Applying artificial intelligence to determination of legal age of majority from radiographic data.

Forensic odontologists use biological patterns to estimate chronological age for the judicial system. The age of majority is a legally significant period with a limited set of reliable oral landmarks. Currently, experts rely on the questionable development of third molars to assess whether litigants can be prosecuted as legal adults. Identification of new and novel patterns may illuminate features more dependably indicative of chronological age, which have, until now, remained unseen. Unfortunately, biased perceptions and limited cognitive capacity compromise the ability of researchers to notice new patterns. The present study demonstrates how artificial intelligence can break through identification barriers and generate new estimation modalities. A convolutional neural network was trained with 4003 panoramic-radiographs to sort subjects into 'under-18' and 'over-18' age categories. The resultant architecture identified legal adults with a high predictive accuracy equally balanced between precision, specificity and recall. Moving forward, AI-based methods could improve courtroom efficiency, stand as automated assessment methods and contribute to our understanding of biological ageing.

Radiographic morphology of canines tested for sexual dimorphism via convolutional-neural-network-based artificial intelligence.

The permanent left mandibular canines have been used for sexual dimorphism when human identification is necessary. Controversy remains whether the morphology of these teeth is actually useful to distinguish males and females. This study aimed to assess the sexual dimorphism of canines by means of a pioneering artificial intelligence approach to this end. A sample of 13,046 teeth radiographically registered from 5838 males and 7208 females between the ages of 6 and 22.99 years was collected. The images were annotated using Darwin V7 software. DenseNet121 was used and tested based on binary answers regarding the sex (male or female) of the individuals for 17 age categories of one year each (i.e. 6-6.99, 7.7.99… 22.22.99). Accuracy rates, receiver operating characteristic (ROC) curves and confusion matrices were used to quantify and express the artificial intelligence's classification performance. The accuracy rates across age categories were between 57-76% (mean: 68%±5%). The area under the curve (AUC) of the ROC analysis was between 0.58 and 0.77. The best performances were observed around the age of 12 years, while the worst were around the age of 7 years. The morphological analysis of canines for sex estimation should be restricted and allowed in practice only when other sources of dimorphic anatomic features are not available.

[Discussion on the diagnosis and treatment of high-grade squamous intraepithelial lesions in post-menopausal women].

Objective: To analyze the performance of colposcopy and investigate the diagnosis and treatment characteristics of high-grade squamous intraepithelial lesion (HSIL) diagnosed by cervical tissue sampling in post-menopausal women. Methods: A retrospective study was performed on 1 449 patients with HSIL diagnosed by cervical tissue sampling under colposcopy and treated by loop electrosurgical excision procedure (LEEP) or extrafascial hysterectomy as the primary therapy at the First Affiliated Hospital of Nanjing Medical University, from November 2015 to October 2017. In order to investigate the diagnosis and treatment of HSIL in post-menopausal women, a case-control study was conducted to compare the difference in performance of colposcopy and treatment modality between 213 post-menopausal patients (14.7%, 213/1 449) and 1 236 pre-menopausal patients (85.3%, 1 236/1 449). Results: (1)The proportion of cases pathologically upgraded to cervical cancer was significantly greater in post-menopausal patients (9.4%, 20/213) compared with pre-menopausal patients (3.8%, 47/1 236; P<0.05). (2) The proportion of ≥HSIL diagnosed by colposcopy showed no significant difference between post-menopausal patients (76.1%, 162/213) and pre-menopausal patients (78.2%, 967/1 236; P=0.479). The proportion of type Ⅲ transformation zone (TZ) was significantly greater in post-menopausal patients (91.1%, 194/213) compared with pre-menopausal patients (59.1%, 731/1 236; P<0.05). The rate of missed diagnosis of cervical cancer was significantly higher in type Ⅲ TZ (6.4%, 59/925) compared with type Ⅰ and(or) Ⅱ TZ (1.5%, 8/524; P<0.05). The proportion of HSIL detected by endocervical curettage alone was greater in post-menopausal patients (9.9%, 21/213) compared with pre-menopausal patients (2.6%, 32/1 236; P<0.05). (3)Initial treatment with LEEP: the positive rate of endocervical margin was significantly greater in post-menopausal patients (20.5%, 36/176) compared with pre-menopausal patients (10.5%, 130/1 236;P<0.05); in patients who were diagnosed as HSIL after LEEP, the positive rate of endocervical margin and the residual rate were both greater in post-menopausal patients compared with pre-menopausal patients [15.4% (25/162) versus 8.8% (105/1 189), P=0.008; 52.0% (13/25) versus 26.7% (28/105), P=0.014]. (4)Thirty-seven post-menopausal patients were treated by extrafascial hysterectomy as the primary therapy, 5 cases (13.5%, 5/37) were diagnosed as cervical cancer (stage Ⅰa1) after the surgery. Conclusions: (1) The lesions of HSIL in post-menopausal patients still have definite features under colposcopy as same as pre-menopausal patients. Endocervical curettage could help detect more HSIL in post-menopausal patients. Compared with pre-menopausal patients, post-menopausal HSIL patients have an increased risk of cervical cancer and are more likely missed by cervical tissue sampling. (2) LEEP has the dual effects of diagnosis and treatment, and is still the recommended treatment for post-menopausal HSIL patients. However, the increase in positive rate of endocervical margin and residual rate requires further active intervention. (3) Considering those post-menopausal HSIL patients who cannot accept conization as the initial treatment, the selection of hysterectomy type requires more thorough study.

Risk and predictors of suicide in colorectal cancer patients: a Surveillance, Epidemiology, and End Results analysis.

BACKGROUND: The risk of suicide is higher for patients with colorectal cancer (crc) than for the general population. Given known differences in morbidity and sites of recurrence, we sought to compare the predictors of suicide for patients with colon cancer and with rectal cancer. METHODS: Using the U.S. Surveillance, Epidemiology, and End Results database, adult patients with confirmed adenocarcinoma of the colon or rectum during 1973-2009 were identified. Parametric and nonparametric tests were used to assess selected variables, and Cox proportional hazards regression models were used to determine predictors of suicide. RESULTS: The database identified 187,996 patients with rectal cancer and 443,368 with colon cancer. Compared with the rectal cancer group, the colon cancer group was older (median age: 70 years vs. 67 years; p < 0.001) and included more women (51% vs. 43%, p < 0.001). Suicide rates were similar in the colon and rectal cancer groups [611 (0.14%) vs. 337 (0.18%), p < 0.001]. On univariate analysis, rectal cancer was a predictor of suicide [hazard ratio (hr): 1.26; 95% confidence interval (ci): 1.10 to 1.43]. However, after adjusting for clinical and pathology factors, rectal cancer was not a predictor of suicide (hr: 1.05; 95% ci: 0.83 to 1.33). In the colon cancer cohort, independent predictors of suicide included older age, male sex, white race, and lack of primary resection. The aforementioned predictors, plus metastatic disease, similarly predicted suicide in the rectal cancer cohort. CONCLUSIONS: The suicide risk in crc patients is low (<0.2%), and no difference was found based on location of the primary tumour. Sex, age, race, distant spread of disease, and intact primary tumour were the main predictors of suicide among crc patients. Further studies and interventions are needed to target these high-risk groups.

A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel.

BACKGROUND: Few prognostic models for overall survival (OS) are available for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with recently approved agents. We developed a prognostic index model using readily available clinical and laboratory factors from a phase III trial of abiraterone acetate (hereafter abiraterone) in combination with prednisone in post-docetaxel mCRPC. PATIENTS AND METHODS: Baseline data were available from 762 patients treated with abiraterone-prednisone. Factors were assessed for association with OS through a univariate Cox model and used in a multivariate Cox model with a stepwise procedure to identify those of significance. Data were validated using an independent, external, population-based cohort. RESULTS: Six risk factors individually associated with poor prognosis were included in the final model: lactate dehydrogenase > upper limit of normal (ULN) [hazard ratio (HR) = 2.31], Eastern Cooperative Oncology Group performance status of 2 (HR = 2.19), presence of liver metastases (HR = 2.00), albumin ≤4 g/dl (HR = 1.54), alkaline phosphatase > ULN (HR = 1.38) and time from start of initial androgen-deprivation therapy to start of treatment ≤36 months (HR = 1.30). Patients were categorized into good (n = 369, 46%), intermediate (n = 321, 40%) and poor (n = 107, 13%) prognosis groups based on the number of risk factors and relative HRs. The C-index was 0.70 ± 0.014. The model was validated by the external dataset (n = 286). CONCLUSION: This analysis identified six factors used to model survival in mCRPC and categorized patients into three distinct risk groups. Prognostic stratification with this model could assist clinical practice decisions for follow-up and monitoring, and may aid in clinical trial design. TRIAL REGISTRATION NUMBERS: NCT00638690.

The perspectives of preceptors regarding clinical assessment for undergraduate nursing students.

AIM: To explore the perspectives of preceptors about clinical assessment for undergraduate nursing students in transition to practice. BACKGROUND: The assessment of clinical competence is a complex process due to the diverse nature of nursing practice. As such, nurse preceptors play a crucial role in clinical assessment for nursing students. Although preceptors may enjoy the process of clinical teaching and assessment, they face challenges that need to be addressed to facilitate students' clinical learning and assessment. METHODS: An exploratory qualitative approach was adopted. A purposive sample of 17 preceptors from two tertiary hospitals in Singapore was recruited to participate in three focus group discussions from March to July 2014. FINDINGS: Five themes emerged from the data analysis: the need for a valid and reliable clinical assessment tool; meaningful reflection and feedback; varied methods in clinical assessment; high level of commitment and struggles with dual roles and the need to enhance the support system for preceptors. CONCLUSIONS: There is no doubt that a valid and reliable clinical assessment tool can serve as a guide for preceptors to enhance their clarity in assessment and feedback. It is essential for all stakeholders to be involved in the development of the clinical assessment tool. Workload, time, support system and formal educational programmes for preceptors influenced their preparation and self-confidence. IMPLICATIONS FOR NURSING AND/OR HEALTH POLICY: The themes that emerged from the focus group discussions could assist in the development of a more reliable and valid clinical assessment tool to evaluate the clinical competence of nursing students in transition to practice. Clinical and educational institutions could collaborate closely to develop an educational programme and a preceptorship handbook, focusing on pedagogical contents for clinical education and assessment.

Clinical outcomes of elderly patients receiving neoadjuvant chemoradiation for locally advanced rectal cancer.

BACKGROUND: Studies of clinical outcomes of elderly patients treated with neoadjuvant chemoradiation (nCRT) for locally advanced rectal cancer (LARC) are limited. Our aim was to assess the impact of age on clinical outcomes in a large multi-institutional database. PATIENTS AND METHODS: Data for patients diagnosed with LARC who received nCRT and curative-intent surgery between 2005 and 2012 were collected from five major Canadian cancer centers. Age was analyzed as a continuous and dichotomous variable (< 70 versus ≥ 70 years) and correlated with disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Cox regression models were used to adjust for important prognostic factors. RESULTS: Of 1172 patients included, 295 (25%) were ≥ 70 years, and they were less likely to receive adjuvant chemotherapy (ACT; 60% versus 79%, P < 0.0001), oxaliplatin-based ACT (12% versus 31%, P < 0.0001), less likely to complete nCT (76% versus 86%, P < 0.001), and more likely to be anemic at initiation of nCRT (42% versus 30%, P = 0.0004). In multivariate analyses, age ≥ 70 years was associated with similar DFS [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.68-1.26, P = 0.63], similar CSS (HR 0.81, 95% CI 0.46-1.41, P = 0.45), and similar OS (HR 1.28, 95% CI 0.88-1.86, P = 0.20), compared with the younger age group. As a continuous variable, increasing age was not predictive of DFS (HR 1.00, 95% CI 0.99-1.02, P = 0.49) or CSS (HR 1.002, 95% CI 0.98-1.02, P = 0.88); however, it correlated with an inferior OS (HR 1.02, 95% CI 1.00-1.03, P = 0.04). CONCLUSIONS: Elderly patients (≥ 70 years) who receive nCRT followed by surgery appear to have similar outcomes compared with younger patients. Decisions regarding eligibility for nCRT and surgery should not be based on age alone.

Anti-VEGF therapy in mRCC: differences between Asian and non-Asian patients.

BACKGROUND: Several reports suggest that vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in Asian vs non-Asian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterised. METHODS: A multicentre, retrospective, cohort study using Asian and non-Asian centres which collected data on ethnicity, dose reductions and outcomes using the International mRCC Database Consortium. RESULTS: This study included 1024 (464 Asian, 560 non-Asian) patients with a 29.4 months median follow-up. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% P=0.1197). When adjusted for risk groups, there was no difference in overall or progression-free survival between non-Asians and Asians. Patients with dose reductions due to toxicity had longer treatment durations and overall survival than those who did not in both non-Asian (10.6 vs 5.0 months, P<0.0001; 22.6 vs 16.1 months, P=0.0016, respectively) and Asian populations (8.9 vs 5.4 months, P=0.0028; 28.0 vs 18.7 months, P=0.0069, respectively). CONCLUSIONS: Adjusting for risk groups, there appears to be no difference in outcome between Asian vs non-Asian patients with mRCC treated with VEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations due to longer treatment durations, but direct comparisons are needed.

First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC.

BACKGROUND: Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design. METHODS: Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria. RESULTS: In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months. CONCLUSIONS: Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.

Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials.

BACKGROUND: Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown. PATIENTS AND METHODS: mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3). RESULTS: Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001). CONCLUSIONS: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

Prognostic significance of absolute lymphocyte count in patients with metastatic renal cell carcinoma receiving first-line combination immunotherapies: results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: Lymphocytes are closely linked to mechanisms of action of immuno-oncology (IO) agents. We aimed to assess the prognostic significance of absolute lymphocyte count (ALC) in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Using the International mRCC Database Consortium (IMDC), patients receiving first-line IO-based combination therapy were analysed. Baseline patient characteristics, objective response rates (ORRs), time to next treatment (TTNT), and overall survival (OS) were compared. RESULTS: Of 966 patients included, 195 (20%) had lymphopenia at baseline, and they had a lower ORR (37% versus 45%; P < 0.001), shorter TTNT (10.1 months versus 24.3 months; P < 0.001), and shorter OS (30.4 months versus 48.2 months; P < 0.001). Among 125 patients with lymphopenia at baseline, 52 (42%) experienced ALC recovery at 3 months, and they had longer OS (not reached versus 30.4 months; P = 0.012). On multivariable analysis for OS, lymphopenia was an independent adverse prognostic factor (hazard ratio 1.68; P < 0.001). Incorporation of lymphopenia into the IMDC criteria improved OS prediction accuracy (C-index from 0.688 to 0.707). CONCLUSIONS: Lymphopenia was observed in one-fifth of treatment-naive patients with mRCC and may serve as an indicator of unfavourable oncologic outcomes in the contemporary IO era.

Risk of infections in renal cell carcinoma (RCC) and non-RCC patients treated with mammalian target of rapamycin inhibitors.

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors are used in a variety of malignancies. Infections have been reported with these drugs. We performed an up-to-date meta-analysis to further characterise the risk of infections in cancer patients treated with these agents. METHODS: Pubmed and oncology conferences' proceedings were searched for studies from January 1966 to June 2012. Studies were limited to phase II and III randomised controlled trials (RCTs) of everolimus or temsirolimus reporting on cancer patients with adequate safety profiles. Summary incidences, relative risks (RRs), and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 3180 patients were included. The incidence of all-grade and high-grade infections due to mTOR inhibitors was 33.1% (95% CI, 24.5-43.0%) and 5.6% (95% CI, 3.8-8.3%), respectively. Compared with controls, the RR of all-grade and high-grade infections due to mTOR inhibitors was 2.00 (95% CI, 1.76-2.28, P<0.001) and 2.60 (95% CI, 1.54-4.41, P<0.001), respectively. Subgroup analysis found no difference in incidences or risks between everolimus and temsirolimus or between different tumour types (renal cell carcinoma (RCC) vs non-RCC). Infections included respiratory tract (61.7%), genitourinary (29.4%), skin/soft tissue (4.2%), and others (4.9%). CONCLUSION: Treatment with mTOR inhibitors is associated with a significant increase in risk of infections. Close monitoring for any signs of infections is warranted.

Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors.

BACKGROUND: Inhibition of the mammalian target of rapamycin (mTOR) is an established treatment for multiple malignancies. We carried out an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors. PATIENTS AND METHODS: PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to approved mTOR inhibitors (everolimus and temsirolimus) and reported on patients with cancer, randomized design and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: In all, 3193 patients from eight randomized, controlled trials (RCTs) were included, 2236 from everolimus trials and 957 from temsirolimus trials. The relative risk (RR) of FAEs related to mTOR inhibitors use was 2.20 (95% CI, 1.25-3.90; P = 0.006) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types [renal cell carcinoma (RCC) versus non-RCC]. No evidence of publication bias was observed. CONCLUSION: The use of mTOR inhibitors is associated with a small but higher risk of FAEs compared to control patients. In the appropriate clinical scenario, the use of these drugs remains justified in their approved indications.

Associations between complications and health-related quality of life in individuals with diabetes.

OBJECTIVE: Type 2 diabetes and associated complications adversely affect health-related quality of life (HRQoL). However, it is unclear whether different complications have the same or different associations with HRQoL. We examined associations between retinopathy, nephropathy, peripheral neuropathy (microvascular), coronary heart disease, stroke and peripheral arterial disease (macrovascular) in diabetes and HRQoL. DESIGN: This study was a follow-up examination between 2004 and 2007 of participants from four previous cross-sectional population-based studies in Singapore. METHODS: Health-related quality of life was assessed through self-administered SF-36 health survey version 2. Diabetes and complications status were assessed through self-report, clinical and laboratory examinations. About 2601 individuals, 2205 healthy and 396 with diabetes, were studied. RESULTS: Lower physical component scores (PCS) were associated with microvascular (2.96 points, P < 0.001) and both macro- and microvascular complications (4.67 points, P < 0.001), but not diabetes alone. Coronary heart disease (3.86 points, P = 0.007), peripheral neuropathy (11.46 points, P < 0.001) and severe retinopathy (4.46 points, P < 0.001) were associated with lower PCS. The greatest reduction in scores was seen in peripheral neuropathy. CONCLUSIONS: Quality of life in patients with diabetes is affected mainly by presence of complications, and not diabetes per se. Peripheral neuropathy was associated with the greatest reduction in quality of life. Improved management to prevent or delay onset of complications may reduce the effect on quality of life in patients with diabetes.

All-cause and cause-specific mortality after hip fracture among Chinese women and men: the Singapore Chinese Health Study.

UNLABELLED: All-cause mortality risk persisted for 5 years after hip fractures in both men and women. There may be gender-specific differences in effect and duration of excess risk for cause-specific mortality after hip fracture. INTRODUCTION: To determine all-cause and cause-specific mortality risk in the first 5 years after hip fracture in an Asian Chinese population. METHODS: The Singapore Chinese Health Study is a population-based cohort of 63,257 middle-aged and elderly Chinese men and women in Singapore recruited between 1993 and 1998. This cohort was followed up for hip fracture and death via linkage with nationwide hospital discharge database and death registry. As of 31 December 2008, we identified 1,166 hip fracture cases and matched five non-fracture cohort subjects by age and gender for each fracture case. Cox proportional hazards and competing risks regression models with hip fracture as a time-dependent covariate were used to determine all-cause and cause-specific mortality risk, respectively. RESULTS: Increase in all-cause mortality risk persisted till 5 years after hip fracture (adjusted hazard ratio, aHR = 1.58 [95 % CI, 1.35-1.86] for females and aHR = 1.64 [95 % CI, 1.30-2.06] for males). Men had higher mortality risk after hip fracture than women for deaths from stroke and cancer up to 1 year post-fracture but women with hip fracture had higher coronary artery mortality risk than men for 5 years post-fracture. Men had higher risk of death from pneumonia while women had increased risk of death from urinary tract infections. There was no difference in mortality risk by types of hip fracture surgery. CONCLUSIONS: All-cause mortality risk persisted for 5 years after hip fractures in men and women. There are gender-specific differences in effect size and duration of excess mortality risk from hip fractures between specific causes of death.

Estimating the lifetime economic burden of Parkinson's disease in Singapore.

BACKGROUND AND PURPOSE: We aimed to estimate the lifetime cost of Parkinson's disease (PD) from the societal perspective. METHODS: A convenience sample of English or Chinese-speaking patients with PD was recruited from a PD and Movement Disorders Centre in Singapore to complete a financial burden questionnaire. Sociodemographic and clinical data were retrieved from hospital databases. Markov cohort model analysis was performed (cycle length, 1-year; duration, death or reached 100 years old). Patients were assumed to progress from one Markov state to the next state or death without skipping states or regressing. All model parameters were based on published local data. RESULTS: In 195 patients with PD (median age: 68.9, male: 51.8%), the simulated lifetime cost of PD was Singapore Dollar (SGD) 60,487 (EUR purchasing power parity 56,253) per patient. Direct medical, non-medical and indirect cost accounted for 18.8%, 12.8% and 68.4% of total lifetime cost, respectively. The top three components of total lifetime cost were productivity losses (67.6%), pharmacotherapy (11.4%) and home care (8.7%). One-way sensitivity analysis and probabilistic sensitivity analyses revealed that estimates were sensitive to cost at H&Y stage 1, 2 and 2.5 and productivity losses. CONCLUSIONS: The lifetime cost of PD is evaluated for the first time. This cost is substantial and comparable to the lifetime cost of intracerebral haemorrhage in at least one study. Our study identified several priority areas for research and policy formulation: reducing productivity losses, reducing cost of pharmacotherapy, avoiding hospitalization and reducing home care cost.

Population pharmacokinetics and pharmacogenetics of alcohol in Chinese and Indians in Singapore.

WHAT IS KNOWN AND OBJECTIVE:   Interindividual variability in alcohol pharmacokinetics is influenced by a number of factors, including polymorphisms in genes mediating alcohol pharmacology, ethnicity, sex and body size. Several studies have evaluated the population pharmacokinetics of alcohol from breath alcohol measures. None of these studies, however, have evaluated ethnicity and alcohol-metabolizing enzyme genotypes as covariates in their population pharmacokinetic modelling. We aimed to develop a population pharmacokinetic model using clinical and genetic factors and to identify covariates that influenced interindividual variability in alcohol clearance and volume of distribution. METHODS:   Hundred and eighty healthy subjects (90 Chinese and 90 Indians; 45 males and 45 females from each ethnic group) ingested a vodka-orange juice mixture to simulate social drinking. Subjects were genotyped for the ADH1B (Arg48His), ALDH2 (Glu504Lys) and CYP2E1 (c.-1293G>C and c.-1053C>T) polymorphisms. A base pharmacokinetic model was developed using the nonmem software (NONMEM Project Group, University of California, San Francisco, San Francisco, CA, USA) to determine the alcohol clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability. RESULTS AND DISCUSSION:   Body weight and sex significantly influenced absorption rate and volume of distribution of alcohol. Body weight and ADH1B Arg48His polymorphism significantly influenced alcohol clearance. The Michaelis-Menten elimination rate (Vmax ) was decreased by 10% in homozygous ADH1B*1/*1 subjects. Ethnicity was not determined to be a significant covariate in the final population pharmacokinetic model. WHAT IS NEW AND CONCLUSION:   Gender and body weight were covariates that contributed most to explaining the observed interindividual alcohol pharmacokinetic variability. Of the four SNPs examined in this study, only ADH1B Arg48His polymorphism had a significant, though modest, effect on the pharmacokinetics of alcohol.

Association between treatment effects on disease progression end points and overall survival in clinical studies of patients with metastatic renal cell carcinoma.

BACKGROUND: The relationship between progression-free survival and time to progression (PFS/TTP) and overall survival (OS) has been demonstrated in a variety of solid tumours but not in metastatic renal cell carcinoma (mRCC). METHODS: A systematic literature search was conducted to identify controlled trials of cytokine or targeted therapies for mRCC reporting information on treatment effects on PFS/TTP and OS for one or more comparison. The associations between treatment effects on PFS/TTP and OS were analysed using linear regression. RESULTS: Thirty-one studies representing 10943 patients, 75 treatment groups, and 41 comparisons were identified. The correlation coefficient between the negative log of the hazard ratio (HR) for PFS/TTP (-ln HR(PFS/TTP)) vs the negative log of the HR for OS (-ln HR(OS)) was 0.80 (P<0.0001). In linear regression, the coefficient on -ln HR(PFS/TTP) vs -ln HR(OS) was 0.64 (95% confidence interval (CI): 0.470.81; R(2)=0.63), suggesting each 10% relative risk reduction (RRR) for PFS/TTP was associated with a 6% RRR for OS. A 1-month gain in median PFS/TTP was associated with a 1.17-month gain in median OS (95% CI: 0.59,1.76; R(2)=0.28). CONCLUSION: In trials of treatments for mRCC, treatment effects on PFS/TTP are strongly associated with treatment effects on OS.

Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy.

BACKGROUND: A subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria. METHODS: Data from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. RESULTS: One thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors. CONCLUSIONS: Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.

Ethnicity modifies the relation between fasting plasma glucose and HbA1c in Indians, Malays and Chinese.

AIMS: To study whether HbA(1c) , and its relationship with fasting plasma glucose, was significantly different among Chinese, Malays and Indians in Singapore. METHODS: A sample of 3895 individuals without known diabetes underwent detailed interview and health examination, including anthropometric and biochemical evaluation, between 2004 and 2007. Pearson's correlation, analysis of variance and multiple linear regression analyses were used to examine the influence of ethnicity on HbA(1c) . RESULTS: As fasting plasma glucose increased, HbA(1c) increased more in Malays and Indians compared with Chinese after adjustment for age, gender, waist circumference, serum cholesterol, serum triglyceride and homeostasis model assessment of insulin resistance (P-interaction < 0.001). This translates to an HbA(1c) difference of 1.1 mmol/mol (0.1%, Indians vs. Chinese), and 0.9 mmol/mol (0.08%, Malays vs. Chinese) at fasting plasma glucose 5.6 mmol/l (the American Diabetes Association criterion for impaired fasting glycaemia); and 2.1 mmol/mol (0.19%, Indians vs. Chinese) and 2.6 mmol/mol (0.24%, Malays vs. Chinese) at fasting plasma glucose 7.0 mmol/l, the diagnostic criterion for diabetes mellitus. CONCLUSIONS: Using HbA(1c) in place of fasting plasma glucose will reclassify different proportions of the population in different ethnic groups. This may have implications in interpretation of HbA(1c) results across ethnic groups and the use of HbA(1c) for diagnosing diabetes mellitus.