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  1. Rasheed MK, Hasan SS, Babar ZU, Ahmed SI
    Lancet Infect Dis, 2019 03;19(3):242-243.
    PMID: 30833059 DOI: 10.1016/S1473-3099(19)30051-9
    Matched MeSH terms: Disease Outbreaks
  2. Agarwal A, Vyas S, Kumar R
    Malays Fam Physician, 2015;10(3):35-7.
    PMID: 27570607
    Wellen's syndrome is a pre-infarction stage of coronary artery disease characterised by predefined clinical and electrocardiographic (ECG) criteria of a subgroup of patients with myocardial ischaemia. Early recognition and appropriate intervention of this syndrome carry significant diagnostic and prognostic value. We report this unusual syndrome in an elderly man who presented with recurrent angina and characteristic ECG changes as T-waves inversion in the precordial leads, especially in V2-V6 during pain-free periods and ECG obtained during episodes of pain demonstrating upright T-waves with possible elevated ST segments from V1-V4. Cardiac enzymes were positive and coronary angiography revealed critical stenosis in the proximal left anterior descending artery. It is important to timely identify this condition and intervene appropriately as these patients may develop extensive myocardial infarction that carries a significant morbidity and mortality.
    Matched MeSH terms: Coronary Artery Disease
  3. Kee YJ, Zakaria L, Mohd MH
    J Appl Microbiol, 2020 Sep;129(3):626-636.
    PMID: 32167647 DOI: 10.1111/jam.14640
    AIMS: To characterize causal pathogen of Sansevieria trifasciata anthracnose through morphology and molecular analysis; to evaluate the host range of the pathogen; and to explicate the infection process by the pathogen histopathologically.

    METHODS AND RESULTS: Symptomatic leaves of S. trifasciata were collected from five states in Malaysia. The causal pathogen was isolated and identified for the first time in Malaysia as C. sansevieriae based on morphological and multi-gene phylogenetic analyses using ITS, TUB2 and GAPDH sequences. Pathogenicity tests were conducted on different hosts. Colletotrichum sansevieriae was not pathogenic towards S. cylindrica, S. masoniana, Furcraea foetida, Chlorophytum comosum, Aloe vera and Gasteria carinata, confirming the exceptionally high host specificity for a species of Colletotrichum. Histopathology was performed using light microscope and scanning electron microscopy to study the infection process of C. sansevieriae on S. trifasciata. Colonization of host leaves by the pathogen was observed 2 days after inoculation.

    CONCLUSIONS: Colletotrichum sansevieriae caused anthracnose of S. trifasciata in Malaysia. It is a host-specific pathogen and colonized the host intracellularly.

    SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of C. sansevieriae causing anthracnose of S. trifasciata in Malaysia. The host range test and understanding of the infection process will provide better understanding of the host-pathogen relationship and beneficial for effective disease management.

    Matched MeSH terms: Disease Management
  4. Cheong FW, Dzul S, Fong MY, Lau YL, Ponnampalavanar S
    Acta Trop, 2020 Jun;206:105454.
    PMID: 32205132 DOI: 10.1016/j.actatropica.2020.105454
    Transmission of Plasmodium vivax still persist in Malaysia despite the government's aim to eliminate malaria in 2020. High treatment failure rate of chloroquine monotherapy was reported recently. Hence, parasite drug susceptibility should be kept under close monitoring. Mutation analysis of the drug resistance markers is useful for reconnaissance of anti-malarial drug resistance. Hitherto, information on P. vivax drug resistance marker in Malaysia are limited. This study aims to evaluate the mutations in four P. vivax drug resistance markers pvcrt-o (putative), pvmdr1 (putative), pvdhfr and pvdhps in 44 isolates from Malaysia. Finding indicates that 27.3%, 100%, 47.7%, and 27.3% of the isolates were carrying mutant allele in pvcrt-o, pvmdr1, pvdhfr and pvdhps genes, respectively. Most of the mutant isolates had multiple point mutations rather than single point mutation in pvmdr1 (41/44) and pvdhfr (19/21). One novel point mutation V111I was detected in pvdhfr. Allelic combination analysis shows significant strong association between mutations in pvcrt-o and pvmdr1 (X2 = 9.521, P < 0.05). In the present study, 65.9% of the patients are non-Malaysians, with few of them arrived in Malaysia 1-2 weeks before the onset of clinical manifestations, or had previous history of malaria infection. Besides, few Malaysian patients had travel history to vivax-endemic countries, suggesting that these patients might have acquired the infections during their travel. All these possible imported cases could have placed Malaysia in a risk to have local transmission or outbreak of malaria. Six isolates were found to have mutations in all four drug resistance markers, suggesting that the multiple-drugs resistant P. vivax strains are circulating in Malaysia.
    Matched MeSH terms: Disease Outbreaks
  5. Global Burden of Disease Study 2013 Collaborators
    Lancet, 2015 Aug 22;386(9995):743-800.
    PMID: 26063472 DOI: 10.1016/S0140-6736(15)60692-4
    BACKGROUND: Up-to-date evidence about levels and trends in disease and injury incidence, prevalence, and years lived with disability (YLDs) is an essential input into global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013), we estimated these quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013.
    METHODS: Estimates were calculated for disease and injury incidence, prevalence, and YLDs using GBD 2010 methods with some important refinements. Results for incidence of acute disorders and prevalence of chronic disorders are new additions to the analysis. Key improvements include expansion to the cause and sequelae list, updated systematic reviews, use of detailed injury codes, improvements to the Bayesian meta-regression method (DisMod-MR), and use of severity splits for various causes. An index of data representativeness, showing data availability, was calculated for each cause and impairment during three periods globally and at the country level for 2013. In total, 35 620 distinct sources of data were used and documented to calculated estimates for 301 diseases and injuries and 2337 sequelae. The comorbidity simulation provides estimates for the number of sequelae, concurrently, by individuals by country, year, age, and sex. Disability weights were updated with the addition of new population-based survey data from four countries.
    FINDINGS: Disease and injury were highly prevalent; only a small fraction of individuals had no sequelae. Comorbidity rose substantially with age and in absolute terms from 1990 to 2013. Incidence of acute sequelae were predominantly infectious diseases and short-term injuries, with over 2 billion cases of upper respiratory infections and diarrhoeal disease episodes in 2013, with the notable exception of tooth pain due to permanent caries with more than 200 million incident cases in 2013. Conversely, leading chronic sequelae were largely attributable to non-communicable diseases, with prevalence estimates for asymptomatic permanent caries and tension-type headache of 2·4 billion and 1·6 billion, respectively. The distribution of the number of sequelae in populations varied widely across regions, with an expected relation between age and disease prevalence. YLDs for both sexes increased from 537·6 million in 1990 to 764·8 million in 2013 due to population growth and ageing, whereas the age-standardised rate decreased little from 114·87 per 1000 people to 110·31 per 1000 people between 1990 and 2013. Leading causes of YLDs included low back pain and major depressive disorder among the top ten causes of YLDs in every country. YLD rates per person, by major cause groups, indicated the main drivers of increases were due to musculoskeletal, mental, and substance use disorders, neurological disorders, and chronic respiratory diseases; however HIV/AIDS was a notable driver of increasing YLDs in sub-Saharan Africa. Also, the proportion of disability-adjusted life years due to YLDs increased globally from 21·1% in 1990 to 31·2% in 2013.
    INTERPRETATION: Ageing of the world's population is leading to a substantial increase in the numbers of individuals with sequelae of diseases and injuries. Rates of YLDs are declining much more slowly than mortality rates. The non-fatal dimensions of disease and injury will require more and more attention from health systems. The transition to non-fatal outcomes as the dominant source of burden of disease is occurring rapidly outside of sub-Saharan Africa. Our results can guide future health initiatives through examination of epidemiological trends and a better understanding of variation across countries.
    FUNDING: Bill & Melinda Gates Foundation.
    Malaysian collaborators: Department of Medicine, Universiti Kebangsaan Malaysia Medical Center, Kuala Lampur, Malaysia (Prof N Mohamed Ibrahim MBBch); Universiti Kebangsaan Malaysia Medical Centre, Bangi, Selangor, Malaysia (R Sahathevan PhD); Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman, Selangor, Malaysia (C T Sreeramareddy MD); WorldFish, Penang, Malaysia (A L Thorne-Lyman ScD); TCM Medical TK SDN BHD TCM, Nusajaya, Johor Bahru, Malaysia (K Yun Kin PhD)
    Matched MeSH terms: Acute Disease/epidemiology*; Chronic Disease/epidemiology*
  6. Elina RA, Husain R, Lang CC
    JUMMEC, 2005;8:9-22.
    Cardiopulmonary exercise testing is a non-invasive physiological test which incorporates the conventional method of exercise stress test with a more advanced breath-to-breath ventilatory analysis. The physiological parameters obtained from the test help to illustrate the cardiovascular, respiratory and metabolic responses to physical exertion. Individual's functional capacity and aerobic fitness is reflected by the value of maximal oxygen consumption (VO2 max) obtained from the cardiopulmonary exercise test. This non-invasive and sophisticated test is regarded as a valuable assessment tool in research and clinical practice. Cardiopulmonary exercise test has been extensively utilized to define the mechanisms of exercise intolerance in various clinical disorders, to evaluate responses to therapy and indicate disease prognosis. Emerging data obtained from the use of the cardiopulmonary exercise testing in the research field, has led to its extensive clinical usage. It is now utilized as an integral part of the patients' clinical evaluation in the field of respiratory and cardiovascular medicine, sports medicine, surgery as well as occupational and rehabilitative medicine. It has a clinical role in assessing patient's functional capacity, monitoring disease progression and response to therapy, predicting prognosis, and perioperative morbidity and mortality, as well as constructing and monitoring training and rehabilitative programs. This article aims to give an overview of the physiological profiles obtained from cardiopulmonary exercise testing, its methodological aspects, as well as its utility in research and clinical practice. KEYWORDS: Cardiopulmonary, exercise, physiology, respiratory medicine, oxygen consumption
    Matched MeSH terms: Disease Progression
  7. Agatonovic-Kustrin S, Chan CKY, Gegechkori V, Morton DW
    J Biomol Struct Dyn, 2020 May;38(8):2402-2411.
    PMID: 31204906 DOI: 10.1080/07391102.2019.1633408
    Aromatherapy with essential oils (EOs) has been linked to improvement of cognitive function in patients with dementia. In order to act systemically, active EO components must be absorbed through the skin, enter the systemic circulation, and cross the blood brain barrier (BBB). Thus, the aim of this work was to develop quantitative structure activity relationships (QSARs), to predict skin and blood barrier penetrative abilities of 119 terpenoids from EOs used in aromatherapy. The first model was based on experimentally measured skin permeability for 162 molecules, and the second model on BBB permeability for 138 molecules. Each molecule was encoded with 63 calculated molecular descriptors and an artificial neural network was used to correlate molecular descriptors to permeabilities. Developed QSAR models confirm that EOs components penetrate through the skin and across the BBB. Some well-known descriptors, such as log P (lipophilicity), molecular size and shape, dominated the QSAR model for BBB permeability. Compounds with the highest predicted BBB penetration were hydrocarbon terpenes with the smallest molecular size and highest lipophilicity. Thus, molecular size is a limiting factor for penetration. Compounds with the highest skin permeability have slightly higher molecular size, high lipophilicity and low polarity. Our work shows that a major disadvantage of novel multitarget compounds developed for the treatment of Alzheimer's disease is the size of molecules, which cause problems in their delivery to the brain. Therefore, there is a need for smaller compounds, which possess more desirable physicochemical properties and pharmacokinetics, in addition to targeted biological effects.Communicated by Ramaswamy H. Sarma.
    Matched MeSH terms: Alzheimer Disease
  8. Krackhardt F, Waliszewski M, Wan Ahmad WA, Kočka V, Toušek P, Janek B, et al.
    PLoS One, 2020;15(1):e0226606.
    PMID: 31929543 DOI: 10.1371/journal.pone.0226606
    BACKGROUND: The objective of this study was to assess regional and ethnic differences in an unselected patient population treated with polymer-free sirolimus-eluting stents (PF-SES) in Asia and Europe.

    METHODS: Two all-comers observational studies based on the same protocol (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were combined for data analysis to assure sufficient statistical power. The primary endpoint was the accumulated target lesion revascularization (TLR) rate at 9-12 months.

    RESULTS: Of the total population of 7243 patients, 44.0% (3186) were recruited in the Mediterranean region and 32.0% (2317) in central Europe. The most prominent Asian region was South Korea (17.6%, 1274) followed by Malaysia (5.7%, 413). Major cardiovascular risk factors varied significantly across regions. The overall rates for accumulated TLR and MACE were low with 2.2% (140/6374) and 4.4% (279/6374), respectively. In ACS patients, there were no differences in terms of MACE, TLR, MI and accumulated mortality between the investigated regions. Moreover, dual antiplatelet therapy (DAPT) regimens were substantially longer in Asian countries even in patients with stable coronary artery disease as compared to those in Europe.

    CONCLUSIONS: PF-SES angioplasty is associated with low clinical event rates in all regions. Further reductions in clinical event rates seem to be associated with longer DAPT regimens.

    Matched MeSH terms: Coronary Artery Disease
  9. Chung YS, Choo BKM, Ahmed PK, Othman I, Shaikh MF
    Front Pharmacol, 2020;11:692.
    PMID: 32477146 DOI: 10.3389/fphar.2020.00692
    Orthosiphon stamineus (OS) or Orthosiphon aristatus var. aristatus (OAA) is commonly known as cat's whiskers or "misai kucing". It is an herbaceous shrub that is popular in many different traditional and complementary medicinal systems. Its popularity has been justified by the plethora of studies that have shown that the secondary metabolites of the plant has effects that range from anti-inflammatory and gastroprotective to anorexic and antihypertensive. As such, OS could also be a potential treatment for Central Nervous System (CNS) disorders. However, a cohesive synthesis of the protective actions of OS was lacking. This systematic review was therefore commenced to elaborate on the various protective mechanisms of OS in the CNS. The PRISMA model was used and five databases (Google Scholar, SCOPUS, SpringerLink, ScienceDirect, and PubMed) were searched with relevant keywords to finally identify four articles that met the inclusion criteria. The articles described the protective effects of OS extracts on Alzheimer's disease, epilepsy, learning and memory, oxidative stress, and neurotoxicity. All the articles found were experimental or preclinical studies on animal models or in vitro systems. The reported activities demonstrated that OS could be a potential neuroprotective agent and might improve CNS conditions like neurodegeneration, neuroinflammation, and oxidative stress.
    Matched MeSH terms: Alzheimer Disease
  10. Pham TH, Lila MAM, Rahaman NYA, Lai HLT, Nguyen LT, Do KV, et al.
    BMC Vet Res, 2020 May 06;16(1):128.
    PMID: 32375821 DOI: 10.1186/s12917-020-02345-z
    BACKGROUND: In view of the current swine fever outbreak and the government aspiration to increase the goat population, a need arises to control and prevent outbreaks of goat pox. Despite North Vietnam facing sporadic cases of goat pox, this most recent outbreak had the highest recorded morbidity, mortality and case fatality rate. Thus, owing to the likelihood of a widespread recurrence of goat pox infection, an analysis of that outbreak was done based on selected signalment, management and disease pattern (signs and pathology) parameters. This includes examination of animals, inspection of facilities, tissue sampling and analysis for confirmation of goatpox along with questionaires.

    RESULTS: It was found that the susceptible age group were between 3 and 6 months old kids while higher infection rate occurred in those under the free-range rearing system. The clinical signs of pyrexia, anorexia, nasal discharge and lesions of pocks were not restricted to the skin but have extended into the lung and intestine. The pathogen had been confirmed in positive cases via PCR as goat pox with prevalence of 79.69%.

    CONCLUSIONS: The epidemiology of the current goat pox outbreak in North Vietnam denotes a significant prevalence which may affect the industry. This signals the importance of identifying the salient clinical signs and post mortem lesions of goat pox at the field level in order to achieve an effective control of the disease.

    Matched MeSH terms: Disease Outbreaks
  11. Gao M, Qu K, Zhang W, Wang X
    Neuroimmunomodulation, 2021;28(2):90-98.
    PMID: 33774633 DOI: 10.1159/000513297
    INTRODUCTION: Pediatric patients with epilepsy are prone to cognitive impairments during growth and long-term use of most antiepileptic drugs (AED). The affected children do not respond to conventional AED and may require novel drugs to manage the disease. Valproic acid, a first-line drug to treat epilepsy, is associated with serious side effects, which precludes its wider use. Thus, in the present study, we intended to develop novel substituted pyrazoles.

    METHODS: The molecules were tested for anticonvulsive activity in Swiss albino mice via maximal electroshock seizure and subcutaneous pentylenetetrazole assays. The most potent molecule among the class was further assayed for its effect on behavioral and CNS depressant activity. The effect of the most potent compounds was also analyzed on various indices of oxidative stress and inflammation in mice.

    RESULTS: The designed compounds showed significant anticonvulsive activity in mice revealing 7h as the most potent anticonvulsive agent. The most potent anticonvulsant molecule 7h further showed no behavioral alteration and considerable CNS depressant activity. It also reduces the level of oxidative stress and inflammation in the mice.

    CONCLUSION: Our study demonstrated utility of pyrazole derivatives as anticonvulsants against epilepsy.

    Matched MeSH terms: Disease Models, Animal
  12. Teoh HL, Aminudin N, Abdullah N
    Int J Med Mushrooms, 2021;23(2):43-56.
    PMID: 33639080 DOI: 10.1615/IntJMedMushrooms.2021037649
    Nonalcoholic fatty liver disease (NAFLD) is currently one of the most common liver diseases worldwide. Lifestyle modifications through the diet are the mainstay of treatment. Auricularia nigricans is a popular edible mushroom known to possess medicinal properties. Gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry analysis indicated that linoleic acid ethyl ester, butyl 9,12-octadecadienoate, 9,12-octadecadienoic acid, ergosta-5,7,22-trien-3-ol, 2(3,4-dihydroxyphenyl)-7-hydroxy-5-benzene propanoic acid, and 3,30-di-0-methyl ellagic acid were present in the A. nigricans ethyl acetate (EA) fraction. The cytotoxicity assay showed that the EA fraction was noncytotoxic to HepG2 cells at concentrations < 100 μg/mL. In the antihepatic steatosis assay, 50 μg/mL of EA fraction caused a decline in absorbance to 0.20 ± 0.02 compared to palmitic acid (PA)-induced cells (0.24 ± 0.02). Furthermore, cells treated with 50 μg/mL and 25 μg/mL of EA fraction contributed an approximately 1.12-fold and 1.08-fold decrease in lipid accumulation compared to PA-induced cells. Coincubation with PA and 25 μg/mL of EA fraction decreased levels of tumor necrosis factor-α, interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 to 140.48 ± 8.12, 91.16 ± 2.40, 184.00 ± 22.68, and 935.88 ± 39.36 pg/mL compared to PA-induced cells. The presence of the EA fraction also suppressed the stress-activated protein kinase/Jun amino-terminal kinase, p-38 mitogen-activated protein kinase, nuclear factor-κB, and signal transducer and activator of transcription 3 signaling pathways. In conclusion, these findings suggest that the A. nigricans EA fraction demonstrates antisteatotic effects involving antioxidant capacity, hypolipidemic effects, and anti-inflammatory capacity in the PA-induced NAFLD pathological cell model.
    Matched MeSH terms: Non-alcoholic Fatty Liver Disease
  13. Ng SC, Kaplan GG, Tang W, Banerjee R, Adigopula B, Underwood FE, et al.
    Am J Gastroenterol, 2019 01;114(1):107-115.
    PMID: 30177785 DOI: 10.1038/s41395-018-0233-2
    INTRODUCTION: Living in an urban environment may increase the risk of developing inflammatory bowel disease (IBD). It is unclear if this observation is seen globally. We conducted a population-based study to assess the relationship between urbanization and incidence of IBD in the Asia-Pacific region.

    METHODS: Newly diagnosed IBD cases between 2011 and 2013 from 13 countries or regions in Asia-Pacific were included. Incidence was calculated with 95% confidence interval (CI) and pooled using random-effects model. Meta-regression analysis was used to assess incidence rates and their association with population density, latitude, and longitude.

    RESULTS: We identified 1175 ulcerative colitis (UC), 656 Crohn's disease (CD), and 37 IBD undetermined (IBD-U). Mean annual IBD incidence per 100 000 was 1.50 (95% CI: 1.43-1.57). India (9.31; 95% CI: 8.38-10.31) and China (3.64; 95% CI, 2.97-4.42) had the highest IBD incidence in Asia. Incidence of overall IBD (incidence rate ratio [IRR]: 2.19; 95% CI: 1.01-4.76]) and CD (IRR: 3.28; 95% CI: 1.83-9.12) was higher across 19 areas of Asia with a higher population density. In China, incidence of IBD (IRR: 2.37; 95% CI: 1.10-5.16) and UC (IRR: 2.63; 95% CI: 1.2-5.8) was positively associated with gross domestic product. A south-to-north disease gradient (IRR: 0.94; 95% CI: 0.91-0.98) was observed for IBD incidence and a west-to-east gradient (IRR: 1.14; 95% CI: 1.05-1.24) was observed for CD incidence in China. This study received IRB approval.

    CONCLUSIONS: Regions in Asia with a high population density had a higher CD and UC incidence. Coastal areas within China had higher IBD incidence. With increasing urbanization and a shift from rural areas to cities, disease incidence may continue to climb in Asia.

    Matched MeSH terms: Crohn Disease
  14. Chan TT, Chan WK, Wong GL, Chan AW, Nik Mustapha NR, Chan SL, et al.
    Am J Gastroenterol, 2020 06;115(6):867-875.
    PMID: 32149781 DOI: 10.14309/ajg.0000000000000588
    OBJECTIVES: Previous exposure to hepatitis B virus (HBV) may increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. We aim to study the impact of previous HBV infection on the severity and outcomes of patients with nonalcoholic fatty liver disease (NAFLD).

    METHODS: This was a multicenter study of 489 patients with biopsy-proven NAFLD and 69 patients with NAFLD-related or cryptogenic HCC. Antihepatitis B core antibody (anti-HBc) was used to detect the previous HBV infection.

    RESULTS: In the biopsy cohort, positive anti-HBc was associated with lower steatosis grade but higher fibrosis stage. 18.8% and 7.5% of patients with positive and negative anti-HBc had cirrhosis, respectively (P < 0.001). The association between anti-HBc and cirrhosis remained significant after adjusting for age and metabolic factors (adjusted odds ratio 2.232; 95% confidence interval, 1.202-4.147). At a mean follow-up of 6.2 years, patients with positive anti-HBc had a higher incidence of HCC or cirrhotic complications (6.5% vs 2.2%; P = 0.039). Among patients with NAFLD-related or cryptogenic HCC, 73.9% had positive anti-HBc. None of the patients had positive serum HBV DNA. By contrast, antihepatitis B surface antibody did not correlate with histological severity.

    DISCUSSION: Positive anti-HBc is associated with cirrhosis and possibly HCC and cirrhotic complications in patients with NAFLD. Because a significant proportion of NAFLD-related HCC may develop in noncirrhotic patients, future studies should define the role of anti-HBc in selecting noncirrhotic patients with NAFLD for HCC surveillance.

    Matched MeSH terms: Non-alcoholic Fatty Liver Disease/complications; Non-alcoholic Fatty Liver Disease/epidemiology*; Non-alcoholic Fatty Liver Disease/pathology
  15. Barnes DR, Rookus MA, McGuffog L, Leslie G, Mooij TM, Dennis J, et al.
    Genet Med, 2020 10;22(10):1653-1666.
    PMID: 32665703 DOI: 10.1038/s41436-020-0862-x
    PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.

    METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.

    RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar.

    CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

    Matched MeSH terms: Genetic Predisposition to Disease
  16. Maddirevula S, AlZahrani F, Anazi S, Almureikhi M, Ben-Omran T, Abdel-Salam GMH, et al.
    Genet Med, 2018 01;20(1):64-68.
    PMID: 28640246 DOI: 10.1038/gim.2017.78
    PurposeGenome-wide association studies (GWAS) have been instrumental to our understanding of the genetic risk determinants of complex traits. A common challenge in GWAS is the interpretation of signals, which are usually attributed to the genes closest to the polymorphic markers that display the strongest statistical association. Naturally occurring complete loss of function (knockout) of these genes in humans can inform GWAS interpretation by unmasking their deficiency state in a clinical context.MethodsWe exploited the unique population structure of Saudi Arabia to identify novel knockout events in genes previously highlighted in GWAS using combined autozygome/exome analysis.ResultsWe report five families with homozygous truncating mutations in genes that had only been linked to human disease through GWAS. The phenotypes observed in the natural knockouts for these genes (TRAF3IP2, FRMD3, RSRC1, BTBD9, and PXDNL) range from consistent with, to unrelated to, the previously reported GWAS phenotype.ConclusionWe expand the role of human knockouts in the medical annotation of the human genome, and show their potential value in informing the interpretation of GWAS of complex traits.
    Matched MeSH terms: Genetic Predisposition to Disease
  17. Ganaraja B, Pavithran P, Ghosh S
    Indian J Med Sci, 2004 Apr;58(4):150-4.
    PMID: 15122050
    BACKGROUND: Plasma ceruloplasmin, a copper containing protein, belongs to a class called acute phase proteins. Reduced level of ceruloplasmin was associated with Wilson's disease and Menke's kinky hair disease in man, primarily affecting copper metabolism. Stress was known to increase Ceruloplasmin. Several stress associated changes were commonly observed in women at menopause and also those who underwent overiectomy. Present experiment investigated the effect of estrogen on ceruloplasmin level in acute stress.

    AIMS: To assess the estradiol induced changes in plasma ceruloplasmin concentration on exposure of the rats to acute stress.

    SETTINGS AND DESIGN: Acute stress was induced by forcing the rats to swim till exhaustion. The rats were overiectomised bilaterally to remove the primary source of sex hormones. And hormone replacement was done later.

    MATERIAL AND METHODS: Wistar albino female rats were used. Acute stress was induced before overiectomy, following recovery from surgery, and again after Estradiol Valerate injection (for 10 days) in same group of rats. The plasma ceruloplasmin was estimated immediately after stress during each stage--that is preoperative control, stressed control, after overiectomy and then following treatment with Estradiol Valerate.

    STATISTICAL ANALYSIS USED: Paired sample T test was applied to analyze the findings.

    RESULTS: We found lowest ceruloplasmin level after stress in overiectomised animals, while on substitution of estradiol the trend appeared to be reversed.

    CONCLUSION: The result suggested a direct effect of estrogen on hepatic ceruloplasmin production/release and this could account for some of the beneficial effects of hormone replacement therapy.

    Matched MeSH terms: Acute Disease
  18. Choon SE, Navarini AA, Pinter A
    Am J Clin Dermatol, 2022 Jan;23(Suppl 1):21-29.
    PMID: 35061227 DOI: 10.1007/s40257-021-00654-z
    Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterized by episodes of widespread sterile macroscopic pustules, with or without systemic inflammation and/or plaque psoriasis. Multiple GPP subtypes have been described, from acute GPP of von Zumbusch to milder, annular pustular psoriasis. Generalized pustular psoriasis mainly affects adults, with a female preponderance, but juvenile GPP also occurs. Flares are a hallmark of GPP and may occur de novo or be provoked by triggers, including withdrawal of systemic corticosteroids, infections, stress, pregnancy, and menstruation. Severity of flares varies widely between patients, and between flares in an individual patient. Significant flares are often accompanied by systemic symptoms, notably fever, general malaise, and extracutaneous manifestations such as arthritis, uveitis, and neutrophilic cholangitis. Common laboratory abnormalities include neutrophilia, elevated C-reactive protein levels, hypocalcemia, and abnormal liver function tests. The clinical course of GPP is highly variable; it can be a relapsing disease with recurrent flares and no pustulation between flares or a persistent disease with perpetual mild pustulation punctuated with flares of greater severity. Patients may have multiple flares per year or a flare every few years. Most flares last 2-5 weeks and approximately 50% require hospitalization. Life-threatening complications include sepsis and renal, hepatic, respiratory, and heart failure. Reported mortality rates are 2-16%.
    Matched MeSH terms: Disease Progression
  19. Kow CS, Hasan SS
    Eur J Clin Pharmacol, 2021 Aug;77(8):1089-1094.
    PMID: 33532896 DOI: 10.1007/s00228-021-03087-z
    OBJECTIVE: We aimed to perform a meta-analysis of randomized controlled trials (RCTs) to summarize the overall effect of tocilizumab on the risk of mortality among patients with coronavirus disease 2019 (COVID-19).

    METHODS: We systematically searched PubMed, Cochrane Central Register of Controlled Trials, Google Scholar, and medRxiv (preprint repository) databases (up to 7 January 2021). Pooled effect sizes with 95% confidence interval (CI) were generated using random-effects and inverse variance heterogeneity models. The risk of bias of the included RCTs was appraised using version 2 of the Cochrane risk-of-bias tool for randomized trials.

    RESULTS: Six RCTs were included: two trials with an overall low risk of bias and four trials had some concerns regarding the overall risk of bias. Our meta-analysis did not find significant mortality benefits with the use of tocilizumab among patients with COVID-19 relative to non-use of tocilizumab (pooled hazard ratio = 0.83; 95% CI 0.66-1.05, n = 2,057). Interestingly, the estimated effect of tocilizumab on the composite endpoint of requirement for mechanical ventilation and/or all-cause mortality indicated clinical benefits, with some evidence against our model hypothesis of no significant effect at the current sample size (pooled hazard ratio = 0.62; 95% CI 0.42-0.91, n = 749).

    CONCLUSION: Despite no clear mortality benefits in hospitalized patients with COVID-19, tocilizumab appears to reduce the likelihood of progression to mechanical ventilation.

    Matched MeSH terms: Disease Progression
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