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.

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.

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.

The prevalence and clinical associations of ultrasound measures of congestion in patients at risk of developing heart failure.

AIMS: Congestion is a cardinal feature of untreated heart failure (HF) and might be detected by ultrasound (US) before overt clinical signs appear. METHODS AND RESULTS: We investigated the prevalence and clinical associations of subclinical congestion in 238 patients with at least one clinical risk factor for HF (diabetes, ischaemic heart disease, or hypertension) using three US variables: (i) inferior vena cava (IVC) diameter; (ii) jugular vein distensibility (JVD) ratio (the ratio of the jugular vein diameter during the Valsalva manoeuvre to that at rest); (iii) the number of B-lines from a 28-point lung US. US congestion was defined as IVC diameter > 2.0 cm, JVD ratio < 4.0 or B-lines count > 14. The prevalence of subclinical congestion (defined as at least one positive US marker of congestion) was 30% (13% by IVC diameter, 9% by JVD ratio and 13% by B-line quantification). Compared to patients with no congestion on US, those with at least one marker had larger left atria and higher plasma concentrations of natriuretic peptides. Patients with raised plasma N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptide had a lower JVD ratio (7.69 vs. 8.80; P = 0.05) and more often had at least one lung B-line (74% vs. 63%; P = 0.05). However, plasma natriuretic peptide concentrations were more closely related to left atrial volume than other US measures of congestion. CONCLUSIONS: Subclinical evidence of congestion by US is common in patients with clinical risk factors for HF. Whether these measurements provide additional value for predicting the development of HF and its prevention deserves consideration.

Prognostic value of the chest X-ray in patients hospitalised for heart failure.

BACKGROUND: Patients admitted to hospital with heart failure will have had a chest X-ray (CXR), but little is known about their prognostic significance. We aimed to report the prevalence and prognostic value of the initial chest radiograph findings in patients admitted to hospital with heart failure (acute heart failure, AHF). METHODS: The erect CXRs of all patients admitted with AHF between October 2012 and November 2016 were reviewed for pulmonary venous congestion, Kerley B lines, pleural effusions and alveolar oedema. Film projection (whether anterior-posterior [AP] or posterior-anterior [PA]) and cardiothoracic ratio (CTR) were also recorded. TRIAL REGISTRATION: ISRCTN96643197 RESULTS: Of 1145 patients enrolled, 975 [median (interquartile range) age 77 (68-83) years, 61% with moderate, or worse, left ventricular systolic dysfunction, and median NT-proBNP 5047 (2337-10,945) ng/l] had an adequate initial radiograph, of which 691 (71%) were AP. The median CTR was 0.57 (IQR 0.53-0.61) in PA films and 0.60 (0.55-0.64) in AP films. Pulmonary venous congestion was present in 756 (78%) of films, Kerley B lines in 688 (71%), pleural effusions in 649 (67%) and alveolar oedema in 622 (64%). A CXR score was constructed using the above features. Increasing score was associated with increasing age, urea, NT-proBNP, and decreasing systolic blood pressure, haemoglobin and albumin; and with all-cause mortality on multivariable analysis (hazard ratio 1.10, 95% confidence intervals 1.07-1.13, p < 0.001). CONCLUSIONS: Radiographic evidence of congestion on a CXR is very common in patients with AHF and is associated with other clinical measures of worse prognosis. Signs of heart failure are highly prevalent in patients presenting to hospital with acute heart failure and when combined into a chest x-ray score, relate to a worse long term risk of death.

Relation Between Thyroid Function and Mortality in Patients With Chronic Heart Failure.

Thyroid dysfunction is common in patients with chronic heart failure (CHF), but there is conflicting evidence regarding its prognostic significance. We investigated the relation between thyroid function and prognosis in a large, well characterized cohort of ambulatory patients with CHF. Heart failure was defined as signs and symptoms of the disease and either left ventricular systolic dysfunction (LVSD) mild or worse (heart failure with reduced ejection fraction [HFrEF]), or no LVSD and raised amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (>125 ng/L; heart failure with normal ejection fraction [HFnEF]). Euthyroid state was defined as a thyroid-stimulating hormone (TSH) level between 0.35 and 4.70 mIU/l, hypothyroidism as TSH >4.70 mIU/l, and hyperthyroidism as TSH <0.35 mIU/l. 2997 patients had HFrEF and 1995 patients had HFnEF. 4491 (90%) patients were euthyroid, 312 (6%) were hypothyroid, and 189 (4%) were hyperthyroid. In univariable analysis, both hypothyroid patients (hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.08 to 1.45) and hyperthyroid patients (HR 1.21, 95% CI 1.01 to 1.46) had a greater risk of death compared with euthyroid patients. There was a U-shaped relation between TSH and outcome. Increasing TSH was a predictor of mortality in univariable analysis (HR 1.02, 95% CI 1.01 to 1.03), but the association disappeared in multivariable analysis. The three strongest predictors of adverse outcome were increasing age, increasing NT-proBNP, and higher NYHA class. In conclusion, although thyroid dysfunction is associated with worse survival in patients with CHF, it is not an independent predictor of mortality.

The effects of empagliflozin vs metformin on endothelial microparticles in overweight/obese women with polycystic ovary syndrome.

CONTEXT: Endothelial microparticles (EMPs) are novel, surrogate biomarkers of endothelial function and have been shown to be elevated in women with polycystic ovary syndrome (PCOS). It remains poorly understood how pharmacological options for managing PCOS affect EMP levels. OBJECTIVE: To characterise and compare the effects of empagliflozin vs metformin on the circulating levels of EMPs in overweight/obese women with PCOS. METHODS: This was a randomised, comparative, 12-week single-centre trial conducted at the Academic Diabetes, Endocrinology and Metabolism Research Centre, Hull, UK. This analysis includes data from 39 overweight/obese women with PCOS who completed the study and were randomised to empagliflozin (15 mg/day) (n = 19) or metformin (1500 mg/day) (n = 20). Blood samples were collected at baseline and 12 weeks after treatment and analysed for specific surface proteins (ICAM-1, VCAM-1, PECAM-1, E-selectin and endoglin) expressed by circulating EMPs using flow cytometry. RESULTS: In the empagliflozin group, ICAM-1 (P = 0.006), E-selectin (P = 0.016) and VCAM-1 (P = 0.001) EMPs increased significantly following 12 weeks of treatment, but no changes were seen in PECAM-1 (P = 0.93) or endoglin (P = 0.13) EMPs. In the metformin group, VCAM-1 EMPs (P < 0.001) increased significantly after 12 weeks of treatment, whereas all other EMPs remained unchanged. When data were expressed as percentage change from baseline in each group, no significant differences were seen between groups for any biomarker (P-values from 0.22 to 0.80). CONCLUSIONS: Short-term administration of empagliflozin and metformin in overweight/obese women with PCOS appear to increase EMPs expressed by endothelial cells during their activation.

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.

Impact of Renal Impairment on Beta-Blocker Efficacy in Patients With Heart Failure.

BACKGROUND: Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy. OBJECTIVES: This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR). METHODS: Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm. RESULTS: Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m2; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m2, and 2,286 (13.7%) 30 to 44 ml/min/1.73 m2. Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m2 lower eGFR (95% confidence interval [CI]: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m2 (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m2 (95% CI: 0.58 to 0.87; p = 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m2) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR. CONCLUSIONS: Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction.

Symptoms and exacerbations in asthma: an apparent paradox?

BACKGROUND: There is a dearth of data on prospectively recorded symptoms in patients with uncontrolled asthma. Asthma symptoms and exacerbation rate are commonly thought to be associated. The aim of this study was to analyse asthma symptoms of cough, wheeze, chest tightness and breathlessness in an uncontrolled asthma cohort. We also examined the effect of maintenance and reliever therapy (MART) on these symptoms and its effect on exacerbation rate. METHODS: Adults with uncontrolled asthma electronically recorded their asthma symptom severity scores twice-daily over a period of 48 weeks following randomisation to beclometasone/formoterol twice daily plus pro re nata (prn) salbutamol or MART. Subjects with symptom scores of ⩾2 (ranging from 0 to 3 for each symptom) were considered more symptomatic, whereas those below a score of 2 were considered less severe. The influence treatment on exacerbation frequency and symptom profiles were then correlated. RESULTS: Of the 1701 subjects in the analyses, 1403 were symptomatic with ⩾100 symptom episodes for one symptom. The remaining 298 subjects were classified as pauci-symptomatic. There was poor association between the frequency and symptom severity score for each symptom. Surprisingly, wheeze was the least reported symptom. Females were more likely to be polysymptomatic. MART compared with prn salbutamol markedly attenuated severe asthma exacerbations. This effect was most notable in subjects with fewer symptoms. CONCLUSIONS: In uncontrolled asthma, there is a poor correlation between reported symptoms and exacerbation frequency. This post hoc analysis suggests that MART should not be reserved for symptomatic subjects but achieves the greatest benefit in pauci-symptomatic patients with asthma. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00861926.

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.

A Randomized, Controlled Trial of Vitamin D Supplementation on Cardiovascular Risk Factors, Hormones, and Liver Markers in Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) increases the risk of metabolic syndrome and non-alcoholic-fatty-liver disease (NAFLD). Vitamin D supplementation may exert positive effects on liver biochemistry in patients with NAFLD; however, its effects on PCOS are unknown. This randomized, double-blind, placebo-controlled study explored the effect of vitamin D supplementation on cardiovascular risk factors (high-sensitivity C-reactive protein (hs-CRP), weight, body mass index (BMI), lipid profile, glucose levels, insulin levels, the homeostatic model assessment-insulin resistance (HOMA-IR), hormones (free androgen index (FAI), testosterone, sex hormone binding globulin (SHBG), and liver markers (alanine aminotransferase (ALT), hyaluronic acid (HA), N-terminal pro-peptide of type III procollagen (PIIINP), tissue inhibitor of metallo-proteinases-1 (TIMP-1), and the enhanced liver fibrosis (ELF) score). Forty women with PCOS were recruited and randomized to vitamin D (3200 IU) or placebo daily for 3 months. All outcomes were measured at baseline and 3 months follow-up (FU). Greater increases in vitamin D levels were shown in the supplementation group (vitamin D, baseline: 25.6 ± 11.4 nmol/L, FU: 90.4 ± 19.5 nmol/L vs. placebo, baseline: 30.9 ± 11.1 nmol/L, FU: 47.6 ± 20.5 nmol/L, p < 0.001). Between groups comparisons (% baseline change) revealed significant differences in ALT (p = 0.042) and a weak effect indicating a greater reduction in the HOMA-IR in the vitamin D group (p = 0.051). No further between group differences were seen in other cardiovascular risk factor, liver markers, or hormones. This study supports beneficial effects of vitamin D supplementation on liver markers and modest improvements in insulin sensitivity in vitamin D deficient women with PCOS.

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.

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.

The Effect of High Dose Isoflavone Supplementation on Serum Reverse T3 in Euthyroid Men With Type 2 Diabetes and Post-menopausal Women.

Background: The health benefits of soy are widely reported but there are queries on the effect of soy isoflavones on thyroid function and the underlying mechanism of action. Materials and Methods: We examined the effect of soy isoflavones on reverse tri-iodothyronine (or 3,3',5'-tri-iodothyronine; rT3) in two studies comprising 400 patients: 200 men (study 1; 3 months) and 200 post-menopausal women (study 2; 6 months) who were randomized to consume 15 g soy protein with 66 mg of isoflavones (SPI) daily, or 15 g soy protein alone without isoflavones (SP) daily. Results: SPI supplementation increased rT3 serum concentration in both men 0.41 (0.12) vs. 0.45 (0.14) nmol/L and women 0.33 (0.12) vs. 0.37 (0.09) nmol/L at 3 months compared to SP that was not seen at 6 months. Thyroid stimulating hormone (TSH) serum concentrations increased while free thyroxine (fT4) concentrations decreased with 3 months of SPI compared to SP supplementation for both men and women. rT3 correlated with TSH in both studies (p = 0.03) but not with either fT3 or fT4. fT3 levels did not differ between the SPI and SP preparations. Conclusion: Soy isoflavones transiently increased rT3 levels within 3 months though reverted to baseline at 6 months. The mechanism for this would be either rT3 degrading deiodinase 1 and/or deiodinase 2 activities are transiently inhibited at 3 months, or inhibition of deiodinase 3, which generates rT3 from T4 is induced at 6 months. These changes were mirrored in the TSH concentrations, suggesting that short-term high dose isoflavone transiently impairs thyroid function in the first 3 months and may impact on general health during this period. ISRCTN Registry: ISRCTN 90604927; ISRCTN34051237.

Dynamic Change in Insulin Resistance Induced by Free Fatty Acids Is Unchanged Though Insulin Sensitivity Improves Following Endurance Exercise in PCOS.

Background: Insulin resistance (IR) is the hallmark of PCOS and it is known that exercise may decrease it. What is unknown is whether exercise may mechanistically alter the underlying IR, attenuating the dynamic lipid induced IR in insulin resistant subjects. Methods: 12 women with polycystic ovary syndrome (PCOS) and 10 age and body mass index matched controls completed an 8 week supervised exercise program at 60% maximal oxygen consumption. Before and after the exercise program, all participants underwent hyperinsulinaemic euglycaemic clamps with either saline or intralipid infusions. Skewed data were log transformed and expressed as mean ± SEM. Results: Before exercise, women with PCOS had a higher HOMA-IR and lower VO2 max than controls. Compared to saline, lipid infusion lowered the rate of insulin stimulated glucose disposal (M value; mg/kg/min) by 67 ± 5% (from 0.5 ± 0.03 to -0.25 ± 0.2, p = 0.01) in PCOS, and by 49 ± 7% (from 0.65 ± 0.06 to 0.3 ± 0.1, p = 0.01) in controls. The M value was significantly less in PCOS compared to controls for both saline (p < 0.01) and lipid (p < 0.05). Endurance exercise in PCOS improved VO2 max and HOMA-IR, but not weight, to those of pre-exercise control subjects. The glucose disposal rate during the lipid infusion was reduced following exercise in PCOS, indicating decreased IR (67 ± 5 vs. 50 ± 7%, p = 0.02), but IR was not altered in controls (49 ± 7 vs. 45 ± 6%, p = 0.58). The incrementally increased IR induced by the lipid infusion did not differ between controls and PCOS. Conclusion: Insulin sensitivity improved with exercise in the PCOS group alone showing that IR can be modified, though likely transiently. However, the maximal IR response to the lipid infusion did not differ within and between control and PCOS subjects, indicating that the fundamental mechanism underlying insulin resistance was unchanged with exercise. Precis: Maximal insulin resistance induced by lipid infusion determined at baseline and 8 weeks after exercise in control and PCOS women did not differ, though insulin sensitivity increased in PCOS after exercise.

The Effect of Phytoestrogen on Thyroid in Subclinical Hypothyroidism: Randomized, Double Blind, Crossover Study.

Objective: Soy phytoestrogens are suggested to impair thyroid function but the effects of pharmacological doses of soy phytoestrogens are unknown; therefore, this study was performed to determine the effect of high dose soy phytoestrogens (66 mg) on thyroid function in subclinical hypothyroidism. Design and setting: Randomized, double-blind, crossover study. Participants: Forty four patients with subclinical hypothyroidism. Intervention: Participants were randomly allocated to either 66 mg phytoestrogen with 30 g soy protein (active) or 0 mg phytoestrogen with 30 g soy protein (placebo) supplementation for 8 weeks, washed out for 8 weeks and then crossed over for another 8 week period. Main outcome measures: The primary outcome was progression to overt hypothyroidism with the secondary outcome measures were changes in thyroid function tests. Results: Two patients in this trial progressed into overt hypothyroidism after high dose phytoestrogen supplementation. TSH, free thyroxine and triiodothyronine did not differ between groups. Conclusion: A pharmacological dose of 66 mg of soy phytoestrogens did not increase the overt thyroid failure rate or alter thyroid function tests in patients with subclinical hypothyroidism.