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PROTACs have emerged as promising therapeutic agents but their cellular uptake is often inefficient. Here, the authors show that reversible covalent warhead chemistry improves PROTAC intracellular accumulation and target engagement, and develop a dual inhibitor/degrader of Bruton’s tyrosine kinase

This study used a well characterized cohort of human immunodeficiency virus type 1 (HIV-1)-infected hemophiliacs to define the relationship between the SDF1-3'A allele, the plasma HIV-1 coreceptor tropism, and the natural history of HIV-1 disease. Subjects heterozygous or homozygous for the SDF1-3'A allele experienced higher rates of decline in CD4+ T cell counts over time than did those without the allele (P=.009). Moreover, they had an increased risk of progression to acquired immunodeficiency syndrome and death, a relationship that persisted even when baseline plasma HIV-1 RNA levels and CD4+ T cell counts or CCR5 Delta 32 and CCR2-64I genotype were controlled for. This relationship was even stronger in a subgroup of subjects for whom tropism data were available. Subjects with the SDF1-3'A allele were also more likely to have detectable X4-tropic viruses (P=.012), and, when tropism was included in the survival analyses, the effect of the SDF1-3'A allele on disease progression was no longer significant. Therefore, the increased frequency of X4-tropic viruses in subjects carrying the SDF1-3'A allele may explain the observed adverse effect that this allele has on the natural history of HIV-1 disease. Copyright © 2005 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

To determine the feasibility of increasing the calcium, protein and calorie intake of osteoporotic fracture patients by repeated dietary counselling delivered by a dietitian, a randomized controlled trial was conducted. Among 189 patients presenting with osteoporotic fractures to an Orthopaedics and Traumatology Department of a large regional hospital, 98 patients were randomized to the intervention group and 91 were randomized to the control group (with usual care). Intervention group received three sessions of dietary counselling with tailored made recommendations over a period of 4 months, while the control group only received dietary assessment and pamphlets on the prevention of osteoporosis. Almost all subjects in both intervention and control groups had calcium intake below the recommended level of 1000 mg at baseline. Half and 60% of subjects in both groups had total energy and protein intake below recommended levels respectively. The mean weights of control and intervention groups at baseline were 51.5 and 50.9 kg respectively, while the body mass index (BMI) were 22.6 (kg m(-2)) and 22.6 (kg m(-2)) respectively. After dietary intervention, significant increase of intake was seen in calcium intake (P = 0.0095 by t-test) in the intervention group. No significant increase was seen in protein or calorie intake. No significant change was observed in the body weight or BMI although there was a positive trend in the intervention group for all these parameters. We concluded that there was general malnutrition in Chinese elderly who presented with osteoporotic fractures. Dietary calcium could be increased by repeated professional dietary counselling. Future studies with longer duration and more objective clinical outcomes will be helpful to further demonstrate the long-term effects of dietary intervention on osteoporosis and other chronic diseases. [ABSTRACT FROM AUTHOR]

Background: Although poor oral health and several lifestyle factors have been found to be associated with cancer risk, their joint relationship has rarely been studied., Methods: We prospectively examined the associations of oral health and healthy lifestyle factors with cancer risk among 0.5 million rural and urban residents from the China Kadoorie Biobank (2004-2015). Oral health status was assessed from self-reported baseline questionnaires. A healthy lifestyle index comprising non-smoking, non-drinking, ideal body shape, physical activity and healthy diet was calculated for each participant, and categorized into favorable, intermediate and unfavorable lifestyle behavior. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) relating oral health and healthy lifestyle index to cancer risk using Cox proportional hazards models. We estimated the population attributable risk percent (PAR%) and 95% CIs using multivariate models., Results: During a median follow-up of 9 years, 23,805 new cancer cases were documented, with 52% from rural areas and 48% from urban areas. Compared with those with good oral health and favorable lifestyle, participants with poor oral health and unfavorable lifestyle had a higher risk of developing cancer in both rural (adjusted HR, 1.55 [95% CI, 1.39-1.74]; P for trend < 0.001) and urban areas (adjusted HR, 1.44 [95% CI, 1.24-1.67]; P for trend < 0.001). A significant multiplicative interaction between oral health and healthy lifestyle index on cancer risk was found in rural residents ( P for interaction = 0.004) rather than in urban residents ( P for interaction = 0.973). Assuming poor oral health as an additional risk factor, the PAR% of total cancer increased by 3.0% and 1.1% for participants with intermediate lifestyle and unfavorable lifestyle, respectively., Conclusions: These findings suggest a joint effect of oral health and common lifestyle factors on cancer risk. Promotion of healthy lifestyle by integration of good oral health would be beneficial to consider in cancer prevention strategies., Competing Interests: The authors declare that they have no competing interests., (© 2023 Chinese National Cancer Center. Published by Elsevier B.V.)

Background: Insufficient or decreasing physical activity is common in older adults. Most studies on physical activity changes and mortality were conducted in adults younger than 80 years old in developed countries. We aimed to investigate the relationship between changes in physical activity and longevity in the oldest old (80 years or older) population using the Chinese Longitudinal Healthy Longevity Survey., Methods: Participants aged 80 or older at baseline were categorized into four groups: 1) remaining physically inactive (n = 14,287), 2) remaining physically active (n = 5411), 3) shifting from being inactive to active (n = 1364), and 4) shifting from being active to inactive (n = 1401). We fitted accelerated failure time Weibull survival regression models, adjusting for baseline sociodemographics, lifestyle factors and disease status. We further examined whether the associations differed by subgroups., Results: A total of 15,707 participants died during follow-up (median duration of follow-up = 3.0 years). Compared with participants who remained physically inactive, those who remained active (fully adjusted event time ratio (ETR): 1.14, 95%CI: 1.11-1.17) or shifted from being inactive to active (fully adjusted ETR: 1.14, 95%CI: 1.08-1.20) had statistically significant longer survival time. No significant association was observed between remaining physically inactive and shifting from being active to inactive. Subgroup analyses showed consistent associations in nearly all strata., Conclusion: Maintaining frequent physical activity or shifting from being physically inactive to active was consistently associated with longer survival time in the oldest old population. Our findings provide evidence for encouraging older adults to regularly engage in physical activity to gain longevity benefits., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

BACKGROUND. Background parenchymal enhancement (BPE) may impact contrast-enhanced mammography (CEM) interpretation, although factors influencing the degree of BPE on CEM are poorly understood. OBJECTIVE. The purpose of our study was to evaluate relationships between clinical factors and the degree of early BPE on CEM. METHODS. This retrospective study included 207 patients (median age, 46 years) who underwent CEM between April 2020 and September 2021. Two radiologists independently assessed the degree of BPE on CEM as minimal, mild, moderate, or marked on the basis of two criteria (criterion 1, using the first of four obtained views; criterion 2, using the first two of four obtained views). The radiologists reached consensus for breast density on CEM. The EMR was reviewed for clinical factors. Radiologists' agreement for degree of BPE was assessed using weighted kappa coefficients. Univariable and multivariable analyses were performed to assess relationships between clinical factors and degree of BPE, treating readers' independent assessments as repeated measurements. RESULTS. Interreader agreement for degree of BPE, expressed as kappa, was 0.80 for both criteria. For both criteria, univariable analyses found degree of BPE to be negatively associated with age (both OR = 0.94), personal history of breast cancer (OR = 0.22-0.30), history of chemotherapy (OR = 0.18-0.21), history of radiation therapy (OR = 0.20-0.21), perimenopausal status (OR = 0.22-0.34), and postmenopausal status (OR = 0.10-0.11) and to be positively associated with dense breasts (OR = 4.13-4.26) and premenopausal status with irregular menstrual cycles (OR = 7.94-14.02). Among premenopausal patients with regular menstrual cycles, degree of BPE was lowest (using postmenopausal patients as reference) for patients in menstrual cycle days 8-14 (OR = 2.56-3.30). In multivariable analysis for both criteria, the only independent predictors of degree of BPE related to menstrual status and time of menstrual cycle (e.g., using premenopausal patients in days 1-7 as reference: OR = 0.21 for both criteria for premenopausal patients in days 8-14 and OR = 0.03-0.04 for postmenopausal patients). CONCLUSION. Clinical factors, including history of breast cancer or breast cancer treatment, breast density, menstrual status, and time of menstrual cycle, are associated with degree of early BPE on CEM. In premenopausal patients, the degree of BPE is lowest on days 8-14 of the menstrual cycle. CLINICAL IMPACT. Given the potential impact of BPE on diagnostic performance, the findings have implications for CEM scheduling and interpretation.

Objective: To examine whether and how sex and age modify the association between accelerometer-based physical activity (PA) and metabolic syndrome (MetS) among American (US) adults., Method: Adults aged ≥20 years old who participated in the mobile center examination during 2003-2006 in the National Health and Nutrition Examination Survey were included for analysis. The total minutes per day of moderate-to-vigorous PA (MVPA) was estimated using ActiGraph. Multivariable logistic regression was used to estimate the odds ratio (OR) of having MetS at an increasing MVPA time. The modification effects of gender and age on the association between MetS and MVPA time were examined by testing for two-way and three-way interaction terms of MVPA time, sex, and age in the model after adjusting for relevant covariates., Results: The prevalence of MetS generally decreased with the MVPA time and was lower in females than in males, although the sex difference varied across age groups. After adjusting for demographic and lifestyle covariates, there was a significant sex difference in how an increased MVPA time lowered the odds of MetS. This interactive effect also varied with age. MVPA benefitted young and middle-age populations up until about 65 years old for both sexes, and the protective effect weakened with age. Although the effect of MVPA was stronger for males than females at young ages, the rate at which it attenuated was quicker in males. The OR of MetS between males and females per unit change of MVPA time was 0.73 (95% CI: [0.57, 0.93]) at age = 25 years, compared to OR = 1.00 (95% CI: [0.88, 1.16]) at age = 60 years. Before the age of 50, the gender difference in the protective effect on MetS was larger at low MVPA levels and became smaller at higher MVPA levels. The male advantage was quite stable with an increasing MVPA time for ages 50-60, and no longer significant at older ages., Conclusions: Young and middle-age populations benefitted from MVPA, lowering the risk of MetS for both sexes. A longer MVPA time was associated with a greater decrease in the risk of MetS in young men than in women, but the sex difference reduced with age and was no longer apparent in older populations.

Background: There is limited research on the associations between serum nutritional biomarkers and mortality risk in patients with metabolic syndrome (MetS). Existing studies merely investigated the single-biomarker effect. Thus, this study aimed to investigate the combined effect of nutritional biomarker mixtures and mortality risk using the Bayesian kernel machine regression (BKMR) model in patients with MetS., Methods: We included the MetS patients, defined according to the 2018 Guideline on the Management of Blood Cholesterol from the National Health and Nutrition Examination Survey (NHANES) 2001-2006. A total of 20 serum nutritional biomarkers were measured and evaluated in this study. The Cox proportional hazard model and restricted cubic spline models were used to evaluate the individual linear and non-linear association of 20 nutritional biomarkers with mortality risk. Bayesian kernel machine regression (BKMR) was used to assess the associations between mixture of nutritional biomarkers and mortality risk., Results: A total of 1455 MetS patients had a median age of 50 years (range: 20-85). During a median of 17.1-year follow-up, 453 (24.72%) died: 146 (7.20%) caused by CVD and 87 (5.26%) by cancer. Non-linear and linear analyses indicated that, in total, eight individual biomarkers (α-carotene, β-carotene, bicarbonate, lutein/zeaxanthin, lycopene, potassium, protein, and vitamin A) were significantly associated with all-cause mortality (all p -values < 0.05). Results from BKMR showed an association between the low levels of the mixture of nutritional biomarkers and high risk of all-cause mortality with the estimated effects ranging from 0.04 to 0.14 (referent: medians). α-Carotene (PIP = 0.971) and potassium (PIP = 0.796) were the primary contributors to the combined effect of the biomarker mixture. The nutritional mixture levels were found to be negatively associated with the risk of cardiovascular disease (CVD) mortality and positively associated with the risk of cancer mortality. After it was stratified by nutrients, the mixture of vitamins showed a negative association with all-cause and CVD mortality, whereas the mixture of mineral-related biomarkers was positively associated with all-cause and cancer mortality., Conclusion: Our findings support the evidence that nutritional status was associated with long-term health outcomes in MetS patients. It is necessary for MetS patients to be concerned with certain nutritional status (i.e., vitamins and mineral elements).

Background: Prior studies on the relationship between bowel health and mortality have generally focused on the individual association of stool frequency or consistency with mortality but did not present a joint association. Therefore, we aimed to systematically evaluate the individual and joint associations of stool frequency and consistency with all-cause and cause-specific mortality in this study., Methods: A total of 14,574 participants from the National Health and Nutrition Examination Survey 2005-2010 were incorporated in this analysis. Survey sample-weighted Cox proportional hazards models adjusted for potential confounders were used to estimate hazard ratios (HRs) between bowel health measures and mortality risks., Results: During a median of 7.6 years of follow-up, 1502 deaths occurred, including 357 cancer deaths and 284 cardiovascular disease (CVD) deaths. The bowel habit of the most participants was 7 times/week (50.7%), and the most common type was "Like a sausage or snake, smooth and soft" (51.8%). Stool frequency displayed a parabolic relationship with all-cause mortality, and less than 7 times/week is a significant risk factor for mortality (HR for 1 time/week: 1.43, p -values = 0.04. HR for 6 times/week: 1.05, p -value = 0.03). Analyzing the joint association of stool frequency and consistency on mortality clarified the limitations of only inspecting the effects of either individual factor. Compared with 7 times/week of normal stool, infrequent soft stools at 4 times/week were associated with 1.78-, 2.42-, and 2.27-times higher risks of all-cause, cancer, and CVD mortality, respectively., Conclusion: Analyses of bowel health should consider the joint effects of stool frequency and stool consistency. Self-appraisal of stool frequency and consistency may be a simple but useful tool for informing about major chronic illnesses.

Objectives: Gamma-glutamyl transpeptidase (GGT) is the most widely used biomarker in the early diagnosis of biliary atresia (BA), but its diagnostic efficacy is questionable in different sub-populations. We aim to identify subgroups that are defined by specific variables with cut-offs and can significantly affect the diagnostic efficacy of GGT for detecting BA., Methods: Clinical data from 1273 infants with neonatal obstructive jaundice (NOJ) diagnosed between January 2012 and December 2017 at the Children's Hospital of Fudan University were enrolled, reviewed, and analyzed. Random forest-based Virtual Twins method was used to identify potential subgroups., Results: Hemoglobin (HGB) and fasting gallbladder filling were selected as defining variables. The diagnostic efficacy of GGT was significantly better (AUC = 0.855) for patients with hemoglobin (HGB) ≤ 105 g/L and a gallbladder that was not or poorly filled. Diagnostic efficacy was worst in the subgroup defined by HGB > 105 g/L (AUC = 0.722). The inclusion of interaction terms between GGT and the subgroups in a logistic regression model significantly improved (p = 0.002) prediction performance., Conclusions: This study provides evidence that the diagnostic efficacy of GGT can differ significantly across different subgroups. Therefore, a GGT diagnostic result should be interpreted cautiously when patients belong to subgroups with low diagnostic efficacy. The development of a prediction model and/or clinical diagnostic pathway for early detection of BA should also account for the heterogeneous diagnostic efficacy of GGT., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Radiomics plays an important role in the field of oncology. Few studies have focused on the identification of factors that may influence the classification performance of radiomics models. The goal of this study was to use contrast-enhanced mammography (CEM) images to identify factors that may potentially influence the performance of radiomics models in diagnosing breast lesions., Methods: A total of 157 women with 161 breast lesions were included. Least absolute shrinkage and selection operator (LASSO) regression and the random forest (RF) algorithm were employed to construct radiomics models. The classification result for each lesion was obtained by using 100 rounds of five-fold cross-validation. The image features interpreted by the radiologists were used in the exploratory factor analyses. Univariate and multivariate analyses were performed to determine the association between the image features and misclassification. Additional exploratory analyses were performed to examine the findings., Results: Among the lesions misclassified by both LASSO and RF ≥ 20% of the iterations in the cross-validation and those misclassified by both algorithms ≤5% of the iterations, univariate analysis showed that larger lesion size and the presence of rim artifacts and/or ripple artifacts were associated with more misclassifications among benign lesions, and smaller lesion size was associated with more misclassifications among malignant lesions (all p <  0.050). Multivariate analysis showed that smaller lesion size (odds ratio [OR] = 0.699, p = 0.002) and the presence of air trapping artifacts (OR = 35.568, p = 0.025) were factors that may lead to misclassification among malignant lesions. Additional exploratory analyses showed that benign lesions with rim artifacts and small malignant lesions (< 20 mm) with air trapping artifacts were misclassified by approximately 50% more in rate compared with benign and malignant lesions without these factors., Conclusions: Lesion size and artifacts in CEM images may affect the diagnostic performance of radiomics models. The classification results for lesions presenting with certain factors may be less reliable., (© 2022. The Author(s).)

Background: There is a strong connection between oral health and overall wellness. We aim to examine the association between poor oral health and the risk of developing or dying of cancer, and whether the association differs by residential area., Methods: Between 2004 and 2008, a total of 510,148 adults free of cancer were included from the China Kadoorie Biobank study and thereafter followed up to 2015. Poor oral health was assessed from a self-reported baseline questionnaire and defined as a combination of rarely brushing teeth and always gum bleeding. We used Cox proportional hazards models to estimate the hazard ratio (HR) of cancer risk and its associated 95% confidence interval (CI) according to oral health status., Findings: Overall, 14.9% of participants (19.7% in rural areas and 8.8% in urban areas) reported poor oral health at baseline. After 4,602,743 person-years of follow-up, we identified 23,805 new cancer cases and 11,973 cancer deaths, respectively. Poor oral health was associated with higher risks of total cancer incidence (HR: 1.08, 95% CI: 1.04-1.12) and death (HR: 1.10, 95% CI: 1.05-1.16). For the site-specific cancers, poor oral health was significantly associated with higher risk of stomach cancer incidence (cases: 2964, HR: 1.10, 95% CI: 1.00-1.22), esophageal cancer incidence (cases: 2119, HR: 1.19, 95% CI: 1.07-1.33), esophageal cancer death (cases: 1238, HR: 1.29, 95% CI: 1.12-1.49), liver cancer incidence (cases: 2565, HR: 1.18, 95% CI: 1.06-1.32), and liver cancer death (cases: 1826, HR: 1.20, 95% CI: 1.05-1.36). This positive association was stronger among rural residents compared to urban residents (interaction test P < 0.01)., Interpretation: Our findings indicate that poor oral health is associated with higher risk for cancers, especially digestive system cancers. Promotion of oral health in the general population, especially for rural residents, could have valuable public health significance in preventing major systemic diseases., Funding: Supported by grants (2021YFC2500400, 2016YFC0900500, 2016YFC0900501, 2016YFC0900504) from the National Key Research and Development Program of China, grants from the Kadoorie Charitable Foundation in Hong Kong and grants grants (088158/Z/09/Z, 104085/Z/14/Z, 202922/Z/16/Z) from Wellcome Trust in the UK. CKB is supported by the Kadoorie Charitable Foundation (KCF) in Hong Kong., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Author(s).)

Background: Previous studies have reported an increased risk for second primary malignancies (SPMs) after cervical cancer (CC). This study aims to quantify and assess the risk of developing SPMs in long-term survivors of CC., Methods: A population-based cohort of CC patients aged 20-79 years was obtained from the Surveillance, Epidemiology, and End Results (SEER) database. A competing risk model and corresponding nomogram were constructed to predict the 3-, 5-, and 10-year cumulative risks of SPMs. A Fine-Gray plot was created to validate the model. Finally, we performed decision curve analysis (DCA) to evaluate the clinical usefulness of the model by calculating the net benefit., Results: A total of 34,295 patients were identified, and approximately 6.3% of the study participants developed SPMs. According to the multivariable competing-risk model, older black CC survivors with localized disease who were treated with radiation therapy were more susceptible to SPMs. The 3-, 5-, and 10-year cumulative incidences of SPMs were 2.5%, 3.6%, and 6.2%, respectively. Calibration curves showed good agreement between the predicted and observed models. The DCA yielded a wide range of risk thresholds at which the net benefits could be obtained from our proposed model., Conclusions: This study provides physicians with a practical, individualized prognostic estimate to assess the risk of SPMs among CC survivors. CC survivors remain at a high risk of developing SPMs, and further surveillance should focus especially on the patients with black race, older age, localized disease, or those having received radiation therapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-2003). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Missing data are common in statistical analyses, and imputation methods based on random forests (RF) are becoming popular for handling missing data especially in biomedical research. Unlike standard imputation approaches, RF-based imputation methods do not assume normality or require specification of parametric models. However, it is still inconclusive how they perform for non-normally distributed data or when there are non-linear relationships or interactions., Methods: To examine the effects of these three factors, a variety of datasets were simulated with outcome-dependent missing at random (MAR) covariates, and the performances of the RF-based imputation methods missForest and CALIBERrfimpute were evaluated in comparison with predictive mean matching (PMM)., Results: Both missForest and CALIBERrfimpute have high predictive accuracy but missForest can produce severely biased regression coefficient estimates and downward biased confidence interval coverages, especially for highly skewed variables in nonlinear models. CALIBERrfimpute typically outperforms missForest when estimating regression coefficients, although its biases are still substantial and can be worse than PMM for logistic regression relationships with interaction., Conclusions: RF-based imputation, in particular missForest, should not be indiscriminately recommended as a panacea for imputing missing data, especially when data are highly skewed and/or outcome-dependent MAR. A correct analysis requires a careful critique of the missing data mechanism and the inter-relationships between the variables in the data.

As China is one of high MDR-TB burden countries, it is important to determine the drug resistant pattern and clinical characteristics of multidrug resistant tuberculosis (MDR-TB). We conducted a comprehensive and nationwide study on MDR-TB in 17 provinces for the period from June 2009 to June 2015, and a total of 1154 cases of MDR-TB were finally investigated. The study sought to assess the clinical features and contrast drug susceptibility profiles of MDR-TB patients in China. Cavitary disease, young age, and long duration of TB disease among MDR-TB patients were important predictors. A high resistance proportion of first-line drugs was observed in Beijing, Shanghai and Tianjin. Resistant proportions of second-line anti-TB drugs in western region for amikacin, aminosalicylic acid, and levofloxacin were higher than eastern and central regions. High levels of drug resistance were seen in earlier cases (before 2011) and outpatients. We found high levels of resistance to 1st- and 2nd-line drugs in all settings, with considerable variabilities in terms of different Directly Observed Treatment Short Course (DOTS) programme, level of economic development(eastern, central and western regions) and patient source (inpatients and outpatients). Timely drug susceptibility testing (DST) and effective management are necessary to ensure an early detection of MDR-TB and its proper treatment., Competing Interests: The authors have declared that no competing interests exist.

Background: Over the past two or three decades, the prevalence of asthma has significantly increased worldwide; therefore, effective treatment without side effects is of utmost importance. Traditional Chinese medicine (TCM) plays a vital role in reducing symptoms and improving the quality of life in persistent-asthma patients. The aim of this study is to evaluate the efficacy of the Jia Wei Yang He (JWYH) formula in the treatment of asthma and to explore the relationship between the airway microbiome and TCM treatment in asthma patients., Methods/design: This multicenter, parallel-arm, randomized, double-blinded, placebo-controlled trial will assess the efficacy of JWYH in asthma patients with usual care. Persistent-asthma patients without life-threatening disease will be enrolled on a random basis and are equally assigned to a high- or a low-dose JWYH plus usual care group, or a placebo plus usual care group. Patients are followed up for 4 months. Accordingly, 240 patients will yield sufficient statistical power to determine a difference between groups. Based on modified intent-to-treat (mITT) analyses, the three groups will be compared at 4 weeks after the beginning of treatment. The primary efficacy measurement is the mean change in the Asthma Control Test (ACT) score from baseline to 4 weeks post treatment. Secondary outcomes include forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), peak expiratory flow (PEF), and asthma exacerbations. This trial also includes analyses of the associations between airway microbiome and asthma treatment., Discussion: In this study, a randomized clinical trial design is described. The results are based on several outcomes that estimate the efficacy of the JWYH formula and prospective links between the airway microbiome and asthma treatment., Trial Registration: ClinicalTrials.gov, ID: NCT03299322 . Registered on 3 October 2017.

Introduction: Atrial fibrillation (AF) is known as one of the independent risk factors for stroke and might significantly increase its risk. Nowadays, direct-acting oral anticoagulants (DOACs) have been developed and demonstrated a more promising option to warfarin, the conclusion for safety is heterogeneous in different studies. It indicates the importance of comprehensive comparison of safety between DOACs and warfarin., Material and Methods: Four studies including ARISTOTLE, ENGAGE AF-TIMI 48, RE-LY and ROCKET-AF were included in the meta-analysis to perform separate meta-analyses for high-dose regimen, low-dose regimen and their combination. The events included major bleeding, intracranial haemorrhage, gastrointestinal bleeding, non-major clinically relevant and minor bleeding., Results: Regardless of high dose or low dose regimen, DOACs were associated with lower risk of intracranial haemorrhage but due to no significant association for gastrointestinal bleeding, the overall effect measured by the major bleeding was also insignificant (High dose: RR=0.86, 95% CI 0.73 to 1.01; Low dose: RR=0.63, 95% CI 0.38 to 1.04). However, the combined result of high-dose and low-dose regimens showed DOACs were associated with lower risk of major bleeding events (RR=0.77, 95% CI 0.63 to 0.95)., Conclusions: Meta-analyses have showed the comparative safety of the direct-acting oral anticoagulants than warfarin in most endpoints and even better in intracranial haemorrhage. Therefore, without the need of INR monitoring, DOACs demonstrated promising alternatives to warfarin in prevention of stroke in patients with AF., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The CONSORT statement requires clinical trials to report confidence intervals, which help to assess the precision and clinical importance of the treatment effect. Conventional sample size calculations for clinical trials, however, only consider issues of statistical significance (that is, significance level and power)., Method: A more consistent approach is proposed whereby sample size planning also incorporates information on clinical significance as indicated by the boundaries of the confidence limits of the treatment effect., Results: The probabilities of declaring a "definitive-positive" or "definitive-negative" result (as defined by Guyatt et al., CMAJ 152(2):169-173, 1995) are controlled by calculating the sample size such that the lower confidence limit under H 1 and the upper confidence limit under H 0 are bounded by relevant cut-offs. Adjustments to the traditional sample size can be directly derived for the comparison of two normally distributed means in a test of nonequality, while simulations are used to estimate the sample size for evaluating the hazards ratio in a proportional-hazards model., Conclusions: This sample size planning approach allows for an assessment of the potential clinical importance and precision of the treatment effect in a clinical trial in addition to considerations of statistical power and type I error.

Objective: To assess the efficacy and safety of the new oral anticoagulants versus warfarin in patients with atrial fibrillation by the meta-analyses performed for 5 studies ARISTOTLE, ENGAGE AF-TIMI 48, RE-LY, ROCKET-AF, and J-ROCKET., Methods: The events including primary efficacy endpoint (stroke and systemic embolism), ischemic stroke, hemorrhagic stroke, all-cause mortality, and myocardial infarction were used for efficacy analysis and those including major bleeding, intracranial hemorrhage, and gastrointestinal bleeding were used for safety analysis. Instead of combining both doses to 1 meta-analysis, the high-dose groups of RE-LY (150 mg twice daily) and ENGAGE AF-TIMI 48 (60 mg twice daily) were combined with the single dose studies ARISTOTLE, ROCKET-AF, and J-ROCKET. A separate meta-analysis was done for the low-dose groups of RE-LY (110 mg twice daily) and ENGAGE AF-TIMI 48 (30 mg twice daily)., Results: The high-dose regimen had better performance than low dose in efficacy. In addition, low-dose regimen demonstrated to significantly reduce the risk of hemorrhagic stroke, all-cause mortality, and intracranial hemorrhage., Conclusions: The new oral anticoagulants demonstrated promising alternatives to warfarin in prevention of stroke in patients with atrial fibrillation.

Background: Multi-dimensional behavioral rating scales like the CBCL and YSR are available for diagnosing psychosocial maladjustment in adolescents, but these are unsuitable for large-scale usage since they are time-consuming and their many sensitive questions often lead to missing data. This research applies multiple imputation to tackle the effects of missing data in order to develop a simple questionnaire-based predictive instrument for psychosocial maladjustment., Methods: Questionnaires from 2919 Chinese sixth graders in 21 schools were collected, but 86% of the students were missing one or more of the variables for analysis. Fifteen (10 training, 5 validation) samples were imputed using multivariate imputation chain equations. A ten-variable instrument was constructed by applying stepwise variable selection algorithms to the training samples, and its predictive performance was evaluated on the validation samples., Results: The instrument had an AUC of 0.75 (95% CI: 0.73 to 0.78) and a calibration slope of 0.98 (95% CI: 0.86 to 1.09). The prevalence of psychosocial maladjustment was 18%. If a score of > 1 was used to define a negative test, then 80% of the students would be classified as negative. The resulting test had a diagnostic odds ratio of 5.64 (95% CI: 4.39 to 7.24), with negative and positive predictive values of 88% and 43%, and negative and positive likelihood ratios of 0.61 and 3.41, respectively., Conclusions: Multiple imputation together with internal validation provided a simple method for deriving a predictive instrument in the presence of missing data. The instrument's high negative predictive value implies that in populations with similar prevalences of psychosocial maladjustment test-negative students can be confidently excluded as being normal, thus saving 80% of the resources for confirmatory psychological testing.

Background: Although much has been written on developing better procedures for variable selection, there is little research on how it is practiced in actual studies. This review surveys the variable selection methods reported in two high-ranking Chinese epidemiology journals., Methods: Articles published in 2004, 2006, and 2008 in the Chinese Journal of Epidemiology and the Chinese Journal of Preventive Medicine were reviewed. Five categories of methods were identified whereby variables were selected using: A--bivariate analyses; B--multivariable analysis; e.g. stepwise or individual significance testing of model coefficients; C--first bivariate analyses, followed by multivariable analysis; D--bivariate analyses or multivariable analysis; and E--other criteria like prior knowledge or personal judgment., Results: Among the 287 articles that reported using variable selection methods, 6%, 26%, 30%, 21%, and 17% were in categories A through E, respectively. One hundred sixty-three studies selected variables using bivariate analyses, 80% (130/163) via multiple significance testing at the 5% alpha-level. Of the 219 multivariable analyses, 97 (44%) used stepwise procedures, 89 (41%) tested individual regression coefficients, but 33 (15%) did not mention how variables were selected. Sixty percent (58/97) of the stepwise routines also did not specify the algorithm and/or significance levels., Conclusions: The variable selection methods reported in the two journals were limited in variety, and details were often missing. Many studies still relied on problematic techniques like stepwise procedures and/or multiple testing of bivariate associations at the 0.05 alpha-level. These deficiencies should be rectified to safeguard the scientific validity of articles published in Chinese epidemiology journals.

Schistosomiasis control in China has, in general, been very successful during the past several decades. However, the rebounding of the epidemic situation in some areas in recent years raises concerns about a sustainable control strategy of which locating active transmission sites (ATS) is a necessary first step. This study presents a systematic approach for locating schistosomiasis ATS by combining the approaches of identifying high risk regions for schisotosmiasis and extracting snail habitats. Environmental, topographical, and human behavioural factors were included in the model. Four significant high-risk regions were detected and 6 ATS were located. We used the normalized difference water index (NDWI) combined with the normalized difference vegetation index (NDVI) to extract snail habitats, and the pointwise 'P-value surface' approach to test statistical significance of predicted disease risk. We found complicated non-linear relationships between predictors and schistosomiasis risk, which might result in serious biases if data were not properly treated. We also found that the associations were related to spatial scales, indicating that a well-designed series of studies were needed to relate the disease risk with predictors across various study scales. Our approach provides a useful tool, especially in the field of vector-borne or environment-related diseases.

A new generalization of the negative binomial distribution (GNBD) is introduced and fitted to counts of Oncomelania hupensis, the intermediate host of Schistosoma japonicum, made, in areas of Chinese lakeland and marshland, early in the winter of 2005 and late in the spring of 2006. The GNBD was found to fit the snail data better than the standard negative binomial distribution (NBD) that has previously been widely used to model the distribution of O. hupensis. With two more parameters than the NBD, the GNBD can integrate many discrete distributions and is more flexible than the NBD in modelling O. hupensis. It also provides a better theoretical distribution for the quantitative study of O. hupensis, especially in building an accurate prediction model of snail density. The justification for adopting the GNBD is discussed. The GNBD allows researchers to broaden the field in the quantitative study not only of O. hupensis and schistosomiasis japonica but also of other environment-related helminthiases and family-clustered diseases that have, traditionally, been modelled using the NBD.

Schistosomiasis epidemic is reemerging in some areas of China. The extensive snail habitat is a major challenge for a sustainable schistosomiasis control. Direct surveillance on snails for the disease control is no longer a desirable disease control approach due to current low density of infected snails and reduced funding. In this study the benefit of indirect monitoring of acute schistosomiasis cases, using spatial methods including disease mapping and spatial clustering analysis was explored in Guichi, China. Significant global clustering existed for acute cases and two statistically significant spatial clusters were detected, and subsequently validated by field surveys. Our study indicates that the application of geographic information system (GIS) and spatial methods are useful in the epidemiologic surveillance and risk assessment for acute schistosomiasis, providing an alternative approach with minimal funds required.

Unlabelled: No large-scale evaluations of osteoporosis screening tools have been done in men. OST and MOST were examined among 4658 US Caucasian and 1914 Hong Kong Chinese men. Both tools have high negative predictive values, accurately screening out men with low risk, and saving a third of DXA tests., Introduction: Prior investigations have studied the performance of osteoporosis screening tools in women, but no large-scale evaluations have been done in men., Methods: This study examines the performance of the Osteoporosis Self-assessment Tool (OST), the Male Osteoporosis Screening Tool (MOST), quantitative ultrasound index (QUI), and body weight as screening tools. Osteoporosis was defined by a dual-energy X-ray absorptiometry (DXA) measured bone mineral density (BMD) T-score < or =-2.5. Four thousand six hundred and fifty-eight US Caucasian and 1914 Hong Kong Chinese men, aged > or =65 years and community-dwelling, were included in the analysis. Receiver operating characteristic (ROC) analysis was used to compare the area under the ROC curve (AUC) between different screening tools., Results: MOST had a significantly larger AUC (> or =0.8) than OST, QUI, and body weight in detecting osteoporosis. Using the second tertile as cutoff, OST and MOST yielded sensitivities of around 90% and negative predictive values (NPVs) of >97%, accurately screening out Caucasian and Chinese men with low risk of osteoporosis., Conclusions: OST and MOST can effectively rule out osteoporosis for both Caucasian and Chinese men, and compared to referring men 65 years and older for BMD DXA testing, they save a third of DXA resources.

Inhibitory antibodies to factors VIII or IX have the potential to affect a broad range of outcomes among people with hemophilia; however, their possible effect on growth and maturation has not been explored. We evaluated skeletal maturation (bone age), pubertal progression, serum testosterone levels, height velocity, and stature in the multicenter Hemophilia Growth and Development Study. A total of 333 children and adolescents (mean age, 12.4 years) were enrolled from 1989 to 1990 and followed for 7 years. Of these, 18% (n = 60) had a history of inhibitors. Bone age among HIV(-) adolescents with a history of inhibitors lagged 9 or more months behind those without inhibitors at every age from 12 to 15 years. Those with a history of inhibitors were older at every Tanner stage transition, attained a lower maximum growth velocity, and their serum testosterone levels were significantly lower compared with those without inhibitors. Delays were greater among HIV(+) patients with a history of inhibitors compared with those without inhibitors; however, the differences were generally small and not statistically significant. The results of this investigation underscore the importance of monitoring the growth and maturation of children and adolescents with hemophilia, particularly those with inhibitors.

Objective: Although it has been suggested that depression is common in patients with chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), few studies on the association between chronic respiratory diseases and depression have been conducted in the community., Method: Data from the baseline examination of two cohort studies, Mr and Ms Os, Hong Kong were used. Three thousand nine hundred and ninety-eight Hong Kong men and women aged 65 to 92 were recruited. Depression was assessed by face-to-face interview, using the short-form of a validated Chinese version of the Geriatric Depression Scale (GDS). Chronic respiratory disease was assessed by subjects' self reports of chronic respiratory disease (chronic bronchitis, emphysema and asthma) diagnosed by medical doctors. Adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CI) for depression among subjects with chronic respiratory diseases relative to those without (controls) were calculated, after adjustments were made for potential confounders., Results: Chronic respiratory disease was associated with a higher prevalence of depressive disorders with an odds ratio of 1.58 (95% CI = 1.12-2.13) after adjustment was made for age, sex, cigarette smoking, alcohol drinking and history of cardiovascular diseases when compared with controls. For those subjects with self report of chronic respiratory disease and who screened positive for depression (n = 44), none were on antidepressants. Among subjects who screened positive for depression without self-report of chronic respiratory disease (n = 328), only 2.74% (n = 9) were on antidepressants., Conclusions: We conclude that chronic respiratory disease is independently associated with depression in Chinese elderly. Moreover, depression in the elderly is under-treated in those with and without chronic respiratory disease. Clinicians, especially primary care physicians in the community, should be more aware of increased prevalence of depression in patients with chronic respiratory disease.

The aim of this study was to establish bone mineral density (BMD) reference norms for Hong Kong Chinese using Hologic QDR 2000 and 4500 densitometers, and to estimate the prevalence of osteoporosis in the population. Altogether, 4,274 subjects (2,415 females and 1,859 males), aged 9-94 years old, were recruited using a combination of private solicitation and public advertising from schools, community centers, nursing homes, housing estates, and the general community in Hong Kong. Among females, BMD increased by 20% at the total hip and 48% at the lumbar spine between ages 10 and 20 but remained essentially constant between ages 20 and 40. Between ages 40 and 70, BMD declined by 17% at the total hip and 23% at the spine. Total hip BMD continued to drop after age 70 but little change in spine BMD was observed. Among males, BMD increased by 45% at the total hip and 77% at the spine between age 10 and 30. Between ages 30 and 80, total hip BMD decreased by 20%. Lumbar spine BMD decrease was milder, showing a loss of 4% between ages 30 to 50 and remaining relatively constant afterwards. The prevalence of osteoporosis was consistently overestimated when using Hologic-supplied Caucasian cutoffs as compared with local Chinese cutoffs. The prevalence of osteoporosis among Chinese women 50 years or older was 37% and 16% at the spine and total hip, respectively, while that among Chinese men 50 years or older was 7% and 6% at the spine and total hip, respectively. Prior studies have been limited by size or restricted to women. This study represents the largest sample of Hong Kong Chinese amassed to date, provides continuous BMD reference values from ages 10 to 85 for both women and men, and yields more reliable estimates of the prevalence of osteoporosis for the population.

Several osteoporosis risk instruments have been proposed to select women for bone densitometry, but no validated instruments are currently available for men. This study aims to address this deficiency by developing and validating a Male Osteoporosis Screening Tool (MOST) for Chinese men. Two thousand ambulatory men, aged 65 and above, were recruited from the general community in Hong Kong, and a cohort of 1,970 men with valid total hip and lumbar spine dual-energy X-ray absorptiometry (DXA) measurements was included in the current analysis. A 60% random sample was selected as the training sample for developing the screening tool, and the remaining 40% constituted the validation sample. Logistic regression and receiver operating characteristic (ROC) analysis were used to identify the simplest combination of risk factors to be included in the screening tool for predicting osteoporosis at the femoral neck, total hip, or lumbar spine. Body weight and quantitative ultrasound index (QUI) were found to contribute significantly to the area under the ROC curve (AUC), yielding an AUC of 0.823 in the training sample. The resulting MOST had a sensitivity of 94% and a specificity of 46% when using a cutoff score of 3. MOST had an AUC of 0.839 in the validation sample. The risk of osteoporosis was 1% among those with MOST scores < or = 2, but 72% among those with MOST scores > 7. Using a cutoff of 3, the negative predictive value was 97.5% which suggests that the 42% with MOST scores < or = 3 may be accurately screened out as being without osteoporosis, thus saving two fifths of our DXA resources. The positive predictive value was 72% when using a cutoff of 7, implying that MOST cannot replace DXA for case-finding purposes. Nevertheless, for resource allocation and patient satisfaction, it is prudent and economical to offer DXA screening first to the 6% with MOST scores > 7.

Background: Several studies have documented the substantial health and economic burdens associated with sarcopenia among the elderly, but there has been no systematic study among Asians. A cross-sectional survey of elderly community-dwelling Chinese volunteers (262 men and 265 women), aged 70 years and older, was undertaken in Hong Kong. The purposes of this study were to evaluate the prevalence of and risk factors for sarcopenia in elderly Chinese, and to compare these observations with those in white persons., Methods: Muscle mass was estimated by dual-energy X-ray absorptiometry. In this study, sarcopenia was defined as a total adjusted skeletal muscle mass two standard deviations or more below the normal mean for young Asian men and women in this study. The relationship between risk factors (alcohol consumption, cigarette smoking, regular exercise, body mass index, medical conditions) and sarcopenia was studied by multiple logistic regression., Results: The prevalence of sarcopenia was 12.3% in Chinese men and 7.6% in Chinese women aged 70 years and older, which was slightly lower than figures observed in white persons. Being underweight was a significant risk factor in both men (odds ratio, 39.1; 95% confidence interval, 11.3 to 134.6) and women (odds ratio, 9.7; 95% confidence interval, 2.8 to 33.8). No other risk factors were found in Chinese men or women., Conclusions: Sarcopenia exists among elderly Chinese men and women, albeit at a lower rate than in white persons. This may be due to the lower muscle mass among young men and women or to an attenuated rate of loss in muscle mass with aging in the Chinese elderly. Being underweight is a major risk factor for sarcopenia in both sexes.

The relationship between hepatitis C virus (HCV) genotype and HCV and human immunodeficiency virus (HIV) type 1 disease is not well defined. The present study analyzed data from a cohort of 207 HIV-1-infected and 126 HIV-1-uninfected children and adolescents with hemophilia who enrolled in the Hemophilia Growth and Development Study and were followed for 7 years. The mean HCV RNA level was higher in the participants in the HCV genotype 1 group than in the participants the HCV non-genotype 1 group, among both the HIV-1-infected (difference, +0.33 log(10) copies/mL; P=.038) and HIV-1-uninfected (difference, +0.59 log(10) copies/mL; P=.008) participants. Although HCV genotype was not associated with differences in HIV-1 RNA level, a significantly lower mean CD4(+) T cell count (difference, -127 cells/ microL; P=.026) and percentage of CD4(+) T cells (difference, -4.3%; P=.027) were observed in the participants in the HCV genotype 1 group, compared with those in the participants in the HCV non-genotype 1 group. In addition, the participants in the HCV genotype 1 group were at increased risk for progression to AIDS-related mortality (hazard ratio, 2.44; P=.037). The present study suggests that HCV infection and genotype may influence the natural history of HCV and HIV-1 disease.

Objectives: Although hydroxyurea is effective in treating adults with sickle-cell anemia (SCA), there is concern that it may adversely affect growth in children. We report the growth characteristics of patients in the Phase I-II pediatric hydroxyurea trial (HUG-KIDS) before and during treatment at the maximum tolerated dose for one year., Study Design: Children and adolescents with SCA (n = 68), aged 5 to 16 years at baseline, reached the maximum tolerated dose and had serial height, weight, and Tanner stage measurements. Data from the Cooperative Study of Sickle Cell Disease (CSSCD) were used for comparison. Mixed-effects models were used to compare serial measurements as a function of age and group., Results: In girls, there were no significant differences in height or weight among the pretreatment, on-treatment, and CSSCD groups. Compared with the CSSCD group, HUG-KIDS boys were heavier starting at age 9 years, and pretreatment HUG-KIDS boys were taller starting at age 7 years. The Tanner stage transitions took place at appropriate ages., Conclusions: Hydroxyurea treatment had no adverse effect on height or weight gain or pubertal development in school-aged children with SCA.

Objectives: We characterized a population-based cohort of school-aged children with severe hemophilia with respect to type of treatment, on-demand versus prophylaxis, and frequency of bleeding episodes in the year before enrollment. We also investigated the association between hemophilia-related morbidity, measured by number of bleeding episodes in the year before enrollment, and academic performance after adjustment for other factors known to have an effect on achievement. Finally, we explored the mechanisms for the association between bleeding episodes and academic achievement., Study Design: This study was a multicenter investigation of boys 6 to 12 years old with severe factor VIII deficiency (clotting factor level <2%) receiving care in US hemophilia treatment centers. Children with a history of inhibitor, severe developmental disorder, significant psychiatric disorder, or insufficient fluency in English were excluded from the study. On-demand treatment was defined as administration of clotting factor on the occurrence of a bleeding episode. Prophylactic therapy was defined as a course of regular infusions for >2 months with a goal of preventing bleeding episodes. Academic achievement was measured by the Wechsler Individual Achievement Test. Quality of life was measured by the Child Health Questionnaire. Of particular interest was the Physical Summary (PhS) measure of the Child Health Questionnaire. The type of information captured by the PhS includes limitations in physical activity, limitations in the kind or amount of schoolwork or social activities the child engaged in, and presence of pain or discomfort., Results: One hundred thirty-one children were enrolled, a median center recruitment rate of 77%. The mean age of the participants was 9.6 years, and approximately half of the participants had completed less than the fourth grade at the time of enrollment. Sixty-two percent of the children were on prophylaxis at enrollment, and 9% had previously been on prophylaxis but were currently on on-demand therapy. Two groups were defined: ever treated with prophylaxis and never treated with prophylaxis. For those ever treated, treatment duration ranged from 2.7 months to 7.7 years, with one half of the children treated with prophylaxis for >40% of their lifetimes; 29% had always been on on-demand therapy. Children in both treatment groups were similar with respect to age, clotting factor level, parents' education, and IQ. The median number of bleeding episodes experienced in the year before enrollment for the cohort as a whole was 12. The median number of bleeding episodes in children on prophylaxis at enrollment was significantly lower than in children on on-demand therapy (6 vs 25.5). The mean achievement scores were within the average range of academic performance: reading, 100.4; mathematics, 101.6; language, 108.1; writing, 95.4; and total achievement, 102.5. When children were categorized as above or below the study group median by number of bleeding episodes, those who had a low number of bleeding episodes (< or =11) had better total achievement (104.4 vs 100.6) and mathematics (103.6 vs 99.6) than children in the higher bleeding episode category (> or =12) after adjusting for child's IQ and parents' education. Treatment with prophylaxis per se was not associated with better test scores, but children who had been treated on a regimen of long-term prophylaxis (>40% of lifetime) and reported < or =11 bleeding episodes in the year before enrollment had significantly higher scores in total achievement (104.9 vs 100.6), mathematics (105.2 vs 99.6), and reading (104.0 vs 98.6) than all other children reporting > or =12 bleeding episodes in the same time period. Increased school absenteeism and hemophilia-related limitations in physical functioning among children with greater frequency of bleeding episodes were proposed as the mechanisms for lower scores. The number of bleeding episodes was positively correlated with school absenteeism (Spearman correlation = 0.23), and children with more school absences had lower scores in mathematics, reading, and total achievement, even after adjusting for the child's IQ and parents' education. Children with fewer bleeding episodes also had better PhS scores than children in the high bleeding episode category (48.4 vs 41.3). The mean PhS for children in the low bleeding episode group (48.4) was similar to that of the general US population (50), but the mean PhS for children in the higher bleeding episode group was almost a full standard deviation lower than the mean for the general US population. PhS scores were positively related to reading and total achievement scores after adjusting for IQ and parents' education. Of interest and concern was a group of children who were reportedly being treated with prophylaxis during the year before enrollment (N = 18) but whose bleeding events were not optimally suppressed. These children were 3 times as likely (33.3% vs 11.1%) to be receiving < or =2 infusions per week as children on prophylaxis who reported < or =11 bleeding episodes during the same period. A review of the sites of bleeding reported for the 18 children revealed that 12 (66.6%) experienced > or =25% of their bleeding episodes in the same joint., Conclusions: Each child should have the opportunity to achieve his or her potential. Control of a chronic disorder must include this important goal as well as the more commonly identified medical outcomes. This study has identified an important association between the number of bleeding episodes experienced and academic achievement in a cohort of school-aged children with severe hemophilia. The data support the assertion that therapeutic care programs in this population must not be evaluated only in terms of financial cost to achieve adequate musculoskeletal outcomes. Also significant are the individual and societal benefits of increased academic accomplishments if adequate suppression of hemorrhagic events can be attained. The number of bleeding episodes experienced, regardless of treatment regimen, should be followed to optimize the child's academic outcome.

Objective: The investigation examined the associations of plasma human immunodeficiency virus (HIV) RNA and CD4(+) T lymphocytes with height, weight, skeletal maturation, testosterone levels, and height velocity for hemophilic children and adolescents with HIV infection in the Hemophilia Growth and Development Study., Study Design: Two hundred seven participants were evaluated over 7 years., Results: A threefold increment in baseline plasma HIV RNA was associated with a 0.98-cm decrease in height and a 1.67-kg decrease in weight; 100-cells/microL decrements in baseline CD4(+) were associated with a 2.51-cm decrease in height and a 3.83-kg decrease in weight. Participants with high plasma HIV RNA (>3125 copies/mL) experienced significant delay in achieving maximum height velocity and lower maximum velocity compared with those with low viral load. The high CD4(+) (>243)/low plasma HIV RNA group had earlier age at maximum height velocity compared with the other 3 groups and higher maximum height velocity compared with the low CD4(+)/high plasma HIV RNA and low CD4(+)/low plasma HIV RNA groups. Decrements in CD4(+) were associated with decreases in bone age and testosterone level., Conclusions: CD4(+) and HIV RNA were important in predicting growth outcomes.

Left-censored data are characteristic of many bioassays due to inherent limit of detection and limit of quantitation (LOQ) in the assays. This paper examines how the left-censoring of plasma HIV RNA measurements, collected for the Hemophilia Growth and Development Study, affects the quantification of viral load and the assessment of its association with a continuous or dichotomous outcome. Data analyses using maximum likelihood estimation are compared to analyses where the LOQ or LOQ/2 value is substituted for the left-censored observations, and also to other methods like multiple imputation. A Gaussian distribution is assumed for the log-transformed plasma HIV RNA data, and simulations are used to explore the sensitivity of the results to changes in the model parameters. The robustness of the estimators is also investigated when the data are generated from a mixture of two Gaussian distributions. Maximum likelihood is in general the least biased method. However, multiple imputation assuming a censored Gaussian imputation model and substituting the censored values with the expectation of its conditional predictive distribution are also competitive to maximum likelihood, and may be appealing because of their simpler computational algorithms., (Copyright 2001 John Wiley & Sons, Ltd.)

Objective: This analysis was undertaken to evaluate the etiology and sequelae of 2- to 5-mm focal white matter hyperintensities on T2-weighted MR images of some participants enrolled in the Hemophilia Growth and Development Study (HGDS)., Materials and Methods: The HGDS is a multicenter study of the growth and development, neurological, neuropsychological, and immune functioning of a cohort of children and adolescents, 62% of whom were infected with HIV through the use of clotting factor concentrates, and their non-hemophiliac, non-HIV infected male siblings. The current investigation was conducted with all three groups of HGDS participants: HIV-positive hemophiliacs (n = 207), HIV-negative hemophiliacs (n = 126), and their siblings (n = 47). Magnetic resonance imaging was performed at each center, with a variety of 0.3 to 1.5 T instruments. Standard examinations included 5-mm-thick T1-weighted sagittal and axial images, intermediate, and T2-weighted axial images. A study of abnormalities of the coagulation system known to be associated with thrombotic events was conducted among a subgroup of participants (n = 51) from eight centers., Results: Lesions were not associated with hemophilia-related factors, immune function, hematologic, or neurologic factors. There were no associations between the presence of white matter lesions and defects of coagulation in any of the assays completed., Conclusion: The 2- to 5-mm focal white matter hyperintensities on T2-weighted MR images of the brain were incidental findings in our study population.

Two methods of analysis are compared to estimate the treatment effect of a comparative study where each treated individual is matched with a single control at the design stage. The usual matched-pairs analysis accounts for the pairing directly in its model, whereas regression adjustment ignores the matching but instead models the pairing using a set of covariates. For a normal linear model, the estimated treatment effect from the matched-pairs analysis (paired t-test) is more efficient. For a Bernoulli logistic model, matched-pairs analysis performs better when the sample size is small, but is inferior to logistic regression for large sample sizes.

Seventy-five homosexual men with lymphadenopathy syndrome (LAS), subsequently shown to be seropositive for the human immunodeficiency virus (HIV), were enrolled in a prospective study in Atlanta in 1982 and 1983. Subjects have been followed up at 3- to 6-month intervals with clinical and immunologic evaluations, including analysis of T-cell subsets. As of February 28, 1991, AIDS had developed in 36 (48%) of the 75 men. The AIDS cases continued to occur through the 10th year after onset of LAS; the 10-year cumulative incidence of AIDS was 56.6% (Kaplan-Meier survival analysis). Six-year incidence rates following the first observation of a T-helper cell count greater than or equal to 500/mm3, 400-499/mm3, 300-399/mm3, 200-299/mm3, and less than 200/mm3 were 29, 35, 50, 58, and 88%, respectively. Among individual symptoms and signs, only thrush conferred a poorer prognosis (odds ratio = 5.80; 95% confidence interval, 2.93, 11.39, p less than 0.001, Mantel-Byar analysis). The risk of AIDS persists 10 years after the onset of LAS. The AIDS incidence is related directly to T-helper cell depletion; with the exception of thrush, the presence or absence of symptoms and signs appears to be of lesser prognostic significance.