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Diabetes mellitus is a heterogeneous clinical syndrome characterized by hyperglycaemia and the long-term complications are retinopathy, neuropathy, nephropathy, and cardiomyopathy. It is a leading cause of blindness. Diabetic retinopathy is the progressive pathological alterations in the retinal microvasculature, leading to areas of retinal nonperfusion, increased vascular permeability, and the pathological proliferation of retinal vessels. Hence, it is beneficial to have regular cost-effective eye screening for diabetes subjects. Nowadays, different stages of diabetes retinopathy are detected by retinal examination using indirect biomicroscopy by senior ophthalmologists. In this work, morphological image processing and support vector machine (SVM) techniques were used for the automatic diagnosis of eye health. In this study, 331 fundus images were analysed. Five groups were identified: normal retina, mild non-proliferative diabetic retinopathy, moderate non-proliferative diabetic retinopathy, severe non-proliferative diabetic retinopathy, and proliferative diabetic retinopathy. Four salient features blood vessels, microaneurysms, exudates, and haemorrhages were extracted from the raw images using image-processing techniques and fed to the SVM for classification. A sensitivity of more than 82 per cent and specificity of 86 per cent was demonstrated for the system developed. [ABSTRACT FROM AUTHOR]

In this paper, the skin blood flow for the stomach and forehead regions of 36 female patients with menstrual symptoms was studied using a moorLDI laser Doppler imager in which the results of 6 typical patients are included. The patterns obtained at the two sites are common to all women in the sample who have menstrual symptoms. Cold stress testing was also investigated to see if it was effective in bringing out any skin blood flow fluctuation at these regions caused by menstrual symptoms. Each patient attended two scanning sessions: one before and the other during menstruation. During each session, the patient was scanned three consecutive times, each on the stomach and the forehead skin regions. For each region, the first measurement was a bare scanning whereas for the second and the third, 85 % denatured ethanol (cold stress test) was applied onto the required scan areas. It was found that cold stress testing was able to bring out distinct differences in LDI perfusion images before and during menstruation. Results were best captured when perfusion images were taken approximately after 85% denatured ethanol had been applied in two layers for 30 s, allowed to evaporate over the next 5 rain (approximately the time taken to obtain one image), reapplied for another 30 s and then finally over the next 30 s allowed to evaporate further. However, it was impossible to deduce conclusively any correlation regarding migraine and skin blood flow since all the patients for this work had menstrual cramps only. [ABSTRACT FROM AUTHOR]

Purpose: Extending previous Canadian-United States cancer survival comparisons in large metropolitan areas, this study compares breast cancer survival in smaller metropolitan areas: Winnipeg, Manitoba and Des Moines, Iowa.Methods: Manitoba and Iowa cancer registries, respectively, provided a total of 2,383 and 1,545 women with breast cancer (1984 to 1992, followed until December 31, 1997). Socioeconomic data for each person's residence at the time of diagnosis was taken from population censuses.Results: Socioeconomic status and breast cancer survival were directly associated in the US cohort, but not in the Canadian cohort. Compared with similar patients in Des Moines, residents of the lowest fifth of income areas in Winnipeg experienced a significant 5-year survival advantage (survival rate ratio [SRR] = 1.14). In these lowest income areas, the Canadian survival advantage was larger among women aged 25 to 64 years (SRR = 1.23), and this was observed in the middle fifth of income areas among this younger cohort (SRR = 1.11). The Canadian survival advantage even seemed apparent in the poorest neighborhoods with relatively high representations of Aboriginal people (SRR = 1.16).Conclusion: This study replicated the finding of advantaged Canadian cancer survival in smaller metropolitan areas that had been consistently observed in larger metropolitan areas. Canada's single payer health care system seems to offer similar advantages across a number of diverse urban contexts. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10 -15 ) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10 -8 ). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease., Competing Interests: Competing interests: Z.G.-O. received consultancy fees from Lysosomal Therapeutics, Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanqua Bio, Congruence Therapeutics, Takeda, Jazz Pharmaceuticals, Guidepoint, Lighthouse and Deerfield. R.N.A. received consultation fees from Biogen, Biohaven, Capsida, Gain Therapeutics, Genzyme/Sanofi, Janssen, Servier, SK Biopharmaceuticals, Takeda and Vanqua Bio. Y.X. holds a stock option in NeoCytogen Therapeutics where she is scientific co-founder and Chief Scientific Officer. M.A.N.’s participation in this project was part of a competitive contract awarded to DataTecnica, LLC by the National Institutes of Health to support open science research. M.A.N. also owns stock in Character Bio, Inc. and Neuron23, Inc. The other authors declare no competing interests., (© 2024. The Author(s).)

UBE2T is an attractive target for drug development due to its linkage with several types of cancers. However, the druggability of ubiquitin-conjugating E2 (UBE2T) is low because of the lack of a deep and hydrophobic pocket capable of forming strong binding interactions with drug-like small molecules. Here, we performed fragment screening using 19 F-nuclear magnetic resonance (NMR) and validated the hits with 1 H- 15 N-heteronuclear single quantum coherence (HSQC) experiment and X-ray crystallographic studies. The cocrystal structures obtained revealed the binding modes of the hit fragments and allowed for the characterization of the fragment-binding sites. Further screening of structural analogues resulted in the identification of a compound series with inhibitory effect on UBE2T activity. Our current study has identified two new binding pockets in UBE2T, which will be useful for the development of small molecules to regulate the function of this protein. In addition, the compounds identified in this study can serve as chemical starting points for the development of UBE2T modulators., (© 2024 The Protein Society.)

Background and Purpose: A genome-wide association study-linked variant (PARK16 rs6679073) modulates the risk of Parkinson's disease (PD). We postulate that there may be differences in clinical characteristics between PARK16 rs6679073 carriers and noncarriers. In a prospective study, we investigate the clinical characteristics between PARK16 rs6679073 A allele carriers and noncarriers over 4 years., Methods: A total of 204 PD patients, comprising 158 PARK16 rs6679073 A allele carriers and 46 noncarriers, were recruited. All patients underwent motor and nonmotor symptom and cognitive assessments yearly over 4 years., Results: PARK16 rs6679073 carriers were less likely to have mild cognitive impairment (MCI) compared to noncarriers at both baseline (48.1% vs. 67.4%, p = 0.027) and 4-year follow-up (29.3% vs. 58.6%, p = 0.007)., Conclusions: PD PARK16 rs6679073 carriers had significantly lower frequency of MCI in a 4-year follow-up study, suggesting that the variant may have a neuroprotective effect on cognitive functions., (© 2023 European Academy of Neurology.)

Background and Objectives : There is scarce data about the epidemiology, clinical features, investigations, diagnosis, treatment, and outcome in patients attending Singapore emergency departments (EDs) with nontraumatic headache. We sought to describe these characteristics of adult patients presenting to the ED with a primary complaint of headache. Materials and Methods : We performed a cross-sectional study on adult patients with nontraumatic headache over 4 consecutive weeks from 18 March 2019 to 14 April 2019 across four EDs in Singapore. Exclusion criteria were history of head trauma within 48 h of presentation, missing records, interhospital transfers, representation with the same headache as a recent previous visit and headache as an associated symptom. Results : During the study period, 579 patients (representing 1.8% of the total ED census) comprising 55.3% males and with a median age of 36 years presented to the four Singapore EDs with a primary complaint of nontraumatic headache. Paracetamol (41.5%), non-steroidal anti-inflammatory drugs (34.4%) and tramadol (31.5%) were the three commonest analgesics used either singly or in combination. Prochlorperazine (22.9%) and metoclopramide (17.4%) were frequent anti-emetic adjuncts. One-third of patients had computed tomography of the brain performed, which found abnormalities among 20.9% of them. ED diagnoses of primary headache conditions were made in 73.6% of patients. Conclusions : Primary headaches constituted most ED headache diagnoses. ED imaging of selected patients yielded a relatively high pick-up rate for significant intracranial abnormalities. Opioid use for symptomatic relief of headaches in the ED was found to be high, underscoring the need for improvement in headache analgesia relief practices in the ED.

Applying machine learning techniques to electrocardiography and photoplethysmography signals and their multivariate-derived waveforms is an ongoing effort to estimate non-occlusive blood pressure. Unfortunately, real ambulatory electrocardiography and photoplethysmography waveforms are inevitably affected by motion and noise artifacts, so established machine learning architectures perform poorly when trained on data of the Multiparameter Intelligent Monitoring in Intensive Care II type, a publicly available ICU database. Our study addresses this problem by applying four well-established machine learning methods, i.e., random forest regression, support vector regression, Adaboost regression and artificial neural networks, to a small, self-sampled electrocardiography-photoplethysmography dataset (n = 54) to improve the robustness of machine learning to real-world BP estimates. We evaluated the performance using a selection of optimal feature morphologies of waveforms by using pulse arrival time, morphological and frequency photoplethysmography parameters and heart rate variability as characterization data. On the basis of the root mean square error and mean absolute error, our study showed that support vector regression gave the best performance for blood pressure estimation from noisy data, achieving an mean absolute error of 6.97 mmHg, which meets the level C criteria set by the British Hypertension Society. We demonstrate that ambulatory electrocardiography- photoplethysmography signals acquired by mobile discrete devices can be used to estimate blood pressure.

Introduction: Detection of atrial fibrillation (AF) is challenging in patients after ischaemic stroke due to its paroxysmal nature. We aimed to determine the utility of a combined clinical, electrocardiographic, and genetic variable model to predict AF in a post-stroke population., Materials and Methods: We performed a cohort study at a single comprehensive stroke centre from November 09, 2009, to October 31, 2017. All patients recruited were diagnosed with acute ischaemic stroke or transient ischaemic attacks. Electrocardiographic variables including p-wave terminal force (PWTF), corrected QT interval (QTc), and genetic variables including single nucleotide polymorphisms (SNPs) at the 4q25 (rs2200733) were evaluated. Clinical, electrocardiographic and genetic variables of patients without AF and those who developed AF were compared. Multiple logistic regression analysis and receiver operating characteristics were performed to identify parameters and determine their ability to predict the occurrence of AF., Results: Out of 709 patients (median age of 59 years, inter-quartile range 52-67) recruited, sixty (8.5%) were found to develop AF on follow-up. Age (odds ratio [OR]): 3.49, 95% confidence interval [CI]: 2.03-5.98, p < 0.0001), hypertension (OR: 2.76, 95% CI: 1.36-5.63, p = 0.0052), and valvular heart disease (OR: 8.49, 95% CI: 2.62-27.6, p < 0.004) were the strongest predictors of AF, with an area under receiver operating value of 0.76 (95% CI: 0.70-0.82), and 0.82 (95% CI: 0.77-0.87) when electrocardiographic variables (PWTF and QTc) were added. SNP did not improve prediction modelling., Conclusion: We demonstrated that a model combining clinical and electrocardiographic variables provided robust prediction of AF in our post-stroke population. Role of SNP in prediction of AF was limited., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Prolonged uncontrolled hyperglycaemia has shown to cause oxidative stress, inflammation, thrombosis and upregulation of angiogenesis in diabetics, which all contributes to diabetic retinopathy development and progression. Vitamin E is found to have anti-inflammatory, anti-oxidative, anti-thrombogenic and anti-angiogenesis which could play an important role in early treatment of diabetic retinopathy. This study aims to investigate the effect of Tocotrienol-rich vitamin E (Tocovid) on the progression of retinal microhaemorrhages and diabetic macular oedema in patients with diabetic retinopathy., Method: This is a multi-centred, randomized, double-blinded, placebo-controlled trial which involved 55 eligible participants. The participants in the treatment group ( n  = 22) received Tocovid 200 mg twice daily while those in the placebo group ( n  = 23) would receive placebo twice daily. Both groups will be on the treatment for a total duration of 12 months. Both retinal signs will be assessed at baseline, 2 months, 6 months and 12 months of treatment to determine the progression of diabetic retinopathy. Serum vascular endothelial growth factor which reflects on the angiogenesis process in the eye was analysed as well at similar time points as the retinal findings., Results: After 12 months of treatment, the placebo group had a significant increase of 23.42% in retinal microhaemorrhages ( p  < 0.05), but the Tocovid group had no significant changes. Moreover, the Tocovid group showed a significant decrease of 48.38% in area of diabetic macular oedema over the 12 months period ( p  < 0.05), but the placebo group had no significant changes. Meanwhile, there was no significant difference in serum vascular endothelial growth factor level when comparing between both groups., Conclusion: These findings could indicate that Tocovid has an important role in preventing early diabetic retinopathy progression., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2022.)

Human sine oculis homeobox homolog (SIX) 1 contains a homeodomain (HD), which is important for binding to DNA. In this study, we carried out structural studies on the HD of human SIX1 using nuclear magnetic resonance (NMR) spectroscopy. Its secondary structures and dynamics in solution were explored. HD is well-structured in solution, and our study shows that it contains three α-helices. Dynamics study indicates that the N- and C-terminal residues of HD are flexible in solution. HD of human SIX1 exhibits molecular interactions with a short double-strand DNA sequence evidenced by the 1 H- 15 N-heteronuclear single quantum correlation (HSQC) and 19 F-NMR experiments. Our current study provides structural information for HD of human SIX1. Further studies indicate that this construct can be utilized to study SIX1 and DNA interactions., (© 2021 European Peptide Society and John Wiley & Sons, Ltd.)

KRAS proteins are small GTPases binding to the cell membrane and playing important roles in signal transduction. KRAS proteins form complexes with GTP and GDP to result in active and inactive conformations favouring interactions with different proteins. Mutations in KRAS have impact on the GTPase activity and some mutants are related to certain types of cancers. In addition to mutation at position 12, the Q61H mutant is also identified as an oncogenic mutant. Here, we describe resonance assignment for Q61H mutant of human KRAS-4B. A construct containing 1-169 residues of KRAS with a point mutation at position 61 (Q to H) was made for solution NMR studies. The backbone and some side chain resonance assignments were obtained using conventional multi-dimensional experiments. The secondary structures were analysed based on the assigned residues. As NMR is a powerful tool in probing target and ligand interactions, the assignment will be useful for later compound binding studies., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Human eyes absent (EYA) proteins possess Tyr phosphatase activity, which is critical for numerous cancer and metastasis promoting activities, making it an attractive target for cancer therapy. In this work, we demonstrate that the inhibitor-bound form of EYA2 does not favour binding to Mg 2+ , which is indispensable for the Tyr phosphatase activity. We further describe characterization and optimization of this class of allosteric inhibitors. A series of analogues were synthesized to improve potency of the inhibitors and to elucidate structure-activity relationships. Two co-crystal structures confirm the binding modes of this class of inhibitors. Our medicinal chemical, structural, biochemical, and biophysical studies provide insight into the molecular interactions of EYA2 with these allosteric inhibitors. The compounds derived from this study are useful for exploring the function of the Tyr phosphatase activity of EYA2 in normal and cancerous cells and serve as reference compounds for screening or developing allosteric phosphatase inhibitors. Finally, the co-crystal structures reported in this study will aid in structure-based drug discovery against EYA2., (© 2021 The Protein Society.)

Background: Genome-wide association studies (GWAS) have shown that variants in the 3-methylcrotonyl-CoA carboxylase (MCCC1)/lysosome-associated membrane protein 3 (LAMP3) loci (rs10513789, rs12637471, rs12493050) reduce the risk of Parkinson's disease (PD) in Caucasians, Chinese and Ashkenazi-Jews while the rs11248060 variant in the diacylglycerol kinase theta (DGKQ) gene increases the risk of PD in Caucasian and Han Chinese cohorts. However, their roles in Malays are unknown. Therefore, this study aims to investigate the association of these variants with the risk of PD in individuals of Malay ancestry., Methods: A total of 1114 subjects comprising of 536 PD patients and 578 healthy controls of Malay ancestry were recruited and genotyped using Taqman® allelic discrimination assays., Results: The G allele of rs10513789 (OR = 0.83, p = 0.001) and A allele of rs12637471 (OR = 0.79, p = 0.007) in the MCCC1/LAMP3 locus were associated with a protective effect against developing PD in the Malay population. A recessive model of penetrance showed a protective effect of the GG genotype for rs10513789 and the AA genotype for rs12637471. No association with PD was found with the other MCCC1/LAMP3 rs12493050 variant or with the DGKQ (rs11248060) variant. No significant associations were found between the four variants with the age at PD diagnosis., Conclusion: MCCC1/LAMP3 variants rs10513789 and rs12637471 protect against PD in the Malay population., (© 2021. Fondazione Società Italiana di Neurologia.)

This research work aims to identify COVID-19 through deep learning models using lung CT-SCAN images. In order to enhance lung CT scan efficiency, a super-residual dense neural network was applied. The experimentation has been carried out using benchmark datasets like SARS-COV-2 CT-Scan and Covid-CT Scan. To mark COVID-19 as positive or negative for the improved CT scan, existing pre-trained models such as XceptionNet, MobileNet, InceptionV3, DenseNet, ResNet50, and VGG (Visual Geometry Group)16 have been used. Taking CT scans with super resolution using a residual dense neural network in the pre-processing step resulted in improving the accuracy, F1 score, precision, and recall of the proposed model. On the dataset Covid-CT Scan and SARS-COV-2 CT-Scan, the MobileNet model provided a precision of 94.12% and 100% respectively., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Long alpha-synuclein gene (SNCA) promoter (Rep1) allele-carriers are linked to higher risk for Parkinson's disease (PD) and faster motor progression. Non-motor symptoms including autonomic, neuropsychiatric, and sleep disorders are common in PD. However, the relationship between SNCA Rep1 microsatellite lengths and non-motor symptoms in early PD remains to be elucidated. 171 consecutive early PD patients were recruited from tertiary clinics and genotyped for Rep1. Multivariable regression analyses were performed to examine associations between Rep1 alleles and non-motor outcome scores. Longer Rep1 alleles significantly associated with higher total Non-Motor Symptom Scale (NMSS) scores ( p =.006) and Hospital Anxiety and Depression Scale (HADS) depression subscale scores ( p =.002), after adjusting for covariates and Bonferroni correction. We demonstrated that SNCA Rep1 allele length influences overall non-motor symptom burden and depression in early PD patients. Further functional studies to evaluate the role of Rep1 in non-dopaminergic systems may unravel new therapeutic targets for non-motor symptoms in PD.

Background: The main motor subtypes of Parkinson's disease (PD) include tremor-dominant (TD) and postural instability gait disorder (PIGD), with varying disease course that warrant the development of biomarkers capable of predicting progression according to motor subtype. The PIGD subtype is associated with a poorer prognosis, hence identification of a biomarker associated with PIGD is clinically relevant. Neurofilament light (NfL) chain is a potential biomarker of disease severity in neurological disorders including PD. However, no study has investigated NfL and PD motor subtypes. Here, we aimed to investigate the diagnostic and prognostic utility of plasma NfL for PD motor subtypes in early Parkinson's disease. Given the higher risk for cognitive and motor decline in PIGD, we hypothesized that plasma NfL is a potential biomarker for PIGD., Methods: Plasma NfL was measured in 199 participants (149 PD and 50 healthy controls, HC) using an ultrasensitive single molecule array. Patients were classified into TD or PIGD based on MDS-UPDRS components. After 2 years, 115 patients were reassessed. Association between NfL and clinical measures in PIGD and TD at baseline and at 2-year follow-up were analysed., Results: At baseline, plasma NfL levels were higher in PD than HC (8.8 ± 3.4 vs 16.2 ± 7.6 pg/ml, p < 0.0001), and differentiated PD from HC with a good diagnostic accuracy (AUC = 0.833, p < 0.001). At 2 years, NfL was higher in PIGD than TD (18.4 ± 14.5 vs 12.6 ± 4.4 pg/ml, p = 0.039). Within the PIGD group, higher NfL associated significantly with worse global cognition and UPDRS motor scores at baseline, and was able to predict motor and cognitive decline at a mean follow-up duration of 1.9 years, controlled for age, sex and disease duration., Conclusions: In this longitudinal study, we demonstrated for the first time the potential utility of plasma NfL as a diagnostic and prognostic biomarker in PIGD even at early stages of PD. These important novel findings will require further confirmation in larger, longitudinal PD cohorts.

Importance: Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian)., Objectives: To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts., Design Setting, and Participants: Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria., Main Outcomes and Measures: Genotypes of common variants, association with disease status, and polygenic risk scores., Results: Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10-3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10-12)., Conclusions and Relevance: This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.

Chronic hyperglycemia increases oxidative stress, activates inflammatory pathways and reduces nerve growth factor (NGF) among diabetic patients, which contribute to development of diabetic peripheral neuropathy (DPN). Tocotrienol-Rich Vitamin E (Tocovid) possesses potent antioxidant and anti-inflammatory properties which are postulated to target these pathogeneses in order to ameliorate DPN. This study aims to evaluate the effects of Tocovid on nerve conduction parameters and serum biomarkers among diabetic patients. This multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial was conducted on 80 eligible participants. The intervention group ( n = 39) was randomly allocated to receive 200 mg of Tocovid twice a day, and the control group ( n = 41) received placebo twice a day. At the end of eight weeks, the nerve conduction parameters, as assessed by nerve conduction study, as well as serum biomarkers (NGF, malondialdehyde, vascular cell adhesion molecule 1, tumor necrosis factor receptor 1 and thromboxane B2) were compared between the two groups. Compared to placebo, Tocovid significantly improves the nerve conduction velocities of all nerves (+1.25 m/s, interquartile range [IQR] 3.35, p < 0.001, median nerve; +1.60 m/s, IQR 1.80, p < 0.001, sural nerve; +0.75 m/s, IQR 2.25, p < 0.001, tibial nerve). Meanwhile, the levels of serum NGF were significantly higher in the Tocovid group as compared to placebo at eight weeks post-intervention. Participants receiving Tocovid illustrated highly significant improvement in terms of nerve conduction velocities for all nerves tested after eight weeks of supplementation. In addition, Tocovid supplementation elevated the levels of serum NGF, in which its increase is postulated to reflect enhanced neuronal functions. This novel finding suggests that Tocovid could be a disease-modifying agent targeting serum NGF to improve nerve conduction velocities.

Zika virus (ZIKV) NS2B-NS3 protease is a validated antiviral target as it is essential for maturation of viral proteins. However, its negatively charged active site hinders the development of orthosteric small-molecule inhibitors. Fragment-based drug discovery (FBDD) is a powerful tool to generate novel chemical starting points against difficult drug targets. In this study, we scre ened a fragment compound library against the Zika protease using a primary thermal shift assay and identified twenty-two fragments which (bind to and) stabilize the protease. We then determined the X-ray crystal structures of two hits from different classes, all of which bind to the S1 pocket of the protease. We confirmed that these two fragments bind to the protease without inducing significant conformational changes using solution NMR spectroscopy. These fragment scaffolds serve as the starting point for subsequent lead compound development., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is characterized by Lewy bodies containing α-synuclein and ubiquitin aggregates, their co-occurrence possibly linked to a failure of the ubiquitin proteasome system. Ubiquitin C-terminal hydrolase L1 (UCHL1) plays an important role in maintenance of nervous system integrity, and overexpression of UCHL1 has been shown to increase ubiquitin levels within neurons. While cerebrospinal fluid ubiquitin levels were reported to be lower in PD vs controls, plasma UCHL1 levels and their relationship with clinical measures in PD has not been reported. We measured plasma UCHL1 levels using single molecule array (Simoa) in 291 subjects (242 PD and 49 healthy controls, HC). We found that UCHL1 levels were significantly higher in PD patients at moderate stages (Hoehn and Yahr, H&Y stage >2) vs milder PD (H&Y ≤2, p <0.001) and HC ( p =0.001). There was no significant difference in UCHL1 levels between PD patients at H&Y stages ≤2 vs HC. Across all PD patients, UCHL1 correlated significantly with UPDRS Part III motor scores ( β =3.87, 95% CI=0.43-7.31, p =0.028), but not with global cognition. Overall, we found that UCHL1 correlates with motor function in PD, with higher levels seen in later disease stages. These findings will be validated in longitudinal studies.

Chronic hyperglycemia in type 2 diabetes mellitus increases oxidative stress and inflammation which contributes to long-term diabetic kidney disease. Tocotrienol-rich vitamin E, as Tocovid, has been shown to reduce oxidative stress and inflammation to ameliorate diabetes in rat models and human subjects. In this prospective, multicenter, double-blinded, placebo-controlled clinical trial, 54 patients (duration = 18.4 years, HbA1c = 8.8%) with diabetic nephropathy were randomized to receive Tocovid 200 mg or placebo for 12 weeks. Fasting blood samples were taken to measure HbA1c, serum creatinine, estimate glomerular filtration rate (eGFR), urine albumin:creatinine ratio, malondialdehyde, tumor necrosis factor receptor-1, vascular cell adhesion molecule-1 (VCAM-1), and thromboxane-B2. Patients were reassessed 6-9 months post-washout. After 12 weeks of supplementation, Tocovid significantly decreased serum creatinine levels (mean difference: -3.3 ± 12.6 versus 5.4 ± 14.2, p  = 0.027) and significantly increase eGFR (mean difference: 1.5 ± 7.6 versus -2.9 ± 8.0, p  = 0.045) compared with placebo. There were no significant changes in HbA1c, blood pressure, and other parameters. Subgroup analysis revealed that in patients with low serum vitamin E concentrations at baseline, Tocovid reduced serum creatinine, eGFR, and VCAM-1 significantly. After 6-9 months of washout, persistent difference in serum creatinine remained between groups (mean difference: 0.82 ± 8.33 versus 11.26 ± 15.47, p  = 0.031), but not eGFR. Tocovid at 400 mg/day significantly improved renal function in 12 weeks of supplementation, as assessed by serum creatinine and eGFR, which remained significant 6-9 months post-washout., Competing Interests: Conflict of interest statement: The authors declare no conflict of interest. The sponsors had no role in the design of the study that included data collection, analyses or interpretation, the writing of the manuscript and in the decision to publish the results., (© The Author(s), 2019.)

EYA proteins (EYA1-4) are critical developmental transcriptional cofactors that contain an EYA domain (ED) harboring Tyr phosphatase activity. EYA proteins are largely downregulated after embryogenesis but are reexpressed in cancers, and their Tyr phosphatase activity plays an important role in the DNA damage response and tumor progression. We previously identified a class of small-molecule allosteric inhibitors that specifically inhibit the Tyr phosphatase activity of EYA2. Herein, we determined the crystal structure of the EYA2 ED in complex with NCGC00249987 (a representative compound in this class), revealing that it binds to an induced pocket distant from the active site. NCGC00249987 binding leads to a conformational change of the active site that is unfavorable for Mg 2+ binding, thereby inhibiting EYA2's Tyr phosphatase activity. We demonstrate, using genetic mutations, that migration, invadopodia formation, and invasion of lung adenocarcinoma cells are dependent on EYA2 Tyr phosphatase activity, whereas growth and survival are not. Further, we demonstrate that NCGC00249987 specifically targets migration, invadopodia formation, and invasion of lung cancer cells, but that it does not inhibit cell growth or survival. The compound has no effect on lung cancer cells carrying an EYA2 F290Y mutant that abolishes compound binding, indicating that NCGC00249987 is on target in lung cancer cells. These data suggest that the NCGC00249987 allosteric inhibitor can be used as a chemical probe to study the function of the EYA2 Tyr phosphatase activity in cells and may have the potential to be developed into an antimetastatic agent for cancers reliant on EYA2's Tyr phosphatase activity., (©2019 American Association for Cancer Research.)

Outdoor thermal comfort studies have proved that urban design has a great influence on pedestrians' thermal comfort and that its assessment helps one to understand the quality and usage of the pedestrian environment. However, the majority of outdoor thermal comfort studies perceive pedestrian thermal comfort as "static". The dynamic multiple uses of urban spaces and the highly inhomogeneous urban morphology in high-density cities of the tropics are seldom considered, which leads to a lack of understanding about how pedestrians respond to the changes of the outdoor environment. This study contributes to the understanding of the dynamic thermal comfort using a longitudinal survey that was conducted to obtain information about how thermal sensation changes throughout the walking route and how it is affected by micro-meteorological conditions and the urban geometry. The large variations in micro-meteorological conditions throughout the walking routes are predominantly influenced by the urban geometry. Additionally, the spatial pattern of thermal sensation varies based on the weather conditions, emphasizing the need to account for such variations in the assessment of pedestrian thermal comfort. The results also show that thermal sensation was associated with participants' short-term thermal experience (2-3 min) and that the urban geometry plays an important role in the time-lag effect of meteorological variables on thermal sensation. The findings of this study contribute to improving urban geometry design in order to mitigate the thermal discomfort and create a better pedestrian environment in high-density cities.

The Zika virus (ZIKV) genome encodes a polyprotein that can be post-translationally processed into functional viral proteins. The viral protease is indispensable in the maturation of viral proteins. The Zika protease comprises of two components crucial for catalysis. The N-terminal region of NS3 contains the catalytic triad and approximately 40 amino acids of NS2B are essential for folding and protease activity. NS2B is a membrane protein with transmembrane domains that are critical for the localization of NS3 to the membrane. In this study, we expressed and purified full-length NS2B from ZIKV in E. coli. Purified NS2B was then reconstituted into lyso-myristoyl phosphatidylglycerol (LMPG) micelles. It was found that compared to wild type NS2B, NS2B C11S mutation in LMPG exhibited dispersed cross peaks in the 1 H 15 N-HSQC spectrum, thereby suggesting the feasibility for structural characterization using solution NMR spectroscopy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study aims to review retrospectively the records of Asian patients diagnosed with abdominal aortic aneurysm to investigate the potential correlations between clinical and morphological parameters within the context of whether the aneurysms were ruptured or unruptured. A machine-learning-based approach is proposed to predict the rupture status of Asian abdominal aortic aneurysm by comparing four different classifiers trained with clinical and geometrical parameters obtained from computed tomography images. The classifiers were applied on 312 patient data sets obtained from a regulatory-approved database. The data sets included 17 attributes under three classes: unruptured abdominal aortic aneurysm, ruptured abdominal aortic aneurysm, and normal aorta without aneurysm. Four different classification models, namely, Decision trees, Naïve Bayes, logistic regression, and support vector machines were applied to the patient data set. The models were evaluated by 10-fold cross-validation and the classifier performances were assessed with classification accuracy, area under the curve of receiver operator characteristic, and F-measures. Data analysis and evaluation were performed using the Weka machine learning application. The results indicated that Naïve Bayes achieved the best performance among the classifiers with a classification accuracy of 95.2%, an area under the curve of 0.974, and an F-measure of 0.952. The clinical implications of this work can be addressed in two ways. The best classifier can be applied to prospectively acquired data to predict the likelihood of aneurysm rupture. Next, it would be necessary to estimate the attributes implicated in rupture risk beyond just maximum aneurysm diameter.

The oncoprotein YAP (Yes-associated protein) requires the TEAD family of transcription factors for the up-regulation of genes important for cell proliferation. Disrupting YAP-TEAD interaction is an attractive strategy for cancer therapy. Targeting TEADs using small molecules that either bind to the YAP-binding pocket or the palmitate-binding pocket is proposed to disrupt the YAP-TEAD interaction. There is a need for methodologies to facilitate robust and reliable identification of compounds that occupy either YAP-binding pocket or palmitate-binding pocket. Here, using NMR spectroscopy, we validated compounds that bind to these pockets and also identify the residues in mouse TEAD4 (mTEAD4) that interact with these compounds. Flufenamic acid (FA) was used as a positive control for validation of palmitate-binding pocket-occupying compounds by NMR. Furthermore, we identify a hit from a fragment screen and show that it occupies a site close to YAP-binding pocket on the TEAD surface. Our results also indicate that purified mTEAD4 can catalyze autopalmitoylation. NMR studies on mTEAD4 revealed that exchanges exist in TEAD as NMR signal broadening was observed for residues close to the palmitoylation site. Mutating the palmitoylated cysteine (C360S mutant) abolished palmitoylation, while no significant changes in the NMR spectrum were observed for the mutant which still binds to YAP. We also show that FA inhibits TEAD autopalmitoylation. Our studies highlight the utility of NMR spectroscopy in identifying small molecules that bind to TEAD pockets and reinforce the notion that both palmitate-binding pocket and YAP-binding pocket are targetable., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

The Zika virus (ZIKV) NS2B-NS3 protease is an important drug target. The conventional flaviviral protease constructs used for structural studies contain the NS2B cofactor region linked to the NS3 protease domain via a glycine-rich flexible linker. Here, we examined the structural dynamics of this conventional Zika protease (gZiPro) using NMR spectroscopy. Although the glycine-rich linker in gZiPro does not alter the overall folding of the protease in solution, gZiPro is not homogenous in ion exchange chromatography. Compared to the unlinked protease construct, the artificial linker affects the chemical environment of many residues including H51 in the catalytic triad. Our study provides a direct comparison of ZIKV protease constructs with and without an artificial linker., (© 2017 Federation of European Biochemical Societies.)

Unplanned readmissions may be avoided by accurate risk prediction and appropriate resources could be allocated to high risk patients. The Length of stay, Acuity of admission, Charlson comorbidity index, Emergency department visits in past six months (LACE) index was developed to predict hospital readmissions in Canada. In this study, we assessed the performance of the LACE index in a Singaporean cohort by identifying elderly patients at high risk of 30-day readmissions. We further investigated the use of additional risk factors in improving readmission prediction performance.Data were extracted from the hospital's electronic health records (EHR) for all elderly patients ≥ 65 years, with alive-discharge episodes from Singapore General Hospital in 2014. In addition to LACE, we also collected patients' data during the index admission, including demographics, medical history, laboratory results, and previous medical utilization.Among the 17,006 patients analyzed, 2051 or 12.1% of them were observed 30-day readmissions. The final predictive model was better than the LACE index in terms of discriminative ability; c-statistic of LACE index and final logistic regression model was 0.595 and 0.628, respectively.The LACE index had poor discriminative ability in identifying elderly patients at high risk of 30-day readmission, even if it was augmented with additional risk factors. Further studies should be conducted to discover additional factors that may enable more accurate and timely identification of patients at elevated risk of readmissions, so that necessary preventive actions can be taken.

Current clinically accepted technologies for cancer treatment still have limitations which lead to the exploration of new therapeutic methods. Since the past few decades, the hyperthermia treatment has attracted the attention of investigators owing to its strong biological rationales in applying hyperthermia as a cancer treatment modality. Advancement of nanotechnology offers a potential new heating method for hyperthermia by using nanoparticles which is termed as magnetic fluid hyperthermia (MFH). In MFH, superparamagnetic nanoparticles dissipate heat through Néelian and Brownian relaxation in the presence of an alternating magnetic field. The heating power of these particles is dependent on particle properties and treatment settings. A number of pre-clinical and clinical trials were performed to test the feasibility of this novel treatment modality. There are still issues yet to be solved for the successful transition of this technology from bench to bedside. These issues include the planning, execution, monitoring and optimization of treatment. The modeling and simulation play crucial roles in solving some of these issues. Thus, this review paper provides a basic understanding of the fundamental and rationales of hyperthermia and recent development in the modeling and simulation applied to depict the heat generation and transfer phenomena in the MFH.

Three-dimensional blood flow in a human left ventricle is studied via a computational analysis with magnetic resonance imaging of the cardiac motion. Formation, growth and decay of vortices during the myocardial dilation are analyzed with flow patterns on various diametric planes. They are dominated by momentum transfer during flow acceleration and deceleration through the mitral orifice. The posterior and anterior vortices form an asymmetric annular vortex at the mitral orifice, providing a smooth transition for the rapid inflow to the ventricle. The development of core vortex accommodates momentum for deceleration and for acceleration at end diastolic atrial contraction. The rate of energy dissipation and that of work done by viscous stresses are small; they are approximately balanced with each other. The kinetic energy flux and the rate of work done by pressure delivered to blood from ventricular dilation is well balanced by the total energy influx at the mitral orifice and the rate change of kinetic energy in the ventricle., (Published by Elsevier Ltd.)

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 64-year old male Parkinson's disease (PD) patient with N551K variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model can complement in vivo PD models for pathophysiological studies and drug screening., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 59-year old male Parkinson's disease (PD) patient with R1628P variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model will provide a good resource for further pathophysiological studies of PD., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Lateral epicondylitis is one of the most common overuse injuries, and has been reported to reduce function and affect daily activities. There is no standard therapy for lateral epicondylitis. In Hong Kong, acupuncture and extracorporeal shockwave therapy (ESWT) have been popular in treating lateral epicondylitis in recent years., Objective: This study is to compare the treatment effects of acupuncture and ESWT on lateral epicondylitis., Methods: In this study, we evaluated 34 patients (34 elbows) with lateral epicondylitis. Seventeen patients were treated by 3-week ESWT, one session per week. Another 17 were treated by 3-week acupuncture therapy, two sessions per week. The outcome measures included pain score by visual analogue scale, maximum grip strength by Jamar dynamometer, and level of functional impairment by disability of arms, shoulders, and hands questionnaire. Participants were assessed at three time points: baseline; after treatment; and 2-week follow-up., Results: The two treatments showed no significant difference at any assessment time-point. Both treatment groups had significant improvement in pain score in longitudinal comparisons. No significant difference was found in maximum grip strength and functional impairment in either treatment group, but a trend of improvement could be observed. In addition, improvement in pain relief stopped when treatment ended for either groups., Conclusions: The treatment effects of acupuncture and ESWT on lateral epicondylitis were similar. The pain relief persisted for at least two weeks after treatment.

The recent outbreak of Zika virus (ZIKV) infections in the Americas represents a serious threat to the global public health. The viral protease that processes viral polyproteins during infection appears as an attractive drug target. Here we report a crystal structure at 1.84 Å resolution of ZIKV non-structural protein NS2B-NS3 protease with the last four amino acids of the NS2B cofactor bound at the NS3 active site. This structure represents a post-proteolysis state of the enzyme during viral polyprotein processing and provides insights into peptide substrate recognition by the protease. Nuclear magnetic resonance (NMR) studies and protease activity assays unravel the protein dynamics upon binding the protease inhibitor BPTI in solution and confirm this finding. The structural and functional insights of the ZIKV protease presented here should advance our current understanding of flavivirus replication and accelerate structure-based antiviral drug discovery against ZIKV.

Objective: To review pathogens, morbidity and mortality in pediatric intensive care unit (PICU) patients with viral and infectious encephalitis., Methods: Retrospective chart review of all patients with encephalitis admitted to the PICU between 2002 and 2014 was done., Results: Encephalitis (n = 46) accounted for 2.7 % of PICU admissions, but 11.8 % PICU mortality over a 12-y period. A microorganism (primarily virus) was identified in 59 % of encephalitis patients in the PICU. Enteroviruses and herpes viruses were isolated from the cerebrospinal fluid (CSF). Respiratory viruses [such as respiratory syncytial virus (RSV) and influenza viruses] and enteric viruses (such as rotavirus and norovirus) were obtained in the nasopharyngeal aspirate and stool respectively, but undetectable from the CSF. More than one-fourth patients with encephalitis died in the PICU. Boys accounted for 85 % of nonsurvivors and 52 % survivors (p = 0.038). Mechanical ventilation, inotrope, intravenous immunoglobulin (IVIG) and corticosteroid usage were significantly higher among non-survivors (p 0.001-0.044). Binomial logistic regression showed that patients who received corticosteroid had a lower chance of survival than those who did not after adjusting for gender, IVIG and mechanical ventilation (adjusted odd ratio = 0.071, 95 % CI 0.006-0.881; p 0.039). Eighteen (55 %) of the survivors had moderate-to-severe neurodevelopmental impairments., Conclusions: Encephalitis is associated with significant mortality despite intensive care. Over 25 % case died and 55 % of survivors had moderate-to-severe neurodevelopmental impairments. There appeared to be no emerging outbreaks of encephalitis during the 15-y study period.

Objective: The aim of this study was to investigate the accuracy of using a newly developed index, the ratio of urine outflow to renal pelvis volume U/V2 (1/s), in evaluating renal obstruction and determining the severity of obstruction., Patients and Methods: A total of 42 patients' renograms (80 kidneys) were studied. Compartmental modelling was used to model the behaviour of tracers flowing through the kidney. The derived model led to the formation of the normalized urine flow rate U/V2. An analysis was carried to test the accuracy of the developed index by comparing the developed model and the clinical evaluation of renograms. The Support Vector Machine algorithm was implemented to predict the renal obstruction status., Results: From the comparison performed between the index and the clinical evaluation from certified experts, it was shown that a higher value of index U/V2 indicated a normal kidney, whereas a lower value indicated an obstructed kidney. The classifier developed could provide a 100% accurate diagnosis of differentiated unobstructed kidneys (42/42) and obstructed kidney (18/18). For further classification of obstructed kidneys, the system grouped the samples into slightly obstructed cases with an accuracy of 100% (9/9) and heavily obstructed cases with an accuracy of 89% (8/9)., Conclusion: The use of the single parameter U/V2 could produce the diagnosis of renal obstruction with a high level of accuracy. This method has the potential to be used as a benchmark to distinguish the severity level of the renal obstruction.

Objectives: To describe the characteristics, diagnoses and outcomes of older adolescents, aged 16-19 years, presenting to a paediatric ED., Methods: A retrospective review of total ED presentations by older adolescents to a tertiary paediatric hospital between 2010 and 2012, inclusive, was undertaken to determine if behavioural or mental health problems were common., Results: A total of 1184 ED presentations by 730 older adolescents were identified. Injury and abdominal pain were the most common complaints for presentations by older adolescents to the ED. The median length of stay in ED was 241 (range: 0-3873) min. More than 60% of the older adolescent ED presentations were triaged urgent or semi-urgent, and 39% of all these presentations resulted in hospital admission. Two-thirds of these older adolescents had a chronic illness, which accounted for 77% of all ED presentations by older adolescents. The history of chronic illness was considered related or relevant in the evaluation and management of over 80% of older adolescents. Of all the ED presentations by older adolescents with chronic illness, only one quarter had transition planning documentation., Conclusions: A high prevalence of chronic illness was found in older adolescents attending the paediatric ED. There was no evidence that behavioural and mental health issues dominated. These findings reflect admission policy., (© 2016 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.)

Early expansion of infarcted zone after Acute Myocardial Infarction (AMI) has serious short and long-term consequences and contributes to increased mortality. Thus, identification of moderate and severe phases of AMI before leading to other catastrophic post-MI medical condition is most important for aggressive treatment and management. Advanced image processing techniques together with robust classifier using two-dimensional (2D) echocardiograms may aid for automated classification of the extent of infarcted myocardium. Therefore, this paper proposes novel algorithms namely Curvelet Transform (CT) and Local Configuration Pattern (LCP) for an automated detection of normal, moderately infarcted and severely infarcted myocardium using 2D echocardiograms. The methodology extracts the LCP features from CT coefficients of echocardiograms. The obtained features are subjected to Marginal Fisher Analysis (MFA) dimensionality reduction technique followed by fuzzy entropy based ranking method. Different classifiers are used to differentiate ranked features into three classes normal, moderate and severely infarcted based on the extent of damage to myocardium. The developed algorithm has achieved an accuracy of 98.99%, sensitivity of 98.48% and specificity of 100% for Support Vector Machine (SVM) classifier using only six features. Furthermore, we have developed an integrated index called Myocardial Infarction Risk Index (MIRI) to detect the normal, moderately and severely infarcted myocardium using a single number. The proposed system may aid the clinicians in faster identification and quantification of the extent of infarcted myocardium using 2D echocardiogram. This system may also aid in identifying the person at risk of developing heart failure based on the extent of infarcted myocardium., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Cross-sectional view echocardiography is an efficient non-invasive diagnostic tool for characterizing Myocardial Infarction (MI) and stages of expansion leading to heart failure. An automated computer-aided technique of cross-sectional echocardiography feature assessment can aid clinicians in early and more reliable detection of MI patients before subsequent catastrophic post-MI medical conditions. Therefore, this paper proposes a novel Myocardial Infarction Index (MII) to discriminate infarcted and normal myocardium using features extracted from apical cross-sectional views of echocardiograms. The cross-sectional view of normal and MI echocardiography images are represented as textons using Maximum Responses (MR8) filter banks. Fractal Dimension (FD), Higher-Order Statistics (HOS), Hu's moments, Gabor Transform features, Fuzzy Entropy (FEnt), Energy, Local binary Pattern (LBP), Renyi's Entropy (REnt), Shannon's Entropy (ShEnt), and Kapur's Entropy (KEnt) features are extracted from textons. These features are ranked using t-test and fuzzy Max-Relevancy and Min-Redundancy (mRMR) ranking methods. Then, combinations of highly ranked features are used in the formulation and development of an integrated MII. This calculated novel MII is used to accurately and quickly detect infarcted myocardium by using one numerical value. Also, the highly ranked features are subjected to classification using different classifiers for the characterization of normal and MI LV ultrasound images using a minimum number of features. Our current technique is able to characterize MI with an average accuracy of 94.37%, sensitivity of 91.25% and specificity of 97.50% with 8 apical four chambers view features extracted from only single frame per patient making this a more reliable and accurate classification., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: In a longitudinal follow-up study, we compared the clinical features and motor progression of patients with Parkinson disease (PD) who are carriers of the leucine-rich repeat kinase 2 (LRRK2) gene risk variants with patients who are noncarriers., Methods: We prospectively evaluated a cohort of patients with PD for their clinical characteristics, disease severity, and LRRK2 genotype. Carriers of risk variants (G2385R, R1628P, S1647T) and noncarriers were classified separately. A longitudinal, linear mixed model analysis of motor score progression was performed to compare motor progression between the 2 groups. Motor score progression was defined as the difference between Unified Parkinson's Disease Rating Scale motor score at baseline and follow-up scores., Results: A total of 184 patients (122 risk variant carriers and 62 noncarriers) were evaluated and followed up for up to 6.5 years. No differences in demographics and baseline disease characteristics were found. In the longitudinal, linear mixed model analysis, risk variant carriers experienced greater rate of motor progression than noncarriers after 4 years from the date of diagnosis (p ≤ 0.018)., Conclusions: PD LRRK2 risk variant carriers showed greater motor progression after 4 years of disease duration compared with noncarrier patients, suggesting that these risk variants may facilitate neurodegeneration with increasing disease duration., (© 2015 American Academy of Neurology.)

Myocardial Infarction (MI) or acute MI (AMI) is one of the leading causes of death worldwide. Precise and timely identification of MI and extent of muscle damage helps in early treatment and reduction in the time taken for further tests. MI diagnosis using 2D echocardiography is prone to inter-/intra-observer variability in the assessment. Therefore, a computerised scheme based on image processing and artificial intelligent techniques can reduce the workload of clinicians and improve the diagnosis accuracy. A Computer-Aided Diagnosis (CAD) of infarcted and normal ultrasound images will be useful for clinicians. In this study, the performance of CAD approach using Discrete Wavelet Transform (DWT), second order statistics calculated from Gray-Level Co-Occurrence Matrix (GLCM) and Higher-Order Spectra (HOS) texture descriptors are compared. The proposed system is validated using 400 MI and 400 normal ultrasound images, obtained from 80 patients with MI and 80 normal subjects. The extracted features are ranked based on t-value and fed to the Support Vector Machine (SVM) classifier to obtain the best performance using minimum number of features. The features extracted from DWT coefficients obtained an accuracy of 99.5%, sensitivity of 99.75% and specificity of 99.25%; GLCM have achieved an accuracy of 85.75%, sensitivity of 90.25% and specificity of 81.25%; and HOS obtained an accuracy of 93.0%, sensitivity of 94.75% and specificity of 91.25%. Among the three techniques presented DWT yielded the highest classification accuracy. Thus, the proposed CAD approach may be used as a complementary tool to assist cardiologists in making a more accurate diagnosis for the presence of MI., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Radiofrequency ablation (RFA) has been increasingly used in treating cancer for multitude of situations in various tissue types. To perform the therapy safely and reliably, the effect of critical parameters needs to be known beforehand. Temperature plays an important role in the outcome of the therapy and any uncertainties in temperature assessment can be lethal. This study presents the RFA case of fixed tip temperature where we've analysed the effect of electrical conductivity, thermal conductivity and blood perfusion rate of the tumour and surrounding normal tissue on the radiofrequency ablation. Ablation volume was chosen as the characteristic to be optimised and temperature control was achieved via PID controller. The effect of all 6 parameters each having 3 levels was quantified with minimum number of experiments harnessing the fractional factorial characteristic of Taguchi's orthogonal arrays. It was observed that as the blood perfusion increases the ablation volume decreases. Increasing electrical conductivity of the tumour results in increase of ablation volume whereas increase in normal tissue conductivity tends to decrease the ablation volume and vice versa. Likewise, increasing thermal conductivity of the tumour results in enhanced ablation volume whereas an increase in thermal conductivity of the surrounding normal tissue has a debilitating effect on the ablation volume and vice versa. With increase in the size of the tumour (i.e., 2-3cm) the effect of each parameter is not linear. The parameter effect varies with change in size of the tumour that is manifested by the different gradient observed in ablation volume. Most important is the relative insensitivity of ablation volume to blood perfusion rate for smaller tumour size (2cm) that is also in accordance with the previous results presented in literature. These findings will provide initial insight for safe, reliable and improved treatment planning perceptively., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Essential tremor (ET) and Parkinson's disease (PD) are two of the most common adult onset movement disorders with overlapping clinical features. PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations may present initially with an ET phenotype. To address the possibility of a common genetic link between ET and PD, we examined the association between a common LRRK2 R1628P gene variant and ET. The LRRK2 R1628P was genotyped in ET cases and matched healthy controls. A total of 1277 subjects comprising of 450 ET cases and 827 controls were included. There were 40 heterozygote (GG to CG) variant out of 450 ET cases (genotypic frequency 8.9%) and 36 heterozygote variant (GG to CG, genotypic frequency 4.3%) and one homozygote variant (GG to CC) out of 827 controls. Subjects carrying the R1628P variant had a twofold increased risk of ET (p = 0.0035, OR = 2.20 and 95% confidence interval is 1.30-3.73). Using a case control methodology, we demonstrated an association between a known PD risk variant, LRRK2 R1628P, with ET. Subjects carrying the R1628P variant had twice the risk of developing ET. The sharing of a similar gene risk variant suggests a possible pathophysiologic link between PD and ET.