Novel use of Siltuximab in a patient with VEXAS Syndrome.

VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an increasingly recognized disorder that occurs due to somatic mutations of a ubiquitin-activating enzyme encoded by ubiquitin-like modifier activating enzyme 1 gene, UBA1. Clinical findings associated with VEXAS syndrome include recurrent fevers, polychondritis, periorbital edema, pleural effusions, myocarditis and/or pericarditis, hepatosplenomegaly, myelodysplastic syndrome, cytopenias, inflammatory arthritis, neutrophilic dermatosis, and deep venous thrombosis. Novel renal manifestations like interstitial nephritis are infrequent, and to our knowledge, acute renal failure due to C3 glomerulonephritis (C3GN) has not yet been reported. Overwhelming systemic inflammation can result in morbid end-organ damage and death. While there is no formal guideline or established protocol for its management, treatment of VEXAS syndrome with tocilizumab, an interleukin-6 (IL-6)-directed therapy, has been described in the literature. Here, we report a case of a 71-year-old male patient presenting with C3GN as an initial manifestation of VEXAS syndrome and explore the rationale for our approach to treatment with IL-6 blockade. Our patient was initially treated with two inpatient doses of tocilizumab with successful transition to siltuximab in the outpatient setting. He continues to benefit from ongoing siltuximab treatment for more than one year to date without any safety issues or relapse of VEXAS syndrome.

Birth Prevalence of Sickle Cell Disease and County-Level Social Vulnerability - Sickle Cell Data Collection Program, 11 States, 2016-2020.

Sickle cell disease (SCD) remains a public health priority in the United States because of its association with complex health needs, reduced life expectancy, lifelong disabilities, and high cost of care. A cross-sectional analysis was conducted to calculate the crude and race-specific birth prevalence for SCD using state newborn screening program records during 2016-2020 from 11 Sickle Cell Data Collection program states. The percentage distribution of birth mother residence within Social Vulnerability Index quartiles was derived. Among 3,305 newborns with confirmed SCD (including 57% with homozygous hemoglobin S or sickle ß-null thalassemia across 11 states, 90% of whom were Black or African American [Black], and 4% of whom were Hispanic or Latino), the crude SCD birth prevalence was 4.83 per 10,000 (one in every 2,070) live births and 28.54 per 10,000 (one in every 350) non-Hispanic Black newborns. Approximately two thirds (67%) of mothers of newborns with SCD lived in counties with high or very high levels of social vulnerability; most mothers lived in counties with high or very high levels of vulnerability for racial and ethnic minority status (89%) and housing type and transportation (64%) themes. These findings can guide public health, health care systems, and community program planning and implementation that address social determinants of health for infants with SCD. Implementation of tailored interventions, including increasing access to transportation, improving housing, and advancing equity in high vulnerability areas, could facilitate care and improve health outcomes for children with SCD.

Adolescents' perceptions of family social status correlate with health and life chances: A twin difference longitudinal cohort study.

Children from lower-income households are at increased risk for poor health, educational failure, and behavioral problems. This social gradient is one of the most reproduced findings in health and social science. How people view their position in social hierarchies also signals poor health. However, when adolescents' views of their social position begin to independently relate to well-being is currently unknown. A cotwin design was leveraged to test whether adolescents with identical family backgrounds, but who viewed their family's social status as higher than their same-aged and sex sibling, experienced better well-being in early and late adolescence. Participants were members of the Environmental Risk Longitudinal Twin Study, a representative cohort of British twins (n = 2,232) followed across the first 2 decades of life. By late adolescence, perceptions of subjective family social status (SFSS) robustly correlated with multiple indicators of health and well-being, including depression; anxiety; conduct problems; marijuana use; optimism; not in education, employment, or training (NEET) status; and crime. Findings held controlling for objective socioeconomic status both statistically and by cotwin design after accounting for measures of childhood intelligence (IQ), negative affect, and prior mental health risk and when self-report, informant report, and administrative data were used. Little support was found for the biological embedding of adolescents' perceptions of familial social status as indexed by inflammatory biomarkers or cognitive tests in late adolescence or for SFSS in early adolescence as a robust correlate of well-being or predictor of future problems. Future experimental studies are required to test whether altering adolescents' subjective social status will lead to improved well-being and social mobility.

Discrimination in healthcare as a barrier to care: experiences of socially disadvantaged populations in France from a nationally representative survey.

BACKGROUND: People in socially disadvantaged groups face a myriad of challenges to their health. Discrimination, based on group status such as gender, immigration generation, race/ethnicity, or religion, are a well-documented health challenge. However, less is known about experiences of discrimination specifically within healthcare settings, and how it may act as a barrier to healthcare. METHODS: Using data from a nationally representative survey of France (N = 21,761) with an oversample of immigrants, we examine rates of reported discrimination in healthcare settings, rates of foregoing healthcare, and whether discrimination could explain disparities in foregoing care across social groups. RESULTS: Rates of both reporting discrimination within healthcare and reporting foregone care in the past 12 months were generally highest among women, immigrants from Africa or Overseas France, and Muslims. For all of these groups, experiences of discrimination potentially explained significant proportions of their disparity in foregone care (Percent disparity in foregone care explained for: women = 17%, second-generation immigrants = 8%, Overseas France = 13%, North Africa = 22%, Sub-Saharan Africa = 32%, Muslims = 26%). Rates of foregone care were also higher for those of mixed origin and people who reported "Other Religion", but foregone healthcare was not associated with discrimination for those groups. CONCLUSIONS: Experiences of discrimination within the healthcare setting may present a barrier to healthcare for people that are socially disadvantaged due to gender, immigration, race/ethnicity, or religion. Researchers and policymakers should consider barriers to healthcare that lie within the healthcare experience itself as potential intervention targets.

Evaluating the Use of Commercially Available Wearable Wristbands to Capture Adolescents' Daily Sleep Duration.

Commercially available wearable devices are marketed as a means of objectively capturing daily sleep easily and inexpensively outside of the laboratory. Two ecological momentary assessment studies-with 120 older adolescents (aged 18-19) and 395 younger adolescents (aged 10-16)-captured nightly self-reported and wearable (Jawbone) recorded sleep duration. Self-reported and wearable recorded daily sleep duration were moderately correlated (r ~ .50), associations which were stronger on weekdays and among young adolescent boys. Older adolescents self-reported sleep duration closely corresponded with estimates from the wearable device, but younger adolescents reported having an hour more of sleep, on average, compared to device estimates. Self-reported, but not wearable-recorded, sleep duration and quality were consistently associated with daily well-being measures. Suggestions for the integration of commercially available wearable devices into future daily research with adolescents are provided.

The high societal costs of childhood conduct problems: evidence from administrative records up to age 38 in a longitudinal birth cohort.

BACKGROUND: Children with conduct problems that persist into adulthood are at increased risk for future behavioral, health, and social problems. However, the longer term public service usage among these children has not been fully documented. To aid public health and intervention planning, adult service usage across criminal justice, health care, and social welfare domains is compared among all individuals from a representative cohort who followed different conduct problem trajectories from childhood into adulthood. METHODS: Participants are from the Dunedin Multidisciplinary Health and Development Study, a prospective, representative cohort of consecutive births (N = 1,037) from April 1972 to March 1973 in Dunedin, New Zealand. Regression analyses were used to compare levels of public service usage up to age 38, gathered via administrative and electronic medical records, between participants who displayed distinct subtypes of childhood conduct problems (low, childhood-limited, adolescent-onset, and life-course persistent). RESULTS: Children exhibiting life-course persistent conduct problems used significantly more services as adults than those with low levels of childhood conduct problems. Although this group comprised only 9.0% of the population, they accounted for 53.3% of all convictions, 15.7% of emergency department visits, 20.5% of prescription fills, 13.1% of injury claims, and 24.7% of welfare benefit months. Half of this group (50.0%) also accrued high service use across all three domains of criminal justice, health, and social welfare services, as compared to only 11.3% of those with low conduct problems (OR = 7.27, 95% CI = 4.42-12.0). CONCLUSIONS: Conduct problems in childhood signal high future costs in terms of service utilization across multiple sectors. Future evaluations of interventions aimed at conduct problems should also track potential reductions in health burden and service usage that stretch into midlife.

Interferon-γ mediates chemokine-dependent recruitment of natural killer cells during viral infection.

Natural killer (NK) cells provide in vivo control of orthopoxvirus infections in association with their expansion in the draining lymph node (LN), where they are normally very rare. The mechanism of this expansion is unclear. Herein, we determined that NK-cell depletion results in enhanced infection following footpad inoculation of cowpox virus, a natural pathogen of rodents. Following cowpox virus infection in normal mice, NK cells were greatly expanded in the draining LN, were not replicating, and displayed markers similar to splenic NK cells, suggesting specific recruitment of splenic NK cells rather than in situ proliferation. Moreover, NK-cell expansion was abrogated by prior injection of clodronate-loaded liposomes, indicating a role for subcapsular sinus macrophages. Furthermore, recruitment of transferred splenic NK cells to the draining LN was pertussis toxin-sensitive, suggesting involvement of chemokine receptors. Comprehensive analysis of chemokine mRNA expression in the draining LN following infection suggested the selective involvement of CCR2, CCR5, and/or CXCR3. Mice deficient for CCR2 or CCR5 had normal NK-cell recruitment, whereas CXCR3-deficient mice displayed a major defect, which was NK cell-intrinsic. Interestingly, both induction of transcripts for CXCR3 ligands (Cxcl9 and Cxcl10) and NK-cell recruitment required IFN-γ. These data indicate that NK-cell recruitment is mediated by subcapsular sinus macrophages, IFN-γ, and CXCR3 during orthopoxvirus infection.

Viral MHC class I inhibition evades CD8+ T-cell effector responses in vivo but not CD8+ T-cell priming.

Although viral MHC class I inhibition is considered a classic immune-evasion strategy, its in vivo role is largely unclear. Mutant cowpox virus lacking its MHC class I inhibitors is markedly attenuated during acute infection because of CD8(+) T-cell-dependent control, but it was not known how CD8(+) T-cell responses are affected. Interestingly, we found no major effect of MHC class I down-regulation on priming of functional cowpox virus-specific CD8(+) T cells. Instead, we demonstrate that, during acute infection in vivo, MHC class I down-regulation prevents primed virus-specific CD8(+) T cells from recognizing infected cells and exerting effector responses to control the infection.

Functional interactions between starch synthase III and isoamylase-type starch-debranching enzyme in maize endosperm.

This study characterized genetic interactions between the maize (Zea mays) genes dull1 (du1), encoding starch synthase III (SSIII), and isa2, encoding a noncatalytic subunit of heteromeric isoamylase-type starch-debranching enzyme (ISA1/ISA2 heteromer). Mutants lacking ISA2 still possess the ISA1 homomeric enzyme. Eight du1(-) mutations were characterized, and structural changes in amylopectin resulting from each were measured. In every instance, the same complex pattern of alterations in discontinuous spans of chain lengths was observed, which cannot be explained solely by a discrete range of substrates preferred by SSIII. Homozygous double mutants were constructed containing the null mutation isa2-339 and either du1-Ref, encoding a truncated SSIII protein lacking the catalytic domain, or the null allele du1-R4059. In contrast to the single mutant parents, double mutant endosperms affected in both SSIII and ISA2 were starch deficient and accumulated phytoglycogen. This phenotype was previously observed only in maize sugary1 mutants impaired for the catalytic subunit ISA1. ISA1 homomeric enzyme complexes assembled in both double mutants and were enzymatically active in vitro. Thus, SSIII is required for normal starch crystallization and the prevention of phytoglycogen accumulation when the only isoamylase-type debranching activity present is ISA1 homomer, but not in the wild-type condition, when both ISA1 homomer and ISA1/ISA2 heteromer are present. Previous genetic and biochemical analyses showed that SSIII also is required for normal glucan accumulation when the only isoamylase-type debranching enzyme activity present is ISA1/ISA heteromer. These data indicate that isoamylase-type debranching enzyme and SSIII work in a coordinated fashion to repress phytoglycogen accumulation.

Functions of heteromeric and homomeric isoamylase-type starch-debranching enzymes in developing maize endosperm.

Functions of isoamylase-type starch-debranching enzyme (ISA) proteins and complexes in maize (Zea mays) endosperm were characterized. Wild-type endosperm contained three high molecular mass ISA complexes resolved by gel permeation chromatography and native-polyacrylamide gel electrophoresis. Two complexes of approximately 400 kD contained both ISA1 and ISA2, and an approximately 300-kD complex contained ISA1 but not ISA2. Novel mutations of sugary1 (su1) and isa2, coding for ISA1 and ISA2, respectively, were used to develop one maize line with ISA1 homomer but lacking heteromeric ISA and a second line with one form of ISA1/ISA2 heteromer but no homomeric enzyme. The mutations were su1-P, which caused an amino acid substitution in ISA1, and isa2-339, which was caused by transposon insertion and conditioned loss of ISA2. In agreement with the protein compositions, all three ISA complexes were missing in an ISA1-null line, whereas only the two higher molecular mass forms were absent in the ISA2-null line. Both su1-P and isa2-339 conditioned near-normal starch characteristics, in contrast to ISA-null lines, indicating that either homomeric or heteromeric ISA is competent for starch biosynthesis. The homomer-only line had smaller, more numerous granules. Thus, a function of heteromeric ISA not compensated for by homomeric enzyme affects granule initiation or growth, which may explain evolutionary selection for ISA2. ISA1 was required for the accumulation of ISA2, which is regulated posttranscriptionally. Quantitative polymerase chain reaction showed that the ISA1 transcript level was elevated in tissues where starch is synthesized and low during starch degradation, whereas ISA2 transcript was relatively abundant during periods of either starch biosynthesis or catabolism.

Perceived social status and mental health among young adolescents: Evidence from census data to cellphones.

Adolescents in the United States live amid high levels of concentrated poverty and increasing income inequality. Poverty is robustly linked to adolescents' mental health problems; however, less is known about how perceptions of their social status and exposure to local area income inequality relate to mental health. Participants consisted of a population-representative sample of over 2,100 adolescents (ages 10-16), 395 of whom completed a 14-day ecological momentary assessment (EMA) study. Participants' subjective social status (SSS) was assessed at the start of the EMA, and mental health symptoms were measured both at baseline for the entire sample and daily in the EMA sample. Adolescents' SSS tracked family, school, and neighborhood economic indicators (|r| ranging from .12 to .30), and associations did not differ by age, race, or gender. SSS was independently associated with mental health, with stronger associations among older (ages 14-16) versus younger (ages 10-13) adolescents. Adolescents with lower SSS reported higher psychological distress and inattention problems, as well as more conduct problems, in daily life. Those living in areas with higher income inequality reported significantly lower subjective social status, but this association was explained by family and neighborhood income. Findings illustrate that adolescents' SSS is correlated with both internalizing and externalizing mental health problems, and that by age 14 it becomes a unique predictor of mental health problems. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A survey of healthcare-seeking practices and related stigma among community- and street-based children in Cambodia.

Background: Globally, street children comprise a growing population of vulnerable children. Understanding how they interact with healthcare systems is fundamental to efforts to improve their health and well-being. Methods: We surveyed 75 street- and community-based children in Battambang, Cambodia regarding their healthcare-seeking practices and related stigma. Results: For demographically similar street and community children, hospitals and pharmacies were preferred healthcare institutions, with this choice being motivated by the caretaker's decision or cost. Street children reported increased fear of being refused treatment. Conclusions: Street children and demographically similar community children have similar healthcare-seeking practices and preferences, although street children face increased stigmatization.