Infantile Hepatitis B in Immunized Children: Risk for Fulminant Hepatitis and Long-Term Outcomes

Background

Infantile hepatitis B after neonatal immunoprophylaxis is a rare yet distinct disease. This study aimed to analyze the long-term outcomes and risk factors in immunized infants with hepatitis B.

Methods

The clinical parameters and outcomes of 41 infants born after universal immunization, and admitted for HBV-positive hepatitis were studied. All patients were followed for at least 6 months (median  = 4.4 years, range 0.6–18.1 years). Patient survival, changes of HBsAg and HBeAg status, and complications were analyzed.

Results

Among the 41 cases (32 males, 9 females), 21 presented with fulminant hepatitis (FH), and 20 with non-fulminant hepatitis (NFH). Ninety-five percent (36/38) of the mothers were positive for hepatitis B surface antigen (HBsAg). Multivariate analyses revealed younger age of onset (age <7 months) and negative maternal hepatitis B e antigen (HBeAg) were associated with FH (p = 0.03 and p = 0.01, respectively). An infantile fulminant hepatitis B risk score using maternal/infant HBeAg positivity and onset age was proposed. Among the FH cases, the rate of mortality, HBsAg clearance, and chronic HBV infection were 47.6%, 38.1%, and 14.3%, respectively. Among the NFH cases, 35% developed chronic infection. Of the 9 chronically infected children received long-term follow-up, 8 had HBeAg seroconversion before 4 years of age. One case of FH developed hepatocellular carcinoma 14 years later.

Conclusions

Maternal HBsAg + /HBeAg- and early onset age were risk factors for FH in immunized infants. A significant portion of patients with FH or NFH evolve to chronic HBV infection, with HBeAg seroconversion in young childhood. Close surveillance for hepatocellular carcinoma is warranted in patients surviving infantile hepatitis B.     

Enhanced HBsAg Synthesis Correlates with Increased Severity of Fibrosis in Chronic Hepatitis B Patients

Background and Aims

Little is known about whether low serum HBsAg levels result from impaired HBsAg synthesis or a reduced number of hepatocytes caused by advanced liver fibrosis. Therefore, we investigated the capacity for HBsAg synthesis in a cross-sectional cohort of treatment-naïve chronic hepatitis B patients.

Methods

Chronic hepatitis B patients (n = 362) were enrolled; liver biopsies were performed and liver histology was scored, and serum HBsAg and HBV DNA levels were investigated. In the enrolled patients, 183 out of 362 have quantitative serum HBsAg levels. Tissue HBsAg was determined by immunohistochemistry.

Results

A positive correlation between serum HBsAg and HBV DNA levels was revealed in HBeAg(+) patients (r = 0.2613, p = 0.0050). In HBeAg(+) patients, serum HBsAg and severity of fibrosis were inversely correlated (p = 0.0094), whereas tissue HBsAg levels correlated positively with the stage of fibrosis (p = 0.0280). After applying the mean aminopyrine breath test as a correction factor, adjusted serum HBsAg showed a strong positive correlation with fibrosis severity in HBeAg(+) patients (r = 0.5655, p<0.0001). The adjusted serum HBsAg values predicted ‘moderate to severe’ fibrosis with nearly perfect performance in both HBeAg(+) patients (area under the curve: 0.994, 95% CI: 0.983–1.000) and HBeAg(−) patients (area under the curve: 1.000, 95% CI: 1.000–1.000).

Conclusions

Although serum HBsAg levels were negatively correlated with fibrosis severity in HBeAg(+) patients, aminopyrine breath test-adjusted serum HBsAg and tissue HBsAg, two indices that are unaffected by the number of residual hepatocytes, were positively correlated with fibrosis severity. Furthermore, adjusted serum HBsAg has an accurate prediction capability.     

Quantitative HBsAg and HBeAg Predict Hepatitis B Seroconversion after Initiation of HAART in HIV-HBV Coinfected Individuals

Objective

Anti-HBe seroconversion and HBsAg loss are important therapeutic endpoints in patients with hepatitis B virus (HBV) infection. Quantitative measures of hepatitis B surface antigen (qHBsAg) and e antigen (qHBeAg) have been identified as potentially useful indicators of therapeutic response in HBV monoinfection. The aim of this study was to examine serological change including quantitative biomarkers in HIV-HBV coinfected patients initiating HBV active antiretroviral therapy (ART).

Methods

HIV-HBV coinfected individuals from Thailand were followed for up to 168 weeks post ART. Rates and associations of qualitative serological change were determined. Longitudinal changes in qHBsAg and qHBeAg were measured and their utility as predictors of response examined.

Results

Forty seven patients were included of whom 27 (57%) were HBeAg positive at baseline. Median CD4 count was 48 cells/mm³. Over a median follow-up of 108 weeks 48% (13/27) lost HBeAg, 12/27 (44%) achieved anti-HBe seroconversion and 13% (6/47) HBsAg loss. Anti-HBe seroconversion was associated with higher baseline ALT (p = 0.034), lower qHBsAg (p = 0.015), lower qHBeAg (p = 0.031) and greater HBV DNA decline to week 24 (p = 0.045). Sensitivity and specificity for qHBsAg and qHBeAg decline of >0.5 log at week 12 and >1.0 log at week 24 were high for both anti-HBe seroconversion and HBsAg loss.

Conclusions

Rates of serological change in these HIV-HBV coinfected individuals with advanced immunodeficiency initiating HBV-active ART were high. Baseline and on treatment factors were identified that were associated with a greater likelihood of subsequent anti-HBe seroconversion, including both quantitative HBsAg and HBeAg, suggesting these biomarkers may have utility in this clinical setting.     

Is Serum Zinc Associated with Pancreatic Beta Cell Function and Insulin Sensitivity in Pre-Diabetic and Normal Individuals? Findings from the Hunter Community Study

Aim

To determine if there is a difference in serum zinc concentration between normoglycaemic, pre-diabetic and type-2 diabetic groups and if this is associated with pancreatic beta cell function and insulin sensitivity in the former 2 groups.

Method

Cross sectional study of a random sample of older community-dwelling men and women in Newcastle, New South Wales, Australia. Beta cell function, insulin sensitivity and insulin resistance were calculated for normoglycaemic and prediabetes participants using the Homeostasis Model Assessment (HOMA-2) calculator.

Result

A total of 452 participants were recruited for this study. Approximately 33% (N = 149) had diabetes, 33% (N = 151) had prediabetes and 34% (N = 152) were normoglycaemic. Homeostasis Model Assessment (HOMA) parameters were found to be significantly different between normoglycaemic and prediabetes groups (p<0.001). In adjusted linear regression, higher serum zinc concentration was associated with increased insulin sensitivity (p = 0.01) in the prediabetic group. There was also a significant association between smoking and worse insulin sensitivity.

Conclusion

Higher serum zinc concentration is associated with increased insulin sensitivity. Longitudinal studies are required to determine if low serum zinc concentration plays a role in progression from pre-diabetes to diabetes.     

Metabolomic Derangements Are Associated with Mortality in Critically Ill Adult Patients

Objective

To identify metabolomic biomarkers predictive of Intensive Care Unit (ICU) mortality in adults.

Rationale

Comprehensive metabolomic profiling of plasma at ICU admission to identify biomarkers associated with mortality has recently become feasible.

Methods

We performed metabolomic profiling of plasma from 90 ICU subjects enrolled in the BWH Registry of Critical Illness (RoCI). We tested individual metabolites and a Bayesian Network of metabolites for association with 28-day mortality, using logistic regression in R, and the CGBayesNets Package in MATLAB. Both individual metabolites and the network were tested for replication in an independent cohort of 149 adults enrolled in the Community Acquired Pneumonia and Sepsis Outcome Diagnostics (CAPSOD) study.

Results

We tested variable metabolites for association with 28-day mortality. In RoCI, nearly one third of metabolites differed among ICU survivors versus those who died by day 28 (N = 57 metabolites, p<.05). Associations with 28-day mortality replicated for 31 of these metabolites (with p<.05) in the CAPSOD population. Replicating metabolites included lipids (N = 14), amino acids or amino acid breakdown products (N = 12), carbohydrates (N = 1), nucleotides (N = 3), and 1 peptide. Among 31 replicated metabolites, 25 were higher in subjects who progressed to die; all 6 metabolites that are lower in those who die are lipids. We used Bayesian modeling to form a metabolomic network of 7 metabolites associated with death (gamma-glutamylphenylalanine, gamma-glutamyltyrosine, 1-arachidonoylGPC(20:4), taurochenodeoxycholate, 3-(4-hydroxyphenyl) lactate, sucrose, kynurenine). This network achieved a 91% AUC predicting 28-day mortality in RoCI, and 74% of the AUC in CAPSOD (p<.001 in both populations).

Conclusion

Both individual metabolites and a metabolomic network were associated with 28-day mortality in two independent cohorts. Metabolomic profiling represents a valuable new approach for identifying novel biomarkers in critically ill patients.     

Genetic Association of Human Leukocyte Antigens with Chronicity or Resolution of Hepatitis B Infection in Thai Population

Background

Previous studies showed that single nucleotide polymorphisms (SNPs) in the HLA-DP, TCF19 and EHMT2 genes may affect the chronic hepatitis B (CHB). To predict the degree of risk for chronicity of HBV, this study determined associations with these SNPs.

Methods

The participants for this study were defined into 4 groups; HCC (n = 230), CHB (n = 219), resolved HBV infection (n = 113) and HBV uninfected subjects (n = 123). The HLA-DP SNPs (rs3077, rs9277378 and rs3128917), TCF19 SNP (rs1419881) and EHMT2 SNP (rs652888) were genotyped.

Results

Due to similar distribution of genotype frequencies in HCC and CHB, we combined these two groups (HBV carriers). The genotype distribution in HBV carriers relative to those who resolved HBV showed that rs3077 and rs9277378 were significantly associated with protective effects against CHB in minor dominant model (OR = 0.45, p<0.001 and OR = 0.47, p<0.001). The other SNPs rs3128917, rs1419881 and rs652888 were not associated with HBV carriers.

Conclusions

Genetic variations of rs3077 and rs9277378, but not rs3128917, rs1419881 and rs652888, were significantly associated with HBV carriers relative to resolved HBV in Thai population.     

Antibody Maturation and Viral Diversification in HIV-Infected Women

Introduction

The Post-exposure Prophylaxis in Infants (PEPI)-Malawi trial evaluated infant antiretroviral regimens for prevention of post-natal HIV transmission. A multi-assay algorithm (MAA) that includes the BED capture immunoassay, an avidity assay, CD4 cell count, and viral load was used to identify women who were vs. were not recently infected at the time of enrollment (MAA recent, N = 73; MAA non-recent, N = 2,488); a subset of the women in the MAA non-recent group known to have been HIV infected for at least 2 years before enrollment (known non-recent, N = 54). Antibody maturation and viral diversification were examined in these women.

Methods

Samples collected at enrollment (N = 2,561) and 12–24 months later (N = 1,306) were available for serologic analysis using the BED and avidity assays. A subset of those samples was used for analysis of viral diversity, which was performed using a high resolution melting (HRM) diversity assay. Viral diversity analysis was performed using all available samples from women in the MAA recent group (61 enrollment samples, 38 follow-up samples) and the known non-recent group (43 enrollment samples, 22 follow-up samples). Diversity data from PEPI-Malawi were also compared to similar data from 169 adults in the United States (US) with known recent infection (N = 102) and known non-recent infection (N = 67).

Results

In PEPI-Malawi, results from the BED and avidity assays increased over time in the MAA recent group, but did not change significantly in the MAA non-recent group. At enrollment, HIV diversity was lower in the MAA recent group than in the known non-recent group. HRM diversity assay results from women in PEPI-Malawi were similar to those from adults in the US with known duration of HIV infection.

Conclusions

Antibody maturation and HIV diversification patterns in African women provide additional support for use of the MAA to identify populations with recent HIV infection.     

Patients with Blepharitis Are at Elevated Risk of Anxiety and Depression

Purpose

Population-based cohort study on the risk of anxiety and depression in patients with blepharitis is limited. This study evaluated whether blepharitis patients are at a higher risk of anxiety and depression.

Design

A retrospective cohort study.

Methods

We used the universal insurance claims data from 1997 to 2010 in Taiwan to identify annually patients with newly diagnosed blepharitis (N = 9764) and without the disease (N = 39056). Incidences, rate ratios (IRR) and hazard ratios (HR) of anxiety and depression were measured for both cohorts by baseline demographic characteristics and comorbidities until the end of 2010.

Results

Compared with the non-blepharitis cohort, the blepharitis cohort had higher incidence of anxiety (15.9 vs. 9.5 per 1000 person-years), with an adjusted HR of 1.58 (95% confidence interval (CI) = 1.46–1.70). The incidence of depression was also higher in the blepharitis cohort (7.66 vs. 5.05 per 1000 person-years), with an adjusted HR of 1.42 (95% CI = 1.28–1.58). The blepharitis cohort to the non-blepharitis cohort IRR decreased from 1.73 in the first quartile to 1.32 in the 4^th quartile for anxiety, and from 1.67 to 1.29 for depression.

Conclusions

Patients with blepharitis are at elevated risks of anxiety and depression. The risk is higher in earlier period after the diagnosis of blepharitis, and declines by time, but remains significantly higher for those with blepharitis than those without blepharitis.     

Role of HLA-DP Polymorphisms on Chronicity and Disease Activity of Hepatitis B Infection in Southern Chinese

Background and Aims

The association between HLA-DP single nucleotide polymorphisms (SNPs) and chronic hepatitis B virus (HBV) infection varies between different populations. We aimed to study the association between HLA-DP SNPs and HBV infection and disease activity in the Chinese population of Hong Kong.

Methods

We genotyped SNPs rs3077 (near HLA-DPA1) and rs9277378 and rs3128917 (both near HLA-DPB1) in 500 HBV carriers (hepatitis B surface antigen [HBsAg]-positive), 245 non-HBV infected controls (HBsAg- and antibody to hepatitis B core protein [anti-HBc]-negative), and 259 subjects with natural HBV clearance (HBsAg-negative, anti-HBc-positive). Inactive HBV carriers state was defined by HBV DNA levels <2,000 IU/ml and persistently normal alanine aminotransferase level for least 12 months.

Results

Compared to the non-HBV infected subjects, the HBV carriers had a significantly lower frequency of the rs3077 T allele (p = 0.0040), rs9277378 A allele (p = 0.0068) and a trend for lower frequency of rs3128917 T allele (p = 0.054). These alleles were associated with an increased chance of HBV clearance (rs3077: OR = 1.41, p = 0.0083; rs9277378: OR = 1.61, p = 0.00011; rs3128917: OR = 1.54, p = 0.00017). Significant associations between HLA-DP genotypes and HBV clearance were also found under different genetic models. Haplotype TAT was associated with an increased chance of HBV clearance (OR = 1.64, p = 0.0013). No association was found between these SNPs and HBV disease activity.

Conclusion

HLA-DP SNPs rs3077, rs9277378 and rs3128917 were associated with chronicity of HBV disease in the Chinese. Further studies are required to determine whether these SNPs influence the disease endemicity in different ethnic populations.     

RDW to Platelet Ratio: A Novel Noninvasive Index for Predicting Hepatic Fibrosis and Cirrhosis in Chronic Hepatitis B

Objective

To develop a simple predictive model for significant fibrosis and cirrhosis in chronic hepatitis B (CHB) using the routine hematological parameters of a complete blood count.

Methods

A total of 458 eligible CHB patients who had undergone a liver biopsy were randomly divided into two cohorts: an estimation group (n = 310) and a validation group (n = 148). Liver histology was assessed according to the Metavir scoring scheme. All common demographics, hematological parameters, HBeAg status, HBV DNA, and liver biochemistry were analyzed.

Results

Based on routinely available clinical parameters (age, sex, HBeAg status, HBV DNA, common hematological parameters of a complete blood cell count), a model for predicting significant fibrosis (Metavir score ≥2) in the estimation group was derived using platelets and red cell distribution width (RDW), and another model for predicting cirrhosis (Metavir score = 4) was derived using platelets, RDW and hemoglobin. A novel index, the RDW to platelet ratio (RPR), was developed to amplify the opposing effects of liver fibrosis on the RDW and platelets. The AUCs of the RPR for predicting significant fibrosis and cirrhosis were 0.825 and 0.884, respectively, which is superior to the AAR, FIB-4 and APRI in the estimation group. Compared with the two derived models, the RPR has a comparable predictive power for significant fibrosis and cirrhosis. Using optimized cutoffs (0.10 and 0.16), the RPR accurately predicted 63.1% of cases with significant fibrosis and 73.7% of cases with cirrhosis and accurately excluded 85.5% of the cases with mild fibrosis and 93.0% of the cases with no cirrhosis.

Conclusion

The RPR, a routinely available, inexpensive and easily calculated index, can predict significant fibrosis and cirrhosis in CHB patients with relatively high accuracy. The application of this index may reduce the need for liver biopsy in CHB patients.     

Influence of a Polyphenol-Enriched Protein Powder on Exercise-Induced Inflammation and Oxidative Stress in Athletes: A Randomized Trial Using a Metabolomics Approach

Objectives

Polyphenol supplementation was tested as a countermeasure to inflammation and oxidative stress induced by 3-d intensified training.

Methods

Water soluble polyphenols from blueberry and green tea extracts were captured onto a polyphenol soy protein complex (PSPC). Subjects were recruited, and included 38 long-distance runners ages 19–45 years who regularly competed in road races. Runners successfully completing orientation and baseline testing (N = 35) were randomized to 40 g/d PSPC (N = 17) (2,136 mg/d gallic acid equivalents) or placebo (N = 18) for 17 d using double-blinded methods and a parallel group design, with a 3-d running period inserted at day 14 (2.5 h/d, 70% VO_2max). Blood samples were collected pre- and post-14 d supplementation, and immediately and 14 h after the third day of running in subjects completing all aspects of the study (N = 16 PSPC, N = 15 placebo), and analyzed using a metabolomics platform with GC-MS and LC-MS.

Results

Metabolites characteristic of gut bacteria metabolism of polyphenols were increased with PSPC and 3 d running (e.g., hippurate, 4-hydroxyhippurate, 4-methylcatechol sulfate, 1.8-, 1.9-, 2.5-fold, respectively, P<0.05), an effect which persisted for 14-h post-exercise. Fatty acid oxidation and ketogenesis were induced by exercise in both groups, with more ketones at 14-h post-exercise in PSPC (3-hydroxybutyrate, 1.8-fold, P<0.05). Established biomarkers for inflammation (CRP, cytokines) and oxidative stress (protein carbonyls) did not differ between groups.

Conclusions

PSPC supplementation over a 17-d period did not alter established biomarkers for inflammation and oxidative stress but was linked to an enhanced gut-derived phenolic signature and ketogenesis in runners during recovery from 3-d heavy exertion.

Trial Registration

ClinicalTrials.gov, U.S. National Institutes of Health, identifier: {"type":"clinical-trial","attrs":{"text":"NCT01775384","term_id":"NCT01775384"}}NCT01775384     

Low Prevalence of Liver Disease but Regional Differences in HBV Treatment Characteristics Mark HIV/HBV Co-Infection in a South African HIV Clinical Trial

Background

Hepatitis B virus (HBV) infection is endemic in South Africa however, there is limited data on the degree of liver disease and geographic variation in HIV/HBV coinfected individuals. In this study, we analysed data from the CIPRA-SA ‘Safeguard the household study’ in order to assess baseline HBV characteristics in HIV/HBV co-infection participants prior to antiretroviral therapy (ART) initiation.

Methods

812 participants from two South African townships Soweto and Masiphumelele were enrolled in a randomized trial of ART (CIPRA-SA). Participants were tested for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV DNA. FIB-4 scores were calculated at baseline.

Results

Forty-eight (5.9%) were HBsAg positive, of whom 28 (58.3%) were HBeAg positive. Of those with HBV, 29.8% had an HBV DNA<2000 IU/ml and ALT<40 IU/ml ; 83.0% had a FIB-4 score <1.45, consistent with absent or minimal liver disease. HBV prevalence was 8.5% in Masiphumelele compared to 3.8% in Soweto (relative risk 2.3; 95% CI: 1.3–4.0). More participants in Masiphumelele had HBeAg-negative disease (58% vs. 12%, p = 0.002) and HBV DNA levels ≤2000 IU/ml, (43% vs. 6% p<0.007).

Conclusion

One third of HIV/HBV co-infected subjects had low HBV DNA levels and ALT while the majority had indicators of only mild liver disease. There were substantial regional differences in HBsAg and HbeAg prevalence in HIV/HBV co-infection between two regions in South Africa. This study highlights the absence of severe liver disease and the marked regional differences in HIV/HBV co-infection in South Africa and will inform treatment decisions in these populations.     

Increased HEV Seroprevalence in Patients with Autoimmune Hepatitis

Background

Hepatitis E virus (HEV) infection takes a clinically silent, self-limited course in the far majority of cases. Chronic hepatitis E has been reported in some cohorts of immunocompromised individuals. The role of HEV infections in patients with autoimmune hepatitis (AIH) is unknown.

Methods

969 individuals were tested for anti-HEV antibodies (MP-diagnostics) including 208 patients with AIH, 537 healthy controls, 114 patients with another autoimmune disease, rheumatoid arthritis (RA), and 109 patients with chronic HCV- or HBV-infection (HBV/HCV). Patients with AIH, RA and HBV/HCV were tested for HEV RNA. HEV-specific proliferative T cell responses were investigated using CFSE staining and in vitro stimulation of PBMC with overlapping HEV peptides.

Results

HEV-antibodies tested more frequently positive in patients with AIH (n = 16; 7.7%) than in healthy controls (n = 11; 2.0%; p = 0.0002), patients with RA (n = 4; 3.5%; p = 0.13) or patients with HBV/HCV infection (n = 2; 2.8%; p = 0.03). HEV-specific T cell responses could be detected in all anti-HEV-positive AIH patients. One AIH patient receiving immunosuppression with cyclosporin and prednisolone and elevated ALT levels had acute hepatitis E but HEV viremia resolved after reducing immunosuppressive medication. None of the RA or HBV/HCV patients tested HEV RNA positive.

Conclusions

Patients with autoimmune hepatitis but not RA or HBV/HCV patients are more likely to test anti-HEV positive. HEV infection should been ruled out before the diagnosis of AIH is made. Testing for HEV RNA is also recommended in AIH patients not responding to immunosuppressive therapy.     

Is There an Association between Work Stress and Diurnal Cortisol Patterns? Findings from the Whitehall II Study

Objective

The evidence on whether there is work stress related dysregulation of the hypothalamic-pituitary-adrenal axis is equivocal. This study assessed the relation between work stress and diurnal cortisol rhythm in a large-scale occupational cohort, the Whitehall II study.

Methods

Work stress was assessed in two ways, using the job-demand-control (JDC) and the effort-reward-imbalance (ERI) models. Salivary cortisol samples were collected six times over a normal day in 2002–2004. The cortisol awakening response (CAR) and diurnal cortisol decline (slope) were calculated.

Results

In this large occupational cohort (N = 2,126, mean age 57.1), modest differences in cortisol patterns were found for ERI models only, showing lower reward (β = −0.001, P-value = 0.04) and higher ERI (β = 0.002, P-value = 0.05) were related to a flatter slope in cortisol across the day. Meanwhile, moderate gender interactions were observed regarding CAR and JDC model.

Conclusions

We conclude that the associations of work stress with cortisol are modest, with associations apparent for ERI model rather than JDC model.     

Indocyanine Green Video Angiography Predicts Outcome of Extravasation Injuries

Background

Extravasation of cytotoxic drugs is a serious complication of systemic cancer treatment. Still, a reliable method for early assessment of tissue damage and outcome prediction is missing. Here, we demonstrate that the evaluation of blood flow by indocyanine green (ICG) angiography in the extravasation area predicts for the need of surgical intervention.

Methods

Twenty-nine patients were evaluated by ICG angiography after extravasation of vesicant or highly irritant cytotoxic drugs administered by peripheral i.v. infusion. Tissue perfusion as assessed by this standardized method was correlated with clinical outcome.

Results

The perfusion index at the site of extravasation differed significantly between patients with reversible tissue damage and thus healing under conservative management (N = 22) versus those who needed surgical intervention due to the development of necrosis (N = 7; P = 0.0001). Furthermore, in patients benefiting from conservative management, the perfusion index was significantly higher in the central extravasation area denoting hyperemia, when compared with the peripheral area (P = 0.0001).

Conclusions

In this patient cohort, ICG angiography as indicator of local perfusion within the extravasation area was of prognostic value for tissue damage. ICG angiography could thus be used for the early identification of patients at risk for irreversible tissue damage after extravasation of cytotoxic drugs.     

Comparison of Results from Different Imputation Techniques for Missing Data from an Anti-Obesity Drug Trial

Background

In randomised trials of medical interventions, the most reliable analysis follows the intention-to-treat (ITT) principle. However, the ITT analysis requires that missing outcome data have to be imputed. Different imputation techniques may give different results and some may lead to bias. In anti-obesity drug trials, many data are usually missing, and the most used imputation method is last observation carried forward (LOCF). LOCF is generally considered conservative, but there are more reliable methods such as multiple imputation (MI).

Objectives

To compare four different methods of handling missing data in a 60-week placebo controlled anti-obesity drug trial on topiramate.

Methods

We compared an analysis of complete cases with datasets where missing body weight measurements had been replaced using three different imputation methods: LOCF, baseline carried forward (BOCF) and MI.

Results

561 participants were randomised. Compared to placebo, there was a significantly greater weight loss with topiramate in all analyses: 9.5 kg (SE 1.17) in the complete case analysis (N = 86), 6.8 kg (SE 0.66) using LOCF (N = 561), 6.4 kg (SE 0.90) using MI (N = 561) and 1.5 kg (SE 0.28) using BOCF (N = 561).

Conclusions

The different imputation methods gave very different results. Contrary to widely stated claims, LOCF did not produce a conservative (i.e., lower) efficacy estimate compared to MI. Also, LOCF had a lower SE than MI.     

Epidemiology of Anorexia Nervosa in Men: A Nationwide Study of Finnish Twins

Background

To examine the epidemiology of anorexia nervosa in men, we screened Finnish male twins born in 1975–79.

Methods and Findings

Men (N = 2122) from FinnTwin16 birth cohorts were screened for lifetime eating disorders by a questionnaire. The screen positives (N = 18), their male co-twins (N = 10) and those with lifetime minimum BMI≤17.5 (N = 21) were administered the Structured Clinical Interview for DSM-IV anorexia nervosa. The incidence rate of anorexia nervosa for the presumed peak age of risk (10–24y) was 15.7 per 100 000 person-years; its lifetime prevalence was 0.24%. All probands had recovered from eating disorders, but suffered from substantial psychiatric comorbidity, which also manifested in their co-twins. Additionally, male co-twins displayed significant dissatisfaction with body musculature, a male-specific feature of body dysmorphic disorder.

Conclusions

Anorexia nervosa in males in the community is more common, transient and accompanied by more substantial comorbidity than previously thought.     

Medically Complex Pregnancies and Early Breastfeeding Behaviors: A Retrospective Analysis

Background

Breastfeeding is beneficial for women and infants, and medical contraindications are rare. Prenatal and labor-related complications may hinder breastfeeding, but supportive hospital practices may encourage women who intend to breastfeed. We measured the relationship between having a complex pregnancy (entering pregnancy with hypertension, diabetes, or obesity) and early infant feeding, accounting for breastfeeding intentions and supportive hospital practices.

Methods

We performed a retrospective analysis of data from a nationally-representative survey of women who gave birth in 2011–2012 in a US hospital (N = 2400). We used logistic regression to examine the relationship between pregnancy complexity and breastfeeding. Self-reported prepregnancy diabetes or hypertension, gestational diabetes, or obesity indicated a complex pregnancy. The outcome was feeding status 1 week postpartum; any breastfeeding was evaluated among women intending to breastfeed (N = 1990), and exclusive breastfeeding among women who intended to exclusively breastfeed (N = 1418). We also tested whether breastfeeding intentions or supportive hospital practices mediated the relationship between pregnancy complexity and infant feeding status.

Results

More than 33% of women had a complex pregnancy; these women had 30% lower odds of intending to breastfeed (AOR = 0.71; 95% CI, 0.52–0.98). Rates of intention to exclusively breastfeed were similar for women with and without complex pregnancies. Women who intended to breastfeed had similar rates of any breastfeeding 1 week postpartum regardless of pregnancy complexity, but complexity was associated with >30% lower odds of exclusive breastfeeding 1 week among women who intended to exclusively breastfeed (AOR = 0.68; 95% CI, 0.47–0.98). Supportive hospital practices were strongly associated with higher odds of any or exclusive breastfeeding 1 week postpartum (AOR = 4.03; 95% CI, 1.81–8.94; and AOR = 2.68; 95% CI, 1.70–4.23, respectively).

Conclusions

Improving clinical and hospital support for women with complex pregnancies may increase breastfeeding rates and the benefits of breastfeeding for women and infants.     

Cognitive Functions in Middle Aged Individuals Are Related to Metabolic Disturbances and Aerobic Capacity: A Cross-Sectional Study

Aims

Metabolic disturbances may contribute to cognitive dysfunction in patients with type 2 diabetes. We investigated the relation between cognitive impairment and metabolic deteriorations, low physical fitness, low-grade inflammation and abdominal obesity in middle aged individuals.

Methods

We conducted a cross-sectional study including 40 to 65 year-old patients with type 2 diabetes and limited co morbidity (N = 56), age-matched individuals with impaired glucose tolerance (N = 56) as well as age-matched controls with normal glucose tolerance (N = 72). Specific cognitive functions were assessed with focus on verbal memory, processing speed, executive functions, and a composite overall mean score. Oral glucose tolerance test, VO₂max test, systemic inflammation, DXA scanning and abdominal MRI were measured.

Results

Multiple linear regression analyses adjusting for age, gender and verbal intelligence demonstrated that a low score in processing speed, executive functions and overall cognitive function were related to high fasting C-peptide, as well as low insulin sensitivity, beta-cell function and VO₂max. Measurements of blood glucose, obesity and inflammation were not associated with cognitive function.

Conclusion

Low cognitive scores are seen in middle aged individuals with hyperinsulinemia, low insulin sensitivity, beta-cell function and low aerobic capacity. These findings emphasize the importance of appropriate lifestyle and not only blood glucose control in prevention of cognitive disability.