Yona K. Cloonan

Hepatitis B Virus–Specific and Global T-Cell Dysfunction in Chronic Hepatitis B

BACKGROUND & AIMS T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). METHODS We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. RESULTS Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3(+)CD127(-) regulatory T cells and CD4(+) T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)(+) than HBeAg(-) patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg(+) than HBeAg(-) patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. CONCLUSIONS HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.

Hemifacial microsomia: From gestation to childhood

Hemifacial microsomia (HFM) is a variable, complex malformation involving asymmetric hypoplasia of the face and ear. Little is known about the risk factors for or consequences of HFM. In this study, we describe 3 studies that have been or are currently being conducted to further our understanding of this malformation. The first completed study examined whether HFM risk is related to maternal exposures that may affect blood flow. In that case-control study, interview data from 230 mothers of children in the case group and 678 mothers of children in the control group suggested that maternal use of vasoactive medications in the first trimester, particularly in combination with cigarette smoking, was associated with increased risks of HFM. The second study is currently underway, in which we are evaluating whether HFM risk is related to genetic variation in pathways associated with vasculogenesis and hemostasis, using DNA collected in the first study. The third ongoing study observes children with HFM to identify psychosocial, cognitive, dental, and medical sequelae. When the children from the original case-control study are 6 or 7 years of age, mothers and teachers complete self-administered questionnaires that cover a wide range of psychosocial development domains. Preliminary analyses of 115 case and 314 control children suggest that children with HFM may have worse teacher-reported academic performance and possibly higher levels of internalizing behavior problems than control children. When data on the full study sample are available, further analyses will determine whether the preliminary findings remain and if they vary by HFM phenotype, parenting style, or indicators of social risk.

Psychosocial Functioning in Children With and Without Orofacial Clefts and Their Parents

Objective To determine whether psychosocial functioning in children with orofacial clefts and their parents differs from that in unaffected controls. Design The study used a nonrandomized, case-control design. Participants Outcomes were evaluated in 93 cases with orofacial clefts and 124 controls, aged 5 to 9 years, who were part of the Massachusetts Center for Birth Defects Research and Prevention registry. Main Outcome Measures Measures included the Child Behavior Checklist, the PedsQL 4.0, the Social Competence Scale, and the Parenting Stress Inventory. Results Group differences were negligible for all measures, and findings changed little with the application of inverse probability weighting to adjust for response bias. Stratified analyses revealed differences according to both sex and age, with worse outcomes observed in male cases and cases aged 7 to 9 years. Conclusions In contrast to previous studies, we found minimal differences in psychosocial functioning among children with orofacial clefts and their parents compared with unaffected controls. This may reflect ascertainment factors, and psychosocial differences may be less apparent in population-based versus clinic-based samples. Alternatively, social-emotional deficits may become apparent in older school-aged children, making the preschool and early elementary school years an optimal time for preventive interventions.

Inflammatory Markers and the Risk of Hip and Vertebral Fractures in Men: the Osteoporotic Fractures in Men (MrOS)

Cytokines play major roles in regulating bone remodeling, but their relationship to incident fractures in older men is uncertain. We tested the hypothesis that men with higher concentrations of pro‐inflammatory markers have a higher risk of fracture. We used a case‐cohort design and measured inflammatory markers in a random sample of 961 men and in men with incident fractures including 120 clinical vertebral, 117 hip, and 577 non‐spine fractures; average follow‐up 6.13 years (7.88 years for vertebral fractures). We measured interleukin (IL)‐6, C‐reactive protein (CRP), tumor necrosis factor alpha (TNFα), soluble receptors (SR) of IL‐6 (IL‐6SR) and TNF (TNFαSR1 and TNFαSR2), and IL‐10. The risk of non‐spine, hip, and clinical vertebral fracture was compared across quartiles (Q) of inflammatory markers using Cox proportional hazard models with tests for linear trend. In multivariable‐adjusted models, men with the highest (Q4) TNFa cytokine concentrations and their receptors had a 2.0–4.2‐fold higher risk of hip and clinical vertebral fracture than men with the lowest (Q1). Results were similar for all non‐spine fractures, but associations were smaller. There was no association between CRP and IL‐6SR and fracture. Men in the highest Q of IL‐10 had a 49% lower risk of vertebral fracture compared with men in Q1. Among men with ≥3 inflammatory markers in the highest Q, the hazard ratio (HR) for hip fractures was 2.03 (95% confidence interval [CI] 1.11–3.71) and for vertebral fracture 3.06 (1.66–5.63). The HRs for hip fracture were attenuated by 27%, 27%, and 15%, respectively, after adjusting for appendicular lean mass (ALM), disability, and bone density, suggesting mediating roles. ALM also attenuated the HR for vertebral fractures by 10%. There was no association between inflammation and rate of hip BMD loss. We conclude that inflammation may play an important role in the etiology of fractures in older men.

Psychosocial Outcomes in Children With and Without Non-Syndromic Craniosynostosis: Findings From Two Studies

Objective To evaluate the hypothesis that children with craniosynostosis and their parents have differences in psychosocial outcomes, as compared with an unaffected control group. Design Two studies were conducted, both which followed children born with and without craniosynostosis. Study 1 ascertained affected children from clinics, and study 2 ascertained affected children from a population-based study of birth defects. Participants Study 1 included 22 children with single-suture craniosynostosis and 18 controls, ages 4 to 5 years. Study 2 included 24 children with nonsyndromic craniosynostosis and 124 unaffected controls, ages 5 to 9 years. Main Outcome Measures Outcome measures included the Child Behavior Checklist, Social Competence Scale, Pediatric Quality of Life Inventory, and Parenting Stress Index. Results We observed lower scores on measures of health-related quality of life in cases versus controls, with adjusted effect sizes ranging from −0.72 to −0.44 (p < .05) on summary measures. Small but statistically nonsignificant increases in behavioral problems were observed in cases versus controls, with no apparent differences in social competence or parenting stress. Conclusions Results provide preliminary evidence suggesting that children with nonsyndromic craniosynostosis may have elevated risk for psychosocial difficulties, particularly health-related quality of life. Continued follow-up through preadolescence and adolescence is warranted.

Plasma Follistatin-Like Protein 1 is Elevated in Kawasaki Disease and May Predict Coronary Artery Aneurysm Formation

OBJECTIVE To determine whether plasma levels of follistatin-like protein 1 (FSTL-1), a pro-inflammatory protein produced by mesenchymal tissue, including cardiac myocytes, correlate with the development of Kawasaki disease (KD) and coronary artery aneurysms (CAA). STUDY DESIGN FSTL-1 plasma levels were measured serially with enzyme-linked immunosorbent assay in 48 patients with KD at time of diagnosis and, when available, 2 weeks, 6 weeks, and 6 months after onset of disease. These were compared with FSTL-1 plasma levels in 23 control subjects. Data were analyzed with generalized estimating equations. RESULTS Plasma FSTL-1 levels were elevated in patients with acute KD compared with control subjects (P = .0086). FSTL-1 levels remained significantly elevated at 2 weeks after disease onset, but returned to control levels by 6 months. Seven patients with CAA had significantly higher FSTL-1 levels at the time of diagnosis than patients in whom aneurysms did not develop (P = .0018). Sensitivity and specificity rates for CAA at a specific FSTL-1 cutoff point (178 ng/mL) were 85% and 71%. CONCLUSIONS Plasma levels of FSTL-1 are elevated in acute KD and may predict cardiac morbidity in this disease. These results suggest a possible role for FSTL-1 in the formation of CAAs.

Diabetes and prediabetes in patients with hepatitis B residing in North America

Diabetes is associated with liver disease progression and increased hepatocellular carcinoma risk, but factors associated with diabetes in patients with chronic hepatitis B virus (HBV) infection in North America are unknown. We aimed to determine factors predictive of diabetes and impaired fasting glucose (IFG) in a large HBV‐infected multiethnic cohort. Adults with chronic HBV not receiving antiviral therapy were enrolled from 21 centers in North America. Diabetes was defined by history/medication use or fasting glucose ≥126 mg/dL and IFG as fasting glucose 100‐125 mg/dL. Of 882 patients included, 47.2% were female, 71.3% Asian, 83.7% foreign born, median age was 44 years, and median body mass index BMI 24.3 kg/m2. In this cohort, 26.0% were hepatitis B envelope antigen (HBeAg) positive, 43.9% had HBV DNA ≥20,000 IU/mL, and 26.7% alanine aminotransferase (ALT) ≥2× upper limit of normal (≥40 U/L women, ≥60 U/L men). Overall, 12.5% had diabetes and 7.8% IFG. The combined prevalence of diabetes or IFG was highest among blacks (36.7%) and those either born in the United States/Canada or foreign born with migration >20 years ago (25.5%). Obesity (odds ratio [OR]: 2.13), hyperlipidemia (OR, 4.13), hypertension (OR, 3.67), high ALT level (OR, 1.86), and family history of diabetes (OR, 3.43) were associated with diabetes. Factors associated with IFG were obesity (OR, 4.13) and hypertension (OR, 3.27), but also HBeAg positivity (OR, 0.39). Recent migration was negatively associated with diabetes among non‐Asians (OR, 0.30). Conclusions: Diabetes is more prevalent in HBV‐infected North American adults than the general population and is associated with known metabolic risk factors and liver damage, as determined by ALT levels. Among the foreign born, longer duration of North America residence predicted diabetes risk in non‐Asians. These results highlight the opportunities for interventions to prevent diabetes especially among at‐risk ethnic groups with HBV. (Hepatology 2015;62:1364–1374)

Race, Sex, and Total Knee Replacement Consideration: Role of Social Support

To determine whether there are racial differences in social support among patients with knee osteoarthritis (OA) and whether the impact of social support on patient preferences for total knee replacement (TKR) varies by race and sex.

Memory and Response Inhibition in Young Children with Single-Suture Craniosynostosis

Using two versions of the A-not-B task, memory and response inhibition were assessed in 17- to 24-month-old children with surgically corrected single-suture craniosynostosis (cases) and unaffected children (controls). Childrens development and language were initially assessed on average at 6–7 months of age and again at this second visit. Cases and controls performed at equivalent levels on average, with cases performing slightly better than controls on several of the variables measured. However, fewer cases than controls were able to complete the more challenging of the two tasks, which may have predictive significance for later functioning. Childrens age and cognitive ability were related to successful performance on the A-not-B task. Among cases, age of cranioplastic surgery was unrelated to performance. Our findings suggest that children with single-suture craniosynostosis show normal development of visual memory and response inhibition in the age range studied here.

Children with Chronic Hepatitis B in the United States and Canada

OBJECTIVES To test the hypothesis that children with chronic hepatitis B living in the US and Canada would have international origins and characteristic hepatitis B virus (HBV) genotypes and laboratory profiles. STUDY DESIGN Clinical characteristics of children enrolled in the Hepatitis B Research Network were collected from 7 US and Canadian centers. RESULTS Children (n = 343) with an age range of 1.0-17.8 years were enrolled; 78% of the children were Asian, 55% were adopted, and 97% had international origins with either the child or a parent born in 1 of 31 countries. The majority had HBV genotype B (43%) or C (32%), and the remainder had genotype A (5%), D (16%), E (4%), or multiple (<1%). Children with genotype B or C were more likely to be Asian (98% and 96%), more consistently hepatitis B envelope antigen positive (95% and 82%), had higher median HBV DNA levels (8.2 and 8.3 log10 IU/mL), and less frequently had elevated alanine aminotransferase values (43% and 57%) compared with children with other genotypes. The percentage of hepatitis B envelope antigen positivity and of those with HBV DNA ≥6 log₁₀ IU/mL declined with age. CONCLUSIONS The majority of children in the Hepatitis B Research Network have HBV genotypes that reflect their international origins. Clinical and laboratory data differ substantially by patient age and HBV genotype. Use of these data can help drive the development of optimal strategies to manage and treat children with chronic hepatitis B.