Seasonal Azithromycin Use in Paediatric Protracted Bacterial Bronchitis Does Not Promote Antimicrobial Resistance but Does Modulate the Nasopharyngeal Microbiome.

Protracted bacterial bronchitis (PBB) causes chronic wet cough for which seasonal azithromycin is increasingly used to reduce exacerbations. We investigated the impact of seasonal azithromycin on antimicrobial resistance and the nasopharyngeal microbiome. In an observational cohort study, 50 children with PBB were enrolled over two consecutive winters; 25/50 at study entry were designated on clinical grounds to take azithromycin over the winter months and 25/50 were not. Serial nasopharyngeal swabs were collected during the study period (12-20 months) and cultured bacterial isolates were assessed for antimicrobial susceptibility. 16S rRNA-based sequencing was performed on a subset of samples. Irrespective of azithromycin usage, high levels of azithromycin resistance were found; 73% of bacteria from swabs in the azithromycin group vs. 69% in the comparison group. Resistance was predominantly driven by azithromycin-resistant S. pneumoniae, yet these isolates were mostly erythromycin susceptible. Analysis of 16S rRNA-based sequencing revealed a reduction in within-sample diversity in response to azithromycin, but only in samples of children actively taking azithromycin at the time of swab collection. Actively taking azithromycin at the time of swab collection significantly contributed to dissimilarity in bacterial community composition. The discrepancy between laboratory detection of azithromycin and erythromycin resistance in the S. pneumoniae isolates requires further investigation. Seasonal azithromycin for PBB did not promote antimicrobial resistance over the study period, but did perturb the microbiome.

Maternal pregnancy vitamin D supplementation increases offspring bone formation in response to mechanical loading: Findings from a MAVIDOS Trial sub-study.

The Maternal Vitamin D Osteoporosis (MAVIDOS) trial reported higher total body bone mineral content in winter-born infants of mothers receiving vitamin D supplementation [1000 IU/day cholecalciferol] compared with placebo from 14 weeks gestation until delivery. This sub-study aimed to determine whether antenatal vitamin D supplementation altered postnatal bone formation in response to mechanical stimulation. Thirty-one children born to MAVIDOS participants randomised to either placebo (n=19) or cholecalciferol (n=12) were recruited at age 4-5 years. Children received whole body vibration (WBV) for 10 minutes on 5 consecutive days. Fasting blood samples for bone homeostasis, 25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and bone turnover markers (Pro-collagen Type 1 N-terminal propeptide, P1NP; Cross-linked C-telopeptide of Type I Collagen, CTX) were collected pre-WBV and on day 8 (D8). Mean changes (D) in P1NP (ng/ml) between baseline and D8 in the vitamin-D intervention and placebo groups were 40.6 and -92.6 respectively and mean changes (Δ) in CTX (ng/ml) were 0.034 (intervention) and -0.084 (placebo) respectively. Between-group DP1NP difference was 133.2ng/ml [95% CI 0.4, 266.0; p=0.049] and ΔCTX 0.05ng/ml (95% CI -0.159, 0.26ng/mL; p=0.62). Antenatal vitamin-D supplementation resulted in increased P1NP in response to WBV, suggesting early life vitamin D supplementation increases the anabolic response of bone to mechanical loading in children.

Effect of vitamin D supplementation on free and total vitamin D: A comparison of Asians and Caucasians.

OBJECTIVES: It is well established that UK Asians typically have lower vitamin D levels than Caucasians. It is also known that vitamin D binding protein (DBP) is lower in some races than Caucasians. To investigate how ethnicity, skin colour and genetic variation affect the response to vitamin D (15000 IU) administered to young Asian and Caucasian men. DESIGN: Prospective, single-centre clinical trial. PARTICIPANTS: Sixty young men (18-25 year) of Asian (n = 30) and Caucasian (n = 30) origin. MEASUREMENTS: We measured serum calcium, phosphate, magnesium, alkaline phosphatase, albumin, parathyroid hormone; total 25 hydroxyvitamin D (25OHD); calculated and directly measured free 25OHD; DBP at baseline and 4 weeks; DBP genotype, skin colour (Fitzpatrick scale), dietary vitamin D and calcium intake at baseline; and urine calcium:creatinine ratio at baseline, 1 and 4 weeks. RESULTS: At baseline, Asians had lower serum total 25OHD (26.4 [13.7] vs 34.1 [12.3] nmol/L P = 0.0272) and DBP (6.7 [3.4] vs 9.6 [4.4] nmol/L; P = 0.0065) but similar free 25OHD (16.7 [10.4] vs 17.8 [7.5] pmol/L P = 0.6530). After dosing, total 25OHD rose similarly in each group (≈56 nmol/L), but measured free 25OHD rose more in Asians (18.1 [9.4] vs 12.2 [13.3] pmol/L P = 0.0464). Lower DBP at baseline, possibly reflecting genotype differences, was associated with a greater change in measured free 25OHD in Caucasians, but not in Asians. CONCLUSIONS: Asian compared with Caucasian males had a larger increment in measured free 25OHD following 150 000 units vitamin D3, possibly reflecting differences in DBP affinity for 25OHD. Ethnicity should be considered when devising guidelines for the treatment of vitamin D deficiency.

Effects of empagliflozin on metabolic parameters in polycystic ovary syndrome: A randomized controlled study.

BACKGROUND: Empagliflozin is a sodium-glucose-cotransporter-2 inhibitor that improves cardiovascular risk and promotes weight loss in patients with type-2 diabetes. Polycystic ovary syndrome (PCOS) is associated with obesity and increased cardiovascular risk; therefore, empagliflozin may be of benefit for these women. The aim of this study was to compare the effects of empagliflozin vs metformin on anthropometric and body composition, hormonal and metabolic parameters in women with PCOS. MATERIALS AND METHODS: A randomized open-label study was conducted in women with PCOS who were randomized to either empagliflozin 25 mg (n = 19) or metformin 1500 mg (n = 20) daily for 12 weeks. The main outcomes assessed were changes in anthropometric and body composition, hormonal and metabolic parameters. RESULTS: Univariate analysis showed significant differences in weight (empagliflozin: -1.4 ± 3.2% vs metformin: 1.2 ± 2.3%; P = 0.006), body mass index (empagliflozin: -1.4 ± 3.2% vs metformin: 1.1 ± 2.2%; P = 0.006), waist circumference (empagliflozin: -1.6 ± 2.8% vs metformin: 0.2 ± 2.1%; P = 0.029) and hip circumference (empagliflozin: -2.0 ± 3.0% vs metformin: 1.1 ± 1.9%; P = 0.001), basal metabolic rate (empagliflozin: -1.8 ± 2.9% vs metformin: 0.1 ± 1.9%, P = 0.024) and fat mass (empagliflozin: -0.7 ± 4.9% vs metformin, 3.2 ± 5.0%; P = 0.023) between the empagliflozin and the metformin groups. These differences were confirmed in linear regression analysis after adjustment for relevant covariates. There were no significant changes in hormonal or metabolic parameters between both groups. CONCLUSION: There was a significant improvement in anthropometric parameters and body composition, in overweight and obese women with PCOS after 12 weeks of treatment with empagliflozin compared to metformin, although no changes were seen in hormonal or metabolic parameters.

Environmental effects of ambient temperature and relative humidity on insulin pharmacodynamics in adults with type 1 diabetes mellitus.

OBJECTIVE: This study aimed to explore the effects of ambient temperature and relative humidity on insulin pharmacodynamics in adults with type 1 diabetes. MATERIALS AND METHODS: A three-way, cross-over, randomised study was performed in adults with type 1 diabetes mellitus (n = 10). The pharmacodynamics profile of a single dose of short-acting insulin (insulin lispro) was investigated, using a controlled environmental chamber, under three environmental conditions: (a) temperature: 15°C and humidity: 10%; (b) temperature: 30°C and humidity: 10%; and (c) temperature: 30°C and humidity: 60%. A euglycaemic glucose clamp technique ensured constant blood glucose of 100 mg/dL (5.5 mmol/L). The following pharmacodynamic endpoints were calculated: maximum glucose infusion rate (GIRmax ), time to GIRmax (tGIRmax ), total area under the curve (AUC) for GIR from 0-6 hours (AUCGIR.0-6h ), and partial AUCs (AUCGIR.0-1h , AUCGIR.0-2h and AUCGIR.2-6h ). RESULTS: Higher temperature (30°C) under 10% fixed humidity conditions resulted in greater GIRmax (P = 0.04) and a later tGIR.max (P = 0.049) compared to lower temperature (15°C). Humidity did not affect any pharmacodynamic parameter. When the combined effects of temperature and humidity were explored, tGIR.max (P = 0.008) occurred earlier, with a lower late insulin pharmacodynamic effect (AUCGIR.2-6h ; P = 0.017) at a temperature of 15°C and humidity of 10% compared to a temperature of 30°C and humidity of 60%. CONCLUSIONS: High ambient temperature resulted in a greater insulin peak effect compared to low ambient temperature, with the contribution of high relative humidity apparent only at high ambient temperature. This suggests that patients with type 1 diabetes mellitus who are entering higher environmental temperatures, with or without high humidity, could experience more hypoglycaemic events.

Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.

Aims: Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40-49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials. Methods and results: Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21-33%), including 575 patients with LVEF 40-49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40-49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34-1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24-0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when < 50% at baseline, but did not improve prognosis. Conclusion: Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF < 40%, but similar benefit was observed in the subgroup of patients with LVEF 40-49%.

STAAR: a randomised controlled trial of electronic adherence monitoring with reminder alarms and feedback to improve clinical outcomes for children with asthma.

BACKGROUND: Suboptimal adherence to inhaled steroids is common in children with asthma and is associated with poor disease control, reduced quality of life and even death. Previous studies using feedback of electronically monitored adherence data have demonstrated improved adherence, but have not demonstrated a significant impact on clinical outcomes. The aim of this study was to determine whether introduction of this approach into routine practice would result in improved clinical outcomes. METHODS: Children with asthma aged 6-16 years were randomised to the active intervention consisting of electronic adherence monitoring with daily reminder alarms together with feedback in the clinic regarding their inhaled corticosteroid (ICS) use or to the usual care arm with adherence monitoring alone. All children had poorly controlled asthma at baseline, taking ICS and long-acting ß-agonists. Subjects were seen in routine clinics every 3 months for 1 year. The primary outcome was the Asthma Control Questionnaire (ACQ) score. Secondary outcomes included adherence and markers of asthma morbidity. RESULTS: 77 of 90 children completed the study (39 interventions, 38 controls). Adherence in the intervention group was 70% vs 49% in the control group (p≤0.001). There was no significant difference in the change in ACQ, but children in the intervention group required significantly fewer courses of oral steroids (p=0.008) and fewer hospital admissions (p≤0.001). CONCLUSIONS: The results indicate that electronic adherence monitoring with feedback is likely to be of significant benefit in the routine management of poorly controlled asthmatic subjects. TRIAL REGISTRATION NUMBER: NCT02451709; pre-result.

Asthma phenotypes: do cough and wheeze predict exacerbations in persistent asthma?

Little is known of the long-term symptom profile in uncontrolled asthma and whether symptoms can predict distinct phenotypes. The primary objective of these analyses was to assess diurnal profile of cough and wheeze in an uncontrolled asthma population. Secondary outcomes were to examine how these symptom profiles influence response to treatment.Twice-daily electronically recorded data from 1701 patients were examined in relation to the population demographics. Reliever treatment with salbutamol was then compared with extra-fine beclometasone/formoterol maintenance and reliever therapy (MART). Exacerbation frequency was then correlated with the symptom profile.Symptoms were commoner in older patients with an increased body mass index. In most patients, reported cough and wheeze were closely correlated (r=0.73). Two phenotypes of cough- and wheeze-predominant patients were identified; the former were overweight, older females and the latter older males. Diurnal symptoms of cough and wheeze were similarly attenuated by both therapies. MART reduced exacerbation frequency by a third compared with salbutamol, and this effect was greatest in patients with fewest reported symptoms.While cough and wheeze are highly correlated in uncontrolled asthma, some patients predominantly have cough whereas others wheeze. Symptoms and exacerbation frequency appear poorly associated, suggesting an alternative pathophysiology. MART may be the preferred option in those with fewest symptoms.

Development of a Human Model for the Study of Effects of Hypoxia, Exercise, and Sildenafil on Cardiac and Vascular Function in Chronic Heart Failure.

BACKGROUND: Pulmonary hypertension is associated with poor outcome in patients with chronic heart failure (CHF) and may be a therapeutic target. Our aims were to develop a noninvasive model for studying pulmonary vasoreactivity in CHF and characterize sildenafil's acute cardiovascular effects. METHODS AND RESULTS: In a crossover study, 18 patients with CHF participated 4 times [sildenafil (2 × 20 mg)/or placebo (double-blind) while breathing air or 15% oxygen] at rest and during exercise. Oxygen saturation (SaO2) and systemic vascular resistance were recorded. Left and right ventricular (RV) function and transtricuspid systolic pressure gradient (RVTG) were measured echocardiographically. At rest, hypoxia caused SaO2 (P = 0.001) to fall and RVTG to rise (5 ± 4 mm Hg; P = 0.001). Sildenafil reduced SaO2 (-1 ± 2%; P = 0.043), systemic vascular resistance (-87 ± 156 dyn·s·cm; P = 0.034), and RVTG (-2 ± 5 mm Hg; P = 0.05). Exercise caused cardiac output (2.1 ± 1.8 L/min; P < 0.001) and RVTG (19 ± 11 mm Hg; P < 0.0001) to rise. The reduction in RVTG with sildenafil was not attenuated by hypoxia. The rise in RVTG with exercise was not substantially reduced by sildenafil. CONCLUSIONS: Sildenafil reduces SaO2 at rest while breathing air, this was not exacerbated by hypoxia, suggesting increased ventilation-perfusion mismatching due to pulmonary vasodilation in poorly ventilated lung regions. Sildenafil reduces RVTG at rest and prevents increases caused by hypoxia but not by exercise. This study shows the usefulness of this model to evaluate new therapeutics in pulmonary hypertension.

The effects of treatment with liraglutide on atherothrombotic risk in obese young women with polycystic ovary syndrome and controls.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with obesity and increased cardiovascular (CV) risk markers. In this study our aim was to assess the effects of six months treatment with liraglutide 1.8 mg od on obesity, and CV risk markers, particularly platelet function, in young obese women with PCOS compared to controls of similar age and weight. METHODS: Carotid intima-media wall thickness (cIMT) was measured by B-mode ultrasonography, platelet function by flow cytometry, clot structure/lysis by turbidimetric assays and endothelial function by ELISA and post-ischaemic reactive hyperemia (RHI). Data presented as mean change (6-month - baseline) ± standard deviation. RESULTS: Nineteen obese women with PCOS and 17 controls, of similar age and weight, were recruited; baseline atherothrombotic risk markers did not differ between the two groups. Twenty five (69.4%) participants completed the study (13 PCOS, 12 controls). At six months, weight was significantly reduced by 3.0 ± 4.2 and 3.8 ± 3.4 kg in the PCOS and control groups, respectively; with no significant difference between the two groups, P = 0.56. Similarly, HOMA-IR, triglyceride, hsCRP, urinary isoprostanes, serum endothelial adhesion markers (sP-selectin, sICAM and sVCAM), and clot lysis area were equally significantly reduced in both groups compared to baseline. Basal platelet P-selectin expression was significantly reduced at six months in controls -0.17 ± 0.26 but not PCOS -0.12 ± 0.28; between groups difference, 95% confidence interval = -0.14 - 0.26, P = 0.41. No significant changes were noted in cIMT or RHI. CONCLUSIONS: Six months treatment with liraglutide (1.8 mg od) equally affected young obese women with PCOS and controls. In both groups, liraglutide treatment was associated with 3-4% weight loss and significant reduction in atherothrombosis markers including inflammation, endothelial function and clotting. Our data support the use of liraglutide as weight loss medication in simple obesity and suggest a potential beneficial effect on platelet function and atherothrombotic risk at 6 months of treatment. TRIAL REGISTRATION: Clinical trial reg. no. ISRCTN48560305. Date of registration 22/05/2012.

Disease progression in chronic heart failure is linear: Insights from multistate modelling.

AIMS: Understanding the pattern of disease progression in chronic heart failure (HF) may inform patient care and healthcare system design. We used a four-state Markov model to describe the disease trajectory of patients with HF. METHODS AND RESULTS: Consecutive patients (n = 4918) were enrolled (median age 75 [67-81] years, 61.3% men, 44% with HF and reduced ejection fraction). We generated a model by observing events during the first 2 years of follow-up. The model yielded surprisingly accurate predictions of how a population with HF will behave during subsequent years. As examples, the predicted transition probability from hospitalization to death was 0.11; the observed probabilities were 0.13, 0.14, and 0.16 at 3, 4, and 5 years, respectively. Similarly, the predicted transition intensity for rehospitalization was 0.35; the observed probabilities were 0.38, 0.34, and 0.35 at 3, 4, and 5 years, respectively. A multivariable model including covariates thought to influence outcome did not improve accuracy. Predicted average life expectancy was approximately 10 years for the unadjusted model and 13 years for the multivariable model, consistent with the observed mortality of 41% at 5 years. CONCLUSIONS: A multistate Markov chain model for patients with chronic HF suggests that the proportion of patients transitioning each year from a given state to another remains constant. This finding suggests that the course of HF at a population level is more linear than is commonly supposed and predictable based on current patient status.

Glycemic control in the 12 months following a change to SI hemoglobin A1c reporting units.

BACKGROUND: Many countries have implemented, or are considering, a change in hemoglobin A1c (Hb A1c) units from traditional percentage values [Diabetes Control and Complications Trial (DCCT)] to the new Système International d'Unités (SI) unit in millimoles per mole. Concern exists that such a large alteration in numeric values might lead, through confusion, to a deterioration in patients' glycemia. This study has assessed Hb A1c in the year before and after the change of units in a UK diabetes population. METHODS: The Hb A1c in the 12 months immediately before the unit change (October 2010 to September 2011) was compared with the 12 months after (October 2011 to September 2012). Also, the subsequent change in Hb A1c in patients who had poor glycemic control [Hb A1c >8% (64 mmol/mol)], either before or after the unit change, was compared. RESULTS: Over the 2 years, 44 721 Hb A1c measurements were requested on 13,197 (7247 male, 5950 female) known diabetes patients. The population Hb A1c was no different between years, with a median [interquartile range (IQR)] value of 7.5% (6.6%-8.7%) after the change and 7.5% (6.5-8.7) before (P = 0.34). The subsequent change in Hb A1c following a raised (>8%) result was the same regardless of whether the initial value reported was in DCCT or SI units [median (IQR) change in Hb A1c -0.2% (-0.9% to 0.3%), n = 4316, following a DCCT result, vs -0.2% (-0.8% to 0.3%), n = 4396, following SI; P = 0.44]. CONCLUSIONS: In this UK diabetes population, a move to SI Hb A1c reporting did not lead to any marked short-term deterioration in glycemia or a different Hb A1c outcome in patients with initial poor glucose control.

Methods of standing from supine and percentiles for time to stand and to run 10 meters in young children.

OBJECTIVE: To assess the method and time to stand from supine and the time to run 10 m for normal young children. STUDY DESIGN: Three hundred twenty-one normal children aged 2.8-7.8 years were recruited from primary schools. After standardization, each test was carried out twice, timed, and videoed. The influence of age, sex, height, weight, body mass index (BMI), and method of standing were analyzed. Charts for time to stand and running time were produced and assessment of reproducibility performed. RESULTS: For the time to stand from supine and the method used, there was a significant correlation with age. More than 50% of young children took >2 seconds. There was no significant association with BMI. Method of standing was associated with standing time in boys but not in girls. A Bland-Altman plot of standing times by 2 observers showed good reproducibility with no clinically significant difference. For the 10-m running test, there was a significant negative correlation with age, height, weight, and BMI. CONCLUSION: There is considerable variability in the method used and time taken to stand from supine in young children. These change with age, permitting the creation of charts showing age-related normal values.

Initial evidence of the reliability and validity of a three-dimensional body rating scale for the congenitally blind.

Research on body dissatisfaction has grown significantly. However, valid and reliable instruments for measuring body dissatisfaction in the congenitally blind have yet to be developed. In three studies, we report on development, test-retest reliability, and concurrent and content validity of the Three-dimensional Body Rating Scale (3BRS) for the congenitally blind. In Study 1, 58 people with congenital blindness (28 women, 30 men; M age = 36.7, SD = 13.1) numerically ordered models of the 3BRS and models of the Two-dimensional Body Rating Scale (2BRS), from very thin to the very fat. In Study 2, the construct validity and reliability of the 38RS was assessed. The same participants from Study 1 chose the 3BRS model that represented their ideal body and the 3BRS model that represented their actual body. Two weeks later, a re-test was done. In Study 3, 16 experts judged the content validity of the 3BRS. The psychometric properties of the 3BRS, its utility, and its limitations are discussed along with considerations for future research.

Atherosclerotic disease of the abdominal aorta and its branches: prognostic implications in patients with heart failure.

Aortic atherosclerosis reduces compliance in the systemic circulation and increases peripheral resistance, afterload and left ventricular wall stress. In patients with heart failure, these changes can impair left ventricular systolic function and energy efficiency, which could reduce exercise capacity. Though the interaction and the impact of aortic atherosclerosis on left ventricular function have been investigated, its prognostic implications in patients with heart failure are unclear. We used cardiac magnetic resonance imaging and gadolinium-enhanced abdominal aortography to investigate the prevalence and prognostic impact of atherosclerotic disease of the abdominal aorta and its side branches in 355 patients with heart failure. Sclerotic abdominal aortic disease was defined as a luminal narrowing >50% of the aorta and its side branches or the presence of abdominal aortic aneurysm. Patients with disease of the aorta and its branches were older (P < 0.0001), had overall longer stay in hospital (P = 0.006) and had more admissions (P = 0.001) and worse prognosis (hazard ratio: 1.97, 95% confidence interval: 1.29-3.00, P = 0.002) than those without. In a multivariable model, increasing age and pulse pressure, diabetes mellitus and increasing left ventricular end-diastolic volume were associated with a worse prognosis, but sclerotic abdominal aortic disease was not independently related to outcome (hazard ratio: 1.06; 95% confidence interval: 0.64-1.74; P = 0.823). These data demonstrate that atherosclerosis of the abdominal aorta and its side branches is common and associated with increased morbidity in patients with chronic heart failure. How such disease should be managed remains uncertain, but its recognition and characterisation are the first steps in finding out.

The effect of parathyroidectomy on neuropsychological symptoms and biochemical parameters in patients with asymptomatic primary hyperparathyroidism.

BACKGROUND: With increased biochemical screening, primary hyperparathyroidism (pHPT) is often discovered incidentally whilst patients are asymptomatic. OBJECTIVE: To assess the impact of parathyroidectomy on neuropsychological symptoms and biochemical parameters in people with asymptomatic pHPT, whilst controlling for the surgical procedure. PATIENTS/DESIGN/MEASUREMENTS: Twenty-four patients with asymptomatic pHPT requiring parathyroidectomy, in accordance with National Institutes for Health recommendations, were recruited prospectively. A control group of 23 subjects was recruited simultaneously from consecutive patients undergoing diagnostic hemithyroidectomy (HT) for benign thyroid nodules. Operations were performed by a single surgeon. Biochemical investigations and neuropsychological symptoms were measured preoperatively and 3 months after surgery. Neuropsychological symptoms were measured using the Hospital Anxiety (HAD-A) and Depression (HAD-D) scales and the Mood Rating Scale (MRS). RESULTS: Postoperatively, calcium and parathyroid hormone normalized in all patients in the pHPT group. Patients with pHPT showed a significant improvement in neuropsychological symptoms with a pre- and postoperative mean change of 2·45 ± 2·57 (P < 0·05) on HAD-A, 2·79 ± 3·85 (P < 0·05) on HAD-D, and 3·2 ± 4·57 (P < 0·05) on MRS, parameters that were unaltered in the HT group. The differences between the two groups remained statistically significant after adjustment for age and sex for HAD-D (mean change 2·8, 95% CI = 0·3, 5·3, P = 0·025) and MRS (mean difference 3·5, 95% CI = 0·4, 6·7, P = 0·027) but not for HAD-A (mean difference 1·5, 95% CI = -0·8, 3·8, P = 0·20). For all three mental health scores, there were no significant associations with either age or sex. CONCLUSIONS: Asymptomatic pHPT is associated with neuropsychological symptoms that improve after parathyroidectomy.

Dynamic risk stratification using Markov chain modelling in patients with chronic heart failure.

AIMS: Risk changes with the progression of disease and the impact of treatment. We developed a dynamic risk stratification Markov chain model using artificial intelligence in patients with chronic heart failure (CHF). METHODS AND RESULTS: We described the pattern of behaviour among 7496 consecutive patients assessed for suspected HF. The following mutually exclusive health states were defined and assessed every 4 months: death, hospitalization, outpatient visit, no event, and leaving the service altogether (defined as no event at any point following assessment). The observed figures at the first transition (4 months) weres 427 (6%), 1559 (21%), 2254 (30%), 1414 (19%), and 1842 (25%), respectively. The probabilities derived from the first two transitions (i.e. from baseline to 4 months and from 4 to 8 months) were used to construct the model. An example of the model's prediction is that at cycle 4, the cumulative probability of death was 14%; leaving the system, 37%; being hospitalized between 12 and 16 months, 10%; having an outpatient visit, 8%; and having no event, 31%. The corresponding observed figures were 14%, 41%, 10%, 15%, and 21%, respectively. The model predicted that during the first 2 years, a patient had a probability of dying of 0.19, and the observed value was 0.18. CONCLUSIONS: A model derived from the first 8 months of follow-up is strongly predictive of future events in a population of patients with chronic heart failure. The course of CHF is more linear than is commonly supposed, and thus more predictable.

Progressive loss of corneal nerve fibers is associated with physical inactivity and glucose lowering medication associated with weight gain in type 2 diabetes.

AIMS/INTRODUCTION: Limited studies have identified risk factors linked to the progression of diabetic peripheral neuropathy (DPN) in type 2 diabetes. This study examined the association of risk factors with change in neuropathy measures over 2 years. MATERIALS AND METHODS: Participants with type 2 diabetes (n = 78) and controls (n = 26) underwent assessment of clinical and metabolic parameters and neuropathy using corneal confocal microscopy (CCM), vibration perception threshold (VPT), and the DN4 questionnaire at baseline and 2 year follow-up. RESULTS: Participants with type 2 diabetes had a lower corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) (P ≤ 0.0001) and a higher VPT (P ≤ 0.01) compared with controls. Over 2 years, despite a modest reduction in HbA1c (P ≤ 0.001), body weight (P ≤ 0.05), and LDL (P ≤ 0.05) the prevalence of DPN (P = 0.28) and painful DPN (P = 0.21) did not change, but there was a significant further reduction in CNBD (P ≤ 0.0001) and CNFL (P ≤ 0.05). CNFD, CNBD, and CNFL decreased significantly in physically inactive subjects (P < 0.05-0.0001), whilst there was no change in CNFD (P = 0.07) or CNFL (P = 0.85) in physically active subjects. Furthermore, there was no change in CNFD (P = 0.82), CNBD (P = 0.08), or CNFL (P = 0.66) in patients treated with glucose lowering medication associated with weight loss, whilst CNBD (P = 0.001) decreased in patients on glucose lowering medication associated with weight gain. CONCLUSIONS: In participants with type 2 diabetes, despite a modest improvement in HbA1c, body weight, and LDL there was a progressive loss of corneal nerve fibers; except in those who were physically active or on glucose lowering medication associated with weight loss.