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Background: Recent sham-controlled randomized clinical trials have confirmed the safety and efficacy of catheter-based renal denervation (RDN). Long-term safety and efficacy data beyond 3 years are scarce. Here, we report on outcomes after RDN in a cohort of patients with resistant hypertension with an average of ≈9-year follow-up (FU). Methods: We recruited patients with resistant hypertension who were previously enrolled in various RDN trials applying radiofrequency energy for blood pressure (BP) lowering. All participants had baseline assessments before RDN and repeat assessment at long-term FU including medical history, automated office and ambulatory BP measurement, and routine blood and urine tests. We analyzed changes between baseline and long-term FU. Results: A total of 66 participants (mean±SD, 70.0±10.3 years; 76.3% men) completed long-term FU investigations with a mean of 8.8±1.2 years post-procedure. Compared with baseline, ambulatory systolic BP was reduced by −12.1±21.6 (from 145.2 to 133.1) mm Hg ( P P P =0.0052). Renal function assessed by estimated glomerular filtration rate fell within the expected age-associated rate of decline from 71.1 to 61.2 mL/min per 1.73 m 2 . Time above target was reduced significantly from 75.0±25.9% at baseline to 47.3±30.3% at long-term FU ( P Conclusions: RDN results in a significant and robust reduction in both office and ambulatory systolic and diastolic BP at ≈9-year FU after catheter-based RDN on less medication and without evidence of adverse consequences on renal function.

Purpose The purpose of this study was to visualise the influence of alignment strategy on bone resection in varus knee phenotypes. The hypothesis was that different amounts of bone resection would be required depending on the alignment strategy chosen. Through visualisation of the corresponding bone sections, it was hypothesised, it would be possible to assess which of the different alignment strategies would require the least amount of change to the soft tissues for the chosen phenotype, whilst still ensuring acceptable alignment of the components, and thus could be considered the most ideal alignment strategy. Methods Simulations of the different alignment strategies (mechanical, anatomical, constrained kinematic and unconstrained kinematic) in relation to their bone resections were performed on five common exemplary varus knee phenotypes. VARHKA174° VARFMA87° VARTMA84°, VARHKA174° VARFMA90° NEUTMA87°, VARHKA174° NEUFMA93° VARTMA84°, VARHKA177° NEUFMA93° NEUTMA87° and VARHKA177° VALFMA96° VARTMA81°. The phenotype system used categorises knees based on overall limb alignment (i.e. hip knee angle) but also takes into account joint line obliquity (i.e. TKA and FMA) and has been applied in the global orthopaedic community since its introduction in 2019. The simulations are based on long-leg radiographs under load. It is assumed that a change of 1° in the alignment of the joint line corresponds to a displacement of the distal condyle by 1 mm. Results In the most common phenotype VARHKA174° NEUFMA93° VARTMA84°, a mechanical alignment would result in an asymmetric elevation of the tibial medial joint line by 6 mm and a lateral distalisation of the femoral condyle by 3 mm, an anatomical alignment only by 0 and 3 mm, a restricted by 3 and 3 mm, respectively, whilst a kinematic alignment would result in no change in joint line obliquity. In the similarly common phenotype 2 VARHKA174° VARFMA90° NEUTMA87° with the same HKA, the changes are considerably less with only 3 mm asymmetric height change on one joint side, respectively, and no change in restricted or kinematic alignment. Conclusion This study shows that significantly different amounts of bone resection are required depending on the varus phenotype and the alignment strategy chosen. Based on the simulations performed, it can, therefore, be assumed that an individual decision for the respective phenotype is more important than the dogmatically correct alignment strategy. By including such simulations, the modern orthopaedic surgeon can now avoid biomechanically inferior alignments and still obtain the most natural possible knee alignment for the patient.

Determining the spatial patterning of tree species can provide inferences on underlying ecological processes. Gonystylus brunnescens is a South-east Asian subcanopy forest tree. To determine the spatial patterns of this species, we recorded the distribution of all individuals in a 0.4 ha sampling plot in eastern Borneo. We found that the pattern deviated from random and was well-described by the Matérn cluster model; clusters had a radius of approximately 4.2 m and contained an average of six seedlings each. This supports the hypothesis of animal-dispersed seeds and, due to a clear lack of association of juveniles with adults, may be due to scatter-hoarding of seeds by small mammal seed dispersers.

Purpose The purpose of this study was to simulate and visualise the influence of the alignment strategy on bone resection in neutral knee phenotypes. It was hypothesised that different amounts of bone resection would be required depending on the alignment strategy chosen. The hypothesis was that by visualising the corresponding bone cuts, it would be possible to assess which of the different alignment strategies required the least change to the soft tissues for the chosen phenotype but still ensured acceptable component alignment and could, therefore, be considered the most ideal alignment strategy. Methods Simulations of the different alignment strategies (mechanical, anatomical, restricted kinematic and unrestricted kinematic) regarding their bone resections were performed on four common exemplary neutral knee phenotypes. NEUHKA0° VARFMA 90° VALTMA90°, NEUHKA0° NEUFMA 93° NEUTMA87°, NEUHKA0° VALFMA 96° NEUTMA87° and NEUHKA0° VALFMA 99° VARTMA84°. The phenotype system used categorises knees based on overall limb alignment (i.e. hip knee angle) but also considers joint line obliquity (i.e. TKA and FMA) and has been used globally since its introduction in 2019. These simulations are based on long leg weightbearing radiographs. It is assumed that a change of 1° in the alignment of the joint line corresponds to correspond to 1 mm of distal condyle offset. Results In the most common neutral phenotype NEUHKA0° NEUFMA 93° NEUTMA87°, with a prevalence of 30%, bone cuts remain below 4 mm regardless of alignment strategy. The greatest changes in the obliquity of the joint line can be expected for the mechanical alignment of the phenotype NEUHKA0° VALFMA 99° VARTMA84° where the medial tibia is raised by 6 mm and the lateral femur is shifted distally by 9 mm. In contrast, the NEUHKA0° VARFMA 90° VALTMA90° phenotype requires no change in joint line obliquity if the mechanical alignment strategy is used. Conclusion Illustrations of alignment strategies help the treating surgeon to estimate the postoperative joint line obliquity. When considering the alignment strategy, it seems reasonable to prefer a strategy where the joint line obliquity is changed as little as possible. Although for the most common neutral knee phenotype the choice of alignment strategy seems to be of negligible importance, in general, even for neutral phenotypes, large differences in bone cuts can be observed depending on the choice of alignment strategy.

Abstract Raised blood pressure (BP) is the leading cause of preventable death in the world. Yet, its global prevalence is increasing, and it remains poorly detected, treated, and controlled in both high- and low-resource settings. From the perspective of members of the International Society of Hypertension based in all regions, we reflect on the past, present, and future of hypertension care, highlighting key challenges and opportunities, which are often region-specific. We report that most countries failed to show sufficient improvements in BP control rates over the past three decades, with greater improvements mainly seen in some high-income countries, also reflected in substantial reductions in the burden of cardiovascular disease and deaths. Globally, there are significant inequities and disparities based on resources, sociodemographic environment, and race with subsequent disproportionate hypertension-related outcomes. Additional unique challenges in specific regions include conflict, wars, migration, unemployment, rapid urbanization, extremely limited funding, pollution, COVID-19-related restrictions and inequalities, obesity, and excessive salt and alcohol intake. Immediate action is needed to address suboptimal hypertension care and related disparities on a global scale. We propose a Global Hypertension Care Taskforce including multiple stakeholders and societies to identify and implement actions in reducing inequities, addressing social, commercial, and environmental determinants, and strengthening health systems implement a well-designed customized quality-of-care improvement framework.

Aims The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an ‘Add-on’ to incorporate CKD measures into these algorithms, using a validated approach. Methods In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997 719 participants from 34 different datasets. Results In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved C-statistic by 0.006 (95%CI 0.004–0.008) and 0.016 (0.010–0.023), respectively, for SCORE2 and 0.012 (0.009–0.015) and 0.024 (0.014–0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57 485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI [e.g. 0.100 (0.062–0.138) for SCORE2] compared to the qualitative approach in the ESC guideline. Conclusion Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD.

Elevated nocturnal blood pressure (BP) is closely associated with increased risk of cardiovascular (CV) events. Circulating extracellular vesicles (EVs) have been proposed as a potential CV risk biomarker and shown to correlate with BP. The present study aimed to assess whether a reduction in BP is paralleled by respective changes in EVs.Fifty-five hypertensive patients (age: 57.7 ± 14.1 years) were included in the study. EVs and BP were assessed at baseline and at 12 weeks follow-up. Interventions to lower BP included advice on life-style modification only or life-style advice combined with additional pharmacotherapy. EVs were evaluated by flow cytometry (CD41+/Annexin V+) and BP by unobserved automated office BP and ambulatory BP monitoring.Nocturnal systolic BP correlated with EV levels at baseline ( P = 0.01). Multivariable regression models showed that changes in nocturnal systolic BP (adjusted R2 = 0.23; P = 0.01) and diastolic BP (adjusted R2 = 0.18; P = 0.02) were associated with respective changes in EV levels. Furthermore, intervention-induced improvement of systolic dipping was associated with a reduction in EVs in the univariate analysis (adjusted R2 = 0.06; P = 0.03). In contrast, systolic office, 24 h- and daytime-BP did not show significant associations with EVs. Patients whose medication was up-titrated at baseline showed a trend towards lower EV levels at follow-up (absolute change of -1.7 ± 1.3 EV/μl; P = 0.057).Circulating platelet-derived EVs were positively associated with nocturnal BP and therapy-induced changes over a 12-week treatment period. EVs may provide an integrated measure of BP changes achieved with pharmacotherapy.

ZusammenfassungDie COVID-19 Pandemie führte im Frühling 2020 zu einer unerwarteten flächendeckenden Unterbrechung des Präsenzunterrichts in allen Schulen der Schweiz und zur Einführung von Fernunterricht. Durch die Verlagerung des Unterrichts in die Familie könnten die ungleichen familiären Ressourcen zu einer Verstärkung der Herkunftseffekte auf den Lernzuwachs der Schüler*innen führen. Wie sehr hatten der sozioökonomische Status und die Familiensprache von Schüler*innen einen Effekt auf den Lernzuwachs während des Fernunterrichts? Diese Frage wurde mit einer Stichprobe von 1321 Schüler*innen, 851 Erziehungsberechtigten und 108 Klassenlehrpersonen aus der Nordwestschweiz, die im Juni/Juli 2020 einen Online-Fragebogen ausfüllten, bearbeitet. Ein Pfadmodell mit Berücksichtigung der Mehrebenenstruktur der Daten zeigte vergleichbare Ergebnisse für die Primarstufe und die Sekundarstufe I sowie für Mädchen und Jungen. Der sozioökonomische Status erklärte den Lernzuwachs im Lehrpersonenurteil vermittelt über das Leistungsniveau der Schüler*innen (Lehrpersonenurteil). Die Familiensprache hat einen indirekten Effekt über das Leistungsniveau der Schüler*innen auf den Lernzuwachs. Das Leistungsniveau der Schüler*innen, die Selbstwirksamkeitserwartung der Eltern und die Verfügbarkeit eines ruhigen Lernortes im Schülerurteil erklären, vermittelt über das Lernverhalten im Elternurteil, den Lernzuwachs der Schüler*innen. Das Modell liefert eine Erklärung zu Bildungsungleichheit während des Fernunterrichts. Allerdings sind in den vorliegenden Daten die Effekte des sozioökonomischen Status und der Fremdsprachigkeit auf den Lernzuwachs nicht stärker als in vergleichbaren Studien zur Situation vor der Pandemie. Die wenigen Wochen Fernunterricht haben daher möglicherweise weniger zu einer Verstärkung der Bildungsungleichheit beigetragen als befürchtet.

We report the discovery and analysis of a planet in the microlensing event OGLE-2018-BLG-0799. The planetary signal was observed by several ground-based telescopes, and the planet-host mass ratio is q = (2.65 ± 0.16) × 10−3. The ground-based observations yield a constraint on the angular Einstein radius θE, and the microlensing parallax vector $\boldsymbol{{\pi} }_{\rm E}$, is strongly constrained by the Spitzer data. However, the 2019 Spitzer baseline data reveal systematics in the Spitzer photometry, so there is ambiguity in the magnitude of the parallax. In our preferred interpretation, a full Bayesian analysis using a Galactic model indicates that the planetary system is composed of an $M_{\rm planet} = 0.26_{-0.11}^{+0.22}M_{\rm J}$ planet orbiting an $M_{\rm host} = 0.093_{-0.038}^{+0.082}~\mathrm{M}_{\odot }$, at a distance of $D_{\rm L} = 3.71_{-1.70}^{+3.24}$ kpc. An alternate interpretation of the data shifts the localization of the minima along the arc-shaped microlens parallax constraints. This, in turn, yields a more massive host with median mass of $0.13 {\, \mathrm{M}_{\odot }}$ at a distance of 6.3 kpc. This analysis demonstrates the robustness of the osculating circles formalism, but shows that further investigation is needed to assess how systematics affect the specific localization of the microlens parallax vector and, consequently, the inferred physical parameters.

Cardiometabolic disorders are associated with a substantial loss in quality of life and pose a large burden on healthcare systems worldwide. Overactivation of the sympathetic nervous system has been shown to be a key player in several aspects relating to cardiometabolic disturbances. While diet- and exercise-induced approaches to help reduce weight remains the main strategy to combat metabolic disorders, this is often difficult to achieve. Current pharmacological approaches result in variable responses in different patient cohorts and long-term efficacy may be limited by medication side effects and non-adherence in the long term. There is a clear clinical need for complementary therapies to curb the burden of cardiometabolic disease. One such approach may include interventional sympathetic neuromodulation of organs relevant to cardiometabolic control. Data from sham-controlled clinical trials demonstrate the feasibility, safety and efficacy of catheter-based renal denervation. In analogy, denervation of the common hepatic artery is now feasible in humans and may prove to be similarly useful in modulating sympathetic overdrive directed towards the liver, pancreas and duodenum. Such a targeted multi-organ neuromodulation strategy may beneficially influence multiple aspects of the cardiometabolic disease continuum including blood pressure, glucose and lipid control.

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There is a critical need for efficacious therapeutic strategies to improve the outcome of patients afflicted by malignant peripheral nerve sheath tumors (MPNST). Multiple lines of evidence suggest a role for deregulated phosphoinositide 3-kinase (PI3K)/mTOR signaling in MPNST, making this axis an attractive target for therapeutic manipulation. On the basis of previous observations obtained from in vitro experimentation, here we aimed to assess the effects of PI3K/mTOR blockade on MPNST growth in vivo. The anti-MPNST impact of XL765, a dual PI3K/mTOR inhibitor currently being evaluated in human cancer clinical trials, was tested in two human MPNST xenograft models (STS26T and MPNST724) and an experimental model of pulmonary metastasis (STS26T). XL765 abrogated human MPNST local and metastatic growth in severe combined immunodeficient mice. Notably, this therapeutic approach failed to induce apoptosis in MPNST cells but rather resulted in marked productive autophagy. Importantly, genetic and pharmacologic autophagy blockade reversed apoptotic resistance and resulted in significant PI3K/mTOR inhibition-induced MPNST cell death. The addition of the autophagy inhibitor, chloroquine, to the therapeutic regimen of MPNST xenografts after pretreatment with XL765 resulted in superior antitumor effects as compared with either agent alone. Together, preclinical studies described here expand our previous findings and suggest that PI3K/mTOR inhibition alone and (most importantly) in combination with autophagy blockade may comprise a novel and efficacious therapy for patients harboring MPNST. Mol Cancer Ther; 11(8); 1758–69. ©2012 AACR.

Purpose: MET signaling has been suggested a potential role in malignant peripheral nerve sheath tumors (MPNST). Here, MET function and blockade were preclinically assessed.Experimental Design: Expression levels of MET, its ligand hepatocyte growth factor (HGF), and phosphorylated MET (pMET) were examined in a clinically annotated MPNST tissue microarray (TMA) incorporating univariable and multivariable statistical analyses. Human MPNST cells were studied in vitro and in vivo; Western blot (WB) and ELISA were used to evaluate MET and HGF expression, activation, and downstream signaling. Cell culture assays tested the impact of HGF-induced MET activation and anti-MET–specific siRNA inhibition on cell proliferation, migration, and invasion; in vivo gel-foam assays were used to evaluate angiogenesis. Cells stably transduced with anti-MET short hairpin RNA (shRNA) constructs were tested for growth and metastasis in severe combined immunodeficient (SCID) mice. The effect of the tyrosine kinase inhibitor XL184 (Exelixis) targeting MET/VEGFR2 (vascular endothelial growth factor receptor 2) on local and metastatic MPNST growth was examined in vivo.Results: All three markers were expressed in MPNST human samples; pMET expression was an independent prognosticator of poor patient outcome. Human MPNST cell lines expressed MET, HGF, and pMET. MET activation increased MPNST cell motility, invasion, angiogenesis, and induced matrix metalloproteinase-2 (MMP2) and VEGF expression; MET knockdown had inverse effects in vitro and markedly decreased local and metastatic growth in vivo. XL184 abrogated human MPNST xenograft growth and metastasis in SCID mice.Conclusions: Informative prognosticators and novel therapies are crucially needed to improve MPNST management and outcomes. We show an important role for MET in MPNST, supporting continued investigation of novel anti-MET therapies in this clinical context. Clin Cancer Res; 17(12); 3943–55. ©2011 AACR.

PDF file - 235K, Survivin knockdown does not impact the expression of other IAP proteins. Fig S2: Survivin KD and YM155 induce apoptosis in MPNST cells.

Purpose: To examine the role of survivin as a therapeutic target in preclinical models of human malignant peripheral nerve sheath tumors (MPNST)Experimental Design: Survivin protein expression levels and subcellular localization were examined immunohistochemically in an MPNST tissue microarray. Human MPNST cells were studied in vitro and in vivo; real-time PCR, Western blotting, and immunocytochemical analyses were used to evaluate survivin expression and localization activation. Cell culture assays were used to evaluate the impact of anti-survivin–specific siRNA inhibition on cell growth and cell-cycle progression and survival. The effect of the small-molecule survivin inhibitor YM155 on local and metastatic MPNST growth was examined in vivo.Results: Survivin was found to be highly expressed in human MPNSTs; enhanced cytoplasmic subcellular localization differentiated MPNSTs from their plexiform neurofibroma premalignant counterparts. Human MPNST cell lines exhibited survivin mRNA and protein overexpression; expression in both nuclear and cytoplasmic compartments was noted. Survivin knockdown abrogated MPNST cell growth, inducing G2 cell-cycle arrest and marked apoptosis. YM155 inhibited human MPNST xenograft growth and metastasis in severe combined immunodeficient (SCID) mice. Antitumor effects were more pronounced in fast-growing xenografts.Conclusions: Our studies show an important role for survivin in human MPNST biology. Patients with MPNSTs should be considered for ongoing or future clinical trials that evaluate anti-survivin therapeutic strategies. Most importantly, future investigations should evaluate additional pathways that can be targeted in combination with survivin for maximal synergistic anti-MPNST effects. Clin Cancer Res; 18(9); 2545–57. ©2012 AACR.

Supplementary Methods, Table 1, Figures 1-4 from Activated MET Is a Molecular Prognosticator and Potential Therapeutic Target for Malignant Peripheral Nerve Sheath Tumors

Supplementary Tables 1-2 from VHL Gene Mutations and Their Effects on Hypoxia Inducible Factor HIFα: Identification of Potential Driver and Passenger Mutations

In soft devices, complex actuation sequences and precise force control typically require hard electronic valves and microcontrollers. Existing designs for entirely soft pneumatic control systems are capable of either digital or analog operation, but not both, and are limited by speed of actuation, range of pressure, time required for fabrication, or loss of power through pull-down resistors. Using the nonlinear mechanics intrinsic to structures composed of soft materials—in this case, by leveraging membrane inversion and tube kinking—two modular soft components are developed: a piston actuator and a bistable pneumatic switch. These two components combine to create valves capable of analog pressure regulation, simplified digital logic, controlled oscillation, nonvolatile memory storage, linear actuation, and interfacing with human users in both digital and analog formats. Three demonstrations showcase the capabilities of systems constructed from these valves: 1) a wearable glove capable of analog control of a soft artificial robotic hand based on input from a human user’s fingers, 2) a human-controlled cushion matrix designed for use in medical care, and 3) an untethered robot which travels a distance dynamically programmed at the time of operation to retrieve an object. This work illustrates pathways for complementary digital and analog control of soft robots using a unified valve design.

ZusammenfassungEmotionsregulation und kooperatives Verhalten in belastenden Situationen spielen eine zentrale Rolle bei der Erklärung von proaktiver und reaktiver Aggression der Kinder. Wie sehr erklären die Emotionsregulation und das kooperative Verhalten den Effekt von Belastungen der Eltern bzw. Lehrpersonen auf die reaktive und proaktive Aggression der Kinder? Ausgewertet wurden querschnittliche Fragebogendaten von Eltern und Lehrpersonen, die N = 158 Kinder mit Verhaltensauffälligkeiten in Kindergarten und Primarstufe einschätzten. Strukturgleichungsmodelle zeigen, dass die Belastung der Eltern bzw. Lehrpersonen mit der Emotionsregulation und dem kooperativen Verhalten indirekt mit der reaktiven und proaktiven Aggression zusammenhängt. Die Ergebnisse verdeutlichen die Bedeutsamkeit einer frühzeitigen Förderung der Emotionsregulation und des kooperativen Verhaltens.

OBJECTIVEWe analyzed whether any change in capillary density in the retinal circulation could be detected in patients with hypertension in the prediabetic stage.RESEARCH DESIGN AND METHODSIn a cross-sectional analysis, we assessed capillary density in the foveal (CDF) and parafoveal retinal areas using optical coherence tomography-angiography in 62 patients with hypertension and normal glucose metabolism and 40 patients with hypertension and prediabetes.RESULTSThe CDF was lower in patients with prediabetes than in those with normal glucose metabolism. Moreover, we found a correlation between CDF and HbA1c and glucose levels for the entire cohort. In patients with HbA1c CONCLUSIONSPatients with hypertension and prediabetes display retinal capillary changes, and an association with markers of glucose metabolism exists, even within a nondiabetic HbA1c range.

Developing new strategies for designing effective vaccines has become a priority for parasitologists worldwide. There is high interest in designing a vaccine against malaria since it is considered one of the most prevalent infectious diseases in the tropics. We evaluated the effects of X-rays irradiation on the erythrocytic stage of Plasmodium berghei ANKA merozoites and schizonts using doses of ionizing radiation ranging between 10 and 300 Gy on parasitized red blood cells (PRBC) to study the attenuating effects of radiation on the merozoites. Parasitic activity diminution was observed starting at 50 Gy, and the dose for complete attenuation was established at 200 Gy, corresponding with a 100% survival rate of mice. In vivo invasion experiments and immunofluorescence assays (IFA) showed inhibition of merozoite invasion of the host red blood cells (RBC). Nonetheless, immunization with irradiated parasitized red blood cells (IPRBC) was ineffective in protective assays. We perform cytoadherence and inhibition of cytoadhesion assays on irradiated merozoites. The results showed that high irradiation doses caused an unspecific cellular adhesion phenomenon independent of the ICAM-1 and CD36 interaction, which was determined by Cytoadhesion assays. Our results show that, even though X-ray irradiation is an effective method to induce complete parasite attenuation, it might affect the parasite's membrane surface structures triggering unspecific adhesion.

Objective Blood pressure (BP) management is a vital aspect of stroke prevention and post-stroke care. Different surgical carotid endarterectomy (CEA) techniques may impact on BP control post-operatively. Specifically, the carotid sinus nerve, which innervates the carotid baroreceptors and carotid body, is commonly left intact during conventional CEA but is routinely transected as part of eversion CEA. The aim of this study was to assess long term BP control after eversion and conventional CEA. Methods Patients from the International Carotid Stenting Study (ICSS cohort) and a personal series of patients from the Stroke Clinical Trials Unit at University College London (UCL cohort) were separately analysed and divided into eversion and conventional CEA groups. Mixed effect linear models were fitted and adjusted for baseline demographic data and antihypertensive treatment to test for changes in BP from baseline over a three year follow up period after the respective procedures. Results There were no differences in changes in baseline BP readings and follow up readings between eversion and conventional CEA in the ICSS or UCL cohorts. In the ICSS cohort a mild but significant systolic (–8.6 mmHg; 95% confidence interval [CI] –10.6 – –6.6) and diastolic (–4.9 mmHg; 95% CI –6.0 – –3.8) BP lowering effect was evident at discharge in the conventional group but not in the eversion CEA group. BP monitoring during follow up did not reveal any consistent BP changes with either conventional or eversion CEA vs. baseline levels. Conclusion Neither conventional nor eversion CEA seem to result in clinically significant long term BP changes. Potential concerns related to either short or long term alterations in BP levels with transection of the carotid sinus nerve during eversion CEA could not be substantiated.

Majority of patients with hypertension and chronic kidney disease (CKD) undergoing renal denervation (RDN) are maintained on antihypertensive medication. However, RDN may impair compensatory responses to hypotension induced by blood loss. Therefore, continuation of antihypertensive medications in denervated patients may exacerbate hypotensive episodes. This study examined whether antihypertensive medication compromised hemodynamic responses to blood loss in normotensive (control) sheep and in sheep with hypertensive CKD at 30 months after RDN (control-RDN, CKD-RDN) or sham (control-intact, CKD-intact) procedure. CKD-RDN sheep had lower basal blood pressure (BP; ≈9 mm Hg) and higher basal renal blood flow (≈38%) than CKD-intact. Candesartan lowered BP and increased renal blood flow in all groups. 10% loss of blood volume alone caused a modest fall in BP (≈6–8 mm Hg) in all groups but did not affect the recovery of BP. 10% loss of blood volume in the presence of candesartan prolonged the time at trough BP by 9 minutes and attenuated the fall in renal blood flow in the CKD-RDN group compared with CKD-intact. Candesartan in combination with RDN prolonged trough BP and attenuated renal hemodynamic responses to blood loss. To minimize the risk of hypotension-mediated organ damage, patients with RDN maintained on antihypertensive medications may require closer monitoring when undergoing surgery or experiencing traumatic blood loss.

The gap fraction (GF) of vegetative canopies is an important property related to the contained bulk of reproductive elements and woody facets within the tree crown volume. This work was developed from the perspectives of porous media theory and computer graphics techniques, considering the vegetative elements in the canopy as a solid matrix and treating the gaps between them as pores to guide volume-based GFvol calculations. Woody components and individual leaves were extracted from terrestrial laser scanning data. The concept of equivalent leaf thickness describing the degrees of leaf curling and drooping was proposed to construct hexagonal prisms properly enclosing the scanned points of each leaf, and cylinder models were adopted to fit each branch segment, enabling the calculation of the equivalent leaf and branch volumes within the crown. Finally, the volume-based GFvol of the tree crown following the definition of the void fraction in porous media theory was calculated as one minus the ratio of the total plant leaf and branch volume to the canopy volume. This approach was tested on five tree species and a forest plot with variable canopy architecture, yielding an estimated maximum volume-based GFvol of 0.985 for a small crepe myrtle and a minimal volume-based GFvol of 0.953 for a sakura tree. The 3D morphology of each compositional element in the tree canopy was geometrically defined and the canopy was considered a porous structure to conduct GFvol calculations based on multidisciplinary theory.

There is increasing evidence that renal denervation is effective in alleviating hypertension associated with elevation of renal sympathetic nerve activity (RSNA) in chronic kidney disease (CKD), but whether this is due to reduction in renal afferent signaling is unclear. We determined the cardiovascular and sympathetic effects of total renal denervation or afferent renal denervation (topical capsaicin) on CKD induced by glomerular layer lesioning of the left kidney and right nephrectomy in conscious rabbits. CKD increased blood pressure by 18±2 mmHg and plasma creatinine by 40% over 2 to 4 weeks (both P P =0.04). After total or afferent renal denervation blood pressure, RSNA and norepinephrine spillover were similar or lower than non-CKD (sham) rabbits. While plasma creatinine in CKD rabbits was not affected by total renal denervation, deafferented rabbits had lower levels ( P =0.017). The greater hypotensive response to pentolinium in CKD was also normalized after total or afferent denervation. Heart rate and RSNA baroreflex gain were similar in all groups. The RSNA response to airjet stress was greater in CKD compared with sham but not after total or afferent renal denervation. By contrast, the sympathetic response to hypoxia was similar in sham and CKD intact or deafferented groups but elevated in total denervated CKD animals. We conclude that the elevated sympathetic activity and blood pressure in this model of CKD is predominantly driven by renal afferents.

Treatment inertia is a recognised barrier to blood pressure control, and simpler, more effective treatment strategies are needed. We hypothesised that a hypertension management strategy starting with a single pill containing ultra-low-dose quadruple combination therapy would be more effective than a strategy of starting with monotherapy.QUARTET was a multicentre, double-blind, parallel-group, randomised, phase 3 trial among Australian adults (≥18 years) with hypertension, who were untreated or receiving monotherapy. Participants were randomly assigned to either treatment, that started with the quadpill (containing irbesartan at 37·5 mg, amlodipine at 1·25 mg, indapamide at 0·625 mg, and bisoprolol at 2·5 mg) or an indistinguishable monotherapy control (irbesartan 150 mg). If blood pressure was not at target, additional medications could be added in both groups, starting with amlodipine at 5 mg. Participants were randomly assigned using an online central randomisation service. There was a 1:1 allocation, stratified by site. Allocation was masked to all participants and study team members (including investigators and those assessing outcomes) except the manufacturer of the investigational product and one unmasked statistician. The primary outcome was difference in unattended office systolic blood pressure at 12 weeks. Secondary outcomes included blood pressure control (standard office blood pressure140/90 mm Hg), safety, and tolerability. A subgroup continued randomly assigned allocation to 12 months to assess long-term effects. Analyses were per intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12616001144404, and is now complete.From June 8, 2017, to Aug 31, 2020, 591 participants were recruited, with 743 assessed for eligibility, 152 ineligible or declined, 300 participants randomly assigned to intervention of initial quadpill treatment, and 291 to control of initial standard dose monotherapy treatment. The mean age of the 591 participants was 59 years (SD 12); 356 (60%) were male and 235 (40%) were female; 483 (82%) were White, 70 (12%) were Asian, and 38 (6%) reported as other ethnicity; and baseline mean unattended office blood pressure was 141 mm Hg (SD 13)/85 mm Hg (SD 10). By 12 weeks, 44 (15%) of 300 participants had additional blood pressure medications in the intervention group compared with 115 (40%) of 291 participants in the control group. Systolic blood pressure was lower by 6·9 mm Hg (95% CI 4·9-8·9; p0·0001) and blood pressure control rates were higher in the intervention group (76%) versus control group (58%; relative risk [RR] 1·30, 95% CI 1·15-1·47; p0·0001). There was no difference in adverse event-related treatment withdrawals at 12 weeks (intervention 4·0% vs control 2·4%; p=0·27). Among the 417 patients who continued, uptitration occurred more frequently among control participants than intervention participants (p0·0001). However, at 52 weeks mean unattended systolic blood pressure remained lower by 7·7 mm Hg (95% CI 5·2-10·3) and blood pressure control rates higher in the intervention group (81%) versus control group (62%; RR 1·32, 95% CI 1·16-1·50). In all randomly assigned participants up to 12 weeks, there were seven (3%) serious adverse events in the intervention group and three (1%) serious adverse events in the control group.A strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting monotherapy. This trial demonstrated the efficacy, tolerability, and simplicity of a quadpill-based strategy.National Health and Medical Research Council, Australia.

A growing number of clinical studies suggest that in heart failure renal denervation (RDN) has beneficial effects on the autonomic control of the heart. There is also experimental evidence that surgical RDN improves sodium handling and clearance in heart failure. The aim of this study was to determine the effects of catheter-based RDN on the sympathetic and parasympathetic control of the heart, and salt and water handling capacity of the kidneys, in sheep with established heart failure. A randomized, controlled study was conducted in 10 sheep with heart failure (ejection fraction

Arterial hypertension is a leading cause of death globally. Due to ageing, the rising incidence of obesity, and socioeconomic and environmental changes, its incidence increases worldwide. Hypertension commonly coexists with Type 2 diabetes, obesity, dyslipidaemia, sedentary lifestyle, and smoking leading to risk amplification. Blood pressure lowering by lifestyle modifications and antihypertensive drugs reduce cardiovascular (CV) morbidity and mortality. Guidelines recommend dual- and triple-combination therapies using renin–angiotensin system blockers, calcium channel blockers, and/or a diuretic. Comorbidities often complicate management. New drugs such as angiotensin receptor-neprilysin inhibitors, sodium–glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists improve CV and renal outcomes. Catheter-based renal denervation could offer an alternative treatment option in comorbid hypertension associated with increased sympathetic nerve activity. This review summarises the latest clinical evidence for managing hypertension with CV comorbidities.

Primary aldosteronism (PA) represents the most common and potentially curable cause of secondary hypertension. However, PA is not commonly screened for, and up to 34% of patients who screen positive do not complete the full diagnostic process. This suggests that the diagnostic process may pose a barrier to patients and may contribute to the under-diagnosis of PA.To evaluate the willingness of the Australian general public to undergo testing for secondary causes of hypertension and identify enablers or barriers to testing from the patients' perspective.An online survey containing questions on knowledge and attitudes towards hypertension, willingness to be tested and enablers/barriers towards testing was distributed to the Australian community.Of 520 adult respondents (mean age 50.4 years, SD 27.3 years; 28.8% hypertensive; 56.0% female), the majority of non-hypertensive and hypertensive respondents (82.7% vs 70.0%; P = 0.03) were willing to undergo testing for a secondary cause of hypertension that involved blood and urine tests. Greater knowledge of hypertensive risk modification strategies and complications was predictive of willingness to be tested, whereas age, sex, education level, geographic location, socio-economic status and cardiovascular comorbidities were not. The top three barriers to testing included fear of a serious underlying condition, lack of belief in further testing and increased stress associated with further testing.A high proportion of patients are willing to engage in testing for a secondary cause of hypertension. Education about the risks associated with hypertension and the testing process may overcome several barriers to testing.

BackgroundAlthough a healthy diet and physical activity have been shown to prevent or delay cardiovascular disease (CVD) hospitalizations and deaths, most adults do not meet current guidelines. Provision of coronary artery calcification (CAC) and carotid ultrasound (CUS) imaging results may motivate beneficial lifestyle changes. We scoped the existing literature for studies providing non-invasive vascular imaging results and reporting diet, physical activity, and/or anthropometric measures to identify knowledge gaps and opportunities for further research.MethodsA systematic search was performed across three electronic databases, in line with PRISMA ScR guidelines and Arksey and O'Malley's scoping review framework.ResultsTwenty studies (thirteen observational and seven randomized controlled trials) examining the impact of provision of CAC/CUS imaging results on diet and/or physical activity behaviors were included. Nearly half the studies did not clearly state whether participants received dietary and physical activity advice along with vascular imaging results, and these were secondary outcomes in most studies, with data assessment and reporting being inconsistent.ConclusionWell-designed clinical trials with consistent and clear messaging based on detailed subjective and objective measures of diet and physical activity are needed to determine whether this approach may stimulate long-term dietary and physical activity change.