High-dimensional immune cell profiling of cerebrospinal fluid from patients with metastatic breast cancer and leptomeningeal disease.

Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer (MBC). In this non-therapeutic study, we enrolled 12 patients with MBC and known or suspected LMD who were undergoing a lumbar puncture as part of clinical care and collected extra cerebrospinal fluid (CSF) and a paired blood sample from each patient at a single time point. Of the 12 patients, 7 patients are confirmed to have LMD based on positive cytology and/or convincing MRI imaging (LMDpos), and 5 patients are deemed not to have LMD based on similar criteria (LMDneg). Using high-dimensional, multiplexed flow cytometry, we profile and compare the CSF and peripheral blood mononuclear cell (PBMCs) immune populations between patients with LMD and those without. Patients with LMD observe a lower overall frequency of CD45+ cells (29.51% vs. 51.12%, p < 0.05), lower frequencies of CD8+ T cells (12.03% vs. 30.40%, p < 0.01), and higher frequency of Tregs than patients without LMD. Interestingly, the frequency of partially exhausted CD8+ T cells (CD38hiTIM3lo) is ~6.5-fold higher among patients with LMD vs. those without (2.99% vs. 0.44%, p < 0.05). Taken together, these data suggest that patients with LMD may have lower overall immune infiltrates than patients without LMD, suggesting a more permissive CSF immune microenvironment but a higher frequency of partially exhausted CD8+ T cells, which may offer an important therapeutic target.

Do studies published in two leading reproduction journals between 2011 and 2020 demonstrate that they followed WHO5 recommendations for basic semen analysis?

STUDY QUESTION: Do publications that involve the interpretation of the results of a basic semen analysis, published in Human Reproduction and Fertility & Sterility between 2011 and 2020, give sufficient evidence in their methodology to demonstrate that they followed the technical methods recommended in the fifth edition of the World Health Organization (WHO) laboratory manual, entitled WHO Laboratory Manual for the Examination and Processing of Human Semen (WHO5)? SUMMARY ANSWER: Evidence of methodological agreement of studies with the WHO5 recommendations was low, despite 70% of papers stating that they followed WHO5 recommendations. WHAT IS KNOWN ALREADY: A basic semen analysis is currently an integral part of infertility investigations of the male, but method standardization in laboratories remains an issue. The different editions of the WHO manual for the basic semen analysis (WHO1-6) have attempted to address this by providing increasingly rigorous methodological protocols to reduce experimental error. However, to what extent these methods are followed by studies that involve the interpretation of the results of basic semen analysis remains unknown. STUDY DESIGN, SIZE, DURATION: A survey of the technical methods used to perform a basic semen analysis was conducted on studies published in two leading reproduction journals (Human Reproduction and Fertility & Sterility) between 2011 and 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: The literature search was performed on the electronic databases PUBMED and MEDLINE Ovid between January 2021 and March 2021. The MeSH terms included in the search were 'sperm concentration' OR 'sperm motility' OR 'sperm morphology' OR 'sperm vitality' OR 'male fertility' AND 'human spermatozoa' NOT 'animals'. A total of 122 studies were available for analysis. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 70% of the studies cited WHO5 in their methods section. Of the remaining studies, 10% cited the fourth edition of the WHO laboratory manual (WHO4), 7% cited both WHO4 and WHO5, 1% cited the third edition of the WHO laboratory manual (WHO3), and 12% did not cite the WHO at all. Overall methodological agreement with WHO5 recommendations was poor, with the main reason for this lack of agreement being that the research studies did not disclose specific details of the technical methods and equipment used. LIMITATIONS, REASONS FOR CAUTION: In the case of studies that did not disclose any specific technical methods that they used, we did not attempt to contact these authors and so were unable to confirm the agreement between their technical methods and WHO5 recommendations. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest there is an urgent need to develop strategies to address standardization in reporting the results of a semen analysis for publication. This is particularly timely given the recent publication of WHO6 and ISO standard 23162 for the basic examination of human semen. STUDY FUNDING/COMPETING INTEREST(S): There was no funding for this project. C.L.R.B., as an employee of the University of Dundee, serves on the Scientific Advisory board of ExSeed Health (from October 2021, financial compensation to the University of Dundee) and is a scientific consultant for Exscientia (from September 2021, financial compensation to the University of Dundee). C.L.R.B. has previously received a fee from Cooper Surgical for lectures on scientific research methods outside the submitted work (2020) and Ferring for a lecture on male reproductive health (2021). C.L.R.B. is Editor for RBMO. TRIAL REGISTRATION NUMBER: N/A.

Cardiac arrhythmias and electrophysiologic responses during spontaneous hyperglycaemia in adults with type 1 diabetes mellitus.

AIM: We examined the effect of spontaneous hyperglycaemia in adults with type 1 diabetes mellitus (T1DM) and without history of cardiovascular disease on heart rate variability (HRV), cardiac repolarisation and incidence of cardiac arrhythmias. METHODS: Thirty-seven individuals with T1DM (age 17-50 years, 19 males, mean duration of diabetes 19.3 SD(9.6) years) underwent 96 h of simultaneous ambulatory 12-lead Holter ECG and blinded continuous interstitial glucose (IG) monitoring (CGM). HRV, QT interval and cardiac repolarisation were assessed during hyperglycaemia (IG ≥ 15 mmol/l) and compared with matched euglycaemia (IG 5-10 mmol/l) on a different day, separately during the day and night. Rates of arrhythmias were assessed by calculating incidence rate differences. RESULTS: Simultaneous ECG and CGM data were recorded for 2395 hours. During daytime hyperglycaemia vs euglycaemia the mean QTc interval duration was 404 SD(21)ms vs 407 SD(20)ms, P = 0.263. T-peak to T-end interval duration corrected for heart rate (TpTendc) shortened: 74.8 SD(16.1)ms vs 79.0 SD(14.8)ms, P = 0.033 and T-wave symmetry increased: 1.62 SD(0.33) vs 1.50 SD(0.39), P = 0.02. During night-time hyperglycaemia vs euglycaemia, the mean QTc interval duration was 401 SD(26)ms vs 404 SD(27)ms, P = 0.13 and TpTend shortened: 62.4 SD(12.0)ms vs 67.1 SD(11.8)ms, P = 0.003. The number of cardiac arrhythmias was low and confined to bradycardia and isolated ectopic beats. A considerable inter-subject and diurnal variability was observed. CONCLUSIONS: Hyperglycaemia in individuals with T1DM without known cardiovascular disease was not associated with clinically important cardiac arrhythmias.

Myeloperoxidase inhibitor AZD5904 enhances human sperm function in vitro.

STUDY QUESTION: Does AZD5904, a myeloperoxidase inhibitor (MPOi), have any effect on human sperm function in vitro? SUMMARY ANSWER: AZD5904 improves sperm function in an in vitro model of oxidative stress (OS) and potentially offers a novel treatment approach for male infertility. WHAT IS KNOWN ALREADY: Male infertility is an underlying or contributory cause in half of all couples experiencing difficulties conceiving, yet there is currently no effective treatment or cure. OS is a common pathology in a significant proportion of infertile men. It can negatively affect sperm motility and the ability to fertilize a mature oocyte, as well as DNA integrity, and therefore represents an attractive target for therapeutic intervention. STUDY DESIGN, SIZE, DURATION: This study included population-based samples from men (23-50 years) attending Ninewells Assisted Conception Unit, Dundee for diagnostic semen analysis, July 2017-September 2018. Semen samples (n = 47) from 45 patients were used. PARTICIPANTS/MATERIALS, SETTING, METHODS: Neutrophils activated using zymosan were incubated with prepared human spermatozoa for 2 h (T2) and 24 h (T24) to create an in vitro model of OS. Parallel samples were co-incubated with AZD5904, an MPOi, to examine its effects. Sperm motility was assessed by computer-assisted sperm analysis at T2 and T24. Functional motility was assessed by sperm penetration assay. Statistical analysis was performed using GraphPad Prism. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in total or progressive sperm motility between any treatment and control groups at T2 or T24. Nonetheless, significant positive effects on sperm function were observed with AZD5904, with 16/45 (35.6%) samples (with both normal and abnormal baseline semen analysis characteristics) displaying a ≥20% increase in sperm penetrated through viscous media (P < 0.003). LIMITATIONS, REASONS FOR CAUTION: This was an in vitro study. WIDER IMPLICATIONS OF THE FINDINGS: Treatment with AZD5904 resulted in significant increased sperm penetration in one of three samples treated, which is likely to represent improvement in sperm function required for fertilization. We are now planning a clinical trial to validate these results and hope that this could represent a new treatment for male infertility. STUDY FUNDING/COMPETING INTEREST(S): AZD5904 was shared through the AstraZeneca Open Innovation program. The study was funded by AstraZeneca and sponsored by the University of Dundee. Additional funding was provided by Chief Scientist Office/NHS Research Scotland (S.J.M.d.S.). A.W. and H.J.S. are both full time employees of AstraZeneca. A.W. and H.J.S. are inventors on a patent filed by AstraZeneca titled MPOi for use in medicine which includes MPOi for use in the treatment of male infertility (WO 2019/016074 Al). S.J.M.d.S. is Associate Editor of Human Reproduction and Editorial Board member of Reproduction & Fertility. C.L.R.B. is Editor of RBMO and has received lecturing fees from Merck and Ferring and is on the Scientific Advisory Panel for Ohana BioSciences. C.L.R.B. was chair of the World Health Organization Expert Synthesis Group on Diagnosis of Male infertility (2012-2016). C.L.R.B. has a patent WO2013054111 A1 issued. The other authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

A randomised controlled trial is not a pilot trial simply because it uses a surrogate endpoint.

BACKGROUND: It has been argued that true endpoints (or 'hard' endpoints) for clinical trials, which are meaningful to clinicians, researchers and patients alike, are limited to those that measure health status, survival and cost. Other endpoints are termed 'surrogate' endpoints and are intended to substitute and predict the true endpoint.  A number of trials that describe using surrogate endpoints use the term 'pilot' in the title of the paper but the reason for this, as related by the authors, is the use of these surrogate endpoints in the trial. The conduct and reporting of such a trial may follow the traditional pattern for a conventional randomised controlled trial (RCT) as defined by the original CONSORT statement, with power-based sample size calculations, and significance tests of the results. However, this is contrary to the guidelines of the CONSORT extension for the reporting of pilot trials. MAIN BODY: We review the definition of a surrogate endpoint and the use of surrogate endpoints in clinical trials. We consider to what extent a trial could be considered a pilot trial if it uses a surrogate endpoint and discuss two examples that illustrate current practice. CONCLUSION: Trials which use surrogate endpoints should only be described as 'pilot' when a definitive trial is a distinct possibility and the authors consider conditions which would indicate whether the definitive main trial was worthwhile and feasible. Simply because a trial uses a surrogate endpoint is not justification for calling it a pilot trial.

Change in diagnostic confidence brought about by using in utero MRI for fetal structural brain pathology: analysis of the MERIDIAN cohort.

AIM: To measure possible change in diagnostic confidence by performing in utero magnetic resonance imaging (iuMRI) studies on fetuses with brain abnormalities recognised on ultrasonography (US). MATERIALS AND METHODS: The analyses are based on the primary cohort from the prospective MERIDIAN study, which consisted of 570 fetuses with brain abnormalities detected on US, with iuMRI performed within 2 weeks of US and complete outcome reference data. The cohort was recruited between July 2011 and August 2014, and written informed consent was obtained for all participants. They all had indicators of diagnostic confidence measured on US by fetal medicine experts and iuMRI by the reporting radiologists. Three assessments were carried out using the conventional uncorrected (C2-C1%) method, the conventional (C2-C1%) with the Omary correction, and the score-based weighted average method. RESULTS: All three assessments showed statistically significant (p<0·0001) positive effects indicating that iuMRI was potentially beneficial when included in the diagnostic pathway for prenatal structural brain anomalies (in terms of diagnostic confidence). CONCLUSION: These results strongly support the routine clinical use of iuMRI as an adjunct to US when assessing fetuses with structural brain abnormalities.

Adjusting for treatment switching in randomised controlled trials - A simulation study and a simplified two-stage method.

Estimates of the overall survival benefit of new cancer treatments are often confounded by treatment switching in randomised controlled trials (RCTs) - whereby patients randomised to the control group are permitted to switch onto the experimental treatment upon disease progression. In health technology assessment, estimates of the unconfounded overall survival benefit associated with the new treatment are needed. Several switching adjustment methods have been advocated in the literature, some of which have been used in health technology assessment. However, it is unclear which methods are likely to produce least bias in realistic RCT-based scenarios. We simulated RCTs in which switching, associated with patient prognosis, was permitted. Treatment effect size and time dependency, switching proportions and disease severity were varied across scenarios. We assessed the performance of alternative adjustment methods based upon bias, coverage and mean squared error, related to the estimation of true restricted mean survival in the absence of switching in the control group. We found that when the treatment effect was not time-dependent, rank preserving structural failure time models (RPSFTM) and iterative parameter estimation methods produced low levels of bias. However, in the presence of a time-dependent treatment effect, these methods produced higher levels of bias, similar to those produced by an inverse probability of censoring weights method. The inverse probability of censoring weights and structural nested models produced high levels of bias when switching proportions exceeded 85%. A simplified two-stage Weibull method produced low bias across all scenarios and provided the treatment switching mechanism is suitable, represents an appropriate adjustment method.

Chronic obstructive pulmonary disease in Welsh slate miners.

BACKGROUND: Exposure to respirable crystalline silica (RCS) causes emphysema, airflow limitation and chronic obstructive pulmonary disease (COPD). Slate miners are exposed to slate dust containing RCS but their COPD risk has not previously been studied. AIMS: To study the cumulative effect of mining on lung function and risk of COPD in a cohort of Welsh slate miners and whether these were independent of smoking and pneumoconiosis. METHODS: The study was based on a secondary analysis of Medical Research Council (MRC) survey data. COPD was defined as forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio <0.7. We created multivariable models to assess the association between mining and lung function after adjusting for age and smoking status. We used linear regression models for FEV1 and FVC and logistic regression for COPD. RESULTS: In the original MRC study, 1255 men participated (726 slate miners, 529 unexposed non-miners). COPD was significantly more common in miners (n = 213, 33%) than non-miners (n = 120, 26%), P < 0.05. There was no statistically significant difference in risk of COPD between miners and non-miners when analysis was limited to non-smokers or those without radiographic evidence of pneumoconiosis. After adjustment for smoking, slate mining was associated with a reduction in %predicted FEV1 [ß coefficient = -3.97, 95% confidence interval (CI) -6.65, -1.29] and FVC (ß coefficient = -2.32, 95% CI -4.31, -0.33) and increased risk of COPD (odds ratio: 1.38, 95% CI 1.06, 1.81). CONCLUSIONS: Slate mining may reduce lung function and increase the incidence of COPD independently of smoking and pneumoconiosis.

Stepped wedge cluster randomised trials: a review of the statistical methodology used and available.

BACKGROUND: Previous reviews have focussed on the rationale for employing the stepped wedge design (SWD), the areas of research to which the design has been applied and the general characteristics of the design. However these did not focus on the statistical methods nor addressed the appropriateness of sample size methods used.This was a review of the literature of the statistical methodology used in stepped wedge cluster randomised trials. METHODS: Literature Review. The Medline, Embase, PsycINFO, CINAHL and Cochrane databases were searched for methodological guides and RCTs which employed the stepped wedge design. RESULTS: This review identified 102 trials which employed the stepped wedge design compared to 37 from the most recent review by Beard et al. 2015. Forty six trials were cohort designs and 45 % (n = 46) had fewer than 10 clusters. Of the 42 articles discussing the design methodology 10 covered analysis and seven covered sample size. For cohort stepped wedge designs there was only one paper considering analysis and one considering sample size methods. Most trials employed either a GEE or mixed model approach to analysis (n = 77) but only 22 trials (22 %) estimated sample size in a way which accounted for the stepped wedge design that was subsequently used. CONCLUSIONS: Many studies which employ the stepped wedge design have few clusters but use methods of analysis which may require more clusters for unbiased and efficient intervention effect estimates. There is the need for research on the minimum number of clusters required for both types of stepped wedge design. Researchers should distinguish in the sample size calculation between cohort and cross sectional stepped wedge designs. Further research is needed on the effect of adjusting for the potential confounding of time on the study power.

A cluster randomized controlled non-inferiority trial of 5-day Dose Adjustment for Normal Eating (DAFNE) training delivered over 1 week versus 5-day DAFNE training delivered over 5 weeks: the DAFNE 5 × 1-day trial.

AIMS: To compare, in a randomized controlled non-inferiority trial, the outcomes of the traditional format for Dose Adjustment for Normal Eating structured education courses; that is, one delivered over 5 consecutive days (1-week course) with a variant of this format delivered 1 day a week for 5 consecutive weeks (5-week course). METHODS: Adults with Type 1 diabetes, from seven UK Dose Adjustment For Normal Eating training centres, were individually randomized, stratified by centre, to receive either a 1-week or 5-week course. A qualitative study was embedded within the trial to explore patients' experiences. RESULTS: In total, 213 patients were randomized and 160 completed the study procedures. In the per-protocol analysis, the difference in HbA1c levels (95% CI) between the arms at 6 months was 0.4 mmol/mol (-2.4, 3.1) or 0.03% (-0.22, 0.28) and -0.9 mmol/mol (-3.9, 2.2) or -0.08% (-0.36, 0.20) at 12 months. All confidence limits were within the non-inferiority margin of ± 5.5 mmol/mol (0.5%) for HbA1c %. For those patients with a baseline HbA1c of ≥ 58 mmol/mol (≥ 7.5%) the mean change (95% CI) in HbA1c was -2.2 mmol/mol (-4.0, -0.4) or -0.20% (-0.37, -0.04) at 6 months (P = 0.016), and -2.0 mmol/mol (-4.1, 0.04) or -0.18% (-0.37 to 0.004) at 12 months (P = 0.055). Episodes of severe hypoglycaemia were decreased by 82% [relative risk 0.18 (95% CI 0.03-0.936); P = 0.042], psychosocial outcomes improved significantly, and the difference between arms was not significant. Qualitative interviews showed that patients overwhelmingly favoured the format of course that they attended. CONCLUSIONS: In summary, 5-week and 1-week Dose Adjustment for Normal Eating courses are equivalent in terms of biomedical and psychosocial outcomes, and we were persuaded that both course formats should be made available in routine care.

Impact of a GP-led walk-in centre on NHS emergency departments.

OBJECTIVE: To determine the impact of the GP-led walk-in centre (WIC) in Sheffield (England) on the demand for emergency department (ED) care. METHODS: A survey of patients visiting the Sheffield GP WIC was conducted over 3 weeks during September and October 2011. A short, postvisit questionnaire was also sent to those who agreed to determine if the patient had used another NHS service for the same problem. Routine data were obtained from the adult and children's EDs and minor injuries unit in Sheffield, 1 year before and 1 year after the opening of the GP WIC. A linear model of the number of minor daytime attendances (GP type) per month was used to estimate the impact of opening the GP WIC, after controlling for seasonal variation and a linear time trend. RESULTS: A total of 529 patients responded to the survey (response rate 51%). Based on their self-reported intentions, 64 of these patients (53 adults and 11 children) were diverted from going to ED in the 3-week survey period as a result of the establishment of the GP WIC. From this we would have expected around a 26% monthly reduction in GP-type attendances at adult ED, and 7% reduction at children's ED. However, routine data only showed an 8% (95% CI 1% to 16%) reduction at the adult ED. Reductions in GP-type attendances at the children's ED and the minor injury unit at the time of the opening of the GP WIC were also found, but were not statistically significant. The estimated impact on children's ED was a 14% reduction (95% CI -38% to 8%), and for minor injuries unit (MIU) a 4% reduction (95% CI -18 to 9%). CONCLUSIONS: There was a statistically significant reduction in GP-type daytime attendances at the adult ED after the opening of the GP WIC. Since this reduction was not mirrored in changes in night-time attendances (when the GP WIC was closed), and our survey responses suggested some people were diverted from going to the ED, it is possible that the opening of the GP WIC caused this reduction.

Substantial reductions in the number of diabetic ketoacidosis and severe hypoglycaemia episodes requiring emergency treatment lead to reduced costs after structured education in adults with Type 1 diabetes.

AIMS: To determine the impact of structured education promoting flexible intensive insulin therapy on rates of diabetic ketoacidosis, and the costs associated with emergency treatment for severe hypoglycaemia and ketoacidosis in adults with Type 1 diabetes. METHODS: Using the Dose Adjustment For Normal Eating research database we compared the rates of ketoacidosis and severe hypoglycaemia during the 12 months preceding Dose Adjustment For Normal Eating training with the rates during the 12-month follow-up after this training. Emergency treatment costs were calculated for associated paramedic assistance, Accident and Emergency department attendance and hospital admissions. RESULTS: Complete baseline and 1-year data were available for 939/1651 participants (57%). The risk of ketoacidosis in the 12 months after Dose Adjustment For Normal Eating training, compared with that before training, was 0.39 (95% CI: 0.23 to 0.65, P < 0.001), reduced from 0.07 to 0.03 episodes/patient/year. For every 1 mmol/mol unit increase in HbA1c concentration, the risk of a ketoacidosis episode increased by 6% (95% CI: 5 to 7%; 88% for a 1% increase), and for each 5-year increase in diabetes duration, the relative risk reduced by 20% (95% CI: 19 to 22%). The number of emergency treatments decreased for ketoacidosis (P < 0.001), and also for severe hypoglycaemia, including paramedic assistance (P < 0.001), Accident and Emergency department attendance (P = 0.029) and hospital admission (P = 0.001). In the study cohort, the combined cost of emergency treatment for ketoacidosis and severe hypoglycaemia fell by 64%, from £119,470 to £42,948. CONCLUSIONS: Structured training in flexible intensive insulin therapy is associated with a 61% reduction in the risk of ketoacidosis and with 64% lower emergency treatment costs for ketoacidosis and severe hypoglycaemia.

Biology of breast cancer in Nigerian women: a pilot study.

BACKGROUND: Compared to the developed world, there are relatively few studies that describe the tumor biology of breast cancer in African women. While little is known about the tumor biology, clinical and epidemiologic studies suggest that breast cancer in African women are characterized by presentation at late stage and poor clinical outcomes. Analysis of the biological features of breast cancers in Nigerian women was designed to bring additional insight to better understand the spectrum of disease, the phenotypes that present, and the types of interventions that might improve outcomes. MATERIALS AND METHODS: We performed histological analyses for hormone receptors (estrogen and progesterone receptors), HER2, and tumor infiltrating macrophages (TAM) on 17 breast cancers, obtained from Abia State University Teaching Hospital (Aba, Nigeria), between November 2008 and October 2009. On a subset of these cases, we investigated the potential role of a virus in the etiology of these aggressive cancers. RESULTS: The majority of cases in this cohort were characterized as high grade (100% were grade III), triple-negative (65%), and occur in young women (mean age 47 years). We observed high infiltration of TAMs in these tumors, but no evidence of a viral etiology. CONCLUSION: Our findings indicate that breast cancers in Nigerian women have a highly aggressive phenotype (high grade, hormone receptor negative), which is similar to other studies from Africa and other developing nations, as well as from African American women, but is significantly different from Caucasian women in the developed world. The presence of high numbers of TAMs in these tumors raises the possibility of targeting the immune microenvironment for therapeutic interventions.

The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes.

AIMS/HYPOTHESIS: Diagnosing MODY is difficult. To date, selection for molecular genetic testing for MODY has used discrete cut-offs of limited clinical characteristics with varying sensitivity and specificity. We aimed to use multiple, weighted, clinical criteria to determine an individual's probability of having MODY, as a crucial tool for rational genetic testing. METHODS: We developed prediction models using logistic regression on data from 1,191 patients with MODY (n = 594), type 1 diabetes (n = 278) and type 2 diabetes (n = 319). Model performance was assessed by receiver operating characteristic (ROC) curves, cross-validation and validation in a further 350 patients. RESULTS: The models defined an overall probability of MODY using a weighted combination of the most discriminative characteristics. For MODY, compared with type 1 diabetes, these were: lower HbA(1c), parent with diabetes, female sex and older age at diagnosis. MODY was discriminated from type 2 diabetes by: lower BMI, younger age at diagnosis, female sex, lower HbA(1c), parent with diabetes, and not being treated with oral hypoglycaemic agents or insulin. Both models showed excellent discrimination (c-statistic = 0.95 and 0.98, respectively), low rates of cross-validated misclassification (9.2% and 5.3%), and good performance on the external test dataset (c-statistic = 0.95 and 0.94). Using the optimal cut-offs, the probability models improved the sensitivity (91% vs 72%) and specificity (94% vs 91%) for identifying MODY compared with standard criteria of diagnosis <25 years and an affected parent. The models are now available online at www.diabetesgenes.org . CONCLUSIONS/INTERPRETATION: We have developed clinical prediction models that calculate an individual's probability of having MODY. This allows an improved and more rational approach to determine who should have molecular genetic testing.

Seasonality of medical contacts in school-aged children with asthma: association with school holidays.

OBJECTIVES: To assess the seasonality of medical contacts in children with asthma, to compare England with Scotland, and to assess the impact of medication compliance on the frequency of medical contacts. STUDY DESIGN: A retrospective study taken from the General Practice Research Database of daily medical contacts from 1999 to 2005 in a population of school-aged (5-16 years) children with a diagnosis of asthma, and age- and gender-matched controls. PRIMARY OUTCOME MEASURE: All unscheduled medical contacts. Prescription frequency for inhaled corticosteroids over the same period was also assessed. RESULTS: Data from 76,924 children were analyzed. There was an increase in unscheduled medical contacts for all children on return to school in September. Unscheduled medical contacts occurred almost twice as frequently in children with asthma compared with non-asthmatic children. The frequency of medical contacts in children with asthma could be predicted from the frequency of medical contacts in non-asthmatic children. In the 3 months from September to December, unscheduled medical contacts were disproportionately greater than would be predicted for children with asthma relative to non-asthmatic children in both England and Scotland. The rise in medical contacts in Scotland preceded that in England by approximately 14 days, reflecting the earlier date for returning to school. The number of prescriptions for inhaled corticosteroids decreased in August. A higher incidence of unscheduled medical contacts was noted during September in those not receiving a prescription in August. CONCLUSIONS: Returning to school after the summer break is associated with a sharp increase in unscheduled medical contacts in school-aged children, particularly in those with asthma. This follows a decrease in the number of prescriptions for inhaled corticosteroids. It is suggested that at least part of the excess numbers of unscheduled contacts in children with asthma is because they do not maintain their inhaled corticosteroids over the summer holidays.

Epidemiology of scabies prevalence in the U.K. from general practice records.

BACKGROUND: Scabies is a contagious parasitic infestation which causes an allergic reaction to just a few mites. OBJECTIVES: To examine the epidemiology of scabies consultations in the U.K. by age, sex, region of the country and time. METHODS: Data were obtained from the THIN (The Health Information Network) database provided by EPIC U.K. in which each consultation episode is coded according to a 'READ' code. Data were available for 1997-2005 inclusive (9 years) for approximately 8·5% of the U.K. population from 12 regions of the U.K. We used harmonic analysis to model the data over time and derived cycle amplitudes and phases for each region in the U.K. RESULTS: There was a significantly greater infestation rate among females with a relative risk of 1·24 (P < 0·001) relative to males. The age group 10-19 years had the highest infestation rates (with rates of 4·55 per 1000 and 5·92 per 1000 for males and females, respectively). The middle age groups had the smallest infestation rates. A cycle with length of between 15 and 17 years was derived, and the phase times of the cycles for each region suggested a progression of the disease originating from the North East, spreading to Northern parts of the U.K. and then to the Midlands and the South. CONCLUSIONS: The study confirms earlier studies with regard to the age/sex distribution of scabies. We suggest a contagious pattern of spread of scabies infestation in the U.K. with an epidemic cycle length of 15-17 years.