Genome-Wide Polygenic Score Predicts Large Number of High Risk Individuals in Monogenic Undiagnosed Young Onset Parkinson's Disease Patients from India.

Parkinson's disease (PD) is a genetically heterogeneous neurodegenerative disease with poorly defined environmental influences. Genomic studies of PD patients have identified disease-relevant monogenic genes, rare variants of significance, and polygenic risk-associated variants. In this study, whole genome sequencing data from 90 young onset Parkinson's disease (YOPD) individuals are analyzed for both monogenic and polygenic risk. The genetic variant analysis identifies pathogenic/likely pathogenic variants in eight of the 90 individuals (8.8%). It includes large homozygous coding exon deletions in PRKN and SNV/InDels in VPS13C, PLA2G6, PINK1, SYNJ1, and GCH1. Eleven rare heterozygous GBA coding variants are also identified in 13 (14.4%) individuals. In 34 (56.6%) individuals, one or more variants of uncertain significance (VUS) in PD/PD-relevant genes are observed. Though YOPD patients with a prioritized pathogenic variant show a low polygenic risk score (PRS), patients with prioritized VUS or no significant rare variants show an increased PRS odds ratio for PD. This study suggests that both significant rare variants and polygenic risk from common variants together may contribute to the genesis of PD. Further validation using a larger cohort of patients will confirm the interplay between monogenic and polygenic variants and their use in routine genetic PD diagnosis and risk assessment.

Sensitization to Local Seafood Allergens in Adult Patients with Atopic Dermatitis in Malaysia.

BACKGROUND: Seafood is an important source of nutrition in Asia. However, it was believed to cause or aggravate atopic dermatitis (AD). OBJECTIVES: We aim to determine relevant seafood sensitization among adults with AD and investigate cross-sensitization to aeroallergens. METHODS: One hundred thirty-two adults with AD who were subjected to skin prick test (SPT) with 7 common local seafood allergens (anchovy, tuna, mackerel, squid, giant freshwater prawn, shrimp, and crab), house dust mites (HDMs), and cockroach were analyzed retrospectively. RESULTS: The median age of the study subjects was 32 years (range 17-77 years) with a male to female ratio of 1:3. The mean duration of AD was 16 years. Eighty-two patients (62.2%) had other atopic conditions. Using SCORAD, 44.7% had mild, 42.4% moderate, and 12.9% severe disease. Eighty-six patients (65.2%) self-reported to have seafood allergy, with the main symptoms of transient pruritus and erythema within 2 h of ingestion. SPT revealed 51.5% of the patients were sensitized to at least 1 of the 7 seafood allergens. The relevant sensitization rate was 45.1%. Interestingly, 46% of those without a history of seafood allergy developed at least 1 positive reaction in the SPT. Prawn, shrimp, and crab were the 3 most frequently sensitized allergens. Nearly all patients (98.3%) who were sensitized to crustaceans were also sensitized to HDMs and/or cockroach. There was no significant correlation between a positive SPT to seafood with age, age of onset of AD, duration, and severity of AD, and the presence of other atopic diatheses. CONCLUSION: The relevant sensitization rate of local seafood among adults with AD was 45.1%.

HLA-B*58: 01 association in allopurinol-induced severe cutaneous adverse reactions: the implication of ethnicity and clinical phenotypes in multiethnic Malaysia.

OBJECTIVE: The association between human leukocyte antigen (HLA)-B*58:01 and risk of allopurinol-induced severe cutaneous adverse reactions (AIS) was observed across different populations. We explore the association between HLA-B*58:01 and AIS risk in multiethnic Malaysian population. The HLA-B*58:01 risk for different AIS clinical phenotypes and ethnicity was determined. METHODS: We performed a case-control association study by genotyping the HLA-B alleles of 55 patients with AIS [11 toxic epidermal necrolysis (TEN), 21 Steven Johnson syndrome (SJS) 22 drug reaction wit eosinophilia and systemic symptoms (DRESS) and one acute generalized exanthematous pustulosis (AGEP)] and 42 allopurinol-tolerant controls (ATC). RESULTS: HLA-B*58:01 was positive in 89.1 and 14.3% of the AIS and ATC study groups [odds ratio (OR) = 49.0, 95% confidence interval (CI) = 14.6-164.4, P < 0.0001)], respectively. Our data showed that 93.8% of the AIS-SJS/TEN patients and 86.4% of the AIS-DRESS patients were HLA-B*58:01 positive (AIS-SJS/TEN, OR = 90, 95% CI = 16.9-470.1, P < 0.0001 and AIS-DRESS OR = 38, 95% CI = 8.5-169.2, P < 0.0001). Stratification by ethnicity and clinical phenotypes revealed a significant increased risk between HLA-B*58:01 and Chinese-AIS patients (OR = 137.5, 95% CI = 11.3-1680.2, P < 0.0001), in particular Chinese patients with AIS-SJS/TEN phenotype (100% HLA-B*58:01 positive). HLA-B*58:01 was positive in 90.9% Chinese AIS-DRESS (P < 0.0001). Highly significant associations of HLA-B*58:01 were observed in Malay AIS-SJS/TEN (OR = 78, 95% CI = 9.8-619.9, P < 0.0001) and Malay AIS-DRESS (OR = 54, 95% CI = 6.6-442.9, P < 0.0001). Although the number of Indian-AIS patients was relatively small (n = 2), both were HLA-B*58:01 positive. CONCLUSION: Our data suggest strong associations between HLA-B*58:01 and AIS in Malaysian population with Chinese and Malays ethnicity. The strong association was also observed in three different clinical phenotypes of AIS, mainly the AIS-SJS/TEN.

High drug related mortality rates following prison release: Assessing the acceptance likelihood of a naltrexone injection and related concerns.

BACKGROUND AND AIMS: High drug related mortality amongst former prisoners in the 4 weeks following release is an internationally recognised problem. Naltrexone injections at release could diminish this by blockading opioid receptors, but naltrexone is not licensed for injection for treating opiate misuse in the United Kingdom and some other countries. This study examined the likelihood of accepting a naltrexone injection at release, and the relationship of this likelihood to other relevant variables. METHOD: Sixty-one male prisoners with a history of heroin use, who were approaching release from two prisons in the north-west of England, provided likelihood ratings for accepting a naltrexone injection if it were to have been available. Additional data was gathered regarding demographic and drug use histories, and also from psychometric instruments relevant to drug misuse and treatment preparedness. RESULTS: Maximum likelihood ratings for accepting a naltrexone injection were recorded by 55.7% of the sample with only 9.8% indicating no likelihood of accepting an injection. Likelihood ratings were positively related to serving a current sentence for an acquisitive offence compared to drug related or violence offences, and negatively related to peak methadone dosages during the current sentence. CONCLUSIONS: Although naltrexone injections were not available to participants in this study, the findings suggest that the potential uptake for this intervention is sufficient to warrant a clinical trial with this population of British prisoners, with a view to potential changes to its current licencing status. However, the importance of individual patient readiness for such an abstinence orientated intervention is emphasised by the negative correlation between the likelihood ratings and recent methadone doses.

Survival rates of cervical cancer patients in Malaysia.

Cervical cancer is the most common malignant cancer of the female reproductive organs worldwide. Currently, cervical cancer can be prevented by vaccination and detected at an early stage via various screening methods. Malaysia, as a developing country faces a heavy disease burden of cervical cancer as it is the second most common cancer among Malaysian women. This population based study was carried out to fulfil the primary aim of determining the survival rates of Malaysian women with cervical cancer and associated factors. Data were obtained from two different sources namely, the Malaysian National Cancer Registry (MNCR) and National Health Informatics Centre (NHIC) from 1st January 2000 to 31st December 2005. Kaplan Meier analyses were conducted to identify the overall survival rates and median survival time. Differences in survival among different ethnic and age group were compared using the log-rank test. A total of 5,859 patients were included. The median survival time for cervical cancer in this study was 65.8 months and the 5-year survival rate was 71.1%. The overall observed survival rates at 1, 3 and 5 years were 94.1%, 79.3% and 71.1% respectively. The log-rank test finding also showed that there were significant differences in the 5-year survival rate among different ethnic groups. Malays had the lowest survival rate of 59.2% followed by Indians (69.5%) and Chinese (73.8%). The overall 5-year survival rate among patients with cervical cancer in Malaysia is relatively good. Age and ethnic groups remain as significant determining factors for cervical cancer survival rate.

Metabolism, lifestyle and bipolar affective disorder.

Lifestyle, illness and treatment factors in people with bipolar disorder (BD) may confer additional risk of morbidity and mortality to the increasing rates of obesity, metabolic syndrome, diabetes mellitus and cardiovascular mortality in the general population.The aim of this review is to examine whether the risk of obesity and related morbidity and mortality are raised in BD, and possible contributory effects of lifestyle, illness and treatment factors to this risk.Systematic search of Medline and Cochrane Collaboration for relevant studies followed by a critical review of literature was carried out.Mortality from cardiovascular causes and pulmonary embolism (standardized mortality ratio approximately 2.0), and morbidity from obesity and type 2 diabetes mellitus may be increased in BD compared to the general population. Reduced exercise and poor diet, frequent depressive episodes, comorbidity with substance misuse and poor quality general medical care contribute to the additional risk of these medical problems in people with BD. There is no evidence that patients with BD are more sensitive than other patients to weight gain and medical problems associated with long-term use of psychotropic medication; in fact long-term treatment with lithium, antipsychotics and tricyclic antidepressants may reduce overall mortality. Psychiatrists, general practitioners and other health professionals should work together to systematically assess and manage weight gain and related medical problems to reduce the morbidity and mortality associated with obesity in BD. There is insufficient evidence to associate any of these factors with specific drug treatments. More research is required to understand how BD changes the risk for physical health comorbidity.