Place-based, intersectional variation in caregiving patterns and health outcomes among informal caregivers in the United States.

Introduction: Informal caregiving is a critical component of the healthcare system despite numerous impacts on informal caregivers' health and well-being. Racial and gender disparities in caregiving duties and health outcomes are well documented. Place-based factors, such as neighborhood conditions and rural-urban status, are increasingly being recognized as promoting and moderating health disparities. However, the potential for place-based factors to interact with racial and gender disparities as they relate to caregiving attributes jointly and differentially is not well established. Therefore, the primary objective of this study was to jointly assess the variability in caregiver health and aspects of the caregiving experience by race/ethnicity, sex, and rural-urban status. Methods: The study is a secondary analysis of data from the 2021 and 2022 Behavioral Risk Factor Surveillance System (BRFSS) from the Centers for Disease Control and Prevention. Multivariable logistic regression or Poisson regression models assessed differences in caregiver attributes and health measures by demographic group categorized by race/ethnicity, sex, and rural-urban status. Results: Respondents from rural counties were significantly more likely to report poor or fair health (23.2% vs. 18.5%), have obesity (41.5% vs. 37.1%), and have a higher average number of comorbidities than urban caregivers. Overall, rural Black male caregivers were 43% more likely to report poor or fair health than White male caregivers (OR 1.43, 95% CI 1.21, 1.69). Urban female caregivers across all racial groups had a significantly higher likelihood of providing care to someone with Alzheimer's disease than rural White males (p < 0.001). Additionally, there were nuanced patterns of caregiving attributes across race/ethnicity*sex*rural-urban status subgroups, particularly concerning caregiving intensity and length of caregiving. Discussion: Study findings emphasize the need to develop and implement tailored approaches to mitigate caregiver burden and address the nuanced needs of a diverse population of caregivers.

Genome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants.

BACKGROUND: Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome-wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. METHODS AND RESULTS: We performed genome-wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2-stage analysis (genome-wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single-stage genome-wide meta-analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2-degrees of freedom joint main and interaction and 1-degree of freedom interaction P values. In 2-stage and single-stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2-degrees of freedom joint main and interaction P value <5×10-8). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single-stage meta-analysis were not reported previously (SPPL2B and RFX6). CONCLUSIONS: We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered.

The relationship between treatment-related changes in total hip bone mineral density measured after 12, 18 and 24 months and fracture risk reduction in osteoporosis clinical trials: the FNIH-ASBMR-SABRE Project.

There is a strong association between total hip bone mineral density (THBMD) changes after 24 months of treatment and reduced fracture risk. We examined whether changes in THBMD after 12- and 18 months of treatment are also associated with fracture risk reduction. We used individual patient data (n = 122 235 participants) from 22 randomised, placebo-controlled, double-blind trials of osteoporosis medications. We calculated the difference in mean percent change in THBMD (active-placebo) at 12, 18, and 24 months using data available for each trial. We determined the treatment-related fracture reductions for the entire follow-up period, using logistic regression for radiologic vertebral fractures and Cox regression for hip, non-vertebral, "all" (combination of non-vertebral, clinical vertebral, and radiologic vertebral) fractures, and all clinical fractures (combination of non-vertebral and clinical vertebral). We performed meta-regression to estimate the study-level association (r2 and 95% confidence interval) between treatment-related differences in THBMD changes for each BMD measurement interval and fracture risk reduction. The meta-regression revealed that for vertebral fractures, the r2 (95% confidence interval) was 0.59 (0.19, 0.75), 0.69 (0.32, 0.82), and 0.73 (0.33, 0.84) for 12, 18 and 24 months, respectively. Similar patterns were observed for hip: r2 = 0.27 (0.00, 0.54), 0.39 (0.02, 0.63), and 0.41 (0.02, 0.65); non-vertebral: r2 = 0.27 (0.01, 0.52), 0.49 (0.10, 0.69), and 0.53 (0.11, 0.72); all fractures: r2 = 0.44 (0.10, 0.64), 0.63 (0.24, 0.77), and 0.66 (0.25, 0.80); and all clinical fractures: r2 = 0.46 (0.11, 0.65), 0.64 (0.26, 0.78), and 0.71 (0.32, 0.83), for 12-, 18- and 24-month changes in THBMD, respectively. These findings demonstrate that treatment-related THBMD changes at 12, 18 and 24 months are associated with fracture risk reductions across trials. We conclude that BMD measurement intervals as short as 12 months could be used to assess fracture efficacy, but the association is stronger with longer BMD measurement intervals.

In this study, we looked at how changes in hip bone density over time relate to the risk of fractures in people taking osteoporosis medications. We analysed data from over 122 000 participants across 22 different clinical trials. We found that the increase in bone density measured after 12, 18, and 24 months of treatment was linked to the risk of fractures. Specifically, greater improvements in bone density were associated with fewer fractures in the spine, hips, and other bones. Using statistical methods, we calculated the strength of this association. We discovered that the later we measured bone mineral density in people taking the medication, the stronger the link between improved bone density and reduced fracture risk became. Our findings suggest that bone density measurements after 12 months of treatment could help predict how well a medication will prevent fractures. However, the best predictions came from bone density changes measured over longer periods.

Genomic profiles and clinical presentation of chordoma.

Chordoma is a rare bone cancer with variable clinical outcomes. Here, we recruited 184 sporadic chordoma patients from the US and Canada and collected their clinical and treatment data. The average age at diagnosis was 45.5 years (Range 5-78) and the chordoma site distribution was 49.2% clivus, 26.2% spinal, and 24.0% sacral. Most patients (97.5%) received surgery as the primary treatment, among whom 85.3% also received additional treatment. Except for the most prevalent cancers like prostate, lung, breast, and skin cancer, there was no discernible enrichment for any specific cancer type among patients or their family members. Among a subset of patients (N = 70) with tumor materials, we conducted omics analyses and obtained targeted panel sequencing and SNP array genotyping data for 51 and 49 patients, respectively. The most recurrent somatic driver mutations included PIK3CA (12%), followed by chromatin remodeling genes PBRM1 and SETD2. Amplification of the 6q27 region, containing the chordoma susceptibility gene TBXT, was detected in eight patients (16.3%). Clival patients appeared to be less likely to carry driver gene mutations, chromosome arm level deletion events (e.g., 5p, 5p, and 9p), or 6q27 amplification compared to sacral patients. After adjusting for age, sex, tumor site, and additional treatment, patients with somatic deletions of 14q (OR = 13.73, 95% CI 1.96-96.02, P = 0.008) and 18p (OR = 13.68, 95% CI 1.77-105.89, P = 0.012) were more likely to have persistent chordoma. The study highlights genomic heterogeneity in chordoma, potentially linked to location and clinical progression.

Microvascular Disease and Early Diabetes Onset Are Associated with Deficits in Femoral Neck Bone Density and Structure Among Older Adults with Longstanding Type 1 Diabetes.

Adults with type 1 diabetes (T1D) have increased hip fracture risk, yet no studies have assessed volumetric bone density or structure at the hip in older adults with T1D. Here, we used previously collected 3D CT scans of the proximal femur from older adults with longstanding T1D and non-diabetic controls to identify bone deficits that may contribute to hip fracture in T1D. In this retrospective cohort study, we identified 101 adults with T1D and 181 age-, sex- and race-matched non-diabetic controls (CON) who received abdominal or pelvis CT exams from 2010-2020. Among adults with T1D, 33 (33%) had mild-to-moderate nephropathy, 61 (60%) had neuropathy and 71 (70%) had retinopathy. Within the whole cohort, adults with T1D tended to have lower FN density, though differences did not reach statistical significance. The subset of the T1D group who were diagnosed before age 15 had lower total bone mineral content (-14%, TtBMC), cortical BMC (-19.5%, CtBMC) and smaller Ct cross-sectional area (-12.6, CtCSA) than their matched controls (P<.05 for all). Individuals with T1D who were diagnosed at a later age did not differ from controls in any bone outcome (P>.21). Furthermore, adults with T1D and nephropathy had lower FN aBMD (-10.6%), TtBMC (-17%), CtBMC (-24%) and smaller CtCSA (-15.4%) compared to matched controls (P<.05 for all). Adults with T1D and neuropathy had cortical bone deficits (8.4-12%, P<.04). In summary, among older adults with T1D, those who were diagnosed before age of 15 yrs, those with nephropathy, and those with neuropathy had unfavorable bone outcomes at the FN that may contribute to high hip fracture risk among patients with T1D. These novel observations highlight the longstanding detrimental impact of T1D when present during bone accrual and skeletal fragility as an additional complication of microvascular disease in individuals with T1D.

Older adults with type 1 diabetes (T1D) are at higher risk for hip fractures, but the reasons for this are unclear. In this study, we analyzed existing clinical CT scans of the hip from older adults with longstanding T1D and those without diabetes. While overall bone density differences were not significant, older adults with T1D who were diagnosed before age 15 or had complications like nephropathy or neuropathy showed worse bone outcomes at the femoral neck. These findings suggest that early-onset T1D and related complications contribute to increased hip fracture risk.

Advances in the Clinical Application of High-throughput Proteomics.

High-throughput proteomics has become an exciting field and a potential frontier of modern medicine since the early 2000s. While significant progress has been made in the technical aspects of the field, translating proteomics to clinical applications has been challenging. This review summarizes recent advances in clinical applications of high-throughput proteomics and discusses the associated challenges, advantages, and future directions. We focus on research progress and clinical applications of high-throughput proteomics in breast cancer, bladder cancer, laryngeal squamous cell carcinoma, gastric cancer, colorectal cancer, and coronavirus disease 2019. The future application of high-throughput proteomics will face challenges such as varying protein properties, limitations of statistical modeling, technical and logistical difficulties in data deposition, integration, and harmonization, as well as regulatory requirements for clinical validation and considerations. However, there are several noteworthy advantages of high-throughput proteomics, including the identification of novel global protein networks, the discovery of new proteins, and the synergistic incorporation with other omic data. We look forward to participating in and embracing future advances in high-throughput proteomics, such as proteomics-based single-cell biology and its clinical applications, individualized proteomics, pathology informatics, digital pathology, and deep learning models for high-throughput proteomics. Several new proteomic technologies are noteworthy, including data-independent acquisition mass spectrometry, nanopore-based proteomics, 4-D proteomics, and secondary ion mass spectrometry. In summary, we believe high-throughput proteomics will drastically shift the paradigm of translational research, clinical practice, and public health in the near future.

Enhancing healthcare accessibility through telehealth for justice impacted individuals.

Telehealth is a great tool that makes accessing healthcare easier for those incarcerated and can help with reentry into the the community. Justice impacted individuals face many hardships including adverse health outcomes which can be mitigated through access to telehealth services and providers. During the federally recognized COVID-19 pandemic the need for accessible healthcare was exacerbated and telehealth use surged. While access to telehealth should be considered a necessity, there are many challenges and barriers for justice impacted individuals to be able to utilize this service. This perspective examines aspects of accessibility, pandemic, policy, digital tools, and ethical and social considerations of telehealth in correctional facilities. Carceral facilities should continue to innovate and invest in telehealth to revolutionize healthcare delivery, and improve health outcomes for justice impacted individuals.

The Depression, Anxiety, and Stress of Student-Athletes from a Pre- to Post-COVID-19 World.

This study explored differences in student-athletes' symptoms of depression, anxiety, and stress pre- to post-COVID-19-pandemic. The WHO reported a 25% increase in depression and anxiety rates worldwide, with young people disproportionately affected. Student-athletes face many stressors related to their sporting and academic feats, but what is not known is how the COVID-19 pandemic affected their experiences of symptoms of mental illness. A multiple-cohort cross-sectional study design was employed, and data collected using physical and online surveys. Participants (cohort 1 M age = 20.18 years, SD = 1.52; cohort 2 M age = 19.75 years, SD = 1.45) were recruited from UK universities (N = 807; 427 pre-pandemic cohort, 380 post-pandemic cohort). Results revealed statistically significant differences in mean depression (F (1, 805) = 23.92, p < 0.001), anxiety (F (1, 806) = 20.15, p < 0.001), and stress symptoms (F (1, 805) = 5.24, p = 0.022) scores between cohorts. Scores for the post-pandemic cohort were significantly higher than pre-pandemic, suggesting a worsening of symptom severity. Distributions of student-athletes across categories of symptom severity also worsened for depressive and anxiety symptoms post-pandemic and were skewed towards more severe categories. Symptoms of depression, anxiety, and stress were a concern pre-pandemic. Rates are higher in the post-pandemic cohort, suggesting a worsening of symptoms. These data add to evidence on student-athletes' symptoms of mental illness by exploring a UK sample and comparing scores pre- and post-pandemic.

A closer examination of the "rural mortality penalty": Variability by race, region, and measurement.

BACKGROUND: Racial health disparities are well documented and pervasive across the United States. Evidence suggests there is a "rural mortality penalty" whereby rural residents experience poorer health outcomes than their urban counterparts. However, whether this penalty is uniform across demographic groups and U.S. regions is unknown. OBJECTIVE: To assess how rural-urban differences in mortality differ by race (Black vs. White), U.S. region, poverty status, and how rural-urban status is measured. METHODS: Age-standardized mortality rates (ASMRs)/100,000 by U.S. county (2015-2019) were obtained by race (Black/White) from the CDC Wonder National Vital Statistics System (2015-2019) and were merged with county-level social determinants from the US Census Bureau and County Health Rankings. Multivariable generalized linear models assessed the associations between rurality (index of relative rurality [IRR] decile, rural-urban continuum codes, and population density) and race-specific ASMR, overall, and by Census region and poverty level. RESULTS: Overall, average ASMR was significantly higher in rural areas than urban areas for both Black (rural ASMR = 949.1 per 100,000 vs. urban ASMR = 857.7 per 100,000) and White (rural ASMR = 903.0 per 100,000 vs. urban ASMR = 791.6 per 100,000) populations. The Black-White difference was substantially higher (p < 0.001) in urban than in rural counties (65.1 per 100,000 vs. 46.1 per 100,000). Black-White differences and patterns in ASMR varied notably by poverty status and U.S. region. CONCLUSION: Policies and interventions designed to reduce racial health disparities should consider and address key contextual factors associated with geographic location, including rural-urban status and socioeconomic status.

Lifetime depression and mania/hypomania risk predicted by neural markers in three independent young adult samples during working memory and emotional regulation.

Objective markers of pathophysiological processes underlying lifetime depression and mania/hypomania risk can provide biologically informed targets for novel interventions to help prevent the onset of affective disorders in individuals with subsyndromal symptoms. Greater activity within and functional connectivity (FC) between the central executive network (CEN), supporting emotional regulation (ER) subcomponent processes such as working memory (WM), the default mode network (DMN), supporting self-related information processing, and the salience network (SN), is thought to interfere with cognitive functioning and predispose to depressive disorders. Using an emotional n-back paradigm designed to examine WM and ER capacity, we examined in young adults: (1) relationships among activity and FC in these networks and lifetime depression and mania/hypomania risk; (2) the extent to which these relationships were specific to lifetime depression risk versus lifetime mania/hypomania risk; (3) whether findings in a first, Discovery sample n = 101, 63 female, age = 23.85 (2.9) could be replicated in a two independent Test samples of young adults: Test sample 1: n = 90, 60 female, age = 21.7 (2.0); Test sample 2: n = 96, 65 female, age = 21.6 (2.1). The Mood Spectrum Self-Report (MOODS-SR-L) assessed lifetime mania/hypomania risk and depression risk. We showed significant clusters of activity to each contrast in similar locations in the anatomic mask in each Test sample as in the Discovery sample, and, using extracted mean BOLD signal from these clusters as IVs, we showed similar patterns of IV-DV relationships in each Test sample as in the Discovery sample. Specifically, in the Discovery sample, greater DMN activity during WM was associated with greater lifetime depression risk. This finding was specific to depression and replicated in both independent samples (all ps<0.05 qFDR). Greater CEN activity during ER was associated with increased lifetime depression risk and lifetime mania/hypomania risk in all three samples (all ps< 0.05 qFDR). These replicated findings provide promising objective, neural markers to better identify, and guide and monitor early interventions for, depression and mania/hypomania risk in young adults.

Association between changes in serum bone metabolism markers and bone microarchitecture changes during basic combat training - The ARMI study.

IMPORTANCE: U.S. Army Basic Combat Training (BCT) improves tibial volumetric bone mineral density (BMD) and structure in most, but not all soldiers. Few studies have investigated whether changes in serum bone biomarkers during BCT are associated with changes in tibial BMD and bone structure following BCT. OBJECTIVE: To characterize bone biomarker changes during BCT and to investigate the relationship between changes in bone biomarkers and changes in tibial BMD and bone structure. METHODS: We enrolled 235 trainees entering BCT in this ten-week prospective observational study. Trainees provided fasted blood samples and questionnaires weekly throughout BCT. Procollagen type 1 N-terminal propeptide (PINP) and C-terminal telopeptide of type 1 collagen (CTX) were measured by enzyme-linked immunoabsorbent assays every two weeks during BCT. We evaluated body composition and mass via dual-energy X-ray absorptiometry and bone structure, microarchitecture, and mineral density at the distal tibia via high-resolution peripheral quantitative computed tomography at baseline and post-BCT. RESULTS: Both male (n = 110) and female trainees (n = 125) were young (20.9 ±â€¯3.7 and 20.7 ±â€¯4.3 years, respectively), with normal to overweight BMIs (25.2 ±â€¯4.1 and 24.2 ±â€¯3.6 kg/m2, respectively). In female trainees, PINP increased during and post-BCT compared to baseline, with the greatest increase in PINP at week four (45.4 % ±â€¯49.6, p < 0.0001), whereas there were no changes in CTX. PINP also increased in male trainees, but only at weeks two and four (21.9 % ±â€¯24.5, p = 0.0027 and 35.9 % ±â€¯35.8, p < 0.0001, respectively). Unlike female trainees, in males, CTX was lower than baseline at weeks four, eight, and post-BCT. The change in PINP from baseline to week four of BCT was positively associated with changes in tibial BMD, Tb.BMD, Tb.Th, Tb.BV/TV, Ct.Th, Ct.Ar, and Ct.Po from the baseline to post-BCT. CONCLUSION: The bone formation marker PINP increases during U.S. Army BCT, especially during the first four weeks. Increases in PINP, but not CTX, were correlated with improved BMD and bone structure in the distal tibia.

Supplementing Systematic Review Findings with Healthcare System Data: Pilot Projects from the Agency for Healthcare Research and Quality Evidence-based Practice Center Program.

OBJECTIVES: The US Agency for Healthcare Research and Quality (AHRQ), through the Evidence-based Practice Center (EPC) Program, aims to provide health system decision makers with the highest-quality evidence to inform clinical decisions. However, limitations in the literature may lead to inconclusive findings in EPC systematic reviews (SRs). The EPC Program conducted pilot projects to understand the feasibility, benefits, and challenges of utilizing health system data to augment SR findings to support confidence in healthcare decision-making based on real-world experiences. STUDY DESIGN AND SETTING: Three contractors (each an EPC located at a different health system) selected a recently completed systematic review conducted by their center and identified an evidence gap that electronic health record (EHR) data might address. All pilot project topics addressed clinical questions as opposed to care delivery, care organization, or care disparities topics that are common in EPC reports. Topic areas addressed by each EPC included infantile epilepsy, migraine, and hip fracture. EPCs also tracked additional resources needed to conduct supplemental analyses. The workgroup met monthly in 2022-2023 to discuss challenges and lessons learned from the pilot projects. RESULTS: Two supplemental data analyses filled an evidence gap identified in the systematic reviews (raised certainty of evidence, improved applicability) and the third filled a health system knowledge gap. Project challenges fell under three themes: regulatory and logistical issues, data collection and analysis, and interpretation and presentation of findings. Limited ability to capture key clinical variables given inconsistent or missing data within the EHR was a major limitation. The workgroup found that conducting supplemental data analysis alongside an SR was feasible but adds considerable time and resources to the review process (estimated total hours to complete pilot projects ranged from 283-595 across EPCs), and that the increased effort and resources added limited incremental value. CONCLUSION: Supplementing existing systematic reviews with analyses of EHR data is resource intensive and requires specialized skillsets throughout the process. While using EHR data for research has immense potential to generate real-world evidence and fill knowledge gaps, these data may not yet be ready for routine use alongside systematic reviews.

Patient-Reported Outcomes Improve with a Virtual Diabetes Care Model that Includes Continuous Glucose Monitoring.

Background: The objective was to examine patient-reported outcomes (PROs) associated with access to a virtual clinic model for diabetes care. Methods: Adults with diabetes (N = 234) received virtual care, including support for continuous glucose monitoring (CGM) over a 6-month study period. Care was led by a Certified Diabetes Care and Education Specialist and focused on optimizing self-management skills and response to glucose values observed on CGM. After 6 months of CGM use and access to diabetes education, participants could opt in to another 6 months of follow-up with access to the virtual care team. Participants completed PRO surveys and had health and glycemic measures collected at baseline, 3, 6, and 12 months. Results: Participants with type 1 diabetes (N = 160) were 44 ± 14 years and had mean baseline HbA1c of 61 mmol/mol (7.7%). Participants with type 2 diabetes (N = 74) were 52 ± 12 years and had mean baseline HbA1c of 66 mmol/mol (8.2%). Compared with baseline levels, at 6 months participants experienced less depression, diabetes distress, and hypoglycemic fears while also experiencing greater satisfaction with glucose monitoring, diabetes technology and specifically with CGM, and confidence for managing hypoglycemic (p < 0.05). For participants with type 1 diabetes, more time in the target range for glucose levels (70-180 mg/dL) was associated with less depression, diabetes distress, and hypoglycemic fears. Conclusions: PROs improved for adults with diabetes utilizing virtual diabetes care, including support for CGM use. Paired with the glycemic improvements observed in this virtual clinic study, there were robust benefits on the quality of life of adults with diabetes. ClinicalTrials.gov Identifier: NCT04765358.

An Ethical Framework for Disclosing the Training Status and Roles of Resident-Level Surgeons to Patients.

The concept of informed consent includes disclosure of all information that a reasonable patient would need to make a well-informed decision about whether to undergo a surgical procedure. This has traditionally been defined as including diagnosis, details about the procedure, prognosis, potential risks, and alternative treatments. The operating surgeon has final say and responsibility for the case, but the actual operation may be done (under supervision) by a surgeon in training. In this paper, we discuss the ethical dimensions of disclosing resident involvement, reviewing considerations such as established legal and professional standards, consequences for patients and for the surgical educators responsible for preparing future generations of surgeons, and patient rights. We conclude by offering a novel ethical framework intended to serve as a guide to disclosing resident involvement as part of the overall consent process.

Human TMEFF1 is a restriction factor for herpes simplex virus in the brain.

Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE.

Linking mitochondrial dysfunction, neurotransmitter, neural network abnormalities and mania: Elucidating neurobiological mechanisms of the therapeutic effect of the ketogenic diet in Bipolar Disorder.

There is growing interest in the ketogenic diet as a treatment for Bipolar Disorder (BD), with promising anecdotal and small case study reports of efficacy. Yet, the neurobiological mechanisms by which diet-induced ketosis might ameliorate BD symptoms remain to be determined, particularly in manic and hypomanic states - defining features of BD. Identifying these mechanisms will therefore provide new markers to guide personalized interventions and provide targets for novel treatment developments for individuals with BD. In this critical review, we describe recent findings highlighting two types of neurobiological abnormalities in BD: 1) mitochondrial dysfunction; and 2) neurotransmitter and neural network functional abnormalities. We will consequently link these abnormalities lead to mania/hypomania and depression in BD and then describe the biological underpinnings by which the ketogenic diet might have a beneficial effect in individuals with BD. We end the review by describing future approaches that can be employed to elucidate the neurobiology underlying the therapeutic effect of the ketogenic diet in BD. In so doing, this may provide marker predictors to identify individuals who will respond well to the ketogenic diet, as well as offer neural targets for novel treatment developments for BD.