Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Computed Tomography Dose in Paediatric Care: Simple Dose Estimation Using Dose Length Product Conversion Coefficients.

BACKGROUND: The use of multislice computed tomography (MSCT) is increasing worldwide; at the same time, there is a growing awareness of the future risk of cancer associated with greater exposure to radiation. Therefore, there is a need for an accessible method of effective dose estimation. This study aims to estimate the effective doses (EDs) of a variety of paediatric computed tomography (CT) examinations in five age groups using recently published age- and region-specific dose length products (DLPs) as effective dose conversion coefficients. METHODS: A retrospective review was performed over a 12-month period. Patients were assigned to one of five age groups: neonatal, 1-, 5-, 10- and 15-years-old. Age- and region-specific conversion coefficients were applied to the DLP data displayed on the CT console in order to estimate the ED. RESULTS: Over the 12-month period, there were a total of 283 CT scans, 211 of which were selected for study. The ED estimates for plain CT brain scans in neonatal, 1-, 5-, 10- and 15-yearolds were 2.5, 1.5, 1.4, 1.3 and 0.8 mSv, respectively. For the corresponding CT abdominal scans, the results were 18.8, 12.9, 7.8, 8.6 and 7.5 mSv; these were the highest values recorded. High-resolution CT (HRCT) temporal scans showed EDs of 2.9, 1.8, 1.5 and 1.1 mSv in 1-, 5-, 10- and 15-years-old, respectively. CT scans of the helical thorax had an estimated ED of 4.8, 4.2 and 7.0 mSv in 5-, 10- and 15-years-old, respectively. CONCLUSION: An inverse relationship between age and effective dose was demonstrated in CT scans of the brain and abdomen/pelvis. In general, our study showed lower overall EDs compared to other centres.

Emergency department visits for attempted suicide and self harm in the USA: 2006-2013.

AIMS: To characterise and identify nationwide trends in suicide-related emergency department (ED) visits in the USA from 2006 to 2013. METHODS: We used data from the Nationwide Emergency Department Sample (NEDS) from 2006 to 2013. E-codes were used to identify ED visits related to suicide attempts and self-inflicted injury. Visits were characterised by factors such as age, sex, US census region, calendar month, as well as injury severity and mechanism. Injury severity and mechanism were compared between age groups and sex by chi-square tests and Wilcoxon rank-sum tests. Population-based rates were computed using US Census data. RESULTS: Between 2006 and 2013, a total of 3 567 084 suicide attempt-related ED visits were reported. The total number of visits was stable between 2006 and 2013, with a population-based rate ranging from 163.1 to 173.8 per 100 000 annually. The frequency of these visits peaks during ages 15-19 and plateaus during ages 35-45, with a mean age at presentation of 33.2 years. More visits were by females (57.4%) than by males (42.6%); however, the age patterns for males and females were similar. Visits peaked in late spring (8.9% of all visits occurred in May), with a smaller peak in the fall. The most common mechanism of injury was poisoning (66.5%), followed by cutting and piercing (22.1%). Males were 1.6 times more likely than females to use violent methods to attempt suicide (OR = 1.64; 95% CI = 1.60-1.68; p < 0.001). The vast majority of patients (82.7%) had a concurrent mental disorder. Mood disorders were the most common (42.1%), followed by substance-related disorders (12.1%), alcohol-related disorders (8.9%) and anxiety disorders (6.4%). CONCLUSIONS: The annual incidence of ED visits for attempted suicide and self-inflicted injury in the NEDS is comparable with figures previously reported from other national databases. We highlighted the value of the NEDS in allowing us to look in depth at age, sex, seasonal and mechanism patterns. Furthermore, using this large national database, we confirmed results from previous smaller studies, including a higher incidence of suicide attempts among women and individuals aged 15-19 years, a large seasonal peak in suicide attempts in the spring, a predominance of poisoning as the mechanism of injury for suicide attempts and a greater use of violent mechanisms in men, suggesting possible avenues for further research into strategies for prevention.

Feasibility of Implementing Chronic Care Model in the Malaysian Public Primary Care Setting.

INTRODUCTION: Non-communicable diseases (NCD) is a global health threat. the Chronic Care Model (CCM) was proven effective in improving NCD management and outcomes in developed countries. Evidence from developing countries including Malaysia is limited and feasibility of CCM implementation has not been assessed. this study intends to assess the feasibility of public primary health care clinics (PHC) in providing care according to the CCM. METHODOLOGY: A cross-sectional survey was conducted to assess the public PHC ability to implement the components of CCM. All public PHC with Family Medicine Specialist in Selangor and Kuala Lumpur were invited to participate. A site feasibility questionnaire was distributed to collect site investigator and clinic information as well as delivery of care for diabetes and hypertension. RESULTS: there were a total of 34 public PHC invited to participate with a response rate of 100%. there were 20 urban and 14 suburban clinics. the average number of patients seen per day ranged between 250-1000 patients. the clinic has a good mix of multidisciplinary team members. All clinics had a diabetic registry and 73.5% had a hypertensive registry. 23.5% had a dedicated diabetes and 26.5% had a dedicated hypertension clinic with most clinic implementing integrated care of acute and NCD cases. DISCUSSION: the implementation of the essential components of CCM is feasible in public PHCs, despite various constraints. Although variations in delivery of care exists, majority of the clinics have adequate staff that were willing to be trained and are committed to improving patient care.

Traditional and Complementary Medicine (TCM) among Study Population with Cardiovascular Risk; use and Substitution for Conventional Medicine in Pahang, Malaysia.

INTRODUCTION: Cardiovascular diseases are the main cause of morbidity and mortality in Malaysia. There is evidence of high traditional and complementary medicine (TCM) use among population with cardiovascular risk and there have been anecdotal reports about substitution of conventional medicines with TCM. We investigated the prevalence of TCM use, treatment preference and substitution of conventional medicines in study population with cardiovascular risk factors in Pahang, Malaysia. METHODS: A cross-sectional survey was conducted using an interviewer-administered questionnaire in five districts of Pahang. A total of 1250 households were chosen through proportionate and systematic sampling. Respondents aged 18 years and above were selected. RESULTS: The study population with cardiovascular risk factors who used TCM was higher than the general population (31.7% versus 25.9%). There were no clear preferences in using TCM by gender, age groups, educational level and income even though other bumiputeras showed a slight inclination towards TCM use. Among the study population with cardiovascular risk factors who consumed TCM, 20-30% of them were using TCM as a substitute for their conventional medications. Respondents from the younger age group (18-40 years) (57.1%), highest educational level (43.2%), other bumiputeras (38.4%) and highest income group (31.4%) preferred the combination of both conventional and traditional medicine. CONCLUSION: TCM use among population with cardiovascular risk factors is high. The high preference for combination therapy of TCM and conventional medications among young adults and the use of TCM to substitute conventional medications show that much research is needed to provide proven TCM therapies to avoid self-mismanagement of cardiovascular risk in Malaysia.

Geographical variation of cardiovascular risk factors in Malaysia.

The purpose of this study was to describe differences in cardiovascular risk factor prevalences and clustering patterns among the states and federal territories of Malaysia. Risk factors considered were abdominal obesity, diabetes, hypertension, hypercholesterolemia and smoking. Using data from the third National Health and Morbidity Survey (NMHS III) in 2006, we estimated the states and federal territories risk factor prevalences and clustering patterns to map the cardiovascular burden distribution in Malaysia. There was a clear geographical variation in the distribution of the individual risk factors as well as in its clustering with remarkable impact seen in Peninsular Malaysia. Perlis, Kedah and Kelantan were the most affected states overall.

Genomic signatures of chromosomal instability and osteosarcoma progression detected by high resolution array CGH and interphase FISH.

Osteosarcoma (OS) is characterized by an unstable karyotype which typically has a heterogeneous pattern of complex chromosomal abnormalities. High-resolution array comparative genomic hybridization (CGH) in combination with interphase fluorescence in situ hybridization (FISH) analyses provides a complete description of genomic imbalances together with an evaluation of the contribution of cell-to-cell variation to copy number changes. There have been no analyses to date documenting genomic signatures consistent with chromosomal instability mechanisms in OS tumors using array CGH. In this study, we utilized high-resolution array CGH to identify and characterize recurrent signatures of genomic imbalances using ten OS tumors. Comparison between the genomic profiles identified tumor groups with low, intermediate and high levels of genomic imbalance. Bands 6p22-->p21, 8q24 and 17p12--> p11.2 were consistently involved in high copy gain or amplification events. Since these three locations have been consistently associated with OS oncogenesis, FISH probes from each cytoband were used to derive an index of cellular heterogeneity for copy number within each region. OS with the highest degree of genomic imbalance also exhibited the most extreme cell-to-cell copy number variation. Significantly, the three OS with the most imbalance and genomic copy number heterogeneity also had the poorest response to preoperative chemotherapy. This genome wide analysis is the first utilizing oligonucleotide array CGH in combination with FISH analysis to derive genomic signatures of chromosomal instability in OS tumors by studying genomic imbalance and intercellular heterogeneity. This comprehensive genomic screening approach provides important insights concerning the mechanisms responsible for generating complex genomes. The resulting phenotypic diversity can generate tumors with a propensity for an aggressive disease course. A better understanding of the underlying mechanisms leading to OS tumor development could result in the identification of prognostic markers and therapeutic targets.

Activated Notch1 signaling cooperates with papillomavirus oncogenes in transformation and generates resistance to apoptosis on matrix withdrawal through PKB/Akt.

Invasive cervical tumors, a major subset of human epithelial neoplasms, are characterized by the consistent presence of papillomavirus oncogenes 16 or 18 E6 and E7 products. Cervical tumors also consistently exhibit cytosolic and nuclear forms of Notch1, suggesting the possible persistent activation of the Notch pathway. Here we show that activated Notch1 synergizes with papillomavirus oncogenes in transformation of immortalized epithelial cells and leads to the generation of resistance to anoikis, an apoptotic response induced on matrix withdrawal. This resistance to anoikis by activated Notch1 is mediated through the activation of PKB/Akt, a key effector of activated Ras in transformation. We suggest that activated Notch signaling may serve to substitute for the lack of activated Ras mutations in the majority of human cervical neoplasms.

Interspecies variations in oral epithelial cytokeratin expression.

The aim of this study was to determine the degree to which the epidermis and oral epithelium of species other than man express cytokeratin (CK) intermediate filaments, which are markers of epithelial differentiation. Fixed, wax-embedded samples of skin, buccal mucosa and gingiva from rhesus monkey, marmoset, cow, sheep, pig, ferret, hamster, axolotl and trout were tested for CK expression using a panel of antihuman CK antibodies and an immunoperoxidase procedure. Human skin and oral mucosa were also stained to act as positive control. The results showed that antihuman CK antibodies stained animal tissues, but the patterns of staining were not always identical to the established human CK profile. Of particular interest was the expression of CK18, typically only detected in 'simple' epithelium in man, in bovine, ferret and hamster stratified epithelium from different sites. However, there was evidence of variable anti-CK antibody cross-reactivity, both as a result of intrinsic variations in CK polypeptide structure and as artifacts of fixation. We conclude that some CK are conserved between species, but that biological variables, for example local functional requirements, and technical factors affect the results. These considerations need to be borne in mind in animal studies of epithelial differentiation employing CK immunohistochemistry. Biochemical characterisation is ultimately necessary to determine specific differences between human and animal CK.

An analysis of glaucoma patients seen at the General Hospital Kuala Lumpur over a five year period: 1986 to 1990.

The records of all the glaucoma patients seen at the General Hospital Kuala Lumpur over a five year period were analysed. The racial, age and sex distribution of patients with primary open angle glaucoma and primary angle closure glaucoma was determined. The causes of secondary glaucoma were analysed. As no previous records of glaucoma statistics are available in Malaysia, it is hoped that these findings will form an initial mosaic to build on in the future.

The outcome of trabeculectomy for primary glaucoma in adult patients in UKM.

A clinical audit was conducted for a 4-year period at the Universiti Kebangsaan Malaysia (UKM) Ophthalmology Department in which 61 eyes of adult patients with primary glaucoma underwent trabeculectomies without antimetabolites. At a 2-year follow-up duration, successful trabeculectomies as defined by intraocular pressure below 20 mm Hg without additional glaucoma medication were 62% for primary open-angle glaucoma, 48% for primary acute angle-closure glaucoma and 43% for chronic angle-closure glaucoma. 50.8% of eyes were without complications while 49.2% had complications. Shallow anterior chamber (22.9%) and hyphaema (19.7%) were the two commonest complications.

Correlation of hydrogen exchange behaviour and thermal stability of lysozyme.

The solvent exchange rates of individual indole NH hydrogens of tryptophan residues of lysozyme have been measured, by using 1H nuclear magnetic resonance spectroscopy, as a function of temperature in the presence of urea and following chemical modification. The results have been interpreted in terms of a low activation energy process which is not dependent on the thermal stability of the protein, and a higher activation energy process that is directly correlated with the thermal stability. The significance of these observations for an understanding of the dynamics of the protein is discussed.