Evaluation of the WHO 2010 Grading and AJCC/UICC Staging Systems in Prognostic Behavior of Intestinal Neuroendocrine Tumors

Background

The increasing incidence and heterogeneous behavior of intestinal neuroendocrine tumors (iNETs) pose a clinicopathological challenge. Our goal was to decribe the prognostic value of the new WHO 2010 grading and the AJCC/UICC TNM staging systems for iNETs. Moreover, outcomes of patients treated with somatostatin analogs were assessed.

Methods

We collected epidemiological and clinicopathological data from 93 patients with histologically proven iNETs including progression and survival outcomes. The WHO 2010 grading and the AJCC/UICC TNM staging systems were applied for all cases. RECIST criteria were used to define progression. Kaplan-Meier analyses for progression free survival (PFS) and overall survival (OS) were performed.

Results

Mean follow-up was 58.6 months (4–213 months). WHO 2010 grading yielded PFS and disease-specific OS of 125.0 and 165.8 months for grade 1 (G1), 100.0 and 144.2 months for G2 and 15.0 and 15.8 months for G3 tumors (p = 0.004 and p = 0.001). Using AJCC staging, patients with stage I and II tumors had no progression and no deaths. Stage III and IV patients demonstrated PFS of 138.4 and 84.7 months (p = 0.003) and disease-specific OS of 210.0 and 112.8 months (p = 0.017). AJCC staging also provided informative PFS (91.2 vs. 50.0 months, p = 0.004) and OS (112.3 vs. 80.0 months, p = 0.005) measures with somatostatin analog use in stage IV patients.

Conclusion

Our findings underscore the complementarity of WHO 2010 and AJCC classifications in providing better estimates of iNETS disease outcomes and extend the evidence for somatostatin analog benefit in patients with metastatic disease.     

The 1973 WHO Classification Is More Suitable than the 2004 WHO Classification for Predicting Prognosis in Non-Muscle-Invasive Bladder Cancer

Background

Predicting the recurrence and progression of Non-muscle-invasive bladder cancer(NMIBC) is critical for urologist. Histological grade provides significant prognostic information, especially for prediction of progression. Currently, the 1973 and the 2004 WHO classification co-exist. Which system is better for predicting rumor recurrence and progression still a matter for debate.

Methodology/Principal Findings

348 patients diagnosed with Non-muscle invasive bladder cancer were enrolled in our retrospective study. Paraffin sections were assessed by an experienced urological pathologist according to both the 1973 and 2004 WHO classifications. Tumor recurrence and progression was followed-up in all patients. During follow-up, corresponding 5-year recurrence-free survival rates of G1, G2 and G3 were 82.1%, 55.9%, 32.1% and the 5-year progression-free survival rates were 95.9%, 84.4% and 43.3%, respectively. The 5-year recurrence-free survival rates of papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade papillary urothelial carcinoma(LGPUC) and high-grade papillary urothelial carcinoma (HGPUC) were 69.8%, 67.1% and 42.0% respectively and the 5-year progression-free survival rates were 100%, 90.9% and 54.8% respectively. In multivariate analysis, the 1973 WHO classification significantly associated with both tumor recurrence and progression(p = 0.010 and p = 0.022, respectively); the 2004 WHO classification correlated with tumor progression(p = 0.019), while was not proved to be a variable that can predict the risk of recurrence(p = 0.547). Kaplan-Meier plots showed that both the 1973 WHO and the 2004 WHO classifications were significantly associated with progression-free survival (p<0.0001, log-rank test). For prediction of recurrence, significant differences were observed between the tumor grades classified using the 1973 WHO grading system (p<0.0001, log-rank test), while a significant overlap was observed between PUNLMP and LG plots using the 2004 WHO grading system(p = 0.616, log-rank test).

Conclusion/Significance

Both the 1973 WHO and the 2004 WHO Classifications are effective in predicting tumor progression in Non-muscle invasive bladder cancer, while the 1973 WHO Classification is more suitable for predicting tumor recurrence.     

Accuracy of the Interpretation of Chest Radiographs for the Diagnosis of Paediatric Pneumonia

Introduction

World Health Organization (WHO) radiological classification remains an important entry criterion in epidemiological studies of pneumonia in children. We report inter-observer variability in the interpretation of 169 chest radiographs in children suspected of having pneumonia.

Methods

An 18-month prospective aetiological study of pneumonia was undertaken in Northern England. Chest radiographs were performed on eligible children aged ≤16 years with clinical features of pneumonia. The initial radiology report was compared with a subsequent assessment by a consultant cardiothoracic radiologist. Chest radiographic changes were categorised according to the WHO classification.

Results

There was significant disagreement (22%) between the first and second reports (kappa = 0.70, P<0.001), notably in those aged <5 years (26%, kappa = 0.66, P<0.001). The most frequent sources of disagreement were the reporting of patchy and perihilar changes.

Conclusion

This substantial inter-observer variability highlights the need for experts from different countries to create a consensus to review the radiological definition of pneumonia in children.     

Interobserver Agreement of Thyroid Imaging Reporting and Data System (TIRADS) and Strain Elastography for the Assessment of Thyroid Nodules

Background

Thyroid Imaging Reporting and Data System (TIRADS) was developed to improve patient management and cost-effectiveness by avoiding unnecessary fine needle aspiration biopsy (FNAB) in patients with thyroid nodules. However, its clinical use is still very limited. Strain elastography (SE) enables the determination of tissue elasticity and has shown promising results for the differentiation of thyroid nodules.

Methods

The aim of the present study was to evaluate the interobserver agreement (IA) of TIRADS developed by Horvath et al. and SE. Three blinded observers independently scored stored images of TIRADS and SE in 114 thyroid nodules (114 patients). Cytology and/or histology was available for all benign (n = 99) and histology for all malignant nodules (n = 15).

Results

The IA between the 3 observers was only fair for TIRADS categories 2–5 (Coheńs kappa = 0.27,p = 0.000001) and TIRADS categories 2/3 versus 4/5 (ck = 0.25,p = 0.0020). The IA was substantial for SE scores 1–4 (ck = 0.66,p<0.000001) and very good for SE scores 1/2 versus 3/4 (ck = 0.81,p<0.000001). 92–100% of patients with TIRADS-2 had benign lesions, while 28–42% with TIRADS-5 had malignant cytology/histology. The negative-predictive-value (NPV) was 92–100% for TIRADS using TIRADS-categories 4&5 and 96–98% for SE using score ES-3&4 for the diagnosis of malignancy, respectively. However, only 11–42% of nodules were in TIRADS-categories 2&3, as compared to 58–60% with ES-1&2.

Conclusions

IA of TIRADS developed by Horvath et al. is only fair. TIRADS and SE have high NPV for excluding malignancy in the diagnostic work-up of thyroid nodules.     

Concomitant Tumor Expression of EGFR and TATI/SPINK1 Associates with Better Prognosis in Colorectal Cancer

Background

Epidermal growth factor receptor (EGFR) activation plays a role in colorectal cancer (CRC) carcinogenesis, and anti-EGFR drugs are used in treatment of advanced CRC. One of the EGFR ligands is tumor-associated trypsinogen inhibitor TATI, also called serine protease inhibitor Kazal type1 (SPINK 1), which we recently showed to be an independent prognostic marker in CRC.

Methods

We studied the prognostic value of immunohistochemical expression of EGFR and concomitant expression of EGFR and TATI/SPINK1 in a series of 619 colorectal cancer patients.

Results

Of the samples, 92% were positive for EGFR. EGFR+/TATI+ was seen in 62.8%, EGFR+/TATI− in 29.5%, EGFR−/TATI+ in 4.9%, and EGFR−/TATI− in 2.7% of patients. EGFR expression correlated with WHO grade (p = 0.040). In univariate analysis, EGFR expression correlated with favourable survival (p = 0.006). EGFR+/TATI+ patients showed better survival than did those with other combinations (p<0.001). In multivariate analysis, EGFR+/TATI+ was an independent prognostic factor of favourable prognosis (p<0.001).

Conclusion

Concomitant positivity of EGFR and TATI/SPINK1 predicts favourable prognosis in CRC.     

Glioma: Application of Whole-Tumor Texture Analysis of Diffusion-Weighted Imaging for the Evaluation of Tumor Heterogeneity

Background and Purpose

To apply a texture analysis of apparent diffusion coefficient (ADC) maps to evaluate glioma heterogeneity, which was correlated with tumor grade.

Materials and Methods

Forty patients with glioma (WHO grade II (n = 8), grade III (n = 10) and grade IV (n = 22)) underwent diffusion-weighted imaging (DWI), and the corresponding ADC maps were obtained. Regions of interest containing the lesions were drawn on every section of the ADC map containing the tumor, and volume-based data of the entire tumor were constructed. Texture and first order features including entropy, skewness and kurtosis were derived from the ADC map using in-house software. A histogram analysis of the ADC map was also performed. The texture and histogram parameters were compared between low-grade and high-grade gliomas using an unpaired student’s t-test. Additionally, a one-way analysis of variance analysis with a post-hoc test was performed to compare the parameters of each grade.

Results

Entropy was observed to be significantly higher in high-grade gliomas than low-grade tumors (6.861±0.539 vs. 6.261±0.412, P  = 0.006). The fifth percentiles of the ADC cumulative histogram also showed a significant difference between high and low grade gliomas (836±235 vs. 1030±185, P = 0.037). Only entropy proved to be significantly different between grades III and IV (6.295±0.4963 vs. 7.119±0.3165, P<0.001). The diagnostic accuracy of ADC entropy was significantly higher than that of the fifth percentile of the ADC histogram (P = 0.0034) in distinguishing high- from low-grade glioma.

Conclusion

A texture analysis of the ADC map based on the entire tumor volume can be useful for evaluating glioma grade, which provides tumor heterogeneity.     

Confirmatory Factor Analysis of the WHO Violence Against Women Instrument in Pregnant Women: Results from the BRISA Prenatal Cohort

Background

Screening for violence during pregnancy is one of the strategies for the prevention of abuse against women. Since violence is difficult to measure, it is necessary to validate questionnaires that can provide a good measure of the phenomenon. The present study analyzed the psychometric properties of the World Health Organization Violence Against Women (WHO VAW) instrument for the measurement of violence against pregnant women.

Methods

Data from the Brazilian Ribeirão Preto and São Luís birth cohort studies (BRISA) were used. The sample consisted of 1,446 pregnant women from São Luís and 1,378 from Ribeirão Preto, interviewed in 2010 and 2011. Thirteen variables were selected from a self-applied questionnaire. Confirmatory factor analysis was used to investigate whether violence is a uni-or-multidimensional construct consisting of psychological, physical and sexual dimensions. The mean-and-variance-adjusted weighted least squares estimator was used. Models were fitted separately for each city and a third model combining data from the two settings was also tested. Models suggested from modification indices were tested to determine whether changes in the WHO VAW model would produce a better fit.

Results

The unidimensional model did not show good fit (Root mean square error of approximation [RMSEA]  = 0.060, p<0.001 for the combined model). The multidimensional WHO VAW model showed good fit (RMSEA = 0.036, p = 0.999 for the combined model) and standardized factor loadings higher than 0.70, except for the sexual dimension for SL (0.65). The models suggested by the modification indices with cross loadings measuring simultaneously physical and psychological violence showed a significantly better fit compared to the original WHO model (p<0.001 for the difference between the model chi-squares).

Conclusions

Violence is a multidimensional second-order construct consisting of psychological, physical and sexual dimensions. The WHO VAW model and the modified models are suitable for measuring violence against pregnant women.     

PNPLA3 I148M Polymorphism,Clinical Presentation,and Survival in Patients with Hepatocellular Carcinoma

Background & Aims

Aim of this study was to evaluate whether the PNPLA3 I148M polymorphism, previously associated with hepatocellular carcinoma (HCC) risk, influences the clinical presentation of HCC and survival.

Methods

we considered 460 consecutive HCC patients referred to tertiary care centers in Northern Italy, 353 with follow-up data.

Results

Homozygosity for PNPLA3 148M at risk allele was enriched in HCC patients with alcoholic liver disease or nonalcoholic fatty liver disease (ALD&NAFLD: relative risk 5.9, 95% c.i. 3.5–9.9; other liver diseases: relative risk 1.9, 95% c.i. 1.1–3.4). In ALD&NAFLD patients, the PNPLA3 148M allele was associated with younger age, shorter history of cirrhosis, less advanced (Child A) cirrhosis at HCC diagnosis, and lower HCC differentiation grade (p<0.05). Homozygosity for PNPLA3 148M was associated with reduced survival in the overall series (p = 0.009), and with a higher number of HCC lesions at presentation (p = 0.007) and reduced survival in ALD&NAFLD patients (p = 0.003; median survival 30, 95% c.i. 20–39 vs. 45, 95% c.i. 38–52 months), but not in those with HCC related to other etiologies (p = 0.86; 48, 95% c.i. 32–64 vs. 55, 95% c.i. 43–67 months). At multivariate Cox regression analysis, homozygosity for PNPLA3 148M was the only negative predictor of survival in ALD&NAFLD patients (HR of death 1.57, 95% c.i. 1.12–2.78).

Conclusions

PNPLA3 148M is over-represented in ALD&NAFLD HCC patients, and is associated with occurrence at a less advanced stage of liver disease in ALD&NAFLD. In ALD&NAFLD, PNPLA3 148M is associated with more diffuse HCC at presentation, and with reduced survival.     

Validity and Reproducibility of a Spanish Dietary History

Objective

To assess the validity and reproducibility of food and nutrient intake estimated with the electronic diet history of ENRICA (DH-E), which collects information on numerous aspects of the Spanish diet.

Methods

The validity of food and nutrient intake was estimated using Pearson correlation coefficients between the DH-E and the mean of seven 24-hour recalls collected every 2 months over the previous year. The reproducibility was estimated using intraclass correlation coefficients between two DH-E made one year apart.

Results

The correlations coefficients between the DH-E and the mean of seven 24-hour recalls for the main food groups were cereals (r = 0.66), meat (r = 0.66), fish (r = 0.42), vegetables (r = 0.62) and fruits (r = 0.44). The mean correlation coefficient for all 15 food groups considered was 0.53. The correlations for macronutrients were: energy (r = 0.76), proteins (r = 0.58), lipids (r = 0.73), saturated fat (r = 0.73), monounsaturated fat (r = 0.59), polyunsaturated fat (r = 0.57), and carbohydrates (r = 0.66). The mean correlation coefficient for all 41 nutrients studied was 0.55. The intraclass correlation coefficient between the two DH-E was greater than 0.40 for most foods and nutrients.

Conclusions

The DH-E shows good validity and reproducibility for estimating usual intake of foods and nutrients.     

Early Stage W.H.O. Grade I and II Follicular Lymphoma Treated with Radiation Therapy Alone

Objectives

This retrospective study was undertaken to evaluate the outcome of patients with stage I or II (limited stage), grade I–II follicular non-Hodgkin’s lymphoma (FL) treated with radiation therapy (RT) alone as initial management.

Methods

Patients with stage I or II and pathologically confirmed WHO grade I or II FL treated initially with RT alone between 1982 and 2008 were identified from a population based cancer registry.

Results

Forty patients with a mean age 61.3 years at diagnosis were identified. The median follow up was 6.9 years from the end of radiation therapy. Stage was I (n = 26) and II (n = 14). None had B symptoms. The Follicular Lymphoma International Prognostic Index (FLIPI) was low risk in 26 patients and intermediate risk in 5. Doses ranged from 15 Gy to 48 Gy, with a median dose of 35 Gy. All patients achieved a complete clinical response (CR). 5 and 10 year overall survival (OS) was 86% and 59%, progression free survival (PFS) 67% and 54%. Age ≥60 at diagnosis was associated with reduced OS, p = 0.029, but did not affect PFS. No other clinical features including grade or FLIPI were significant for outcomes. Local failure was uncommon occurring in 8% (3/40) although this was 21% (3/14) of all recurrences.

Conclusions

OS and PFS outcomes for radiation alone in limited stage low grade FL patients from this single institution study are consistent with previously published data. No predictors were prognostic for PFS. A dose of ≤35 Gy may be appropriate. In this highly selected homogeneous group the FLIPI loses discriminating ability. Local control is excellent, and a majority of patients are free of disease after 5 years.     

Morphological and Volumetric Analysis of Left Atrial Appendage and Left Atrium: Cardiac Computed Tomography-Based Reproducibility Assessment

Objectives

Left atrial appendage (LAA) dilatation and morphology may influence an individual''s risk for intracardiac thrombi and ischemic stroke. LAA size and morphology can be evaluated using cardiac computed tomography (cCT). The present study evaluated the reproducibility of LAA volume and morphology assessments.

Methods

A total of 149 patients (47 females; mean age 60.9±10.6 years) with suspected cardioembolic stroke/transient ischemic attack underwent cCT. Image quality was rated based on four categories. Ten patients were selected from each image quality category (N = 40) for volumetric reproducibility analysis by two individual readers. LAA and left atrium (LA) volume were measured in both two-chamber (2CV) and transversal view (TV) orientation. Intertechnique reproducibility was assessed between 2CV and TV (200 measurement pairs). LAA morphology (A = Cactus, B = ChickenWing, C = WindSock, D = CauliFlower), LAA opening height, number of LAA lobes, trabeculation, and orientation of the LAA tip was analysed in all study subjects by three individual readers (447 interobserver measurement pairs). The reproducibility of volume measurements was assessed by intra-class correlation (ICC) and the reproducibility of LAA morphology assessments by Cohen''s kappa.

Results

The intra-observer and interobserver reproducibility of LAA and LA volume measurements was excellent (ICCs>0.9). The LAA (ICC = 0.954) and LA (ICC = 0.945) volume measurements were comparable between 2CV and TV. Morphological classification (ĸ = 0.24) and assessments of LAA opening height (ĸ = 0.1), number of LAA lobes (ĸ = 0.16), trabeculation (ĸ = 0.15), and orientation of the LAA tip (ĸ = 0.37) was only slightly to fairly reproducible.

Conclusions

LA and LAA volume measurements on cCT provide excellent reproducibility, whereas visual assessment of LAA morphological features is challenging and results in unsatisfactory agreement between readers.     

Effects of an Internet-Based Cognitive Behavioral Therapy (iCBT) Program in Manga Format on Improving Subthreshold Depressive Symptoms among Healthy Workers: A Randomized Controlled Trial

Objective

The purpose of this study was to develop a new Internet-based computerized cognitive behavior therapy (iCBT) program in Manga format, the Japanese cartoon, for workers and to examine the effects of the iCBT program on improving subthreshold depression using a randomized controlled trial (RCT) design among workers employed in private companies in Japan.

Method

All workers in a company (n = 290) and all workers in three departments (n = 1,500) at the headquarters of another large company were recruited by an invitation e-mail. Participants who fulfilled the inclusion criteria were randomly allocated to intervention or control groups (N = 381 for each group). A six-week, six-lesson iCBT program using Manga (Japanese comic) story was developed. The program included several CBT skills: self-monitoring, cognitive restructuring, assertiveness, problem solving, and relaxation. The intervention group studied the iCBT program at a frequency of one lesson per week. Depression (Beck Depression Inventory II; BDI-II) was assessed as a primary outcome at baseline, and three- and six-month follow-ups for both intervention and control groups were performed.

Results

The iCBT program showed a significant intervention effect on BDI-II (t = −1.99, p<0.05) with small effect sizes (Cohen''s d: −0.16, 95% Confidence Interval: −0.32 to 0.00, at six-month follow-up).

Conclusions

The present study first demonstrated that a computerized cognitive behavior therapy delivered via the Internet was effective in improving depression in the general working population. It seems critical to improve program involvement of participants in order to enhance the effect size of an iCBT program.

Trial Registration

UMIN Clinical Trials Registry UMIN000006210 https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R000007341&type=summary&language=E     

A Randomized Controlled Trial of Multicomponent Exercise in Older Adults with Mild Cognitive Impairment

Background

To examine the effect of multicomponent exercise program on memory function in older adults with mild cognitive impairment (MCI), and identify biomarkers associated with improvement of cognitive functions.

Methodology/Principal Findings

Subjects were 100 older adults (mean age, 75 years) with MCI. The subjects were classified to an amnestic MCI group (n = 50) with neuroimaging measures, and other MCI group (n = 50) before the randomization. Subjects in each group were randomized to either a multicomponent exercise or an education control group using a ratio of 1∶1. The exercise group exercised for 90 min/d, 2 d/wk, 40 times for 6 months. The exercise program was conducted under multitask conditions to stimulate attention and memory. The control group attended two education classes. A repeated-measures ANOVA revealed that no group × time interactions on the cognitive tests and brain atrophy in MCI patients. A sub-analysis of amnestic MCI patients for group × time interactions revealed that the exercise group exhibited significantly better Mini-Mental State Examination (p = .04) and logical memory scores (p = .04), and reducing whole brain cortical atrophy (p<.05) compared to the control group. Low total cholesterol levels before the intervention were associated with an improvement of logical memory scores (p<.05), and a higher level of brain-derived neurotrophic factor was significantly related to improved ADAS-cog scores (p<.05).

Conclusions/Significance

The results suggested that an exercise intervention is beneficial for improving logical memory and maintaining general cognitive function and reducing whole brain cortical atrophy in older adults with amnestic MCI. Low total cholesterol and higher brain-derived neurotrophic factor may predict improvement of cognitive functions in older adults with MCI. Further studies are required to determine the positive effects of exercise on cognitive function in older adults with MCI.

Trial Registration

UMIN-CTR UMIN000003662 ctr.cgi&quest;function&hairsp;&equals;&hairsp;brows&amp;action&hairsp;&equals;&hairsp;brows&amp;type&hairsp;&equals;&hairsp;summary&amp;recptno&hairsp;&equals;&hairsp;R000004436&amp;language&hairsp;&equals;&hairsp;J.     

Effectiveness of a Multimodal Community Intervention Program to Prevent Suicide and Suicide Attempts: A Quasi-Experimental Study

Background

Multilevel and multimodal interventions have been suggested for suicide prevention. However, few studies have reported the outcomes of such interventions for suicidal behaviours.

Methods

We examined the effectiveness of a community-based multimodal intervention for suicide prevention in rural areas with high suicide rates, compared with a parallel prevention-as-usual control group, covering a total of 631,133 persons. The effectiveness was also examined in highly populated areas near metropolitan cities (1,319,972 persons). The intervention started in July 2006, and continued for 3.5 years. The primary outcome was the incidence of composite outcome, consisting of completed suicides and suicide attempts requiring admission to an emergency ward for critical care. We compared the rate ratios (RRs) of the outcomes adjusted by sex, age group, region, period and interaction terms. Analyses were performed on an intention-to-treat basis and stratified by sex and age groups.

Findings

In the rural areas, the overall median adherence of the intervention was significantly higher. The RR of the composite outcome in the intervention group decreased 7% compared with that of the control group. Subgroup analyses demonstrated heterogeneous effects among subpopulations: the RR of the composite outcome in the intervention group was significantly lower in males (RR = 0.77, 95% CI 0.59–0.998, p = 0.0485) and the RR of suicide attempts was significantly lower in males (RR = 0.39, 95% CI 0.22–0.68, p = 0.001) and the elderly (RR = 0.35, 95% CI 0.17–0.71, p = 0.004). The intervention had no effect on the RR of the composite outcome in the highly populated areas.

Interpretation

Our findings suggest that this community-based multimodal intervention for suicide prevention could be implemented in rural areas, but not in highly populated areas. The effectiveness of the intervention was shown for males and for the elderly in rural areas.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00737165","term_id":"NCT00737165"}}NCT00737165 UMIN Clinical Trials Registry UMIN000000460     

A Clinical Index to Predict Progression from Mild Cognitive Impairment to Dementia Due to Alzheimer's Disease

Background

Mild cognitive impairment is often a precursor to dementia due to Alzheimer''s disease, but many patients with mild cognitive impairment never develop dementia. New diagnostic criteria may lead to more patients receiving a diagnosis of mild cognitive impairment.

Objective

To develop a prediction index for the 3-year risk of progression from mild cognitive impairment to dementia relying only on information that can be readily obtained in most clinical settings.

Design and Participants

382 participants diagnosed with amnestic mild cognitive impairment enrolled in the Alzheimer''s Disease Neuroimaging Initiative (ADNI), a multi-site, longitudinal, observational study.

Main Predictors Measures

Demographics, comorbid conditions, caregiver report of participant symptoms and function, and participant performance on individual items from basic neuropsychological scales.

Main Outcome Measure

Progression to probable Alzheimer''s disease.

Key Results

Subjects had a mean (SD) age of 75 (7) years and 43% progressed to probable Alzheimer''s disease within 3 years. Important independent predictors of progression included being female, resisting help, becoming upset when separated from caregiver, difficulty shopping alone, forgetting appointments, number of words recalled from a 10-word list, orientation and difficulty drawing a clock. The final point score could range from 0 to 16 (mean [SD]: 4.2 [2.9]). The optimism-corrected Harrell''s c-statistic was 0.71(95% CI: 0.68–0.75). Fourteen percent of subjects with low risk scores (0–2 points, n = 124) converted to probable Alzheimer''s disease over 3 years, compared to 51% of those with moderate risk scores (3–8 points, n = 223) and 91% of those with high risk scores (9–16 points, n = 35).

Conclusions

An index using factors that can be obtained in most clinical settings can predict progression from amnestic mild cognitive impairment to probable Alzheimer''s disease and may help clinicians differentiate between mild cognitive impairment patients at low vs. high risk of progression.     

Treating and Preventing Influenza in Aged Care Facilities: A Cluster Randomised Controlled Trial

Background

Influenza is an important cause of morbidity and mortality for frail older people. Whilst the antiviral drug oseltamivir (a neuraminidase inhibitor) is approved for treatment and prophylaxis of influenza during outbreaks, there have been no trials comparing treatment only (T) versus treatment and prophylaxis (T&P) in Aged Care Facilities (ACFs). Our objective was to compare a policy of T versus T&P for influenza outbreaks in ACFs.

Methods and Findings

We performed a cluster randomised controlled trial in 16 ACFs, that followed a policy of either “T”—oseltamivir treatment (75 mg twice a day for 5 days)—or “T&P”—treatment and prophylaxis (75 mg once a day for 10 days) for influenza outbreaks over three years, in addition to enhanced surveillance. The primary outcome measure was the attack rate of influenza. Secondary outcomes measures were deaths, hospitalisation, pneumonia and adverse events. Laboratory testing was performed to identify the viral cause of influenza-like illness (ILI) outbreaks. The study period 30 June 2006 to 23 December 2008 included three southern hemisphere winters. During that time, influenza was confirmed as the cause of nine of the 23 ILI outbreaks that occurred amongst the 16 ACFs. The policy of T&P resulted in a significant reduction in the influenza attack rate amongst residents: 93/255 (36%) in residents in T facilities versus 91/397 (23%) in T&P facilities (p = 0.002). We observed a non-significant reduction in staff: 46/216 (21%) in T facilities versus 47/350 (13%) in T&P facilities (p = 0.5). There was a significant reduction in mean duration of outbreaks (T = 24 days, T&P = 11 days, p = 0.04). Deaths, hospitalisations and pneumonia were non-significantly reduced in the T&P allocated facilities. Drug adverse events were common but tolerated.

Conclusion

Our trial lacked power but these results provide some support for a policy of “treatment and prophylaxis” with oseltamivir in controlling influenza outbreaks in ACFs.

Trail Registration

Australian Clinical Trials Registry ACTRN12606000278538     

Clinical Evaluation of Rega 8: An Updated Genotypic Interpretation System That Significantly Predicts HIV-Therapy Response

Introduction

Clinically evaluating genotypic interpretation systems is essential to provide optimal guidance in designing potent individualized HIV-regimens. This study aimed at investigating the ability of the latest Rega algorithm to predict virological response on a short and longer period.

Materials & Methods

9231 treatment changes episodes were extracted from an integrated patient database. The virological response after 8, 24 and 48 weeks was dichotomized to success and failure. Success was defined as a viral load below 50 copies/ml or alternatively, a 2 log decrease from the baseline viral load at 8 weeks. The predictive ability of Rega version 8 was analysed in comparison with that of previous evaluated version Rega 5 and two other algorithms (ANRS v2011.05 and Stanford HIVdb v6.0.11). A logistic model based on the genotypic susceptibility score was used to predict virological response, and additionally, confounding factors were added to the model. Performance of the models was compared using the area under the ROC curve (AUC) and a Wilcoxon signed-rank test.

Results

Per unit increase of the GSS reported by Rega 8, the odds on having a successful therapy response on week 8 increased significantly by 81% (OR = 1.81, CI = [1.76–1.86]), on week 24 by 73% (OR = 1.73, CI = [1.69–1.78]) and on week 48 by 85% (OR = 1.85, CI = [1.80–1.91]). No significant differences in AUC were found between the performance of Rega 8 and Rega 5, ANRS v2011.05 and Stanford HIVdb v6.0.11, however Rega 8 had the highest sensitivity: 76.9%, 76.5% and 77.2% on 8, 24 and 48 weeks respectively. Inclusion of additional factors increased the performance significantly.

Conclusion

Rega 8 is a significant predictor for virological response with a better sensitivity than previously, and with rules for recently approved drugs. Additional variables should be taken into account to ensure an effective regimen.     

Suitability of Pharmacokinetic Models for Dynamic Contrast-Enhanced MRI of Abdominal Aortic Aneurysm Vessel Wall: A Comparison

Purpose

Increased microvascularization of the abdominal aortic aneurysm (AAA) vessel wall has been related to AAA progression and rupture. The aim of this study was to compare the suitability of three pharmacokinetic models to describe AAA vessel wall enhancement using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Materials and Methods

Patients with AAA underwent DCE-MRI at 1.5 Tesla. The volume transfer constant (K^trans), which reflects microvascular flow, permeability and surface area, was calculated by fitting the blood and aneurysm vessel wall gadolinium concentration curves. The relative fit errors, parameter uncertainties and parameter reproducibilities for the Patlak, Tofts and Extended Tofts model were compared to find the most suitable model. Scan-rescan reproducibility was assessed using the interclass correlation coefficient and coefficient of variation (CV). Further, the relationship between K^trans and AAA size was investigated.

Results

DCE-MRI examinations from thirty-nine patients (mean age±SD: 72±6 years; M/F: 35/4) with an mean AAA maximal diameter of 49±6 mm could be included for pharmacokinetic analysis. Relative fit uncertainties for K^trans based on the Patlak model (17%) were significantly lower compared to the Tofts (37%) and Extended Tofts model (42%) (p<0.001). K^trans scan-rescan reproducibility for the Patlak model (ICC = 0.61 and CV = 22%) was comparable with the Tofts (ICC = 0.61, CV = 23%) and Extended Tofts model (ICC = 0.76, CV = 22%). K^trans was positively correlated with maximal AAA diameter (Spearman’s ρ = 0.38, p = 0.02) using the Patlak model.

Conclusion

Using the presented imaging protocol, the Patlak model is most suited to describe DCE-MRI data of the AAA vessel wall with good K^trans scan-rescan reproducibility.     

Verbal Autopsy: Reliability and Validity Estimates for Causes of Death in the Golestan Cohort Study in Iran

Background

Verbal autopsy (VA) is one method to obtain valid estimates of causes of death in the absence of valid medical records. We tested the reliability and validity of a VA questionnaire developed for a cohort study in Golestan Province in northeastern Iran.

Method

A modified version of the WHO adult verbal autopsy was used to assess the cause of death in the first 219 Golestan Cohort Study (GCS) subjects who died. The GCS cause of death was determined by two internists who independently reviewed all available medical records. Two other internists (“reviewers”) independently reviewed only the VA answers and classified the cause of death into one of nine general categories; they repeated this evaluation one month later. The reliability of the VA was measured by calculating intra-reviewer and inter-reviewer kappa statistics. The validity of the VA was measured using the GCS cause of death as the gold standard.

Results

VA showed both good validity (sensitivity, specificity, PPV, and NPV all above 0.81) and reliability (kappa>0.75) in determining the general cause of death independent of sex and place of residence. The overall multi-rater agreement across four reviews was 0.84 (95%CI: 0.78–0.89). The results for identifying specific cancer deaths were also promising, especially for upper GI cancers (kappa = 0.95). The multi-rater agreement in cancer subgroup was 0.93 (95%CI: 0.85–0.99).

Conclusions

VA seems to have good reliability and validity for determining the cause of death in a large-scale adult follow up study in a predominantly rural area of a middle-income country.