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.

Clinical utility of bone turnover markers in monitoring the withdrawal of treatment with oral bisphosphonates in postmenopausal osteoporosis.

Bone markers may be useful to monitor response to treatment withdrawal in osteoporosis. We used two criteria for investigating the change in BTMs after withdrawal of bisphosphonate treatment. A larger increase in BTMs was associated with greater bone loss. Bone markers may be useful in monitoring of patients taking a pause from treatment. INTRODUCTION: Measurement of bone turnover markers (BTMs) may be useful to monitor offset of treatment with bisphosphonates (BP) in osteoporosis. We assessed the effect of withdrawal of BP treatment by comparing the changes in BTMs and total hip (TH) bone density (BMD). METHODS: We studied postmenopausal osteoporotic women who had completed a randomised study of three oral BPs. After 2 years of treatment, participants with BMD T-score > - 2.5 and in whom it was considered clinically appropriate to discontinue treatment, were invited to participate in a further 2-year observational study. Biochemical response was assessed using BTMs (CTX and PINP) with offset being defined by two criteria: (1) an increase greater than the least significant change (LSC) and (2) an increase above the reference mean value. RESULTS: Fifty women completed the study. At 48 weeks after stopping BPs, CTX was greater than the LSC for 66% of women and PINP 72%; CTX was above the reference mean for 64% of women and PINP 42%. The decrease in THBMD was greater for women with the largest increase in BTM compared to those with continued suppression (mean difference for CTX was - 2.98%, 95%CI - 4.75 to - 1.22, P < 0.001, PINP - 2.25%, 95% CI - 4.46 to - 0.032, P = 0.046). CONCLUSION: The measurement of BTM after withdrawal of BPs is potentially useful to evaluate patients that are taking a pause from treatment. An increase in BTMs more than the LSC and/or reference mean reflects loss of treatment effect and identifies patients that are likely to have a decrease in BMD. Such changes could provide an indication for reintroduction of treatment.

Salbutamol-induced electrophysiological changes show no correlation with electrophysiological changes during hyperinsulinaemic-hypoglycaemic clamp in young people with Type 1 diabetes.

AIMS: Hypoglycaemia causes QT-interval prolongation and appears pro-arrhythmogenic. Salbutamol, a ß2 -adrenoreceptor agonist also causes QT-interval prolongation. We hypothesized that the magnitude of electrophysiological changes induced by salbutamol and hypoglycaemia might relate to each other and that salbutamol could be used as a non-invasive screening tool for predicting an individual's electrophysiological response to hypoglycaemia. METHODS: Eighteen individuals with Type 1 diabetes were administered 2.5 mg of nebulized salbutamol. Participants then underwent a hyperinsulinaemic-hypoglycaemic clamp (2.5 mmol/l for 1 h). During both experiments, heart rate and serum potassium (and catecholamines during the clamp) were measured and a high-resolution electrocardiogram (ECG) was recorded at pre-set time points. Cardiac repolarization was measured by QT-interval duration adjusted for heart rate (QTc ), T-wave amplitude (Tamp ), T-peak to T-end interval duration (Tp Tend ) and T-wave area symmetry (Tsym ). The maximum changes vs. baseline in both experiments were assessed for their linear dependence. RESULTS: Salbutamol administration caused QTc and Tp Tend prolongation and a decrease in Tamp and Tsym . Hypoglycaemia caused increased plasma catecholamines, hypokalaemia, QTc and Tp Tend prolongation, and a decrease in Tamp and Tsym . No significant correlations were found between maximum changes in QTc [r = 0.15, 95% confidence interval (95% CI) -0.341 to 0.576; P = 0.553), Tp Tend (r = 0.075, 95% CI -0.406 to 0.524; P = 0.767), Tsym (r = 0.355, 95% CI -0.132 to 0.706; P = 0.149) or Tamp (r = 0.148, 95% CI -0.347 to 0.572; P = 0.558) in either experiment. CONCLUSIONS: Both hypoglycaemia and salbutamol caused pro-arrhythmogenic electrophysiological changes in people with Type 1 diabetes but were not related in any given individual. Salbutamol does not appear useful in assessing an individual's electrophysiological response to hypoglycaemia.

Observational study of the development and evaluation of a fertility preservation patient decision aid for teenage and adult women diagnosed with cancer: the Cancer, Fertility and Me research protocol.

INTRODUCTION: Women diagnosed with cancer and facing potentially sterilising cancer treatment have to make time-pressured decisions regarding fertility preservation with specialist fertility services while undergoing treatment of their cancer with oncology services. Oncologists identify a need for resources enabling them to support women's fertility preservation decisions more effectively; women report wanting more specialist information to make these decisions. The overall aim of the 'Cancer, Fertility and Me' study is to develop and evaluate a new evidence-based patient decision aid (PtDA) for women with any cancer considering fertility preservation to address this unmet need. METHODS AND ANALYSIS: This is a prospective mixed-method observational study including women of reproductive age (16 years +) with a new diagnosis of any cancer across two regional cancer and fertility centres in Yorkshire, UK. The research involves three stages. In stage 1, the aim is to develop the PtDA using a systematic method of evidence synthesis and multidisciplinary expert review of current clinical practice and patient information. In stage 2, the aim is to assess the face validity of the PtDA. Feedback on its content and format will be ascertained using questionnaires and interviews with patients, user groups and key stakeholders. Finally, in stage 3 the acceptability of using this resource when integrated into usual cancer care pathways at the point of cancer diagnosis and treatment planning will be evaluated. This will involve a quantitative and qualitative evaluation of the PtDA in clinical practice. Measures chosen include using count data of the PtDAs administered in clinics and accessed online, decisional and patient-reported outcome measures and qualitative feedback. Quantitative data will be analysed using descriptive statistics, paired sample t-tests and CIs; interviews will be analysed using thematic analysis. ETHICS AND DISSEMINATION: Research Ethics Committee approval (Ref: 16/EM/0122) and Health Research Authority approval (Ref: 194751) has been granted. Findings will be published in open access peer-reviewed journals, presented at conferences for academic and health professional audiences, with feedback to health professionals and program managers. The Cancer, Fertility and Me patient decision aid (PtDA) will be disseminated via a diverse range of open-access media, study and charity websites, professional organisations and academic sources. External endorsement will be sought from the International Patient Decision Aid Standards (IPDAS) Collaboration inventory of PtDAs and other relevant professional organisations, for example, the British Fertility Society. TRIAL REGISTRATION NUMBER: NCT02753296; pre-results.

Response of bone turnover markers to raloxifene treatment in postmenopausal women with osteopenia.

UNLABELLED: We used two methods of identifying women who reached the target for raloxifene treatment with bone turnover markers. Both approaches identified women that responded to treatment but did not fully agree and may be complementary. INTRODUCTION: The change in bone turnover markers (BTMs) in response to osteoporosis therapy can be assessed by a decrease beyond the least significant change (LSC) or below the mean of the reference interval (RI). We compared the performance of these two approaches in women treated with raloxifene. METHODS: Fifty postmenopausal osteopenic women (age 51-72 years) were randomised to raloxifene or no treatment for 2 years. Blood samples were collected for the measurement of BTM. The LSC for each marker was calculated from the untreated women and the RI obtained from healthy premenopausal women (age 35-40 years). Bone mineral density (BMD) was measured at the spine and hip. RESULTS: There was a decrease in BTM in response to raloxifene treatment, percentage change at 12 weeks: C terminal telopeptide of type I collagen (CTX) -39 % (95 % CI -48 to -28) and N terminal propeptide of type I procollagen (PINP) -32 % (95 % CI -40 to -23) P < 0.001. The proportion of women classified as responding to treatment using LSC at 12 weeks was as follows: CTX 38 % and PINP 52 % and at 48 weeks CTX 60 % and PINP 65 %. For the RI approach, the proportion of women classified as responding to treatment at 12 weeks was CTX and PINP 38 % and at 48 weeks CTX 40 % and PINP 45 %. There was a significant difference in the change in spine BMD in the raloxifene-treated group compared to the no-treatment group at week 48: difference 0.031 g/cm(2) (95 % CI 0.016 to 0.046, P < 0.001). CONCLUSIONS: The two approaches identified women that reached the target for treatment using BTM. Both LSC and RI criteria appear useful in identifying treatment response, but the two approaches do not fully overlap and may be complementary.

Response of bone turnover markers to three oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO study.

UNLABELLED: We used bone turnover markers to identify women who responded to bisphosphonate treatment for osteoporosis. Response was more likely with alendronate and ibandronate than risedronate. There was a greater decrease in bone markers if baseline bone turnover markers were higher and if the patient took more than 80 % of her medication. INTRODUCTION: Biochemical response to bisphosphonate therapy can be assessed using either a decrease in bone turnover marker beyond the least significant change (LSC) or a reduction to within a reference interval (RI). We compared the performance of these target responses and determined whether response was related to the type of bisphosphonate, compliance and baseline bone turnover markers. METHODS: Biochemical responses to three oral bisphosphonates were assessed in an open, controlled trial comprising 172 postmenopausal osteoporotic women (age 53-84 years), randomised to alendronate, ibandronate or risedronate, plus calcium and vitamin D supplementation for 2 years. The LSC for each marker was derived within the study population, whereas RIs were obtained from a control group of healthy premenopausal women (age 35-40 years). RESULTS: Over 70 % of women achieved a target response for serum CTX and PINP, irrespective of the approach used. The percentage decrease at 12 weeks was greater for women with baseline PINP above the RI -63 % (difference 13 %, 95 % CI 0 to 27.1, P = 0.049) and good compliance -67 % (difference 15.9 %, 95 % CI 6.3 to 25.5, P = 0.001). Responders had a greater increase in spine bone density compared to nonresponders; for example 6.2 vs. 2.3 % (difference 3.9 %, 95 % CI 1.6 to 6.3, P = 0.0011) for PINP LSC. The magnitude of change in bone markers was greater with ibandronate and alendronate than risedronate. CONCLUSIONS: Both approaches to response identified similar proportions of women as responders. Nonresponders had smaller increases in BMD, and we suggest that biochemical assessment of response is a useful tool for the management of women with postmenopausal osteoporosis.

Twice- rather than once-daily basal insulin is associated with better glycaemic control in Type 1 diabetes mellitus 12 months after skills-based structured education in insulin self-management.

AIM: This study investigates the relationship between basal insulin regimen and glycaemic outcomes 12 months after skills-based structured education in the UK Dose Adjustment for Normal Eating (DAFNE) programme for Type 1 diabetes mellitus. METHOD: Retrospective analysis of data from 892 DAFNE participants from 11 UK centres. RESULTS: Mean HbA1c 12 months after DAFNE was lower in those using twice- rather than once-daily basal insulin after correcting for differences in baseline HbA1c , age and duration of diabetes; difference -2 (95% CI -3 to -1) mmol/mol [-0.2 (-0.3 to -0.1)%], P = 0.009. The greatest fall in HbA1c of -5 (-7 to -3) mmol/mol [-0.4 (-0.6 to -0.3)%], P < 0.001 occurred in those with less good baseline control, HbA1c  ≥ 58 mmol/mol, who switched from once- to twice-daily basal insulin. There was no difference in the 12-month HbA1c between users of glargine, detemir and NPH insulin after correcting for other variables. Relative risk of severe hypoglycaemia fell by 76% and ketoacidosis by 63% 12 months after DAFNE. The rate of severe hypoglycaemia fell from 0.82 to 0.23 events/patient year in twice-daily basal insulin users. In the group with greatest fall in HbA1c , the estimated relative risk for severe hypoglycaemia in twice-daily basal insulin users versus once daily at 12 months was 1.72 (0.88-3.36, P = 0.110). CONCLUSION: After structured education in adults with Type 1 diabetes mellitus, use of basal insulin twice rather than once daily was associated with lower HbA1c , independent of insulin type, with significant reductions in severe hypoglycaemia and ketoacidosis in all groups.

Leptin may play a role in bone microstructural alterations in obese children.

CONTEXT: Bone mass is low and fracture risk is higher in obese children. Hormonal changes in relation to skeletal microstructure and biomechanics have not been studied in obese children. OBJECTIVE: The objective of the study was to ascertain the relationships of obesity-related changes in hormones with skeletal microstructure and biomechanics. DESIGN: High resolution peripheral quantitative computed tomography (HR-pQCT) was used to compare three-dimensional cortical and trabecular microstructure and biomechanics at load-bearing and nonload bearing sites in obese and lean children. The relationship between leptin, adiponectin, testosterone, estrogen, osteocalcin and sclerostin and skeletal microstructure was also determined. SETTING: The study was conducted at a tertiary pediatric endocrine unit in the United Kingdom. PARTICIPANTS: Obese and lean children were matched by gender and pubertal stage. RESULTS: Radial cortical porosity (mean difference -0.01 [95% CI: -0.02, -0.004], P = .003) and cortical pore diameter (mean difference -0.005 mm [95% CI: -0.009, -0.001], P = .011) were lower in obese children. Tibial trabecular thickness was lower (mean difference -0.009 mm [95% CI: -0.014, -0.004], P = .003), and trabecular number was higher (mean difference 0.23 mm(-1) [95% CI: 0.08, 0.38], P = .004) in obese children. At the radius, fat mass percentage negatively correlated with cortical porosity (r = -0.57, P < .001) and pore diameter (r = -0.38, P = .02) and negatively correlated with trabecular thickness (r = -0.62, P < .001) and trabecular von Mises stress (r = -0.39, P = .019) at the tibia. No difference was observed in the other biomechanical parameters of the radius and tibia. Leptin was higher in obese children (805.3 ± 440.6 pg/ml vs 98.1 ± 75.4 pg/ml, P < .001) and was inversely related to radial cortical porosity (r = 0.60, 95% CI: [-0.80, -0.30], P < .001), radial cortical pore diameter (r = 0.51, 95% CI [-0.75, -0.16], P = .002), tibial trabecular thickness (r = 0.55, 95% CI: [-0.78, -0.21], P = .001) and tibial trabecular von Mises stress (r = -0.39, 95% CI: -0.65, 0.04, P = .02). CONCLUSION: Childhood obesity alters radial and tibial microstructure. Leptin may direct these changes. Despite this, the biomechanical properties of the radius and tibia do not adapt sufficiently in obese children to withstand the increased loading potential from a fall. This may explain the higher incidence of fracture in obese children.

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.

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.

Verapamil in major (psychotic) depression.

Dramatic response of major (psychotic) depression to verapamil in an 82-year-old woman suggests that further study of the use of the drug in affective disorders is required, particularly in the light of a possible aetiological role for calcium.