Juliet Usher-Smith

Factors associated with the presence of diabetic ketoacidosis at diagnosis of diabetes in children and young adults: a systematic review

Objective To identify the factors associated with diabetic ketoacidosis at diagnosis of type 1 diabetes in children and young adults. Design Systematic review. Data sources PubMed, EMBASE, Web of Science, Scopus, and Cinahl and article reference lists. Study selection Cohort studies including unselected groups of children and young adults presenting with new onset type 1 diabetes that distinguished between those who presented in diabetic ketoacidosis and those who did not and included a measurement of either pH or bicarbonate in the definition of diabetic ketoacidosis. There were no restrictions on language of publication. Results 46 studies involving more than 24 000 children in 31 countries were included. Together they compared 23 different factors. Factors associated with increased risk were younger age (for <2 years old v older, odds ratio 3.41 (95% confidence interval 2.54 to 4.59), for <5 years v older, odds ratio 1.59 (1.38 to 1.84)), diagnostic error (odds ratio 3.35 (2.35 to 4.79)), ethnic minority, lack of health insurance in the US (odds ratio 3.20 (2.03 to 5.04)), lower body mass index, preceding infection (odds ratio 3.14 (0.94 to 10.47)), and delayed treatment (odds ratio 1.74 (1.10 to 2.77)). Protective factors were having a first degree relative with type 1 diabetes at the time of diagnosis (odds ratio 0.33 (0.08 to 1.26)), higher parental education (odds ratios 0.4 (0.20 to 0.79) and 0.64 (0.43 to 0.94) in two studies), and higher background incidence of type 1 diabetes (correlation coefficient –0.715). The mean duration of symptoms was similar between children presenting with or without diabetic ketoacidosis (16.5 days (standard error 6.2) and 17.1 days (6.0) respectively), and up to 38.8% (285/735) of children who presented with diabetic ketoacidosis had been seen at least once by a doctor before diagnosis. Conclusions Multiple factors affect the risk of developing diabetic ketoacidosis at the onset of type 1 diabetes in children and young adults, and there is potential time, scope, and opportunity to intervene between symptom onset and development of diabetic ketoacidosis for both parents and clinicians.

Variation between countries in the frequency of diabetic ketoacidosis at first presentation of type 1 diabetes in children: a systematic review

Aims/hypothesisType 1 diabetes is the most frequent endocrine disease in children, with 65,000 children diagnosed worldwide every year. Up to 80% of these children present with diabetic ketoacidosis (DKA), which is associated with both short-term risks and long-term consequences. This study aimed to characterise the worldwide variation in presentation of type 1 diabetes to inform future interventions to reduce this excess morbidity and mortality.MethodsThis was a systematic review of studies indexed on PubMed, EMBASE, Web of Science, Scopus or CINAHL before March 2011 that included unselected groups of children presenting with new-onset type 1 diabetes, reported the proportion presenting with DKA and used a definition of DKA based on measurement of pH or bicarbonate.ResultsSixty-five studies of cohorts comprising over 29,000 children in 31 countries were included. The frequency of DKA at diagnosis ranged from 12.8% to 80%, with highest frequencies in the United Arab Emirates, Saudi Arabia and Romania, and the lowest in Sweden, the Slovak Republic and Canada. Multivariable modelling showed the frequency of DKA was inversely associated with gross domestic product, latitude and background incidence of type 1 diabetes.Conclusions/interpretationThis is the first description of the variation in frequency of DKA at presentation of type 1 diabetes in children across countries. It demonstrates large variations that may, at least in part, be explained by different levels of disease awareness and healthcare provision and suggests ways to decrease the excess morbidity and mortality associated with DKA at diagnosis.

Properties of the demarcation membrane system in living rat megakaryocytes.

The demarcation membrane system (DMS) is the precursor of platelet cell membranes yet little is known of its properties in living megakaryocytes. Using confocal microscopy, we now demonstrate that demarcation membranes in freshly isolated rat marrow megakaryocytes are rapidly stained by styryl membrane indicators such as di-8-ANEPPS and FM 2-10, confirming that they are invaginations of the plasma membrane and readily accessible from the extracellular space. Two-photon excitation of an extracellular indicator displayed the extensive nature of the channels formed by the DMS throughout the extranuclear volume. Under whole-cell patch clamp, the DMS is electrophysiologically contiguous with the peripheral plasma membrane such that a single capacitative component can account for the biophysical properties of all surface-connected membranes in the majority of recordings. Megakaryocyte capacitances were in the range of 64-694 pF, equivalent to 500-5500 platelets (mean value 1850). Based upon calculations for a spherical geometry, the DMS results in a 4- to 14-fold (average 8.1-fold) increase in specific membrane capacitance expressed per unit spherical surface area. This indicates a level of plasma membrane invagination comparable with mammalian skeletal muscle. Whole-cell capacitance measurements and confocal imaging of membrane-impermeant fluorescent indicators therefore represent novel approaches to monitor the DMS during megakaryocytopoiesis and thrombopoiesis.

Evaluation of the cost savings and clinical outcomes of switching patients from atorvastatin to simvastatin and losartan to candesartan in a Primary Care setting

This study was carried out in a Primary Care practice in the UK to assess the clinical and practical implications, cost savings and patients’ perspective of switching to generic drugs. In the 70 patients switched from atorvastatin to simvastatin there was no significant change in mean total cholesterol 4 months after the switch (4.07 ± 0.55 mmol/L prior to the switch and 4.10 ± 0.73 mmol/L post‐switch) and only one patient switched back because of side effects. One hundred and fifteen patients were switched from losartan to candesartan. Seven switched back but in those that remained on candesartan there was a small, significant (p = 0.0006), reduction in blood pressure after the switch (138.9/78.7 ± 13.2/7.0 to 136.3/76.1 ± 14.7/8.4 mmHg). No adverse events attributable to the switch were reported in either group and the net annualised savings for the year 2005–2006 were £12,715.58 for the statin and £13,374.40 for the antihypertensive switch, respectively.

Risk prediction models for melanoma: A systematic review

Melanoma incidence is increasing rapidly worldwide among white-skinned populations. Earlier diagnosis is the principal factor that can improve prognosis. Defining high-risk populations using risk prediction models may help targeted screening and early detection approaches. In this systematic review, we searched Medline, EMBASE, and the Cochrane Library for primary research studies reporting or validating models to predict risk of developing cutaneous melanoma. A total of 4,141 articles were identified from the literature search and six through citation searching. Twenty-five risk models were included. Between them, the models considered 144 possible risk factors, including 18 measures of number of nevi and 26 of sun/UV exposure. Those most frequently included in final risk models were number of nevi, presence of freckles, history of sunburn, hair color, and skin color. Despite the different factors included and different cutoff values for sensitivity and specificity, almost all models yielded sensitivities and specificities that fit along a summary ROC with area under the ROC (AUROC) of 0.755, suggesting that most models had similar discrimination. Only two models have been validated in separate populations and both also showed good discrimination with AUROC values of 0.79 (0.70–0.86) and 0.70 (0.64–0.77). Further research should focus on validating existing models rather than developing new ones. Cancer Epidemiol Biomarkers Prev; 23(8); 1450–63. ©2014 AACR.

Risk Prediction Models for Colorectal Cancer: A Systematic Review.

Colorectal cancer is the second leading cause of cancer-related death in Europe and the United States. Survival is strongly related to stage at diagnosis and population-based screening reduces colorectal cancer incidence and mortality. Stratifying the population by risk offers the potential to improve the efficiency of screening. In this systematic review we searched Medline, EMBASE, and the Cochrane Library for primary research studies reporting or validating models to predict future risk of primary colorectal cancer for asymptomatic individuals. A total of 12,808 papers were identified from the literature search and nine through citation searching. Fifty-two risk models were included. Where reported (n = 37), half the models had acceptable-to-good discrimination (the area under the receiver operating characteristic curve, AUROC >0.7) in the derivation sample. Calibration was less commonly assessed (n = 21), but overall acceptable. In external validation studies, 10 models showed acceptable discrimination (AUROC 0.71–0.78). These include two with only three variables (age, gender, and BMI; age, gender, and family history of colorectal cancer). A small number of prediction models developed from case–control studies of genetic biomarkers also show some promise but require further external validation using population-based samples. Further research should focus on the feasibility and impact of incorporating such models into stratified screening programmes. Cancer Prev Res; 9(1); 13–26. ©2015 AACR. See related article by Frank L. Meyskens, Jr., p. 11

Control of cell volume in skeletal muscle.

Regulation of cell volume is a fundamental property of all animal cells and is of particular importance in skeletal muscle where exercise is associated with a wide range of cellular changes that would be expected to influence cell volume. These complex electrical, metabolic and osmotic changes, however, make rigorous study of the consequences of individual factors on muscle volume difficult despite their likely importance during exercise. Recent charge‐difference modelling of cell volume distinguishes three major aspects to processes underlying cell volume control: (i) determination by intracellular impermeant solute; (ii) maintenance by metabolically dependent processes directly balancing passive solute and water fluxes that would otherwise cause cell swelling under the influence of intracellular membrane‐impermeant solutes; and (iii) volume regulation often involving reversible short‐term transmembrane solute transport processes correcting cell volumes towards their normal baselines in response to imposed discrete perturbations. This review covers, in turn, the main predictions from such quantitative analysis and the experimental consequences of comparable alterations in extracellular pH, lactate concentration, membrane potential and extracellular tonicity. The effects of such alterations in the extracellular environment in resting amphibian muscles are then used to reproduce the intracellular changes that occur in each case in exercising muscle. The relative contributions of these various factors to the control of cell volume in resting and exercising skeletal muscle are thus described.

The spectrum effect in tests for risk prediction, screening, and diagnosis

The spectrum effect describes the variation between settings in performance of tests used to predict, screen for, and diagnose disease. In particular, the predictive use of a test may be different when it is applied in a general population rather than in the study sample in which it was first developed. This article discusses the impact of the spectrum effect on measures of test performance, and its implications for the development, evaluation, application, and implementation of such tests.

The effect of intracellular acidification on the relationship between cell volume and membrane potential in amphibian skeletal muscle

The relationship between cell volume (Vc) and membrane potential (Em) in Rana temporaria striated muscle fibres was investigated under different conditions of intracellular acidification. Confocal microscope xz‐scanning monitored the changes in Vc, whilst conventional KCl and pH‐sensitive microelectrodes measured Em and intracellular pH (pHi), respectively. Applications of Ringer solutions with added NH4Cl induced rapid reductions in Vc that rapidly reversed upon their withdrawal. These could be directly attributed to the related alterations in extracellular tonicity. However: (1) a slower and persistent decrease in Vc followed the NH4Cl withdrawal, leaving Vc up to 10% below its resting value; (2) similar sustained decreases in resting Vc were produced by the addition and subsequent withdrawal of extracellular solutions in which NaCl was isosmotically replaced with NH4Cl; (3) the same manoeuvres also produced a marked intracellular acidification, that depended upon the duration of the preceding exposure to NH4Cl, of up to 0.53 ± 0.10 pH units; and (4) the corresponding reductions in Vc similarly increased with this exposure time. These reductions in Vc persisted and became more rapid with Cl− deprivation, thus excluding mechanisms involving either direct or indirect actions of pHi upon Cl−‐dependent membrane transport. However they were abolished by the Na+,K+‐ATPase inhibitor ouabain. The Em changes that accompanied the addition and withdrawal of NH4+ conformed to a Nernst equation modified to include realistic NH4+ permeability terms, and thus the withdrawal of NH4+ restored Em to close to control values despite a persistent change in Vc. Finally these Em changes persisted and assumed faster kinetics with Cl− deprivation. The relative changes in Vc, Em and pHi were compared to predictions from the recent model of Fraser and Huang published in 2004 that related steady‐state values of Vc and Em to the mean charge valency (zx) of intracellular membrane‐impermeant anions, X−i. By assuming accepted values of intracellular buffering capacity (βi), intracellular acidification was shown to produce quantitatively predictable decreases in Vc. These findings thus provide experimental evidence that titration of the anionic zx by increased intracellular [H+] causes cellular volume decrease in the presence of normal Na+,K+‐ ATPase activity, with Cl−‐dependent membrane fluxes only influencing the kinetics of such changes.

The influence of intracellular lactate and H+ on cell volume in amphibian skeletal muscle

The combined effects of intracellular lactate and proton accumulation on cell volume, Vc, were investigated in resting Rana temporaria striated muscle fibres. Intracellular lactate and H+ concentrations were simultaneously increased by exposing resting muscle fibres to extracellular solutions that contained 20–80 mm sodium lactate. Cellular H+ and lactate entry was confirmed using pH‐sensitive electrodes and 1H‐NMR, respectively, and effects on Vc were measured using confocal microscope xz‐scanning. Exposure to extracellular lactate up to 80 mm produced significant changes in pH and intracellular lactate (from a pH of 7.24 ± 0.03, n= 8, and 4.65 ± 1.07 mm, n= 6, respectively, in control fibres, to 6.59 ± 0.03, n= 4, and 26.41 ± 0.92 mm, n= 3, respectively) that were comparable to those observed following fatiguing stimulation (6.30–6.70 and 18.04 ± 1.78 mm, n= 6, respectively). Yet, the increase in intracellular osmolarity expected from such an increase in intracellular lactate did not significantly alter Vc. Simulation of these experimental results, modified from the charge difference model of Fraser & Huang, demonstrated that such experimental manoeuvres produced changes in intracellular [H+] and [lactate] comparable to those observed during muscle fatigue, and accounted for this paradoxical conservation of Vc through balancing negative osmotic effects resulting from the net cation efflux that would follow a titration of intracellular membrane‐impermeant anions by the intracellular accumulation of protons. It demonstrated that with established physiological values for intracellular buffering capacity and the permeability ratio of lactic acid and anionic lactate, PLacH: PLac−, this would provide a mechanism that precisely balanced any effect on cell volume resulting from lactate accumulation during exercise.