Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator.

A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.

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.

The Effect of a Very-Low-Calorie Diet (VLCD) vs. a Moderate Energy Deficit Diet in Obese Women with Polycystic Ovary Syndrome (PCOS)-A Randomised Controlled Trial.

We performed an open-label, randomised controlled trial to compare the effects of a very-low-calorie diet (VLCD) vs. moderate energy deficit approach on body weight, body composition, free androgen index (FAI), and metabolic markers in obese women with polycystic ovary syndrome (PCOS). Forty eligible patients were randomly assigned to a VLCD (n = 21) or a conventional energy deficit approach (n = 19) over the same period. After eight weeks, both groups experienced significant weight loss; however, this was greater in the VLCD arm (-10.9% vs. -3.9%, p < 0.0001). There was also a trend towards a reduction in FAI in the VLCD group compared to the energy deficit group (-32.3% vs. -7.7%, p = 0.07). In the VLCD arm, two women (18%) had a biochemical remission of PCOS (FAI < 4); this was not the case for any of the participants in the energy deficit arm. There was a significant within-group increase in the sex-hormone-binding globulin (p = 0.002) and reductions in fasting blood glucose (p = 0.010) and waist to hip ratio (p = 0.04) in the VLCD arm, but not in the energy deficit arm. The VLCD resulted in significantly greater weight reduction and was accompanied by more pronounced improvements in hyperandrogenaemia, body composition, and several metabolic parameters in obese women with PCOS as compared to the energy deficit approach.

PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors.

PURPOSE: Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI). EXPERIMENTAL DESIGN: HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC. RESULTS: VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group. CONCLUSIONS: By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.

Embedding new technology into clinical ultrasound practice: Is role extension for sonographers the key to improving patient pathways?

Introduction: MicroUS is a new imaging technique that may have potential to reliably monitor prostate disease and therefore release capacity in MRI departments. Firstly, however, it is essential to identify which healthcare staff may be suitable to learn to use this modality. Based on previous evidence, UK sonographers may be well placed to harness this resource. Topic: Currently, there is sparse evidence on the performance of MicroUS for monitoring prostate disease but early findings are encouraging. Although its uptake is increasing, it is believed that only two sites in the UK have MicroUS systems and only one of those uses just sonographers to undertake and interpret this new imaging technique. Discussion: UK sonographers have a history of role extension dating back several decades and have proven repeatedly that they are reliable and accurate when measured against a gold standard. We explore the background of UK sonographer role extension and postulate that sonographers are best placed to adopt and embed new imaging techniques and technology into routine clinical practice. This is of particular importance given the dearth of ultrasound focussed radiologists in the UK. To effectively introduce challenging new work streams, multi-professional collaboration in imaging, alongside sonographer role extension, will ensure precious resources are maximised thus ensuring optimum patient care. Conclusion: UK sonographers have repeatedly demonstrated reliability in many areas of role extension in various clinical settings. Early data indicate that the adoption of MicroUS for use in prostate disease surveillance may be another role suited to sonographers.

Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors.

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26, a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway biology in vitro and in vivo, with pharmacokinetics suitable for once-a-day oral dosing in mice.

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.

Bisphosphonate Treatment Alters the Skeletal Response to Mechanical Stimulation in Children With Osteogenesis Imperfecta: A Pilot Study.

Children with osteogenesis imperfecta (OI) are commonly treated with bisphosphonates. We investigated the skeletal response to mechanical stimulation in children with OI before and after bisphosphonate treatment. Twelve children with OI, naïve to bisphosphonate treatment, stood on a high-frequency (30 Hz), low-amplitude (50 to 200 µ) vibrating platform (Marodyne LivMD) for 10 minutes daily (2.5 minutes × 4 with interspersed 1-minute rest periods) for 7 days (whole body vibration [WBV] 1; day (D) 1-7), followed successively by 5 weeks' monitoring without intervention, 6 weeks' risedronate treatment, 1 week of WBV (WBV2; D85-91), and 1 week without intervention (D92-98). Procollagen type I N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BSALP), and carboxy-terminal telopeptide of type I collagen cross-link (CTX) were measured at baseline and intervals bracketing periods of vibration and risedronate treatment. Both P1NP and CTX rose to D8 (18.4%, 13.8%, p < 0.05, respectively), plateaued, then rose again at D43 (19.8%, 19.2%, respectively, p < 0.05 versus baseline). At D85 (after risedronate) both P1NP and CTX had fallen to pre-WBV1 levels. A significantly smaller increase in P1NP was found after WBV2 (D85-91) at D92 (3.5%, 9.2%, respectively) and D99 versus after WBV1 (both p < 0.05). BSALP changed little after WBV1, fell during risedronate, and rose toward baseline after WBV2. We thus showed that WBV increased bone formation and resorption; that increase was attenuated after risedronate. The early increase in P1NP and CTX (D8) after WBV1 suggests increased osteoid formation within existing remodeling units but not increased mineralization. Later increases in P1NP/CTX (D42) suggest increased remodeling cycle initiation after WBV. Risedronate suppressed both biomarkers. The lower increase in P1NP/CTX after WBV2 suggests limited capacity to increase osteoid formation from existing "early stage" osteoblasts and a possible "hangover" effect of risedronate on remodeling activation. These results provide insights into both the response to WBV, ie, mechanical stimulation, and the effect of antiresorptive therapy in children with OI. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

The role of diagnostic ultrasound imaging for patients with known prostate cancer within an active surveillance pathway: A systematic review.

BACKGROUND: The use of multiparametric magnetic resonance imaging (mpMRI) within active surveillance of prostate cancer programmes is identified by the UK National Institute for Health and Care Excellence (NICE guideline NG 131 2019) as having a role for monitoring disease. The widespread demands on mpMRI capacity may limit its use in surveillance. It is therefore timely to review the options that modern ultrasound imaging present to this cohort of patients in the monitoring of prostate cancer. METHODS: Between April and September 2020, 10 databases were searched to recruit studies for the review. Three reviewers evaluated the publications for inclusion. Characteristics including the inclusion criteria for the study cohort, how disease was determined, identification of disease progression, and the modality and mode of imaging used were reviewed. Given the paucity of full text articles, a meta-analysis was not possible. A narrative review was undertaken. RESULTS: In total, 12 studies, utilising the range of ultrasound parameters of B-mode, micro-ultrasound, colour Doppler, contrast ultrasound and elastography were included. The review demonstrated that micro-ultrasound offers promise as an imaging tool comparable with mpMRI. However, this is an emerging technology with limited availability. Analysis of the data further demonstrated that by combining the diagnostic features provided by multiple modes reviewed, ultrasound has a role in the diagnostic imaging of patients on active surveillance. CONCLUSION: Providing a multiparametric approach is utilised, stable ultrasound findings may allow for increased intervals between biopsy for men on surveillance. The advent of micro-US offers promise as an imaging modality within an active surveillance pathway but requires further verification.

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.

Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors.

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of the three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) that regulates protein synthesis, alleviates cellular ER stress and has been implicated in tumorigenesis and prolonged cancer cell survival. In this study, we report a series of 2-amino-3-amido-5-aryl-pyridines that we have identified as potent, selective, and orally bioavailable PERK inhibitors. Amongst the series studied herein, compound (28) a (R)-2-Amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-isopropylnicotinamide has demonstrated potent biochemical and cellular activity, robust pharmacokinetics and 70% oral bioavailability in mice. Given these data, this compound (28) was studied in the 786-O renal cell carcinoma xenograft model. We observed dose-dependent, statistically significant tumor growth inhibition, supporting the use of this tool compound in additional mechanistic studies.

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.

High-fidelity simulation and virtual reality: an evaluation of medical students' experiences.

Background: Simulation technology is widely used in medical education, providing an environment in which students can develop and practise a multitude of skills that are relevant to clinical practice, without the risk of harm to patients. Methods: We conducted a mixed methods cross-over study with quantitative and qualitative outcomes. This analysed students' perceptions of two simulation technologies: a high-fidelity patient simulator and virtual reality. Twenty final year medical students completed a questionnaire after having experienced both simulation modalities. Results: Students scored the patient simulator higher in domains such as developing team working and 'ABCDE assessment skills', whereas the virtual reality simulation was more immersive and fun. Participants found the patient simulator more useful in preparing them for clinical practice. Conclusion: Medical students in this study expressed that a high-fidelity patient simulator, in a simulated clinical environment, was of greater value to their preparation for clinical practice than virtual reality simulation of a similar environment. However, the virtual reality simulation offered a near comparable experience, and was found to be was enjoyable, immersive and easily portable.

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.

An audit of COPD: diagnosis and management in general practice.

INTRODUCTION: COPD is a spectrum of disorders primarily caused by smoking and characterised by progressive, not fully reversible airflow obstruction with a forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7. METHODS: From November 2016 to March 2017 we audited patients with COPD in five general practices in Hull and East Riding, UK. We looked at deviation from the locally agreed guidelines. We extracted data on severity, exacerbations, medication and eosinophil count. RESULTS: We assessed 1088 records. Median age was 70.9 years; 577 (53%) were male. About two-thirds of patients on the COPD register have an FEV1/FVC ratio in the diagnostic range for COPD, however, 388 (36%) out of 1088 had a ratio of ≥0.7. In the patients with a ratio of ≥0.7, 259 (67%) out of 388 had an FEV1 <80% of predicted. Patients with frequent exacerbations were more likely to be prescribed inhaled corticosteroid (ICS)-containing inhalers (incidence rate ratio of 2). FEV1 % predicted was a poor indicator of exacerbation frequency; however, the presence of elevated blood eosinophil counts (EOS) on at least two occasions was highly predictive of exacerbations. When ICSs, FEV1, EOS were examined in combination, they were highly significant predictors for exacerbations. CONCLUSION: FEV1 maybe a more accurate diagnostic parameter in primary care. Historical evidence of blood eosinophilia is a better predictor than FEV1. The combination of biomarkers may prove more accurate indicator of future exacerbation frequency, leading to targeted intervention.

Normative reference values for estimated cardiorespiratory fitness in apparently healthy British men and women.

OBJECTIVES: To develop normative reference standards for estimated cardiorespiratory fitness (eCRF) measured from treadmill-based incremental exercise testing in ~12 000 British men and women. METHODS: Cross-sectional study using retrospectively collected eCRF data from five preventative health screening clinics in the United Kingdom. Reference centiles were developed using a parametric approach by fitting fractional polynomials. We selected the 'best' powers by considering both the smallest deviance, and clinical knowledge from the following set of a priori decided powers (-2,-1,-0.5, 0, 0.5,1,2,3). A series of fractional polynomials (FPs) were investigated with three-parameters (median, standard deviation and skewness). The following reference centiles were plotted (3, 5, 10, 25, 50, 75, 90, 95, 97). RESULTS: We included 9 204 males (median [25th,75th centiles] age 48 [44, 53] years; BMI 27 {25, 29] kg∙m-2; peak VO2 36.9 [30.5, 44.7] ml∙kg-1∙min-1) and 2 687 females (age 48, [41, 51] years; BMI 24 {22, 27] kg∙m-2; peak VO2 36.5 [30.1, 44.8] ml∙kg-1∙min-1) in our analysis to develop the normative values. CONCLUSION: Reference values and nomograms for eCRF were derived from a relatively large cohort of preventative health care screening examinations of apparently healthy British men and women. Age- and sex-specific eCRF percentiles were similar to data from international cohort studies. The adoption of submaximal exercise testing protocols reduces individual risk when exercise history is unknown and testing is conducted in a community-based setting. Our findings can be used by health professionals to help guide clinical decision making.

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.