Decision making during a phase III randomized controlled trial

Experiments such as clinical trials should be carried out with specific objectives. For example, in a trial designed to prevent disease, specific considerations should be made concerning the impact of the trial on the health of the target population, including the participants in the trial. These objectives should be assessed continually in light of data accumulating from the trial. Accumulating evidence should be judged in the context of changing circumstances external to the trial, and the trial's design possibly modified. An important type of modification is stopping the trial. This is a sequential decision problem that can be addressed using a Bayesian approach and the methods of dynamic programming. As an example we consider a vaccine trial for the prevention of haemophilus influenzae type b. The objective we consider is minimizing the number of cases of this disease in a Native American population over a specified horizon. We assess the prior probability distribution of vaccine efficacy. We also assess the probability of regulatory approval for widespread use of the vaccine, depending on the data presented to the regulatory officials. In deciding whether to continue the trial we weigh the impact of the possible future results by their (predictive) probabilities. We address the sensitivity of the optimal stopping policy to the prior probability distribution, to the assessed probability of regulatory approval, and to the horizon.     

Obstructive sleep apnea treatment with dental appliance

The case of a 40-year-old male patient with obstructive sleep apnea syndrome (OSAS) is reported, with emphasis on treatment with a dental appliance. This therapeutic approach, which has been focused on recent research, has as its objective, the posturing of the mandibule and, consequently, the tongue more anteriorly, thus in turn leading to an increase in the posterior oropharyngeal airway space (PAS). Cephalometry contributed determining in this case whereby enlargement limits were observed in the PAS with mandibular displacement. Clinical and polysomnographic controls showed subjective reduction of the excessive daytime sleepiness and objective decrease in apneas intensity to normal limits. Eight months follow-up evidenced the steady improvement.     

Mohs' surgery of periocular basal cell carcinoma using formalin-fixed sections and delayed closure

Mohs' surgery of periocular basal cell carcinoma (BCC) ensures a high cure rate with maximal preservation of normal tissue. The formalin-fixed paraffin-embedded tissue technique allows Mohs' surgery to be performed using routine pathology facilities and permits the efficient use of operating room personnel and theatre time. The inevitable delay between excision and closure may potentially result in a poor functional and cosmetic outcome, particularly around the eye. We prospectively studied all patients with periocular BCC treated with this technique at our unit between 1985 and 1996. One hundred and twenty-three periocular BCCs in 120 patients were treated. Microscopic clearance was achieved in all cases. Closure was performed on average 5 days after the initial excisional stage. Closing procedures included direct closure, flaps and grafts. Significant complications affecting outcome were noted in only two patients. Eighty-eight per cent of patients assessed had a functional and cosmetic result regarded as excellent, good or adequate. Mohs' surgery of periocular BCC using formalin-fixed paraffin-embedded tissue and delayed closure results in a satisfactory functional and cosmetic outcome and offers a viable alternative to the frozen section fresh tissue technique.     

The provision of orthodontic services by general dental practitioners. 1. Methods and descriptive results

Information regarding orthodontic service provision by general dental practitioners in Australia is limited. The aim of this survey was to determine the amount and variety of orthodontic services provided by general dental practitioners in the Melbourne Statistical Division, Victoria, Australia. A random sample of 307 dentists drawn from the Victorian Dentists Register was surveyed by mailed questionnaire: 218 (71%) replied. Data were collected using a fortnight log. During this time 59 per cent of the dentists saw at least one orthodontic patient; one dentist saw 66 orthodontic patients. Removable orthodontic appliances were used by 35 per cent of the dentists and fixed orthodontic appliances by 18 per cent. Twenty-six per cent provided comprehensive orthodontic treatment, 22 per cent aligned incisors, and 21 per cent corrected anterior crossbites. The general dental practitioners surveyed provided a wide range of preventive and interceptive orthodontic services to generally a small percentage of their patients.     

Clinical applications of composite and realtime megavoltage imaging

The versatility of electronic portal imaging devices (EPIDs) is best demonstrated by their ability to perform novel megavoltage imaging protocols, which are still pertinent to good radiotherapy practice. This paper examines two such techniques: composite and realtime imaging. Our EPID can be programmed to acquire and manipulate images very easily, allowing images from segmented treatment protocols to be mixed and displayed, giving a composite image of the effective treatment result. Its use for verifying the efficacy of spinal shielding using a segmented, offset collimator technique is described. By acquiring images very quickly, realtime imaging sequences can be obtained and used to analyse anatomical movement within a single treatment field. The technique is employed here to investigate movement in radical lung, breast, abdomen, pelvis and thyroid treatments. Our results show that the protocol is vital for treatment sites involving the lungs; changes up to 5 mm have been observed in the maximum lung depth for breast treatments, and displacements up to 16 mm for radical lung treatments. It is also useful in other anatomical sites for ensuring that no movement occurs.     

Incidence, timing, and causes of cerebral ischemia during carotid endarterectomy with regional anesthesia

PURPOSE: Controversy exists regarding the best technique to identify cerebral ischemia during carotid endarterectomy (CEA). Regional anesthesia allows continuous evaluation of neurologic function and therefore can help determine the incidence, timing, and causes of cerebral ischemia. METHODS: The timing and clinical manifestations of any neurologic event during CEA and as long as 30 days afterward was determined by review of operative reports, hospital charts, and outpatient records of consecutive patients who underwent CEA under regional anesthesia over a 68-month period. RESULTS: Two hundred patients underwent CEA; indications were asymptomatic stenosis > 60% in 25%, transient ischemic attack with stenosis > 50% in 52%, and prior stroke with stenosis > 50% in 23%. Eight patients (4%) were converted to general anesthesia for non-ischemic reasons. Of the remaining 192 patients, 183 (95.5%) underwent the procedure with regional anesthesia and no shunt, 2% had cerebral ischemia and underwent shunt placement, and 2.5% had cerebral ischemia, were converted to general anesthesia, and underwent shunt placement. Cerebral ischemia developed in nine patients after carotid cross-clamping, manifested by loss of consciousness in four, confusion in two, dysarthria and confusion in one, and decreased contralateral motor strength in two. Immediate cerebral ischemia developed in four of the nine patients within 1 minute of cross-damping; all four underwent shunt placement. In five of the nine patients, cerebral ischemia occurred between 20 and 30 minutes after cross-clamping; all occurred during relative intraoperative hypotension (average reduction of 35 mm Hg in the systolic pressure). All awake patients in whom ischemic symptoms developed immediately regained and maintained normal neurologic function with shunt placement. Five of 26 patients (19%) with contralateral occlusion required a shunt; none had postoperative ischemia. The mean carotid cross-clamp time was 27 minutes. Postoperative (30 day) complications included a 0.5% stroke rate, a 0.5% rate of postoperative transient ischemic attack, a 0.5% rate of worsening of preexisting acute stroke, and a 0.5% rate of myocardial infarction (no deaths). Of the nine patients who had intraoperative ischemic changes, none had a postoperative neurologic deficit; the three patients who had postoperative neurologic changes had no intraoperative ischemic symptoms. CONCLUSIONS: CEA with regional anesthesia allows continuous neurologic monitoring and can be performed safely even when contralateral occlusion coexists; intraoperative shunting for ischemia is necessary in 4.5% of all cases and in 19% of patients with contralateral occlusion. Intraoperative ischemia was flow-related in our patients; it occurred early from ipsilateral carotid clamping and late from reduced collateral flow as a result of hypotension. Monitoring should be continued throughout cross-clamping to identify late cerebral ischemia. Postoperative cerebral ischemia is not associated with intraoperative ischemia, if corrected.     

A hydrophobic cluster between transmembrane helices 5 and 6 constrains the thyrotropin-releasing hormone receptor in an inactive conformation

We have studied the role of a highly conserved tryptophan and other aromatic residues of the thyrotropin-releasing hormone (TRH) receptor (TRH-R) that are predicted by computer modeling to form a hydrophobic cluster between transmembrane helix (TM)5 and TM6. The affinity of a mutant TRH-R, in which Trp279 was substituted by alanine (W279A TRH-R), for most tested agonists was higher than that of wild-type (WT) TRH-R, whereas its affinity for inverse agonists was diminished, suggesting that W279A TRH-R is constitutively active. We found that W279A TRH-R exhibited 3.9-fold more signaling activity than WT TRH-R in the absence of agonist. This increased basal activity was inhibited by the inverse agonist midazolam, confirming that the mutant receptor is constitutively active. Computer-simulated models of the unoccupied WT TRH-R, the TRH-occupied WT TRH-R, and various TRH-R mutants predict that a hydrophobic cluster of residues, including Trp279 (TM6), Tyr282, and Phe199 (TM5), constrains the receptor in an inactive conformation. In support of this model, we found that substitution of Phe199 by alanine or of Tyr282 by alanine or phenylalanine, but not of Tyr200 (by alanine or phenylalanine), resulted in a constitutively active receptor. We propose that a hydrophobic cluster including residues in TM5 and TM6 constrains the TRH-R in an inactive conformation via interhelical interactions. Disruption of these constraints by TRH binding or by mutation leads to changes in the relative positions of TM5 and TM6 and to the formation of an active form of TRH-R.     

Molecular mimicry in chronic inflammatory demyelinating polyneuropathy and melanoma

Polyclonal immunoglobulin M antibodies to the monosialoganglioside GM2, sulfoglucuronyl glycolipids, and sulfatide were detected by thin-layer chromatography and enzyme-linked immunosorbent assay in the serum of a patient with melanoma and chronic inflammatory demyelinating polyneuropathy. Both the patient's serum and polyclonal antibodies against GM2 reacted strongly with a biopsy of melanomatous tissue from the patient, suggesting a process of molecular mimicry.     

Dorsalis pedis flap donor site: acceptable or not?

The dorsalis pedis flap has been used successfully for 20 years, both as a pedicled transfer for local foot reconstruction and as a free microvascular transfer. Proponents cite the reliable vascularity, versatility, ease of harvest, and thinness. Although significant donor-site morbidity has been recognized previously, published reports have inadequately documented the long-term effects of dorsalis pedis flap harvest. The purpose of the present study was to obtain long-term follow-up data regarding the donor site on a total of 10 male patients who underwent dorsalis pedis flap harvest during the period from 1982 to 1984. Standardized questionnaires and chart reviews were completed, and physical examinations and photographs of each patient were carried out when possible. Eight patients were reviewed, and seven of them were examined and photographed (mean follow-up 13 years). All patients had initially experienced delayed donor-site healing (mean 18 months; range 3 to 36 months). In addition, soft-tissue infections (five of eight cases), osteomyelitis (one of eight cases), wound breakdown (seven of eight cases), scarring and contracture (four of seven cases), pain or other uncomfortable sensations in the foot (six of seven cases), and requirement for reoperation (three of eight cases) were significant complications of the procedure. Most patients were able to attain their preoperative level of physical activity (five of eight cases). Although generally favorable reconstructive results were obtained in this series, the long-term follow-up of donor-site healing indicates that this flap should be used with caution. In particular, delayed donor-site healing, need for wound revision, and long-term and possibly permanent donor-site symptoms are common.