NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo.

The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation in vitro and in vivo. NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration in vitro and in vivo, enabling future research on the regenerative potential of the YAP/Hippo pathway.

Arterial Stiffness: From Basic Primers to Integrative Physiology.

The elastic properties of conductance arteries are one of the most important hemodynamic functions in the body, and data continue to emerge regarding the importance of their dysfunction in vascular aging and a range of cardiovascular diseases. Here, we provide new insight into the integrative physiology of arterial stiffening and its clinical consequence. We also comprehensively review progress made on pathways/molecules that appear today as important basic determinants of arterial stiffness, particularly those mediating the vascular smooth muscle cell (VSMC) contractility, plasticity and stiffness. We focus on membrane and nuclear mechanotransduction, clearance function of the vascular wall, phenotypic switching of VSMCs, immunoinflammatory stimuli and epigenetic mechanisms. Finally, we discuss the most important advances of the latest clinical studies that revisit the classical therapeutic concepts of arterial stiffness and lead to a patient-by-patient strategy according to cardiovascular risk exposure and underlying disease.

Comparison of Tonotopic and Default Frequency Fitting for Speech Understanding in Noise in New Cochlear Implantees: A Prospective, Randomized, Double-Blind, Cross-Over Study.

OBJECTIVES: While cochlear implants (CIs) have provided benefits for speech recognition in quiet for subjects with severe-to-profound hearing loss, speech recognition in noise remains challenging. A body of evidence suggests that reducing frequency-to-place mismatch may positively affect speech perception. Thus, a fitting method based on a tonotopic map may improve speech perception results in quiet and noise. The aim of our study was to assess the impact of a tonotopic map on speech perception in noise and quiet in new CI users. DESIGN: A prospective, randomized, double-blind, two-period cross-over study in 26 new CI users was performed over a 6-month period. New CI users older than 18 years with bilateral severe-to-profound sensorineural hearing loss or complete hearing loss for less than 5 years were selected in the University Hospital Centre of Rennes in France. An anatomical tonotopic map was created using postoperative flat-panel computed tomography and a reconstruction software based on the Greenwood function. Each participant was randomized to receive a conventional map followed by a tonotopic map or vice versa. Each setting was maintained for 6 weeks, at the end of which participants performed speech perception tasks. The primary outcome measure was speech recognition in noise. Participants were allocated to sequences by block randomization of size two with a ratio 1:1 (CONSORT Guidelines). Participants and those assessing the outcomes were blinded to the intervention. RESULTS: Thirteen participants were randomized to each sequence. Two of the 26 participants recruited (one in each sequence) had to be excluded due to the COVID-19 pandemic. Twenty-four participants were analyzed. Speech recognition in noise was significantly better with the tonotopic fitting at all signal-to-noise ratio (SNR) levels tested [SNR = +9 dB, p = 0.002, mean effect (ME) = 12.1%, 95% confidence interval (95% CI) = 4.9 to 19.2, standardized effect size (SES) = 0.71; SNR = +6 dB, p < 0.001, ME = 16.3%, 95% CI = 9.8 to 22.7, SES = 1.07; SNR = +3 dB, p < 0.001 ME = 13.8%, 95% CI = 6.9 to 20.6, SES = 0.84; SNR = 0 dB, p = 0.003, ME = 10.8%, 95% CI = 4.1 to 17.6, SES = 0.68]. Neither period nor interaction effects were observed for any signal level. Speech recognition in quiet ( p = 0.66) and tonal audiometry ( p = 0.203) did not significantly differ between the two settings. 92% of the participants kept the tonotopy-based map after the study period. No correlation was found between speech-in-noise perception and age, duration of hearing deprivation, angular insertion depth, or position or width of the frequency filters allocated to the electrodes. CONCLUSION: For new CI users, tonotopic fitting appears to be more efficient than the default frequency fitting because it allows for better speech recognition in noise without compromising understanding in quiet.

2024 Recommendations for Validation of Noninvasive Arterial Pulse Wave Velocity Measurement Devices.

BACKGROUND: Arterial stiffness, as measured by arterial pulse wave velocity (PWV), is an established biomarker for cardiovascular risk and target-organ damage in individuals with hypertension. With the emergence of new devices for assessing PWV, it has become evident that some of these devices yield results that display significant discrepancies compared with previous devices. This discrepancy underscores the importance of comprehensive validation procedures and the need for international recommendations. METHODS: A stepwise approach utilizing the modified Delphi technique, with the involvement of key scientific societies dedicated to arterial stiffness research worldwide, was adopted to formulate, through a multidisciplinary vision, a shared approach to the validation of noninvasive arterial PWV measurement devices. RESULTS: A set of recommendations has been developed, which aim to provide guidance to clinicians, researchers, and device manufacturers regarding the validation of new PWV measurement devices. The intention behind these recommendations is to ensure that the validation process can be conducted in a rigorous and consistent manner and to promote standardization and harmonization among PWV devices, thereby facilitating their widespread adoption in clinical practice. CONCLUSIONS: It is hoped that these recommendations will encourage both users and developers of PWV measurement devices to critically evaluate and validate their technologies, ultimately leading to improved consistency and comparability of results. This, in turn, will enhance the clinical utility of PWV as a valuable tool for assessing arterial stiffness and informing cardiovascular risk stratification and management in individuals with hypertension.

2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA).

DOCUMENT REVIEWERS: Luis Alcocer (Mexico), Christina Antza (Greece), Mustafa Arici (Turkey), Eduardo Barbosa (Brazil), Adel Berbari (Lebanon), Luís Bronze (Portugal), John Chalmers (Australia), Tine De Backer (Belgium), Alejandro de la Sierra (Spain), Kyriakos Dimitriadis (Greece), Dorota Drozdz (Poland), Béatrice Duly-Bouhanick (France), Brent M. Egan (USA), Serap Erdine (Turkey), Claudio Ferri (Italy), Slavomira Filipova (Slovak Republic), Anthony Heagerty (UK), Michael Hecht Olsen (Denmark), Dagmara Hering (Poland), Sang Hyun Ihm (South Korea), Uday Jadhav (India), Manolis Kallistratos (Greece), Kazuomi Kario (Japan), Vasilios Kotsis (Greece), Adi Leiba (Israel), Patricio López-Jaramillo (Colombia), Hans-Peter Marti (Norway), Terry McCormack (UK), Paolo Mulatero (Italy), Dike B. Ojji (Nigeria), Sungha Park (South Korea), Priit Pauklin (Estonia), Sabine Perl (Austria), Arman Postadzhian (Bulgaria), Aleksander Prejbisz (Poland), Venkata Ram (India), Ramiro Sanchez (Argentina), Markus Schlaich (Australia), Alta Schutte (Australia), Cristina Sierra (Spain), Sekib Sokolovic (Bosnia and Herzegovina), Jonas Spaak (Sweden), Dimitrios Terentes-Printzios (Greece), Bruno Trimarco (Italy), Thomas Unger (The Netherlands), Bert-Jan van den Born (The Netherlands), Anna Vachulova (Slovak Republic), Agostino Virdis (Italy), Jiguang Wang (China), Ulrich Wenzel (Germany), Paul Whelton (USA), Jiri Widimsky (Czech Republic), Jacek Wolf (Poland), Grégoire Wuerzner (Switzerland), Eugene Yang (USA), Yuqing Zhang (China).

How to measure arterial stiffness independently of blood pressure: the QKD method.

OBJECTIVE: Arterial stiffness, an important predictor of cardiovascular event, has two components: one linked to the nonlinear elastic behaviour of the arterial wall and dependent of the blood pressure (BP) at the time of measurement, and the other linked to the structural modifications of the arterial wall as the consequences of the long-term effects of all cardiovascular risk factors, including BP. This second component is certainly the most important one and can be assessed with 24-h ambulatory monitoring of cardio-arm pulse transmission time (QKD method). METHODS: The working hypothesis of this study is that QKD100-60, the value of the QKD for a 100 mmHg SBP and 60 bpm heart rate is independent of 24-h SBP in both normotensive volunteers and treated hypertensive patients, in whom the long-term influence of BP is limited, whereas QKD100-60 is not independent of 24-h SBP in untreated hypertensive patients in whom high BP was able to damage the arterial wall on the long term. So we studied the relationships of QKD100-60 with 24-h BP and heart rate together with age, sex, height in multivariate regression analysis in three groups of patients; normal, untreated and treated hypertensive patients. QKD was measured with Novacor devices. RESULTS: In the normal population (n = 323, aged 29 ±â€Š10 years) and in the treated hypertensive population (n = 425, aged 58 ±â€Š13 years) the QKD100-60 was indeed not significantly related to 24-h SBP. In the untreated hypertensive population (n = 614, aged 51 ±â€Š13 years) the QKD100-60 was weakly but significantly related to 24-h SBP (r = 0.249, P < 0.0001). CONCLUSION: Ambulatory monitoring of QKD provides indices of arterial stiffness independent of BP level at the time of measurement and most interestingly of 24-h BP with the potential to refine risk in patients with low traditional risk scores.

Microcirculation and Macrocirculation in Hypertension: A Dangerous Cross-Link?

Microcirculation and macrocirculation are tightly interconnected into a dangerous cross-link in hypertension. Small artery damage includes functional (vasoconstriction, impaired vasodilatation) and structural abnormalities (mostly inward eutrophic remodeling). These abnormalities are major determinants of the increase in total peripheral resistance and mean blood pressure (BP) in primary hypertension, which in the long term induces large artery stiffening. In turn, large artery stiffening increases central systolic and pulse pressures, which are further augmented by wave reflection in response to the structural alterations in small resistance arteries. Finally, transmission of high BP and flow pulsatility to small resistance arteries further induces functional and structural abnormalities, thus leading to increased total peripheral resistance and mean BP, thus perpetuating the vicious circle. Hyperpulsatility, in addition to higher mean BP, exaggerates cardiac, brain, and kidney damages and leads to cardiovascular, cerebral, and renal complications. The dangerous cross-link between micro and macrocirculation can be reversed into a virtuous one by ACE (angiotensin-converting enzyme) inhibitors, sartans, and calcium channel blockers. These three pharmacological classes are more potent than ß-blockers and diuretics for reducing arterial stiffness and small artery remodeling. The same ranking was observed for their effectiveness at reducing left ventricular hypertrophy, preserving glomerular filtration rate, and preventing dementia, suggesting that they can act beyond brachial BP reduction, by breaking the micro/macrocirculation vicious circle.

SPARTE Study: Normalization of Arterial Stiffness and Cardiovascular Events in Patients With Hypertension at Medium to Very High Risk.

[Figure: see text].

Sleep Apnea is Associated With Accelerated Vascular Aging: Results From 2 European Community-Based Cohort Studies.

Background The mechanisms underlying the association between obstructive sleep apnea (OSA) and cardiovascular disease may include accelerated vascular aging. The aim was to compare the magnitude of vascular aging in patients with high versus low risk of OSA. Methods and Results In 2 community-based studies, the PPS3 (Paris Prospective Study 3) and the Maastricht Study, high risk of OSA was determined with the Berlin questionnaire (a screening questionnaire for OSA). We assessed carotid artery properties (carotid intima-media thickness, Young's elastic modulus, carotid-femoral pulse wave velocity, carotid pulse wave velocity, carotid diameter using high precision ultrasound echography), and carotid-femoral pulse wave velocity (in the Maastricht Study only). Regression coefficients were estimated on pooled data using multivariate linear regression. A total of 8615 participants without prior cardiovascular disease were included (6840 from PPS3, 62% men, mean age 59.5±6.2 years, and 1775 from the Maastricht Study, 51% men, 58.9±8.1 years). Overall, high risk of OSA prevalence was 16.8% (n=1150) in PPS3 and 23.8% (n=423) in the Maastricht Study. A high risk of OSA was associated with greater carotid intima-media thickness (ß=0.21; 0.17-0.26), Young's elastic modulus (ß=0.21; 0.17-0.25), carotid-femoral pulse wave velocity (ß=0.24; 0.14-0.34), carotid pulse wave velocity (ß=0.31; 0.26-0.35), and carotid diameter (ß=0.43; 0.38-0.48), after adjustment for age, sex, total cholesterol, smoking, education level, diabetes mellitus, heart rate, and study site. Consistent associations were observed after additional adjustments for mean blood pressure, body mass index, or antihypertensive medications. Conclusions These data lend support for accelerated vascular aging in individuals with high risk of OSA. This may, at least in part, underlie the association between OSA and cardiovascular disease.

EBI2 Is Temporarily Upregulated in MO3.13 Oligodendrocytes during Maturation and Regulates Remyelination in the Organotypic Cerebellar Slice Model.

The EBI2 receptor regulates the immune system and is expressed in various immune cells including B and T lymphocytes. It is also expressed in astrocytes in the central nervous system (CNS) where it regulates pro-inflammatory cytokine release, cell migration and protects from chemically induced demyelination. Its signaling and expression are implicated in various diseases including multiple sclerosis, where its expression is increased in infiltrating immune cells in the white matter lesions. Here, for the first time, the EBI2 protein in the CNS cells in the human brain was examined. The function of the receptor in MO3.13 oligodendrocytes, as well as its role in remyelination in organotypic cerebellar slices, were investigated. Human brain sections were co-stained for EBI2 receptor and various markers of CNS-specific cells and the human oligodendrocyte cell line MO3.13 was used to investigate changes in EBI2 expression and cellular migration. Organotypic cerebellar slices prepared from wild-type and cholesterol 25-hydroxylase knock-out mice were used to study remyelination following lysophosphatidylcholine (LPC)-induced demyelination. The data showed that EBI2 receptor is present in OPCs but not in myelinating oligodendrocytes in the human brain and that EBI2 expression is temporarily upregulated in maturing MO3.13 oligodendrocytes. Moreover, we show that migration of MO3.13 cells is directly regulated by EBI2 and that its signaling is necessary for remyelination in cerebellar slices post-LPC-induced demyelination. The work reported here provides new information on the expression and role of EBI2 in oligodendrocytes and myelination and provides new tools for modulation of oligodendrocyte biology and therapeutic approaches for demyelinating diseases.

Gut-inhabiting Clostridia build human GPCR ligands by conjugating neurotransmitters with diet- and human-derived fatty acids.

Human physiology is regulated by endogenous signalling compounds, including fatty acid amides (FAAs), chemical mimics of which are made by bacteria. The molecules produced by human-associated microbes are difficult to identify because they may only be made in a local niche or they require a substrate sourced from the host, diet or other microbes. We identified a set of uncharacterized gene clusters in metagenomics data from the human gut microbiome. These clusters were discovered to make FAAs by fusing exogenous fatty acids with amines. Using an in vitro assay, we tested their ability to incorporate 25 fatty acids and 53 amines known to be present in the human gut, from which the production of six FAAs was deduced (oleoyl dopamine, oleoyl tyramine, lauroyl tryptamine, oleoyl aminovaleric acid, α-linolenoyl phenylethylamine and caproyl tryptamine). These molecules were screened against panels of human G-protein-coupled receptors to deduce their putative human targets. Lauroyl tryptamine is found to be an antagonist to the immunomodulatory receptor EBI2 against its native oxysterol ligand (0.98 µM half-maximal inhibitory concentration), is produced in culture by Eubacterium rectale and is present in human faecal samples. FAAs produced by Clostridia may serve as a mechanism to modulate their host by mimicking human signalling molecules.

Predictive Importance of Blood Pressure Characteristics With Increasing Age in Healthy Men and Women: The MORGAM Project.

[Figure: see text].

Arterial Stiffness and Hypertension in the Elderly.

Hypertension prevalence increases with age. Age and high blood pressure are the two main determinants of arterial stiffness. In elderly hypertensives, large arteries stiffen and systolic and pulse pressures increase, due to wave reflections. A major reason for measuring arterial stiffness in clinical practice in elderly hypertensive patients comes from the repeated demonstration that arterial stiffness and wave reflections have a predictive value for CV events. A large body of evidence has been published during the last two decades, concerning the epidemiology, pathophysiology, and pharmacology of large arteries in hypertension in various settings of age. Particularly, two expert consensus documents have reviewed the methodological agreements for measuring arterial stiffness. The concepts of Early Vascular Aging (EVA) and Supernormal Vascular Aging (SUPERNOVA) help to better understand on which determinants of arterial stiffness it is possible to act, in order to limit target organ damage and cardiovascular complications. This review will address the issues of the cellular and molecular mechanisms of arterial stiffening in elderly hypertensives, the consequences of arterial stiffening on central systolic and pulse (systolic minus diastolic, PP) pressures and target organs, the methodology for measuring arterial stiffness, central pulse pressure and wave reflection, the epidemiological determinants of arterial stiffening in elderly hypertensives, the pharmacology of arterial destiffening, and how the concepts of EVA and SUPERNOVA apply to the detection of organ damage and prevention of CV complications.

Training outcomes for audiology students using virtual reality or traditional training methods.

Due to limited space and resources, it can be difficult to train students on audiological procedures adequately. In the present study, we compared audiology training outcomes between a traditional approach and a recently developed immersive virtual reality (VR) approach in audiology students. Twenty-nine first-year audiology students participated in the study; 14 received traditional training ("TT group"), and 15 received the VR training ("VRT group"). Pre- and post-training evaluation included a 20-item test developed by an audiology educator. Post-training satisfaction and self-confidence were evaluated using Likert scales. Mean post-training test scores improved by 6.9±9.8 percentage points in the TT group and by 21.1±7.8 points in the VRT group; the improvement in scores was significant for both groups. After completing the traditional training, the TT group was subsequently trained with the VR system, after which mean scores further improved by 7.5 points; there was no significant difference in post-VR training scores between the TT and VRT groups. After training, the TT and VRT groups completed satisfaction and self-confidence questionnaires. Satisfaction and self-confidence ratings were significantly higher for the VR training group, compared to the traditional training group. Satisfaction ratings were "good" (4 on Likert scale) for 74% of the TT group and 100% of the VRT group. Self-confidence ratings were "good" for 71% of the TT group and 92% of the VRT group. These results suggest that a VR training approach may be an effective alternative or supplement to traditional training for audiology students.

Early and Supernormal Vascular Aging: Clinical Characteristics and Association With Incident Cardiovascular Events.

Pulse wave velocity is an established marker of early vascular aging but may also help identifying individuals with supernormal vascular aging. We tested the hypothesis that individuals with the largest difference (Δ-age) between chronological and vascular age show the lowest rate of cardiovascular events and may thus be defined as supernormal vascular aging. Vascular age was defined as the predicted age in the best fitting multivariable regression model including classical risk factors and treatment and pulse wave velocity, in a subset of the Reference Values for Arterial Stiffness Collaboration Database (n=3347). Δ-age was then calculated as chronological age minus vascular age, and the 10th and 90th percentiles were used to define early (Δ-age<-5.7 years), normal (Δ-age -5.7 to 6.8 years) and supernormal vascular aging (Δ-age>6.8 years). The risk for fatal and nonfatal cardiovascular events associated with vascular aging categories was investigated in the Malmö Diet and Cancer Study cohort (n=2642). In the Malmö Diet and Cancer Study Cohort (6.6-year follow-up, 286 events), Δ-age was significantly (P<0.01) and inversely associated with cardiovascular events. Compared with normal vascular aging, supernormal vascular aging had lower risk (hazard ratio, 0.59 [95% CI, 0.41-0.85]), whereas early vascular aging had higher risk (hazard ratio, 2.70 [95% CI, 1.55-4.70]) of cardiovascular events, in particular coronary events. There was no significant association with all-cause mortality. This study represents the first validation of the clinical significance of the supernormal vascular aging concept, based on prospective data. Its further characterization may help discovering novel protective molecular pathways and providing preventive strategies for successful vascular aging.

The use of single-pill combinations as first-line treatment for hypertension: translating guidelines into clinical practice.

: The 2008 European Society of Cardiology/European Society of Hypertension guidelines recommend the first-line prescription of two antihypertensive drugs in single-pill combinations (SPCs), also known as fixed-dose combinations, for the treatment of most patients with hypertension. This recommendation is based on a large amount of data, which shows that first-line treatment with SPCs supports reaching blood pressure targets rapidly and reducing cardiovascular outcome risk while keeping the therapeutic strategies as simple as possible and fostering adherence and persistence. As this approach constitutes a big shift from the stepped-care approaches that have been dominant for many years, practicing physicians have expressed concerns about using SPCs as first-line agents. In this review, we will discuss the barriers to the uptake of this recommendation. We will also offer suggestions to reduce the impact of these barriers and address specific concerns that have been raised.