Performance of the Aktiia optical blood pressure measurement device in the elderly: a comparison with double blinded auscultation in different body positions.

BACKGROUND: Accurate blood pressure (BP) measurement is essential for the correct diagnosis and management of hypertension (HTN) especially in the elderly population. As with of all BP devices, the accuracy of cuffless devices must be verified. This study (NCT04027777) aimed to evaluate the performance of a wrist cuffless optical BP device in an elderly population cohort in different body positions with auscultation as the reference measurement. DESIGN AND METHODS: Patients aged 65-85 years with different BP categories but without diabetes were recruited. After an initial calibration based on auscultatory measurements, BP estimation from the Aktiia Bracelet (Aktiia SA, Switzerland) were compared to reference double-blinded auscultatory measurements in sitting, standing and lying positions on four separate visits distributed over one month. In the absence of a universal standard for cuffless BP device at the time of the study, modified ISO81060-2 criteria were used for performance analysis. RESULTS: Thirty-five participants were included in the analysis fulfilling the inclusion requirements of ISO 81060-2. A total of 469 paired measurements were obtained with overall 83% acceptance rate. Differences (mean ± SD)   between Aktiia Bracelet and auscultation for systolic BP were -0.26 ± 9.96 mmHg for all body positions aggregated (sitting 1.23 ± 7.88 mmHg, standing -1.81 ± 11.11 mmHg, lying -1.8 ± 9.96 mmHg). Similarly, differences for diastolic BP were -0.75 ± 7.0 mmHg (0.2 ± 5.55 mmHg, -5.35 ± 7.75 mmHg and -0.94 ± 7.47 mmHg, respectively). Standard deviation of the averaged differences per subject for systolic/diastolic BP was 3.8/2.5 mmHg in sitting and 4.4/3.7 mmHg for all body positions aggregated. CONCLUSIONS: Overall, this study demonstrates a similar performance of the Aktiia Bracelet compared to auscultation in an elderly population in body positions representative of daily activities. The use of more comfortable, non-invasive, and non-occlusive BP monitors during long periods may facilitate e-health and may contribute to better management of HTN, including diagnosis and treatment of HTN, in the elderly.

Accuracy of blood pressure measurements is essential in the diagnosis and the follow-up of patients with high blood pressure. As with any blood pressure measuring device, a validation is necessary. In this study including a elderly population, we compared values obtained by the cuffless Aktiia Bracelet (Aktiia SA, Switzerland) after an initial calibration with the reference auscultatory method during four separate study days distributed over one month. We show that the accuracy of the Aktiia Bracelet is similar to auscultation. The accuracy varies depending on the position in which the measurement is performed. Overall, the accuracy is not modified by a higher age category. The use of a cuffless device in the elderly population characterized by high prevalence of hypertension may facilitate the follow-up of blood pressure with more comfort and minimal constraints.

Model biomolecular condensates have heterogeneous structure quantitatively dependent on the interaction profile of their constituent macromolecules.

Biomolecular condensates play numerous roles in cells by selectively concentrating client proteins while excluding others. These functions are likely to be sensitive to the spatial organization of the scaffold proteins forming the condensate. We use coarse-grained molecular simulations to show that model intrinsically-disordered proteins phase separate into a heterogeneous, structured fluid characterized by a well-defined length scale. The proteins are modelled as semi-flexible polymers with punctate, multifunctional binding sites in good solvent conditions. Their dense phase is highly solvated with a spatial structure that is more sensitive to the separation of the binding sites than their affinity. We introduce graph theoretic measures to quantify their heterogeneity, and find that it increases with increasing binding site number, and exhibits multi-timescale dynamics. The model proteins also swell on passing from the dilute solution to the dense phase. The simulations predict that the structure of the dense phase is modulated by the location and affinity of binding sites distant from the termini of the proteins, while sites near the termini more strongly affect its phase behaviour. The relations uncovered between the arrangement of weak interaction sites on disordered proteins and the material properties of their dense phase can be experimentally tested to give insight into the biophysical properties, pathological effects, and rational design of biomolecular condensates.

Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBα complex.

The nuclear receptor REV-ERBα integrates the circadian clock with hepatic glucose and lipid metabolism by nucleating transcriptional comodulators at genomic regulatory regions. An interactomic approach identified O-GlcNAc transferase (OGT) as a REV-ERBα-interacting protein. By shielding cytoplasmic OGT from proteasomal degradation and favoring OGT activity in the nucleus, REV-ERBα cyclically increased O-GlcNAcylation of multiple cytoplasmic and nuclear proteins as a function of its rhythmically regulated expression, while REV-ERBα ligands mostly affected cytoplasmic OGT activity. We illustrate this finding by showing that REV-ERBα controls OGT-dependent activities of the cytoplasmic protein kinase AKT, an essential relay in insulin signaling, and of ten-of-eleven translocation (TET) enzymes in the nucleus. AKT phosphorylation was inversely correlated to REV-ERBα expression. REV-ERBα enhanced TET activity and DNA hydroxymethylated cytosine (5hmC) levels in the vicinity of REV-ERBα genomic binding sites. As an example, we show that the REV-ERBα/OGT complex modulates SREBP-1c gene expression throughout the fasting/feeding periods by first repressing AKT phosphorylation and by epigenomically priming the Srebf1 promoter for a further rapid response to insulin. Conclusion: REV-ERBα regulates cytoplasmic and nuclear OGT-controlled processes that integrate at the hepatic SREBF1 locus to control basal and insulin-induced expression of the temporally and nutritionally regulated lipogenic SREBP-1c transcript.

Glucose sensing O-GlcNAcylation pathway regulates the nuclear bile acid receptor farnesoid X receptor (FXR).

UNLABELLED: Bile acid metabolism is intimately linked to the control of energy homeostasis and glucose and lipid metabolism. The nuclear receptor farnesoid X receptor (FXR) plays a major role in the enterohepatic cycling of bile acids, but the impact of nutrients on bile acid homeostasis is poorly characterized. Metabolically active hepatocytes cope with increases in intracellular glucose concentrations by directing glucose into storage (glycogen) or oxidation (glycolysis) pathways, as well as to the pentose phosphate shunt and the hexosamine biosynthetic pathway. Here we studied whether the glucose nonoxidative hexosamine biosynthetic pathway modulates FXR activity. Our results show that FXR interacts with and is O-GlcNAcylated by O-GlcNAc transferase in its N-terminal AF1 domain. Increased FXR O-GlcNAcylation enhances FXR gene expression and protein stability in a cell type-specific manner. High glucose concentrations increased FXR O-GlcNAcylation, hence its protein stability and transcriptional activity by inactivating corepressor complexes, which associate in a ligand-dependent manner with FXR, and increased FXR binding to chromatin. Finally, in vivo fasting-refeeding experiments show that FXR undergoes O-GlcNAcylation in fed conditions associated with increased direct FXR target gene expression and decreased liver bile acid content. CONCLUSION: FXR activity is regulated by glucose fluxes in hepatocytes through a direct posttranslational modification catalyzed by the glucose-sensing hexosamine biosynthetic pathway.

Validation of the Aktiia blood pressure cuff for clinical use according to the ANSI/AAMI/ISO 81060-2:2013 protocol.

OBJECTIVE: Assess the accuracy and precision of the Aktiia initialization oscillometric upper-arm cuff device (Aktiia SA, Neuchâtel, Switzerland) for home blood pressure (BP) monitoring in the general population according to the American National Standards Institute / Association for the Advancement of Medical Instrumentation/International Organization for Standardization (ANSI/AAMI/ISO) 81060-2:2013 standard. METHODS: Three trained observers validated BP measurements performed using the Aktiia cuff versus BP measurements performed using a standard mercury sphygmomanometer. Two ISO 81060-2 criteria were used to validate the Aktiia cuff. Criterion 1 evaluated, for both SBP and DBP, whether the mean error between BP readings performed by the Aktiia cuff and auscultation was ≤±5 mmHg, and whether the SD of the error was ≤8 mmHg. Criterion 2 assessed whether, for the SBP and DBP of each individual subject, the SD of the averaged paired determinations per subject of the Aktiia cuff and of the auscultation met the criteria listed in the table of Averaged Subject Data Acceptance. RESULTS: Mean differences between the Aktiia cuff and the standard mercury sphygmomanometer (criterion 1) were 1.3 ± 7.11 mmHg for SBP and -0.2 ± 5.46 mmHg for DBP. The SD of the averaged paired differences per subject (criterion 2) was 6.55 mmHg for SBP and 5.15 mmHg for DBP. CONCLUSION: Aktiia initialization cuff complies with the requirements of the ANSI/AAMI/ISO guidelines and can be safely recommended for BP measurements in the adult population.

Aktiia cuffless blood pressure monitor yields equivalent daytime blood pressure measurements compared to a 24-h ambulatory blood pressure monitor: Preliminary results from a prospective single-center study.

In this preliminary study, we compared daytime blood pressure (BP) measurements performed by a commercially available cuffless-and continual-BP monitor (Aktiia monitor, Neuchâtel, Switzerland) and a traditional ambulatory BP monitor (ABPM; Dyasis 3, Novacor, Paris, France) from 52 patients enrolled in a 12-week cardiac rehabilitation (CR) program (Neuchâtel, Switzerland). Daytime (9am-9pm) systolic (SBP) and diastolic (DBP) BP from 7-day averaged data from Aktiia monitor were compared to 1-day averaged BP data from ABPM. No significant differences were found between the Aktiia monitor and the ABPM for SBP (µ ± σ [95% confidence interval]: 1.6 ± 10.5 [-1.5, 4.6] mmHg, P = 0.306; correlation [R2]: 0.70; ± 10/ ± 15 mmHg agreements: 60%, 84%). Marginally non-significant bias was found for DBP (-2.2 ± 8.0 [-4.5, 0.1] mmHg, P = 0.058; R2: 0.66; ±10/±15 mmHg agreements: 78%, 96%). These intermediate results show that daytime BP measurements using the Aktiia monitor generate data comparable to that of an ABPM monitor.

Hepatic transcriptomic signatures of statin treatment are associated with impaired glucose homeostasis in severely obese patients.

BACKGROUND: Clinical data identified an association between the use of HMG-CoA reductase inhibitors (statins) and incident diabetes in patients with underlying diabetes risk factors such as obesity, hypertension and dyslipidemia. The molecular mechanisms however are unknown. METHODS: An observational cross-sectional study included 910 severely obese patients, mean (SD) body mass index (BMI) 46.7 (8.7), treated with or without statins (ABOS cohort: a biological atlas of severe obesity). Data and sample collection took place in France between 2006 and 2016. Transcriptomic signatures of statin treatment in human liver obtained from genome-wide transcriptomic profiling of five different statin drugs using microarrays were correlated to clinico-biological phenotypes and also assigned to biological pathways and mechanisms. Patients from the non-statin-users group were matched to patients in the statin users group by propensity score analysis to minimize confounding effects from age, gender, parental familial history of diabetes, BMI, waist circumference, systolic and diastolic blood pressure and use of anti-hypertensive drugs as pre-specified covariates. RESULTS: We determined the hepatic, statin-related gene signature from genome-wide transcriptomic profiling in severely obese patients with varying degrees of glucose tolerance and cardio-metabolic comorbidities. One hundred and fifty seven patients on statin treatment in the matched cohort showed higher diabetes prevalence (OR = 2.67; 95%CI, 1.60-4.45; P = 0.0002) and impairment of glucose homeostasis. This phenotype was associated with molecular signatures of increased hepatic de novo lipogenesis (DNL) via activation of sterol regulatory element-binding protein 1 (SREBP1) and concomitant upregulation of the expression of key genes in both fatty acid and triglyceride metabolism. CONCLUSIONS: A DNL gene activation profile in response to statins is associated with insulin resistance and the diabetic status of the patients. Identified molecular signatures thus suggest that statin treatment increases the risk for diabetes in humans at least in part via induction of DNL. TRIAL REGISTRATION: NCT01129297 . Registered May 242,010 (retrospectively registered).

The RBM14/CoAA-interacting, long intergenic non-coding RNA Paral1 regulates adipogenesis and coactivates the nuclear receptor PPARγ.

Adipocyte differentiation and function relies on a network of transcription factors, which is disrupted in obesity-associated low grade, chronic inflammation leading to adipose tissue dysfunction. In this context, there is a need for a thorough understanding of the transcriptional regulatory network involved in adipose tissue pathophysiology. Recent advances in the functional annotation of the genome has highlighted the role of non-coding RNAs in cellular differentiation processes in coordination with transcription factors. Using an unbiased genome-wide approach, we identified and characterized a novel long intergenic non-coding RNA (lincRNA) strongly induced during adipocyte differentiation. This lincRNA favors adipocyte differentiation and coactivates the master adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARγ) through interaction with the paraspeckle component and hnRNP-like RNA binding protein 14 (RBM14/NCoAA), and was therefore called PPARγ-activator RBM14-associated lncRNA (Paral1). Paral1 expression is restricted to adipocytes and decreased in humans with increasing body mass index. A decreased expression was also observed in diet-induced or genetic mouse models of obesity and this down-regulation was mimicked in vitro by TNF treatment. In conclusion, we have identified a novel component of the adipogenic transcriptional regulatory network defining the lincRNA Paral1 as an obesity-sensitive regulator of adipocyte differentiation and function.

Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk.

The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation. Here, we performed a mass spectrometry-based search for FXR-interacting proteins in human hepatoma cells and identified AMPK as a coregulator of FXR. FXR interacted with the nutrient-sensitive kinase AMPK in the cytoplasm of target cells and was phosphorylated in its hinge domain. In cultured human and murine hepatocytes and enterocytes, pharmacological activation of AMPK inhibited FXR transcriptional activity and prevented FXR coactivator recruitment to promoters of FXR-regulated genes. Furthermore, treatment with AMPK activators, including the antidiabetic biguanide metformin, inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis, and worsened liver injury. Together, our data indicate that AMPK directly phosphorylates and regulates FXR transcriptional activity to precipitate liver injury under conditions favoring cholestasis.

The hepatic orosomucoid/α1-acid glycoprotein gene cluster is regulated by the nuclear bile acid receptor FXR.

The α-1-acid glycoprotein/orosomucoids (ORMs) are members of the lipocalin protein family. Encoded by 3 polymorphic genes in mouse (2 in man, 1 in rat), ORMs are expressed in hepatocytes and function as acute-phase proteins secreted in plasma under stressful conditions. In addition to their role of nanocarrier, ORMs are involved in several pathophysiological processes such as immunosuppression, cardioprotection, and inflammatory bowel disease. The nuclear bile acid receptor farnesoid X receptor (FXR) regulates bile acid homeostasis and lipid and glucose metabolism and is an important modulator of enterohepatic functions. Here we report that hepatic FXR deletion in mice affects the expression of several members of the lipocalin family, among which ORMs are identified as direct FXR target genes. Indeed, a FXR response element upstream of the mouse Orm1 promoter was identified to which hepatic, but not ileal, FXR can bind and activate ORM expression in vitro and in vivo. However, ORMs are regulated in a species-specific manner because the ORM cluster is regulated by FXR neither in human nor rat cell lines. Consistent with these data, chromatin immunoprecipitation sequencing analysis of the FXR genomic binding sites did not detect any FXR response element in the vicinity of the human or rat ORM gene cluster. Thus, bile acids and their cognate nuclear receptor, FXR, are regulators of ORM expression, with potential implications for the species-specific metabolic and inflammation control by FXR because the expression of the proinflammatory genes in epididymal white adipose tissue was dependent on liver FXR activation.