Examining associations between genetic and neural risk for externalizing behaviors in adolescence and early adulthood.

BACKGROUND: Researchers have identified genetic and neural risk factors for externalizing behaviors. However, it has not yet been determined if genetic liability is conferred in part through associations with more proximal neurophysiological risk markers. METHODS: Participants from the Collaborative Study on the Genetics of Alcoholism, a large, family-based study of alcohol use disorders were genotyped and polygenic scores for externalizing (EXT PGS) were calculated. Associations with target P3 amplitude from a visual oddball task (P3) and broad endorsement of externalizing behaviors (indexed via self-report of alcohol and cannabis use, and antisocial behavior) were assessed in participants of European (EA; N = 2851) and African ancestry (AA; N = 1402). Analyses were also stratified by age (adolescents, age 12-17 and young adults, age 18-32). RESULTS: The EXT PGS was significantly associated with higher levels of externalizing behaviors among EA adolescents and young adults as well as AA young adults. P3 was inversely associated with externalizing behaviors among EA young adults. EXT PGS was not significantly associated with P3 amplitude and therefore, there was no evidence that P3 amplitude indirectly accounted for the association between EXT PGS and externalizing behaviors. CONCLUSIONS: Both the EXT PGS and P3 amplitude were significantly associated with externalizing behaviors among EA young adults. However, these associations with externalizing behaviors appear to be independent of each other, suggesting that they may index different facets of externalizing.

Alcohol milestones and internalizing, externalizing, and executive function: longitudinal and polygenic score associations.

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency.

Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.

Genetic nurture effects for alcohol use disorder.

We tested whether aspects of the childhood/adolescent home environment mediate genetic risk for alcohol problems within families across generations. Parental relationship discord and parental divorce were the focal environments examined. The sample included participants of European ancestry (N = 4806, 51% female) and African ancestry (N = 1960, 52% female) from the high-risk Collaborative Study on the Genetics of Alcoholism. Alcohol outcomes in the child generation included lifetime criterion counts for DSM-5 Alcohol Use Disorder (AUD), lifetime maximum drinks in 24 h, age at initiation of regular drinking, and age at first alcohol intoxication. Predictors in the parent generation included relationship discord, divorce, alcohol measures parallel to those in the child generation, and polygenic scores for alcohol problems. Parental polygenic scores were partitioned into alleles that were transmitted and non-transmitted to the child. The results from structural equation models were consistent with genetic nurture effects in European ancestry families. Exposure to parental relationship discord and parental divorce mediated, in part, the transmission of genetic risk for alcohol problems from parents to children to predict earlier ages regular drinking (ßindirect = -0.018 [-0.026, -0.011]) and intoxication (ßindirect = -0.015 [-0.023, -0.008]), greater lifetime maximum drinks (ßindirect = 0.006 [0.002, 0.01]) and more lifetime AUD criteria (ßindirect = 0.011 [0.006, 0.016]). In contrast, there was no evidence that parental alleles had indirect effects on offspring alcohol outcomes via parental relationship discord or divorce in the smaller number of families of African ancestry. In conclusion, parents transmit genetic risk for alcohol problems to their children not only directly, but also indirectly via genetically influenced aspects of the home environment. Further investigation of genetic nurture in non-European samples is needed.

Genomic risk for post-traumatic stress disorder in families densely affected with alcohol use disorders.

Recent genome-wide association studies (GWAS) have identified genetic markers of post-traumatic stress disorder (PTSD) in civilian and military populations. However, studies have yet to examine the genetics of PTSD while factoring in risk for alcohol dependence, which commonly co-occur. We examined genome-wide associations for DSM-IV PTSD among 4,978 trauma-exposed participants (31% with alcohol dependence, 50% female, 30% African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA). We also examined associations of polygenic risk scores (PRS) derived from the Psychiatric Genomics Consortium (PGC)-PTSD Freeze 2 (N = 3533) and Million Veterans Program GWAS of PTSD (N = 5200) with PTSD and substance dependence in COGA, and moderating effects of sex and alcohol dependence. 7.3% of COGA participants met criteria for PTSD, with higher rates in females (10.1%) and those with alcohol dependence (12.3%). No independent loci met genome-wide significance in the PTSD meta-analysis of European (EA) and African ancestry (AA) participants. The PGC-PTSD PRS was associated with increased risk for PTSD (B = 0.126, p < 0.001), alcohol dependence (B = 0.231, p < 0.001), and cocaine dependence (B = 0.086, p < 0.01) in EA individuals. A significant interaction was observed, such that EA individuals with alcohol dependence and higher polygenic risk for PTSD were more likely to have PTSD (B = 0.090, p < 0.01) than those without alcohol dependence. These results further support the importance of examining substance dependence, specifically alcohol dependence, and PTSD together when investigating genetic influence on these disorders.

Evaluation of the Selectivity of Several Organic Anion Transporting Polypeptide 1B Biomarkers Using Relative Activity Factor Method.

In recent years, some endogenous substrates of organic anion transporting polypeptide 1B (OATP1B) have been identified and characterized as potential biomarkers to assess OATP1B-mediated clinical drug-drug interactions (DDIs). However, quantitative determination of their selectivity to OATP1B is still limited. In this study, we developed a relative activity factor (RAF) method to determine the relative contribution of hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1, and sodium-taurocholate co-transporting polypeptide (NTCP) on hepatic uptake of several OATP1B biomarkers, including coproporphyrin I (CPI), coproporphyrin I CPIII, and sulfate conjugates of bile acids: glycochenodeoxycholic acid sulfate (GCDCA-S), glycodeoxycholic acid sulfate (GDCA-S), and taurochenodeoxycholic acid sulfate (TCDCA-S). RAF values for OATP1B1, OATP1B3, OATP2B1, and NTCP were determined in cryopreserved human hepatocytes and transporter transfected cells using pitavastatin, cholecystokinin, resveratrol-3-O-ß-D-glucuronide, and taurocholic acid (TCA) as reference compounds, respectively. OATP1B1-specific pitavastatin uptake in hepatocytes was measured in the absence and presence of 1 µM estropipate, whereas NTCP-specific TCA uptake was measured in the presence of 10 µM rifampin. Our studies suggested that CPI was a more selective biomarker for OATP1B1 than CPIII, whereas GCDCA-S and TCDCA-S were more selective to OATP1B3. OATP1B1 and OATP1B3 equally contributed to hepatic uptake of GDCA-S. The mechanistic static model, incorporating the fraction transported of CPI/III estimated by RAF and in vivo elimination data, predicted several perpetrator interactions with CPI/III. Overall, RAF method combined with pharmacogenomic and DDI studies is a useful tool to determine the selectivity of transporter biomarkers and facilitate the selection of appropriate biomarkers for DDI evaluation. SIGNIFICANCE STATEMENT: The authors developed a new relative activity factor (RAF) method to quantify the contribution of hepatic uptake transporters organic anion transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, and sodium taurocholate co-transporting polypeptide (NTCP) on several OATP1B biomarkers and evaluated their predictive value on drug-drug interactions (DDI). These studies suggest that the RAF method is a useful tool to determine the selectivity of transporter biomarkers. This method combined with pharmacogenomic and DDI studies will mechanistically facilitate the selection of appropriate biomarkers for DDI prediction.

Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts.

Substance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (NEUR = 12,659) and African (NAFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37-1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11-1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09-1.18). The full model explained 6-13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86-8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications.

Alcohol use polygenic risk score, social support, and alcohol use among European American and African American adults.

Alcohol use is influenced by genetic and environmental factors. We examined the interactive effects between genome-wide polygenic risk scores for alcohol use (alc-PRS) and social support in relation to alcohol use among European American (EA) and African American (AA) adults across sex and developmental stages (emerging adulthood, young adulthood, and middle adulthood). Data were drawn from 4,011 EA and 1,274 AA adults from the Collaborative Study on the Genetics of Alcoholism who were between ages 18-65 and had ever used alcohol. Participants completed the Semi-Structured Assessment for the Genetics of Alcoholism and provided saliva or blood samples for genotyping. Results indicated that social support from friends, but not family, moderated the association between alc-PRS and alcohol use among EAs and AAs (only in middle adulthood for AAs); alc-PRS was associated with higher levels of alcohol use when friend support was low, but not when friend support was high. Associations were similar across sex but differed across developmental stages. Findings support the important role of social support from friends in buffering genetic risk for alcohol use among EA and AA adults and highlight the need to consider developmental changes in the role of social support in relation to alcohol use.

Implementation science to design, test and scale up effective Kangaroo Mother Care in Oromia region, Ethiopia.

AIM: To develop a locally tested and optimised Kangaroo Mother Care (KMC) scale-up model to achieve high population-based effective coverage of KMC in Oromia region. METHOD: We conducted an implementation research study to design and test KMC scale-up models from March 2017 to March 2019 in five hospitals and 39 health centres covering a population of 1.1 million in Oromia region, Ethiopia. We evaluated the models by measuring effective KMC coverage (at least 8 hours of skin-to-skin care plus exclusive breastfeeding) for newborns weighing <2000 g in the 24 hours before discharge from the KMC facility and on the 7th-day post-discharge. RESULTS: After three cycles of iterative model implementation, we developed a KMC scale-up model that resulted in increased population-based effective KMC coverage. We enhanced the existing health system by strengthening the health system, reinforcing the linkages between the health system and communities and improving community engagement. Our final model achieved effective KMC coverage of 54%: 95% CI [49, 60] in the 24 hours before discharge from the facility and 38%: 95% CI [32, 43] on the 7th-day post-discharge. CONCLUSION: Through iterative testing and adaptations, a model to scale up KMC that achieves 54% population-based effective coverage of KMC can be developed.

Multiple Roads to Success: A Latent Class Analysis on Successful Ageing Among Hong Kong Near-Centenarians and Centenarians (NCC).

Notwithstanding the oldest-old cohort being the fastest-growing population in most ageing societies, characterizing successful ageing in adults of advanced age, such as nonagenarians and centenarians, remains challenging. This study investigated the successful ageing subphenotypes using the data from Hong Kong Centenarian Study 2. Between April 2021 and September 2022, 146 family caregivers of community-dwelling older adults aged 95 or above were interviewed by phone. Latent class analysis identified three classes-Overall Frail (46.6%) with poor mobility, cognitive and functional health, Nonambulant (37.0%) but good functional health, and Robust (16.4%) with overall good health-from 11 indicators based on caregivers' reports. Although we found a low prevalence of fulfillment of all indicators of successful ageing, our findings will help care professionals appreciate the heterogeneity underlying partial successful ageing in this vulnerable cohort for segmented and targeted healthy longevity interventions.

Principal Component Analysis Reduces Collider Bias in Polygenic Score Effect Size Estimation.

In this study, we test principal component analysis (PCA) of measured confounders as a method to reduce collider bias in polygenic association models. We present results from simulations and application of the method in the Collaborative Study of the Genetics of Alcoholism (COGA) sample with a polygenic score for alcohol problems, DSM-5 alcohol use disorder as the target phenotype, and two collider variables: tobacco use and educational attainment. Simulation results suggest that assumptions regarding the correlation structure and availability of measured confounders are complementary, such that meeting one assumption relaxes the other. Application of the method in COGA shows that PC covariates reduce collider bias when tobacco use is used as the collider variable. Application of this method may improve PRS effect size estimation in some cases by reducing the effect of collider bias, making efficient use of data resources that are available in many studies.

A genome-wide association study of interhemispheric theta EEG coherence: implications for neural connectivity and alcohol use behavior.

Aberrant connectivity of large-scale brain networks has been observed among individuals with alcohol use disorders (AUDs) as well as in those at risk, suggesting deficits in neural communication between brain regions in the liability to develop AUD. Electroencephalographical (EEG) coherence, which measures the degree of synchrony between brain regions, may be a useful measure of connectivity patterns in neural networks for studying the genetics of AUD. In 8810 individuals (6644 of European and 2166 of African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Multi-Trait Analyses of genome-wide association studies (MTAG) on parietal resting-state theta (3-7 Hz) EEG coherence, which previously have been associated with AUD. We also examined developmental effects of GWAS findings on trajectories of neural connectivity in a longitudinal subsample of 2316 adolescent/young adult offspring from COGA families (ages 12-30) and examined the functional and clinical significance of GWAS variants. Six correlated single nucleotide polymorphisms located in a brain-expressed lincRNA (ENSG00000266213) on chromosome 18q23 were associated with posterior interhemispheric low theta EEG coherence (3-5 Hz). These same variants were also associated with alcohol use behavior and posterior corpus callosum volume, both in a subset of COGA and in the UK Biobank. Analyses in the subsample of COGA offspring indicated that the association of rs12954372 with low theta EEG coherence occurred only in females, most prominently between ages 25 and 30 (p < 2 × 10-9). Converging data provide support for the role of genetic variants on chromosome 18q23 in regulating neural connectivity and alcohol use behavior, potentially via dysregulated myelination. While findings were less robust, genome-wide associations were also observed with rs151174000 and parieto-frontal low theta coherence, rs14429078 and parieto-occipital interhemispheric high theta coherence, and rs116445911 with centro-parietal low theta coherence. These novel genetic findings highlight the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

Montreal cognitive assessment as a screening instrument for cognitive impairment in systemic lupus erythematosus patients without overt neuropsychiatric manifestations.

OBJECTIVES: The Montreal Cognitive Assessment (MoCA) is an increasingly used screening tool for cognitive impairment. The aim of this study was to examine how MoCA performed in identifying cognitive impairment (CI) domains in SLE patients compared with formal standardized neuropsychological testing (NPT). Factors related to SLE disease, immunologic and psychological state associated with CI were also explored. METHODS: This cross-sectional study recruited 50 SLE patients without overt neuropsychiatric manifestations from April 2017 to May 2018. The patients were evaluated with MoCA, formal NPT and the Depression, Anxiety, and Stress Scales (DASS) 42-item self-report questionnaire. Values of sensitivity and specificity were computed for different cut-offs of MoCA within each cognitive domain of NPT and descriptive analysis was used to identify the factors affecting cognitive function. RESULTS: The median score for MoCA was 27.5 (range 22-30). Using a MoCA cutoff of <26, 18 (36%) were identified to have CI using NPT compared to 8 (16%) using MoCA. The most frequently affected cognitive domain was executive functioning with 15 affected patients. Sensitivities and specificities of the MoCA range from 50% to 100% and 5.7% to 16.7%, respectively, across cognitive domains. A lower MoCA cutoff of <25 improve sensitivity of identifying impairment in executive functioning from 60% to 80%. In univariate analysis, DASS scores, disease activity, presence of antiphospholipid antibodies, presence of concurrent autoimmune disease, current, and cumulative corticosteroid therapy did not predict cognitive performance. CONCLUSION: MoCA may be a useful screening tool to identify the most frequently affected cognitive domain which is executive functioning using a lower cutoff of <25 in SLE patients without overt neuropsychiatric manifestations.

Evaluating risk for alcohol use disorder: Polygenic risk scores and family history.

BACKGROUND: Early identification of individuals at high risk for alcohol use disorder (AUD) coupled with prompt interventions could reduce the incidence of AUD. In this study, we investigated whether Polygenic Risk Scores (PRS) can be used to evaluate the risk for AUD and AUD severity (as measured by the number of DSM-5 AUD diagnostic criteria met) and compared their performance with a measure of family history of AUD. METHODS: We studied individuals of European ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM-5 diagnostic criteria were available for 7203 individuals, of whom 3451 met criteria for DSM-IV alcohol dependence or DSM-5 AUD and 1616 were alcohol-exposed controls aged ≥21 years with no history of AUD or drug dependence. Further, 4842 individuals had a positive first-degree family history of AUD (FH+), 2722 had an unknown family history (FH?), and 336 had a negative family history (FH-). PRS were derived from a meta-analysis of a genome-wide association study of AUD from the Million Veteran Program and scores from the problem subscale of the Alcohol Use Disorders Identification Test in the UK Biobank. We used mixed models to test the association between PRS and risk for AUD and AUD severity. RESULTS: AUD cases had higher PRS than controls with PRS increasing as the number of DSM-5 diagnostic criteria increased (p-values ≤ 1.85E-05 ) in the full COGA sample, the FH+ subsample, and the FH? subsample. Individuals in the top decile of PRS had odds ratios (OR) for developing AUD of 1.96 (95% CI: 1.54 to 2.51, p-value = 7.57E-08 ) and 1.86 (95% CI: 1.35 to 2.56, p-value = 1.32E-04 ) in the full sample and the FH+ subsample, respectively. These values are comparable to previously reported ORs for a first-degree family history (1.91 to 2.38) estimated from national surveys. PRS were also significantly associated with the DSM-5 AUD diagnostic criterion count in the full sample, the FH+ subsample, and the FH? subsample (p-values ≤6.7E-11 ). PRS remained significantly associated with AUD and AUD severity after accounting for a family history of AUD (p-values ≤6.8E-10 ). CONCLUSIONS: Both PRS and family history were associated with AUD and AUD severity, indicating that these risk measures assess distinct aspects of liability to AUD traits.

Toward an empirically based Developmental Trauma Disorder diagnosis and semi-structured interview for children: The DTD field trial replication.

OBJECTIVE: Developmental trauma disorder (DTD) is a childhood psychiatric syndrome designed to include sequelae of trauma exposure not fully captured by PTSD. This study aimed to determine whether the assessment of DTD with an independent sample of children in mental health treatment will replicate results from an initial validation study. METHODS: The DTD semi-structured interview (DTD-SI) was administered to a convenience sample in six sites in the United States (N = 271 children in mental health care, 8-18 years old, 47% female, 41% Black or Latinx) with measures of trauma history, DSM-IV PTSD, probable DSM-IV psychiatric diagnoses, emotion regulation/dysregulation, internalizing/externalizing problems, and quality of life. Confirmatory factor (CFA) and item response theory (IRT) analyses tested DTD's structure and DTD-SI's information value. Bivariate and multivariate analyses tested DTD's criterion and convergent validity. RESULTS: A three-factor solution (i.e., emotion/somatic, attentional/behavioral, and self/relational dysregulation) best fit the data (CFI = 0.91; TLI = 0.89; BIC = 357.17; RMSEA = 0.06; SRMR = 0.05). DTD-SI items were informative across race/ethnicity, gender, and age with three exceptions. Emotion dysregulation was the most informative item at low levels of DTD severity. Non-suicidal self-injury was rare but discriminative in identifying children with high levels of DTD severity. Results supported the criterion and convergent validity of the DTD construct. CONCLUSION: This replication provides empirical support for DTD as a construct and potential psychiatric syndrome, and the DTD-SI's validity as a clinical research tool.

Characterisation of Staphylococci species from neonatal blood cultures in low- and middle-income countries.

BACKGROUND: In low- and middle-income countries (LMIC) Staphylococcus aureus is regarded as one of the leading bacterial causes of neonatal sepsis, however there is limited knowledge on the species diversity and antimicrobial resistance caused by Gram-positive bacteria (GPB). METHODS: We characterised GPB isolates from neonatal blood cultures from LMICs in Africa (Ethiopia, Nigeria, Rwanda, and South Africa) and South-Asia (Bangladesh and Pakistan) between 2015-2017. We determined minimum inhibitory concentrations and performed whole genome sequencing (WGS) on Staphylococci isolates recovered and clinical data collected related to the onset of sepsis and the outcome of the neonate up to 60 days of age. RESULTS: From the isolates recovered from blood cultures, Staphylococci species were most frequently identified. Out of 100 S. aureus isolates sequenced, 18 different sequence types (ST) were found which unveiled two small epidemiological clusters caused by methicillin resistant S. aureus (MRSA) in Pakistan (ST8) and South Africa (ST5), both with high mortality (n = 6/17). One-third of S. aureus was MRSA, with methicillin resistance also detected in Staphylococcus epidermidis, Staphylococcus haemolyticus and Mammaliicoccus sciuri. Through additional WGS analysis we report a cluster of M. sciuri in Pakistan identified between July-November 2017. CONCLUSIONS: In total we identified 14 different GPB bacterial species, however Staphylococci was dominant. These findings highlight the need of a prospective genomic epidemiology study to comprehensively assess the true burden of GPB neonatal sepsis focusing specifically on mechanisms of resistance and virulence across species and in relation to neonatal outcome.

Humoral response to heterologous prime-booster vaccination in heart transplant recipients aged 18-70 years primed with a viral vector SARS-CoV-2 vaccine.

Solid organ transplant recipients have demonstrated a blunted immune response to standard 2-dose vaccination against SARS-CoV-2. This study sought to determine the humoral response to heterologous booster vaccination (viral vector vaccine dose 1 and 2 + mRNA booster). Heart transplant recipients, aged 18 to 70 years of age who initially received two doses of the viral vector ChAdOx1 nCoV-19 vaccine followed by a BNT162b2 mRNA booster were recruited. A detectable antibody response in the absence of prior SARS-CoV-2 was the primary outcome measured. This was defined as an anti-spike titre of ≥0.8 U/mL on the Elecsys anti-SARS-CoV-2 S immunoassay. A total of 80 heart transplant patients (mean age 49 ± 13 years, 28% female) were included. Blood samples were drawn at a median of 30 (IQR 28-33) days after the BNT162b2 mRNA booster. The frequency of a detectable antibody response increased from 37.5% (n = 30) after dose 2 to 56% (n = 45) post dose 3 (p < 0.001). A non-detectable antibody response was significantly more common in recipients with a shorter time interval from transplantation (p < 0.001), lower likelihood of cardiac allograft vasculopathy (p = 0.003) and in those prescribed a triple versus dual immunosuppressant regime (p = 0.009) and a tacrolimus versus cyclosporine basedregimen (p = 0.007). Despite heterologous prime-booster vaccination 44% of this vulnerable population ultimately continue to have no detectable antibodies.

Deriving a Measure of Social Recovery Capital From the Important People and Activities Instrument: Construction and Psychometric Properties.

AIM: This study presents a measure of Social Recovery Capital (SRC) derived from the Important People and Activities instrument (IPA). METHODS: The sample comprised young adults who participated in the Collaborative Study on the Genetics of Alcoholism, a high-risk family study of alcohol use disorder (N = 2472). Exploratory and confirmatory factor analysis identified influential items and factor structure, adjusting for family relatedness. The final scale was tested for reliability and validity. RESULTS: Factor analysis retained 10 items loading on three factors (Network Abstinence Behaviors, Basic Network Structure and Network Importance) that together explained 42% of the variance in SRC. The total model showed adequate fit (Comparative Fit Index = 0.95; Tucker Lewis Index = 0.93; Root Mean Square Error of Approximation = 0.06; Standardized Root Mean Squared Residual = 0.05) and acceptable reliability (α = 0.60; McDonald's ω = 0.73) and correlated with validation measures mostly in the weak to moderate range. Due to variable factor scores for reliability and validity, we only recommend using the total score. CONCLUSION: The SRC-IPA is a novel measure of SRC derived from the IPA that captures social network data and has applications in research and clinical work. Secondary data analyses using the SRC-IPA in studies that collected the IPA can further demonstrate the interaction of SRC with a wide variety of clinical indicators and demographic characteristics, making it a valuable addition to other measures of SRC.

The role of parental genotype in the intergenerational transmission of externalizing behavior: Evidence for genetic nurturance.

The purpose of this study was to examine possible pathways by which genetic risk associated with externalizing is transmitted in families. We used molecular data to disentangle the genetic and environmental pathways contributing to adolescent externalizing behavior in a sample of 1,111 adolescents (50% female; 719 European and 392 African ancestry) and their parents from the Collaborative Study on the Genetics of Alcoholism. We found evidence for genetic nurture such that parental externalizing polygenic scores were associated with adolescent externalizing behavior, over and above the effect of adolescents' own externalizing polygenic scores. Mediation analysis indicated that parental externalizing psychopathology partly explained the effect of parental genotype on children's externalizing behavior. We also found evidence for evocative gene-environment correlation, whereby adolescent externalizing polygenic scores were associated with lower parent-child communication, less parent-child closeness, and lower parental knowledge, controlling for parental genotype. These effects were observed among participants of European ancestry but not African ancestry, likely due to the limited predictive power of polygenic scores across ancestral background. These results demonstrate that in addition to genetic transmission, genes influence offspring behavior through the influence of parental genotypes on their children's environmental experiences, and the role of children's genotypes in shaping parent-child relationships.

Barriers for recruitment to treatment of youths with co-occurring substance use disorders and depression.

BACKGROUND AND OBJECTIVES: Recruitment challenges for treatment trials of adolescents with substance use disorder (SUD) and co-occurring depression (COD) have not been reported. The objective is to examine whether recruitment and engagement during the pretreatment assessment phase differ between adolescents in a SUD-COD versus SUD-only treatment study. METHODS: A similar recruitment approach compared five-stage progressions in the pretreatment phase between a SUD-only (n = 252) and SUD-COD (n = 212) study. We examined the "gradient" of recruitment and retention along four stages after referral/inquiries; (a) screening for eligibility by phone, (b) meeting eligibility in an interview, (c) completion of baseline assessment, and (d) participation in the first psychotherapy session of each study. RESULTS: Compared to SUD-only, the retention of adolescents with SUD-COD was significantly poorer from referral/inquiry to all subsequent stages. In particular, the odds ratio and 95% confidence interval from referral/inquiry to screening for eligibility by phone, meeting eligibility in an interview, completion of baseline assessment, and participation in the first psychotherapy session were all less than one. Male attrition rates were slightly higher than females but were not statistically significant. DISCUSSION AND CONCLUSIONS: A high proportion of referred adolescents did not meet the study criteria. This indicates a need to examine (1) potential strategies for overcoming recruitment challenges in adolescents and their engagement in the pretreatment phase for studies of COD and (2) baseline variables for predictors and moderators for adequately powered studies. SCIENTIFIC SIGNIFICANCE: This is the first study to assess recruitment challenges for adolescents with COD.