Safety, pharmacokinetics and antiviral activity of ABI-H2158, a hepatitis B virus core inhibitor: A randomized, placebo-controlled phase 1 study.

Treatment for chronic hepatitis B virus infection (cHBV) is mostly indefinite, with new finite-duration therapies needed. We report safety, pharmacokinetics and antiviral activity of the investigational HBV core inhibitor ABI-H2158. This Phase 1a/b study (NCT03714152) had three parts: Part A, participants received a single ascending oral dose of ABI-H2158 (5-500 mg) or placebo; Part B, participants received multiple doses of ABI-H2158 300 mg once (QD) or twice (BID) daily or placebo, for 10 days; Part C, cHBV patients received ABI-H2158 (100, 300, or 500 mg QD or 300 mg BID) or placebo, for 14 days. Ninety-three participants enrolled. In Parts A/B, there were no serious adverse events (SAEs) or deaths, and all treatment-emergent AEs (TEAEs) were Grade 1. In Part C, two patients had Grade 3 TEAEs unrelated to ABI-H2158; there were no deaths, SAEs or Grade 4 TEAEs. In Part A, median time to maximum ABI-H2158 plasma concentration (Tmax ) and mean terminal elimination half-life (t½ ) were 1-4 and 9.8-20.7 h, and area under the plasma concentration-time curve increased dose proportionally. In Part B, Day 10 Tmax was 2 h, mean t½ was 15.5-18.4 h, and exposure accumulated 1.7- to 3.1-fold. In Part C, Day 14 Tmax was 1 h, exposure accumulated 1.4- to 1.8-fold, and ABI-H2158 was associated with >2 log10 declines in HBV nucleic acids. In conclusion, ABI-H2158 in cHBV patients following 14 days of dosing was well tolerated and demonstrated potent antiviral activity. Safety and pharmacokinetics supported future QD dosing.

Heterogeneous effects of spanking on child protective services involvement in early childhood: A propensity score stratification analysis.

Background: Extant literature has primarily employed linear models to estimate the average effect of spanking on children. Less is known about child and parent characteristics that may predict differential risks of children's exposure to spanking (i.e., pre-treatment heterogeneity) and the effect of spanking on child outcomes that may differ by the propensity for spanking (i.e., post-treatment heterogeneity). Objective: The present study examines pre- and post-treatment heterogeneity in the association between maternal spanking at child age 3 and subsequent household Child Protective Services (CPS) involvement that were reported by mothers between child ages 3 to 5. Methods: The sample consisted of 2,422 families from the Fragile Families and Child Wellbeing Study, a birth cohort study that oversampled children born to unmarried families. A propensity score stratification analysis procedure examined pre- and post-treatment heterogeneity in the association between spanking and subsequent household CPS involvement. Children were stratified into three strata depending on their propensity for experiencing spanking. Subsequently, the association between spanking and household CPS involvement was examined for each stratum. Results: Disadvantaged socio-economic characteristics, negative psychosocial conditions of the mother, and dysregulated temperament of the child were associated with elevated risk of spanking. The odds of subsequent household CPS involvement increased by 2.4 times (ß = 0.869, p <.01) for children in the stratum with the lowest propensity for experiencing spanking. Conclusions: Results emphasize the importance of promoting alternative disciplinary strategies to families who would be considered low-risk before they may come into contact with the child welfare system.

Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV. METHODS: HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24. RESULTS: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury. CONCLUSIONS: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile. CLINICAL TRIAL NUMBER: NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.

Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs. METHODS: Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS: Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS: In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. CLINICAL TRIALS NUMBER: NCT03576066. LAY SUMMARY: Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.

Adverse Childhood Experiences and Spanking Have Similar Associations with Early Behavior Problems.

OBJECTIVES: To examine whether adverse childhood experiences (ACEs) and physical punishment (ie, spanking) are unique risk factors for behavior problems in early childhood, and whether ACEs moderate the associations of spanking with child behavior problems. STUDY DESIGN: We conducted prospective, longitudinal analyses on 2380 families in the Fragile Families and Child Wellbeing Study. Mothers reported outcomes of externalizing and internalizing behavior problems at age 5 years; and the main predictors, ACEs and spanking, at age 3 years. ACEs included 9 items: physical abuse, emotional abuse, physical neglect, emotional neglect, mother's exposure to intimate partner violence, parental mental health problem, parental substance use, parental incarceration, and parental death. Multilevel models examined the associations between ACEs, spanking, and behavior problems, and the moderating effect of ACEs in the associations of spanking with behavior problems. Analyses were adjusted for preexisting behavior problems, demographics, and neighborhood conditions. RESULTS: ACEs (ß = 0.028; P < .001) and spanking (ß = 0.041; P < .001) at 3 years were unique risk factors for increased externalizing behavior problems at 5 years, after controlling for covariates. The magnitude of the associations of ACEs and spanking with externalizing behavior were statistically indistinguishable. ACEs did not moderate the association between spanking and externalizing behavior. CONCLUSIONS: ACEs and spanking have similar associations in predicting child externalizing behavior. Results support calls to consider physical punishment as a form of ACE. Our findings also underscore the importance of assessing exposure to ACEs and physical punishment among young children and providing appropriate intervention to children at risk.

Does community violence exposure moderate the associations between maternal spanking and early child behavior problems?

A robust research literature links parental spanking with negative behavioral outcomes for children, however, it remains unclear whether conditions in the community may moderate the associations between spanking and behavior problems in early childhood. In the current study, we examined whether community violence exposure moderated the associations of maternal spanking with externalizing and internalizing behavior problems of young children. The sample used in this study was urban families and their children ages 3-5 (n = 2,472). We used fixed effects regression models, which yield stronger statistical control for baseline behavior problems, selection bias, and omitted variables bias. Mother's spanking was associated with elevated levels of both externalizing (ß = .037, p < .001) and internalizing (ß = .016, p < .001) behavior problems. Community violence exposure also predicted higher levels of externalizing (ß = .071, p < .01) and internalizing (ß = .043, p < .05) behavior problems. Community violence exposure did not moderate the associations between maternal spanking and behavior problems. Professionals working with families should promote the use of nonphysical disciplinary practices, regardless of the level of violence and crime in the community in which the family resides.

Neighborhood predictors of bullying perpetration and victimization trajectories among South Korean adolescents.

AIMS: This study examined latent trajectories of bullying perpetration and victimization, and identified neighborhood antecedents of these trajectories among South Korean adolescents. METHODS: Nationally representative individual-level data from waves 2 to 6 (middle school to high school) of the Korean Children and Youth Panel Survey were merged with neighborhood-level data drawn from the Korean Census and the Korean Ministry of Education. Latent class growth analysis (N = 2,178) and logistic regression were conducted (N = 2,021). RESULTS: Three unique trajectories of bullying experience-low-risk (80.8%), transient (13.3%), high-risk (5.9%)-were identified. Neighborhood factors (e.g., public assistance receipt, marital status, official bullying incidents, collective efficacy) predicted these distinct developmental paths. CONCLUSION: Joint trajectories of perpetration and victimization can inform service or policy decisions as each developmental path may represent unique experiences for youth in need of specific resources for treatment or intervention. Neighborhood indicators are important predictors of developmental trajectories of bullying experience among adolescents.

Predictors of Parental Use of Corporal Punishment in Ukraine.

Despite a great deal of evidence that corporal punishment is harmful, corporal punishment is still very prevalent worldwide. We examine predictors of different types of corporal punishment among Ukrainian mothers in 12 communities across Ukraine. Findings suggest that maternal spirituality, maternal coping styles, family communication, and some demographic characteristics are predictive of mothers' use of corporal punishment.

Prevalence of Resistance-Associated Substitutions in HCV NS5A, NS5B, or NS3 and Outcomes of Treatment With Ledipasvir and Sofosbuvir.

BACKGROUND & AIMS: We evaluated the effects of baseline hepatitis C virus (HCV) NS5A, NS5B, and NS3 resistance-associated substitutions (RASs) on response to the combination of ledipasvir and sofosbuvir, with or without ribavirin, in patients with HCV genotype 1 infection. METHODS: We analyzed data from 2144 participants in phase 2 and 3 studies of patients with HCV genotype 1a or b infection who received the combination of ledipasvir (90 mg) and sofosbuvir (400 mg) (ledipasvir/sofosbuvir) once daily, with or without ribavirin twice daily. Population and/or deep sequence analyses of the HCV NS3, NS5A, and NS5B genes were performed on blood samples collected at baseline. RESULTS: Overall, 16.0% of patients had detectable baseline RASs in NS5A. Among patients with HCV genotype 1b infection, there was no significant effect of baseline RASs in NS5A on sustained viral response 12 weeks after the end of treatment (SVR12) with ledipasvir/sofosbuvir and only a small effect in patients with HCV genotype 1a infection. RASs in NS5A that increased the half-maximal effective concentration to ledipasvir by more than 100-fold reduced the rate of SVR12 in treatment-naive patients given ledipasvir/sofosbuvir for 8 weeks (P = .011), but not for 12 weeks. These same baseline NS5A RASs reduced the percentage of treatment-experienced patients who achieved an SVR12 to 12 weeks (but not 24 weeks) ledipasvir/sofosbuvir (P < .001). These RASs had a small effect in patients given ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks. Overall, 2.5% of patients had baseline NS5B nucleotide inhibitor RASs (L159F, N142T, S282G, or L320S) and all achieved an SVR12. Of patients previously treated with protease inhibitors, 53.7% had RASs in NS3 and 96.5% achieved an SVR12. CONCLUSIONS: Baseline RASs in NS5A have minimal effects on patient responses to ledipasvir/sofosbuvir therapy. When these RASs do have effects, they could be largely overcome by extending treatment duration or through treatment intensification.

Analysis of Reach-to-Grasp by School-Aged Children with Down Syndrome Elucidates Limitations in Upper Extremity Motor Control.

AIMS: To identify limitations in preparatory planning (PP) and movement execution that constrain performance of reach-to-grasp (RTG) movements in school-aged children with Down syndrome (DS) and examine the effect of chronological age (CA) on performance. METHODS: Nine children with DS ages 6 to 12 years and nine with typical development (TD) participated in this pilot descriptive study. Three-dimensional kinematic analysis was applied to RTG movements performed in the context of two functional tasks. RESULTS: PP variables focused on the coordination of reach and grasp. Compared to the group with TD, the group with DS demonstrated significant limitations in anticipatory slowing down of hand transport and orientation of the hand in preparation for object contact. There was also relatively late onset of preparatory grip formation in the group with DS. In regard to movement execution, reach trajectories of the group with DS showed significantly greater deviation from the straight path. Correlations of study variables with CA were low and insignificant in both groups. CONCLUSIONS: Motor control mechanisms that mediate both PP and execution of the fundamental RTG movement are potential factors limiting upper extremity activity in school-aged children with DS. They should be addressed in future intervention-based research.

Concordance of sustained virological response 4, 12, and 24 weeks post-treatment with sofosbuvir-containing regimens for hepatitis C virus.

UNLABELLED: Historically, clinical trials of regimens to treat chronic infection with hepatitis C virus (HCV) have used, as their primary efficacy endpoint, a sustained virological response (SVR)­defined as HCV RNA levels below a designated threshold of quantification­24 weeks after the end of treatment (SVR24). More recently, regulatory authorities have begun to accept SVR at 12 weeks post-treatment (SVR12) as a valid efficacy endpoint because of its high rate of concordance with SVR24. However, the concordance between SVR12 and SVR24 has not been systematically assessed with new regimens of recently approved direct-acting antiviral agents. The aim of this study was to assess the concordance between SVR at various post-treatment time points in phase III clinical trials of sofosbuvir (SOF)-containing regimens. We conducted a retrospective analysis of five trials enrolling 863 patients infected with HCV genotypes 1-6. The concordance between SVR at 4 weeks post-treatment (SVR4) and SVR12, and between SVR12 and SVR24, were determined, as well as positive predictive values (PPVs) and negative predictive values (NPVs). Overall, 779 of 796 patients (98.0%) with an SVR4 also achieved an SVR12, making the PPV of SVR4 for SVR12 98% and the NPV 100%. Of the 779 patients with an SVR12, 777 (99.7%) also achieved an SVR24, making the PPV of SVR12 for SVR24 >99% and the NPV 100%. Of patients who relapsed post-therapy, 77.6% did so within 4 weeks of completing therapy. CONCLUSION: Data from phase III studies demonstrate that with SOF-based regimens, with or without interferon, SVR12 and SVR24 correlate closely. Thus, SVR12 can be used effectively to determine "cure" rates in trials and in clinical practice.

Acetabular Remodeling After a Varus Derotational Osteotomy in Children With Cerebral Palsy.

BACKGROUND: The optimal surgical intervention for hip dysplasia in cerebral palsy (CP) is controversial. The purpose of this study was to determine (1) whether an isolated varus derotation osteotomy (VDRO) for the treatment of CP hip dysplasia allows for acetabular remodeling as measured by acetabular depth ratio (ADR), (2) the predictive factors for acetabular remodeling after an isolated VDRO for the treatment of CP hip dysplasia, and (3) to establish the normal ADR in typical children for comparison. METHODS: Eighty-seven CP patients (174 hips) treated with an isolated VDRO between 2003 and 2009 were retrospectively reviewed. The average age at surgery was 4.6 years (range, 2.4 to 10.6 y) and the average follow-up period was 5.1 years (range, 1.1 to 9.9 y). Acetabular remodeling was assessed on radiographs by the ADR. Changes in preoperative and postoperative ADR were analyzed using linear mixed-effects models. Patients were divided into 2 different groups for the postoperative ADR analysis: Gross Motor Function Classification System (GMFCS) levels I, II, and III compared with GMFCS levels IV and V. The progression of ADR versus age was determined in a set of 917 normal children (1834 hips) for comparison. RESULTS: There was a statistically significant increase (improvement) in ADR postsurgically for the collective CP set (P<0.001) and for both GMFCS categories (I/II/III, IV/V: P<0.001). GMFCS level, sex, and intraoperative neck shaft angle (NSA) were determined to be significant predictors for postoperative ADR improvement. GMFCS level was the most significant predictor for an increase in ADR after surgery (P<0.001). Less improvement in ADR was observed in patients of GMFCS levels IV and V compared with patients of GMFCS levels I, II, and III (P<0.001). A lower intraoperative NSA resulted in greater postoperative increase in ADR (P<0.05). CONCLUSIONS: Overall, isolated VDRO allowed for acetabular remodeling in CP hip dysplasia. Acetabular remodeling was increased in patients of GMFCS levels I, II, and III compared with patients of GMFCS levels IV and V. Increased varization at the time of VDRO improved acetabular remodeling. This study recommends considering GMFCS level and intraoperative NSA during surgical planning for CP hip dysplasia.

Rate of Correction and Recurrence of Ankle Valgus in Children Using a Transphyseal Medial Malleolar Screw.

BACKGROUND: Transphyseal medial malleolar screw (TMMS) hemiepiphysiodesis is an effective treatment for ankle valgus in children. There is limited evidence on the effect of age and diagnosis on the rate of correction as well as the deformity recurrence after screw removal. The purpose of this study was to determine (1) the rate of correction of ankle valgus after hemiepiphysiodesis using a TMMS, (2) the effects of clinical diagnosis and age at surgery on the rate of correction, and (3) the rate of valgus recurrence after TMMS removal. METHODS: In this retrospective study we included 16 male and 21 female patients (63 ankles) with an average age at surgery of 11.0 years (range, 5.4 to 14.8 y) who underwent TMMS hemiepiphysiodesis for the treatment of ankle valgus. There was a mean radiographic follow-up of 1.6 years (range, 0.4 to 4.9 y) before screw removal. For subjects who received screw removal (43 ankles), the average time from insertion to removal of the screw was 1.4 years (range, 0.4 to 5.2 y). Valgus deformity was assessed on anteroposterior ankle radiographs by measurement of tibiotalar angle. Linear mixed effects models were used to determine rates of correction and valgus recurrence. RESULTS: The average rate of correction in tibiotalar angle was 0.37±0.04 degrees per month (P<0.001). Clinical diagnosis and age at surgery significantly affected the amount of postoperative correction in tibiotalar angle (P<0.05). Eighteen of 22 ankles (81.8%) demonstrated recurrence of ankle valgus after screw removal. The average recurrence rate in patients who underwent screw removal was 0.28±0.08 degrees per month (22 ankles, P=0.002). CONCLUSIONS: This study supports the effectiveness of the TMMS hemiepiphysiodesis for treating pediatric ankle valgus, but the effects of additional skeletal growth should be considered as the ankle may rebound into valgus after correction and screw removal. The results from this study can help with surgical planning to predict the amount of correction that may be achieved depending on underlying diagnosis and age at surgery. LEVEL OF EVIDENCE: Level IV-retrospective study.

Final Outcomes from a Phase 2 Trial of Posoleucel in Allogeneic Hematopoietic Cell Transplant Recipients.

Allogeneic hematopoietic cell transplantation (allo-HCT) recipients are susceptible to viral infections. We conducted a phase 2 trial evaluating the safety and rate of clinically significant infections (CSIs; viremia requiring treatment or end-organ disease) following infusion of posoleucel, a partially HLA-matched, allogeneic, off-the-shelf, multivirus-specific T cell investigational product for preventing CSIs with adenovirus, BK virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, or JC virus. This open-label trial enrolled high-risk allo-HCT recipients based on receiving grafts from umbilical cord blood, haploidentical, mismatched, or matched unrelated donors; post-HCT lymphocytes <180/mm3; or use of T cell depletion. Posoleucel dosing was initiated within 15-49 days of allo-HCT and subsequently every 14 days for up to seven doses. The primary endpoint was the number of CSIs due to the six target viruses by week 14. Of the 26 patients enrolled just three (12%) had a CSI by week 14, each with a single target virus. In vivo expansion of functional virus-specific T cells detected via interferon-γ ELISpot assay was associated with viral control. Persistence of posoleucel-derived T cell clones for up to 14 weeks after the last infusion was confirmed by T cell receptor deep-sequencing. Five patients (19%) had acute GVHD grade II-IV. No patient experienced cytokine release syndrome. All six deaths were due to relapse or disease progression. High-risk allo-HCT patients who received posoleucel had low rates of CSIs from six targeted viruses. Repeat posoleucel dosing was generally safe and well tolerated and associated with functional immune reconstitution. www.clinicaltrials.gov NCT04693637.

Long-term open-label vebicorvir for chronic HBV infection: Safety and off-treatment responses.

Background & Aims: The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs). Methods: Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment. Results: Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred ≥4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off-treatment or NrtI-restart phases. No drug-drug interactions between VBR + NrtI and no cases of treatment-emergent resistance among patients who adhered to treatment were observed. Conclusions: Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24-week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This first-generation core inhibitor administered with NrtI for at least 52 weeks was not sufficient for HBV cure. Clinical trial number: NCT03780543. Impact and implications: Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies with finite treatment duration producing greater therapeutic responses that can be sustained off treatment. First-generation core inhibitors, such as vebicorvir, have mechanisms of action orthogonal to standard-of-care therapies that deeply suppress HBV viral replication during treatment; however, to date, durable virologic responses have not been observed after treatment discontinuation. The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir.

Profiles of adverse childhood experiences (ACEs) and psychosocial adjustment in South Korea: Comparison between probation and non-probation youth.

BACKGROUND: Adverse Childhood Experiences (ACEs) are risk factors affecting adolescent psychosocial adjustment. Youth involved in the juvenile justice system are more likely to have ACEs, but few studies have investigated this topic outside the western context. OBJECTIVE: This study aims to (1) compare latent profiles of ACEs among probation and non-probation youth in South Korea and (2) examine which profiles pose the greatest risk of maladaptive psychosocial adjustment (offline risk-taking, online risk-taking, school adjustment, and happiness). PARTICIPANTS AND SETTING: South Korean data adopting survey questions from the Fourth International Self-Report Delinquency Study was analyzed. Adolescents with complete information on regression covariates were included (non-probation: 1846/probation: 368). METHODS: Latent profile analysis was utilized to identify distinctive patterns of ACEs. Multiple linear regression and logistic regression were performed to predict the maladjustment experiences of each latent subgroup. RESULTS: Four ACE profiles emerged for probation and non-probation samples. Three profiles were common (i.e., emotional/physical abuse, emotional neglect, high maltreatment/domestic violence) and one profile was unique (high maltreatment with family dysfunction for the probation sample; moderate maltreatment for the non-probation sample). In the probation sample, compared to the emotional neglect group, the other three profiles showed poorer adjustment in at least one domain. In the non-probation sample, profiles with high emotional/physical abuse and high maltreatment/family dysfunction had poorer outcomes than the emotional neglect group. CONCLUSIONS: These findings indicate the need for a comprehensive approach toward adolescents and their family environments for preventing delinquency and promoting positive youth adjustment.

Associations between 11 parental discipline behaviours and child outcomes across 60 countries.

OBJECTIVES: To test associations between 11 caregiver aggressive and non-aggressive discipline behaviours and outcomes (aggression, distraction and prosocial peer relations) of children under 5 years in low-income and middle-income countries (LMICs). PARTICIPANTS: Data came from the fourth (2009-2013) and fifth (2012-2017) rounds of the UNICEF Multiple Indicator Cluster Surveys. Analyses were restricted to households with children under 5 years, leaving a sample of 229 465 respondents across 60 LMICs. Data were analysed using Bayesian multilevel logistic regression. RESULTS: Verbal reasoning (80%) and shouting (66%) were the most common parental discipline behaviours towards young children. Psychological and physical aggression were associated with higher child aggression and distraction. Compared with not using verbal reasoning, verbal reasoning was associated with lower odds of aggression (OR)=0.92, 95% credible interval (CI)=0.86 to 0.99) and higher odds of prosocial peer relations (OR=1.30, 95% CI=1.20 to 1.42). Taking away privileges was associated with higher odds of distraction (OR=1.09, 95% CI=1.03 to 1.15) and lower odds of prosocial peer relations (OR=0.92, 95% CI=0.87 to 0.98). Giving the child something else to do was associated with higher odds of distraction (OR=1.06, 95% CI=1.01 to 1.12). The results indicated country-level variation in the associations between parenting behaviours and child socioemotional outcomes. CONCLUSIONS: Psychological and physical aggression were disadvantageous for children's socioemotional development across countries. Only verbal reasoning was associated with positive child socioemotional development. No form of psychological aggression or physical aggression benefited child socioemotional development in any country. Greater emphasis should be dedicated to reducing parental use of psychological and physical aggression across cultural contexts.

Relationship between Discordance in Parental Monitoring and Behavioral Problems among Chilean Adolescents.

This study investigated the role of discrepancies between parent and youth reports of perceived parental monitoring in adolescent problem behaviors with a Chilean sample (N= 850). Higher levels of discordance concerning parental monitoring predicted greater levels of maladaptive youth behaviors. A positive association between parent-youth discordance and externalizing problems indicated that large adult-youth disagreement in parental monitoring may impose a great risk, despite protective efforts of parental monitoring. Although the direct relationship between parental monitoring and youth internalizing behaviors was not significant, parent-youth incongruence in monitoring was associated with greater levels of internalizing behaviors. Therefore, differing assessments of parental behaviors, as an indicator of less optimal family functioning, may provide important information about youth maladjustment and may potentially provide a beginning point for family-focused intervention.

Physical punishment, physical abuse, and child behavior problems in South Korea.

BACKGROUND: Prior literature has demonstrated the associations of parental physical punishment with child behavior problems and increased risk of physical abuse. In South Korea, physical punishment is a common parenting practice. In 2021, legislative reforms eliminated legal grounds for parental physical punishment in South Korea. However, research on physical punishment, physical abuse, and child behavior problems in the Korean context is scarce. OBJECTIVE: This study examined whether physical punishment and physical abuse have unique associations with child behavior problems and whether physical punishment is associated with increased exposure to physical abuse. PARTICIPANTS AND SETTING: Data came from the 2010 Korean Child and Youth Panel Survey (KCYPS), a nationally representative sample of South Korean children who attended 1st grade in 2010. Our analyses were based on three waves of the KCYPS (N = 2,180). METHODS: We employed fixed-effects regression to examine the associations of physical punishment and physical abuse with child behavior problems and the association of physical punishment with physical abuse after controlling for time-invariant characteristics. RESULTS: Exposure to physical punishment and physical abuse was associated with higher levels of aggression, depression, and lower levels of academic behavior regulation. Physical punishment was associated with increased risk of physical abuse. CONCLUSIONS: Our findings suggest that physical punishment is a risk for child behavior problems and physical abuse in South Korea. Child maltreatment prevention efforts should focus on shifting favorable social norms around physical punishment and promoting non-physical disciplinary practices.