Effect of a 24-week concurrent exercise intervention on neck adiposity and its distribution in young adults: the ACTIBATE randomized controlled trial

Neck adipose tissue (NAT) accumulation and neck circumference are independent predictors of cardiometabolic risk (CMR) and low-grade chronic inflammation in young adults. The present study examines whether a 24-week concurrent exercise intervention can reduce NAT volume and neck circumference in young adults, and whether any changes in these variables are related to changes in body composition, CMR, and the inflammatory profile. Seventy-four participants (51 women, age 22 & PLUSMN; 2 years) were included in the main analyses, after being randomly assigned to either a (a) control (n = 34), (b) moderate-intensity exercise (n = 19), or (c) vigorous-intensity exercise (n = 21) group. Participants in the exercise groups trained 3-4 days/ week (endurance + resistance exercise training). NAT volume and NAT distribution across different depots were estimated using computed tomography before and after the intervention. Anthropometric variables, body composition (determined by dual-energy X-ray absorptiometry), and CMR/inflammatory markers were also recorded. The exercise intervention did not reduce the total NAT volume, nor was NAT distribution affected (p > .05). However, it did reduce neck circumference in the vigorous-intensity exercise group compared with the moderate-intensity exercise and control groups (by 0.8 and 1 cm, respectively, p <_ .05). Changes in total NAT and neck circumference were positively, albeit weakly, related (adj. R2: .05-.21, all p <_ .05) to changes in body weight and adiposity, leptin (only total NAT), and CMR (only neck circumference). Altogether 24 weeks of concurrent exercise does not appear to reduce NAT accumulation in young adults, but may slightly reduce neck circumference in those who in exercise.Metabolic health: pathophysiological trajectories and therap

IN PRAISE OF ENLIGHTENED PARTICULARITY

Autor u svojoj studiji analizira odnos opće kulture i njenih posebnih segmenata unutar jedinstvene političke zajednice te zaključuje: dok god, dakle, postoje građani, postojat će i sukob između općega i posebnog, i pritom će se uvijek iznova pokazivati da posredovanje između te dvije kategorije nikada nije konačno, nego da uvijek iznova treba određivati što je primjereno, što je ono pravo i obvezujuće. U tome se očituje snaga prosuđivanja kojoj su shematske orijentacije poput univerzalizma i partikularizma potrebne samo da bi se ukazalo na ono što nedostaje, te da bi se to nadopunilo.In this study, the author analyses the relationship between general culture and its particularistic segments within the integral political community and concludes: as long as there are citizens, there will be a conflict between the general and the singular; also, the mediation between these two categories is never final; instead, one should repeatedly define what is appropriate, right and compulsory. This is the strength of the type of reasoning to which the schematic landmarks such as universalism and particularism are necessary only as reminders of what is missing in order to fill in the gaps

Structure and Function of the Hair Cell Ribbon Synapse

Faithful information transfer at the hair cell afferent synapse requires synaptic transmission to be both reliable and temporally precise. The release of neurotransmitter must exhibit both rapid on and off kinetics to accurately follow acoustic stimuli with a periodicity of 1 ms or less. To ensure such remarkable temporal fidelity, the cochlear hair cell afferent synapse undoubtedly relies on unique cellular and molecular specializations. While the electron microscopy hallmark of the hair cell afferent synapse — the electron-dense synaptic ribbon or synaptic body — has been recognized for decades, dissection of the synapse’s molecular make-up has only just begun. Recent cell physiology studies have added important insights into the synaptic mechanisms underlying fidelity and reliability of sound coding. The presence of the synaptic ribbon links afferent synapses of cochlear and vestibular hair cells to photoreceptors and bipolar neurons of the retina. This review focuses on major advances in understanding the hair cell afferent synapse molecular anatomy and function that have been achieved during the past years

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Congruent validity and inter-day reliability of two breath by breath metabolic carts to measure resting metabolic rate in young adults

Diabetes mellitus: pathophysiological changes and therap

911PD - A first-in-human phase I/II trial of the oral HIF-2a inhibitor PT2977 in patients with advanced RCC

Hypoxia-inducible factor (HIF)-2α is a transcription factor that is a key oncogenic driver in renal cell carcinoma (RCC). PT2977 is a potent and selective small molecule HIF-2α inhibitor that prevents HIF-2α from heterodimerizing with HIF-1β, blocking the expression of HIF-2α target genes in tumour cells, and inducing regressions in mouse xenograft RCC models. Patients with advanced solid tumours were treated with PT2977 in a dose-escalation design to determine the recommended Phase 2 dose (RP2D). Patients with advanced clear cell RCC who had received at least one prior therapy were enrolled in an expansion cohort at the RP2D of 120mg orally once daily. 55 pts were treated with PT2977 120mg (three in dose escalation; 52 in expansion). Median number of prior therapies was 3 (1-9). 73% of patients were intermediate risk and 18% were poor risk by IMDC criteria. As of March 15, 2019, the most common all-grade, all-cause adverse events (AEs) > 25% are anemia (75%), fatigue (64%), dyspnea (44%), nausea (33%), peripheral edema (29%) and cough (27%). Anemia (20%) and hypoxia (11%) are the most common Grade 3 AEs and on-target effects of HIF2α inhibition. Discontinuation due to a treatment-related AE was reported in 2 patients (4%). 13 patients (24%) experienced a confirmed PR and 30 patients (54%) had SD, with a clinical benefit rate of 78%. Follow-up for all patients has been at least 40 weeks and the probability of PFS at 40 weeks is 50.1%. PT2977 is well tolerated and has a favorable safety profile. The clinical activity of PT2977 shows promise for the treatment of RCC. A PT2977 monotherapy Phase 3 trial in previously treated advanced RCC patients is planned. NCT02974738. Peloton Therapeutics, Inc. Peloton Therapeutics, Inc. E. Jonasch: Advisory / Consultancy, Research grant / Funding (self): Exelixis; Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ipsen. E.R. Plimack: Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Incyte; Advisory / Consultancy: Janssen; Advisory / Consultancy: AstraZeneca. T. Bauer: Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): ARMO Biosciences; Research grant / Funding (institution): Foundation Medicine; Research grant / Funding (institution): Phosplatin Therapeutics; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Top Alliance BioScience; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Moderna Therapeutics; Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): Aileron Therapeutics; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Calithera Biosciences; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Immugen. J.R. Merchan: Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy: Exelixis; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): Vyriad; Research grant / Funding (institution): Silagen; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): RepImmune; Research grant / Funding (institution): Rexahn. K.P. Papadopoulos: Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): ARMO Biosciences; Advisory / Consultancy, Research grant / Funding (institution): ArQule; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): 3D Medicines; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Syros Pharmaceuticals; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Jounce Therapeutics; Research grant / Funding (institution): MabSpace Biosciences; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Regereron; Research grant / Funding (institution): Sanofi. D.F. McDermott: Advisory / Consultancy, Research grant / Funding (institution): Peloton Therapeutics; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Exelixis; Honoraria (self), Advisory / Consultancy: Array BioPharm; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: EMD Serono; Research grant / Funding (institution): Prometheus Laboratories; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Jounce Therapeutics. M.D. Michaelson: Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck; Advisory / Consultancy: Exelixis. L.J. Appleman: Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Acerta; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Tokai; Research grant / Funding (institution): AVEO; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Inovio; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Eli Lilly. S. Thamake: Shareholder / Stockholder / Stock options, Full / Part-time employment: Peloton Therapeutics. N. Zojwalla: Shareholder / Stockholder / Stock options, Full / Part-time employment: Peloton Therapeutics. T.K. Choueiri: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Tracon; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Foundation Medicine; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Exelixis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / F

Seasonal aspects of the energy-water nexus: The case of a run-of-the-river hydropower plant

The energy-water nexus presents important implications at seasonal scale. For instance, electricity prices and streamflow have complex seasonal patterns and changes in both may adversely impact hydropower plant revenue. In order to quantify the effect of changes in price and water seasonality on future revenue distribution and its related uncertainty, we consider the case of a run-of-the-river plant. To this end, we integrate a hydrologic model, a hydropower model, two glacier inventories, six climate scenarios and five electricity price seasonal scenarios. Our results show that the impact of climate change on streamflow of the considered run-of-the-river plant will decrease the revenue by 20% in a business-as-usual price sce- nario. This decrease is mostly driven by a reduction of the annual streamflow due to glacier shrinkage rather than by the evolution of seasonality. From this perspective, the difference between the various cli- mate scenarios is low. In contrast, change in electricity price seasonality induces a marked uncertainty in revenue. According to our scenarios, which assume no change in the mean annual electricity price, a change in price seasonality may indeed exacerbate or mitigate the impact of climate by 50 or 33% respec- tively, compared to the business-as-usual scenario. Our analysis highlights the need for considering intra- annual dynamics when investigating the energy-water nexus

Thyroid function is not associated with brown adipose tissue volume and F-18-fluorodeoxyglucose uptake in young adults

Purpose: Thyroid hormones (THs) are important mediators of brown adipose tissue (BAT) differentiation. However, the association of TH concentrations with human BAT is unclear. The present work examines the associations between circulating thyroid-stimulating hormone (TSH) and THs concentrations (i.e. free triiodothyronine, FT3, and free thyroxine, FT4), under thermoneutral (22-23 degrees C) and cold-induced conditions, and BAT volume, F-18-fluorodeoxyglucose (F-18-FDG) uptake and mean radiodensity.Methods: A total of 106 young healthy, euthyroid adults (34 men/72 women; 22.0 +/- 2.1 years old; 24.9 +/- 4.6 kg/m(2)) participated in this cross-sectional study. BAT volume, F-18-FDG uptake and mean radiodensity were assessed after 2 h of personalized (i.e. contemplating each individual's shivering threshold) cold exposure via positron emission tomography/computed tomography (PET/CT) static scanning. TSH and THs levels were determined before (thermoneutral) and 1 h after the cold exposure.Results: Cold exposure increased circulating FT4 (P = 0.038) and reduced TSH levels (P 0.111) or cold-induced levels (all P > 0.067) and BAT volume, F-18-FDG uptake and mean radiodensity. These findings were independent of sex and BMI.Conclusions: Thyroid function is modulated by cold exposure, yet it is not associated with BAT volume or glucose metabolism assessed after 2 h of cold exposure in young healthy, euthyroid adults.Diabetes mellitus: pathophysiological changes and therap

Higher Physical Activity Is Related to Lower Neck Adiposity in Young Men, but to Higher Neck Adiposity in Young Women: An Exploratory Study

The role of lifestyle behaviors on neck adipose tissue (NAT), a fat depot that appears to be involved in the pathogenesis of different cardiometabolic diseases and in inflammatory status, is unknown. In this cross-sectional and exploratory study, the authors examined the relationship between sedentary time and physical activity (PA) with neck adiposity in young adults. A total of 134 subjects (69% women, 23 +/- 2 years) were enrolled. The time spent in sedentary behavior and PA of different intensity were objectively measured for 7 consecutive days (24 hr/day), using a wrist (nondominant)-worn accelerometer. The NAT volume was assessed using computed tomography, and the compartmental (subcutaneous, intermuscular, and perivertebral) and total NAT volumes were determined at the level of vertebra C5. Anthropometric indicators and body composition (by dual-energy X-ray absorptiometry) were determined. The time spent in light physical activity and moderate physical activity (MPA) and the overall PA were inversely associated with the intermuscular NAT volume in men, as were the MPA and overall PA with total NAT volume (all ps .05). These findings suggest that the specific characteristics of PA (time and intensity) might have sex-dependent implications in the accumulation of NAT.Diabetes mellitus: pathophysiological changes and therap

Energy Expenditure and Macronutrient Oxidation in Response to an Individualized Nonshivering Cooling Protocol

Objective This study aimed to describe the energy expenditure (EE) and macronutrient oxidation response to an individualized nonshivering cold exposure in young healthy adults. Methods Two different groups of 44 (study 1: 22.1 [SD 2.1] years old, 25.6 [SD 5.2] kg/m(2), 34% men) and 13 young healthy adults (study 2: 25.6 [SD 3.0] years old, 23.6 [SD 2.4] kg/m(2), 54% men) participated in this study. Resting metabolic rate (RMR) and macronutrient oxidation rates were measured by indirect calorimetry under fasting conditions in a warm environment (for 30 minutes) and in mild cold conditions (for 65 minutes, with the individual wearing a water-perfused cooling vest set at an individualized temperature adjusted to the individual's shivering threshold). Results In study 1, EE increased in the initial stage of cold exposure and remained stable for the whole cold exposure (P < 0.001). Mean cold-induced thermogenesis (9.56 +/- 7.9 kcal/h) was 13.9% +/- 11.6% of the RMR (range: -14.8% to 39.9% of the RMR). Carbohydrate oxidation decreased during the first 30 minutes of the cold exposure and later recovered up to the baseline values (P < 0.01) in parallel to opposite changes in fat oxidation (P < 0.01). Results were replicated in study 2. Conclusions A 1-hour mild cold exposure individually adjusted to elicit maximum nonshivering thermogenesis induces a very modest increase in EE and a shift of macronutrient oxidation that may underlie a shift in thermogenic tissue activity.Diabetes mellitus: pathophysiological changes and therap