Characterisation of transgenic pigs expressing a human T cell-depleting anti-CD2 monoclonal antibody.

BACKGROUND: Pig islet xenotransplantation is a potential treatment for type 1 diabetes. We have shown that maintenance immunosuppression is required to protect genetically modified (GM) porcine islet xenografts from T cell-mediated rejection in baboons. Local expression of a depleting anti-CD2 monoclonal antibody (mAb) by the xenograft may provide an alternative solution. We have previously reported the generation of GGTA1 knock-in transgenic pigs expressing the chimeric anti-CD2 mAb diliximab under an MHC class I promoter (MHCIP). In this study, we generated GGTA1 knock-in pigs in which MHCIP was replaced by the ß-cell-specific porcine insulin promoter (PIP), and compared the pattern of diliximab expression in the two lines. METHODS: A PIP-diliximab knock-in construct was prepared and validated by transfection of NIT-1 mouse insulinoma cells. The construct was knocked into GGTA1 in wild type (WT) porcine fetal fibroblasts using CRISPR, and knock-in cells were used to generate pigs by somatic cell nuclear transfer (SCNT). Expression of the transgene in MHCIP-diliximab and PIP-diliximab knock-in pigs was characterised at the mRNA and protein levels using RT-qPCR, flow cytometry, ELISA and immunohistochemistry. Islets from MHCIP-diliximab and control GGTA1 KO neonatal pigs were transplanted under the kidney capsule of streptozotocin-diabetic SCID mice. RESULTS: NIT-1 cells stably transfected with the PIP-diliximab knock-in construct secreted diliximab into the culture supernatant, confirming correct expression and processing of the mAb in ß cells. PIP-diliximab knock-in pigs showed a precise integration of the transgene within GGTA1. Diliximab mRNA was detected in all tissues tested (spleen, kidney, heart, liver, lung, pancreas) in MHCIP-diliximab pigs, but was not detectable in PIP-diliximab pigs. Likewise, diliximab was present in the serum of MHCIP-diliximab pigs, at a mean concentration of 1.8 µg/mL, but was not detected in PIP-diliximab pig serum. An immunohistochemical survey revealed staining for diliximab in all organs of MHCIP-diliximab pigs but not of PIP-diliximab pigs. Whole genome sequencing (WGS) of a PIP-diliximab pig identified a missense mutation in the coding region for the dixilimab light chain. This mutation was also found to be present in the fibroblast knock-in clone used to generate the PIP-diliximab pigs. Islet xenografts from neonatal MHCIP-diliximab pigs restored normoglycemia in diabetic immunodeficient mice, indicating no overt effect of the transgene on islet function, and demonstrated expression of diliximab in situ. CONCLUSION: Diliximab was widely expressed in MHCIP-diliximab pigs, including in islets, consistent with the endogenous expression pattern of MHC class I. Further investigation is required to determine whether the level of expression in islets from the MHCIP-diliximab pigs is sufficient to prevent T cell-mediated islet xenograft rejection. The unexpected absence of diliximab expression in the islets of PIP-diliximab pigs was probably due to a mutation in the transgene arising during the generation of the knock-in cells used for SCNT.

Concurrent, Convergent, and Discriminant Validity of the DSM-5 Section III Psychopathy Specifier.

Section III of the fifth iteration of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) includes an alternative model of personality disorder diagnosis that conceptualizes antisocial personality disorder as an interpersonal, rather than behavioral, construct. However, the diagnostic specifier for psychopathy has been met with recent controversy due to its conceptual and empirical overlap with triarchic boldness, which has been debated as a necessary and sufficient domain of psychopathy. This study examined the concurrent, convergent, and discriminant validity of the specifier using canonical correlation analysis in samples of undergraduate students (N = 224) and community adults with prior criminal involvement (N = 306). Findings highlight the specifier as a multidimensional construct with divergent associations across its three facets. There was limited validity evidence for two of the three facets, raising concerns regarding the clinical utility of the psychopathy specifier.

Increasing the Utility of the Comprehensive Assessment of Psychopathic Personality-Lexical Rating Scale (CAPP-LRS): Instrument Adaptation and Simplification.

The Comprehensive Assessment of Psychopathic Personality-Lexical Rating Scale (CAPP-LRS) is a self-report instrument designed to index psychopathy according to the CAPP psychopathy framework. Developed with the expressed goal of advancing the state of knowledge regarding the specific features of psychopathy, the CAPP model and associated instruments have garnered increasing attention and support in the field. Despite the conceptual strength of the CAPP model, the advanced lexical structure of its primary research tool (the CAPP-LRS) has led researchers to question the utility of the instrument for use with some populations of interest (e.g., forensic/correctional and adolescent/young adult samples). The aim of the present work was to address this issue by creating a lexically simplified, though functionally equivalent, version of the CAPP-LRS to increase accessibility to critically relevant populations. A set of two studies (N = 602) describes the adaptation protocol and the initial validation of the modified instrument.

Content Validation of the Comprehensive Assessment of Psychopathic Personality-Basic Version (CAPP-Basic) Using Prototypical Analysis.

The Comprehensive Assessment of Psychopathic Personality (CAPP) is a lexically based conceptual model of psychopathy. Despite widespread use in research settings, the Lexical Rating Scale for the CAPP (CAPP-LRS) requires an advanced reading level for completion. The present study is the first to evaluate the content validity of the CAPP-Basic, a lexically simplified version of the CAPP-LRS designed for use with individuals possessing lower verbal skills. Symptoms were rated by mental health professionals (N = 121). Findings were largely in line with results of previous studies, indicating good content validity of the CAPP-Basic at the domain and symptom level.

Maternal depressed mood and child development over the first five years of life in South Africa.

BACKGROUND: While the negative impact of peri-natal depression is well-documented in high-income countries, the long-term effects across the life course in low and middle-income countries is less clear. Children's adjustment over the first five years is examined as a function of patterns of maternal depressed mood. METHODS: Pregnant women in 24 peri-urban townships (N = 1,238) were randomized to a home-visiting intervention or standard care and reassessed five times, with high retention. There were no intervention effects on children past 18 months. Multilevel regression models examined the impact of depressed mood on child outcomes. Using the Edinburgh Postnatal Depression Scale, four patterns of maternal depressed mood were identified: never (40.6%); antenatal (13.0%); early childhood (26.1%); and recurrent episodes of depressed mood (20.3 %). FINDINGS: Mothers' patterns of depressive symptoms and child outcomes were similar, regardless of intervention. Never depressed mothers were significantly younger, had higher income, less food insecurity, were more likely to have electricity, be living with HIV or have an HIV positive partner, and had fewer problems with alcohol than depressed mothers. Children of mothers who experienced depressed mood weighed less, were more aggressive, and were hospitalized more often than children of never depressed mothers, but were similar in cognitive and social development. INTERPRETATIONS: Depressed mood, has significant negative impacts on South African children's growth and aggressive behavior. The timing of maternal depressed mood was less important than never having a depressed mood or a recurrent depressed mood. FUNDING: There were no funding conflicts in executing this trial.

Construct Validity of the Comprehensive Assessment of Psychopathic Personality (CAPP): Examining the Internal Structure and Generalizability of CAPP Self-Ratings Across Gender and Ethnicity.

The Comprehensive Assessment of Psychopathic Personality (CAPP) is a recently developed conceptual model of psychopathy designed to index the disorder across 33 personality traits. Although recent research has evidenced support for the CAPP model with respect to the convergent, criterion, and predictive validity of CAPP instruments, little work has examined the optimal internal structure and generalizability of the model and associated measures. The present study sought to elaborate on the construct validity and psychometric properties of the CAPP Lexical Self Rating Scale and determine the utility of the instrument across men and women, and individuals of Caucasian and East Asian descent. Within a large sample of self-identified offenders (N = 1,414), we found strong support for a three-factor model comprising domains reflecting interpersonal dominance, behavioral disinhibition, and deficient emotional attachment. Analyses examining the generalizability of the model provide further insight into its applicability for diverse populations.

Do Community Structural Characteristics Moderate the Association Between Mental Health and the Frequency and Severity of Violent-Behavioral Outcomes in Community Respondents?

In this prospective study, we examined the association between three types of mental health symptom clusters (i.e., psychotic, internalizing, and externalizing) and the frequency and severity of violent-behavioral outcomes, and whether community disadvantage, residential instability, and criminogenic facility density moderated these associations. Study data were derived from 258 community-dwelling adults nested in 60 postal forward sortation areas (FSAs) in a large metropolitan area in Western Canada who were assessed twice over a 6-month period. In addition, census and administrative data were obtained on the same areas. Controlling for sociodemographic characteristics (i.e., age, gender, ethnicity, relationship status, and employment status), lifetime history of violent-behavioral outcomes, and community structural characteristics, internalizing and externalizing mental health symptoms were significantly positively associated with the frequency and severity of subsequent violence perpetration and with the severity of subsequent violent victimization. Several significant interactions were observed: internalizing symptoms increased the risk of frequent and severe violence perpetration in FSAs with high but not low disadvantage, and externalizing symptoms increased the risk of frequent violent victimization in FSAs with a high but not low criminogenic facility density. Only the interactive association of internalizing symptoms and community disadvantage with the severity of violence perpetration, however, remained significant after Bonferroni correction was applied. These findings provide tentative support that associations between mental health and violent-behavioral outcomes can vary with community context. The implication of these findings for assessing and managing violent-behavioral outcomes in the community is discussed.

Suptavumab for the Prevention of Medically Attended Respiratory Syncytial Virus Infection in Preterm Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of childhood medically attended respiratory infection (MARI). METHODS: We conducted a randomized, double-blind, placebo-controlled phase 3 trial in 1154 preterm infants of 1 or 2 doses of suptavumab, a human monoclonal antibody that can bind and block a conserved epitope on RSV A and B subtypes, for the prevention of RSV MARI. The primary endpoint was proportion of subjects with RSV-confirmed hospitalizations or outpatient lower respiratory tract infection (LRTI). RESULTS: There were no significant differences between primary endpoint rates (8.1%, placebo; 7.7%, 1-dose; 9.3%, 2-dose). Suptavumab prevented RSV A infections (relative risks, .38; 95% confidence interval [CI], .14-1.05 in the 1-dose group and .39 [95% CI, .14-1.07] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .0499), while increasing the rate of RSV B infections (relative risk 1.36 [95% CI, .73-2.56] in the 1-dose group and 1.69 [95% CI, .92-3.08] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .12). Sequenced RSV isolates demonstrated no suptavumab epitope changes in RSV A isolates, while all RSV B isolates had 2-amino acid substitution in the suptavumab epitope that led to loss of neutralization activity. Treatment emergent adverse events were balanced across treatment groups. CONCLUSIONS: Suptavumab did not reduce overall RSV hospitalizations or outpatient LRTI because of a newly circulating mutant strain of RSV B. Genetic variation in circulating RSV strains will continue to challenge prevention efforts. CLINICAL TRIALS REGISTRATION: NCT02325791.

Comparing a Practice-Based Model with a Research-Based Model of social skills interventions for children with autism in schools.

Background: Social impairment is the most challenging core deficit for children with autism spectrum disorder (ASD). Several evidence-based interventions address social impairment in children with ASD; however, adoption, use, and implementation of these interventions in schools is challenging. Method: Ninety-two children with ASD who received one of three intervention models: a) School personnel adapted and implemented evidence-based social skills intervention (Practice-Based Model; n = 14); b) University researcher developed and implemented evidence-based social skills intervention (Research-Based Model; n = 45); or c) standard educational practices model (Inclusion Only Model; n = 33) participated. The average age was 8.4 (SD = 1.6) years; majority was male (88%) and white (52.2%). Typically developing classmates completed sociometric ratings to determine children's social network inclusion, and independent raters observed children on the playground using a time-interval behavior coding system to record solitary engagement and frequency of initiations. Results: Separate linear regression models were conducted. Children in the Research-Based Model had significantly higher social network inclusion than children in the other two settings (p = .05). Children in the Practice-Based Model had significantly lower solitary engagement (p = .04) and more initiations on the playground than children in the University Developed Model (p = .04). Conclusions: The results suggest that researchers: 1) may learn from public school stakeholders who have lived experiences to better understand the context in which implementation occurs; and 2) should partner with schools to learn about their processes of adaptation and adoption in order to facilitate successful implementation of evidence-based practices for children with ASD. Interventions designed with implementation in mind may be more feasible and increase the chances of use in schools.

A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease.

BACKGROUND: Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS: We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS: A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10-12) and AST (P=6.2×10-10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS: A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.).

Maternal patterns of antenatal and postnatal depressed mood and the impact on child health at 3-years postpartum.

OBJECTIVE: The consequences of maternal depressed mood on children's growth, health, and cognitive and language development are examined over the first 3 years of life. METHOD: Pregnant women in 24 periurban township neighborhoods in Cape Town, South Africa (N = 1,238 mothers) were randomized by neighborhood to a home visiting intervention or a standard care condition. Reassessments were conducted for 93%-85% of mothers at 2-weeks, 6-, 18-, and 36-months postbirth. Regressions were conducted on measures of children's growth, behavior, language, and cognition to examine the impact of four patterns of depressed mood: antenatal only (n = 154, 13.8%), postnatal only (n = 272, 24.3%), antenatal and postnatal (n = 220, 19.7%), and no depressed mood on any assessment (n = 473, 42.3%). RESULTS: Patterns of depressed mood were similar across intervention conditions. Depressed mothers were significantly less educated, had lower incomes, were less likely to be employed or to have electricity; were more likely to report problematic drinking of alcohol, experience food insecurity, interpersonal partner violence, and to be HIV seropositive. At 36 months, the pattern of maternal depressed mood over time was significantly associated with children's compromised physical growth, both in weight and height, and more internalizing and externalizing symptoms of behavior problems. Measures of language and cognition were similar across maternal patterns of depressed mood. CONCLUSIONS: Mothers who report depressed mood face significantly more life challenges, both environmental stressors related to poverty and other problematic behaviors. More proximal, postnatal depressed mood appears to have a larger influence on their children, compared with antenatal depressed mood. (PsycINFO Database Record

Family Coaching as a delivery modality for evidence-based prevention programs.

Family Coaching is proposed as a new delivery format for evidence-based prevention programs (EBPPs). Three recent developments in health promotion support the potential efficacy of Family Coaching: (1) renewed interest in integrated prevention programs for multiple risk factors and behavior changes, (2) broad and long-term impacts of family-based interventions, and (3) popular acceptance of "coaching" as a nonstigmatizing, goal-focused intervention strategy. Family coaches are community members and paraprofessionals trained in common elements of EBPP. Family Coaching has specific goals, is short term, and has definable outcomes. Coaches frame the program's goals to be consistent with the family's values, normalize the family's experience, assess their strengths, and help the family set goals and develop skills and routines to problem solve challenging situations. Broad dissemination of EBPP will be facilitated with delivery formats that are flexible to meet families' priorities and providers' desires and capacities to tailor programs to local contexts.

Neonatal immune activation depletes the ovarian follicle reserve and alters ovarian acute inflammatory mediators in neonatal rats.

Normal ovarian development is crucial for female reproductive success and longevity. Interruptions to the delicate process of initial folliculogenesis may lead to ovarian dysfunction. We have previously demonstrated that an early life immune challenge in the rat, induced by administration of lipopolysaccharide (LPS) on postnatal day (PND) 3 and 5, depletes ovarian follicle reserve long term. Here, we hypothesized that this neonatal immune challenge leads to an increase in peripheral and ovarian inflammatory signaling, contributing to an acute depletion of ovarian follicles. Morphological analysis of neonatal ovaries indicated that LPS administration significantly depleted PND 5 primordial follicle populations and accelerated follicle maturation. LPS exposure upregulated circulating interleukin 6, tumor necrosis factor alpha (TNFa), and C-reactive protein on PND 5, and upregulated ovarian mRNA expression of Tnfa, mitogen-activated protein kinase 8 (Mapk8/Jnk1), and growth differentiation factor 9 (Gdf9) (P < 0.05). Mass spectrometry and cell signaling pathway analysis indicated upregulation of cellular pathways associated with acute phase signaling, and cellular survival and assembly. Apoptosis assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling indicated significantly increased positive staining in the ovaries of LPS-treated neonates. These findings suggest that increased proinflammatory signaling within the neonatal ovary may be responsible for the LPS-induced depletion of the primordial follicle pool. These findings also have implications for female reproductive health, as the ovarian reserve is a major determinate of female reproductive longevity.

Replicating Evidence-Based Practices with Flexibility for Perinatal Home Visiting by Paraprofessionals.

Introduction Strategies are needed to improve the efficacy of paraprofessional home visitors for pregnant women in the United States. This study evaluates the maternal and child outcomes when evidence-based practices (EBP) are replicated with flexibility, rather than fidelity to a manualized intervention. Methods Pregnant mothers (N = 203) in five clinics were recruited in the waiting rooms and randomized to standard clinic care as the control condition (n = 104) or standard care plus home visiting (n = 99). Home visitors (n = 9) were selected, trained in foundational skills common to EBP and four problem domains (weight control, breastfeeding, daily habits, and depression). Independent interviewers assessed targeted outcomes at birth (82%) and 6 months later (83%). RESULTS: Home visitors, called Mentor Mothers [MM], made an average of 14.9 home visits or telephone contacts (SD = 9; total contacts = 1491) addressing maternal daily habits, breastfeeding, and depression. Intervention and control mothers were similar in weight, Body Mass Index (BMI), depression and social support at baseline and 6 months later. The percentage of low birth weight babies was similar; intervention infants' growth (weight/height Z score) tended to be significantly better compared to the control condition. DISCUSSION: There are many explanations for the failure to find significant benefits: insufficient statistical power; the benefits of repeated assessments by warm, supportive peers to improve outcomes; or the failure of EBP and the need to maintain replication with fidelity. All study mothers had better outcomes than documented among comparable published samples of low-income, Latina and Korean-American mothers in Los Angeles, CA. ClinicalTrials.gov registration NCT01687634.

Adapting Current Strategies to Implement Evidence-Based Prevention Programs for Paraprofessional Home Visiting.

This paper describes a strategy for using evidence-based interventions (EBI) that does not require replication and fidelity. Eight parents, identified as positive role models, conducted home visits for 101 low-income Latina and Korean pregnant women. The home visitors, called mentor mothers (MM), were trained in 10 of the practice elements common to 80% of child-focused EBI and how to apply these skills to support mothers in obesity prevention, to increase the duration of breastfeeding, and to reduce depression. MM reported the content and skills utilized on each home visit on mobile phones. Each MM made an average of 153 home visits (SD = 173.3), with 28 of these visits being phone contacts. Body mass index (BMI) at 6 months was significantly associated with the frequency of MM focused on coping with depression (r = .24), but was not related to practice elements used by MM. The duration of breastfeeding was significantly related to the frequency with which MM focused on the topic of breastfeeding (r = .28) and parenting (r = .3), and MM use of attending (r = .24) and relaxation (r = .27). Depression was significantly correlated with the frequency of addressing depression (r = .27), but not to practice elements. MM did use different strategies in the first 150 visits compared to their last 150 visits, reflecting data-informed supervision. Evidence synthesized from EBI was used as a novel training method, with real-time monitoring and data-informed supervision providing evidence of iterative quality improvements in MM behaviors over time, as well as a way for linking implementation processes to outcomes.

Brief Report: Examining Executive and Social Functioning in Elementary-Aged Children with Autism.

There is a paucity of literature examining the relationship between executive and social functioning in children with autism spectrum disorder (ASD). Twenty-three school-aged children with ASD participated. Executive functioning was measured using the Developmental Neuropsychological Assessment, Second Edition and Differential Ability Scales, Second Edition, and the teacher-rated Behavior Rating of Inventory of Executive Function. Independent assessors observed children's social functioning on the playground while children with ASD and their peers completed a survey to measure peer friendships and rejections. Overall, poorer executive functioning was associated with increased playground isolation and less engagement with peers. This suggests that metacognitive skills such as initiation, working memory, and planning and organization are associated with children's social functioning.

Early life peripheral lipopolysaccharide challenge reprograms catecholaminergic neurons.

Neonatal immune challenge with the bacterial mimetic lipopolysaccharide has the capacity to generate long-term changes in the brain. Neonatal rats were intraperitoneally injected with lipopolysaccharide (0.05 mg/kg) on postnatal day (PND) 3 and again on PND 5. The activation state of tyrosine hydroxylase (TH) was measured in the locus coeruleus, ventral tegmental area and substantia nigra on PND 85. In the locus coeruleus there was an approximately four-fold increase in TH activity. This was accompanied by a significant increase in TH protein together with increased phosphorylation of all three serine residues in the N-terminal region of TH. In the ventral tegmental area, a significant increase in TH activity and increased phosphorylation of the serine 40 residue was seen. Neonatal lipopolysaccharide had no effect on TH activation in the substantia nigra. These results indicate the capacity of a neonatal immune challenge to generate long-term changes in the activation state of TH, in particular in the locus coeruleus. Overall, the current results demonstrate the enduring outcomes of a neonatal immune challenge on specific brain catecholaminergic regions associated with catecholamine synthesis. This highlights a novel mechanism for long-term physiological and behavioural alterations induced by this model.