes. Incidence rates were compared using Poisson regression with inverse probability of treatment weighting when there was ≥80 % power to detect a relative risk (RR) of 5 for anaphylaxis and RR of 3 for other outcomes. Chart review to confirm new-onset diagnosis was conducted for outcomes with statistically significant elevated risk. RESULTS: There were 31,183 HepB-CpG and 38,442 HepB-alum recipients (overall 49.0 % female, 48.5 % age ≥50 years, and 49.6 % Hispanic). Among immune-mediated events that occurred frequently enough for formal comparison, rates among HepB-CpG versus Hep-B-alum recipients were similar except for rheumatoid arthritis (RA) (adjusted RR 1.53 [95 % CI: 1.07, 2.18]). After chart confirmation of new-onset RA, the adjusted RR was 0.93 (0.34, 2.49). The adjusted RR for HZ was 1.06 (0.89, 1.27). Anaphylaxis occurred in 0 HepB-CpG and 2 HepB-alum recipients. CONCLUSIONS: This large post-licensure study did not identify evidence of safety concerns for HepB-CpG compared to HepB-alum for immune-mediated diseases, HZ, or anaphylaxis.

Assessment of microbial bioburden on portable medical equipment in a hospital setting.

Objectives: Although routine disinfection of portable medical equipment is required in most hospitals, frontline staff may not be able to disinfect portable medical equipment at a rate that adequately maintains low bioburden on high-use equipment. This study quantified bioburden over an extended time period for two types of portable medical equipment, workstations on wheels and vitals machines, across three hospital wards. Methods: Bioburden was quantified via press plate samples taken from high touch surfaces on 10 workstations on wheels and 5 vitals machines on each of 3 medical surgical units. The samples were taken at three timepoints each day over a 4-week period, with random rotation of timepoints and portable medical equipment, such that frontline staff were not aware at which timepoint their portable medical equipment would be sampled. The mean bioburden from the different locations and portable medical equipment was estimated and compared with Bayesian multilevel negative binomial regression models. Results: Model estimated mean colony counts (95% credible interval) were 14.4 (7.7-26.7) for vitals machines and 29.2 (16.1-51.1) for workstations on wheels. For the workstations on wheel, colony counts were lower on the mouse, 0.22 (0.16-0.29), tray, 0.29 (0.22, 0.38), and keyboard, 0.43 (0.32-0.55), when compared to the arm, as assessed by incident rate ratios. Conclusions: Although routine disinfection is required, bioburden is still present across portable medical equipment on a variety of surfaces. The difference in bioburden levels among surfaces likely reflects differences in touch patterns for the different portable medical equipment and surfaces on the portable medical equipment. Although the association of portable medical equipment bioburden to healthcare-associated infection transmission was not assessed, this study provides evidence for the potential of portable medical equipment as a vector for healthcare-associated infection transmission despite hospital disinfection requirements.

BNT162b2 Against COVID-19-Associated Emergency Department and Urgent Care Visits Among Children 5-11 Years of Age: A Test Negative Design.

In a 1:1 matched test-negative design among 5- to 11-year-olds in the Kaiser Permanente Southern California health system (n = 3984), BNT162b2 effectiveness against the omicron-related emergency department or urgent care encounters was 60% [95%CI: 47-69] <3 months post-dose-two and 28% [8-43] after ≥3 months. A booster improved protection to 77% [53-88].

Analysis of mRNA COVID-19 Vaccine Uptake Among Immunocompromised Individuals in a Large US Health System.

Importance: Immunocompromised individuals are at increased risk for severe outcomes due to SARS-CoV-2 infection. Given the varying and complex nature of COVID-19 vaccination recommendations, it is important to understand COVID-19 vaccine uptake in this vulnerable population. Objective: To assess mRNA COVID-19 vaccine uptake and factors associated with uptake among immunocompromised individuals from December 14, 2020, through August 6, 2022. Design, Setting, and Participants: This cohort study was conducted with patients of Kaiser Permanente Southern California (KPSC), an integrated health care system in the US. The study included patients aged 18 years or older who were immunocompromised (individuals with an immunocompromising condition or patients who received immunosuppressive medications in the year prior to December 14, 2020) and still met criteria for being immunocompromised 1 year later. Exposures: Age, sex, self-identified race and ethnicity, prior positive COVID-19 test result, immunocompromising condition, immunomodulating medication, comorbidities, health care utilization, and neighborhood median income. Main Outcomes and Measures: Outcomes were the number of doses of mRNA COVID-19 vaccine received and the factors associated with receipt of at least 4 doses, estimated by hazard ratios (HRs) and 95% Wald CIs via Cox proportional hazards regression. Statistical analyses were conducted between August 9 and 23, 2022. Results: Overall, 42 697 immunocompromised individuals met the study eligibility criteria. Among these, 18 789 (44.0%) were aged 65 years or older; 20 061 (47.0%) were women and 22 635 (53.0%) were men. With regard to race and ethnicity, 4295 participants (10.1%) identified as Asian or Pacific Islander, 5174 (12.1%) as Black, 14 289 (33.5%) as Hispanic, and 17 902 (41.9%) as White. As of the end of the study period and after accounting for participant censoring due to death or disenrollment from the KPSC health plan, 78.0% of immunocompromised individuals had received a third dose of mRNA COVID-19 vaccine. Only 41.0% had received a fourth dose, which corresponds to a primary series and a monovalent booster dose for immunocompromised individuals. Uptake of a fifth dose was only 0.9% following the US Centers for Disease Control and Prevention (CDC) recommendation to receive a second monovalent booster (ie, fifth dose). Adults aged 65 years or older (HR, 3.95 [95% CI, 3.70-4.22]) were more likely to receive at least 4 doses compared with those aged 18 to 44 years or 45 to 64 years (2.52 [2.36-2.69]). Hispanic and non-Hispanic Black adults (HR, 0.77 [95% CI, 0.74-0.80] and 0.82 [0.78-0.87], respectively, compared with non-Hispanic White adults), individuals with prior documented SARS-CoV-2 infection (0.71 [0.62-0.81] compared with those without), and individuals receiving high-dose corticosteroids (0.88 [0.81-0.95] compared with those who were not) were less likely to receive at least 4 doses. Conclusions and Relevance: These findings suggest that adherence to CDC mRNA monovalent COVID-19 booster dose recommendations among immunocompromised individuals was low. Given the increased risk for severe COVID-19 in this vulnerable population and the well-established additional protection afforded by booster doses, targeted and tailored efforts to ensure that immunocompromised individuals remain up to date with COVID-19 booster dose recommendations are warranted.

Associations of sNfL with clinico-radiological measures in a large MS population.

OBJECTIVE: Evaluation of serum neurofilament light chain (sNfL), measured using high-throughput assays on widely accessible platforms in large, real-world MS populations, is a critical step for sNfL to be utilized in clinical practice. METHODS: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high-throughput, scalable immunoassay. RESULTS: Elevated sNfL levels for age (sNfL-E) were found in 1238 MS participants (17.8%). Factors associated with sNfL-E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease-modifying therapy was associated with lower odds of sNfL-E. MS participants with sNfL-E exhibited worse neurological function (patient-reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short-term rates of whole brain atrophy in sNfL-E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL-E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age-normative sNfL Z-scores as a continuous variable. INTERPRETATION: Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking.

Effects of prenatal opioid exposure on synaptic adaptations and behaviors across development.

In this review, we focus on prenatal opioid exposure (POE) given the significant concern for the mental health outcomes of children with parents affected by opioid use disorder (OUD) in the view of the current opioid crisis. We highlight some of the less explored interactions between developmental age and sex on synaptic plasticity and associated behavioral outcomes in preclinical POE research. We begin with an overview of the rich literature on hippocampal related behaviors and plasticity across POE exposure paradigms. We then discuss recent work on reward circuit dysregulation following POE. Additional risk factors such as early life stress (ELS) could further influence synaptic and behavioral outcomes of POE. Therefore, we include an overview on the use of preclinical ELS models where ELS exposure during key critical developmental periods confers considerable vulnerability to addiction and stress psychopathology. Here, we hope to highlight the similarity between POE and ELS on development and maintenance of opioid-induced plasticity and altered opioid-related behaviors where similar enduring plasticity in reward circuits may occur. We conclude the review with some of the limitations that should be considered in future investigations. This article is part of the Special Issue on 'Opioid-induced addiction'.

Involvement of Lateral Habenula Dysfunction in Repetitive Mild Traumatic Brain Injury-Induced Motivational Deficits.

Affective disorders including depression (characterized by reduced motivation, social withdrawal, and anhedonia), anxiety, and irritability are frequently reported as long-term consequences of mild traumatic brain injury (mTBI) in addition to cognitive deficits, suggesting a possible dysregulation within mood/motivational neural circuits. One of the important brain regions that control motivation and mood is the lateral habenula (LHb), whose hyperactivity is associated with depression. Here, we used a repetitive closed-head injury mTBI model that is associated with social deficits in adult male mice and explored the possible long-term alterations in LHb activity and motivated behavior 10-18 days post-injury. We found that mTBI increased the proportion of spontaneous tonically active LHb neurons yet decreased the proportion of LHb neurons displaying bursting activity. Additionally, mTBI diminished spontaneous glutamatergic and GABAergic synaptic activity onto LHb neurons, while synaptic excitation and inhibition (E/I) balance was shifted toward excitation through a greater suppression of GABAergic transmission. Behaviorally, mTBI increased the latency in grooming behavior in the sucrose splash test suggesting reduced self-care motivated behavior following mTBI. To show whether limiting LHb hyperactivity could restore motivational deficits in grooming behavior, we then tested the effects of Gi (hM4Di)-DREADD-mediated inhibition of LHb activity in the sucrose splash test. We found that chemogenetic inhibition of LHb glutamatergic neurons was sufficient to reverse mTBI-induced delays in grooming behavior. Overall, our study provides the first evidence for persistent LHb neuronal dysfunction due to an altered synaptic integration as causal neural correlates of dysregulated motivational states by mTBI.

Repetitive mild traumatic brain injury induces persistent alterations in spontaneous synaptic activity of hippocampal CA1 pyramidal neurons.

Mild traumatic brain injury (mTBI) or concussion is the most common form of TBI which frequently results in persistent cognitive impairments and memory deficits in affected individuals [1]. Although most studies have investigated the role of hippocampal synaptic dysfunction in earlier time points following a single injury, the long-lasting effects of mTBI on hippocampal synaptic transmission following multiple brain concussions have not been well-elucidated. Using a repetitive closed head injury (3XCHI) mouse model of mTBI, we examined the alteration of spontaneous synaptic transmission onto hippocampal CA1 pyramidal neurons by recording spontaneous excitatory AMPA receptor (AMPAR)- and inhibitory GABAAR-mediated postsynaptic currents (sEPSCs and sIPSCs, respectively) in adult male mice 2-weeks following the injury. We found that mTBI potentiated postsynaptic excitatory AMPAR synaptic function while depressed postsynaptic inhibitory GABAAR synaptic function in CA1 pyramidal neurons. Additionally, mTBI slowed the decay time of AMPAR currents while shortened the decay time of GABAAR currents suggesting changes in AMPAR and GABAAR subunit composition by mTBI. On the other hand, mTBI reduced the frequency of sEPSCs while enhanced the frequency of sIPSCs resulting in a lower ratio of sEPSC/sIPSC frequency in CA1 pyramidal neurons of mTBI animals compared to sham animals. Altogether, our results suggest that mTBI induces persistent postsynaptic modifications in AMPAR and GABAAR function and their synaptic composition in CA1 neurons while triggering a compensatory shift in excitation/inhibition (E/I) balance of presynaptic drives towards more inhibitory synaptic drive to hippocampal CA1 cells. The persistent mTBI-induced CA1 synaptic dysfunction and E/I imbalance could contribute to deficits in hippocampal plasticity that underlies long-term hippocampal-dependent learning and memory deficits in mTBI patients long after the initial injury.