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BackgroundNicotine preloading means using nicotine replacement therapy prior to a quit date while smoking normally. The aim is to reduce the drive to smoke, thereby reducing cravings for smoking after quit day, which are the main cause of early relapse. A prior systematic review showed inconclusive and heterogeneous evidence that preloading was effective and little evidence of the mechanism of action, with no cost-effectiveness data.ObjectivesTo assess (1) the effectiveness, safety and tolerability of nicotine preloading in a routine NHS setting relative to usual care, (2) the mechanisms of the action of preloading and (3) the cost-effectiveness of preloading.DesignOpen-label randomised controlled trial with examination of mediation and a cost-effectiveness analysis.SettingNHS smoking cessation clinics.ParticipantsPeople seeking help to stop smoking.InterventionsNicotine preloading comprised wearing a 21 mg/24 hour nicotine patch for 4 weeks prior to quit date. In addition, minimal behavioural support was provided to explain the intervention rationale and to support adherence. In the comparator group, participants received equivalent behavioural support. Randomisation was stratified by centre and concealed from investigators.Main outcome measuresThe primary outcome was 6-month prolonged abstinence assessed using the Russell Standard. The secondary outcomes were 4-week and 12-month abstinence. Adverse events (AEs) were assessed from baseline to 1 week after quit day. In a planned analysis, we adjusted for the use of varenicline (Champix®; Pfizer Inc., New York, NY, USA) as post-cessation medication. Cost-effectiveness analysis took a health-service perspective. The within-trial analysis assessed health-service costs during the 13 months of trial enrolment relative to the previous 6 months comparing trial arms. The base case was based on multiple imputation for missing cost data. We modelled long-term health outcomes of smoking-related diseases using the European-study on Quantifying Utility of Investment in Protection from Tobacco (EQUIPT) model.ResultsIn total, 1792 people were eligible and were enrolled in the study, with 893 randomised to the control group and 899 randomised to the intervention group. In the intervention group, 49 (5.5%) people discontinued preloading prematurely and most others used it daily. The primary outcome, biochemically validated 6-month abstinence, was achieved by 157 (17.5%) people in the intervention group and 129 (14.4%) people in the control group, a difference of 3.02 percentage points [95% confidence interval (CI) –0.37 to 6.41 percentage points; odds ratio (OR) 1.25, 95% CI 0.97 to 1.62;p = 0.081]. Adjusted for use of post-quit day varenicline, the OR was 1.34 (95% CI 1.03 to 1.73;p = 0.028). Secondary abstinence outcomes were similar. The OR for the occurrence of serious AEs was 1.12 (95% CI 0.42 to 3.03). Moderate-severity nausea occurred in an additional 4% of the preloading group compared with the control group. There was evidence that reduced urges to smoke and reduced smoke inhalation mediated the effect of preloading on abstinence. The incremental cost-effectiveness ratio at the 6-month follow-up for preloading relative to control was £710 (95% CI –£13,674 to £23,205), but preloading was dominant at 12 months and in the long term, with an 80% probability that it is cost saving.LimitationsThe open-label design could partially account for the mediation results. Outcome assessment could not be blinded but was biochemically verified.ConclusionsUse of nicotine-patch preloading for 4 weeks prior to attempting to stop smoking can increase the proportion of people who stop successfully, but its benefit is undermined because it reduces the use of varenicline after preloading. If this latter effect could be overcome, then nicotine preloading appears to improve health and reduce health-service costs in the long term. Future work should determine how to ensure that people using nicotine preloading opt to use varenicline as cessation medication.Trial registrationCurrent Controlled Trials ISRCTN33031001.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 22, No. 41. See the NIHR Journals Library website for further project information.

Swedish population reference standards for height, weight and body mass index (BMI) attained at 6 to 16 years (girls) or 19 years (boys) are presented. Data were obtained from two independent nationwide samples of Swedish children; one (740 children) born in 1955, the other (2907 children) born in 1967. The weights of the children born in 1955 were adjusted to equal those born in 1967; heights did not differ. These reference standards refer therefore to Swedish children born at around 1970. The observations were fitted by the power transformation, or L, M, S method of Cole and Green. Weights and BMIs were thus normalized and valid SD scores for individuals obtained. Centile charts are given for clinical use. The means of the present, nationwide standards were 1-2 cm and 1-2 kg greater than those of the Solna-based standards currently in use.

Summary. The paper discusses the contribution of R. A. Fisher to the theory and practice of statistics and tries to place these in their historical context.

Airway resistance using the interrupter technique (Rint) can be measured using commercial devices which employ different algorithms for estimating pressure change. We aim to describe differences in Rint due to algorithm. We compared Rint and change in Rint after bronchodilator, using four algorithms to estimate pressure change following interruption: 1) two-point back-extrapolation to interruption from points 70 msec and 30 msec from interruption, and similarly 2) to 15 msec from interruption, 3) at two-thirds from interruption, and 4) near end-interruption. Flow was measured immediately before interruption. Our subjects were 39 asymptomatic children 2–5 years old with previous intermittent wheeze. Rint differed significantly with algorithm. Geometric mean Rint (95% confidence interval (CI)) for algorithms 1–4 were 1.21 kPa · l−1 · sec (1.18–1.24 kPa · l−1 · sec), 1.31 kPa · l−1 · sec (1.28–1.34 kPa · l−1 · sec), 1.57 kPa · l−1 · sec (1.54–1.61 kPa · l−1 · sec) and 1.71 kPa · l−1 · sec (1.67–1.75 kPa · l−1 · sec), respectively. Measurement of change in Rint following bronchodilator (BDR) did not differ on average with algorithm. Geometric means (95% CI) for BDR measurements for algorithms 1–4 were 29.9% (26.0–34.0%), 30.4% (26.4–34.5%), 32.9% (28.8–37.1%), and 31.7% (27.6–35.8%), respectively. However, measurement of change in individuals could differ by up to 40%, depending on algorithm. In conclusion, there are significant differences in Rint, depending on algorithm used to estimate pressure change. Measurement of change in Rint is unaffected on average, although in individuals there could be significant differences. Each laboratory should state its method and use the same algorithm for longitudinal and group data. Pediatr Pulmonol. 2004; 37:31–36. © 2004 Wiley-Liss, Inc.

Since the introduction of new growth charts in the mid 1990s, there has been confusion about which charts should be used, with many districts using more than one version. Because of this uncertainty, an expert working party, the Growth Reference Review Group, was convened by the Royal College of Paediatrics and Child Health to provide guidance on the validity and comparability of the different charts currently in use. This paper describes the technical background to the construction and evaluation of growth charts and outlines the group's findings on the validity of each growth reference in relation to contemporary British children. The group concluded that for most clinical purposes the UK90 reference is superior and for many measures is the only usable reference that can be recommended, while the original Tanner-Whitehouse and the Gairdner-Pearson charts are no longer reliable for use at any age. After the age of 2 the revised Buckler-Tanner references are still suitable for assessing height. There are presently no reliable head circumference reference charts for use beyond infancy. The group propose that apart from refinements of chart design and layout, the new UK90 reference should now be "frozen", with any future revisions only undertaken after careful planning and widespread consultation.

We have assessed the medium-term effect of a short course of high-dose, alternate-day prednisolone on adult nephrotic patients with membranous nephropathy, using a randomized, prospective, double-blind, controlled trial. Patients were entered over the period 1981 to 1984 and were observed for a minimum of three years. One hundred and seven adult patients who had not previously received immunosuppressive treatment were included in the trial. One hundred and sixty further patients, excluded from the trial, but with membranous nephropathy were identified, followed and assesed retrospectively at the end of the trial. At 36 months there was no significant difference between control and treatment group in plasma creatinine, creatinine clearance or 24-h excretion of protein. At between three and six months serum albumin concentrations were higher and protein excretions lower in the treatment group compared to controls. No significant benefit was therefore observer on renal function in the medium term.

On the basis of 1090 x-ray films from 225 boys and 225 girls ages 8 to 16 years-participants in the Project Heartbeat longitudinal study who were living in a generally above-average income environment near Houston, Tex.-we provide Tanner-Whitehouse Mark 2 RUS (radius, ulna, and selected metacarpals and phalanges) bone age reference values for North American children of European origin. We designate these values as US90 (for the 1990s) reference values, in contrast to the original British bone age standards, called UK60 (for the 1960s). The US90 children matured considerably earlier than those on which the UK60 standards were based, though only about 3 months earlier than contemporary Spanish children. A study of 190 x-ray films from a research longitudinal series of 23 healthy boys in Virginia yielded values very close to the Houston values, confirming that our US90 reference values should be used in North America, pending a more extensive survey.

BACKGROUND: The pattern of growth of the uterus was examined by ultrasound examinations of 358 girls who attended a paediatric endocrine outpatient department but were shown not to have any endocrine defect. METHOD: The uterus was measured in length and width at the cervix and at the fundus (cm). Endometrial thickness was measured (mm). Scans were divided by Tanner breast stage and the dimensions compared by one way analysis of variance (ANOVA, with the Student Newman Keuls post hoc test). RESULTS: There was an increase in uterine length, diameter of the fundus, and endometrial thickness at each breast stage from 1 to 5 (ANOVA, p < 0.05), and in the diameter of the cervix with each breast stage from 1 to 4 (ANOVA, p < 0.05). The ratio of the fundus to the cervix increased from 0.95 to 1.29 between breast stages 1 and 4. CONCLUSION: The onset of puberty is marked by an increase in the dimensions of the uterus and in endometrial thickness, but also by a change in the shape of the uterus from a tubular to a pear shaped organ.

If a court fails to convict a defendant because of incomplete evidence, does that establish his innocence beyond doubt? Not necessarily. Indeed in Scotland, if sufficient uncertainty remains, the court can give a verdict of “not proven” instead of “not guilty”. If a randomised controlled trial (RCT) fails to show a significant difference between the treatment and the control group, does that prove that the treatment has no useful clinical effect? Again, not necessarily. The treatment may work, but the trial may have been unable to prove it.1 Despite this, many such “negative” trials,1 2 including many published in this journal, may wrongly be taken as evidence that the treatment is not clinically useful. For example, in an RCT of women at risk of preterm delivery that was not published as a full report,3 respiratory distress syndrome (RDS) occurred in three of 23 babies born to the treated group and three of 22 babies born to the untreated group. The difference is not significant (2p > 0.9). Had this been the first and only study of this treatment, many people might have decided that it was not effective and thus lost interest. In fact, overviews of this,3 and at least 14 other trials, eventually showed that the treatment—antenatal steroids—is highly effective because it reduced RDS and neonatal mortality in over 3500 preterm infants by about half.4 5 Note that the results of the single trial were quite consistent with this finding.3 The correct conclusion from that single trial …

OBJECTIVE--To determine whether admitting elderly patients to hospital to give temporary relief to their carers is associated with increased mortality. DESIGN--Prospective multicentre study comparing the mortality of patients admitted on a one off or rotational basis with that experienced while they were awaiting admission. SETTING--A wide range of urban and rural district general, geriatric or long stay, and general practitioner hospitals. PATIENTS--474 Patients aged 70 or over who had 601 admissions. MAIN OUTCOME MEASURE--Death. RESULTS--16 (3.4%) Of the 474 patients (2.7% of all 601 admissions) died while in hospital during an average stay of 15.7 days whereas 23 (4.9%) patients died while awaiting admission (average waiting time was 34.2 days). The 16 deaths in hospital and the 23 deaths during the longer waiting period correspond to death rates of 19.9 and 12.5 per 10,000 person days respectively. The difference between these of 7.4 is not statistically significant (95% confidence interval -3.6 to 18.3). The estimated relative risk of dying in hospital is 1.59 but the 95% confidence interval is wide (0.84 to 3.01). CONCLUSION--Although the death rates are slightly higher in those admitted to hospital for relief care than in those awaiting admission, the difference was not significant, and the death rate in both groups was reassuringly small.

Regional cerebral blood flow (CBF), oxygen extraction ratio (OER), oxygen utilization (CMRO2) and blood volume (CBV) were measured in a group of 34 healthy volunteers (age range 22–82 yrs) using the 15O steady-state inhalation method and positron emission tomography. Between subjects CBF correlated positively with CMRO2, although the interindividual variability of the measured values was large. OER was not dependent on CMRO2, but highly negatively correlated with CBF. CBV correlated positively with CBF. When considering the values of all the regions of interest within a single subject, a strict coupling between CMRO2 and CBF, and between CBF and CBV was found, while OER was constant and independent of CBF and CMRO2. In ‘pure’ grey and white matter regions CMRO2, CBF and CBV decreased with age approximately 0.50% per year. In other regions the decline was less evident, most likely due to partial volume effects. OER did not change or showed a slight increase with age (maximum in the grey matter region 0.35%/yr). The results suggest diminished neuronal firing or decreased dendritic synaptic density with age.

Editor—Dr Marlow’s interesting annotation on high frequency ventilation,1 with its pithy epigraph, adopts a common attitude to the methodology of medical research. This holds that, to be “scientific,” a study must specify a null hypothesis and then attempt, using data, to disprove it. This agrees with the writings of Karl Popper, but goes back further to the founding father of modern statistics, R A Fisher, who2 wrote: “Every experiment may …

The injection of pregnant mice with Coxsackievirus B3 results in a reduction of fetal weights and retarded development of the albumin/α1-fetoprotein ratio which can be measured by using the Laurell two-dimensional immunoelectrophoretic technique. The litter weights tended to be lower in litters with a low albumin/α1-fetoprotein ratio and from an analysis of covariance the results indicate that the effect of the virus on fetal weights can not all be accounted for by the effect on maturation.

A method is described which assesses results obtained from an ELISA system for the determination of human serum levels of IgG class antibodies to Aspergillus fumigatus. The method is used to discriminate positive from negative samples, and significant antibody activity may be reported to the clinician, relative to a reference positive control serum monitored simultaneously under the same test conditions. Antibody content is expressed as the absorbance of a certain dilution of serum. Duplicate samples were analysed at a single serum dilution and their absorbtion values obtained from a semi-automated ELISA microplate reader. These were entered into a computer programmed to convert the data into units on a logarithmic scale. In parallel experiments, ELISA results were compared with those obtained by the techniques of counterimmunoelectrophoresis and double diffusion which measure precipitating antibody of all classes. A relatively good degree of correlation between tests was found only among sera with a high level of antibody.

SUMMARY This paper shows that the notion of minimizing the disagreement between parallel assessments of the same quantity unifies a number of current methods of scaling and leads to straightforward extensions to cover new problems. Applications are found in the assessment of physical maturity, the measurement of children's behaviour, and in longitudinal studies with sets of items at several occasions.

Two experiments were carried out to determine whether 5% of dried grass meal as a source of carotene, together with 1 i.u./g. of synthetic vitamin D3 (cholecalciferol), can satisfactorily replace cod-liver oil in providing vitamins. A and D3 in chick mashes, and to assess the stability of these vitamins in normal commercial storage for up to 16 weeks. The rate of loss of carotene varied for different mashes and averaged 1% per week; grass meal stored alone lost only 0.5% of its carotene per week. The vitamin-D supplement proved ample at the end of the storage period, and with dried grass of good quality satisfactorily supplied the needs of chicks.

Various points were discussed by the 22 participants in the Symposium (doctors, statisticians and pharmacologists) under the following main headings: choice of subjects for a clinical trial, choice of treatments, criteria of assessment, trial design and “optimum” number of subjects. Difficulties most frequently met in each of these areas, open problems and hints at solutions are briefly reviewed in the report, special attention being paid to the alternative (especially relevant and critical in such fields as cancer clinical experimentation) between the two attitudes which are possible in a clinical trial context: the “explanatory” attitude (aimed at gaining basic knowledge about treatments) and the “pragmatic” attitude (aimed at guiding the decision on how to treat particular patients). Les auteurs presentent un bref rapport concernant un symposium sur les essais cliniques organise sous les auspices de l'UICC, qui s'est tenu en septembre 1969 a la Division de la recherche statistique de l'Institut National de la Sante et de la Recherche Medicale, a Villejuif. Plusieurs questions ont ete etudiees par les 22 participants au symposium (medecins, statisticiens et pharmacologues) sous les grandes rubriques suivantes: choix de sujets pour un essai clinique, choix des traitements, criteres d'evaluation, plan de l'essai et nombre optimal de sujets. Les difficultes les plus frequemment rencontrees dans chacun de ces domaines, les problemes non resolus et les indications qui laissent entrevoir la solution sont brievement analyses dans le rapport, sous l'angle particulier de l'option (particulierement utile et critique dans des domaines tels que l'experimentation clinique du cancer) entre les deux attitudes pouvant ětre adoptees dans le contexte d'un essai clinique: Vattitude” explicative” (visant a l'acquisition de connaissances fondamentales sur les traitements) et Vattitude “pragmatique” (visant a orienter la prise de decisions quant a la facon de traiter tel ou tel malade).

Ten skull characters were measured on each of 300 specimens ofCrocidura suaveolens(Pallas) and 99 specimens ofC. russulaHermann from five of the Scilly Isles, four of the Channel Isles and one locality on the mainland of France. No place contained both species. The characters were skull length, skull width, lengths of upper and lower tooth rows, distance between the third upper molars, distance between the upper premolars, length from the palate to the foramen magnum, the combined length in ventral aspect of the third upper incisor and canine and the mandibular height. The means of each measurement at each locality were calculated. Analyses of variance were also calculated and from these variance components within locality groups were obtained. An analysis into canonical variates was made with a view to accounting for the largest possible part of the variation between groups using a limited number of linear combinations of the original measurements. Most of the variance (82%) was contained in the first canonical variate and from the dispersion of the means of the samples the popula­tions ofCrociduraseparated into two main groups. One contained animals from Alderney, Guernsey and Cap Gris Nez (C. russula) and the other the remainder (C. suaveolens). The latter group subdivided, particularly with reference to the second canonical variate, into animals from Sark and Jersey and those from the Isles of Scilly. Differences between popula­tions from the Scilly Isles are very small, suggesting origin from a common stock. The shrews from Sark and Jersey differ more from each other than do any pair of Scilly Island popula­tions. The three populations ofC. russulado not form as close a cluster as the Scilly Island ones. The analyses of variance agree with these findings although for certain characters highly significant differences often occur between localities in a particular group.

Certain anatomical features of the pectoral girdle can be demonstrated to be functionally significant in the locomotor employment of the forelimb in different primate forms. In an earlier study, nine such shoulder features, examined individually, revealed the presence, within the Anthropoidea, of a graded contrast between brachiators, semibrachiators (progressing sometimes quadrupedally, sometimes by arm swinging) and quadrupeds. Within the Prosimii, corresponding contrasts obtain between hangers (resembling brachiators and semibrachiators in the frequent subjection of the arm to tensile forces) and quadrupeds (wherein, during locomotion, the arm functions as a strut). The compounding by canonical analysis of these nine features into mathematical functions best separating the means obtained for individual genera, reveals more detailed correlations between anatomical structure and locomotor pattern. Thus the first function disposes the Anthropoidea in a spectrum from the extreme brachiator Hylobates through the lesser brachiators Pan and Gorilla to such obtrusive semibrachiators as Ateles and Brachyteles, thence through intermediate members of the semibrachiator group to forms such as the infrequently arm-swinging Presbytis, thence to more agile, arboreal quadrupeds like Pithecia and Cacajao, and finally through intermediate members of this last group (e.g. Macaca) to such wholly terrestrial forms as Papio and Erythrocebus. The second function provides further information in that the genera are arranged in a sequence which extends from largely or wholly terrestrial forms at one extreme (e.g. Gorilla from among brachiators, low canopy species of Presbytis from among semibrachiators, Papio and Erythrocebus from among quadrupeds), to almost exclusively arboreal forms at the other extreme (e.g. Pongo among the brachiators, Brachyteles and Rhinopithecus among semibrachiators, Pithecia and Cacajao among quadrupeds). For the Prosimii, neither of these functions yields information additional to their separation into hangers and quadrupeds (coincident respectively with the semibrachiators and quadrupeds of the Anthropoidea) established by study of individual dimensions. All the subhuman primate genera lie close to the plane of the diagram formed by a combination of functions one and two, i.e. the third (and subsequent) functions are ineffective in their further separation. But, by the third function, man, whose individual dimensions agree sometimes with one group, sometimes with another, is clearly distinguished from all other primate forms—a distinction correlating with the unique functional activity of the human shoulder. Although this analysis separates various primate taxonomic groups below familial level, the particular locomotor features themselves do not (either singly or in combination) differentiate between Prosimii and Anthropoidea, nor between prosimian infraorders, or superfamilies of the Anthropoidea. However, other features of the shoulder girdle may make such a differentiation, and if so, a fossil form, studied in relation thereto and in relation to the analysis of locomotor features set out in this present study, could be interpreted both taxonomically and in terms of probable shoulder activity.

A series of nineteen different biometrical characters have been measured on the scutal and tergal valves of the boreo-arctic Balanus balanoides collected from over its whole area of distribution; these values attempt to define the shape of the valves.

RESP?

The Tables for using Behren's test of significance of the difference between the means of two Normal samples are already available to reasonable accuracy for all cases save those involving very small samples (Statistical Tables, Tables VI, V2). In some experimental work, however, such small samples occur in conditions in which only Behren's test is appropriate. The calculation of values for such cases is greatly facilitated by the explicit expressions developed in this note for the probability integral, when the numbers of degrees of freedom are both odd.

IN THlE critical study of the results of large-scale sample surveys it is frequently necessary to consider data classified in several different ways, and to attempt to disentangle the effects of the various classifications which will usually not be orthogonal to one another. One way of doing this is to fit constants by least squares, assuming the effects implied by the classifications to be additive; for a discussion of the method, see Yates [6, p. 137 et seq.]. The process of fitting involves the solution of the normal equations, a set of simultaneous equations equal in number to the total number of categories in all the classifications. If this number is at all large, the computations become very lengthy, and it is desirable to use Hollerith machinery, more especially as the main computations of the survey will often be done on Hollerith machines, and the data will already be punched on cards. At least two methods of solving simultaneous equations with the aid of Hollerith machines have been published [3, 4]. Both employ a technique of pivotal condensation, and demand the use of a range of machines outside the scope of a small installation. In the present coiltext the large number of equations may lead to a serious accumulation of rounding errors, and there are advantages in the alternative technique of successive approximation, as described, for example, by Stevens [5]. The present paper gives a method of mechanising this technique, using only the basic Hollerith machines, the sorter and tabulator. For producing the working pack, a reproducer is desirable though not essential.

Measurements of ten skull characters were made on each of 352 specimens ofApodemus sylvaticus(L.) and 37 specimens ofA. flavicollis(Melch.). The latter were obtained from southern England and the former from five of the Channel Islands, two localities in southern England and one in northern France. The characters were greatest length, greatest width, interorbital breadth, cranial breadth, width of foramen magnum, length of maxillary tooth row, length of palatal foramen, distance between ventro-posterior processes of pterygoids, length of mesopterygoid fossa and minimum distance between first upper molars. The ages of the skulls were ascertained by means of a tooth-wear measurement. A regression adjustment was used to bring all the characters to a uniform age class. The sexes were separate throughout the analyses. The unadjusted and adjusted means have been calculated of each character for every locality. Appreciable variation occurs between the populations examined, with the females slightly smaller than the males but following the same general pattern of variation. An analysis into canonical variates was made with a view to accounting for the largest possible part of the variation between groups using a limited number of linear combinations of the original measurements. Almost all the variance was contained in the first four canonical variates and from these it appeared that the populations separated into three groups. The first contained the mainland mice from Hampshire, Cornwall and Cap Gris Nez, the second those from the Channel Islands and the third the collection ofA. flavicollis.The analysis confirms that in the British IslesA. flavicollisis distinct fromA. sylvaticusand that the Channel Island mice, although larger than the mainlandA. sylvaticus, probably belong to that species. Differences between populations from the Channel Islands are small, although the mice from Herm and Sark are relatively large. It is possible that the Channel Island mice could have been derived from a common stock.

The ready availability of multiple chemical and haematological measurements brings with it the possibility of increased diagnostic usefulness. Abnormalities that are not apparent in single measurements may be shown up when several measurements are suitably combined. However, multiple measurements bring problems as well as benefits; it is possible for several measurements to be less powerful in detecting abnormality than a single measurement would be, especially if the type of abnormality is ill-defined.