Antifungal Therapy with Azoles Induced the Syndrome of Acquired Apparent Mineralocorticoid Excess: a Literature and Database Analysis.

We aimed to estimate the risk of varied antifungal therapy with azoles causing the syndrome of acquired apparent mineralocorticoid excess (AME) in real-world practice. First, we conducted a disproportionality analysis based on data from the FDA Adverse Event Reporting System (FAERS) database to characterize the signal differences of triazoles-related AME. Second, a systematic review was conducted, and clinical features of AME cases reported in clinical practice were described. In the FAERS database, we identified 27 cases of triazoles-AME, posaconazole [ROR = 865.37; 95%CI (464.14; 1613.45)], and itraconazole [ROR = 556.21; 95% (303.05; 1020.85)] significantly increased the risk of AME events, while fluconazole, voriconazole, and isavuconazole did not affect any of the mineralocorticoid excess targets. Eighteen studies with 39 cases raised evidence of AME following posaconazole and itraconazole treatment, and another 27 cases were identified by analysis of the description of clinical features in the FAERS database. The average age of 66 patients was 55.5 years (6-87 years). AME mainly occurs in patients with posaconazole concentrations above 3 µg/mL (mean = 4.4 µg/mL, range 1.8∼9.5 µg/mL), and is less likely to occur when levels are below 2 µg/mL (6%). The median time to event onset was 11.5 weeks, and 50% of the adverse events occurred within 3 months for posaconazole. The presented study supports very recent findings that posaconazole and itraconazole, but not the other three azole antifungals investigated, are associated with AME and that the effects are dose-dependent, which allows for a dose de-escalation strategy and for substitution with fluconazole, isavuconazole, or voriconazole to resolve the adverse effects.

Economic and disease burden of Japanese encephalitis in Zhejiang Province, 2013-2018.

BACKGROUND: Japanese encephalitis (JE) is a mosquito-borne disease and associated with high mortality and disability rate among symptomatic cases. In the absence of local data, this study estimated the economic burden and the disability-adjusted life years (DALYs) due to JE in Zhejiang Province, China during 2013-2018, to increase disease awareness and provide evidence for effective health policy. METHODOLOGY/PRINCIPLE FINDINGS: We merged multiple data sources, including National Notifiable Disease Registry System (NNDRS), patient interviews and medical records from corresponding hospitals for JE cases which occurred during 2013-2018 in Zhejiang Province. Direct costs were extracted from hospitals' billing systems and patient interviews. Indirect costs and disease burden were calculated based on questionnaire survey from patient interviews and follow-up assessment by general practitioners. Given under-reporting, an expansion factor (EF) was applied to extrapolate the JE burden to the provincial level. The total economic burden of JE during 2013-2018 was estimated at US $12.01 million with an EF = 3. Of this, $8.32 million was due to direct economic cost and $3.69 million to indirect cost. The disease burden of JE was 42.75 DALYs per million population (28.44 YLD, 14.28 YLL) according to the 1990 Global Burden of Disease (GBD 1990) methodology and 80.01 DALYs (53.67YLD, 26.34YLL) according to the GBD 2010 methodology. Sensitivity analysis demonstrated that the overall economic burden varied from US$ 1.73-36.42 million. The greatest variation was due to the prognosis of illness (-85.57%-203.17%), followed by occupation (-34.07%-134.12%) and age (-72.97%-47.69%). CONCLUSIONS/SIGNIFICANCE: JE imposes a heavy burden for families and society in Zhejiang Province. This study provides comprehensive empirical estimates of JE burden to increase awareness and strengthen knowledge of the public. These data may support provincial level public health decision making for prevention and control of JE. Ongoing surveillance for acute meningitis and encephalitis syndrome (AEMS) in sentinel hospitals, is needed to further refine estimates of JE burden.

Serological and molecular epidemiology of Japanese Encephalitis in Zhejiang, China, 2015-2018.

BACKGROUND: Shifts have occurred in the epidemiological characteristics of Japanese encephalitis (JE), extending from the molecular level to the population level. The aim of this study was to investigate the seroprevalence of JE neutralizing antibodies in healthy populations from different age groups in Zhejiang Province, and to conduct mosquito monitoring to evaluate the infection rate of Japanese encephalitis virus (JEV) among vectors, as well as the molecular characteristics of the E gene of isolated JEV strains. METHODOLOGY/PRINCIPAL FINDINGS: A total of 1190 sera samples were screened by a microseroneutralization test, including 429 infants (28d-11m) and 761 participants (2y-82y). For those under 1 year old, the geometric mean titers (GMTs) of the JE neutralizing antibody was 9.49 at birth and significantly declined as the age of month increased (r = -0.225, P<0.001). For those above 1-year old, seropositive proportions were higher in subjects aged 1-3 years old as well as ≥25 years old (65%-75%), and relatively lower in subjects aged between 4-25 years old (22%-55%). Four or more years after the 2nd dose of JEV-L (first dose administered at 8 months and the second at 2 years of age), the seropositive proportion decreased to 32.5%, and GMTs decreased to 8.08. A total of 87,201 mosquitoes were collected from livestock sheds in 6 surveillance sites during 2015-2018, from which 139 E gene sequences were successfully amplified. The annual infection rate according to bias-corrected maximum likelihood estimation of JEV in Culex tritaeniorhynchus was 1.56, 2.36, 5.65 and 1.77 per 1000, respectively. JEV strains isolated during 2015-2018 all belonged to Genotype I. The E gene of amplified 139 samples differed from the JEV-L vaccine strain at fourteen amino acid residues, including the eight key residues related to virulence and virus attenuation. No divergence was observed at the sites related to antigenicity. CONCLUSIONS/SIGNIFICANCE: Zhejiang Province was at a high risk of JE exposure due to relatively lower neutralizing antibody levels among the younger-aged population and higher infection rates of JEV in mosquitoes. Continuous, timely and full coverage of JE vaccination are essential, as well as the separation of human living areas and livestock shed areas. In addition, annual mosquito surveillance and periodic antibody level monitoring are important for providing evidence for improvement in JE vaccines and immunization schedules.

Human papillomavirus vaccine-associated premature ovarian insufficiency and related adverse events: data mining of Vaccine Adverse Event Reporting System.

We detected disproportionate reports of premature ovarian insufficiency (POI) and related events, including amenorrhea, menstruation irregular, FSH increased, and premature menopause, following human papillomavirus (HPV) vaccine from FDA Vaccine Adverse Event Reporting System (VAERS). The signal was detected by the methods of Bayesian Confidence Propagation Neural Network (BCPNN) and Multi-item Gamma Poisson Shrinker (MGPS). When both methods detected a positive result, a signal was generated. Besides, time-scan map is drawn based on the IC value and 95%CI of BCPNN, if the IC curve showed a steady upward trend and the 95%CI narrowed, the signal was stable and strong association.The results showed that there were not POI reports of HPV vaccine, but VAERS received a total of 2, 389, 27 POI related events for HPV2, HPV4, HPV9 respectively from the year of marketed to 2018. No signal was detected for HPV2. HPV4-POI ralated events were all detected as signals by two methods. There was only one signal of menstruation irregular for HPV9. Time scan of HPV4-POI ralated events showed those signals were stability and strong association, but not for HPV9. Our results only represent statistical association between HPV vaccine and POI related events, causal relationship needs further investigation.

Cardiovascular risk of sitagliptin in treating patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (T2DM) have a very high risk of cardiovascular related events, and reducing complications is an important evaluation criterion of efficacy and safety of hypoglycemic drugs. Previous studies have shown that the dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP4i), such as sitagliptin, might reduce the incidence of major cardiovascular events (MACEs). However, the safety and efficacy of sitagliptin remains controversial, especially the safety for cardiovascular related events. Here, a systematic review was conducted to assess the cardiovascular safety of sitagliptin in T2DM patients. The literature research dating up to October 2018 was performed in the electronic database. The clinical trials about sitagliptin for T2DM patients were included. Two reviewers independently screened literature according to the inclusion and exclusion criteria. The primary outcome was the MACE, and the secondary outcome was all-cause mortality. Finally, 32 clinical trials composed of 16082 T2DM patients were included in this meta-analysis. The results showed that: there was no significant difference between sitagliptin group and the control group on MACE (odds ratio (OR) = 0.85, 95% confidence intervals (CIs) = 0.63-1.15), myocardial infarction (MI) (OR = 0.66, 95% CI = 0.38-1.16), stroke (OR = 0.83, 95% CI = 0.44-1.54) and mortality (OR = 0.52, 95% CI = 0.26-1.07). These results demonstrated that sitagliptin did not increase the risk of cardiovascular events in patients with T2DM.

Adverse Event Profiles of Anti-CTLA-4 and Anti-PD-1 Monoclonal Antibodies Alone or in Combination: Analysis of Spontaneous Reports Submitted to FAERS.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs)-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1) monoclonal antibodies (mAbs)-either as single agents or in combination have become the standard of care for an increasing number of indications. Understanding both the ICI-associated adverse events (AEs) and the possible rank-order of these drugs in terms of susceptibility is essential if we are to improve the curative effect and reduce toxicity. METHODS: We detected signals of the AEs of ICIs by data mining using the US Food and Drug Administration (FDA) AEs Reporting System (FAERS) database. The definition relied on the preferred terms (PTs) and the standardized MedDRA Queries (SMQs) provided by the Medical Dictionary for Regulatory Activities (MedDRA). Disproportionality analysis was performed by calculating the reporting odds ratios (ROR) with 95% confidence intervals (CIs). RESULTS: Adverse effects of CTLA-4 and PD-1 mAbs were most commonly observed in the skin, gastrointestinal tract, endocrine systems, liver, and lung, and they included rash, diarrhea, colitis, and thyroid dysfunction. Thyroid dysfunction, type 1 diabetes mellitus, and pneumonitis were more closely associated with the use of anti-PD-1, whereas colitis, diarrhea, hypophysitis, and adrenal insufficiency were more closely associated with anti-CTLA-4; rash and hepatitis occurred similarly in both. Disproportionality signals for less common AEs in other organ systems, including the renal, neurological, cardiac, ocular, musculoskeletal, and hematologic systems, were also detected. Nivolumab and pembrolizumab have very similar safety profiles, but the signal strength of AEs increased when combined with ipilimumab. CONCLUSIONS: The results of this study are in agreement with clinical observations, suggesting the usefulness of pharmacovigilance in "real-world" safety monitoring.

Adverse drug events in Chinese pediatric inpatients and associated risk factors: a retrospective review using the Global Trigger Tool.

Understanding the epidemiology and risk factors of adverse drug events (ADEs) in pediatric inpatient is essential if we are to prevent, reduce or ameliorate the harm experienced. The Global Trigger Tool (GTT) is a method of retrospective medical record review that measures harm in hospitalized children. We employed a three-stage retrospective chart review of random samples of 1800 pediatric inpatients discharged from January 2013 to December 2015. 31 kinds of pediatric-specific triggers were made based on the previous trigger tool studies developed for use in adult or pediatric. Positive predictive value (PPV) of individual triggers, as well as ADEs detection rates were calculated. Stepwise logistic regression was performed to investigate risk factors associated with ADEs. Of 1746 patients, detected in 221 patients (12.7%) with 247 ADEs. The PPV of the trigger tool was 13.3%. Of the 247 ADEs, 82.6% were identified as category E, 11.7% category F and 5.7% category H. The pediatric-focused trigger tool is a feasible and useful tool for detecting pediatric ADEs. Especially for patients who have had more drugs, more doses or more admissions which needs to be closely monitored as triggers to improve the safety.

Sero-Molecular Epidemiology of Japanese Encephalitis in Zhejiang, an Eastern Province of China.

BACKGROUND: Sporadic Japanese encephalitis (JE) cases still have been reported in Zhejiang Province in recent years, and concerns about vaccine cross-protection and population-level immunity have been raised off and on within the public health sphere. Genotype I (GI) has replaced GIII as the dominant genotype in Asian countries during the past few decades, which caused considerable concerns about the potential change of epidemiology characteristics and the vaccine effectiveness. The aim of this study was to investigate the prevalence of JE neutralizing antibody and its waning antibody trend after live attenuated JE vaccine immunization. Additionally, this study analyzed the molecular characteristics of the E gene of Zhejiang Japanese encephalitis virus (JEV) strains, and established genetic relationships with other JEV strains. METHODOLOGY/PRINCIPAL FINDINGS: A total of 570 serum specimens were sampled from community population aged from 0 to 92 years old in Xianju county of Zhejiang Province in 2013-2014. Microseroneutralization test results were analyzed to estimate the population immunity and to observe antibody dynamics in vaccinated children. E genes of 28 JEV strains isolated in Zhejiang Province were sequenced for phylogenetic tree construction and molecular characteristics analysis with other selected strains. Positive JE neutralizing antibody rates were higher in residents ≥35 years old (81%~98%) and lower in residents <35 years old (0~57%). 7 or 8 years after the 2nd live attenuated vaccine dose, the antibodies against for 4 different strains with microseroneutralization test were decreased by 55%~73% on seropositive rates and by 25%~38% on GMTs respectively. JEV strains isolated in recent years were all grouped into GI, while those isolated in the 1980s belonged to GIII. On important amino acid sites related to antigenicity, there was no divergence between the Zhejiang JE virus strains and the vaccine strain (SA14-14-2). CONCLUSION/SIGNIFICANCES: JE neutralizing antibody positive rates increase in age ≥10 years old population, likely reflecting natural infection or natural boosting of immunity through exposure to wild virus. JE seropositivity rates were quite low in <35 years old age groups in Zhejiang Province. Waning of neutralizing antibody after live attenuated vaccine immunization was observed, but the clinical significance should be further investigated. Both the peripheral antibody response and genetic characterization indicate that current live attenuated JE vaccine conferred equal neutralizing potency against GI or GIII of wild strains. GI has replaced GIII as the dominant genotype in Zhejiang in the past few decades. Although the chance of exposure to wild JE virus has reduced, the virus still circulates in nature; therefore, it is necessary to implement immunization program for children continually and to conduct surveillance activity periodically.

The dynamics of hypertension prevalence, awareness, treatment, control and associated factors in Chinese adults: results from CHNS 1991-2011.

OBJECTIVES: To analyze the trends in blood pressure (BP), and the prevalence, awareness, treatment and control of hypertension and associated factors in Chinese adults from 1991 to 2011. METHODS: On the basis of the longitudinal data of China Health and Nutrition Survey, 75 526 records of 24 410 adults were selected according to the eligibility criteria. The age-standardized levels of SBP, DBP, prevalence, awareness, treatment and control of hypertension were calculated by sex and age group within each year. Generalized estimating equation was employed to investigate the associations between demographic factors and status of hypertension, awareness, treatment and control. RESULTS: From 1991 to 2011, the BP level elevated (SBP 120.0-124.5 mmHg, DBP 76.7-79.3 mmHg) and the prevalence of hypertension increased from 23.4 to 28.6%. The increasing levels of BP and hypertension prevalence were more apparent among men and older patients. The rates of hypertension awareness, treatment and control also increased while kept at low levels. Factors such as age, sex, smoking habit, drinking habit, household income, health insurance, BMI, residential region, marital status, educational level and nationality were significantly associated with the status of hypertension, awareness, treatment and control. CONCLUSION: The BP level and hypertension prevalence have increased among Chinese adults in recent years. However, levels of hypertension awareness, treatment and control were quite low. To reduce the disease burden of the hypertension, improvements in health education programs, detection and treatment strategies are warranted.

[Analysis on coverage rate of primary immunization of measles vaccine among migrant children in Yiwu, Zhejiang province from 2007 to 2010].

OBJECTIVE: To investigate the coverage rate of primary immunization of measles containing vaccine (MCV1) among migrant children in Yiwu,Zhejiang province. METHODS: Household cluster sampling survey and probability proportion to size sampling method were adopted. A total of 967 migrant children born from 1st July 2007 to 1st July 2010 and their caregivers were selected as target population. Standard face-to-face interviews were conducted to investigate the subjects' knowledge, attitude, practice (KAP) of immunization, MCV1 vaccination and determinants. Multi-variable weighted average score method was adopted to evaluate the result of our survey on KAP. Kaplan-Meier analysis was adopted to assess the coverage of MCV1 and Cox regression analysis was adopted to explore the influencing factors associated with the coverage of MCV1. RESULTS: Out of the 967 children, 104 were born in 2007, accounting for 10.8%; 301 were born in 2008, accounting for 31.1%; 343 were born in 2009, accounting for 35.5% and 219 were born in 2010, accounting for 22.6%. Among the surveyed caregivers, 71.9% (695/967) were mothers and 90.2% (872/976) were migrant from other provinces. According to the result of survey on KAP among caregivers, 56.2% (543/967) scored ≥ 4 points on knowledge, 75.8% (734/967) scored ≥ 4 points on attitude and 48.7% (471/967) scored ≥ 4 points on behavior. 86.6% (838/967) of surveyed caregivers' education levels were under junior middle school.85.9% (831/967) of the migrant children were born in hospitals.36.3% (351/967) of the surveyed families' household income were under 2000 yuan per month.32.7% (316/967) of surveyed caregivers waited less than 15 min for immunization for each time. Coverage rate of MCV1 was 85.9% (831/967; 95%CI: 83.7%-88.1%). The timely coverage rates at 8 months, 12 months, and 24 months were 58.8% (569/967; 95%CI: 55.5%-62.1%), 88.2% (853/967; 95%CI: 86.0%-90.4%) and 98.6% (953/967; 95%CI: 97.8%-99.4%), respectively. The average age of MCV1 immunization for each birth cohort between 2007 and 2010 were 10.4, 10.1, 10.1 and 9.3 month, respectively; without statistical significance (χ(2) = 0.722, P = 0.398). According to the analysis by Cox regression, the caregivers aged ≤ 25 years (24.3% (235/967), RR = 1.520 (95%CI: 1.280-1.800)), the caregivers' education level above college (2.8% (27/967), RR = 3.841 (95%CI: 2.287-6.451)), delivered in county-level hospital (49.4% (478/967), RR = 6.048 (95%CI: 4.311-8.485)), household income > 4000 yuan per month (21.7% (210/967), RR = 1.366 (95%CI:1.163-1.604)), the average score of attitude towards immunization ≥ 4 points (75.9%(734/967), RR = 2.613 (95%CI: 1.026-6.655)), the average waiting time for each vaccination ≤ 15 min (32.7% (316/967), RR = 2.116 (95%CI: 1.341-3.339)) were the important factors to improve the timely immunization coverage rate of MCV1 among migrant children. CONCLUSION: The coverage of MCV1 were obviously delayed among migrant children in Yiwu, Zhejiang province. We suggest that the investigation of migrant children should be strengthened and remind or recall mechanism for immunization should be established. Increasing the open days for immunization clinics and reducing the waiting time for vaccination could also improve the coverage and timeliness of the MCV vaccination.

[Study on the molecular characteristics of Japanese encephalitis virus living in vector mosquitoes, in Zhejiang province, 2009 - 2010].

OBJECTIVE: To investigate the molecular characteristics of Japanese encephalitis virus (JEV) living in vector mosquitoes, from Zhejiang province. METHODS: A total of 13 620 mosquitoes were collected from the monitoring stations located in Cixi city and Xianju county in Zhejiang province, in July and August, 2009 - 2010. Nucleic acid of JEV from the mosquitoes was monitored by using real-time RT-PCR. The virus strains were isolated with BHK-21 cell line, with E genes of the isolated viruses amplified, sequenced and their phylogeny and homology analyzed. RESULTS: The positive rates of JEV for those mosquitoes collected in the stations of Cixi and Xianju were 17.0% (27/159) and 3.4% (1/29), respectively. Twenty-two JEV strains were isolated, accounted for 15.4% among the 143 batches of mosquitoes collected in 2010. All E genes in the 6 sequenced virus isolates contained 1500 nucleotides encoding 500 amino acids, in which no inserts and deletions were identified. The identity rates of nucleotide and amino acid in E gene were 99.2% - 99.8% and 100.0% among the 6 JEV strains isolated from Zhejiang, 99.1% - 99.3% and 99.2% - 99.8% between the Zhejiang strains in 2009 - 2010 and the Zhejiang strains in 2007 - 2008, respectively, 87.6% - 88.0% and 97.8% between the 6 Zhejiang strains and the vaccine strain SA14-14-2 of JEV, respectively. The phylogeny tree of E gene indicated that the JEV isolates in Zhejiang during 2009 - 2010 was located in the branch of the genotype I. CONCLUSION: Mosquitoes collected from Cixi and Xianju areas carried JEV, with the rate of JEV in Cixi higher than in Xianju. All the Zhejiang isolates in 2009 - 2010 were proven to be the genotype I of JEV.