Lessons from IAVI-006, a phase I clinical trial to evaluate the safety and immunogenicity of the pTHr.HIVA DNA and MVA.HIVA vaccines in a prime-boost strategy to induce HIV-1 specific T-cell responses in healthy volunteers

IAVI-006 was the first large randomised, double-blinded, placebo-controlled Phase I clinical trial to systematically investigate the prime-boost strategy for induction of HIV-1 specific CD8+ cytotoxic T-lymphocytes (CTL) in a factorial trial design using (i) priming with 0.5 mg or 2 mg of pTHr.HIVA DNA vaccine, followed by (ii) two booster vaccinations with 5 x 10(7) MVA.HIVA at weeks 8 and 12 (early boost) or weeks 20 and 24 (late boost). This study set the basis for later clinical trials and demonstrated the safety of these candidate HIV vaccines. The safety and immunogenicity results are presented and the lessons derived from this clinical trial are discussed.     

Continuous response variable trial design in motor neuron disease: long term treatment with a TRH analogue (RX77368).

The continuous response variable controlled trial design is developed as a model for the efficient screening of candidate treatments in motor neuron disease. A TRH analogue (RX77368) and placebo were randomly allocated to 15 matched pairs of patients with motor neuron disease. With validated composite interval scores, this trial excluded a 50% or greater improvement with RX77368 at month 12 in scores of respiratory, lower limb, and activities of daily living function with greater than 90% power, and in bulbar function scores with 80% power. For upper limbs, 52% and 75% improvements were excluded at months 9 and 12 respectively with 80% power. Patients who died during the study had faster deterioration rates in bulbar and respiratory scores than their surviving pairs. The feasibility of screening drugs for significant biological effects with small sample sizes and good statistical power is shown. The difficulties of handling deaths and dropouts when using this design are discussed. Comparisons are made with sample sizes required using other scores and rating scales, as well as with those required in hazard and event rate studies. A simple clinical grading scale for motor neuron disease, with its corresponding composite interval scores, is described.     

Neural basis of new clinical vestibular tests: otolithic neural responses to sound and vibration

Extracellular single neuron recording and labelling studies of primary vestibular afferents in Scarpa's ganglion have shown that guinea‐pig otolithic afferents with irregular resting discharge are preferentially activated by 500 Hz bone‐conducted vibration (BCV) and many also by 500 Hz air‐conducted sound (ACS) at low threshold and high sensitivity. Very few afferent neurons from any semicircular canal are activated by these stimuli and then only at high intensity. Tracing the origin of the activated neurons shows that these sensitive otolithic afferents originate mainly from a specialized region, the striola, of both the utricular and saccular maculae. This same 500 Hz BCV elicits vestibular‐dependent eye movements in alert guinea‐pigs and in healthy humans. These stimuli evoke myogenic potentials, vestibular‐evoked myogenic potentials (VEMPs), which are used to test the function of the utricular and saccular maculae in human patients. Although utricular and saccular afferents can both be activated by BCV and ACS, the differential projection of utricular and saccular afferents to different muscle groups allows for differentiation of the function of these two sensory regions. The basic neural data support the conclusion that in human patients in response to brief 500 Hz BCV delivered to Fz (the midline of the forehead at the hairline), the cervical VEMP indicates predominantly saccular function and the ocular VEMP indicates predominantly utricular function. The neural, anatomical and behavioural evidence underpins clinical tests of otolith function in humans using sound and vibration.     

Neck muscle responses evoked by transcranial magnetic stimulation of the human frontal eye fields

Transcranial magnetic stimulation (TMS) provides a non-invasive means of investigating brain function. Whereas TMS of the human frontal eye fields (FEFs) does not induce saccades, electrical stimulation of the monkey FEF evokes eye-head gaze shifts, with neck muscle responses evoked at stimulation levels insufficient to evoke a saccade. These animal results motivated us to examine whether TMS of the FEF (TMS-FEF) in humans evokes a neck muscle response. Subjects performed memory-guided saccades to the left or right while TMS (two pulses at 20?Hz) was delivered on 30% of trials to the left FEF coincident with saccade instruction. As reported previously, TMS-FEF decreased contralateral saccade reaction times. We simultaneously recorded the activity of splenius capitis (SPL) (an ipsilateral head turner). TMS-FEF evoked a lateralized increase in the activity of the right SPL but not the left SPL, consistent with the recruitment of a contralateral head-turning synergy. In some subjects, the evoked neck muscle response was time-locked to stimulation, whereas in others the evoked response occurred around the time of the saccade. Importantly, evoked responses were greater when TMS was applied to the FEF engaged in contralateral saccade preparation, with even greater evoked responses preceding shorter latency saccades. These results provide new insights into both the nature of TMS and the human oculomotor system, demonstrating that TMS-FEF engages brainstem oculomotor circuits in a manner consistent with a general role in eye-head gaze orienting. Our results also suggest that pairing neck muscle recordings with TMS-FEF provides a novel way of assaying the covert preparation of oculomotor plans.     

Nationwide questionnaire survey of the contemporary surgical management of pancreatic cancer in the United Kingdom & Ireland

This paper reports the results of a questionnaire-based survey of pancreatic surgical specialists in the United Kingdom addressing aspects of staging, resection volume and outcome. A postal survey was undertaken of the 517 members of the Association of upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS). 57 surgeons undertook pancreatic resection from 162 overall respondents. Cross-checking with the list of members of the Pancreatic Society of Great Britain and Ireland yielded 64 pancreatic surgeons. 734 pancreaticoduodenectomy (PD) were reported by respondents compared with 822 procedures according to Government maintained Hospital Episode Statistics. The modal resection volume performed per annum was 6-10. There were 24 in-hospital deaths in 732 resections (3%) mortality. For individual respondents the modal percentage mortality was 5% (0 to 16%). All clinicians with mortality rates in excess of 10% did less than 10 resections per annum. Respondents favoured "amylase rich discharge beyond 7th post-operative day" as optimal for definition of post-resection pancreatic fistula. Accepting the limitations of questionnaire surveys, the results provide an important overview of pancreatic surgical practice: pancreaticoduodenectomy is carried out by a range of specialists, lower volume resectionists appear to have poorer outcomes and this study shows widespread agreement on optimum terminology for post-operative pancreatic fistula.     

Accessing cancer services in North West England: the Chinese population

Relatively few Chinese patients access tertiary cancer services in North West England. We investigated the reasons behind this using a culturally sensitive questionnaire. The questionnaire, completed by 214 Chinese people in English, Cantonese or Mandarin, evaluated the Chinese population's access and satisfaction with primary care, understanding of cancer and awareness of local cancer services. Ninety‐five per cent of respondents were registered with a general practitioner (GP) and 75% had accessed primary care in the last year. Satisfaction with GP consultations was high but a third of respondents reported a lack of confidence in local National Health Service (NHS) services. Only 57% of eligible women had attended cervical screening programmes. The overall understanding of the causes and treatment of cancer and cancer services in the North West was poor. Despite registration with primary healthcare, the Chinese population under‐utilise cancer prevention programmes and tertiary cancer services because of a lack of awareness and understanding of cancer services in the North West. A significant proportion of the population is dissatisfied with the perceived slow service and lack confidence in services, with 41% considering using healthcare abroad. These data highlight the critical need to engage with, educate and support the Chinese population if they are to access NHS cancer services.     

Acquired tracheoesophageal fistula following blunt trauma to the chest

Tracheoesophageal fistula following blunt chest trauma is rare. Typically the patient is a young male with an elastic chest wall who is involved in a motor vehicle accident. In this case the victim was a motorcyclist who collided with a stationary lorry. He underwent surgery 4 weeks after the injury made an uncomplicated recovery.