Aspirin & clopidogrel non-responsiveness & its association with genetic polymorphisms in patients with myocardial infarction

Background & objectives: Cytochrome P450, P2Y 12, cyclooxygenase-1 (COX1) and glycoprotein V1 (GPVI) gene polymorphisms are known to affect patient responsiveness towards aspirin and clopidogrel dual antiplatelet therapy (DAPT). The present study was undertaken to identify aspirin and clopidogrel non-responsiveness and its association with genetic polymorphism in patients with myocardial infarction (MI). Methods: A total of 207 MI patients who were on DAPT, were included. The DAPT non-responsiveness was determined by light transmittance aggregometry using arachidonic acid and adenosine diphosphate and high platelet reactivity by collagen. Platelet activation biomarkers, thromboxane B2 (TxB2)andsoluble CD40 ligand (sCD40L) were measured in plasma. Patient compliance was checked by estimating drug and its metabolite levels (aspirin and clopidogrel) in plasma using liquid chromatography-mass spectrometry/mass spectrometry. Genomic DNA was extracted, amplified by polymerase chain reaction and subsequently sequenced to identify CYP450, P2Y 12, COX1 and GPVI gene polymorphisms. Results: Of the 207 patients, 32 were non-responders. The DAPT non-responsiveness was found in 15.5 per cent patients. The non-responsiveness showed a significant and an independent association with gender [odds ratio (OR)=0.18, 95% confidence interval (CI)=0.01-0.78, P=0.023], TxB2(OR=1.00, 95% CI=1.00-1.01, P=0.013), CYP2C19*2 G>A (OR=3.33, 95% CI=1.04-10.69, P=0.044) and GPVI T>C (OR=0.23, 95% CI=0.08-0.67, P=0.007) after adjusting the demographic, clinical and genetic confounding factors when assessed between non-responder and responder compliant patients. Interpretation & conclusions: The study showed a significant association of genetic polymorphisms (CYP2C19*2 G>A and GPVI T>C) with DAPT non-responsiveness in MI patients. The findings of this study need further validation in a large cohort of patients with clinical follow up.

A prospective cohort study on the risk of HBV infection in preschool children without immune response to hepatitis B vaccine / 中华疾病控制杂志

@# Objective To evaluate the risk of hepatitis B virus(HBV) infection among preschool children who were the non-responders to hepatitis B vaccine in future. Methods A prospective cohort study was conducted. Children aged 2 to 5 years were selected from 64 kindergartens.These children were inoculated three doses of hepatitis b vaccine at 0, 1 and 6 months after birth. Hepatitis B surface antigen (HBsAg)and Hepatitis B surface antibody (anti-HBs)were detected during the period from March to May 2015. The children who were HBsAg negative were enrolled in the study. The subjects were divided into exposure group (anti-HBs negative) and control group (anti-HBs positive) . The follow-up began on June 1, 2015 and ended on June 1, 2016. Serum HBsAg of children in the cohort was then collected and detected from June 1 to 30, 2016. At the end of the study, the HBsAg positive rates between two groups were compared. Results 83 children who received hepatitis B vaccine again during the follow-up period were excluded from 1 907 non-responders. The actual number in non-responders group was 1 824. 151 children were lost at the end of the study. The actual number of follow-up was 1 673 and 5 children were found to be positive for HBsAg and the infection rate was 0.30% (5/1673). In the respondent goup, 2 054 were enrolled and followed. Finally, 140 children were lost and none of the remaining 1 914 people were HBsAg positive at the end of the study. HBsAg positive rate was higher in the non-responder group than in the responder group (P=0.023). Conclusion There is a risk of HBV infection in the children who are non-responders to hepatitis B vaccine in future.

Safety and immunogenicity evaluation of 60μg recombinant hepatitis B vaccine (Saccharomyces Cerecisiae) in population aged 16 and above / 预防医学

Objective To evaluate the safety of 60μg recombinant hepatitis B vaccine(Saccharomyces Cerecisiae)in healthy population over 16 years old and immunogenicity in non-responders.Methods A total of 4345 eligible subjects over 16 years old were selected and vaccinated with 60 μg recombinant hepatitis B vaccine, including 3415 participants who have never been vaccined before and 930 non-responders. All participants were monitored for any adverse events occurring within 30 min after each injection and instructed to record selected injection-site reactions and systemic reactions on the day of vaccination and the subsequent 28 days. Blood samples were collected from non-responders at pre-vaccination and one month after vaccination,in order to determine anti-HBs levels,positive rates of anti-HBs and the mean geometric titre(GMT)of anti-HBs.Results Among 4345 vaccinated participants,16.39 % of them reported at least one injection-site or systemic adverse reaction. The most common injection-site and systemic adverse reactions were Grade 1 adverse reactions with the incidence of 15.12 %(657/4345)and 4.05%(176/4345)respectively. No serious adverse events were observed. Among 930 non-responders,the positive rate of anti-HBs was 87.03 % with active responder of 76.74 %(551 / 718)and the GMT of anti-HBs was 479.28 mIU / ml. The positive rate of anti-HBs was not associated with gender or age (P>0.05). The GMT of anti-HBs demonstrated significant differences between female and male(560.66 mIU / mL VS. 404.91 mIU / mL,P<0.05),but there was no significant differences in different age groups (P>0.05).Conclusion 60μg recombinant hepatitis B vaccine was safe for healthy adults above 16 years and had good immunity efficacy among non-responders who had no or low response to standard immunization regimen of hepatitis B vaccine.

Prevalence of non-responsiveness to an indigenous recombinant hepatitis B vaccine: A study among South Indian health care workers in a tertiary hospital.

Background and Aim: Health care workers (HCW) are at higher risk of contracting HBV infection. Non-response to HBV vaccine is one of the major impediments to prevent healthcare associated HBV infection (HAHI). We estimated the prevalence of non-responsiveness to initial 3-dose regimen of an indigenous recombinant HBV vaccine (GeneVac-B) among South Indian HCWs and typed the HLA in non-responders. Study Design and Method: Of the 778 subjects screened over 1 year, 454 completed all three doses of the hepatitis B vaccination. Anti-HBs titers were estimated by microparticle enzyme immunoassay AxSYM AUSAB, (Abbott, Germany). HLA typing was done using SSP-PCR assay AllSet+™ Gold SSP (Invitrogen, USA). Results: The overall seroconversion rate (anti-HBs > 10 mIU/mL) was 98.89% wherein 90.8% had titers >1000mIU/mL, 7.6% had titers 100–1000mIU/mL, 0.43% had titers < 100 mIU/mL and 1.1% were non-responsive (<10 mIU/mL) to the initial 3-dose regimen. Antibody titers <1000 mIU/mL were signifi cantly associated with the highest quartile of body mass index (BMI) (P < 0.001). We found no signifi cant difference in seroprotection rate between gender (P = 0.088). There was no difference in seroprotection rates among various ethnic groups (P = 0.62). Subjects who were non-responsive in our study had at least one HLA allele earlier known to be associated with non-responsiveness to the vaccine. Conclusion: Our fi ndings suggest that non-response to HBV vaccine is not a major impediment to prevent HAHI. Robust seroprotection rates can be achieved using this indigenous HBV vaccine. However, gender and BMI might infl uence the level of anti-HBs titers. We recommend the use of this cost effective HBV vaccine as well as postvaccination anti-HBs testing to prevent HAHI among HCWs.

Revisiting epidermal growth factor receptor in glioblastoma multiforme: Does it play a role in response to therapy.

Background and Aim: Glioblastoma multiforme (GBM) are the most aggressive class of cancer of central nervous system with hallmark characteristics that include rampant proliferation, necrosis, and endothelial proliferation. Epidermal growth factor receptor (EGFR) has been implicated as the primary contributor to glioblastoma initiation and succession. The present study was designed to evaluate EGFR protein expression in GBM as predictor of response to therapy and survival. Materials and Methods: Epidermal growth factor receptor was assessed by immunohistochemistry as a percentage of positive tumor cells in hot spots (10 high-power fields). The study group comprised of 35 cases of GBM. All cases underwent surgical resection and subsequently underwent radiotherapy (n = 17) or radiotherapy with adjuvant temozolomide chemotherapy (n = 18). Immediate response to therapy was assessed at 3 months using World Health Organization response evaluation criteria in solid tumors criteria and cases followed up for survival. Results: Twenty-four cases (68.6%) expressed EGFR while 11/35 (31.4%) cases were negative. Response to therapy was evident in 21/35 cases (60.0%) and 14/35 were (40.0%) nonresponders. Mean EGFR protein expression in responders was 37.23 ± 33.70 and in nonresponders was 59.5 ± 39.46 (P = 0.542). The percentage of responders which were EGFR negative was 72.7% and while response in EGFR positive cases was observed in 54.2%. Mean survival in EGFR positive and negative GBM was 394.37 ± 189.11 and 420.54 ± 191.23 days, respectively. Conclusion: The EGFR negative cases appear to respond better to therapy, however, the difference is not statistically significant (P = 0.298). Further, EGFR protein expression does not play a definitive role in predicting survival. This is an original study evaluating EGFR in terms of therapeutic response.

HPV vaginal self-sampling among women non-adherent to Papanicolaou screening in Chile / Autotoma vaginal para detección de virus del papiloma humano en mujeres no adherentes a tamizaje con Papanicolaou en Chile

OBJECTIVE: To evaluate acceptance, preference and compliance with referral of vaginal self-sampling for the detection of Human papillomavirus (HPV) among women non-adherent to Papanicolaou (Pap) screening in Santiago, Chile. MATERIALS AND METHODS: Using multistage sampling we identified women aged 30-64 years who reported not receiving a Pap test in the previous three years and offered them Pap testing at the health center or vaginal self-sampling for HPV testing at home. Self-collected samples were analyzed with hybrid capture. All HPV+ women were referred for colposcopy, biopsy and treatment when needed. RESULTS: 1 254 eligible women were contacted; 86.5% performed self-sampling and 8.1% refused; 124 women were HPV+ (11.4%: 95%CI 9.6-13.5) of whom 85.5% attended colposcopy; 12 had CIN2+ (1.1%: 95 %CI 0.5-1.7). CONCLUSION: HPV vaginal self-sampling can be easily implemented in Chile and could improve coverage, successfully reaching women who drop out of the screening program.

OBJETIVO: Evaluar la aceptación, preferencia y adherencia a seguimiento de la autotoma vaginal para detección del virus del papiloma humano (VPH) en mujeres inasistentes a Papanicolaou (Pap) en Santiago, Chile. MATERIAL Y MÉTODOS: Mediante un muestreo polietápico se identificaron mujeres entre 30 y 64 años inasistentes a Pap por < 3 años, invitándolas a realizarse un Pap en su centro de salud o una autotoma vaginal a domicilio. Las muestras fueron analizadas con captura de híbridos. Las mujeres VPH+ fueron referidas a colposcopía, biopsia y tratamiento en caso necesario. RESULTADOS: 1 254 mujeres elegibles fueron contactadas; 86.5% aceptó la autotoma vaginal y 8.1% la rechazó; 124 mujeres resultaron VPH+ (11.4%: IC95% 9.6-13.5) de las que 85.5% asistió a colposcopía; 12 tenían CIN2+ (1.1%: IC95% 0.5-1.7). CONCLUSIÓN: La autotoma vaginal para detección de VPH es implementable en Chile y su utilización podría mejorar la cobertura del programa rescatando a mujeres inasistentes.

Bone Response to Hormone Therapy according to Basal Bone Mineral Density and Previous Response to Hormone Therapy / 대한폐경학회지

OBJECTIVES: To investigate bone responses to hormone therapy (HT) according to basal bone mineral density (BMD) and previous responses to HT, as well as the frequency and clinical characteristics of HT non-responders in Korean postmenopausal women. METHODS: We retrospectively reviewed a total of 1,836 postmenopausal women who received HT from seven university hospitals. BMD data at the lumbar spine (LS), femur neck (FN), femur trochanter (FT) and total hip (TH) before HT, and at one, two, and three years after HT were collected. All patients were divided into three groups according to basal BMD: normal, osteopenia, and osteoporosis. RESULTS: Women with a greater loss of BMD during the first year of HT were more likely to gain BMD in the second year at any of the four skeletal sites. Bone responses to HT during the third year were not related to the responses during the first year. Mean BMD changes during the first year were significantly higher in the osteoporosis group, but mean BMD changes during the second year were not different between three groups except in LS. The frequency of non-responder (annual BMD losses more than 3%) during the first year was significantly higher in the normal basal BMD group. Mean basal BMDs were higher in the two-year consecutive non-responder group at LS, FN and FT, but those of the three-year consecutive non-responder group were not significantly higher except in FN. CONCLUSION: Most women who lose BMD after HT are likely to gain BMD during the next year. The frequency of non-responders is higher in the higher basal BMD group, and patients with lower basal BMD will be likely to respond better to HT.

Kawasaki Disease: Laboratory Findings and an Immunopathogenesis on the Premise of a "Protein Homeostasis System"

Kawasaki disease (KD) is a self-limited systemic inflammatory illness, and coronary artery lesions (CALs) are a major complication determining the prognosis of the disease. Epidemiologic studies in Asian children suggest that the etiologic agent(s) of KD may be associated with environmental changes. Laboratory findings are useful for the diagnosis of incomplete KD, and they can guide the next-step in treatment of initial intravenous immunoglobulin non-responders. CALs seem to develop in the early stages of the disease before a peak in inflammation. Therefore early treatment, before the peak in inflammation, is mandatory to reduce the risk of CAL progression and severity of CALs. The immunopathogenesis of KD is more likely that of acute rheumatic fever than scarlet fever. A hypothetical pathogenesis of KD is proposed under the premise of a "protein homeostasis system"; where innate and adaptive immune cells control pathogenic proteins that are toxic to host cells at a molecular level. After an infection of unknown KD pathogen(s), the pathogenic proteins produced from an unknown focus, spread and bind to endothelial cells of coronary arteries as main target cells. To control the action of pathogenic proteins and/or substances from the injured cells, immune cells are activated. Initially, non-specific T cells and non-specific antibodies are involved in this reaction, while hyperactivated immune cells produce various cytokines, leading to a cytokine imbalance associated with further endothelial cell injury. After the emergence of specific T cells and specific antibodies against the pathogenic proteins, tissue injury ceases and a repair reaction begins with the immune cells.

Management of HCV infection: Current issues and future options.

Hepatitis C virus (HCV) is a common cause of chronic liver disease (CLD). Presently the standard regime comprises a combination of PEG-IFN and ribavirin. Sustained virologic response (SVR) is defined as the absence of HCV RNA in the serum six months after the end of treatment . With standard treatment, in patients with genotype1 infections, SVR lies between 42% to 56%, whereas for genotypes 2 and 3 the SVR is from 76% to 82%. Thus, a large percentage of patients fail to achieve SVR even with improvised standard treatment. Such patients may be divided initially into relapsers and nonresponders. The decision to re-treat should be based on the presence of clinical, virological and histological factors that predict the possibility of successful outcome with further therapy. Both the type of previous therapy and previous response are very important factors in guiding re-treatment. The development of new therapeutic agents is critical for further improvement in the management of chronic hepatitis C as current therapeutic options have rather low efficacy in certain subgroups, such as those with HCV genotype 1 or patients with advanced liver disease, and most probably in nonresponders and relapsers. Moreover, pegylated IFNa and/or ribavirin are associated with frequent side effects and have a negative impact on the patient’s quality of life. Therefore, the development of new effective and safe drugs is a matter of significant clinical importance.

Comparison of the seroconversion rate after primary hepatitis B vaccination and after revaccination of non-responders in full-term infants according to mother's HBsAg seropositivity / 소아과

PURPOSE: This study aimed to identify the true extent of non-responsiveness in full-term infants born from HBsAg-negative or HBsAg-positive mothers and vaccinated against hepatitis B virus (HBV) at 0, 1, and 6 months of age and to evaluate the effect of revaccination among non-responders. METHODS: The study included 716 full-term infants born in 2004-2007. Of 716, 662 infants (A group) were born to HBsAg- negative mothers and 54 infants (B group: 50, except HBsAg-positive infants) were born to HBsAg-positive mothers. All infants were administered DNA recombinant vaccines at 0, 1, and 6 months of age. B group infants received hepatitis B immunoglobulin at birth. Anti-HBs titers were tested at 7-12 and 9-15 months in A and B groups, respectively. Three revaccination doses were administered to non-responders whose anti-HBs titers were under 10 mIU/ml; revaccinated infants were retested at 1-3 months after last vaccination. The association between HBeAg seropositivity of mother and the failure of HBV immunoprophylaxis was evaluated. RESULTS: The seroconversion rates after primary hepatitis B vaccination were higher in A group (94.1%) than in B group (78%, P<0.001). The seroconversion rates were high in revaccinated infants (A group non-responders: 96.9%, B group non- responders: 87.5%). The failure of HBV immunoprophylaxis was significantly associated with maternal HBeAg seropositivity (P<0.001). CONCLUSION: The seroconversion rates after primary hepatitis B vaccination were low in B group infants. Revaccination of non-responders in B group was very effective. Therefore, anti-HBs testing and revaccination of B group is very important. Revaccination of non-responders in A group was also very effective. Thus, testing the immune status of infants born to HBsAg-negative mothers even after primary hepatitis B vaccination should be considered. However, to realize this, further studies on the cost-effectiveness of anti-HBs testing in healthy full-term infants are necessary.

Coronary Complication according to Retreatment of Immune Globulin in Kawasaki Disease

PURPOSE: Recently most of patients with Kawasaki disease (KD) get treatment within several days of illness. But, some patients still suffer from coronary complication (CC) despite early initial treatment with intravenous immune globulin (IVIG) and even the additional therapy. We investigated the risk factors of CC in non-responders to initial therapy who needed additional IVIG infusion among patients with KD. METHODS: Forty five non-responders to initial IVIG who got additional IVIG infusion were reviewed from 1996 to 2007. We devided patients into two groups with CC (group A, n=17) or without CC (group B, n=28). Clinical characteristics, timing of additional IVIG infusion and laboratory results were reviewed. And we investigated the differences between the two groups and tried to find risk factors of CC. RESULTS: In comparison between the two groups, CC, clinical characteristics and timing of IVIG infusion were not different between two groups. But, total febrile days were significantly longer and peak platelets counts were significantly higher in group A (P=0.006, P=0.013). On the logistic regression analysis, total febrile days longer than 10.5 days was the only risk factor of CC in these patients. CONCLUSION: Our results showed that patients with CC inspite of repeated IVIG therapy had longer fever duration. So, additional therapy besides re-treatment with IVIG aiming at shortening total duration of fever seems to be important in refractory KD to prevent CC.

The risk factors of the nonresponders after hepatitis B vaceinatio and the immunogenecity after a double-dose revaccination in the nonresponders

BACKGROUND: Korea is an endemic area of viral hepatitis B with a rate of 5~10% carrier state. Therefore, hepatitis B vaccination is performed nationwide. But 5~15% of healthy individuals fail to respond adequately to the vaccine and an approved guideline for the nonresponders has not been developed yet. This study is designed to identify risk factors for those who lack anti-HBs after hepatitis B vaccination and to document the results of a double-dose revaccination in such nonresponders to the primary vaccination. METHODS: From Feb. 1996 to Aug, 1997, we assessed 51 healthy subjects(HBs Ag negative, anti-HBs negative, anti-HBc negative and a normal LFT). All subjects were vaccinated with Hepavax- B, 1.0ml, 24 by a rapid schedule(0, 1, and 2 months) and 27 by a standard schedule(0, 1, and 6 months). Anti-HBs titers were evaluated 3 months after the third vaccine and assessed the nonre-sponders (anti-HBs titer<2mIu/ml) and the hyporesponders(2~10mK/ml). All 13 nonresponders were revaccinated with 2ml of Hepavax-B 3 months after the primary vaccination. Anti-HBs titers were evaluated 1 month later. RESULTS: The differences in age(p<0.01) and smoking amount(p<0.05) between the responders and the hypo and the nonresponders were statistically significant. There were more males and higher body mass index in the hypo and the nonresponders but not statistically significant. The seroconversion rate after the double-dose vaccination was 92.3%(12/13) with an average titer of 5K08mlU/ ml(1-132.4mIU/ml). CONCLUSIONS: Increase in age and smoking amount were the risk factors of the nonresponders after the primary vaccination. Most of the hypo and the nonresponders to the primary vaccination responded adequately to the double-dose revaccination.