Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation.

Multiple sclerosis (MS) is characterized by pathological inflammation that results from the recruitment of lymphoid and myeloid immune cells from the blood into the brain. Due to subset heterogeneity, defining the functional roles of the various cell subsets in acute and chronic stages of MS has been challenging. Here, we used index and transcriptional single-cell sorting to characterize the mononuclear phagocytes that infiltrate the central nervous system from the periphery in mice with experimentally induced autoimmune encephalomyelitis, a model of MS. We identified eight monocyte and three dendritic cell subsets at acute and chronic disease stages in which the defined transcriptional programs pointed toward distinct functions. Monocyte-specific cell ablation identified Cxcl10+ and Saa3+ monocytic subsets with a pathogenic potential. Transfer experiments with different monocyte and precursor subsets indicated that these Cxcl10+ and Saa3+ pathogenic cells were not derived from Ly6C+ monocytes but from early myeloid cell progenitors. These results suggest that blocking specific pathogenic monocytic subsets, including Cxcl10+ and Saa3+ monocytes, could be used for targeted therapeutic interventions.

Author Correction: Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Publisher Correction: Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ERAP-1 and ERAP-2 Variants in Liver Injury After COVID-19 mRNA Vaccination: A US Multicenter Study.

INTRODUCTION: The aim of this study is to describe the presenting features, genetic factors, and outcomes of 23 adults who developed liver injury after coronavirus disease 2019 (COVID-19) mRNA vaccination. METHODS: Patients with suspected COVID-19 vaccine hepatitis were enrolled into the Drug-Induced Liver Injury Network. Causality was assessed using the Drug-Induced Liver Injury Network expert opinion score. High-resolution HLA sequencing was undertaken using Illumina platform. RESULTS: Amongst the 16 high causality cases, median time to onset was 16 days, median age was 63 years, and 75% were female. The injury was hepatocellular in 75% with a median alanine aminotransferase of 497 U/L, and 37% had jaundice. An antinuclear antibody and smooth muscle antibody were detectable in 27% and 36%, but only 12% had an elevated immunoglobulin G level. During follow-up, 37% received a short course of corticosteroids, and 88% fully recovered by 6 months with no deaths observed. HLA alleles associated with autoimmune hepatitis were not overrepresented compared with controls, but an ERAP-2 variant (rs1263907) and the ERAP-1 Hap6 haplotype were significantly overrepresented in the high causality cases vs controls ( P = 0.026 and 5 × 10 -5 , respectively). DISCUSSION: Acute liver injury may arise within 8 weeks of COVID-19 mRNA vaccination that is generally mild and self-limited in most patients. The absence of an association with the AIH HLA alleles combined with the significant ERAP-2 and ERAP-1 Hap6 haplotype associations implicates a unique but very rare host immune response to vaccine-derived antigens in the pathogenesis of COVID-19 vaccine hepatotoxicity.

Character strength traits, states, and emotional well-being: A daily diary study.

OBJECTIVE: Does whole trait theory work for character strengths? This study examines the daily within- and between-person variability of the manifestations of positively valued lower-order personality characteristics, namely character strengths, their convergence with trait character strengths, and their relationships to daily measures of affect. BACKGROUND: Manifestations of personality traits vary both between- and within people. So far, research has focused on between-person differences in character strengths, while within-person differences have been neglected. METHODS: German-speaking participants (N = 199, 84.3% women; mean age = 26.0 years) participated in a two-week daily diary study. They completed a baseline measure of character strength traits and daily measures of character strength states and positive and negative affect. RESULTS: Results suggested that character strength traits converged well with aggregated states. Further, we observed high within-person variability in most character strengths. The trait-state convergence and the amount of within-person variability were predicted by whether the character strengths were rather phasic (i.e., more dependent on situational characteristics) or rather tonic (i.e., less dependent on situational characteristics). Higher within-person variability in character strengths was related to trait levels of perspective, honesty, social intelligence, and fairness. Regarding relationships between character strengths and affect, within-person associations were widely parallel to previously reported between-person associations and largely independent of trait levels of character strengths. CONCLUSION: These findings inform research on whole trait theory and character-strengths-based interventions.

Functional Independence of Children With Arthrogryposis.

BACKGROUND: Arthrogryposis (AMC) is a descriptive term to characterize a child born with multiple joint contractures. Treatment aims to improve functional independence, yet the literature objectively describing functional independence in this population is scarce. This study aimed to describe the functional independence of children with AMC through the lens of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) and observational activities of daily living (ADL) tasks. METHODS: Patients with AMC between the ages of 3 and 12 years participated in this prospective study. Parents completed the PEDI-CAT while a trained occupational therapist observed children as they completed a checklist of functional ADL tasks. Patients were grouped according to developmental age groups: "preschoolers" (3 to 5 y), "early school-age" (6 to 9 y), and "late school-age" (10 to 12 y). Patient's PEDI-CAT normative scores were described, comparing the study population to typically developing children, and differences in each domain were examined between developmental age groups. The observed ADL tasks completed were also described, and differences in scores were examined between developmental age groups. RESULTS: Forty-four patients (mean age of 7±2.86 y) were enrolled. The distribution between age groups was nearly even. Mean daily activities T -score for patients with AMC was 25.80±11.98 and the mean mobility T -score was 17.39±9.77. Late school-age children scored significantly lower than preschool-age children in both of these domains ( P <0.01). Observed ADL tasks demonstrated a high level of required assistance for patients (range: 27.3% to 61.4%), although older school-age children did show greater independence with tested activities than preschool-age children ( P =0.05). CONCLUSION: Children with AMC are significantly limited in functional independence, particularly regarding age-appropriate daily activities and mobility. Outcomes from this study provide a reference to help gauge the results of nonoperative and surgical treatment toward improving functional independence in this population. LEVEL OF EVIDENCE: Level III: prognostic study.

Association Between End-Stage Liver Disease and Incident Heart Failure in an Integrated Health System.

BACKGROUND: End-stage liver disease (ESLD) and heart failure (HF) often coexist and are associated with significant morbidity and mortality. However, the true incidence of HF among patients with ESLD remains understudied. OBJECTIVE: This study aims to evaluate the association between ESLD and incident HF in a real-world clinical cohort. DESIGN AND PARTICIPANTS: A retrospective electronic health records database analysis of individuals with ESLD and frequency-matched controls without ESLD in a large integrated health system. MAIN MEASURES: The primary outcome was incident HF, which was defined by the International Classification of Disease codes and manually adjudicated by physician reviewers. The Kaplan-Meier method was used to estimate the cumulative incidence of HF. Multivariate proportional hazards models adjusted for shared metabolic factors (diabetes, hypertension, chronic kidney disease, coronary heart disease, body mass index) were used to compare the risk of HF in patients with and without ESLD. KEY RESULTS: Of 5004 patients (2502 with ESLD and 2502 without ESLD), the median (Q1-Q3) age was 57.0 (55.0-65.0) years, 59% were male, and 18% had diabetes. Over a median (Q1-Q3) follow-up of 2.3 (0.6-6.0) years, 121 incident HF cases occurred. Risk for incident HF was significantly higher for patients with ESLD compared with the non-ESLD group (adjusted HR: 4.67; 95% CI: 2.82-7.75; p < 0.001), with the majority of the ESLD group (70.7%) having HF with preserved ejection fraction (ejection fraction ≥ 50%). CONCLUSION: ESLD was significantly associated with a higher risk of incident HF, independent of shared metabolic risk factors, with the predominant phenotype being HF with preserved ejection fraction.

Paragons of character-Character strengths and well-being of moral, creative, and religious exemplars.

OBJECTIVE: Which traits best describe individuals who are recognized as exemplary in different domains? And can self-rated positively valued personality traits distinguish such individuals from the general population? BACKGROUND: The study of exemplary individuals' personality traits traditionally focused on general and broad traits. Using character strengths, which are narrower and designed to describe desirable behavior, could provide new insights. METHOD: In this study, we examined 204 outstanding individuals-exemplars who received or were nominated for a public award recognizing their exemplary behavior (e.g., a Carnegie Rescuers Award; n = 119), individuals holding a patent (n = 62), and individuals living in a religious order (n = 23). We compared these exemplars to comparison samples matched based on demographic variables. All participants completed self-report questionnaires assessing character strengths and well-being (e.g., satisfaction with life). RESULTS: Results showed that the three groups of exemplars differed meaningfully in their character strengths and well-being from the matched comparison groups. Compared with matched counterparts, moral exemplars scored higher on the strengths related to the virtues of courage, humanity, and justice as well as the character strength of humility, creative exemplars scored higher on the character strengths of creativity and honesty, and religious exemplars scored higher on gratitude and spirituality. CONCLUSION: Overall, our findings suggest that character strengths are a useful framework for studying exemplary behavior.

Convergence and Psychometric Properties of Character Strengths Measures: The VIA-IS and the VIA-IS-R.

This study compares the German versions of the original measure of character strengths (VIA-IS) with its latest revision (VIA-IS-R) regarding reliability and convergent, discriminant, and criterion-related validity. A sample of 499 German-speaking adults (79% women, mean age: 33.3 years) provided self-reports of character strengths (VIA-IS, VIA-IS-R) and several criteria: Core virtues, thriving, and moral behaviors. Results suggested that both measures showed satisfactory internal consistency and converged well in a multitrait-multimethod analysis. Further, both measures were comparable regarding their relationships with the criteria. Overall, the results of the current study suggest that both questionnaires are reliable and valid, and that findings based on these instruments can be considered highly comparable.

Cost evaluation of integrating local HIV and housing data to facilitate service coordination in four demonstration sites.

As part of the evaluation of a federal initiative to integrate HIV medical and housing data at four local jurisdictions in the U.S., we estimated the financial costs of implementing data integration occurring from June 2016 to August 2018. We collected data on labor, non-labor, and overhead expenses based on invoices and surveys of staff time, staff compensation, and non-labor expenses. Non-labor expenses were directly charged or allocated to the project using the number of full-time equivalents as the allocation basis. Reported indirect cost rates were used to estimate overhead expenses. Demonstration sites spent an average of $273,656 over the full 27-month period, with an average monthly spending of $10,010 in 2018 U.S. dollars. There was sizable variation in the data integration costs across sites, implementation phases, and data integration models. Findings may help policymakers and potential adopters of similar data integration efforts customize parameters for local conditions and estimate resources required.

Towards understanding oxygen heterocycle-forming biocatalysts: a selectivity study of the pyran synthase PedPS7.

Intramolecular oxa-Michael addition-catalysing cyclases are widespread in polyketide biosynthetic pathways. Although they have significant potential in biotechnology and chemoenzymatic synthesis of chiral heterocycles, they have only scarcely been studied. Here, we present detailed investigations on the selectivity profile of the pyran synthase PedPS7 showing that it combines broad substrate tolerance with high selectivity for the formation of up to two new stereocentres and relaxed precursor stereoisomer discrimination. Two of the four possible tetrahydropyran stereoisomers are reliably accessible by this enzyme. The results indicate fundamental differences between the individual subtypes of intramolecular oxa-Michael addition-catalysing cyclases.

Character strengths and fluid intelligence.

OBJECTIVE: Research on the associations between cognitive and noncognitive personality traits has widely neglected character strengths, that means positively and morally valued personality traits that constitute good character. METHOD: The present study aimed to bridge this gap by studying the associations between character strengths and fluid intelligence using different operationalizations of character strengths (including self- and informant-reports) and fluid intelligence in children, adolescents, and adults. RESULTS: The results, based on four samples (N = 193/290/330/324), suggested that morally valued personality traits are independent of fluid intelligence, with the exception of love of learning, which showed small but robust positive relationships with fluid intelligence across all samples. CONCLUSIONS: Nonetheless, we argue for further research on the associations with other cognitive abilities and interactions between character strengths and intelligence when examining their relationships with external criteria.

Patient-reported Outcomes for Children With Unilateral Congenital Below Elbow Deficiency.

BACKGROUND: The Patient Reported Outcomes Measurement Information System (PROMIS ® ) is a validated tool used to evaluate different domains of function in patients with chronic health conditions. This tool has not been validated in children with unilateral congenital below elbow deficiency (UCBED). The purpose of this study was to determine whether PROMIS discerns functional impairment for children with UCBED and whether children with UCBED differ from the general population with respect to PROMIS outcomes. We hypothesized that children with UCBED report mild impairment in upper extremity function but normal mobility, pain interference and peer relations. METHODS: A retrospective chart review of children aged 5 to 17 years with a diagnosis of UCBED who completed a PROMIS questionnaire at their clinic visit at the [blinded locations] was conducted between April 1, 2017 and March 31, 2020. The mean PROMIS scores of UCBED patients were compared with that of the general reference population. Mann Whitney and ANOVA tests were used to explore the differences across the PROMIS upper extremity function domain by arm length and prosthesis use. RESULTS: Fifty-five children (28 boys) with a mean age of 11±3.6 years met the inclusion criteria. Children with UCBED had similar PROMIS scores as the reference population in mobility (51.9±6.2), peer relations (53.5±9.4), and pain interference (40.1±7.2), with mild impairment in the upper extremity function (44.3±10.7). Compared with the 8 to 17-year-old cohort, the parent-proxy (5 to 7-year-old group) reported significantly more upper extremity function impairment (31.3±5.9) vs (48.0±8.8) ( P =0.000). The two age groups did not differ with respect to mobility, pain interference and peer relations. CONCLUSIONS: Our study confirms previous findings that children with UCBED report upper extremity function, peer relationships, pain interference, and mobility, similar to the reference population. In addition, parents of younger children with UCBED report more upper extremity functional impairment than is self-reported by older children with UCBED. LEVEL OF EVIDENCE: Prognostic Level III (comparison with reference population).

Rehabilitation across the lifespan for individuals with arthrogryposis.

Arthrogryposis multiplex congenita (AMC) can be a perplexing diagnosis that consists of limited range of motion (ROM) and decreased muscle strength in multiple joints. The person with AMC often possesses a certain tenacity and "spunk" that assists them with adjusting and adapting to the realities of daily life. The rehabilitation process assists the individual with AMC in achieving and maintaining the maximal active and passive range of motion and strength in order to participate in activities of daily living (ADL) throughout the developmental stages. The result of this life-long process is greatly impacted by collaboration among the multidisciplinary teams. Ultimately, rehabilitation should focus on three levels of treatment: (a) body structure, (b) activity, and (c) participation. This article describes rehabilitation across the lifespan-focusing on the therapeutic needs in the infant, toddler, school age and teenage/adult years-while also highlighting opportunities for improvement.

Insights into the Dual Activity of a Bifunctional Dehydratase-Cyclase Domain.

Oxygen-containing heterocycles are a common structural motif in polyketide natural products and contribute significantly to their biological activity. Here, we report structural and mechanistic investigations on AmbDH3, a polyketide synthase domain with dual activity as dehydratase (DH) and pyran-forming cyclase in ambruticin biosynthesis. AmbDH3 is similar to monofunctional DH domains, using H51 and D215 for dehydration. V173 was confirmed as a diagnostic residue for cyclization activity by a mutational study and enzymatic in vitro experiments. Similar motifs were observed in the seemingly monofunctional AmbDH2, which also shows an unexpected cyclase activity. Our results pave the way for mining of hidden cyclases in biosynthetic pathways. They also open interesting prospects for the generation of novel biocatalysts for chemoenzymatic synthesis and pyran-polyketides by combinatorial biosynthesis.

Testing the Situationism Scale in Europe: Scale validation, self-regulation and regional differences.

The term situationism refers to an individual's belief about the importance of a behaviour's context. This study tested whether the degree of situationism expressed by individuals in various regions of Europe was consistent with self-regulation and cross-cultural theories. The English version of a Situationism Scale (measuring beliefs about the relation between the environment and one's own behaviour) was translated into five additional languages: Dutch, German, Hungarian, Italian and Slovenian. Young adults (N = 1106, MAge = 22.9 years, 79% female) across Europe responded to one of the six language versions of the scale as part of a larger survey. Results indicated that: new language versions were psychometrically valid; there was a positive relation between situationism and the use of situation-control strategies; and situationism was higher for individuals from regions that are Eastern European and relatively more interdependent, compared with individuals from regions that are Western European and relatively less interdependent. As the first evaluation of the Situationism Scale outside America, this study supports the Scale's validity and suggests not only may some effects of situationism be universal, but between- and within-culture differences in situationism exist. Overall, when making judgments and decisions about the self, cultural background and individual differences in situationism may come into play.

Selective Control of the Upper Extremity Scale: validation of a clinical assessment tool for children with hemiplegic cerebral palsy.

AIM: The ability to determine the relationship between selective motor control and upper extremity function in children with unilateral cerebral palsy (CP), and to measure the functional outcome and efficacy of interventions designed to improve selective motor control, has been limited by the lack of an objective, validated tool. The primary objective of this study is to describe the development of a clinical tool entitled Selective Control of the Upper Extremity Scale (SCUES), and present evidence of its validity and reliability. METHOD: Content validity was established through an expert panel (eight clinicians, mean and median of 17y of clinical experience, range 2-30y). Intra- and interrater reliability was determined by six occupational therapists who scored 10 participant studies. Construct validity of the SCUES was established by comparison to the spontaneous functional analysis section of the Shriners Hospitals Upper Extremity Evaluation, the Manual Ability Classification System, and the Box and Block test for 25 children with unilateral CP. RESULTS: The content validity ratio values were greater than 0 (indicating >50% agreement) for 33 of the 34 items (97%), and equal or greater than 0.5 (indicating ≥75% agreement) for 26 of the 34 items (76%). Intrarater reliability was excellent (intraclass correlation coefficient [ICC] >0.75) for all segments and joints of the affected extremity. Interrater reliability was excellent for all segments and joints of the affected extremity except the shoulder (ICC=0.72). The SCUES was strongly correlated with the SHUEE (Spearman's rho=0.69, p=0.003). The SCUES was not correlated with the Manual Ability Classification System (rho=-0.24, p=0.369) or the Box and Block test (rho=0.47, p=0.066). INTERPRETATION: Psychometric analysis of the SCUES revealed comparable validity to other accepted video-based clinical assessment tools for the upper extremity in children with CP.

WIC Peer Counselors Support Breastfeeding Among WIC Participants.

BACKGROUND: The Special Supplemental Nutrition Program for Women, Infants, and Children, also known as WIC, is associated with improved health outcomes for participants. The role of WIC Peer Counselors was created to support breastfeeding among WIC participants. OBJECTIVE: This Naturalistic Inquiry study explored the perceptions and experiences of 9 WIC Peer Counselors located in Southeast Texas. METHODS: The WIC Peer Counselors were recruited via purposive and snowball sampling and participated in semi-structured face-to-face interviews. Data collection, analysis, and trustworthiness adhered to established guidelines. RESULTS: Study findings revealed the novel approaches the WIC Peer Counselors used to encourage, initiate, support, and sustain WIC participants' breastfeeding, including using tools of their craft, involving and educating family members, making themselves accessible 24/7, and identifying the need for equipment and supplies. CONCLUSIONS: The WIC Peer Counselors' understanding of the breastfeeding culture of their WIC clients and their unique ability to establish and maintain rapport with them make WIC Peer Counselors ideally suited resources to meet the WIC goal of increasing breastfeeding and thereby improving the health of the nation. Health care providers should recognize the valuable, yet unrecognized and underutilized, contributions of WIC Peer Counselors and consider referring pregnant and postpartum dyads to WIC for breastfeeding education and support.

Reduced bacterial load in stallion semen by modified single layer centrifugation or sperm washing.

The presence of bacteria poses a significant challenge to the quality of stallion semen used in artificial insemination. The bacterial content of insemination doses arises from various sources, such as the healthy stallion, environment, and collection equipment, and is implicated in fertility problems as well as reduced sperm quality during storage. The conventional approach of adding antibiotics to semen extenders raises concerns about antimicrobial resistance and potential negative effects on sperm characteristics, and may not be effective in inhibiting all bacteria. The objective of this study was to determine whether an innovative alternative to antibiotic usage - centrifugation through a single layer of a low density colloid (SLC) - could reduce the bacterial load in stallion semen, and to compare sperm characteristics in samples arising from this procedure, or simple extension of the ejaculate in semen extender, or from sperm washing, i.e. adding extender and then centrifuging the sample to allow the removal of most of the seminal plasma and extender. Eighteen semen samples were collected from six stallions. The semen samples were split and extended prior to washing or SLC, or received no further treatment other than extension. After preparation aliquots from each type of sample were sent for bacteriological examination; the remaining samples were stored for up to 72 h, with daily checks on sperm quality. The low density colloid SLC outperformed sperm washing or extension for bacterial reduction, effectively removing several bacterial species. The bacterial load in the samples was as follows: extended semen, 16 ± 6.7 × 105; washed, 5.8 ± 2.0 × 105; SLC, 2.3 ± 0.88 × 105, p < 0.0001. In addition, SLC completely removed some bacterial species, such as Staphylococcus xylosus. Although there is no selection for robust spermatozoa with the low density colloid, sperm motility, membrane integrity, and DNA fragmentation were not different to washed sperm samples. These findings suggest that SLC with a low density colloid offers a promising method for reducing bacterial contamination in stallion semen without resorting to antibiotics.

Do stigma and efficacy mediate the association between training and suicide prevention behavior among Army noncommissioned officers?

INTRODUCTION: Rates of suicide in the Active Component of the military have significantly increased since 2010, with particularly high rates among Army service members. One element of the Army's approach to suicide prevention relies on noncommissioned officers (NCOs) as gatekeepers who have regular contact with soldiers. NCOs receive suicide prevention training, but there is limited evidence that such training leads to behavior change. METHODS: We surveyed 2468 Army NCOs participating in leadership development courses to determine (a) if training on suicide prevention and soft skills (e.g., active listening) was associated with gatekeeper behavior and use of soft skills; and (b) whether that association was explained by two potential barriers, stigma and perceptions of efficacy. RESULTS: Both the number of suicide prevention training topics and soft skills trained were associated with increased gatekeeper behavior; these relationships were explained in part by lower stigma and higher efficacy for use of soft skills. The use of interactive training methods and receiving coaching after training were not associated with stigma or efficacy, though both methods were associated with more frequent use of soft skills. CONCLUSION: Results suggest that the content and format of training is important to preparing NCOs to fulfill a gatekeeper role.