Search

In a previous paper we considered how pharmaceutical statistics had changed between 1980 and 2000. In this paper we go on to consider some of the likely influences and changes in the world of pharmaceutical statistics over the next twenty years. Statistical research by pharmaceutical companies is supported, although its direct value in boosting company profits is challenged. The duality between fraud and conflict of interest is explored, particularly with regard to data and safety monitoring boards. Political correctness within clinical trials and (allegedly) better patient-oriented outcomes is questioned and the whole notion of intention-to-treat and per-protocol analyses is rejected in favour of pragmatic trials and explanatory trials. The dominance of SAS software within the industry is explored and the possibility for change considered. Finally, whilst the future of pharmaceutical companies is not addressed, the impact of future mergers, collaborations and take-overs between clinical research organizations is considered. Copyright © 2002 John Wiley & Sons, Ltd.

Pharmaceutical statistics has changed significantly in the last twenty years. This paper reviews some of the changes in that time, from a past dominated by the P-value to the present day. Although the last twenty years have seen significant improvements, statistical shortcomings are not a rarity, and the impact of the public perception of statistics, medicine and the pharmaceutical industry on pharmaceutical statistics is assessed. Copyright © 2002 John Wiley & Sons, Ltd.

This article places phase IV trials in context with other phases (most typically phase III). The design and objectives of phase IV trials may often be very similar to those of phase III trials, but some much broader aims and objectives such as postmarketing surveillance, quality of life, broad acceptability of treatments, and health economics may also be studied. Trials with different purposes may need different design considerations. Keywords: Generalizability; health economics; postmarketing; quality of life

This article discusses open-labeled studies; that is, studies that are not blinded. It is usually assumed that lack of blinding is “total,” not just single-blinded (either patient- or investigator-blinded). Different levels and aspects of blinding can often be achieved so that trials may be only partially open label. In some cases, open-label trials might be practically more acceptable, and in some studies, they may even be preferred to blinded studies. Keywords: blinding; masking; concealment; bias; endpoints; pragmatic trials

In recent months one of the most controversially discussed topics among regulatory agencies, the pharmaceutical industry, journal editors, and academia has been the sharing of patient-level clinical trial data. Several projects have been started such as the European Medicines Agency´s (EMA) “proactive publication of clinical trial data”, the BMJ open data campaign, or the AllTrials initiative. The executive director of the EMA, Dr. Guido Rasi, has recently announced that clinical trial data on patient level will be published from 2014 onwards (although it has since been delayed). The EMA draft policy on proactive access to clinical trial data was published at the end of June 2013 and open for public consultation until the end of September 2013. These initiatives will change the landscape of drug development and publication of medical research. They provide unprecedented opportunities for research and research synthesis, but pose new challenges for regulatory authorities, sponsors, scientific journals, and the public. Besides these general aspects, data sharing also entails intricate biostatistical questions such as problems of multiplicity. An important issue in this respect is the interpretation of multiple statistical analyses, both prospective and retrospective. Expertise in biostatistics is needed to assess the interpretation of such multiple analyses, for example, in the context of regulatory decision-making by optimizing procedural guidance and sophisticated analysis methods.

Continuing medical education (CME) is now one of the key areas of development in medical education. This paper describes the development of an intramural continuing medical education programme de novo in a newly opened cancer institute in Italy, which provided a unique opportunity to study attitudes towards the concepts and goals of continuing medical education as most of the individuals involved in this programme were exposed to continuing medical education for the first time. The continuing medical education programme was overseen by a CME committee for 1 year. Three 1-hour sessions were delivered each week and one credit point was awarded for each session. The sessions included grand rounds, clinical-based teaching and a 3-weekly rotating schedule of pathology, radiology and research. Participants were all the medical doctors attending the European Institute of Oncology. Attendance at greater than 50% of the total sessions available yearly qualified the individual for certification by the CME committee of the Institute. A questionnaire was circulated to all medical doctors at the Institute at the end of the academic year to assess attitudes to CME in general. Forty-six out of 84 questionnaires were returned. The majority of those involved in this CME intramural programme undertook self-directed CME activities and at least 50% had not previously attended either grand rounds or research seminars. Most felt that CME should not be mandatory but that its activities should be monitored. The greatest difficulty with CME was in its timing.

Geological evidence suggests that during a future eruption, Cumbre Vieja Volcano on the Island of La Palma may experience a catastrophic failure of its west flank, dropping 150 to 500 km³ of rock into the sea. Using a geologically reasonable estimate of landslide motion, we model tsunami waves produced by such a collapse. Waves generated by the run-out of a 500 km³ (150 km³) slide block at 100 m/s could transit the entire Atlantic Basin and arrive on the coasts of the Americas with 10–25 m (3–8 m) height.

Internal pilot studies used for establishing the required sample size for a clinical trial part way through that trial are attractive when one is faced with difficulties in determining underlying variances or underlying event rates. By extrapolating a known curio of post-hoc sample size calculations, it is demonstrated how a sample size calculation may be obtained from a blind internal pilot that increases the study size even though, had a decision been made to stop the study and unblind it, enough information existed to reject the null hypothesis. The questions of whether to continue recruiting and how much further to recruit may be considered. This will be influenced by the determination of the final (relative to the initial) study size determined from the internal pilot and the current perceived interest in the research question. If a study is stopped at the point of the recalculation, the reasons for the early stopping need to be carefully considered to decide if any bias may result. The decision to stop may be unconditional or conditional on the data. The two cases are distinguished through a variety of examples and their possible biases are considered.

We have identified a null HLA-A*02 allele, HLA-A*0232N, by using a combination of serology, flow cytometry, polymerase chain reaction using sequence-specific primers (PCR-SSP) and full-length sequencing. The null HLA-A2 allele was identified in an Asian individual originally typed by serology as an apparently homozygous HLA-A3, B51. Subsequent genotyping by PCR-SSP identified the genotype as HLA-A*0201, *0301, B*51, Cw*1402. The serological type and lack of detectable HLA-A2 was confirmed using monoclonal antibody typing reagents. Flow cytometry studies failed to identify any cell surface HLA-A2 expression on the patient's peripheral blood lymphocytes. Genotyping using a PCR-SSP set designed to detect null alleles revealed the mutation had not been previously described. Full-length sequencing of the allele identified an allele which was subsequently named HLA-A*0232N. This allele is identical to HLA-A*0201 except for a novel point mutation (T for C) at position 493 which creates a premature stop codon. The sequencing enabled the development of a monospecific A*0232N PCR-SSP reaction which was used to screen 973 DNA samples: no further examples of A*0232N were identified.

Fogo island is a large and extremely steepsided oceanic island volcano in the Cape Verde archipelago. It has a large (ca. 9 km across) east facing summit collapse structure, the Monte Amarelo collapse, with a probable volume of at least 150–200 km3. For most of its history the Monte Amarelo volcano had a small but productive central vent complex and radial rift zones fed by laterally propagating dykes. Shortly before the collapse the latter were replaced by north–south-trending arrays of en echelon, vertically propagating dykes. Since the Monte Amarelo collapse the scar has partly filled with a new volcano, the Cha das Caldeiras volcano. The summit cone of this volcano, the Pico do Fogo, is a very young feature but has been abandoned in the most recent phase of activity, from the 18th century onwards. The same period has also seen the abandonment of earlier radial rift zones with laterally propagating dykes and their replacement with en echelon arrays of vents fed by vertically propagating dykes. These form an N–S-trending array within the older collapse structure and are associated with seaward displacement of the eastern flank of the volcano within the old collapse structure. The most recent eruptions, those of 1951 and 1995, appear to be associated with episodes of flank instability manifested in N–S surface fissuring and east facing normal faults. These recent structural changes in the volcano parallel those which took place in the Monte Amarelo volcano prior to its collapse.

Seismic data recorded in the vicinity of the active vent of the 1995 Fogo eruption [Global Volcanism Network Bulletin, 1995, 20(3) 2–4.] is used to constrain the associated stress field and deformation. Using the frequency content of the seismograms to distinguish between brittle fracture of cold host rock and deformation in the vicinity of the intruding magma, a sub-vertical dyke with 060° strike is identified as the feeder of the eruption, and delineated down to a depth of about 4 km. The local stress field during the eruption is estimated from composite focal mechanisms. Besides the expected σ3 direction normal to the dyke, a group of focal solutions point to a stress field with nearly dyke-parallel σ3, which is interpreted as a re-adjustment of the edifice following the eruption, maybe partially controlled by gravity. This effect may have increased the instability of the steep eastern flank of the island, since the deformation detected during the magma drainback is compatible with predominantly dip-slip motion on east-dipping surfaces.

A novel HLA-B51 allele, B*5113 Note, was identified in a Kolla Amerindian individual from North-West Argentina. HLA-B*5113 1 differs from B*51011 by two nucleotide substitutions, one synonymous, the other non-synonymous. The resulting amino acid difference at residue 116 in the HLA-B molecule’s peptide binding site is likely to affect the nature of the peptides which bind to this molecule. The finding of this novel allele supports previous findings of increased diversity at HLA-B in Amerindian groups.

OBJECTIVE: To compare partner notification practice and outcomes at a provincial and a metropolitan clinic. DESIGN: Prospective study, following standardisation of partner notification policy. SETTINGS: Sheffield Department of Genitourinary Medicine, Royal Hallamshire Hospital and Jefferiss Wing Centre for Sexual Health, St Mary's Hospital, London. SUBJECTS: Consecutive patients with culture positive gonorrhoea between October 1994 and March 1996 who were interviewed by a health adviser. RESULTS: In Sheffield, 235 cases reported 659 outstanding contacts, of whom 129 (20%) were subsequently screened, and 65 (50%) had gonorrhoea. At St Mary's 510 cases reported 2176 outstanding contacts, of whom 98 (5%) were known to have been screened, and 53 (54%) had gonorrhoea. Patient or provider referral agreements appeared more productive in Sheffield, where 60% resulted in contact attendance, compared with 13% at St Mary's. Provider referral was used more frequently in Sheffield, for 44% of referrals, compared with 1% at St Mary's. Multivariate analysis showed that partner notification was less effective for casual and short term (< 7 days) partnerships in both centres, and for homosexual men at St Mary's. CONCLUSION: Partner notification outcomes were better in the provincial setting where contact attendance could be recorded more reliably and provider referral was used more extensively. The high proportion of contacts who remained untraced in both settings indicates the need for complementary screening and prevention initiatives.

We aimed to describe and compare sexual links among people with gonorrhoea, by studying patients in 2 UK departments of genitourinary medicine. Interviews were completed for 510 and 235 cases in London and Sheffield respectively. There was a greater proportion of cases in men, homosexual men, non-white and non-British people and fewer female sex workers in London. Total networks of 1738 people in London and 570 people in Sheffield were described. Large linked heterosexual networks identified in Sheffield were associated with local contact, including men with higher numbers of sexual partners. Condom use for vaginal sex was reported for 11% of heterosexual partnerships in Sheffield, and 27% in London, with little difference between regular and casual partners. It was more difficult to define networks in London due to a high proportion of relatively anonymous contacts. These difficulties suggest that research and interventions may profitably focus upon venues for meeting partners as well as partner notification.

Combined unspiked K–Ar dating and detailed mapping have established the eruptive chronology of the Cumbre Vieja volcano in the Canary islands. The CV volcano is a large polygenetic volcano (subaerial area: 220 km2, subaerial volume: 125 km3, elevation above sea level: 2000 m), which rests on the southern flank of the older Taburiente-Cumbre Nueva volcano. We defined two stratigraphic units by their relationship to the development of coastal cliffs developed around the Cumbre Vieja volcano: a cliff-forming series and a scree-forming series which is draped over the cliffs and forms the coastal platforms at their bases. K–Ar ages were measured from 20 samples from the two series. There are no discrepancies between K–Ar ages and the stratigraphy, the K–Ar ages of one flow compare well with 14 C determinations ( 14 C : 3.2±0.1 ka; K–Ar: 4±2 ka). The ages of the scree-forming series range from 3±2 ka to 21±2 ka. The cliff-forming series ages range from 20±2 ka to 123±3 ka, but as the base of the sequence is not exposed the growth of the Cumbre Vieja volcano must have begun substantially earlier. The boundary between the two coincides with the low sea-level stand in the last glacial maximum, which we infer to have been a period of intense coastal erosion. Dated samples from the upper part of the Taburiente-Cumbre Nueva volcano range in age from 853±10 ka to 566±8 ka. The age of the youngest Taburiente-Cumbre Nueva volcano sample provides an upper bound on the age of the subsequent Cumbre Nueva giant lateral collapse.

Non-welded, lithic-rich ignimbrites, hereintermed the Roque Nublo ignimbrites, are the most distinctive deposits of the Pliocene Roque Nublo group, which forms the products of second magmatic cycle on Gran Canaria. They are very heterogeneous, with 35–55% volume lithic fragments, 15-30% mildly vesiculated pumice, 5–7% crystals and 20–30% ash matrix. The vitric components (pumice fragments and ash matrix) are largely altered and transformed into zeolites and subordinate smectites. The Roque Nublo ignimbrites originated from hydrovolcanic eruptions that caused rapid and significant erosion of vents thus incorporating a high proportion of lithic clasts into the eruption columns. These columns rapidly became too dense to be sustained as vertical eruption columns and were transformed into tephra fountains which fed high-density pyroclastic flows. The deposits from these flows were mainly confined to palaeovalleys and topographic depressions. In distal areas close to the coast line, where these palaeovalleys widened, most of the pyroclastic flows expanded laterally and formed numerous thin flow units. The combined effect of the magma–water interaction and the high content of lithic fragments is sufficient to explain the characteristic low emplacement temperature of the Roque Nublo ignimbrites. This fact also explains the transition from pyroclastic flows into lahar deposits observed in distal facies of the Roque Nublo ignimbrites. The existence of hydrovolcanic eruptions generating high-density pyroclastic flows, unable to efficiently separate the water vapour from the vitric components during transport, also accounts for the intense zeolitic alteration in these deposits.

Background The evaluation of treatments for rare diseases presents a number of challenges for trial practitioners, regulators and policy makers. Small sample sizes mean that ‘standard’ approaches to trial design and analysis may not be appropriate and alternatives such as Bayesian trial designs have been recommended [Lilford et al 1995]. However, little is known about the design and analysis approaches that have been implemented in practice.

New multibeam bathymetry data are presented for the South Sandwich intra-oceanic arc which occupies the small Sandwich plate in the South Atlantic, and is widely considered to be a simple end-member in the range of intra-oceanic arc types. The images show for the first time the distribution of submarine volcanic, tectonic and erosional–depositional features along the whole length of the 540 km long volcanic arc, allowing systematic investigation of along-arc variations. The data confirm that the volcanic arc has a simple structure composed of large volcanoes which form a well-defined volcanic front, but with three parallel cross-cutting seamount chains extending 38–60 km from near the volcanic front into the rear-arc. There is no evidence for intra-arc rifting or extinct volcanic lines. Topographic evidence for faulting is generally absent, except near the northern and southern plate boundaries. Most of the volcanic arc appears to be built on ocean crust formed at the associated back-arc spreading centre, as previously proposed from magnetic data, but the southern part of the arc appears to be underlain by older arc or continental crust whose west-facing rifted margin facing the back-arc basin is defined by the new bathymetry. The new survey shows nine main volcanic edifices along the volcanic front and ca. 20 main seamounts. The main volcanoes form largely glaciated islands with summits 3.0–3.5 km above base levels which are 2500–3000 m deep in the north and shallower at 2000–2500 m deep in the south. Some of the component seamounts are interpreted to have been active since the last glacial maximum, and so are approximately contemporaneous with the volcanic front volcanism. Seven calderas, all either submarine or ice-filled, have been identified: Adventure volcano, a newly discovered submarine volcanic front caldera volcano is described for the first time. All but one of the calderas are situated on summits of large volcanoes in the southern part of the arc, and most are associated with current or historic volcanic or hydrothermal activity. Shallow shelves around the islands are generally 1–10 km wide. Submerged banks up to 1100 m deep are interpreted as subsided erosional surfaces. Seamounts and emergent volcanoes experienced a range of mass wasting processes including by landsliding and smaller mass flows.

To quantify uncertainty in a formal manner, statisticians play a vital role in identifying a prior distribution for a Bayesian-designed clinical trial. However, when expert beliefs are to be used to form the prior, the literature is sparse on how feasible and how reliable it is to elicit beliefs from experts. For late-stage clinical trials, high importance is placed on reliability; however, feasibility may be equally important in early-stage trials. This article describes a case study to assess how feasible it is to conduct an elicitation session in a structured manner and to form a probability distribution that would be used in a hypothetical early-stage trial. The case study revealed that by using a structured approach to planning, training and conduct, it is feasible to elicit expert beliefs and form a probability distribution in a timely manner. We argue that by further increasing the published accounts of elicitation of expert beliefs in drug development, there will be increased confidence in the feasibility of conducting elicitation sessions. Furthermore, this will lead to wider dissemination of the pertinent issues on how to quantify uncertainty to both practicing statisticians and others involved with designing trials in a Bayesian manner. Copyright © 2013 John Wiley & Sons, Ltd.

Objective: To discuss the calculation and application of confidence intervals in pharmacoeconomic studies. Data Synthesis: The increasing frequency with which pharmacoeconomic evaluations are made within clinical trials makes it possible to obtain information on the outputs and costs of an intervention in each patient of a sample under study. This allows the same statistical principles commonly used in clinical trials to be applied to cost or cost-effectiveness data. The methodology described in this article would allow expression of cost-effectiveness ratios in the form of confidence intervals. The calculation of the cost-effectiveness ratio by means of a confidence interval may have important practical consequences, both in decision-making on the choice of 1 intervention versus another and in calculating the size of the sample necessary to identify statistically significant differences, from both clinical and economic points of view. Conclusions: The complementary use of confidence intervals and sensitivity analysis makes it possible to measure uncertainty related and unrelated to variability in sample data, allowing the decision to adopt 1 technology or another to be based on the most objective information available. Although several ethical and methodologic concerns remain to be addressed, this methodology may contribute to improving the more rational and efficient use of drugs.

List of Contributors Foreword Bill McGuire and Mark Maslin Chapter 1: Hazardous responses of the solid Earth to a changing climate Bill McGuire Chapter 2: Future climate changes in the context of geological and geomorphological hazards Felicity Liggins, Richard Betts and Bill McGuire Chapter 3: Climate change and collapsing volcanoes: evidence from Mount Etna, Sicily Kim Deeming, Bill McGuire and Paul Harrop Chapter 4: Melting ice and volcanic hazards in the twenty-first century Hugh Tuffen Chapter 5: Multiple effects of ice load changes and associated stress change on magmatic systems Freysteinn Sigmundsson and others Chapter 6: Response of faults to climate-driven changes in ice and water volumes at the surface of the Earth Andrea Hampel, Ralf Hetzel and Georgios Maniatis Chapter 7: Does the El-Nino Southern Oscillation and influence earthquake activity in the eastern tropical Pacific? Serge Guillas, Simon Day and Bill McGuire Chapter 8: Submarine landslides and tsunamis in a changing climate Dave Tappin Chapter 9: Heat waves and slope stability in high mountain terrain Christian Huggel and others Chapter 10: Impacts of recent and future climate change on natural hazards in the European Alps Jasper Knight, Margreth Keiler and Stephan Harrison Chapter 11: Assessing the past and future stability of global gas hydrate reservoirs Mark Maslin, Matthew Owen, Richard Betts, Simon Day, Tom Dunkley Jones and Andrew Ridgwell Chapter 12: Methane hydrate instability: a view from the Palaeogene Tom Dunkley Jones, Andrew Ridgwell, D. J. Lunt, Mark Maslin, D. N. Schmidt and Paul Valdez Index

We develop the idea of using data from the first 'few' patients entered in a clinical trial to estimate the final trial size needed to have specified power for rejecting H0 in favour of H1 if a real difference exists. When comparing means derived from Normally distributed data, there is no important effect on test size, power or expected trial size, provided that a minimum of about 20 degrees of freedom are used to estimate residual variance. Relative advantages and disadvantages of using larger internal pilot studies are presented. These revolve around crude expectations of the final study size, recruitment rate, duration of follow-up and practical constraints on the ability to prevent the circulation of unblinded randomization codes to investigators and those involved in editing and checking data.

This chapter discusses the meaning of evidence-based medicine and where it relates to randomised controlled trials, but also where it does not. The need for good quality evidence is stressed through a discussion of high failure rates in drug development and arguments against access to unlicensed (and largely untested) treatments are set out (despite the good intentions of those who advocate such access to treatments).Good quality, reliable evidence does not always have to come from clinical trials. Other forms of evidence are discussed. Meta-analyses of individual trials may help to resolve the problem that, in rare diseases, it may be very difficult or impossible to do adequately powered clinical trials - but that does not imply those trials have no value at all.The importance of patients' choices is stressed but the difficulties of making choices and the general poor understanding of risk can make patients and caregivers, as well as healthcare professionals, very vulnerable to making poor decisions. All stakeholders need to be adequately guided through the evidence to make proper informed decisions.

Gas hydrates are ice-like deposits containing a mixture of water and gas; the most common gas is methane. Gas hydrates are stable under high pressures and relatively low temperatures and are found underneath the oceans and in permafrost regions. Estimates range from 500 to 10 000 giga tonnes of carbon (best current estimate 1600–2000 GtC) stored in ocean sediments and 400 GtC in Arctic permafrost. Gas hydrates may pose a serious geohazard in the near future owing to the adverse effects of global warming on the stability of gas hydrate deposits both in ocean sediments and in permafrost. It is still unknown whether future ocean warming could lead to significant methane release, as thermal penetration of marine sediments to the clathrate–gas interface could be slow enough to allow a new equilibrium to occur without any gas escaping. Even if methane gas does escape, it is still unclear how much of this could be oxidized in the overlying ocean. Models of the global inventory of hydrates and trapped methane bubbles suggest that a global 3 ° C warming could release between 35 and 940 GtC, which could add up to an additional 0.5 ° C to global warming. The destabilization of gas hydrate reserves in permafrost areas is more certain as climate models predict that high-latitude regions will be disproportionately affected by global warming with temperature increases of over 12 ° C predicted for much of North America and Northern Asia. Our current estimates of gas hydrate storage in the Arctic region are, however, extremely poor and non-existent for Antarctica. The shrinking of both the Greenland and Antarctic ice sheets in response to regional warming may also lead to destabilization of gas hydrates. As ice sheets shrink, the weight removed allows the coastal region and adjacent continental slope to rise through isostacy. This removal of hydrostatic pressure could destabilize gas hydrates, leading to massive slope failure, and may increase the risk of tsunamis.

New multibeam (swath) bathymetric sonar data acquired using an EM120 system on the RRS James Clark Ross, supplemented by sub-bottom profiling, reveals the underwater morphology of a not, vert, similar 12,000 km2 area in the northern part of the mainly submarine South Sandwich volcanic arc. The new data extend between 55° 45′S and 57° 20′S and include Protector Shoal and the areas around Zavodovski, Visokoi and the Candlemas islands groups. Each of these areas is a discrete volcanic center. The entirely submarine Protector Shoal area, close to the northern limit of the arc, forms a 55 km long east–west-trending seamount chain that is at least partly of silicic composition. The seamounts are comparable to small subaerial stratovolcanoes in size, with volumes up to 83 km3, indicating that they are the product of multiple eruptions over extended periods. Zavodovski, Visokoi and the Candlemas island group are the summits of three 3–3.5 km high volcanic edifices. The bathymetric data show evidence for relationships between constructional volcanic features, including migrating volcanic centers, structurally controlled constructional ridges, satellite lava flows and domes, and mass wasting of the edifices. Mass wasting takes place mainly by strong erosion at sea level, and dispersal of this material along chutes, probably as turbidity currents and other mass flows that deposit in extensive sediment wave fields. Large scale mass wasting structures include movement of unconsolidated debris in slides, slumps and debris avalanches. Volcanism is migrating westward relative to the underlying plate and major volcanoes are asymmetrical, being steep with abundant recent volcanism on their western flanks, and gently sloping with extinct, eroded volcanic sequences to their east. This is consistent with the calculated rate of subduction erosion of the fore-arc.

This chapter discusses the meaning of evidence-based medicine and where it relates to randomised controlled trials, but also where it does not. The need for good quality evidence is stressed through a discussion of high failure rates in drug development and arguments against access to unlicensed (and largely untested) treatments are set out (despite the good intentions of those who advocate such access to treatments). Good quality, reliable evidence does not always have to come from clinical trials. Other forms of evidence are discussed. Meta-analyses of individual trials may help to resolve the problem that, in rare diseases, it may be very difficult or impossible to do adequately powered clinical trials – but that does not imply those trials have no value at all. The importance of patients’ choices is stressed but the difficulties of making choices and the general poor understanding of risk makes patients very vulnerable to making poor decisions. They need to be adequately guided through the evidence to make proper informed decisions.

We have identified an HLA-B*07 variant allele, B*0716, in a Caucasoid cadaver kidney donor. The HLA class I type by polymerase chain reaction using sequence-specific primers (PCR-SSP) was A*01, 32; B*07, 08; Cw*07. Serological typing, using monoclonal and polyclonal anti-HLA antisera, gave disparate results for the B antigens. Monoclonal antibodies identified B7 and B8 antigens but polyclonal antisera recognised only the B8 antigen. PCR using sequencing based typing (PCR-SBT) confirmed the presence of both B*0703 and B*0801 alleles but with a mutation in one of the alleles. The HLA-B*07 allele was isolated by allele-specific PCR and was shown to have a mutation, GT, at 292 in exon 2. This mutation changes codon 74, which encodes aspartic acid (GAC) present in all previously identified B*07 alleles, to tyrosine (TAC) in the variant. The serological results suggest that codon 74 is a crucial part of a B7 antigen-specific epitope recognised by tissue typing polyclonal antisera ( Note).

Extinct volcanic islands in the Bismarck volcanic arc are fringed by well-developed coral reefs. Drowned platforms offshore from these islands provide evidence for subsidence in the central section of the arc, north of the Finisterre Terrane–Australia collision. Bathymetric and backscatter data collected onboard the R/V Kilo Moana in 2004 reveal regularly spaced (~200 m interval) drowned platforms at depths as much as 1,100 m below sea level. However, the adjacent mainland coast has well documented raised terraces indicating long-term uplift. Local subsidence may be due to cessation of magmatic activity and cooling, flexural loading by the uplifting Finisterre Range, loading by nearby active volcanic islands, and/or sediment loading on the seafloor north of the Finisterre Range. We present some simple models in order to test whether flexural loading can account for local subsidence. We find that volcanic and sedimentary loading can explain the inferred relative subsidence.

[1] We present a new interpretation of the geological evolution of the western branch of the Bismarck Sea Seismic Lineation (BSSL) region, offshore the northwestern coast of Papua New Guinea, from mapping and interpretation of bathymetry and backscatter data acquired aboard R/V Kilo Moana in 2004. At present, the Schouten Islands parallel the Papua New Guinea coast, but this distribution results from the left-lateral displacement of some of these volcanic islands by the Bismarck Sea Seismic Lineation. The trend of the islands and seamounts was initially aligned N-S and then displaced by the BSSL. Wei Island lies on a large submarine edifice that may have formed as part of a leaky transform. Subsequent to forming, Wei Island was bisected, and its pieces were displaced 45 km. Using this distance together with the strike-slip rate for the Bismarck Sea Seismic Lineation (predicted from the North Bismarck Plate–South Bismarck Plate pole), the division occurred approximately 385,000 years ago.

Ninety four neurologists in the United Kingdom, China, and West Germany responded to two structured questionnaires. The first assessed the diagnostic weighting assigned to a number of symptoms, signs, and clinical investigations ascertained from classical descriptions and case notes of patients with motor neuron disease (MND). The second tested the likelihood and consistency of diagnosis in a series of case summaries representing the clinical data of 10 patients with clinically and pathologically documented motor neuron disease. There was a wide measure of agreement concerning the common clinical features of the disease, especially regarding fasciculation of the tongue, fasciculation associated with weakness seen in more than one limb, and dysphagia. In the case summaries, however, there was clear variation in the ranked likelihood of the diagnosis of MND and in the consistency of diagnostic behaviour in the different groups of neurologists. These findings support the need for internationally agreed criteria in the diagnosis of MND. Any such criteria will need to be tested against a standardised data set to establish their validity.

Methods for estimating required sample size for comparing two population means have been published. Most involve the use of complicated formulae and tables. These methods are limited to comparing two groups. Although techniques exist to determine sample sizes for comparing more than two groups, they are intrinsically far more complicated. A simple linear nomogram is proposed as a solution to these problems, and its use is illustrated with examples of parallel group, ordered parallel group and factorial designs.

A description of a course designed to standardise leg ulcer management.

The relation between intrarectal volume and pressure during increasing rectal distension by a latex balloon were studied on repeated occasions in 10 healthy adult volunteers to define variations within and between individuals. A wide intersubject variation in the maximum tolerable volume (58-908 ml) and pressure (12.2-108.8 cm H2O) at this end point was seen, and these two values were correlated (r = 0.78). Intrasubject variation in maximum tolerable volume also occurred which was related to study order and progressively reduced with repeated study. In 26 unselected patients with pain predominant irritable bowel syndrome similar intersubject variation was noted and virtually all patients data fell within the calculated 95% confidence limits of the normal individuals. Differentiation between patients and normal subjects was not possible from knowledge of rectal responses. These noticeable inter- and intrasubject variations in rectal responses to distension need to be considered whenever similar techniques are proposed for use in the study of rectal disease or of rectal response to treatment.

The implementation of echo planar imaging at 4.7 T is demonstrated using a homebuilt gradient and radiofrequency assembly. The application of such a technique to the study of the isolated perfused rat heart is demonstrated. Langendorff and working heart perfusion preparations are compared and changes in the left ventricular volume shown are to be much larger in the working heart preparation. Such a methodology is expected to provide a useful model for the study of cardiac function and dynamics in the normal and diseased states under controlled perfusion conditions.

Primarily focused at military and security environments where there is a need to identify humans covertly and remotely; this paper outlines how recovering human gait biometrics from a multi-spectral imaging system can overcome the failings of traditional biometrics to fulfil those needs. With the intention of aiding single camera human gait recognition, an algorithm was developed to accurately segment a walking human from multi-spectral imagery. 16-band imagery from the image replicating imaging spectrometer (IRIS) camera system is used to overcome some of the common problems associated with standard change detection techniques. Fusing the concepts of scene segmentation by spectral characterisation and background subtraction by image differencing gives a uniquely robust approach. This paper presents the results of real trials with human subjects and a prototype IRIS camera system, and compares performance to typical broadband camera systems.