Infection drives meningeal engraftment by inflammatory monocytes that impairs CNS immunity.

Tissue macrophages have an embryonic origin and can be replenished in some tissues under steady-state conditions by blood monocytes. However, little is known about the residency and properties of infiltrating monocytes after an inflammatory challenge. The meninges of the central nervous system (CNS) are populated by a dense network of macrophages that act as resident immune sentinels. Here we show that, following lymphocytic choriomeningitis virus infection, resident meningeal macrophages (MMs) acquired viral antigen and interacted directly with infiltrating cytotoxic T lymphocytes, which led to macrophage depletion. Concurrently, the meninges were infiltrated by inflammatory monocytes that engrafted the meningeal niche and remained in situ for months after viral clearance. This engraftment led to interferon-γ-dependent functional changes in the pool of MMs, including loss of bacterial and immunoregulatory sensors. Collectively, these data indicate that peripheral monocytes can engraft the meninges after an inflammatory challenge, imprinting the compartment with long-term defects in immune function.

Effectiveness of mRNA Covid-19 Vaccine among U.S. Health Care Personnel.

BACKGROUND: The prioritization of U.S. health care personnel for early receipt of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), allowed for the evaluation of the effectiveness of these new vaccines in a real-world setting. METHODS: We conducted a test-negative case-control study involving health care personnel across 25 U.S. states. Cases were defined on the basis of a positive polymerase-chain-reaction (PCR) or antigen-based test for SARS-CoV-2 and at least one Covid-19-like symptom. Controls were defined on the basis of a negative PCR test for SARS-CoV-2, regardless of symptoms, and were matched to cases according to the week of the test date and site. Using conditional logistic regression with adjustment for age, race and ethnic group, underlying conditions, and exposures to persons with Covid-19, we estimated vaccine effectiveness for partial vaccination (assessed 14 days after receipt of the first dose through 6 days after receipt of the second dose) and complete vaccination (assessed ≥7 days after receipt of the second dose). RESULTS: The study included 1482 case participants and 3449 control participants. Vaccine effectiveness for partial vaccination was 77.6% (95% confidence interval [CI], 70.9 to 82.7) with the BNT162b2 vaccine (Pfizer-BioNTech) and 88.9% (95% CI, 78.7 to 94.2) with the mRNA-1273 vaccine (Moderna); for complete vaccination, vaccine effectiveness was 88.8% (95% CI, 84.6 to 91.8) and 96.3% (95% CI, 91.3 to 98.4), respectively. Vaccine effectiveness was similar in subgroups defined according to age (<50 years or ≥50 years), race and ethnic group, presence of underlying conditions, and level of patient contact. Estimates of vaccine effectiveness were lower during weeks 9 through 14 than during weeks 3 through 8 after receipt of the second dose, but confidence intervals overlapped widely. CONCLUSIONS: The BNT162b2 and mRNA-1273 vaccines were highly effective under real-world conditions in preventing symptomatic Covid-19 in health care personnel, including those at risk for severe Covid-19 and those in racial and ethnic groups that have been disproportionately affected by the pandemic. (Funded by the Centers for Disease Control and Prevention.).

Differential Sensing Approach as a Pattern-based Discrimination for Biological Samples.

The differential sensing approach uses fingerprint patterning to distinguish uncharacterized biological samples. Inspired by natural sensory systems, an array of cross-reactive sensors generates unique response fingerprint depending on the samples. Until today, this array system has been developed using various materials, including the library of surface-charged nanoparticles and chemosensors. Many differential array systems have demonstrated accurate identification of bacterial species, viral subtypes, and cancer cells, as well as distinguishing disease states in blood or urine. This capability is particularly important for distinguishing between normal and abnormal states when specific marker molecules have not yet been identified, providing a powerful diagnostic tool. In this concept, we summarized representative outcomes of differential sensing applications for biological sample discrimination.

Characterization of Regolith And Trace Economic Resources (CRATER): An Orbitrap-based laser desorption mass spectrometry instrument for in situ exploration of the Moon.

RATIONALE: Characterization of Regolith And Trace Economic Resources (CRATER), an Orbitrap™-based laser desorption mass spectrometry instrument designed to conduct high-precision, spatially resolved analyses of planetary materials, is capable of answering outstanding science questions about the Moon's formation and the subsequent processes that have modified its (sub)surface. METHODS: Here, we describe the baseline design of the CRATER flight model, which requires <20 000 cm3  volume, <10 kg mass, and <60 W peak power. The analytical capabilities and performance metrics of a prototype that meets the full functionality of the flight model are demonstrated. RESULTS: The instrument comprises a high-power, solid-state, pulsed ultraviolet (213 nm) laser source to ablate the surface of the lunar sample, a custom ion optical interface to accelerate and collimate the ions produced at the ablation site, and an Orbitrap mass analyzer capable of discriminating competing isobars via ultrahigh mass resolution and high mass accuracy. The CRATER instrument can measure elemental and isotopic abundances and characterize the organic content of lunar surface samples, as well as identify economically valuable resources for future exploration. CONCLUSION: An engineering test unit of the flight model is currently in development to serve as a pathfinder for near-term mission opportunities.

Reasons for Migration and Their Associations with HIV Risk and Prevention Among Cisgender Sexual Minority Men: A Latent Class Analysis.

The immigrant population in the United States (U.S.) is rapidly growing; yet there is limited knowledge about how reasons for migrating to the U.S. are associated with HIV prevention behaviors. Using data from the American Men's Internet Survey (2018-2020), we performed a Latent Class Analysis (LCA) to identify patterns in reasons for migration among cisgender gay, bisexual, and other sexual minority men (SMM) who born outside the U.S. We used multivariable logistic regression controlling for demographic characteristics to assess class associations with the following in the past 12 months: condomless anal sex (CAS), illicit drug use, marijuana use, HIV testing, and PrEP use. LCA identified six distinct patterns in reasons for migration among the sample (n = 1,657): (1) Family and friends (14%); (2) Financial (17%); (3) Personal freedom related to being gay (10%); (4) Pursuit of opportunities while living openly as SMM (12%); (5) Educational purposes (18%); (6) Not my decision (29%). While HIV testing (range = 57.6-65.4%) and PrEP use (range = 15.6-21.4%) did not vary by class (p > .05 for all), CAS and illicit drug use were significantly different (p < .05). SMM who migrated to pursue opportunities while living openly and whose reasons were not their decision had greater odds of CAS than SMM who migrated for educational purposes (aOR:1.72, 95% confidence interval [95%CI]:1.15-2.59; 1.57, 1.13-2.19, respectively). Reasons for migration among SMM were associated with behaviors that can increase HIV risk, but not testing or PrEP. Push and pull factors related to migration should be considered when developing behavioral HIV interventions for immigrant SMM.

RESUMEN: La población inmigrante en los Estados Unidos (EE. UU.) está creciendo rápidamente; sin embargo, hay un conocimiento limitado acerca de cómo las razones para migrar a los EE. UU. se asocian con comportamientos de prevención del VIH. Utilizando datos del American Men's Internet Survey (2018­2020), realizamos un Análisis de Clases Latentes (ACL) para identificar patrones en las razones de migración entre hombres cisgénero gays, bisexuales y otros hombres de minorías sexuales (HMS) que reportaron haber nacido fuera de los EE. UU. Utilizamos regresión logística multivariable controlando las características demográficas para evaluar las asociaciones de clases con los siguientes comportamientos en los últimos 12 meses: sexo anal sin condón (SAC), consumo de drogas ilícitas, uso de marihuana, prueba del VIH y uso de PrEP. El ACL identificó seis patrones distintos en las razones de migración en la muestra (n = 1,657): (1) Familia y amigos (14%); (2) Motivos financieros (17%); (3) Libertad personal relacionada con ser gay (10%); (4) Búsqueda de oportunidades mientras viven abiertamente como HMS (12%); (5) Propósitos educativos (18%); (6) No fue decisión propia (29%). Mientras que las pruebas del VIH (rango = 57.6­65.4%) y el uso de PrEP (rango = 15.6­21.4%) no variaron según la clase (p > .05 para todos), el SAC y el consumo de drogas ilícitas fueron significativamente diferentes (p < .05). Los HMS que emigraron para perseguir oportunidades mientras vivían abiertamente, y aquellos cuyas razones no fueron decisión propia, tuvieron mayores probabilidades de tener SAC que los HMS que emigraron con propósitos educativos (razón de probabilidades ajustada [aOR]: 1.72, intervalo de confianza del 95% [IC 95%]: 1.15­2.59; 1.57, 1.13­2.19, respectivamente). Las razones de migración a los EE. UU. entre los HMS estuvieron asociadas con comportamientos que pueden aumentar el riesgo de VIH, pero no con pruebas o PrEP. Los factores que impulsan y atraen relacionados con la migración deben considerarse al desarrollar intervenciones de prevención del VIH para HMS inmigrantes.

Histone variant H3.3 promotes metastasis in alveolar rhabdomyosarcoma.

The relatively quiet mutational landscape of rhabdomyosarcoma (RMS) suggests that epigenetic deregulation could be central to oncogenesis and tumour aggressiveness. Histone variants have long been recognised as important epigenetic regulators of gene expression. However, the role of histone variants in RMS has not been studied hitherto. In this study, we show that histone variant H3.3 is overexpressed in alveolar RMS (ARMS), an aggressive subtype of RMS. Functionally, knockdown of H3F3A, which encodes for H3.3, significantly impairs the ability of ARMS cells to undertake migration and invasion and reduces Rho activation. In addition, a striking reduction in metastatic tumour burden and improved survival is apparent in vivo. Using RNA-sequencing and ChIP-sequencing analyses, we identified melanoma cell adhesion molecule (MCAM/CD146) as a direct downstream target of H3.3. Loss of H3.3 resulted in a reduction in the presence of active marks and an increase in the occupancy of H1 at the MCAM promoter. Cell migration and invasion were rescued in H3F3A-depleted cells through MCAM overexpression. Moreover, we identified G9a, a lysine methyltransferase encoded by EHMT2, as an upstream regulator of H3F3A. Therefore, this study identifies a novel H3.3 dependent axis involved in ARMS metastasis. These findings establish the potential of MCAM as a therapeutic target for high-risk ARMS patients. © 2022 The Pathological Society of Great Britain and Ireland.

Incidence and Risk Factors of Hypomagnesemia in Patients With Bone Metastasis From Solid Malignancies Treated With Denosumab: A Retrospective Chart Review.

BACKGROUND: Hypomagnesemia is associated with poor clinical outcomes in cancer patients. Patients with bone metastasis from solid malignancies receiving denosumab (Dmab) to prevent skeletal-related events often receive concurrent antineoplastic agents for cancer treatment. The incidence and risk factors of hypomagnesemia in patients receiving Dmab and the optimal frequency of monitoring serum magnesium (Mg) levels have not been studied in these patient populations. OBJECTIVE: The objective is to investigate the incidence and potential risk factors of hypomagnesemia and the optimal frequency of monitoring serum Mg levels. METHODS: A retrospective chart review identified patients with solid malignancies with bone metastases treated with Dmab at the Loma Linda University Cancer Center between January 2013 and February 2024. The incidence of hypomagnesemia was determined using the number of patients with hypomagnesemia and the total number of patients in the study. Univariate and multivariate logistic regression analyses identified risk factors for hypomagnesemia. RESULTS: Hypomagnesemia was observed in 19% (29/153) of patients, the majority of whom were on concurrent antineoplastic agents with ≥15% hypomagnesemia incidence (high-hypomagnesemic antineoplastics) or nonantineoplastic drugs with documented cases or incidence of hypomagnesemia (hypomagnesemic nonantineoplastics) in addition to high-hypomagnesemic antineoplastics. Multivariate analysis showed increased odds of developing hypomagnesemia with high-hypomagnesemic antineoplastics (odds ratio [OR]: 174.93, 95% confidence interval [CI]: 12.82 to 387.43, P < 0.001); hypomagnesemic nonantineoplastics plus high-hypomagnesemic antineoplastics (OR: 210.09, 95% CI: 11.80 to 3740.12, P < 0.001); and Mg level ≤ 0.85 prior to Dmab administration (OR: 16.79, 95% CI: 2.30 to 122.41, P = 0.005). CONCLUSION AND RELEVANCE: This study describes the incidence and potential risk factors for hypomagnesemia in patients with solid malignancies and metastatic bone disease treated with Dmab. This study's findings provide additional clinical insight into potential risk factors for hypomagnesemia and the need for more frequent serum Mg level monitoring of at-risk patients. Future prospective studies are needed to determine the exact frequencies most appropriate in monitoring serum Mg levels in this group of patients.

Whether Weather Matters with Migraine.

PURPOSE OF REVIEW: Many patients with migraine report their attacks are triggered by various weather anomalies. Studies have shown mixed results regarding the association of migraine to weather changes. The purpose of the current review is to compile the most up-to-date research studies on how weather may affect migraine. In addition, we explore the association between weather and other inflammatory disease states as well as neurotransmitters. RECENT FINDINGS: Migraine attacks can be related to weather variables such as barometric pressure, humidity, and wind. However, the results of recent studies are inconsistent; weathers' effect on migraine attacks is around 20%. However, very strong weather factors have a more significant effect on migraine attack variables. Many individuals identify weather as a migraine attack trigger, yet we see no causative relationship between weather and migraine patterns. The outcomes of studies indicate mixed results and reflect individual variation in how weather can impact migraine patterns. Similar relationships can be seen with other rheumatologic and pain conditions in general. Overall, the combination of weather plus other factors appears to be a more significant migraine trigger.

Characterizing the Communication Networks of Spanish- and English-Speaking Latinx Sexual Minority Men and Their Roles in Pre-Exposure Prophylaxis Uptake.

While pre-exposure prophylaxis (PrEP) has demonstrated efficacy in preventing HIV transmission, disparities in access persist in the United States, especially among Hispanic/Latinx sexual minority men (SMM). Language barriers and differences in how Latinx SMM obtain information may impact access to PrEP and HIV prevention. This study used data from the 2021 American Men's Internet Survey (AMIS) to examine differences in communication networks and PrEP use among Latinx SMM by primary language (Spanish vs. English). We examined the associations between Latinx SMM's individual- and meso-level communication networks and PrEP-related outcomes using modified Poisson regression with robust variances. Spanish-speaking Latinx SMM in the study were less likely to test for HIV, be aware of PrEP, and use daily PrEP, compared to English-speaking participants. Sexuality disclosure to a healthcare provider was positively associated with PrEP uptake among all participants and predicted STI testing over the past 12 months among English-speaking Latinx SMM. Findings highlight disparities in PrEP awareness and uptake among Latinx SMM, especially among those whose primary language is Spanish. Addressing these disparities through targeted interventions, including improved communication with healthcare providers, may help facilitate PrEP access and use in this population.

Food insecurity and its relationship to mental health and oral health in older adults.

BACKGROUND AND OBJECTIVES: Poor oral health disproportionately affects low-income older adults, for whom food insecurity and poor mental health may affect dental health. We explored the associations between food insecurity, mental health, and dental health. Furthermore, we examined whether mental health impacted the associations between food insecurity and dental health. MATERIALS AND METHODS: We conducted a cross-sectional study with a convenience sample of 226 older adults (aged 50+), employing survey and dental screening data. Participants were recruited from seven community-based organisations in Washington State, USA. We calculated descriptive statistics and conducted Chi-square tests, t tests, and logistic regression analyses to assess the associations between aspects of dental health (untreated decay, gum disease, and unmet dental needs), mental health (depression and cognitive function), and food insecurity. RESULTS: In our sample, food insecurity was observed in 28.4%, 40.6% had untreated decay, 31.6% gum disease, and 42.5% unmet dental needs. Food insecurity was associated with a higher occurrence of untreated decay and unmet dental needs. Participants experiencing food insecurity had higher odds of gum disease (aOR = 2.3; 95% CI: 1.1, 5.2) and unmet dental needs (aOR = 3.2; 95% CI:1.4, 7.6). Greater gum disease due to food insecurity was observed among individuals with lower levels of cognitive impairment. CONCLUSION: Food insecurity is associated with poorer oral health among older adults and cognitive function may modify this relationship. These findings underscore the importance of addressing both food insecurity and cognitive impairment as integral components of efforts to improve the oral health of older adults.

A Review of Syphilis Infection in Pediatric Patients.

Nearly half of all sexually transmitted infections occur in adolescents and young adults. Among them, syphilis infections are on the rise in the United States. Sexually active adolescents, especially those who do not use condoms consistently or are men who have sex with men, are at particular risk for syphilis infection. With the rise in acquired syphilis infections, the incidence of congenital syphilis has also increased. Syphilis can have a variety of presentations based on infectious stage and central nervous system involvement. Careful physical examination and history can elicit the diagnosis. Screening with a nontreponemal test followed by treponemal testing can confirm the diagnosis, and staging is determined clinically. Testing for all sexually transmitted infections should be pursued because coinfections are common. Penicillin is the first-line treatment for syphilis, and duration of therapy depends on the presence of neurologic symptoms; all infants with possible congenital syphilis should receive treatment. Posttreatment monitoring is essential to confirm successful eradication of syphilis. All sexually active, at-risk patients, including pregnant persons, should be screened for syphilis, and those diagnosed as having syphilis should be counseled on disclosure to partners. Although not often found in a pediatric population, with the increasing incidence of syphilis infections in the United States, pediatric providers should have a low threshold for syphilis screening in adolescents and a high index of suspicion for congenital syphilis in infants.

Association between short-term exposure to ambient air pollutants and biomarkers indicative of inflammation and oxidative stress: a cross-sectional study using KoGES-HEXA data.

BACKGROUND: Air pollution-induced systemic inflammation and oxidative stress are hypothesized to be the major biological mechanisms underlying pathological outcomes. We examined the association between short-term exposure to ambient air pollutants and biomarkers of inflammation and oxidative stress in 2199 general middle-aged Korean population residing in metropolitan areas. METHODS: Serum levels of inflammatory cytokines (interleukin [IL]-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor [TNF]-α) and urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured. Daily concentrations of a series of air pollutants (particulate matter [PM]10, PM2.5, SO2, NO2, CO, and O3) were predicted using the Community Multiscale Air Quality modeling system, and participant-level pollutant exposure was determined using geocoded residential addresses. Short-term exposure was defined as the 1- to 7-day moving averages. RESULTS: The multivariable-adjusted linear models controlling for the sociodemographic, lifestyle, temporal, and meteorological factors identified positive associations of PM with IL-1ß, IL-8, IL-10, TNF-α, and 8-OHdG levels; SO2 with IL-10 levels, CO with IL-1ß, IL-10, and TNF-α levels; and O3 with IL-1ß, IL-8, and 8-OHdG levels. O3 levels were inversely associated with IL-10 levels. For each pollutant, the strongest associations were observed for the 7-day average PM and CO with IL-1ß (per 10-µg/m3 increase in PM10: 2.7%, 95% confidence interval [CI] = 0.6-4.8; per 10-µg/m3 increase in PM2.5: 6.4%, 95% CI = 2.4-10.5; per 0.1-ppm increase in CO: 3.3%, 95% CI = 0.3-6.5); the 2-day average SO2 with IL-10 levels (per 1-ppb increase in SO2: 1.1%, 95% CI = 0.1-2.1); and the 7-day average O3 with IL-8 levels (per 1-ppb increase in O3: 1.3%, 95% CI = 0.7-1.9). CONCLUSIONS: Short-term exposure to ambient air pollutants may induce oxidative damage and pro-inflammatory roles, together with counter-regulatory anti-inflammatory response.

Care biography: A concept analysis.

In this article, we investigate how the concept of Care Biography and related concepts are understood and operationalised and describe how it can be applied to advancing our understanding and practice of holistic and person-centred care. Walker and Avant's eight-step concept analysis method was conducted involving multiple database searches, with potential or actual applications of Care Biography identified based on multiple discussions among all authors. Our findings demonstrate Care Biography to be a novel overarching concept derived from the conjunction of multiple other concepts and applicable across multiple care settings. Concepts related to Care Biography exist but were more narrowly defined and mainly applied in intensive care, aged care, and palliative care settings. They are associated with the themes of Meaningfulness and Existential Coping, Empathy and Understanding, Promoting Positive Relationships, Social and Cultural Contexts, and Self-Care, which we used to inform and refine our concept analysis of Care Biography. In Conclusion, the concept of Care Biography, can provide a deeper understanding of a person and their care needs, facilitate integrated and personalised care, empower people to be in control of their care throughout their life, and help promote ethical standards of care.

Cross-informant agreement between caregivers and teachers for prosocial behavior across child welfare settings.

Healthy social functioning has been a growing focus for understanding children's positive development and well-being. Despite the flexibility and cost-effectiveness of behavior rating scales, there has been a rising issue of concern in both practice and research applications regarding rating scales and its low cross-informant agreement. The present study aimed to analyze the extent to which caregivers and teachers agree about children's prosocial behaviors, identify whether there were differences in the degree of agreement across child welfare settings, and ultimately offer recommendations for assessing behavior for children involved with child welfare services. To do so, the reports of 1,224 children, caregivers, and teachers from the National Survey of Child and Adolescent Well-Being (NSCAW) I who have been investigated by Child Protective Services (CPS) for abuse and/or neglect have been examined. Intra-class correlation coefficients (ICCs) of caregiver and teacher assessment of children's prosocial functioning were calculated to understand the degree of agreement in their perceptions of children's prosocial behaviors. ICC values presented show that agreement was low but significant across all samples and subscales (ICC range, .11-.22). It is suggested that future researchers pursue examination of the underlying mechanisms or factors that contribute to informant discrepancies.

Digital Interventions to Enhance PrEP Uptake and Adherence Through Stigma Reduction.

PURPOSE OF REVIEW: Although pre-exposure prophylaxis (PrEP) is effective for reducing risk of HIV transmission, stigma persists as a barrier to HIV prevention. Digital technologies present opportunities to access hard-to-reach populations and increase the efficiency of established interventions. This review examines current digital interventions addressing stigma to improve PrEP-related outcomes. RECENT FINDINGS: Digital technologies are increasingly used for HIV prevention and include a wide range of formats. Recent interventions focused on stigma and PrEP tend to engage mobile phone-related technology and focus on younger populations with particular attention to men who have sex with men and transgender women. Digital interventions that address stigma are promising for improving PrEP-related outcomes. No single technology currently demonstrates consistent superiority. Limited access to PrEP and heightened stigma in under-resourced countries present challenges for interventions supporting diverse communities. Further research should examine how digital interventions can reduce stigma beyond the individual level to enhance PrEP use and explore opportunities to improve and integrate approaches to stigma measurement.

Reactions to Testing HIV Negative: An Assessment of Measurement Invariance and Associations with Condomless Anal Sex among English and Spanish-speaking Latinx Sexual Minority Men in the United States.

Among the many effective prevention strategies, frequent HIV testing continues to be promoted to reduce the risk of HIV transmission among sexual minority men (SMM). Testing negative for HIV can result in varied reactions that influence subsequent HIV transmission behaviors, yet the extant research has primarily been conducted in English. The current study examined measurement invariance of a Spanish-translated Inventory of Reactions to Testing HIV Negative (IRTHN). The study also examined whether the IRTHN was associated with subsequent condomless anal sex. Data were drawn from 2,170 Latinx SMM subsample of the UNITE Cohort Study. We conducted a multigroup confirmatory factor analysis to test for measurement invariance between participants who opted to take the survey in English (n = 2,024) and those who opted to take it in Spanish (n = 128). We also examined if the IRTHN is associated with subsequent CAS. The results were suggestive of partial invariance. The subscales of Luck and Invulernability were associated with CAS at the 12-month follow-up. Practice and research-based implications are discussed.

Contractile pericytes determine the direction of blood flow at capillary junctions.

The essential function of the circulatory system is to continuously and efficiently supply the O2 and nutrients necessary to meet the metabolic demands of every cell in the body, a function in which vast capillary networks play a key role. Capillary networks serve an additional important function in the central nervous system: acting as a sensory network, they detect neuronal activity in the form of elevated extracellular K+ and initiate a retrograde, propagating, hyperpolarizing signal that dilates upstream arterioles to rapidly increase local blood flow. Yet, little is known about how blood entering this network is distributed on a branch-to-branch basis to reach specific neurons in need. Here, we demonstrate that capillary-enwrapping projections of junctional, contractile pericytes within a postarteriole transitional region differentially constrict to structurally and dynamically determine the morphology of capillary junctions and thereby regulate branch-specific blood flow. We further found that these contractile pericytes are capable of receiving propagating K+-induced hyperpolarizing signals propagating through the capillary network and dynamically channeling red blood cells toward the initiating signal. By controlling blood flow at junctions, contractile pericytes within a functionally distinct postarteriole transitional region maintain the efficiency and effectiveness of the capillary network, enabling optimal perfusion of the brain.

Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant wobbler mice, a model of motor neuron degeneration.

Numerous mutations that impair retrograde membrane trafficking between endosomes and the Golgi apparatus lead to neurodegenerative diseases. For example, mutations in the endosomal retromer complex are implicated in Alzheimer's and Parkinson's diseases, and mutations of the Golgi-associated retrograde protein (GARP) complex cause progressive cerebello-cerebral atrophy type 2 (PCCA2). However, how these mutations cause neurodegeneration is unknown. GARP mutations in yeast, including one causing PCCA2, result in sphingolipid abnormalities and impaired cell growth that are corrected by treatment with myriocin, a sphingolipid synthesis inhibitor, suggesting that alterations in sphingolipid metabolism contribute to cell dysfunction and death. Here we tested this hypothesis in wobbler mice, a murine model with a homozygous partial loss-of-function mutation in Vps54 (GARP protein) that causes motor neuron disease. Cytotoxic sphingoid long-chain bases accumulated in embryonic fibroblasts and spinal cords from wobbler mice. Remarkably, chronic treatment of wobbler mice with myriocin markedly improved their wellness scores, grip strength, neuropathology, and survival. Proteomic analyses of wobbler fibroblasts revealed extensive missorting of lysosomal proteins, including sphingolipid catabolism enzymes, to the Golgi compartment, which may contribute to the sphingolipid abnormalities. Our findings establish that altered sphingolipid metabolism due to GARP mutations contributes to neurodegeneration and suggest that inhibiting sphingolipid synthesis might provide a useful strategy for treating these disorders.

The association of food insecurity with tooth decay and periodontitis among middle-aged and older adults in the United States and Korea.

INTRODUCTION: Food insecurity is an important social determinant of health, but there is limited understanding of its relationship with adult oral health. This study examined the associations between food insecurity and dental diseases (caries and periodontitis) among middle-aged and older adults in the United States and South Korea. METHODS: This study focused on middle-aged (40-59 years) and older adults (>59 years) who participated in the 2011-2016 US National Health and Nutrition Examination Surveys (NHANES) or the 2013-2015 South Korean NHANES. The exposure was food insecurity severity (food secure/early-stage food insecurity/middle-stage or severe food insecurity) assessed using the 18-item US Household Food Security Survey Module. The two outcomes were any untreated tooth decay and periodontitis measured using the Modified Community Periodontal Index of Treatment Needs. Covariate-adjusted odds ratios (OR) with 95% confidence intervals (CI) were generated using multivariable logistic regression models. RESULTS: Middle or severe food insecurity was associated with significantly higher odds of having untreated tooth decay than no food insecurity, but only among middle-aged adults in the United States (OR: 1.4, 95% CI 1.2, 1.9; P = .037) and Korea (OR = 1.8; 95% CI:1.0, 3.2; P = .036) and older adults in the United States (OR: 2.6, 95% CI 1.7, 4.0; P < .001). The associations between food insecurity and periodontitis were inconsistent across age group and country. CONCLUSION: Differing cultural norms and access to dental services in the United States and South Korea may influence the relationship between food insecurity and oral health. Future research should explore how addressing food insecurity could help to promote the oral health of middle-aged and older adults in diverse sociocultural contexts.

The relationship between diurnal cortisol slope and cognitive development among children maltreated as infants.

Little is known about the role of hypothalamic-pituitary-adrenal (HPA) axis functioning for children's cognitive development, especially among vulnerable groups. The current study explores the relationship between diurnal cortisol slope and cognitive outcomes among children at the ages of 5 and 6 who have been maltreated as infants and involved with child protective services, using data from the National Survey of Child and Adolescent Well-Being (NSCAW) I (N=158). Multiple regression analyses showed that a greater decline in salivary cortisol from morning to evening was positively associated with scores on applied problems and expressive communication, even after adjustment for confounding. It was also associated with lower odds of cognitive disability. There were null associations with letter-word identification, passage comprehension, auditory comprehension, matrices, and vocabulary. Results suggest that children involved with child protective services as infants, and thus exposed early to likely 'toxic' levels of stressors, may face dysregulation of the HPA axis and particular difficulties in some aspects of cognitive function. Potential explanations and implications for policy are discussed.