A large outbreak of the Kappa mutation of COVID-19 in Cork, Ireland, April-May 2021.

BACKGROUND: In May 2021, the B.1.617 variant of SARS-CoV-2 emerged in Ireland, and both Delta and Kappa sub-lineages were initially deemed variants of concern (VOCs) on a precautionary basis. We describe a large outbreak of SARS-CoV-2 B.1.617.1 (Kappa mutation) linked to a private gathering among third level students in Cork, Ireland. METHODS: Surveillance data were available from the Health Service Executive COVID Care Tracker. The epidemiological sequence of infection for each new case in this outbreak was tracked and whole genome sequencing was requested on all linked cases. Enhanced public health control measures were implemented by the Department of Public Health HSE-South to contain onward spread of VOCs, including retrospective contact tracing, lengthy isolation and quarantine periods for cases and close contacts. Extensive surveillance efforts were used to describe and control onward transmission. RESULTS: There were 146 confirmed SARS-CoV-2 cases linked to the outbreak. All sequenced cases (53/146; 36%) confirmed Kappa mutation. The median age was 21 years (range 17-65). The majority (88%) had symptoms of SARS-CoV-2 infection. There were 407 close contacts; the median was 3 per case (range 0-14). There were no known hospitalisations, ICU admissions or deaths. Vaccination data was unavailable, but the outbreak pre-dated routine availability of COVID-19 vaccines among younger adults in Ireland. CONCLUSION: Enhanced public health control measures for new and emerging variants of SARS-CoV-2 may be burdensome for cases and close contacts. The overall public health benefit of enhanced controls may only become apparent when evidence on disease transmissibility and severity becomes more complete.

Cardiopulmonary Exercise Testing Versus Frailty, Measured by the Clinical Frailty Score, in Predicting Morbidity in Patients Undergoing Major Abdominal Cancer Surgery.

BACKGROUND: The primary outcome of this study is to investigate the association between the cardiopulmonary exercise testing (CPET) variables: anaerobic threshold (AT), peak oxygen uptake (VO2 peak), peak work rate (WR), ventilatory equivalence of CO2 (VE/VCO2) at the anaerobic threshold (AT) with frailty, measured by the clinical frailty scale (CFS) in patients planned to undergo major abdominal cancer surgery. The secondary outcome is to compare the CPET variables (VO2 peak, peak WR, VE/VCO2 at AT) with frailty measured by the CFS in predicting postoperative surgical morbidity in patients following major abdominal cancer surgery. METHODS: This study was a single-centre prospective cohort analysis of consecutive adult patients undergoing CPET and CFS scoring as part of their pre-operative work-up for major abdominal cancer surgery. RESULTS: A total of n = 317 patients underwent CPET and CFS assessment ahead of planned abdominal oncological surgery. Negative correlations were observed between the CPET variables: AT - 0.42 p < 0.01; VO2 peak - 0.53 p < 0.01; peak WR - 0.54 p < 0.01 with CFS scores and a positive correlation between CFS scores and VE/VCO2 0.29 p < 0.01. Only CFS remained statistically significant in a multivariate model OR 2.11 (1.42-3.15) 95% CI associated with Clavien-Dindo (CD) ≥ 1 defined morbidity including the significant univariate variables (VO2 peak, peak WR and CFS scores). No variables were associated with CD ≥ 3 morbidity. CONCLUSIONS: In patients scheduled to have major abdominal cancer surgery there was a weak association between poor performance on CPET and increasing frailty measured by the CFS. The CFS score unlike CPET was associated with all post-operative morbidity, but not major complications alone, in these patients. This suggests that CFS may be used as a less expensive alternative to CPET for predicting any postoperative morbidity in major abdominal cancer surgery.

Cancer and breast cancer awareness interventions in an intellectual disability context: A review of the literature.

BACKGROUND: Women with an intellectual disability (ID) have a similar risk of developing breast cancer as women in the general population yet present with later stage breast cancers, which have poorer outcomes. AIM: To identify whether there is a need to develop a breast cancer awareness intervention for women with an ID. METHODS: Interventions aimed at increasing cancer awareness and breast cancer awareness for people with an ID were identified and critically appraised. RESULTS: Five interventions to increase cancer awareness or breast cancer awareness in people with an ID were identified. CONCLUSION: The review highlighted the paucity of theoretically underpinned breast cancer awareness interventions specifically aimed at women with an ID. Facilitating breast cancer awareness for women with an ID could potentially lead to earlier presentation of potential symptoms of breast cancer, earlier treatment, better prognosis and ultimately, improved survival. This article establishes that there is a need for an intervention underpinned by theory to increase breast cancer awareness in women with an ID.

A validated photonumeric scale for infraorbital dark circles and its application in evaluating the efficacy of a cosmetic treatment product in a split-face randomized clinical trial.

OBJECTIVE: As a result of their complex aetiology and periodicity, dark circles are difficult to characterize and measure, with current assessment techniques relying on specialist equipment, image analysis or proprietary grading scales. There is therefore a need to develop and validate a photonumeric scale for assessing infraorbital dark circles, which can provide an objective and consumer relevant tool for evaluating this condition and the efficacy of treatment products and procedures. METHODS: A panel of expert clinical evaluators reviewed approximately three thousand facial photographs collected over a 5-year period and selected images representing a dynamic range of dark circles. A 10-point photonumeric scale was created, with corresponding descriptors and images for each grade of the scale. To rigorously validate the scale, linearity, sensitivity and precision were assessed by colorimetry and in-clinic evaluation. Reproducibility was assessed photographically with both experienced and inexperienced clinical evaluators, whereas intragrader repeatability was assessed live in-clinic. The scale was then employed in a split-face randomized clinical trial on 58 subjects to evaluate the efficacy of a cosmetic treatment product over 8 weeks. RESULTS: Colour analysis of the images showed the scale was linear, with statistically significant correlations observed when colour data (CIElab; Individual Typology Angle) were plotted against the corresponding grades (r > 0.9, P < 0.001). Colour difference (Delta E) was calculated between the infraorbital zone and the surrounding skin, and when data were plotted against the grades, a statistically significant correlation was observed (r = 0.99, P < 0.01). The magnitude of the Delta E suggested that changes in grade are visibly perceptible to the human eye, and therefore, the scale is sensitive and clinically relevant. Intergrader reproducibility showed strong correlation (0.96) and >90% agreement between experienced evaluators, whereas intragrader repeatability assessment showed >90% perfect agreement between grades. Use of this scale in a clinical trial demonstrated the efficacy of a cosmetic product, with a mean statistically significant (P < 0.001) decrease in grade of 0.74 compared to baseline, and 0.59 versus the untreated control, after 8 weeks of treatment. CONCLUSION: Our photonumeric scale for infraorbital dark circles is sensitive and robust and provides an objective and easy-to-use tool to evaluate dark circles and their treatment.

OBJECTIF: En raison de leur étiologie et de leur périodicité complexes, les cernes sont difficiles à caractériser et à mesurer, les techniques d'évaluation actuelles reposant sur des équipements spécialisés, l'analyse d'images ou des échelles de notation exclusives. Il est donc nécessaire de développer et de valider une échelle photonumérique pour évaluer les cernes infraorbitaires, laquelle peut fournir un outil objectif et pertinent pour le consommateur et tester l'efficacité des produits et des procédures de traitement. MÉTHODES: Un panel d'évaluateurs cliniques experts a examiné environ trois mille photographies du visage recueillies sur une période de 5 ans, ainsi que des images sélectionnées représentant une plage dynamique de cernes. Une échelle photonumérique à 10 points a été créée, avec des descripteurs et des images correspondants à chaque grade de l'échelle. Afin de valider rigoureusement l'échelle, la linéarité, la sensibilité et la précision ont été évaluées par colorimétrie et en clinique. La reproductibilité a été évaluée sur le plan photographique par des évaluateurs cliniques expérimentés et inexpérimentés, tandis que la répétabilité intragrade a été évaluée en direct en clinique. L'échelle a ensuite été utilisée dans un essai clinique randomisé à deux parties sur 58 sujets, afin d'évaluer l'efficacité d'un produit de traitement cosmétique sur 8 semaines. RÉSULTATS: L'analyse des couleurs des images a montré que l'échelle était linéaire, avec des corrélations statistiquement significatives observées lorsque les données de couleurs (CIElab ; angle de typologie individuel) ont été tracées par rapport aux grades correspondants (r > 0,9, P < 0,001). La différence de couleur (Delta E) a été calculée entre la zone infraorbitaire et la peau environnante, et lorsque les données ont été tracées par rapport aux grades, une corrélation statistiquement significative a été observée (r = 0,99, P < 0,01). L'ampleur du delta E a suggéré que les changements de grade sont visiblement perceptibles à l'œil humain, l'échelle étant par conséquent sensible et cliniquement pertinente. La reproductibilité intergrade a montré une forte corrélation (0,96) et une concordance > 90 % entre les évaluateurs expérimentés, tandis que l'évaluation de la répétabilité intragrade a montré une concordance parfaite > 90 % entre les grades. L'utilisation de cette échelle lors d'un essai clinique a démontré l'efficacité d'un produit cosmétique, avec une diminution moyenne statistiquement significative (P < 0,001) du grade de 0,74 par rapport à la référence, et de 0,59 par rapport au témoin non traité, après 8 semaines de traitement. CONCLUSION: Notre échelle photonumérique pour les cernes infraorbitaires est sensible et robuste, fournissant un outil objectif et facile à utiliser afin d'évaluer les cernes et leur traitement.

Deprescribing in older people.

Polypharmacy and multimorbidity are both currently rising. The number of medicines taken is the single biggest predictor of adverse drug events. Deprescribing is an approach to managing polypharmacy and reducing adverse outcomes. Multiple international evidence-based guidelines are emerging to promote discontinuation of high-risk medications, and use of alternative medical and non-pharmacological management. This review outlines the evidence base behind deprescribing, and suggests some pragmatic approaches to decision making around medication review.

Impact of insufficient admission vitamin D serum concentrations on sepsis incidence and clinical outcomes in patients with thermal injury.

INTRODUCTION: In burn patients, vitamin D has been studied primarily in the pediatric population and focused mainly on the correlation with bone marker measurements and incidence of fractures. There is an association between vitamin D deficiency and the development of sepsis in non-burn critically-ill patients. However, there is limited data on vitamin D concentrations and clinical outcomes in burn patients, such as sepsis. The objective of this study is to evaluate the impact of vitamin D concentrations on the incidence of sepsis in adult burn patients. METHODS: This was a retrospective cohort of patients 18 years of age and older admitted between February 1, 2016 and February 28, 2018 to an American Burn Association (ABA) verified burn center with diagnosis of burn injury. The primary endpoint was incidence of sepsis using the ABA 2007 Sepsis Consensus Criteria between patients with adequate vitamin D concentrations (25[OH]D > 20 ng/mL) and insufficient vitamin D (25[OH]D < 20 ng/mL) concentrations measured on admission. Descriptive statistics were used for baseline demographics. Univariate analysis was conducted using Chi-square, Fisher's exact test or Mann-Whitney U test, as appropriate. RESULTS: A total of 115 patients were screened and 107 patients were included in this study. Sixty three patients (58.9%) had insufficient vitamin D concentrations. Patient demographics were overall similar between groups. The median total body surface area burned was 14.6% in the insufficient vitamin D group, and 12.1% in the adequate vitamin D group (p = 0.2). There was a trend towards greater incidence of sepsis in the insufficient vitamin D group in the univariate analysis (15.9% vs. 4.5%, p = 0.07). The multivariable logistic regression analysis found that adequate vitamin D concentrations was associated with a reduction in the incidence of sepsis (OR 0.10, 95% CI 0.01-0.88). The insufficient vitamin D group had a longer median hospital LOS (19 [IQR 11-37] vs 11.5 [IQR 7-20] days, p < 0.05), longer intensive care unit LOS (17 [IQR 10-37] vs 5 [IQR 2-19.5] days, p < 0.05) and fewer ventilator free days (26 [IQR 18-28] vs 28 [IQR 27-28] days, p < 0.05). There was no difference in mortality between groups (p = 0.69). CONCLUSIONS: Patients with adequate vitamin D concentrations on admission had a reduction in the incidence of sepsis as compared to patients with insufficient vitamin D concentrations. Insufficient vitamin D concentrations may contribute to other worsened clinical outcomes in burn patients. Our findings set the stage for future, multicenter studies to determine the role of vitamin D supplementation in burn patients.

An Audit of Neural Tube Defects in the Republic Of Ireland for 2012-2015.

Neural tube defects (NTD) are potentially preventable in two-thirds of cases by periconceptional maternal Folic Acid (FA) supplementation. A national audit for the years 2009-11 showed no decline in NTD rates over twenty years. The aim of this national audit was to determine trends/rates and inform revision of national FA supplementation and food fortification strategies. Of 274,732 live and stillbirths there were 121(42.0%) cases of anencephaly, 136(47.2%) cases of spina bifida and 31(10.8%) cases of encephalocoele giving a total of 288 and overall rate of 1.05/1000 compared with 1.04/1000 in 2009-11(NS). In the 184 women where the information was available, only 29.9%(n=55) reported starting FA before pregnancy. The number of cases diagnosed antenatally was 91%(n=262) and 53%(n=154) were live-born. This audit confirms that over a generation, healthcare interventions have not succeeded in decreasing the number of pregnancies in Ireland complicated by NTD, and that revised strategies need to be developed and implemented.

A theoretical and experimental study of the temporal reduction in UV protection provided by a facial day cream.

OBJECTIVE: To investigate how the UV protection provided by a facial day cream reduces over the course of a day. METHODS: We developed a theoretical model using a Monte Carlo random sampling approach to estimate the variation in local thickness, and hence local effective SPF, at several different sites over the face. The input variables, which are labelled SPF, average application thickness, homogeneity of the product on the skin and the ability of the product to bind to the skin, allow examination of how these different factors affect the delivered photoprotection. We compared the results of our modelling with experimental determination of the binding of an oil-in-water moisturizing day cream with a rated SPF of 15 at various times over the course of a day by means of UV photography and digital image analysis. RESULTS: We demonstrated good agreement between our theoretical predictions of the temporal reduction in product thickness and the experimental observations. We used our modelling approach to show that a substantial reduction in lifetime UV burden on the face could be achieved by a daycare product delivering 3-fold (or greater) protection over the face. CONCLUSION: Comparison with experimental data confirmed the robustness and validity of our model, which predicts that products intended for daily use need to be formulated carefully and applied uniformly, and to have a half-life of binding to the skin of several hours. Products that bind less well to the skin, or are applied non-uniformly, are likely to be providing inadequate protection with regards to influencing the rate of photoaging of the skin. Our data suggest that after a single, realistic application of a day cream rated SPF15, consumers' faces remain protected to at least an average of 5-fold around the middle of the day, especially pertinent to indoor workers who are likely to be exposed to maximum UV levels as they venture outside during their lunch break.

A telephone interview version of the middle childhood HOME Observation Measurement of the Environment.

BACKGROUND: The Home Observation Measurement of the Environment (HOME) is a 59-item observation and interview tool used to measure how suitable a child's home is for a child of his or her developmental age and has been used extensively in research. The HOME is usually performed in the child's home, which has cost implications. We wished to develop a telephone version of the HOME. METHODS: We developed a 54-item telephone interview version of the HOME and used it to measure the home environment in 77 children aged 6-10 years inclusive attending a child and adolescent mental health clinic, followed by a home visit and HOME assessment. The results of the telephone home assessment were then compared with the results of the original HOME. RESULTS: Our sample had a mean HOME score of 47.6, standard deviation (SD) = 5.5 and a mean telephone home score of 42.6, SD = 5.1. No difference was found in comparison of the subscale mean scores of the HOME with the telephone home assessment. The agreement of 54 items in common between the HOME and telephone home assessment ranged from 73% agreement to 100% agreement. Forty-three of 50 items had moderate to almost perfect agreement using kappa analysis (kappa = 0.41-0.99); three had 100% agreement. CONCLUSIONS: The telephone version of the HOME compares favourably with the HOME.

Adverse drug reactions in special populations - the elderly.

The International Conference on Harmonization considers older people a 'special population', as they differ from younger adults in terms of comorbidity, polypharmacy, pharmacokinetics and greater vulnerability to adverse drug reactions (ADRs). Medical practice is often based on single disease guidelines derived from clinical trials that have not included frail older people or those with multiple morbidities. This presents a challenge caring for older people, as drug doses in trials may not be achievable in real world patients and risks of ADRs are underestimated in clinical trial populations. The majority of ADRs in older people are Type A, potentially avoidable and associated with commonly prescribed medications. Several ADRs are particularly associated with major adverse consequences in the elderly and their reduction is therefore a clinical priority. Falls are strongly associated with benzodiazepines, neuroleptics, antidepressants and antihypertensives. There is good evidence for medication review as part of a multifactorial intervention to reduce falls risk in community dwelling elderly. Multiple medications also contribute to delirium, another multifactorial syndrome resulting in excess mortality particularly in frail older people. Clostridium difficile associated with use of broad spectrum antibiotics mainly affects frail older people and results in prolonged hospital stay with substantial morbidity and mortality. Antipsychotics increase the risk of stroke by more than three-fold in patients with dementia. Inappropriate prescribing can be reduced by adherence to prescribing guidelines, suitable monitoring and regular medication review. Given the heterogeneity within the older population, providing individualized care is pivotal to preventing ADRs.

Confined crystallization of fenofibrate in nanoporous silica.

Producing stable nanocrystals confined to porous excipient media is a desirable way to increase the dissolution rate and improve the bioavailability of poorly water soluble pharmaceuticals. The poorly soluble pharmaceutical fenofibrate was crystallized in controlled pore glass (CPG) of 10 different pore sizes between 12 nm and 300 nm. High drug loadings of greater than 20 wt% were achieved across all pore sizes greater than 20 nm. Nanocrystalline fenofibrate was formed in pore sizes greater than 20 nm and showed characteristic melting point depressions following a Gibbs-Thomson relationship as well as enhanced dissolution rates. Solid-state Nuclear Magnetic Resonance (NMR) was employed to characterize the crystallinity of the confined molecules. These results help to advance the fundamental understanding of nanocrystallization in confined pores.

Neural tube defects in the Republic of Ireland in 2009-11.

BACKGROUND: Neural tube defects (NTDs) are associated with deficient maternal folic acid peri-conceptionally. In Ireland, there is no mandatory folic acid food fortification, partly due to declining NTD rates in recent years. The aim of this study was to ascertain the incident rate of NTD during the period 2009-11 and describe epidemiologically NTD in Ireland. METHODS: Cases were ascertained through multiple sources, including three regional congenital anomaly registers, all maternity hospitals nationally and paediatric hospitals providing care for children with spina bifida in the Republic of Ireland during the period 2009-11. RESULTS: From 225 998 total births, 236 NTDs were identified, giving an incidence of 1.04/1 000 births, increasing from 0.92/1 000 in 2009 to 1.17/1 000 in 2011. Of all cases, 45% (n = 106) had anencephaly, 49% (n = 115) had spina bifida and 6% (n = 15) had an encephalocoele; 78% (n = 184) were liveborn or stillborn and 22% (n = 52) were terminations abroad. Peri-conceptional folic acid supplement intake was 13.7% among the 52.5% (n = 124) of cases whose folic acid supplement intake was known. CONCLUSION: The incidence of NTDs in the Republic of Ireland appears to be increasing. Renewed public health interventions, including mandatory folic acid food fortification, must be considered to reduce the incidence of NTD.

Comparison of modelling techniques for milk-production forecasting.

The objective of this study was to assess the suitability of 3 different modeling techniques for the prediction of total daily herd milk yield from a herd of 140 lactating pasture-based dairy cows over varying forecast horizons. A nonlinear auto-regressive model with exogenous input, a static artificial neural network, and a multiple linear regression model were developed using 3 yr of historical milk-production data. The models predicted the total daily herd milk yield over a full season using a 305-d forecast horizon and 50-, 30-, and 10-d moving piecewise horizons to test the accuracy of the models over long- and short-term periods. All 3 models predicted the daily production levels for a full lactation of 305 d with a percentage root mean square error (RMSE) of ≤ 12.03%. However, the nonlinear auto-regressive model with exogenous input was capable of increasing its prediction accuracy as the horizon was shortened from 305 to 50, 30, and 10 d [RMSE (%)=8.59, 8.1, 6.77, 5.84], whereas the static artificial neural network [RMSE (%)=12.03, 12.15, 11.74, 10.7] and the multiple linear regression model [RMSE (%)=10.62, 10.68, 10.62, 10.54] were not able to reduce their forecast error over the same horizons to the same extent. For this particular application the nonlinear auto-regressive model with exogenous input can be presented as a more accurate alternative to conventional regression modeling techniques, especially for short-term milk-yield predictions.

Prevalence and risk of Down syndrome in monozygotic and dizygotic multiple pregnancies in Europe: implications for prenatal screening.

OBJECTIVE: To determine risk of Down syndrome (DS) in multiple relative to singleton pregnancies, and compare prenatal diagnosis rates and pregnancy outcome. DESIGN: Population-based prevalence study based on EUROCAT congenital anomaly registries. SETTING: Eight European countries. POPULATION: 14.8 million births 1990-2009; 2.89% multiple births. METHODS: DS cases included livebirths, fetal deaths from 20 weeks, and terminations of pregnancy for fetal anomaly (TOPFA). Zygosity is inferred from like/unlike sex for birth denominators, and from concordance for DS cases. MAIN OUTCOME MEASURES: Relative risk (RR) of DS per fetus/baby from multiple versus singleton pregnancies and per pregnancy in monozygotic/dizygotic versus singleton pregnancies. Proportion of prenatally diagnosed and pregnancy outcome. STATISTICAL ANALYSIS: Poisson and logistic regression stratified for maternal age, country and time. RESULTS: Overall, the adjusted (adj) RR of DS for fetus/babies from multiple versus singleton pregnancies was 0.58 (95% CI 0.53-0.62), similar for all maternal ages except for mothers over 44, for whom it was considerably lower. In 8.7% of twin pairs affected by DS, both co-twins were diagnosed with the condition. The adjRR of DS for monozygotic versus singleton pregnancies was 0.34 (95% CI 0.25-0.44) and for dizygotic versus singleton pregnancies 1.34 (95% CI 1.23-1.46). DS fetuses from multiple births were less likely to be prenatally diagnosed than singletons (adjOR 0.62 [95% CI 0.50-0.78]) and following diagnosis less likely to be TOPFA (adjOR 0.40 [95% CI 0.27-0.59]). CONCLUSIONS: The risk of DS per fetus/baby is lower in multiple than singleton pregnancies. These estimates can be used for genetic counselling and prenatal screening.

Anorectal malformations and pregnancy-related disorders: a registry-based case-control study in 17 European regions.

OBJECTIVE: To identify pregnancy-related risk factors for different manifestations of congenital anorectal malformations (ARMs). DESIGN: A population-based case-control study. SETTING: Seventeen EUROCAT (European Surveillance of Congenital Anomalies) registries, 1980-2008. POPULATION: The study population consisted of 1417 cases with ARM, including 648 cases of isolated ARM, 601 cases of ARM with additional congenital anomalies, and 168 cases of ARM-VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects), along with 13 371 controls with recognised syndromes or chromosomal abnormalities. METHODS: Multiple logistic regression analyses were used to calculate adjusted odds ratios (ORs) for potential risk factors for ARM, such as fertility treatment, multiple pregnancy, primiparity, maternal illnesses during pregnancy, and pregnancy-related complications. MAIN OUTCOME MEASURES: Adjusted ORs for pregnancy-related risk factors for ARM. RESULTS: The ARM cases were more likely to be firstborn than the controls (OR 1.6, 95% CI 1.4-1.8). Fertility treatment and being one of twins or triplets seemed to increase the risk of ARM in cases with additional congenital anomalies or VACTERL (ORs ranging from 1.6 to 2.5). Maternal fever during pregnancy and pre-eclampsia were only associated with ARM when additional congenital anomalies were present (OR 3.9, 95% CI 1.3-11.6; OR 3.4, 95% CI 1.6-7.1, respectively), whereas maternal epilepsy during pregnancy resulted in a five-fold elevated risk of all manifestations of ARM (OR 5.1, 95% CI 1.7-15.6). CONCLUSIONS: This large European study identified maternal epilepsy, fertility treatment, multiple pregnancy, primiparity, pre-eclampsia, and maternal fever during pregnancy as potential risk factors primarily for complex manifestations of ARM with additional congenital anomalies and VACTERL.

Trends in the prevalence, risk and pregnancy outcome of multiple births with congenital anomaly: a registry-based study in 14 European countries 1984-2007.

OBJECTIVE: To assess the public health consequences of the rise in multiple births with respect to congenital anomalies. DESIGN: Descriptive epidemiological analysis of data from population-based congenital anomaly registries. SETTING: Fourteen European countries. POPULATION: A total of 5.4 million births 1984-2007, of which 3% were multiple births. METHODS: Cases of congenital anomaly included live births, fetal deaths from 20 weeks of gestation and terminations of pregnancy for fetal anomaly. MAIN OUTCOME MEASURES: Prevalence rates per 10,000 births and relative risk of congenital anomaly in multiple versus singleton births (1984-2007); proportion prenatally diagnosed, proportion by pregnancy outcome (2000-07). Proportion of pairs where both co-twins were cases. RESULTS: Prevalence of congenital anomalies from multiple births increased from 5.9 (1984-87) to 10.7 per 10,000 births (2004-07). Relative risk of nonchromosomal anomaly in multiple births was 1.35 (95% CI 1.31-1.39), increasing over time, and of chromosomal anomalies was 0.72 (95% CI 0.65-0.80), decreasing over time. In 11.4% of affected twin pairs both babies had congenital anomalies (2000-07). The prenatal diagnosis rate was similar for multiple and singleton pregnancies. Cases from multiple pregnancies were less likely to be terminations of pregnancy for fetal anomaly, odds ratio 0.41 (95% CI 0.35-0.48) and more likely to be stillbirths and neonatal deaths. CONCLUSIONS: The increase in babies who are both from a multiple pregnancy and affected by a congenital anomaly has implications for prenatal and postnatal service provision. The contribution of assisted reproductive technologies to the increase in risk needs further research. The deficit of chromosomal anomalies among multiple births has relevance for prenatal risk counselling.

Medication prescribing in frail older people.

PURPOSE: While some people remain fit and active as they grow older, others experience complex problems: disease, dependency and disability. Frailty is a term used to describe this latter group, capturing differences in health status among older people. Many frail older people have multiple chronic co-morbidities and functional impairments and, according to guidelines for the management of individual conditions, should be prescribed long lists of medications. However, older people (particularly those who are frail) are often excluded from drug trials, and treatment decisions are therefore based on evidence extrapolated from more robust patient groups with fewer physiological deficits. The risk of adverse drug reactions (ADRs) increases with increasing patient frailty, and polypharmacy has negative consequences above and beyond the risks of individual drugs. Increasing numbers of medications are associated with a higher likelihood of non-adherence and a significantly greater risk of ADRs. Older people taking five or more medications are at higher risk of delirium and falls, independent of medication indications. METHODS: This is a short review of the different approaches to defining and measuring frailty. We summarise the factors contributing to ADRs in frail older people and describe the pharmacokinetic and pharmacodynamics changes associated with ageing and frailty. By considering goals of care for frail older people, we explore how the appropriateness of medication prescribing for older people could be improved. CONCLUSION: Since all physicians are likely to provide care for this group of vulnerable patients, understanding the concept of frailty may help to optimise medication prescribing for older people. The incorporation of frailty measures into future clinical studies of drug effects and pharmacokinetics is important if we are to improve medication use and guide drug doses for fit and frail older people.

Dyspnoea and mortality in older people in the community: a 10-year follow-up.

BACKGROUND: examine baseline dyspnoea and subsequent 10-year mortality adjusting for age and gender and determine whether dyspnoea is related to early or late mortality or both. Examine the relationship between dyspnoea and mortality adjusting for confounding effects of underlying diseases. METHODS: we sent modified Medical Research Council (MRC) dyspnoea questionnaire to identify breathlessness in 1,404 randomly selected subjects from general practitioner lists of 5,002 subjects aged 70 years and over living in the community. A further random sample of 500 subjects underwent clinical assessment including pulmonary function tests, electrocardiography and echocardiography. Subjects were followed up for 10 years and all deaths were recorded, using general practitioner records and the local death registry. RESULTS: prevalence of dyspnoea was 32.3%. Breathlessness was associated with early mortality and late mortality. At 2 years 10.1% breathless subjects died compared with 3.4% non-breathless (P=0.02). At 10 years 63.3% breathless had died compared with 40.5% non-breathless (P=0.0001). Increasing grade of MRC dyspnoea was associated with 10 mortality. Advancing age (OR: 2.27), male gender (OR: 1.95), breathlessness (OR: 2.53), left ventricular dysfunction (OR: 5.01) and chronic airways disease (OR: 3.04) were all significantly associated with 10-year mortality. After adjustment of age, gender and underlying diseases breathlessness was associated with 10-year mortality (P=0.02). CONCLUSION: dyspnoea is a predictor of early and late mortality and increasing grade of dyspnoea is associated with a higher rate of mortality. Dyspnoea is an independent risk factor for mortality after adjustment for age, gender and underlying diseases.

Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial.

BACKGROUND: Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer. METHODS: We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452. FINDINGS: 459 patients were randomly assigned (115 to each of groups A-C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3-7·5] vs 4·5 months [2·8-6·4]; hazard ratio 0·84, 95% CI 0·69-1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14-1·52), less widespread disease (1·51, 1·05-2·19), and use of oxaliplatin (0·57, 0·39-0·82) were predictive of better OTU. INTERPRETATION: FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial. On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met. Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit. FUNDING: Cancer Research UK and the Medical Research Council.