Ischemic Stroke Predicted Length Of Stay From Admission Characteristics And Associated With CD40-1C/T Single Nucleotide Polymorphism

Chapter1Ischemic stroke predicted length of stay fromadmission characteristicsBackground:Ischemic stroke (IS), a commonly aged disease, isassociated with high disability and handicap(ranging from60%to70%),about25%stroke patient recurrence, high mortality in the acutephase(ranging from13to27%in the first month and from18to33%inthe first3months). And, only10%of stroke patients recover completely.Ischemic stroke is a heavy economic and health burden for the patients,society and health services regardless of developed countries anddeveloping countries, including prolonged length of stay (LOS),increased cost of hospitalization, long-term disability, and death. From ahealth economics perspective, LOS is an important surrogate marker forefficiency and is a principal target for cost containment, and should beconsidered along with the incidence and prevalence of diseases andassociated medical expenses. However, LOS is an index of the quantity ofmedical services whose perspective differs from that of medical expenses. There are differences in ethnic group, therapeutics and care to diseases,medical insurance status, hospital types, primary care,admission/discharge policies, and socio-cultural environment amongstdifferent countries and areas. That is, the same LOS can result indifferences in medical expenses according to disease severity, and theLOS can differ from the same medical expenses, depending on the type ofdisease. LOS and medical expenses can result in differences due todifferent types of hospitals and discrepancy treatment of same diseases.Predictor factors of LOS by admission characteristics, and evaluation aswell as influential factors of costs in ischemic stroke patients had beenwidely studied. LOS was not only a factor in determining inpatientshort-term prognosis but also a direct or indirect indicator of long-termsurvival. Accurate estimates and predictors of LOS were important forstroke patients, their families and society. For medical institutions,precise prediction of LOS facilitated flexibility in managing bedoccupancy, and the effectiveness of various treatments and clinicalmanagement can be investigated by analysis of LOS. For the nationalinsurance authority, surveying LOS between hospitals at the same ordifferent levels, comparing LOS between areas, assessing thecost-effectiveness of current treatment strategies, and preparingrandomized trials for outcome oriented evaluations also depend onaccurate LOS predictions. As yet,only little information had been explored about the evaluation amongst admission characteristics and LOS,and evaluation as well as influential factors of costs for ischemic stroke inChina.Objective: To investigate relation between hospital LOS andadmission characteristics, and costs as well as its subtypes correlated withmedical insurance status inpatients with ischemic stroke. At the sametime, evidences of theory and practice were demonstrated for clinicalpaths of diseases, prevention and cure of diseases, and health care reform.Methods: We retrospectively collected data on557consecutivepatients with principal diagnosis of ischemic stroke in an ordinary tertiarygeneral hospitals in a medium-sized city in China for1years, includingdemographic characteristics (age and gender), medical insurancestatus(new cooperative medical scheme (NCMS) and state medicine),previous history(prior stroke, smoker, and alcohol consumption),comorbidity/risk factors(hypertensive disease, diabetes mellitus, coronaryheart disease(CHD), chronic obstructive pulmonary disease(COPD), andhyperlipidemia), stroke severity on admission(National Institutes ofHealth Stroke Scale (NIHSS) scores, Glasgow coma scale(GCS) scores,and Functional Independence Measure(FIM) motor and cognitive scores),Oxfordshire Community Stroke Project(OCSP) classification, laboratorytests on admission(complete blood count,and blood fat examination). Theassociation between the above-mentioned parameters and LOS of inpatients with ischemic stroke was estimated by univariate analysis andmultivariate regression model. To avoid overfitting the model, variableswere found to be significant(P≤0.10) in the univariate analysis wereincluded. The costs and its subtypes(drugs costs, diagnostics costs,nursing care costs, imaging costs, therapeutics costs, laboratory analysiscosts, accommodation costs, and non-medical carecosts) wereinvestigated between state medicine and NCMSResults: The mean LOS was18.5±13.7d (median=16d,25th–75thpercentile=8.5-23.5d) in inpatients with ischemic stroke. The univariateanalysis showed that variables included medical insurance status, priorstroke, hypertensive disease, CHD, diabetes mellitus, COPD,hyperlipidemia, comorbidity numbers, stroke severity onadmission(NIHSS scores, GCS scores, and FIM motor and cognitivescores), OCSP classification, and some items of laboratory tests onadmission(triglyceride, very low density lipoprotein cholesterol, andwhite blood cell) were significantly associated with LOS (P value <0.1).Age variable (P=0.12) was entranced multivariate regression modelbecause some studies believed that relation of age and LOS wassignificant. Our analysis demonstrated that medical insurance status,stroke severity on admission (NIHSS scores, FIM cognitive and motorscores, GCS scores), OCSP classification, some comorbidities (CHD,COPD, and hyperlipemia), and raised white blood cell were the main explanatory factors for LOS by stepwise multiple regressionmodel(P<0.05). Especially, medical insurance status, FIM cognitivescores, GCS scores, OCSP classification, and CHD were the strongestpredictors(P<0.0001). The negative sign of some variables indicated thatit was inversely associated with LOS. This model explainedapproximately30%of the total variance of LOS.Conclusion: Medical insurance status, stroke severity on admission,OCSP classification, some comorbidities, and raised white blood cell atadmission may help to predict LOS for ischemic stroke patients.Healthcare expenditures were heavy burdens to inhabitants. Statemedicine patients could shorten unnecessary LOS to improve theresources allocation and cost-efficiency. Chapter2Ischemic stroke was associated with CD40-1C/Tsingle nucleotide polymorphismBackground: Ischemic stroke(IS), one of the most common types ofstroke is a highly complex disease consisting of a group of heterogeneousdisorders with multiple genetic and environmental risk factors, andviewed as a paradigm for late-onset, complex polygenic disease. Thepathophysiology of ischemic stroke was known to including both pro-thrombotic and pro-atherosclerosis components which was chronicinflammatory process. Smoking may predispose individuals toatherogenic and thrombotic problems, significantly increasing the risk forstroke. Chiefs among these including age (the single most important riskfactor), hypertension, coronary heart disease, diabetes mellitus, obesity,hyperlipidemia, sickle cell disease, and hyperhomocysteinemia and otherdiseases were strongly correlated with cerebrovascular accidents. Geneticfactors accounted for66%to74.9%of the total variation of ischemicstroke. Multiple genetic predisposing genes have been identified, andwere involved in the development of stroke. Candidate genes includedthose genes which related to hemostasis system, the ACE gene of renin-angiotensin-aldosterone system, MTHFR gene in homocysteine,lipoprotein metabolism, and so on. However, single genetic susceptibilitygene explained only a small fraction of the inherited risk andpathogenesis of ischemic stroke. Better knowledge of the geneticbackground and disease susceptibility genes would probably help usconfirm early diagnosis and treatment on right subjects and improveischemic stroke outcome in the affected patients.CD40is a membrane glycoprotein that is a member of tumornecrosis factor receptor superfamily, and is expressed by a wide range ofcell types which included lymphocytes, monocytes, macrophages,platelets, dendritic cells, endothelial cells, as well as neuronal cells. CD40 played an important role in neuronal development, maintenance andprotection in vitro and in vivo. CD40deficiency would lead to nerve celldysfunction. In the central nervous system, CD40is markedlyupregulated after inflammatory stimulation on a variety of cells, includingmicroglia, astrocytes, smooth muscle cells, and vascular endothelial cells.And, CD40was associated with the expansion of the lesion in ischemicstroke. It was indicated that CD40gene was important in pathogenesis ofischemic stroke. To date, a lot of studies focused on5'-untranslatedregion mutation (5'-UTR) in CD40to determine the association betweensingle nucleotide polymorphism(SNP) of CD40and diseases geneticsusceptibility. A functional polymorphism (-1C/T, rs1883832) in the5'-UTR of CD40gene has been reported to affect CD40expression andbe associated with several chronic inflammatory and autoimmunediseases, such as acute coronary syndrome, breast cancer, Graves' disease,chronic obstructive pulmonary disease(COPD), lymphoma, multiplesclerosis. To our best knowledge, the association between the CD40-1C/T SNP(rs1883832) and ischemic stroke has not been reported.Objective: To investigate the association of CD40-1C/Tpolymorphism (rs1883832) with ischemic stroke risk in a case-controlstudy of ischemic stroke patients and control subjects derived from thegeneral Chinese population. The association between CD40-1C/T SNPand risk factors, TOAST classification, and stroke severity on admission(NIHSS scale) was estimated by stratified analyses in ischemicstroke patients. It was evaluated that CD40-1C/T polymorphism wasimportant in pathogenesis of ischemic stroke in gene level, and providedthe theory foundation for the diagnosis, therapy and precaution ofischemic stroke.Methods: The investigation was conducted by case-control study,including286patients with ischemic stroke and336health controls. The-1C/T polymorphism (rs1883832) in CD40was genotyped by polymerasechain reaction-restriction fragment length polymorphism(PCR-RFLP)and direct sequencing. Hardy-Weinberg equilibrium (HWE) wasevaluated by the chi-square test. The genotype and allele frequencies ofCD40-1C/T polymorphisms between the cases and controls wereevaluated by the chi-square test or Fisher's exact test. The associationbetween the genotype and ischemic stroke risk was estimated bymultivariate logistic regression analyses after adjusting by gender, age,and smoking status. Stratified analyses in cases were estimated using thechi-square test or Fisher's exact test. A two-sided P value <0.05wastaken as the level for statistical significance. The relative risk associatedwith rare alleles was analyzed by an odds ratio (OR) with a95%confidence interval (CI).Results: Genotype distributions of the CD40-1C/T polymorphism(rs1883832) in control subjects were in agreement with that expected under the HWE(P>0.05). It was indicated that our samples can representthe group in the area. There were CC, CT, and TT genotype in-1C/Tpolymorphism of CD40gene in both cases and controls. The frequency ofthe allele C of CD40-1C/T polymorphism in controls and ischemic strokepatients was59.08%and53.15%, respectively; and the frequency of theallele T was40.92%and46.85%, respectively. The frequency of the alleleT of CD40-1C/T polymorphism in ischemic stroke patients held asignificantly higher risk of ischemic stroke when compared to healthycontrols(P=0.036, OR=0.786,95%CI=0.627-0.984). The frequency of-1CT genotypes of CD40(68.53%) in ischemic stroke patients weresignificantly higher than that of healthy controls(51.49%). There wassignificant difference between cases and healthy controls(P=0.049,OR=1.605,95%CI=1.000-2.576). And, after adjusting by sex, age, andsmoking status, similar results were obtained(P=0.045, OR=1.658,95%CI=1.099-2.783). However, we failed to find that the CC and CC/CTgenotypes of CD40-1C/T polymorphism were associated betweenischemic stroke patients and healthy controls (even after adjusting by sex,age, and smoking status), respectively(p>0.05). Stratified analysisaccorded with environmental risk factors by heterozygote comparisonmodel(TT vs CT) and homozygote comparison model(TT vs CC),respectively. We found that the CC genotypes was significantly differentcompared with TT genotype in subjects with history of stroke(P=0.003, OR=0.153,95%CI=0.039-0.604). No significant difference was foundunder heterozygote comparison model. However, there was nosignificance between susceptibility to ischemic stroke and demographiccharacteristics (gender, and age according to median), risk factors(obesity,smoking status, hypertensive disease, diabetes mellitus, CHD, andhyperlipidemia), stroke severity on admission(NIHSS scale according tomedian), as well as TOAST classification (P>0.05). However, noevidence of gene-environment interaction was found.Conclusions: The present study provides evidence that CD40-1C/Tpolymorphism was associated with a significantly increased risk ofischemic stroke in a Chinese population, indicating that the CD40-1C/Tpolymorphism contributed to the pathogenesis of ischemic stroke.