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Ipatasertib is a selective, small molecule Akt inhibitor that is currently being developed for the treatment of metastatic castration-resistant prostate cancer. Darolutamide is an androgen receptor (AR) inhibitor that is approved for the treatment of non-metastatic castration-resistant prostate cancer. Ipatasertib is metabolized by CYP3A4 to form a less active metabolite M1 (G-037720). Ipatasertib is also a weak time-dependent CYP3A4 inhibitor. Darolutamide is a mild CYP3A4 inducer and is metabolized into an active keto-darolutamide metabolite via CYP3A4. In this Phase 1b open-label, single sequence crossover study, ipatasertib pharmacokinetics safety and tolerability were evaluated in combination with darolutamide in metastatic castration-resistant prostate cancer (n = 15 patients). Specifically, the effect of 600 mg BID of darolutamide on 400 mg QD ipatasertib was evaluated in this study. Based on pharmacokinetic analysis, a mild reduction in ipatasertib AUC0–24 h,ss and Cmax,ss exposures was observed (~8% and ~21%, respectively) when administered in combination with darolutamide, which is considered not clinically meaningful. M1 exposures were similar with and without darolutamide administration. Darolutamide and keto-darolutamide exposures in combination with ipatasertib were similar to previously reported exposures for single agent darolutamide. Overall, the combination appears to be well-tolerated in the metastatic castration-resistant prostate cancer indication with very few AEs.

Ipatasertib, an AKT inhibitor, in combination with prednisone and abiraterone, is under evaluation for the treatment of metastatic castration‐resistant prostate cancer (mCRPC). Hyperglycemia is an on‐target effect of ipatasertib. An open‐label, single‐arm, single‐sequence, signal‐seeking study (n = 25 mCRPC patients) was conducted to evaluate the glucose changes across four different treatment periods: ipatasertib alone, ipatasertib‐prednisone combination, ipatasertib‐prednisone‐abiraterone combination (morning dose), and ipatasertib‐prednisone‐abiraterone combination (evening dose). Continuous glucose monitoring (CGM) was used in this study to compare the dynamic glucose changes across the different treatment periods. Four key parameters: average glucose, peak glucose and % time in range (70–180 and >180 mg/dl) were evaluated for this comparison. Ipatasertib‐prednisone‐abiraterone combination when administered in the morning after an overnight fast significantly increased average glucose, peak glucose and % time in range >180 mg/dl compared to ipatasertib monotherapy. Ipatasertib, when co‐administered with abiraterone, increased ipatasertib and M1 (G‐037720) metabolite exposures by approximately 1.5‐ and 2.2‐fold, respectively. Exposure–response analysis results show that increased exposures of ipatasertib in combination with abiraterone are associated with increased glucose levels. When ipatasertib‐prednisone‐abiraterone combination was administered as an evening dose compared to a morning dose, lowered peak glucose and improved % time in range was observed. The results from this study suggest that dosing ipatasertib after an evening meal followed by overnight fasting can be an effective strategy for managing increased glucose levels.

Evidence of the efficacy of high-intensity, low-volume interval training (HIIT-low volume) in treating insulin resistance (IR) in patients with metabolic disorders is contradictory. In addition, it is unknown whether this effect is mediated through muscle endocrine function, which in turn depends on muscle mass and fiber type composition. Our aims were to assess the efficacy of HIIT-low volume compared to continuous aerobic exercise (CAE) in treating IR in adults with metabolic syndrome (MS) and to establish whether musclin, apelin, muscle mass and muscle composition are mediators of the effect. Methods: This is a controlled, randomized, clinical trial using the minimization method, with blinding of those who will evaluate the outcomes and two parallel groups for the purpose of showing superiority. Sixty patients with MS and IR with ages between 40 and 60 years will be included. A clinical evaluation will be carried out, along with laboratory tests to evaluate IR (homeostatic model assessment (HOMA)), muscle endocrine function (serum levels of musclin and apelin), thigh muscle mass (by dual energy x-ray absorptiometry (DXA) and thigh muscle composition (by carnosine measurement with proton magnetic resonance spectroscopy (H–MRS)), before and after 12 weeks of a treadmill exercise program three times a week. Participants assigned to the intervention (n = 30) will receive HIIT-low volume in 22-min sessions that will include six intervals at a load of 90% of maximum oxygen consumption (VO2 max) for 1 min followed by 2 min at 50% of VO2 max. The control group (n = 30) will receive CAE at an intensity of 60% of VO2 max for 36 min. A theoretical model based on structural equations will be proposed to estimate the total, direct and indirect effects of training on IR and the proportion explained by the mediators. Discussion: Compared with CAE, HIIT-low volume can be effective and efficient at improving physical capacity and decreasing cardiovascular risk factors, such as IR, in patients with metabolic disorders. Studies that evaluate mediating variables of the effect of HIIT-low volume on IR, such as endocrine function and skeletal muscle structure, are necessary to understand the role of skeletal muscle in the pathophysiology of MS and their regulation by exercise. Trial registration: NCT03087721. High-intensity Interval, Low Volume Training in Metabolic Syndrome (Intraining-MET). Registered on 22 March 2017, retrospectively registered.

PurposeWe carried out a randomized, clinical trial in adults of both sexes with metabolic syndrome (MS) to assess the efficacy of high-intensity, low-volume interval training (HIIT) compared to moderate-intensity continuous training (MICT) on insulin resistance (IR), muscle mass, muscle activation, and serum musclin.MethodsFasting glycemia, insulinemia, and glycated haemoglobin were determined by conventional methods, IR by Homeostatic model assessment (HOMA), lean mass by Dual-Energy X-ray Absorptiometry, muscle activation through carnosine by Proton Magnetic Resonance Spectroscopy, and musclin by Enzyme-Linked ImmunoSorbent Assay before and after a supervised, three-times/week, 12-week treadmill programme. HIIT (n = 29) consisted of six intervals with one-minute, high-intensity phases at 90% of peak oxygen consumption (VO2peak). MICT (n = 31) trained at 60% of VO2peak for 30 min.ResultsPatients had a mean age of 50.8 ± 6.0 years, body mass index of 30.6 ± 4.0 kg/m2, and VO2peak of 29.0 ± 6.3 mL.kg−1.min−1. Compared to MICT, HIIT was not superior at reducing Ln HOMA-IR (adjusted mean difference: 0.083 [95%CI − 0.092 to 0.257]), carnosine or musclin or at increasing thigh lean mass. HIIT increased carnosine by 0.66 mmol/kg.ww (95% CI 0.08–1.24) after intervention. Both interventions reduced IR, body fat percentage and increased total lean mass/height2 and VO2peak. Musclin showed a non-significant reduction with a small effect size after both interventions.ConclusionCompared to MICT, HIIT is not superior at reducing IR, carnosine or musclin or at increasing skeletal muscle mass in adults with MS. Both training types improved IR, muscle mass and body composition. NCT03087721, March 22nd, 2017.Trial registration numberNCT03087721. Registered March 22nd, 2017.

Background and aimHeadache attributed to intracranial endovascular procedures is described in the ICHD-3. Our aim was to study the frequency and characteristics of headache specifically related to thrombectomy in patients with ischemic stroke.MethodsProspective evaluation of clinical features of headache after thrombectomy using an ad hoc questionnaire.ResultsOne hundred seventeen patients were included (52.1% females). Most had an anterior circulation artery occlusion (91.5%). 93 (79.5%) received general anaesthesia. 111 (94.9%) required stent retriever, 21 (24.4%) angioplasty and 19 (16.2%) aspiration thrombectomy. 31 (26.5%; 95% CI 18.8–35.5%) had headache related to thrombectomy, and it was associated with a history of primary headache (p = 0.004). No differences about sex, initial NIHSS score, or the type or complexity of the procedure were observed. Headache was usually moderate and oppressive, ipsilateral to the artery occlusion and usually lasted less than 48 hours.ConclusionsAlmost one-third of patients with ischemic stroke who undergo endovascular thrombectomy experience headache in the first 24 hours, occurring more frequently in patients who had a previous history of headaches regardless of the procedure complexity.Highlights- About one third of the patients who undergo a thrombectomy for acute stroke experience headache directly related to the procedure.- Having a previous history of primary headache is associated with the presence of headache after thrombectomy.- Headache related to thrombectomy usually coincides with the distribution of the affected artery, although it is bilateral in 45% of the cases, mostly oppressive, of an average duration between 1 and 2 days and of a moderate intensity.

Background: Although biochemical markers have been used to monitor training loads (TL), it is unknown if they can be used to predict muscle injuries (MI) in professional football (soccer) players (PFP).Objectives: To evaluate the relationship between the incidence of MI, serum concentration of creatine phosphokinase (CPK) and urea, as well as TL in PFP.Methods: Twenty-three PFP from a Colombian first-division team were enrolled in a retrospective cohort study. CPK, urea, TL and new MI were measured during 19 weeks. CPK and urea serum levels within 4 weeks before a diagnosed MI were compared to those measured preseason. CPK and urea relationship with TL were analyzed using a mixed-effects model.Results: The subjects had an age of 25.3[+ or -]4.2 years. Nine subjects presented with MI during follow-up, 66.6% of which were localized to hamstrings. Serum CPK and urea profiles were constructed for each player along the season. Injured players had a significant elevation of these markers within 4 weeks before the injury was clinically evident when compared to their own preseason values. Expected individual increases in CPK and urea according to TL during the season were estimated.Conclusions: Since CPK and urea values rose several weeks before the MI became overt, constructing CPK and urea profiles for each player during the whole preseason and season may help identify peaks in their concentration as early markers of MI. A tight biochemical control of training may become a preventive strategy for MI, but the use of published reference values is discouraged.Keywords: Creatine Phosphokinase (CPK), Urea, Muscle Injuries, Sports Injuries, Football, Soccer, Biological Markers

The human serum protein transthyretin (TTR) is highly fibrillogenic in vitro and is the fibril precursor in both autosomal dominant (familial amyloidotic polyneuropathy [FAP] and familial amyloidotic cardiomyopathy [FAC]) and sporadic (senile systemic amyloidosis [SSA]) forms of human cardiac amyloidosis. We have produced mouse strains transgenic for either wild-type or mutant (TTRLeu55Pro) human TTR genes. Eighty-four percent of C57Bl/6xDBA/2 mice older than 18 months, transgenic for the wild-type human TTR gene, develop TTR deposits that occur primarily in heart and kidney. In most of the animals, the deposits are nonfibrillar and non-Congophilic, but 20% of animals older than 18 months that bear the transgene have human TTR cardiac amyloid deposits identical to the lesions seen in SSA. Amino terminal amino acid sequence analysis and mass spectrometry of the major component extracted from amyloid and nonamyloid deposits revealed that both were intact human TTR monomers with no evidence of proteolysis or codeposition of murine TTR. This is the first instance in which the proteins from amyloid and nonfibrillar deposits in the same or syngeneic animals have been shown to be identical by sequence analysis. It is also the first time in any form of amyloidosis that nonfibrillar deposits have been shown to systematically occur temporally before the appearance of fibrils derived from the same precursor in the same tissues. These findings suggest, but do not prove, that the nonamyloid deposits represent a precursor of the fibril. The differences in the ultrastructure and binding properties of the deposits, despite the identical sizes and amino terminal amino acid sequences of the TTR and the dissociation of deposition and fibril formation, provide evidence that in vivo factors, perhaps associated with aging, impact on both systemic precursor deposition and amyloid fibril formation.

The United Nations Conference on Sustainable Development, Rio+20, will address the challenges for sustainable development (SD), 'green economy and poverty eradication' and the 'institutional structure of sustainable development'. Therefore it will address the governance needed to achieve such goals. This paper discusses the structure of global, regional and national governance of and for health and environment in the context of SD. Among other global actions, the Millenium Development Goals were a significant recent political effort, but despite its advances, it fails when ignores the structural causes of production and consumption patterns and the unequal distribution of power, which are responsible for inequities and impede true development. To achieve SD, proposals must avoid reductionism, advancing conceptually and methodologically to face the challenges of the socio-environmental determinants of health through intersectoral action, including social participation and all levels of government. It is paramount to continue the implementation of Agenda 21, to meet the MDGs and to create 'Sustainable Development Goals'. Regarding the health field, Rio+20 Summit must reassure the connection between health and sustainability - as a part of the Social pillar of sustainable development - inspiring politics and actions in multiple levels.

In a scenario where ecosystemic services are being eroded and there is high social inequity, a new model of development is necessary, namely one capable of promoting social development with a reduction of its ecological footprint. The 'Green Economy' model is one of the proposed models. This paper seeks to analyze the environmental, social and individual impacts on human health in the context of a 'brown economy', and discusses the contributions of a green economy on the promotion of equity and health. The assumption is that economic development and environmental sustainability are not incompatible and both contribute to the eradication of poverty. The transition to a sustainable economy depends on political decisions, and transcends technological developments. Above all, it should instigate new models of production, consumption and social organization, which promote socio-environmental justice, encouraging social participation and democratic forms of governance to define a solid agenda for the implementation of sustainable development and mechanisms to implement them at all levels.

In recent years, there are still companies which have not opted yet to diversify, boost or develop the promotion of their range of services in the hotel industry, focusing the vitality of their sales in seasons of high tourist flow, but their level of demand is declining in regular periods. This is due to among other factors, to changes in the behavior of today's customers, who place their trust in verified and licensed channels which are part of digital marketing. Therefore, digital marketing has gained great relevance in business, which is originated by the technological advance of media, positioning digital marketing as a strategic and a necessary tool to publicize a service and significantly increase customer demand. In this case, the objective of this research is to determine the digital marketing strategies to increase demand in a hotel company in a country with an emerging economy. The methodology used in the research is a mixed type, because the information was collected through a qualitative and quantitative approach, the sample is non-probabilistic and intentional, a questionnaire was applied to customers and also interviews to administrative staff. The data was processed through Ms Excel software and presented in frequency tables and figures for interpretation. The results show the great importance of the use of digital marketing strategies such as Search Engine Optimization (SEO), Social Media Marketing (SMM) and Pay per Click, which present applications with great flexibility to acquire services, a great scope of visibility in search engines and all web content updates. Finally, it is concluded that the digital marketing strategies identified were decisive in increasing demand in the hotel industry.