[The protective effect of interleukin-5 in septic mice].

To investigate the protective effect of interleukin-5 (IL-5) in septic mice, male C57BL/6 mice were divided into three groups including sepsis group with intraperitoneal injection of lipopolysaccharide (LPS, 20 mg/kg), study group with combined IL-5 (1 µg per mouse) and LPS (20 mg/kg), control group with normal saline.Pathological changes were tested including lung, heart and kidney tissues. The serum cardiac troponin I (cTnI), serum creatinine (SCr), blood urea nitrogen (BUN), tumor necrosis factor α (TNFα), IL-6, IL-1ß, and the chemokine (C-X-C motif) ligand 1(CXCL1) were measured and the survival at 7 d after treatment were recorded. Compared with sepsis group, tissue damages of lung, heart and kidney in IL-5 intervention group were ameliorated. The cTnI, SCr, BUN levels in study group were significantly decreased at 24 h (P<0.05).In addition,TNFα was significantly decreased at 3 h (P<0.05), and CXCL1 decreased at 12 h (P<0.05), while IL-6 and IL-1ß were similar at each time point (P>0.05). The mortality at 7 d was less in IL-5 treatment group. In summary, IL-5 has a protective effect and reduces the inflammatory response in septic mice.

[Post-marketing observation on safety of inactivated enterovirus A71 vaccine (human diploid cell)].

Objective: To evaluate the post-marketing safety of inactivated Enterovirus type 71 (EV-A71) vaccine (human diploid cell) . Methods: A total of 20 191 healthy children aged 6 to 59 months were invited to receive 2 doses of EV-A71 vaccine in Zhejiang Province from September 2016 to December 2017. Child caregivers were followed up on the 4(th) or 5(th) day after each EV-A71 vaccination, and the incidence of local, systemic, and other adverse events within 3 days after vaccination was recorded to assess vaccine safety. Describe the differences in adverse events among children with different characteristics. Results: A total of 32 230 doses were observed in this study, of which 20 191 and 12 039 were vaccinated for the first and the second dose, respectively; and the incidence of adverse events within 3 days was 2.045% (413 doses) and 1.611% (194 doses), respectively. After the first and the second dose, the number of systemic adverse events was the highest, 371 and 175 cases, respectively, with an incidence of 1.837% and 1.454%, respectively; the number of local adverse events was the lowest, 14 and 2 doses, respectively, with an incidence of 0.069% and 0.017%. Local adverse events occurred after vaccination were generally mild, and only 2 patients had level of 3; among the systemic adverse events, 39 patients had a fever level of 3 or higher, accounting for 8.2% of the total fever. Most of the symptoms in the local adverse events did not require treatment, only 3 cases of vaccination site rash and 2 cases of pruritus were self-purchased drugs or outpatient treatment; except for 5 cases of fever, the other symptoms were not hospitalized in the case of systemic adverse events. Conclusion: The incidence of adverse events within 3 days after vaccination with EV-A71 vaccine was low in children, mainly systemic adverse events, and the prognosis was good.

[Post-marketing safety analysis of inactivated enterovirus A71 vaccines].

Objectives: To evaluate the safety of inactivated enterovirus A71(EV-A71) vaccines after large-scale immunization in the community. Methods: We selected EV-A71 susceptible people (healthy children) aged 6-59 months in vaccination clinics from 89 counties in Zhejiang Province between April 2016 and March 2018. All local and systematic adverse actions were collected by 30 min on-site inspection, within 3 days and 4-30 days follow-up. Chi-square test and Fisher's exact test were used to compare the difference of AEs incidence in various characteristics among two groups. Results: A total of 71 663 doses of vaccines were included for active safety analysis, which included 37 331 doses in boys and 34 332 doses in girls. Among all the doses, children aged 6 to 11 months, 12 to 23 months and 24 to 59 months were received 13 707, 32 639 and 25 317 doses respectively. The incidence of adverse reactions within 30 min, 3 days and 4-30 days were 0.33% (239 doses), 1.58% (1 133 doses) and 0.34% (244 doses) respectively. Adverse reactions within 3 days were 1 372 doses, with a incidence of 1.91%; among all the cases, 539 doses (0.75%) were grade 1, 677 doses (0.94%) were grade 2 and 156 doses (0.22%) were grade 3, no grade-4 adverse reaction was reported. The common local adverse reactions were redness, swelling and pruritus, with the incidence rates were 0.05% (39 doses), 0.02% (16 doses) and 0.02% (12 doses), respectively, while the most common systemic adverse reaction was pyrexia with an incidence of 1.19% (856 doses), followed by diarrhea and anorexia with the incidence rates were 0.15% (104 doses) and 0.13% (90 doses) respectively. Conclusion: Most adverse actions of EV-A71 vaccines were mild and moderate and majority of them were common adverse actions. No new adverse reactions were found in the study.

Is the optimal intervention policy UC superior to the suboptimal policy MFPT over inferred probabilistic Boolean network models?

A salient problem in translational genomics is the use of gene regulatory networks to determine therapeutic intervention strategies. Theoretically, in a complete network, the optimal policy performs better than the suboptimal policy. However, this theory may not hold if we intervene in a system based on a control policy derived from imprecise inferred networks, especially in the small-sample scenario. In this paper, we compare the performance of the unconstrained (UC) policy with that of the mean-first-passage-time (MFPT) policy in terms of the quality of the determined control gene and the effectiveness of the policy. Our simulation results reveal that the quality of the control gene determined by the robust MFPT policy is better in the small-sample scenario, whereas the sensitive UC policy performs better in the large-sample scenario. Furthermore, given the same control gene, the MFPT policy is more efficient than the UC policy for the small-sample scenario. Owing to these two features, the MFPT policy performs better in the small-sample scenario and the UC policy performs better only in the large-sample scenario. Additionally, using a relatively complex model (gene number N is more than 1) is beneficial for the intervention process, especially for the sensitive UC policy.

Acute pulmonary embolism caused by highly aggregated intravenous immunoglobulin.

BACKGROUND AND OBJECTIVES: Six patients died and one patient survived following infusion of a specific lot of intravenous immunoglobulin (IVIG) within half an hour in May 2008. This study elucidated the underlying pathogenesis. MATERIALS AND METHODS: A variety of protein fractionation and identification approaches were employed to determine the abnormal components in IVIG products obtained from the hospital where the patients were treated. Animal studies using mice and monkeys were conducted to elucidate the pathophysiological mechanisms. In animal experiments, the effect and distribution of immunoglobulin was investigated using HE staining and immunohistochemistry (IHC) separately, while platelets and fibrinogen depletion were utilized to determine a possible link between thromboembolism formation in animals and the lethal effect of the IVIG. The size and distribution of the protein aggregates were determined with Coulter Counter Multisizer-3 after the dilution of the IVIG with plasma, and the lethal effect of the protein aggregates was simulated with artificial microparticles. RESULTS: The IVIG retrieved from the hospital was found to have striking similarities to the heat-treated IVIG in terms of protein aggregation profiles and lethal effects. Post-mortem examination indicated that immunoglobulin aggregates were mainly found in the lung of the animals, while depletion of platelets and fibrinogen from the IVIG preparations failed to prevent the death of the animals. Similar amount of artificial microparticles caused animal death in similar fashion. CONCLUSIONS: Our findings indicate that the retrieved IVIG exerted its lethal effects by blocking the pulmonary circulation without markedly altering the coagulation cascade or immunological events.

The establishment of a new en bloc combined liver-small bowel transplantation model in rats.

In order to facilitate preclinical research, we established a new combined liver-small bowel transplantation rat model. Male inbred Wistar rats were chosen as donors and recipients. An en bloc liver-small bowel graft was harvested. During the donor operation, the inferior vena cava in the chest was removed to be used as an interpositional venous graft to anastomose to the portal vein. In the recipient operation the portal veins of donor and recipient were quickly anastomosed using a cuff technique instead of the traditional suture method. Rearterialization was achieved by anastomosing the superior mesenteric artery of graft to the right renal artery of the recipient. The recipient small bowel was resected and intestinal continuity restored simultaneously by two end-to-end anastomoses. The postoperative 5-day survival rate was 77.5% (31/40) and 60-day survival rate, 72.5% (29/40). Recipient rats that tolerated the operation remained healthy. Liver and renal function was normal. The liver and intestinal grafts showed normal histological architecture in all rats surviving for 2 months postoperatively. Our results demonstrated that the present model is feasible, allowing preclinical experimental research on combined liver-small bowel transplantation.

The human amylin analog, pramlintide, corrects postprandial hyperglucagonemia in patients with type 1 diabetes.

Mealtime amylin replacement with the human amylin analog pramlintide as an adjunct to insulin therapy improves postprandial glycemia and long-term glycemic control in type 1 diabetes. Preclinical animal studies indicate that these complementary effects may result from at least 2 independent mechanisms: a slowing of nutrient delivery to the small intestine and a suppression of nutrient-stimulated glucagon secretion. The former effect of pramlintide has previously been demonstrated in patients with type 1 diabetes. The present studies characterize the effect of pramlintide on postprandial glucagon secretion in this patient population. Plasma glucagon and glucose concentrations were measured before and after a standardized liquid meal in 2 separate randomized, double-blind, placebo-controlled studies of pramlintide administration to patients with type 1 diabetes. In a 2-day crossover study, 18 patients received a 5-hour intravenous infusion of pramlintide (25 microg/h or 50 microg/h) or placebo in addition to subcutaneous (SC) insulin injections. In a 14-day parallel-group study, 84 patients received SC injections of 30, 100, or 300 microg of pramlintide or placebo 3 times daily in addition to SC injections of insulin. In both studies plasma glucagon concentrations increased in response to the meal in the placebo-plus-insulin group but not in any of the pramlintide-treated groups (all pramlintide treatment arms v placebo, P <.05). We conclude that mealtime amylin replacement with pramlintide prevents the abnormal meal-related rise in glucagonemia in insulin-treated patients with type 1 diabetes, an effect that likely contributes to its ability to improve postprandial glucose homeostasis and long-term glycemic control.

Estimation of mean quality adjusted survival time.

In clinical studies, we often consider not only patients' survival time, but also their quality of life. Quality adjusted life years (QALY) is an integrated measure of medical outcome that combines a patient's quantity and quality of life. Estimation of mean QALY for a group of patients is complicated by the fact that some patients are censored. The conventional approach is to obtain the Kaplan-Meier estimate of the survival function associated with individual QALYs and then use the area under the Kaplan-Meier curve as an estimate of mean QALY. Glasziou, Simes and Gelber showed that this method is biased because censoring at the nominal time scale is informative for predicting unobserved QALYs. In this paper, we propose a methodology for consistent estimation of mean QALY. Simulation studies are conducted to investigate the relative performance of the new method and the conventional method.

Two-sample continual reassessment method.

We discuss an extension of the continual reassessment method (CRM) for use in phase I dose-finding studies. The extension enables the method to be applied to two groups of patients to determine the appropriate dose levels for each group. The method takes the specification of a simple relationship between the dose-toxicity curves for the two groups and runs the CRM on the bivariate model using maximum likelihood. We prove consistency of the method under fairly weak conditions and provide several simulations to give an idea how the method works in practice. We also undertake an evaluation of its performance by considering three possible situations: The first is the two-sample CRM, which directly uses a working model for the relationship between the two groups, carrying out a single trial using this method; the second situation carries out single trials for each of the two groups separately using the original (one-sample) CRM. The third situation is the case where such heterogeneity is ignored and the two groups are pooled into a single group, again using the original (one-sample) CRM. Simulations are carried out under a large class of model misspecifications, both of the dose-toxicity relationships and of the functional form linking the groups, and are backed up by asymptotic results. Our conclusions match intuition: The first scheme gives the most favorable results when the two groups are different but share some features. When the groups are very different, the second scheme performs similarly to the first for finite sample sizes while having some advantages in terms of asymptotic efficiency. The third, as expected, gives the best results in the absence of patient heterogeneity. The two-sample method appears particularly advantageous when there may not be enough subjects in one of the subgroups for it to be feasible to carry out two trials.

Significant differences in estradiol bioavailability from two similarly labelled estradiol matrix transdermal systems.

OBJECTIVE: To compare the bioavailabilities of estradiol delivered by two transdermal estradiol matrix systems; Alora and Evorel. STUDY DESIGN: A single-center, open-label, randomized, two-period cross-over study in 33 postmenopausal women. The subjects received two successive 84-h applications of either Alora or Evorel (each labelled to deliver 50 micrograms/day 17 beta-estradiol) in a randomized sequence. Serial serum samples, collected over the 84-h period following the application of the second patch, were analyzed for estradiol using a validated radioimmunoassay method. RESULTS: The fluctuation index produced by Evorel was significantly higher than that produced by Alora (Evorel, 135%; Alora, 76%; p < 0.0005). In addition, the estradiol baseline-corrected area under the curve for Evorel was significantly lower than that for Alora (Alora, 2871.8 pg h/ml; Evorel, 1870.6 pg h/ml; p < 0.0005). Both patches were found to be generally well tolerated. CONCLUSION: Alora delivered a higher, more consistent concentration of estradiol into the systemic circulation over the entire dosing interval than did Everol. Although the full clinical significance of these findings is currently unknown, this study demonstrates that there are significant differences in estradiol delivery from these two products, although they are labelled with the same nominal delivery rate.

Sample size determination for controlling the upper confidence limit of incidence rate of a binomial endpoint.

Assume that in a comparative clinical study the primary endpoint is a binary event, such as life or death. A new treatment or therapy is tested for a significant reduction of the incidence of the binary event compared with a control group. Another objective is to ensure that the incidence in the new treatment group is below some clinically acceptable value. This is done by calculating the exact upper 95% confidence limit for the probability of the event. The study is considered successful if the upper confidence limit is lower than a historical threshold, as well as if there is a significant reduction in the incidence of the event by the new treatment. In this article, we provide an exact method for calculating the sample size so that there will be adequate power to ensure that the exact upper confidence limit is below the threshold. Based on this we can design a study to achieve both objectives.

Continual reassessment method: a likelihood approach.

The continual reassessment method as described by O'Quigley, Pepe, and Fisher (1990, Biometrics 46, 33-48) leans to a large extent upon a Bayesian methodology. Initial experimentation and sequential updating are carried out in a natural way within the context of a Bayesian framework. In this paper we argue that such a framework is easily changed to a more classic one leaning upon likelihood theory. The essential features of the continual reassessment method remain unchanged. In particular, large sample properties are the same unless the prior is degenerate. For small samples and as far as the final recommended dose level is concerned, simulations indicate that there is not much to choose between a likelihood approach and a Bayesian one. However, for in-trial allocation of dose levels to patients, there are some differences and these are discussed. In contrast to the Bayesian approach, a likelihood one requires some extra effort to get off the ground. This is because the likelihood equation has no solution until we observe a toxicity. Initially then we suggest working with either a standard Up-and-Down scheme or standard continual reassessment method until toxicity is observed and then switching to the new scheme.