Duration of Thyroid Dysfunction Correlates with All-Cause Mortality. The OPENTHYRO Register Cohort

Introduction and Aim

The association between thyroid dysfunction and mortality is controversial. Moreover, the impact of duration of thyroid dysfunction is unclarified. Our aim was to investigate the correlation between biochemically assessed thyroid function as well as dysfunction duration and mortality.

Methods

Register-based follow-up study of 239,768 individuals with a serum TSH measurement from hospitals and/or general practice in Funen, Denmark. Measurements were performed at a single laboratory from January 1st 1995 to January 1st 2011. Cox regression was used for mortality analyses and Charlson Comorbidity Index (CCI) was used as comorbidity score.

Results

Hazard ratios (HR) with 95% confidence intervals (CI) for mortality with decreased (<0.3 mIU/L) or elevated (>4.0 mIU/L) levels of TSH were 2.22; 2.14–2.30; P<0.0001 and 1.28; 1.22–1.35; P<0.0001, respectively. Adjusting for age, gender, CCI and diagnostic setting attenuated the risk estimates (HR 1.23; 95% CI: 1.19–1.28; P<0.0001, mean follow-up time 7.7 years, and HR 1.07; 95% CI: 1.02–1.13; P = 0.004, mean follow-up time 7.2 years) for decreased and elevated values of TSH, respectively. Mortality risk increased by a factor 1.09; 95% CI: 1.08–1.10; P<0.0001 or by a factor 1.03; 95% CI: 1.02–1.04; P<0.0001 for each six months a patient suffered from decreased or elevated TSH, respectively. Subdividing according to degree of thyroid dysfunction, overt hyperthyroidism (HR_overt 1.12; 95% CI: 1.06–1.19; P<0.0001), subclinical hyperthyroidism (HR_subclinical 1.09; 95% CI: 1.02–1.17; P = 0.02) and overt hypothyroidism (HR_overt 1.57; 95% CI: 1.34–1.83; P<0.0001), but not subclinical hypothyroidism (HR_subclinical 1.03; 95% CI: 0.97–1.09; P = 0.4) were associated with increased mortality.

Conclusions and Relevance

In a large-scale, population-based cohort with long-term follow-up (median 7.4 years), overt and subclinical hyperthyroidism and overt but not subclinical hypothyroidism were associated with increased mortality. Excess mortality with increasing duration of decreased or elevated serum TSH suggests the importance of timely intervention in individuals with thyroid dysfunction.     

PIK3CA Gene Mutations and Overexpression: Implications for Prognostic Biomarker and Therapeutic Target in Chinese Esophageal Squamous Cell Carcinoma

Aims

To evaluate PIK3CA gene mutations and PIK3CA expression status in Chinese esophageal squamous cell carcinoma (ESCC) patients, and their correlation with clinicopathological characteristics and clinical outcomes.

Methods

Direct sequencing was applied to investigate mutations in exons 9 and 20 of PIK3CA in 406 Chinese ESCC patients. PIK3CA expression was evaluated using immunohistochemistry analysis. The associations of PIK3CA gene mutations and PIK3CA expression with clinicopathological characteristics and clinical outcome were examined.

Results

Thirty somatic point mutations (30/406, 7.4%) were identified in exon 9 whereas no mutations were detected in exon 20. PIK3CA mutations were not correlated with clinicopathological characteristics or clinical outcomes. However in the ESCC patients with family cancer history, PIK3CA mutations were independently correlated with worse overall survival (multivariate hazard ratio (HR) = 10.493, 95% CI: 2.432–45.267, P = 0.002). Compared to normal esophageal tissue, PIK3CA was significantly overexpressed in cancer tissue (P<0.001). PIK3CA overexpression was independently associated with higher risk of local recurrence (multivariate HR  = 1.435, 95% CI: 1.040–1.979, P = 0.028). In female ESCC patients, PIK3CA overexpression was independently correlated with worse overall survival (multivariate HR  = 2.341, 95% CI: 1.073–5.108, P = 0.033).

Conclusions

Our results suggest PIK3CA gene mutation and overexpression could act as biomarkers for individualized molecular targeted therapy for Chinese ESCC patients.     

Altered Mitochondrial Function and Oxidative Stress in Leukocytes of Anorexia Nervosa Patients

Context

Anorexia nervosa is a common illness among adolescents and is characterised by oxidative stress.

Objective

The effects of anorexia on mitochondrial function and redox state in leukocytes from anorexic subjects were evaluated.

Design and setting

A multi-centre, cross-sectional case-control study was performed.

Patients

Our study population consisted of 20 anorexic patients and 20 age-matched controls, all of which were Caucasian women.

Main outcome measures

Anthropometric and metabolic parameters were evaluated in the study population. To assess whether anorexia nervosa affects mitochondrial function and redox state in leukocytes of anorexic patients, we measured mitochondrial oxygen consumption, membrane potential, reactive oxygen species production, glutathione levels, mitochondrial mass, and complex I and III activity in polymorphonuclear cells.

Results

Mitochondrial function was impaired in the leukocytes of the anorexic patients. This was evident in a decrease in mitochondrial O₂ consumption (P<0.05), mitochondrial membrane potential (P<0.01) and GSH levels (P<0.05), and an increase in ROS production (P<0.05) with respect to control subjects. Furthermore, a reduction of mitochondrial mass was detected in leukocytes of the anorexic patients (P<0.05), while the activity of mitochondrial complex I (P<0.001), but not that of complex III, was found to be inhibited in the same population.

Conclusions

Oxidative stress is produced in the leukocytes of anorexic patients and is closely related to mitochondrial dysfunction. Our results lead us to propose that the oxidative stress that occurs in anorexia takes place at mitochondrial complex I. Future research concerning mitochondrial dysfunction and oxidative stress should aim to determine the physiological mechanism involved in this effect and the physiological impact of anorexia.     

Comparison of Long-Term Survival of Patients with Solitary Large Hepatocellular Carcinoma of BCLC Stage A after Liver Resection or Transarterial Chemoembolization: A Propensity Score Analysis

Background

The aim of this study was to compare the long-term outcome of patients with a solitary large (>5 cm) hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) stage A who received liver resection (LR) or transarterial chemoembolization (TACE).

Methods

Our study examined 128 patients treated by LR and 90 treated by TACE. To reduce bias in patient selection, we conducted propensity score analysis in the present study and 54 pairs of patients after propensity score matching were generated, their long-term survival was compared using the Kaplan–Meier method. Independent predictors of survival were identified by multivariate analysis.

Results

Long-term survival was significantly better for the LR group by log-rank test (P<0.001). In multivariate analysis, tumor size, serum ALT level and TACE independently predicted survival. Despite similar baseline characteristics after propensity score matching, LR group still had significantly better survival (1 year, 68.5 vs. 55.0%; 3 years, 47.6 vs. 21.2%; 5 years, 41.3 vs. 18.5%; P = 0.007) than TACE group. The LR and TACE groups had comparable 30- and 90-day post-treatment mortality. Multivariate analysis showed that serum ALT level, serum AFP level and TACE independently predicted survival by multivariate analysis after propensity score matching.

Conclusion

Our propensity-score-matched study suggested that LR provided significantly better long-term survival than TACE for a solitary large HCC of the BCLC stage A, regardless of tumor size.     

Comparison of artificial neural network and logistic regression models for predicting in-hospital mortality after primary liver cancer surgery

Background

Since most published articles comparing the performance of artificial neural network (ANN) models and logistic regression (LR) models for predicting hepatocellular carcinoma (HCC) outcomes used only a single dataset, the essential issue of internal validity (reproducibility) of the models has not been addressed. The study purposes to validate the use of ANN model for predicting in-hospital mortality in HCC surgery patients in Taiwan and to compare the predictive accuracy of ANN with that of LR model.

Methodology/Principal Findings

Patients who underwent a HCC surgery during the period from 1998 to 2009 were included in the study. This study retrospectively compared 1,000 pairs of LR and ANN models based on initial clinical data for 22,926 HCC surgery patients. For each pair of ANN and LR models, the area under the receiver operating characteristic (AUROC) curves, Hosmer-Lemeshow (H-L) statistics and accuracy rate were calculated and compared using paired T-tests. A global sensitivity analysis was also performed to assess the relative significance of input parameters in the system model and the relative importance of variables. Compared to the LR models, the ANN models had a better accuracy rate in 97.28% of cases, a better H-L statistic in 41.18% of cases, and a better AUROC curve in 84.67% of cases. Surgeon volume was the most influential (sensitive) parameter affecting in-hospital mortality followed by age and lengths of stay.

Conclusions/Significance

In comparison with the conventional LR model, the ANN model in the study was more accurate in predicting in-hospital mortality and had higher overall performance indices. Further studies of this model may consider the effect of a more detailed database that includes complications and clinical examination findings as well as more detailed outcome data.     

Prognostic Nomograms for Predicting Survival and Distant Metastases in Locally Advanced Rectal Cancers

Aim

To develop prognostic nomograms for predicting outcomes in patients with locally advanced rectal cancers who do not receive preoperative treatment.

Materials and Methods

A total of 883 patients with stage II–III rectal cancers were retrospectively collected from a single institution. Survival analyses were performed to assess each variable for overall survival (OS), local recurrence (LR) and distant metastases (DM). Cox models were performed to develop a predictive model for each endpoint. The performance of model prediction was validated by cross validation and on an independent group of patients.

Results

The 5-year LR, DM and OS rates were 22.3%, 32.7% and 63.8%, respectively. Two prognostic nomograms were successfully developed to predict 5-year OS and DM-free survival rates, with c-index of 0.70 (95% CI = [0.66, 0.73]) and 0.68 (95% CI = [0.64, 0.72]) on the original dataset, and 0.76 (95% CI = [0.67, 0.86]) and 0.73 (95% CI = [0.63, 0.83]) on the validation dataset, respectively. Factors in our models included age, gender, carcinoembryonic antigen value, tumor location, T stage, N stage, metastatic lymph nodes ratio, adjuvant chemotherapy and chemoradiotherapy. Predicted by our nomogram, substantial variability in terms of 5-year OS and DM-free survival was observed within each TNM stage category.

Conclusions

The prognostic nomograms integrated demographic and clinicopathological factors to account for tumor and patient heterogeneity, and thereby provided a more individualized outcome prognostication. Our individualized prediction nomograms could help patients with preoperatively under-staged rectal cancer about their postoperative treatment strategies and follow-up protocols.     

Capsaicin Cough Sensitivity and the Association with Clinical Parameters in Bronchiectasis

Background

Cough hypersensitivity has been common among respiratory diseases.

Objective

To determine associations of capsaicin cough sensitivity and clinical parameters in adults with clinically stable bronchiectasis.

Methods

We recruited 135 consecutive adult bronchiectasis patients and 22 healthy subjects. History inquiry, sputum culture, spirometry, chest high-resolution computed tomography (HRCT), Leicester Cough Questionnaire scoring, Bronchiectasis Severity Index (BSI) assessment and capsaicin inhalation challenge were performed. Cough sensitivity was measured as the capsaicin concentration eliciting at least 2 (C₂) and 5 coughs (C₅).

Results

Despite significant overlap between healthy subjects and bronchiectasis patients, both C₂ and C₅ were significantly lower in the latter group (all P<0.01). Lower levels of C₅ were associated with a longer duration of bronchiectasis symptoms, worse HRCT score, higher 24-hour sputum volume, BSI and sputum purulence score, and sputum culture positive for P. aeruginosa. Determinants associated with increased capsaicin cough sensitivity, defined as C₅ being 62.5 µmol/L or less, encompassed female gender (OR: 3.25, 95%CI: 1.35–7.83, P<0.01), HRCT total score between 7–12 (OR: 2.57, 95%CI: 1.07–6.173, P = 0.04), BSI between 5–8 (OR: 4.05, 95%CI: 1.48–11.06, P<0.01) and 9 or greater (OR: 4.38, 95%CI: 1.48–12.93, P<0.01).

Conclusion

Capsaicin cough sensitivity is heightened in a subgroup of bronchiectasis patients and associated with the disease severity. Gender and disease severity, but not sputum purulence, are independent determinants of heightened capsaicin cough sensitivity. Current testing for cough sensitivity diagnosis may be limited because of overlap with healthy subjects but might provide an objective index for assessment of cough in future clinical trials.     

The Increased Risk for Autoimmune Diseases in Patients with Eating Disorders

Objective

Research suggests autoimmune processes to be involved in psychiatric disorders. We aimed to address the prevalence and incidence of autoimmune diseases in a large Finnish patient cohort with anorexia nervosa, bulimia nervosa, and binge eating disorder.

Methods

Patients (N = 2342) treated at the Eating Disorder Unit of Helsinki University Central Hospital between 1995 and 2010 were compared with general population controls (N = 9368) matched for age, sex, and place of residence. Data of 30 autoimmune diseases from the Hospital Discharge Register from 1969 to 2010 were analyzed using conditional and Poisson regression models.

Results

Of patients, 8.9% vs. 5.4% of control individuals had been diagnosed with one or more autoimmune disease (OR 1.7, 95% CI 1.5–2.0, P<0.001). The increase in endocrinological diseases (OR 2.4, 95% CI 1.8–3.2, P<0.001) was explained by type 1 diabetes, whereas Crohn''s disease contributed most to the risk of gastroenterological diseases (OR 1.8, 95% CI 1.4–2.5, P<0.001). Higher prevalence of autoimmune diseases among patients with eating disorders was not exclusively due to endocrinological and gastroenterological diseases; when the two categories were excluded, the increase in prevalence was seen in the patients both before the onset of the eating disorder treatment (OR 1.5, 95% CI 1.1–2.1, P = 0.02) and at the end of the follow-up (OR 1.4, 95% CI 1.1–1.8, P = 0.01).

Conclusions

We observed an association between eating disorders and several autoimmune diseases with different genetic backgrounds. Our findings support the link between immune-mediated mechanisms and development of eating disorders. Future studies are needed to further explore the risk of autoimmune diseases and immunological mechanisms in individuals with eating disorders and their family members.     

Semen Abnormalities,Sperm DNA Damage and Global Hypermethylation in Health Workers Occupationally Exposed to Ionizing Radiation

Background

Cytogenetic studies have demonstrated that low levels of chronic radiation exposure can potentially increase the frequency of chromosomal aberrations and aneuploidy in somatic cells. Epidemiological studies have shown that health workers occupationally exposed to ionizing radiation bear an increased risk of hematological malignancies.

Objectives

To find the influence of occupational radiation exposure on semen characteristics, including genetic and epigenetic integrity of spermatozoa in a chronically exposed population.

Methods

This cross sectional study included 134 male volunteers of which 83 were occupationally exposed to ionizing radiation and 51 were non-exposed control subjects. Semen characteristics, sperm DNA fragmentation, aneuploidy and incidence of global hypermethylation in the spermatozoa were determined and compared between the non-exposed and the exposed group.

Results

Direct comparison of the semen characteristics between the non-exposed and the exposed population revealed significant differences in motility characteristics, viability, and morphological abnormalities (P<0.05–0.0001). Although, the level of sperm DNA fragmentation was significantly higher in the exposed group as compared to the non-exposed group (P<0.05–0.0001), the incidence of sperm aneuploidy was not statistically different between the two groups. However, a significant number of hypermethylated spermatozoa were observed in the exposed group in comparison to non-exposed group (P<0.05).

Conclusions

We provide the first evidence on the detrimental effects of occupational radiation exposure on functional, genetic and epigenetic integrity of sperm in health workers. However, further studies are required to confirm the potential detrimental effects of ionizing radiation in these subjects.     

Prognostic Significance of Complications after Laparoscopic Colectomy for Colon Cancer

Aims

This study sought to evaluate the prognostic significance of postoperative complications for colon cancer patients undergoing laparoscopic surgery.

Methods

From May 2006 to May 2009, a total 224 patients who underwent laparoscopic curative resection (R0) for colon cancer were included in our retrospective study. Postoperative complications were evaluated according to a standardized grading system. The main outcome measurements of our study were overall survival (OS) and relapse-free survival (RFS), which were then compared between the no complication and complication groups. Univariate and multivariate analysis were used to assess the correlation between complications and prognosis.

Results

Fifty-nine postoperative complications occurred in 43 patients. The overall morbidity rate was 26.3%. The 5-year OS in the complication group was 41.4% compared with 78.5% in the no complication group (P<0.001). The cumulative incidence of relapse was also more aggressive in patients with complications (5-year RFS: complication group 40.9% vs. no complication group 82.1%, P<0.001). Multivariate analysis identified complications as a significant factor increasing the risk for both OS (RR 2.737; 95% CI 1.512–4.952; P = 0.001) and RFS (RR 4.247; 95% CI 2.291–7.876; P<0.001).

Conclusion

Postoperative complications could pose a significant adverse impact not only on OS but also on RFS in patients with colon cancer even when laparoscopic R0 resection is available.     

Epidemiology of Acute Pancreatitis in Hospitalized Children in the United States from 2000–2009

Background

Single-center studies suggest an increasing incidence of acute pancreatitis (AP) in children. Our specific aims were to (i) estimate the recent secular trends, (ii) assess the disease burden, and (iii) define the demographics and comorbid conditions of AP in hospitalized children within the United States.

Methods

We used the Healthcare Cost and Utilization Project Kids’ Inpatient Database, Agency for Healthcare Research and Quality for the years 2000 to 2009. Extracted data were weighted to generate national-level estimates. We used the Cochrane-Armitage test to analyze trends; cohort-matching to evaluate the association of AP and in-hospital mortality, length of stay, and charges; and multivariable logistic regression to test the association of AP and demographics and comorbid conditions.

Results

We identified 55,012 cases of AP in hospitalized children (1–20 years of age). The incidence of AP increased from 23.1 to 34.9 (cases per 10,000 hospitalizations per year; P<0.001) and for all-diagnoses 38.7 to 61.1 (P<0.001). There was an increasing trend in the incidence of both primary and all-diagnoses of AP (P<0.001). In-hospital mortality decreased (13.1 to 7.6 per 1,000 cases, P<0.001), median length of stay decreased (5 to 4 days, P<0.001), and median charges increased ($14,956 to $22,663, P<0.001). Children with AP compared to those without the disease had lower in-hospital mortality (adjusted odds ratio, aOR 0.86, 95% CI, 0.78–0.95), longer lengths of stay (aOR 2.42, 95% CI, 2.40–2.46), and higher charges (aOR 1.62, 95% CI, 1.59–1.65). AP was more likely to occur in children older than 5 years of age (aORs 2.81 to 5.25 for each 5-year age interval). Hepatobiliary disease was the comorbid condition with the greatest association with AP.

Conclusions

These results demonstrate a rising incidence of AP in hospitalized children. Despite improvements in mortality and length of stay, hospitalized children with AP have significant morbidity.     

Associations of Tobacco Use and Alcohol Drinking with Laryngeal and Hypopharyngeal Cancer Risks among Men in Karunagappally,Kerala, India -Karunagappally Cohort Study

Background

From among a cohort of 65,553 men aged 30–84 in Karunagappally Taluk, Kerala, India, 52 hypopharyngeal cancer cases and 85 laryngeal cancer cases were identified by the Karunagappally Cancer Registry during the period between 1990 and 2009.

Methods

We conduct Poisson regression analysis of grouped data, taking into account age and education.

Results

This study showed that the incidence rates of cancers of the hypopharynx and the larynx were strongly related to the number of bidis smoked a day (P<0.001 for both hypopharyngeal and laryngeal cancers) and duration of bidi smoking (P=0.009; P<0.001). Laryngeal cancer risk was significantly increased by bidi smoking (P<0.001), cigarette smoking (P=0.013) and regular alcohol use (P=0.005).

Conclusion

The present study, the first cohort study to examine the association of hypopharyngeal and laryngeal cancer incidence rates with bidi smoking in South Asia, clearly showed dose–response relationships between those cancer risks and bidi smoking; larger amounts of bidi smoked a day and longer durations of bidi smoking increased the incidence rates of those cancers. Tobacco chewing was found not related to the risk of hypopharynx or larynx cancer.     

Nosocomial Infection in Adult Admissions with Hematological Malignancies Originating from Different Lineages: A Prospective Observational Study

Background

Nosocomial infection (NI) causes prolonged hospital stays, increased healthcare costs, and higher mortality among patients with hematological malignancies (HM). However, few studies have compared the incidence of NI according to the HM lineage.

Objective

To compare the incidence of NI according to the type of HM lineage, and identify the risk factors for NI.

Methods

This prospective observational study monitored adult patients with HM admitted for >48 hours to the General Hospital of the People''s Liberation Army during 2010–2013. Attack rates and incidences of NI were compared, and multivariable logistic regression was used to control for confounding effects.

Results

This study included 6,613 admissions from 1,922 patients. During these admissions, 1,023 acquired 1,136 NI episodes, with an attack rate of 15.47% and incidence of 9.6‰ (95% CI: 9.1–10.2). Higher rates and densities of NIs were observed among myeloid neoplasm (MN) admissions, compared to lymphoid neoplasm (LN) admissions (28.42% vs. 11.00%, P<0.001 and 11.4% vs. 8.4‰, P<0.001). NI attack rates in acute myeloid leukemia (AML) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN) were higher than those in MDS (30.69% vs. 20.19%, P<0.001; 38.89% vs. 20.19%, P = 0.003). Attack rates in T/NK-cell neoplasm and B-cell neoplasm were higher than those in Hodgkin lymphoma (15.04% vs. 3.65%; 10.94% vs. 3.65%, P<0.001). Multivariable regression analysis indicated prolonged hospitalization, presence of central venous catheterization, neutropenia, current stem cell transplant, infection on admission, and old age were independently associated with higher NI incidence. After adjusting for these factors, MN admissions still had a higher risk of infection (odds ratio 1.34, 95% CI: 1.13–1.59, P<0.001).

Conclusion

Different NI attack rates were observed for HM from different lineages, with MN lineages having a higher attack rate and incidence than LN lineages. Special attention should be paid to MN admissions, especially AML and MDS/MPN admissions, to control NI incidence.     

Passive Smoking Exposure from Partners as a Risk Factor for ER+/PR+ Double Positive Breast Cancer in Never-Smoking Chinese Urban Women: A Hospital-Based Matched Case Control Study

Background

The relationship between passive smoking exposure (PSE) and breast cancer risk is of major interest.

Objective

To evaluate the relationship between PSE from partners and breast cancer risk stratified by hormone-receptor (HR) status in Chinese urban women population.

Design

Hospital-based matched case control study.

Setting

Chinese urban breast cancer patients without current or previous active smoking history in China Medical University 1st Hospital, Liaoning Province, China between Jan 2009 and Nov 2009.

Patients

Each breast cancer patient was matched 1∶1 with healthy controls by gender and age (±2 years) from the same hospital.

Measurements

The authors used unconditional logistic regression analyses to estimate odds ratio for women with PSE from partners and breast cancer risk.

Results

312 pairs were included in the study. Women who endured PSE had significantly increased risk of breast cancer (adjusted OR: 1.46; 95% CI: 1.05–2.03; P = 0.027), comparing with unexposed women. Women who exposed to >5 cigarettes/day also had significant increased risk (adjusted OR: 1.99; 95% CI: 1.28–3.10; P = 0.002), as were women exposed to passive smoke for 16–25 years (adjusted OR: 1.87 95% CI: 1.22–2.86; P = 0.004), and those exposed to > 4 pack-years (adjusted OR: 1.71 95% CI: 1.17–2.50; P = 0.004). Similar trends were significant for estrogen receptor (ER)/progesterone receptor (PR) double positive subgroup(adjusted OR: 1.71; 2.20; 1.99; 1.92, respectively), but not for ER+/PR−, ER−/PR+, or ER−/PR− subgroups.

Limitations

limitations of the hospital-based retrospective study, lack of information on entire lifetime PSE and low statistical power.

Conclusions

Our findings provide further evidence that PSE from partners contributes to increased risk of breast cancer, especially for ER/PR double positive breast cancer, in Chinese urban women.     

A Straightforward but Not Piecewise Relationship between Age and Lymph Node Status in Chinese Breast Cancer Patients

Purpose

To investigate the relationship between age and axillary lymph node (LN) involvement in Chinese breast cancer patients, and to replicate a recently identified piecewise relationship between age and LN involvement.

Methods

A dataset, consisting of 3,715 patients (with complete information on study variables) with operable breast cancer consecutively surgically treated between 1996 and 2006, was derived from the database of Shanghai Cancer Hospital. Univariate and multivariate logistic regression were employed to analyze the relationship between age and LN. We subsequently performed a similar analysis on another dataset including 1,832 consecutive patients treated between 2007 and 2008 to replicate our findings in the first dataset.

Results

A U-shaped relationship (previously observed in two European populations) between age and LN status failed to be replicated in our dataset of Chinese patients. Instead, we observed a linear rather than piecewise relationship. After multivariate adjustment, the linear relationship was still present. Moreover, the interaction between age and LN involvement was not modified by tumor size. The odds of LN involvement decreased by 1.5% for each year increase in age (OR 0.985, 95% CI 0.979–0.991, P<0.001). Breast cancer subtypes were also associated with LN status. Proportions of basal-like and ERBB2+ subtypes decreased with increasing age. The observations in the first dataset were successfully replicated in a second independent dataset.

Conclusion

We confirmed a straightforward but not piecewise relationship between age and LN status in Chinese patients. The different pattern between Chinese and European elderly patients should be considered when making clinical decisions.     

Kinetics of IL-7 and IL-15 Levels after Allogeneic Peripheral Blood Stem Cell Transplantation following Nonmyeloablative Conditioning

Background

We analysed kinetics of IL-7 and IL-15 levels in 70 patients given peripheral blood stem cells after nonmyeloablative conditioning.

Methods

EDTA-anticoagulated plasma and serum samples were obtained before conditioning and about once per week after transplantation until day 100. Samples were aliquoted and stored at −80°C within 3 hours after collection until measurement of cytokines. IL-7 and IL-15 levels were measured by ELISAs.

Results

Median IL-7 plasma levels remained below 6 pg/L throughout the first 100 days, although IL-7 plasma levels were significantly higher on days 7 (5.1 pg/mL, P = 0.002), 14 (5.2 pg/mL, P<0.001), and 28 (5.1 pg/mL, P = 0.03) (but not thereafter) than before transplantation (median value of 3.8 pg/mL). Median IL-15 serum levels were significantly higher on days 7 (12.5 pg/mL, P<0.001), 14 (10.5 pg/mL, P<0.001), and 28 (6.2 pg/mL, P<0.001) than before transplantation (median value of 2.4 pg/mL). Importantly, IL-7 and IL-15 levels on days 7 or 14 after transplantation did not predict grade II–IV acute GVHD.

Conclusions

These data suggest that IL-7 and IL-15 levels remain relatively low after nonmyeloablative transplantation, and that IL-7 and IL-15 levels early after nonmyeloablative transplantation do not predict for acute GVHD.     

Effects of High Doses of Cholecalciferol in Normal Subjects: A Randomized Double-Blinded,Placebo-Controlled Trial

Background

Vitamin D repletion with high doses of vitamin D is often recommended to patients and healthy subjects. The safety, especially concerning changes in urinary calcium excretion is of great importance.

Methods

In a double-blinded, placebo-controlled study in 40 healthy volunteers, we examined the changes in mineral metabolism during supplementation with 3000 IU of oral cholecalciferol daily during 4 months.

Results

Both 25(OH)vitamin D and 1,25(OH)₂vitamin D increased significantly in the active treated group as compared to the placebo group (186% versus 14% (P<0.001) and 28% versus – 8% (P<0.001)). No change was observed in urinary calcium excretion in the active group compared to the placebo group (P = 0.891). Fibroblast growth factor 23 increased significantly by 10% (P<0.018) in the active group. However, there was no difference in changes in FGF23 between treatment groups (P = 0.457).

Conclusion

High dose cholecalciferol significantly increases 25(OH)vitamin D and 1,25(OH)₂vitamin D levels compared to placebo. No changes in urinary calcium excretion or other measured components of the mineral metabolism were found between groups.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00952562","term_id":"NCT00952562"}}NCT00952562.     

Predicting expected progeny difference for marbling score in Angus cattle using artificial neural networks and Bayesian regression models

Background

Artificial neural networks (ANN) mimic the function of the human brain and are capable of performing massively parallel computations for data processing and knowledge representation. ANN can capture nonlinear relationships between predictors and responses and can adaptively learn complex functional forms, in particular, for situations where conventional regression models are ineffective. In a previous study, ANN with Bayesian regularization outperformed a benchmark linear model when predicting milk yield in dairy cattle or grain yield of wheat. Although breeding values rely on the assumption of additive inheritance, the predictive capabilities of ANN are of interest from the perspective of their potential to increase the accuracy of prediction of molecular breeding values used for genomic selection. This motivated the present study, in which the aim was to investigate the accuracy of ANN when predicting the expected progeny difference (EPD) of marbling score in Angus cattle. Various ANN architectures were explored, which involved two training algorithms, two types of activation functions, and from 1 to 4 neurons in hidden layers. For comparison, BayesCπ models were used to select a subset of optimal markers (referred to as feature selection), under the assumption of additive inheritance, and then the marker effects were estimated using BayesCπ with π set equal to zero. This procedure is referred to as BayesCpC and was implemented on a high-throughput computing cluster.

Results

The ANN with Bayesian regularization method performed equally well for prediction of EPD as BayesCpC, based on prediction accuracy and sum of squared errors. With the 3K-SNP panel, for example, prediction accuracy was 0.776 using BayesCpC, and ranged from 0.776 to 0.807 using BRANN. With the selected 700-SNP panel, prediction accuracy was 0.863 for BayesCpC and ranged from 0.842 to 0.858 for BRANN. However, prediction accuracy for the ANN with scaled conjugate gradient back-propagation was lower, ranging from 0.653 to 0.689 with the 3K-SNP panel, and from 0.743 to 0.793 with the selected 700-SNP panel.

Conclusions

ANN with Bayesian regularization performed as well as linear Bayesian regression models in predicting additive genetic values, supporting the idea that ANN are useful as universal approximators of functions of interest in breeding contexts.     

Predicting hospital-acquired infections by scoring system with simple parameters

Background

Hospital-acquired infections (HAI) are associated with increased attributable morbidity, mortality, prolonged hospitalization, and economic costs. A simple, reliable prediction model for HAI has great clinical relevance. The objective of this study is to develop a scoring system to predict HAI that was derived from Logistic Regression (LR) and validated by Artificial Neural Networks (ANN) simultaneously.

Methodology/Principal Findings

A total of 476 patients from all the 806 HAI inpatients were included for the study between 2004 and 2005. A sample of 1,376 non-HAI inpatients was randomly drawn from all the admitted patients in the same period of time as the control group. External validation of 2,500 patients was abstracted from another academic teaching center. Sixteen variables were extracted from the Electronic Health Records (EHR) and fed into ANN and LR models. With stepwise selection, the following seven variables were identified by LR models as statistically significant: Foley catheterization, central venous catheterization, arterial line, nasogastric tube, hemodialysis, stress ulcer prophylaxes and systemic glucocorticosteroids. Both ANN and LR models displayed excellent discrimination (area under the receiver operating characteristic curve [AUC]: 0.964 versus 0.969, p = 0.507) to identify infection in internal validation. During external validation, high AUC was obtained from both models (AUC: 0.850 versus 0.870, p = 0.447). The scoring system also performed extremely well in the internal (AUC: 0.965) and external (AUC: 0.871) validations.

Conclusions

We developed a scoring system to predict HAI with simple parameters validated with ANN and LR models. Armed with this scoring system, infectious disease specialists can more efficiently identify patients at high risk for HAI during hospitalization. Further, using parameters either by observation of medical devices used or data obtained from EHR also provided good prediction outcome that can be utilized in different clinical settings.     

Disease-free survival after hepatic resection in hepatocellular carcinoma patients: a prediction approach using artificial neural network

Background

A database for hepatocellular carcinoma (HCC) patients who had received hepatic resection was used to develop prediction models for 1-, 3- and 5-year disease-free survival based on a set of clinical parameters for this patient group.

Methods

The three prediction models included an artificial neural network (ANN) model, a logistic regression (LR) model, and a decision tree (DT) model. Data for 427, 354 and 297 HCC patients with histories of 1-, 3- and 5-year disease-free survival after hepatic resection, respectively, were extracted from the HCC patient database. From each of the three groups, 80% of the cases (342, 283 and 238 cases of 1-, 3- and 5-year disease-free survival, respectively) were selected to provide training data for the prediction models. The remaining 20% of cases in each group (85, 71 and 59 cases in the three respective groups) were assigned to validation groups for performance comparisons of the three models. Area under receiver operating characteristics curve (AUROC) was used as the performance index for evaluating the three models.

Conclusions

The ANN model outperformed the LR and DT models in terms of prediction accuracy. This study demonstrated the feasibility of using ANNs in medical decision support systems for predicting disease-free survival based on clinical databases in HCC patients who have received hepatic resection.