The importance of the patient voice in vaccination and vaccine safety-are we listening?

Much has been written about the patient-physician relationship over the years. This relationship is essential in maintaining trust in the complex arena of modern diagnostic techniques, treatment and prevention, including vaccines and vaccine safety. However, a great deal of this material was written from the viewpoint of clinicians and academics. The patient voice may be positive or negative, fragmented or complex. Information sources are weighed and treated differently, according to the value system and risk perceptions of the individual. In post-trust societies, when people have less confidence in health authorities, communication needs to be more than a paternalistic top-down process. Notions of empowerment and individual patient choice are becoming crucial in medical care. The 'voice of the patient', which includes healthy individuals receiving vaccines, needs to be heard, considered and addressed. With respect to childhood immunizations, this will be the voice of the parent or caregiver. The key to addressing any concerns could be to listen more and to develop a communication style that is trust-based and science-informed. Regulatory agencies are encouraging clinical and patient-reported outcomes research under the umbrella of personalized medicine, and this is an important step forward. This paper attempts to reflect the paradigm shift towards increasing attention to the patient voice in vaccination and vaccine safety.

Sedation in digestive endoscopy: the Athens international position statements.

BACKGROUND: Guidelines and practice standards for sedation in endoscopy have been developed by various national professional societies. No attempt has been made to assess consensus among internationally recognized experts in this field. AIM: To identify areas of consensus and dissent among international experts on a broad range of issues pertaining to the practice of sedation in digestive endoscopy. METHODS: Thirty-two position statements were reviewed during a 1 (1/2)-day meeting. Thirty-two individuals from 12 countries and four continents, representing the fields of gastroenterology, anaesthesiology and medical jurisprudence heard evidence-based presentations on each statement. Level of agreement among the experts for each statement was determined by an open poll. RESULTS: The principle recommendations included the following: (i) sedation improves patient tolerance and compliance for endoscopy, (ii) whenever possible, patients undergoing endoscopy should be offered the option of having the procedure either with or without sedation, (iii) monitoring of vital signs as well as the levels of consciousness and pain/discomfort should be performed routinely during endoscopy, and (iv) endoscopists and nurses with appropriate training can safely and effectively administer propofol to low-risk patients undergoing endoscopic procedures. CONCLUSIONS: While the standards of practice vary from country to country, there was broad agreement among participants regarding most issues pertaining to sedation during endoscopy.

Creative and innovative statistics in clinical research and development.

OBJECTIVES: The aim of this paper is to show that even in a highly regulated area such as clinical research and development in pharmaceutical industry, there are needs and ample opportunities for statisticians and other medical informatics professionals to further creatively develop and implement methods in order to support the collection, analysis and interpretation of clinical data. METHODS: The recently published "Critical Path" initiative of the US Food and Drug Administration discusses the decline in new drug submissions in the last decade and illustrates potential causes in the present clinical development process. Areas where statisticians can and have begun to look for new innovative ways to overcome these shortcomings are presented and examples of such novel approaches that have been developed by statistical methodologists in the pharmaceutical industry together with statisticians in academia are given. RESULTS: In Early Development, i.e., in the first studies in man with a new compound, a combination of Bayesian methods and modeling approaches is particularly promising to increase the efficiency of decision making whereas in later phases (IIb and III) a marriage of modeling and classical frequentist approaches together with novel adaptive designs is expected help to chose the right dose regimen and to perform the trials more efficiently in reduced time. CONCLUSIONS: The combination of known statistical methods and thinking and the development of new approaches are in line with the present paradigm of "learning and confirming" in regulated clinical development while increasing the efficiency of both.

Immunity against vaccine-preventable potentially neurotropic diseases in children treated for malignant brain tumours with HIT-91 chemo- and radiotherapy.

Following surgery, chemotherapy and/or irradiation, patients with malignant brain tumours are at risk of neurotropic diseases, although these are partly vaccine-preventable. In a retrospective, controlled, observational study, the impact of the German-Austrian chemo- and radiotherapy protocol (HIT-91) on antibody concentrations against vaccine-preventable diseases and on vaccination behaviour was analysed. A significant level of seronegativity for measles- and mumps-IgG, and a reduced protection induced by inactivated vaccines was observed after HIT-91 therapy. Failure of seroconversion following measles and mumps live vaccinations was assessed in the HIT-91-treated group and in a group with benign brain tumours (BBT). Analysis of cellular immunological parameters revealed significant aberrations in the HIT-91-treated group 36 months after completion of HIT-91 therapy. A retrospective analysis of the patient's vaccination history revealed an incorrect risk perception concerning the choice of vaccinations. We therefore recommend clinical vaccination with serosurveillance in patients who have undergone treatment for brain tumours.

Sequential tests for noninferiority and superiority.

The problem of simultaneous sequential tests for noninferiority and superiority of a treatment, as compared to an active control, is considered in terms of continuous hierarchical families of one-sided null hypotheses, in the framework of group sequential and adaptive two-stage designs. The crucial point is that the decision boundaries for the individual null hypotheses may vary over the parameter space. This allows one to construct designs where, e.g., a rigid stopping criterion is chosen, rejecting or accepting all individual null hypotheses simultaneously. Another possibility is to use monitoring type stopping boundaries, which leave some flexibility to the experimenter: he can decide, at the interim analysis, whether he is satisfied with the noninferiority margin achieved at this stage, or wants to go for more at the second stage. In the case where he proceeds to the second stage, he may perform midtrial design modifications (e.g., reassess the sample size). The proposed approach allows one to "spend," e.g., less of alpha for an early proof of noninferiority than for an early proof of superiority, and is illustrated by typical examples.

Reconsidering some aspects of the two-trials paradigm.

A common standard for the demonstration of efficacy in a clinical submission is a statistically significant outcome in at least two pivotal trials ("two-trials convention"). When the data structures in different trials are sufficiently similar to allow pooling of the data across trials for a combined analysis, we argue here that such an analysis is a more logical and efficient basis for a judgment regarding efficacy. Criteria for combined analyses may be established, which ensure the same false positive rate protection as the two-trials convention. A combined analysis will generally have much more power than the corresponding application of the two-trials approach that has the same false positive rate protection. In addition, we describe the behavior of modified versions of pure combined analysis, which incorporate a formal standard for reproducibility of trial results by limiting the larger of the individual trial p-values. These modifications are shown to maintain the desirable behavior of the pure combined analysis, namely, higher power compared to the two-trials convention.

Redefining the preoperative evaluation process and the role of the anesthesiologist.

STUDY OBJECTIVE: To assess the effects of implementing an ambulatory and same-day surgery preoperative evaluation patient triage system over a 3-year period. DESIGN: Retrospective analysis of 63,941 ambulatory surgical patients presenting for elective surgery. SETTING: Tertiary care, academic medical institution. INTERVENTIONS: The following preoperative evaluation model components were implemented over a 3-year period: HealthQuest, which is an outpatient preoperative assessment computer program developed by the Department of General Anesthesiology; a general internal medicine clinic designated specifically for preoperative evaluation and medical optimization; disease specific algorithms for both preoperative patient assessment and management; and a preoperative anesthesia clinic that no longer performs preoperative medical optimization. MEASUREMENTS AND MAIN RESULTS: During the 3-year study period ambulatory and same-day surgical case volume increased 34.7%. A total of 50,967 patients used HealthQuest as part of their preoperative evaluation. Of these patients 22,744 (35.6%) did not need to see an anesthesiologist until the day of surgery as guided by both a computer-assigned HealthQuest score and surgical classification scheme. Also, 41,197 patients were evaluated in our anesthesia preoperative clinic with a cost per evaluation of $24.86, which increased only 0.9% per year. In addition, both patient interview time and patient dissatisfaction with the preoperative process decreased over the 3-year period. There were 20, 088 patient encounters in the general internal medicine clinic for patient medical evaluation and optimization. The average monthly preoperative surgical delay rate decreased 49% during the study period. Finally, significant monetary saving resulted due to decreased unnecessary laboratory testing. CONCLUSIONS: Efficient, cost-effective patient care can be provided by using this preoperative evaluation model. Some institutions may find portions of this preoperative model applicable to their current situation.

Vaccine nomenclature: the three-letter code. OMCL Vaccine Nomenclature Drafting Group.

With increasing worldwide use of combined vaccines a short and informative system of names or codes for vaccines is essential. In addition, within the EU eleven official languages exist and some more are used. Due to these facts an increasing risk of medication errors for vaccines is emerging. A three-letter code naming system was first developed as part of the Note for guidance on pharmaceutical and biological aspects of combined vaccines (CPMP/BWP/477/97), but was deleted there later. Then a second approach was initiated by the European OMCL Network in order to implement this three-letter code system in the common nomenclature guideline within the Ph. Eur. (Index of standard terms). Both activities have not been successful until now to implement this system. Therefore we now present the three-letter code system in order to initiate either its voluntary use by vaccine manufacturers or to accelerate the obligatory implementation within the EU legislative framework. This coding system is thought to be used in addition to the brand name of the vaccine on the label of the final vaccine container, in order to have a safe last minute check whether the appropriate antigens are given.

Determinants of mortality after cardiac surgery: results of the registry of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK) on 10 525 patients.

BACKGROUND: Mortality from cardiac surgery is an essential indicator of quality and forms the basis of treatment strategy decisions in eligible patients. No contemporary complete data on unselected adult cardiac surgery patients are available in Germany. METHODS AND RESULTS: A registry was started in June 1997 of all patients referred to surgery from 85 cardiology centres in Germany. The registry was intended to include 10 000 patients and this number was reached in March 1998. Follow-up of the patients was by simple questionnaire, reporting the date of surgery, major complications, and symptomatic improvement. If the questionnaire was not returned, a reminder letter was sent and, if necessary, further telephone investigations were performed. This resulted in 99.9% complete data. Of 10 525 patients operated on, 3.91% had died by 30 days after surgery. The overall operative mortality was 4.57%, which included 69 patients who died after more than 30 days from complications related to surgery. By multivariate analysis, the following predictors of mortality were identified: previous surgery, emergency or complex operation; age >75 years, female gender, cardiac failure, angina CCS class IV, and three-vessel coronary disease. An integral part of the registry was a pre-operative prediction of surgical risk in five categories. This risk estimate revealed a surprisingly correct prediction of the mortality observed. CONCLUSIONS: In a representative unselected group of cardiac surgery patients, operative mortality was 4.57%. Several procedural and clinical parameters were significantly correlated with mortality, but the risk increment by each of these factors was small. Unstructured clinical judgement reliably predicted the operative risk.

Characterization of recombinant Arabidopsis thaliana threonine synthase.

Threonine synthase (TS) catalyses the last step in the biosynthesis of threonine, the pyridoxal 5'-phosphate dependent conversion of L-homoserine phosphate (HSerP) into L-threonine and inorganic phosphate. Recombinant Arabidopsis thaliana TS (aTS) was characterized to compare a higher plant TS with its counterparts from Escherichia coli and yeast. This comparison revealed several unique properties of aTS: (a) aTS is a regulatory enzyme whose activity was increased up to 85-fold by S-adenosyl-L-methionine (SAM) and specifically inhibited by AMP; (b) HSerP analogues shown previously to be potent inhibitors of E. coli TS failed to inhibit aTS; and (c) aTS was a dimer, while the E. coli and yeast enzymes are monomers. The N-terminal region of aTS is essential for its regulatory properties and protects against inhibition by HSerP analogues, as an aTS devoid of 77 N-terminal residues was neither activated by SAM nor inhibited by AMP, but was inhibited by HSerP analogues. The C-terminal region of aTS seems to be involved in dimer formation, as the N-terminally truncated aTS was also found to be a dimer. These conclusions are supported by a multiple amino-acid sequence alignment, which revealed the existence of two TS subfamilies. aTS was classified as a member of subfamily 1 and its N-terminus is at least 35 residues longer than those of any nonplant TS. Monomeric E. coli and yeast TS are members of subfamily 2, characterized by C-termini extending about 50 residues over those of subfamily 1 members. As a first step towards a better understanding of the properties of aTS, the enzyme was crystallized by the sitting drop vapour diffusion method. The crystals diffracted to beyond 0.28 nm resolution and belonged to the space group P222 (unit cell parameters: a = 6.16 nm, b = 10.54 nm, c = 14.63 nm, alpha = beta = gamma = 90 degrees).

Vitamin B6 biosynthesis: formation of pyridoxine 5'-phosphate from 4-(phosphohydroxy)-L-threonine and 1-deoxy-D-xylulose-5-phosphate by PdxA and PdxJ protein.

In Escherichia coli the coenzyme pyridoxal 5'-phosphate (PLP) is synthesised de novo by a pathway that is thought to involve the condensation of 4-(phosphohydroxy)-L-threonine and 1-deoxy-D-xylulose, catalysed by the enzymes PdxA and PdxJ, to form either pyridoxine (vitamin B6) or pyridoxine 5'-phosphate (PNP). Here we show that incubation of PdxJ with PdxA, 4-(phosphohydroxy)-L-threonine, NAD and 1-deoxy-D-xylulose-5-phosphate, but not 1-deoxy-D-xylulose, results in the formation of PNP. The PNP formed was characterised by (i) cochromatography with an authentic standard, (ii) conversion to pyridoxine by alkaline phosphatase treatment, and (iii) UV and fluorescence spectroscopy. Furthermore, when [2-(14)C]1-deoxy-D-xylulose-5-phosphate was used as a substrate, the radioactivity was incorporated into PNP. These results clarify the previously unknown role of PdxJ in the de novo PLP biosynthetic pathway. The sugar used as substrate by PdxJ is 1-deoxy-D-xylulose-5-phosphate rather than the previously assumed 1-deoxy-D-xylulose. The first vitamin B6 vitamer synthesised is PNP, and not pyridoxine.

Creation of a Perioperative Medicine Curriculum for an Anesthesiology Residency Program.

Because of the increasing expansion of the practice of anesthesiology beyond the borders of the operating room, there is attention being paid to Perioperative Medicine (PM) within anesthesiology training programs. With the elements of PM incorporated into the newest requirements for anesthesiology residency programs by the Residency Review Committee (RRC) for Anesthesiology of the American College of Graduate Medical Education (ACGME), programs are obliged to develop PM curriculum. At the Cleveland Clinic, a PM curriculum was created from existing, diverse elements of the clinical practice. Clinical supervision of the Pre-Anesthesia testing center, the Same-Day-Surgery unit, In-House Consultation and the Post-Anesthesia Care Unit were combined into a single teaching service. A didactic curriculum was created, resident function within these units was defined, and weekly teaching sessions were created. The result has been increased clinical teaching of PM, satisfaction of RRC requirements, and improved opportunity for resident learning in these areas. Residents have rated PM within the top 10% of rotations for the first two years of existence. We conclude that a combined service is an excellent approach to the creation of a PM curriculum.

Comparison of neuromuscular effects, efficacy and safety of rocuronium and atracurium in ambulatory anaesthesia.

PURPOSE: To compare the neuromuscular effects, efficacy, and safety of equi-effective doses of rocuronium and atracurium in ambulatory female patients undergoing surgery. METHODS: Forty-one patients undergoing laparoscopic gynaecological surgery were randomized to receive 2 X ED90 rocuronium (0.6 mg.kg-1; n = 20) or atracurium (0.5 mg.kg-1; n = 21) during intravenous propofol/alfentanil anaesthesia with N2O/O2 ventilation. Neuromuscular block was measured with a mechanomyogram eliciting a train-of-four (TOF) response at the wrist. Intubation conditions 60 sec after administration of muscle relaxant and immediate cardiovascular disturbances or adverse events during the hospital stay were noted by blinded observers. RESULTS: Compared with atracurium, rocuronium was associated with a shorter onset time (59.0 +/- 22.2 vs 98.6 +/- 41.4 sec; P < 0.001) and clinical duration of action (33.3 +/- 7.1 vs 44.7 +/- 7.2 min; P < 0.001), but longer spontaneous recovery index (9.6 +/- 2.41 vs 6.9 +/- 1.89 min; P = 0.023) and a similar time to spontaneous recovery to TOF 70%; 53 +/- 6.31 vs 59.2 +/- 7.59 min; P = 0.139). Tracheal intubation was accomplished in < 90 sec in all patients receiving rocuronium but in only 14 of 21 patients receiving atracurium. The incidence of adverse events and the cardiovascular profiles for the two drugs were similar, although one patient receiving atracurium experienced transient flushing of the head and neck. CONCLUSION: Rocuronium has minimal side effects, provides conditions more suitable for rapid tracheal intubation, and is associated with a shorter clinical duration than atracurium. Once begun, the spontaneous recovery profile of rocuronium is slightly slower than that of atracurium.

Testing strategies in multi-dose experiments including active control.

Inferential test strategies for multi-arm trials are adapted or proposed for the special situation when more than one dose of a test treatment, placebo and active control(s) are compared. This includes between doses, dose-placebo and dose-active-control comparisons. The procedures refer to situations when detailed comparisons make sense only if the sensitivity of the trial has been shown, for example, if a dose-response relationship or a difference between active control and placebo has been established. Split strategies, hierarchical (assuming an order restriction among doses) or linked procedures are introduced. In linked procedures, equivalence to the active control will be established only if the dose is also shown to be effective as compared to placebo. All the inferential procedures control the experimentwise error rate in the strong sense for the respective sets of null hypotheses considered.

HBW 023 (recombinant hirudin) for the acceleration of thrombolysis and prevention of coronary reocclusion in acute myocardial infarction: results of a dose-finding study (HIT-II) by the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte.

OBJECTIVE: To define an optimal dose of hirudin that would improve early coronary artery Thrombolysis in Myocardial Infarction grade 3 (TIMI 3) patency and prevent reocclusions in patients with acute myocardial infarction treated with front-loaded recombinant tissue-type plasminogen activator (rt-PA). METHODS: Recombinant hirudin (HBW 023) was tested in a sequential dose-escalating study as adjunct to front-loaded rt-PA in 143 patients with acute myocardial infarction. The sequential model was assigned two 'decision boundaries': it triggered an increase in dosage if the 60-min TIMI 3 flow rate in a dosage group was statistically not consistent with a target patency rate of 75%, or if the deterioration in coronary blood flow (of at least one TIMI grade, from TIMI 2 or 3, from one angiography to the next) exceeded 5%. RESULTS: The decision boundary for TIMI 3 flow grade at 60 min was crossed when 18 patients were treated with 0.1/0.06 mg/kg (bolus/infusion per hour over 48 h) r-hirudin (dosage group I), 42 patients treated with 0.2/0.1 mg/kg (dosage group II), and 83 patients with 0.4/0.15 mg/kg (dosage group III). TIMI 3 flow at 60 min was 50%, 58%, and 63% in dosage groups I-III, respectively (P = 0.15). Early, complete, and sustained patency (TIMI 3 flow at 60 min, 90 min and 48 h) were 44%, 55% and 64% (P = 0.07). Reocclusion between 90-min and 48-h angiograms or reinfarction occurred in 0 to 15, two of 36, and one of 72 patients, respectively (P = 0.5). Four patients (2.8%) died in hospital and 14 patients suffered a major bleeding event, but no intracranial bleeding was encountered. CONCLUSIONS: With increasing doses of hirudin, there was a trend towards greater early and complete patency, but no clear dose--response relationship was observed. A borderline significant effect was observed with respect to early, complete, and sustained patencies. In all groups, reocclusions or reinfarctions were rare. Neither clinical nor laboratory data predicted the imbalance in haemorrhagic events observed in a subsequent, prematurely terminated, phase III trial with hirudin and rt-PA.