Jonathan Hartzel

Ten year follow-up of healthy children who received one or two injections of varicella vaccine.

Background. The rate of varicella and persistence of varicella antibody after a one dose vs. a two dose regimen of varicella virus vaccine live Oka/Merck (VARIVAX®; Merck & Co., Inc., West Point, PA) in ∼2000 children were compared during a 9- to 10-year follow-up period. Methods. Children 12 months to 12 years of age with a negative history of varicella were randomized in late 1991 to early 1993 to receive either one or two injections of varicella vaccine given 3 months apart. Subjects were actively followed for varicella, any varicella-like illness or zoster and any exposures to varicella or zoster on a yearly basis for 10 years after vaccination. Persistence of varicella antibody was measured yearly for 9 years. Results. Most cases of varicella reported in recipients of one or two injections of vaccine were mild. The risk of developing varicella >42 days postvaccination during the 10-year observation period was 3.3-fold lower (P < 0.001) in children who received two injections than in those who received one injection (2.2%vs. 7.3%, respectively). The estimated vaccine efficacy for the 10-year observation period was 94.4% for one injection and 98.3% for two injections (P < 0.001). Measurable serum antibody persisted for 9 years in all subjects. Conclusions. Administration of either one or two injections of varicella vaccine to healthy children results in long term protection against most varicella disease. The two dose regimen was significantly more effective than a single injection.

Effect of an Investigational Vaccine for Preventing Staphylococcus aureus Infections After Cardiothoracic Surgery: A Randomized Trial

IMPORTANCE Infections due to Staphylococcus aureus are serious complications of cardiothoracic surgery. A novel vaccine candidate (V710) containing the highly conserved S. aureus iron surface determinant B is immunogenic and generally well tolerated in volunteers. OBJECTIVE To evaluate the efficacy and safety of preoperative vaccination in preventing serious postoperative S. aureus infection in patients undergoing cardiothoracic surgery. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, event-driven trial conducted between December 2007 and August 2011 among 8031 patients aged 18 years or older who were scheduled for full median sternotomy within 14 to 60 days of vaccination at 165 sites in 26 countries. INTERVENTION Participants were randomly assigned to receive a single 0.5-mL intramuscular injection of either V710 vaccine, 60 μg (n = 4015), or placebo (n = 4016). MAIN OUTCOME MEASURES The primary efficacy end point was prevention of S. aureus bacteremia and/or deep sternal wound infection (including mediastinitis) through postoperative day 90. Secondary end points included all S. aureus surgical site and invasive infections through postoperative day 90. Three interim analyses with futility assessments were planned. RESULTS The independent data monitoring committee recommended termination of the study after the second interim analysis because of safety concerns and low efficacy. At the end of the study, the V710 vaccine was not significantly more efficacious than placebo in preventing either the primary end points (22/3528 V710 vaccine recipients [2.6 per 100 person-years] vs 27/3517 placebo recipients [3.2 per 100 person-years]; relative risk, 0.81; 95% CI, 0.44-1.48; P = .58) or secondary end points despite eliciting robust antibody responses. Compared with placebo, the V710 vaccine was associated with more adverse experiences during the first 14 days after vaccination (1219/3958 vaccine recipients [30.8%; 95% CI, 29.4%-32.3%] and 866/3967 placebo recipients [21.8%; 95% CI, 20.6%-23.1%], including 797 [20.1%; 95% CI, 18.9%-21.4%] and 378 [9.5%; 95% CI, 8.6%-10.5%] with injection site reactions and 66 [1.7%; 95% CI, 1.3%-2.1%] and 51 [1.3%; 95% CI, 1.0%-1.7%] with serious adverse events, respectively) and a significantly higher rate of multiorgan failure during the entire study (31 vs 17 events; 0.9 [95% CI, 0.6-1.2] vs 0.5 [95% CI, 0.3-0.8] events per 100 person-years; P = .04). Although the overall incidence of vaccine-related serious adverse events (1 in each group) and the all-cause mortality rate (201/3958 vs 177/3967; 5.7 [95% CI, 4.9-6.5] vs 5.0 [95% CI, 4.3-5.7] deaths per 100 person-years; P = .20) were not statistically different between groups, the mortality rate in patients with staphylococcal infections was significantly higher among V710 vaccine than placebo recipients (15/73 vs 4/96; 23.0 [95% CI, 12.9-37.9] vs 4.2 [95% CI, 1.2-10.8] per 100 person-years; difference, 18.8 [95% CI, 8.0-34.1] per 100 person-years). CONCLUSIONS AND RELEVANCE Among patients undergoing cardiothoracic surgery with median sternotomy, the use of a vaccine against S. aureus compared with placebo did not reduce the rate of serious postoperative S. aureus infections and was associated with increased mortality among patients who developed S. aureus infections. These findings do not support the use of the V710 vaccine for patients undergoing surgical interventions. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00518687.

Multinomial logit random effects models

This article presents a general approach for logit random effects modelling of clustered ordinal and nominal responses. We review multinomial logit random effects models in a unified form as multivariate generalized linear mixed models. Maximum likelihood estimation utilizes adaptive Gauss-Hermite quadrature within a quasi-Newton maximization algorithm. For cases in which this is computationally infeasible, we generalize a Monte Carlo EM algorithm. We also generalize a pseudo-likelihood approach that is simpler but provides poorer approximations for the likelihood. Besides the usual normality structure for random effects, we also present a semi-parametric approach treating the random effects in a non-parametric manner. An example comparing reviews of movie critics uses adjacent-categories logit models and a related baseline-category logit model.

Strategies for comparing treatments on a binary response with multi-centre data

This paper surveys methods for comparing treatments on a binary response when observations occur for several strata. A common application is multi-centre clinical trials, in which the strata refer to a sample of centres or sites of some type. Questions of interest include how one should summarize the difference between the treatments, how one should make inferential comparisons, how one should investigate whether treatment-by-centre interaction exists, how one should describe effects when interaction exists, whether one should treat centres and centre-specific treatment effects as fixed or random, and whether centres that have either 0 successes or 0 failures should contribute to the analysis. This article discusses these matters in the context of various strategies for analysing such data, in particular focusing on special problems presented by sparse data.

Continuous Passive Motion after Repair of the Rotator Cuff. A Prospective Outcome Study

Despite the apparent success of continuous passive motion after soft-tissue procedures or joint replacements, its effect after repair of the rotator cuff is still unknown. The purpose of this prospective, randomized outcome study was to compare the results of continuous passive motion with those of manual passive range-of-motion exercises after repair of the rotator cuff. Thirty-one patients (thirty-two rotator cuffs) were randomly assigned to one of two types of postoperative management: continuous passive motion (seventeen patients) or manual passive range-of-motion exercises (fifteen patients). There were seventeen women and fourteen men, and the mean age was sixty-three years (range, thirty to eighty years). The patients were followed for a mean of twenty-two months (range, six to forty-five months). Five tears of the rotator cuff were small, eighteen were medium, and nine were large. All of the operations were performed by one surgeon. The patients who were managed with continuous passive motion used the device for the first four weeks postoperatively. The patients who were managed with manual passive range-of-motion exercises were assisted by a trained relative, friend, or home-care nurse. After the four-week period, the two groups were managed similarly for two to five months. According to the Shoulder Pain and Disability Index, a valid and reliable self-administered questionnaire, the treatment was extremely successful in both groups. The overall score was excellent for twenty-seven shoulders (84 per cent), good for two (6 per cent), fair for two (7 per cent), and poor for one (3 per cent). With the numbers available, we could detect no significant differences (p > 0.05) between the two groups with respect to the score according to the Index, pain (according to a visual-analog scale), range of motion, or isometric strength. Manual passive range-of-motion exercises were more cost-effective than continuous passive motion. The limited number of physical-therapy visits associated with the manual passive range-of-motion exercises in the present study appeared to be more cost-effective than a traditional physical-therapy schedule of three visits per week. Postoperative therapy with continuous passive motion or manual passive range-of-motion exercises appears to yield favorable results after repair of a small, medium, or large tear of the rotator cuff.

Safety and Immunogenicity of a Combination: Measles, Mumps, Rubella and Varicella Vaccine (ProQuad®)

Background: A combination measles, mumps, rubella, and varicella vaccine (ProQuad®, Merck & Co., Inc, West Point, PA) was evaluated in 5 clinical trials. Use of ProQuad® would result in fewer injections for children and would facilitate universal immunization against all 4 diseases. Objective: To describe the combined results obtained from the studies conducted during the clinical development program for ProQuad®. Methods: A total of 5833 healthy children, 12-23 months of age, and 399 healthy children, 4-6 years of age, received 1 or 2 doses of ProQuad® in 5 controlled clinical trials. M-M-R®II and VARIVAX® were used as the control for most studies. Safety was evaluated for 6 weeks postvaccination and immunogenicity was assessed 6 weeks after each dose by a sensitive assay (ELISA or gpELISA). Results: A single dose of ProQuad® in 12- to 23-month-old children was shown to be as immunogenic as a single dose of M-M-R®II and VARIVAX® and was generally well tolerated. ProQuad® can be used concomitantly with other vaccines (hepatitis B and Haemophilus influenzae b). A higher rate of fever was reported after 1 dose of ProQuad® compared to M-M-R®II and VARIVAX®, but fever episodes were transient without long-term sequelae. Both a 2-dose regimen of ProQuad® in 12- to 23-month-olds and use of ProQuad® in place of M-M-R®II at 4-6 years were shown to be immunogenic and well tolerated. The incidence of adverse experiences following a second dose of ProQuad® was lower than that following the initial dose. Conclusions: A single dose of ProQuad® is as immunogenic as M-M-R®II and VARIVAX® and is well tolerated in a 1- or 2-dose schedule. ProQuad® should easily fit into the routine immunization schedule.

A comparison of safety, tolerability and immunogenicity of Oka/Merck varicella vaccine and VARILRIX in healthy children.

This study compared safety, tolerability, and immunogenicity of the Oka/Merck varicella vaccine and VARILRIX [Oka-RIT strain SmithKline Beecham Biologicals] in healthy children 12-24 months of age. Subjects were randomized in this double blind study to receive either a single dose of Oka/Merck varicella vaccine, (approximately 50,000 plaque forming units (PFU), Group A or approximately 16,000 PFU, Group B) or 1 dose of VARILRIX, (approximately 40,000 PFU/dose, Group C). Safety profiles in each treatment group were similar. The proportions of subjects achieving a 6-week postvaccination titer> or = 5 gpELISA units in Groups A, B or C were 97.1, 95.2 and 85.6%, respectively.

Safety and immunogenicity of a measles, mumps, rubella and varicella vaccine given with combined Haemophilus influenzae type b conjugate/hepatitis B vaccines and combined diphtheria-tetanus-acellular pertussis vaccines.

Background: A study was conducted to assess administration of a combination measles, mumps, rubella and varicella vaccine (MMRV) with other childhood vaccines. Methods: In this open, multicenter trial, 1915 healthy children ages 12–15 months were randomized into 3 groups: group 1, MMRV, combined Haemophilus influenzae type b conjugate-hepatitis B vaccines (Hib/HepB) and combined diphtheria-tetanus-acellular pertussis vaccines (DTaP) concomitantly; group 2, MMRV followed by Hib/HepB and DTaP 42 days later; group 3, MMR and varicella vaccine followed by Hib/HepB and DTaP 42 days later. Results: Antibody responses to measles, mumps, rubella, varicella, Hib, HepB, diphtheria and tetanus were similar between groups 1 and 2 (all >95%, except varicella, 89.7% in group 1 and 90.9% in group 2). Pertussis toxin and filamentous hemagglutinin responses were significantly lower in group 1 than in group 2 (group 1, 74.1 and 67.1%; group 2, 90.4 and 86.8%, respectively). An exploratory analysis suggested that the difference in and pertussis toxin and filamentous hemagglutinin responses was likely the result of study design rather than interference among vaccine components because the groups differed in age of receipt of DTaP (group 1, ∼12 months; group 2, ∼13.5 months). When the groups were matched for age, sample size was sufficient for comparison only in children ≥13.5 months old. Pertussis toxin and filamentous hemagglutinin responses were similar in these children. The safety profiles for each vaccination regimen were comparable. Conclusions: The immunogenicity data support concomitant administration of MMRV with Hib/HepB. Limited data from an exploratory analysis indicate that MMRV can be administered concomitantly with DTaP. Concomitant administration of MMRV, Hib/HepB and DTaP is well-tolerated.

The immunogenicity and safety of different formulations of a novel Staphylococcus aureus vaccine (V710): Results of two Phase I studies

Merck V710 is a novel vaccine that contains the highly conserved Staphylococcus aureus iron surface determinant B (IsdB) protein. V710 has induced positive immune responses in healthy subjects. The purpose of the two studies described herein was to evaluate the immunogenicity and safety of two different formulations of V710. Both studies were randomized, controlled, double-blind, parallel-group trials. Study 1 compared liquid, aluminum-adjuvanted V710 (30 μg) with liquid, non-adjuvanted V710 (30 μg) in a 1:1 ratio in 64 healthy adults (18-70 years). Study 2 compared non-adjuvanted lyophilized V710 (60 μg) with saline placebo in a 4:1 ratio in 51 healthy adults (18-80 years). Blood was collected at screening and up to Day 360 postvaccination in Study 1, and at screening and up to Day 84 postvaccination in Study 2. Sera were analyzed for IsdB-specific antibodies using a total IgG assay. The primary endpoints in Study 1 were the proportion of patients with a positive immune response (≥2-fold rise in IsdB-specific IgG antibody level) the geometric mean concentration (GMC), and the geometric mean-fold rise (GMFR), all from baseline at Day 14. The primary endpoint in Study 2 was the GMFR in IsdB-specific IgG antibody concentration from baseline at Day 14. In Study 1, 84.4% responded in the adjuvanted V710 group, and 71.9% in the non-adjuvanted V710 group. The GMC was 115.4 μg/mL in the adjuvanted group and 99.1 μg/mL in the nonadjuvanted group. The GMFR in antibody concentration in the group receiving aluminum-adjuvanted V710 was 4.5 and the GMFR in the group receiving non-adjuvanted V710 was 4.0. In Study 2, the GMFR in antibody concentration in the V710 group was 5.3, and 80.5% had a positive immune response. None responded in the placebo group. Positive immune response was seen in the active treatment groups over the full duration of each study. There were no serious adverse experiences (AE) in either study, and no patients discontinued due to an AE. There were no clinically meaningful differences in AEs between groups in either study. In conclusion, V710, both with and without aluminum adjuvant, and in both liquid and lyophilized formulations, was immunogenic within 14 days of vaccination. All treatments showed similar safety profiles.

Dynamic versus static grip strength: How grip strength changes when the wrist is moved, and why dynamic grip strength may be a more functional measurement*

The synergistic relationship between wrist/forearm range of motion (ROM) and grip strength (GS) is arguably one of the most important aspects of hand function. Clinically, GS is measured with the wrist in a standardized static position, and the results of such tests have been deemed valid and reliable. The question remains, however, whether this static GS (SGS) measurement is an accurate indication of how an individual functionally grips objects--that is, most functional tasks require the fingers to grasp an object forcibly while moving the proximal joints such as the wrist and forearm. Therefore, further analysis of an individuals dynamic GS (DGS) during wrist/forearm movements may improve the clinicians understanding of hand function and provide more pertinent guidelines for assessing functional gripping, e.g., for vocational and avocational tasks and in designing workstations. The purpose of this study is twofold: to describe and assess a DGS testing device that utilizes optically encoded gyroscopes and a strain-gauge dynamometer to simultaneously measure GS and wrist/forearm position over real time; and to assess and compare grip force production differences in SGS and DGS in uninjured wrists, using this novel device. Twenty-nine uninjured wrists of men (n = 15) and women (n = 14)--age range, 21 to 43 years--were tested with the DGS device. Subjects were excluded if they had any previous wrist/forearm fracture, pain, or limitation of motion. The DGS device was designed and fabricated with two optically encoded gyroengines, a vertical gyroscope with two axes for measuring flexion/extension and radial/ulnar deviation, and a directional gyroscope with one axis for measuring supination/pronation, mounted on a strain-gauge dynamometer. The signals from the gyroscopes and dynamometer were processed by means of a data aquisition board and analog-to-digital circuitry and collected on a 486-MHz computer. The methods included repeated testing of each gyroscope axis to known angular measurements, and randomly assigned maximal gripping trials from the 29 subjects. The standard deviation of gyroengines is 1 degree to 2 degrees for each ROM axis. Maximal DGS is significantly less (mean 14%) than SGS, and SGS is 29% less than DGS at the same three-dimensional ROM positions. Gyroengines are feasible three-dimensional tracking devices that can be used to monitor wrist/forearm ROM in conjunction with GS.