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Background: Clinical practice guidelines for patients with chronic kidney disease (CKD) recommend regular monitoring and management of kidney function and CKD risk factors. However, the majority of patients with stage 3 CKD lack a diagnosis code, and data on the implementation of these recommendations in the real world are limited., Aim: To assess the implementation of guideline-directed monitoring and management practices in the real world in patients with stage 3 CKD without a recorded diagnosis code., Methods: REVEAL-CKD (NCT04847531) is a multinational, observational study of patients with stage 3 CKD. Eligible patients had ≥2 consecutive estimated glomerular filtration rate (eGFR) measurements indicative of stage 3 CKD recorded >90 and ≤730 days apart, lacked an International Classification of Diseases 9/10 diagnosis code corresponding to CKD any time before and up to 6 months after the second eGFR measurement. Testing of key measures of care quality were assessed., Results: The study included 435,971 patients from 9 countries. In all countries, the prevalence of urinary albumin-creatinine ratio and albuminuria testing was low. Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker and statin prescriptions were highly variable, and sodium-glucose cotransporter-2 inhibitor prescriptions remained below 21%. Blood pressure measurements were recorded in 20.2%-89.9% of patients., Conclusions: Overall, a large proportion of patients with evidence of stage 3 CKD did not receive recommended, guideline-directed monitoring and management. The variability in standard of care among countries demonstrates a clear opportunity to improve monitoring and management of these patients, most likely improving long-term outcomes., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Cardiovascular diseases (CVD) continue to be the leading cause of deaths and disability worldwide and the major contributor is hypertension. Despite all the improvements in detecting hypertension together with technological advances and affordable, efficacious and relatively free of adverse effects anti-hypertensive agents, we continue to struggle to prevent the onset of hypertension and to control blood pressure (BP) to acceptable targets. The poor control of hypertension is commonly due to non-adherence to medications. Another reason is the failure to adopt diet and lifestyle changes. Reduction of dietary salt intake is important for lowering BP but the role of potassium intake is also important. Globally the intake of sodium is double that of the recommended 2 gm per day (equivalent to 5 gm of sodium chloride/salt) and half that of the daily recommended intake of potassium of 3500 mg/day, giving a sodium-to-potassium ratio of >1, when ideally it should be <1. Many studies have shown that a higher potassium intake is associated with lower BPs, particularly when coupled concurrently with a lower sodium intake giving a lower sodium to potassium ratio. Most hypertension guidelines, while recommending reduction of salt intake to a set target, do not specifically recommend a target for potassium intake nor potassium supplementation. Here we review the role of potassium and salt substitution with potassium in the management of hypertension. Hence, the focus of dietary changes to lower BP and improve BP control should not be on reduction of salt intake alone but more importantly should include an increase in potassium intake., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Community-based health check kiosks provide opportunities to improve the detection and long-term monitoring of hypertension. We describe the sociodemographic and cardiovascular characteristics of first-time and repeat users of these kiosks., Method: This was an observational study. Deidentified data collected from 430 SiSU Health consumer-facing health check stations in pharmacies across Australia between January 2018 and November 2020 were analyzed. Using a logistic regression, we identified factors associated with repeat checks in the overall cohort and in those with possible hypertension presented as adjusted odds ratios (aOR) and 95% CIs., Results: A total of 982 122 unique checks were conducted; 54% (n=530 139) of the health check users were female, and the average age of all users was 38.2 (SD, 16.0) years. Notably, 13% used the kiosks more than once. Overall, 22% met the definition of possible hypertension, 16% (n=136 345) had blood pressure (BP) ≥140/90 mm Hg, 4% (n=34 349) had BP >160/100 mm Hg, and 13% (121 282) reported taking BP medicines. In the adjusted analysis, first-time users who were aged 50 to 69 years (aOR, 0.91 [95% CI, 0.87-0.96]) or ≥70 years (aOR, 0.68 [95% CI, 0.62-0.74]) were less likely than young users (18-29 years) to return for a second health check. Those in very remote areas were 61% (aOR, 0.39 [95% CI, 0.19-0.72]), and smokers were 13% less likely to return (aOR, 0.87 [95% CI, 0.83-0.91]). People taking BP medications were more likely to return (aOR, 1.16 [95% CI, 1.09-1.22])., Conclusions: Community-based health checks may identify people with high BP and could provide an option for self-monitoring. Broader implementation is needed to increase the reach in rural areas and among the elderly population.

Background: Single-pill combinations (SPCs) of three low-dose antihypertensive drugs can improve hypertension control but are not widely available. A key issue for any combination product is the contribution of each component to efficacy and tolerability. This trial compared a new triple SPC called GMRx2, containing telmisartan, amlodipine, and indapamide, with dual combinations of components for efficacy and safety., Methods: In this international, randomised, double-blind, active-controlled trial, we enrolled adults with hypertension receiving between zero and three antihypertensive drugs, with a screening systolic blood pressure (SBP) ranging from 140-179 mm Hg (on no drugs) to 110-150 mm Hg (on three drugs). Participants were recruited from Australia, the Czech Republic, New Zealand, Poland, Sri Lanka, the UK, and the USA. In a 4-week active run-in, existing medications were switched to GMRx2 half dose (telmisartan 20 mg, amlodipine 2·5 mg, and indapamide 1·25 mg). Participants were then randomly allocated (2:1:1:1) to continued GMRx2 half dose or to each possible dual combination of components at half doses (telmisartan 20 mg with amlodipine 2·5 mg, telmisartan 20 mg with indapamide 1·25 mg, or amlodipine 2·5 mg with indapamide 1·25 mg). At week 6, doses were doubled in all groups, unless there was a clinical contraindication. The primary efficacy outcome was mean change in home SBP from baseline to week 12, and the primary safety outcome was withdrawal of treatment due to an adverse event from baseline to week 12. Secondary efficacy outcomes included differences in clinic and home blood pressure levels and control rates. This study is registered with ClinicalTrials.gov, NCT04518293, and is completed., Findings: The trial was conducted between July 9, 2021 and Sept 1, 2023. We randomly allocated 1385 participants to four groups: 551 to GMRx2, 276 to telmisartan-indapamide, 282 to telmisartan-amlodipine, and 276 to amlodipine-indapamide groups. The mean age was 59 years (SD 11), 712 (51%) participants self-reported as female and 673 (48·6%) male, and the mean clinic blood pressure at the screening visit was 142/85 mm Hg when taking an average of 1·6 blood pressure medications. Following the run-in on GMRx2 half dose, the mean clinic blood pressure level at randomisation was 133/81 mm Hg and the mean home blood pressure level was 129/78 mm Hg. At week 12, the mean home SBP was 126 mm Hg in the GMRx2 group, which was lower than for each of the dual combinations: -2·5 (95% CI -3·7 to -1·3, p<0·0001) versus telmisartan-indapamide, -5·4 (-6·8 to -4·1, p<0·0001) versus telmisartan-amlodipine, and -4·4 (-5·8 to -3·1, p<0·0001) versus amlodipine-indapamide. For the same comparisons, differences in clinic blood pressure at week 12 were 4·3/3·5 mm Hg, 5·6/3·7 mm Hg, and 6·3/4·5 mm Hg (all p<0·001). Clinic blood pressure control rate below 140/90 mm Hg at week 12 was superior with GMRx2 (74%) to with each dual combination (range 53-61%). Withdrawal of treatment due to adverse events occurred in 11 (2%) participants in the GMRx2 group, four (1%) in telmisartan-indapamide, three (1%) in telmisartan-amlodipine, and four (1%) in amlodipine-indapamide, with none of the differences being statistically significant., Interpretation: A novel low-dose SPC product of telmisartan, amlodipine, and indapamide provided clinically meaningful improvements in blood pressure reduction compared with dual combinations and was well tolerated. This SPC provides a new therapeutic option for the management of hypertension and its use could result in a substantial improvement in blood pressure control in clinical practice., Funding: George Medicines., Competing Interests: Declaration of interests AR, AS, AES, CG, MS, XL, and NW are employed at The George Institute for Global Health (TGI), which holds an interest in George Medicines via its social enterprise arm, George Institute Ventures. None of the TGI staff has a personal financial interest in George Medicines. AR is seconded part-time to George Medicines. TGI holds patents for ultra-low-dose, fixed-dose combination products for the treatment of hypertension and diabetes, and AR is listed as one of the inventors (granted: US 10 369 156, US 10 799 487, US 10 322 117, US 11 033 544, US 11 478 462; pending: US 17/932 982, US 18/446 268, US 17/598 122, US 17/317 614, US 17/527 084, US 17/527 085, US 17/527 087). AR does not have a financial interest in these patents. None of the other authors has a financial interest in George Medicines or has received funding for their independent contribution to the GMRx2 programme. AR reports consulting fees as a data and safety monitoring board member for Idorsia; and a fellowship grant from the National Health and Medical Research Council of Australia (GNT 1160743). AES reports consulting fees or speaker honoraria from OMRON Healthcare, Aktiia, Medtronic, Servier, Abbott, Sanofi, Sun Pharmaceuticals, Novartis, and Skylabs; being co-chair of the National Hypertension Taskforce Australia; being a board member for Hypertension Australia and the Australian Cardiovascular Alliance; and an investigator grant from the National Health and Medical Research Council of Australia (GNT 2017504). DBO reports speaker honoraria from Novartis, AstraZeneca, Servier, Swipha, and Boehringer Ingelheim for speaking at educational meetings. KN reports speaker and consulting honoraria from Bausch Health, Berlin-Chemie/Menarini, Egis, Idorsia, Janssen, Gedeon Richter, Gilead, Krka, Novo Nordisk, Polpharma, Recordati, Sandoz, and Servier; and honoraria from or participation on advisory boards for Polpharma and Zentiva. MPS reports consulting fees or travel and research support from Medtronic, Abbott, Recor, Novartis, Servier, Pfizer, and Boehringer Ingelheim; and being current President of Hypertension Australia and Treasurer of the World Hypertension League. WCC reports institutional grants from Recor and George Medicines; and consulting fees from Alnylam Pharmaceuticals. NRP reports consultancy fees from Servier and Aktiia; support for research projects and staff from Servier and Pfizer; support for arranging and speaking at educational meetings from AstraZeneca, LRI-Therapharma, Napi, Servier, Sanofi, EVA Pharma, Pfizer, Emcure, Dr Reddy's Laboratories, and Zydus; and support by the National Institute for Health Research Senior Investigator Awards, Biomedical Research Centre funding, and the British Heart Foundation Research Centre Excellence Award. DEG reports funding to his department as part of the EU Horizon Hypermarker project. BW reports trial steering committee appointments for Novartis and AstraZeneca; lecture fees for Servier and Novartis; and an unremunerated role as President of the International Society of Hypertension. JTW reports institutional grants from the National Institutes of Health, the Ohio Department of Medicaid, and the Agency for Healthcare Research and Quality; travel support and participation on an advisory board for Medtronic; being chair of the data safety monitoring board for the IMPACTS MIND Trial at Tulane University; and being on the Northeast Ohio Neighbourhood Health Center Community Board of Directors. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Provision of non-invasive vascular imaging results to individuals has been shown to improve cardiovascular disease risk factor control: its impact on diet remains uncertain. In this two-arm, single-blind, parallel, 12-week randomized controlled trial, 240 participants, 57.5% females aged 60-80 y had abdominal aortic calcification and clinical assessments performed at a hospital clinic. Participants were randomized 1:1 to receive (intervention n = 121) or not (control n = 119) their calcification results. Both groups received educational resources on cardiovascular disease risk control and were unblinded to the intervention. Outcome measures were performed at baseline and 12 weeks. The primary outcomes of the study were changes in fruit and vegetable intake measures over 12 weeks assessed using plasma carotenoid concentrations (biomarkers of FV intake) and a food frequency questionnaire. Secondary outcomes included 12-week changes in other aspects of the diet, physical activity, body weight, blood pressure, heart rate, lipid profile, glucose concentrations, estimated cardiovascular disease risk score, and medication use. Between-group differences were tested using linear mixed-effects regression. There were no between-group differences in the primary outcomes at 12 weeks: plasma carotenoids (mean difference +0.03 µg/mL [95%CI -0.06, 0.13]) and fruit and vegetable intakes (+18 g/d [-37, 72]). However, the provision of calcification results led to between-group differences in serum total (-0.22 mmol/L [-0.41, -0.04]) and non-HDL (-0.19 mmol/L [-0.35, -0.03]) cholesterol, and estimated cardiovascular disease risk score (-0.24% [-0.47, -0.02]). No between-group differences were seen for other secondary outcomes. In this work, providing vascular imaging results did not improve diet but did improve some cardiovascular disease risk factors (Australian and New Zealand Clinical Trials Registry ACTRN12618001087246)., (© 2024. The Author(s).)

Background: Primary aldosteronism, characterized by renin-independent aldosterone production, is associated with adverse cardiovascular remodeling and outcomes. Elevated cardiovascular risk is observed even in subclinical forms of primary aldosteronism according to studies conducted primarily in middle-aged and elderly populations. This study aimed to assess whether early changes in primary aldosteronism biomarkers during young adulthood are associated with arterial stiffness and left ventricular mass index (LVMI) before the onset of overt disease., Methods: The Raine Study is a longitudinal, population-based cohort study in Western Australia that enrolled women during pregnancy. We analyzed the data from the offspring of these women at 17 (2006-2009) and 27 (2016-2018) years of age. Participants with elevated high-sensitivity C-reactive protein (>10 mg/L) and female participants who were on oral contraception were excluded. Pulse wave velocity and aortic augmentation index were measured by SphygmoCor Pulse Wave System at both ages, and aortic distensibility and LVMI were measured by cardiac magnetic resonance imaging at 27 years. Multivariable linear regression was used to examine the relationship between plasma renin, aldosterone, or aldosterone-to-renin ratio and arterial stiffness and LVMI. Mediation analysis was used to test the role of systolic blood pressure., Results: This study included 859 participants at 17 (38.0% female) and 758 participants at 27 (33.2% female) years of age. Females had lower renin concentration at both 17 (20.7 mU/L versus 25.7 mU/L; P <0.001) and 27 (12.0 mU/L versus 15.4 mU/L; P <0.001) years of age; hence, the aldosterone-to-renin ratio was significantly higher at both 17 (18.2 versus 13.5; P <0.001) and 27 (21.0 versus 15.6; P <0.001) years of age in females compared with males. At 27 years of age, a significant association was detected between aldosterone and LVMI in males (β=0.009 [95% CI, 0.001-0.017]; P =0.027) and between aldosterone-to-renin ratio and LVMI in females (β=0.098 [95% CI, 0.001-0.196]; P =0.050) independently of systolic blood pressure and other confounders. No association was found between primary aldosteronism biomarkers and measures of arterial stiffness (pulse wave velocity, aortic augmentation index, and aortic distensibility) at either age., Conclusions: Aldosterone concentration and aldosterone-to-renin ratio were positively associated with the LVMI in young males and females, respectively, independently of systolic blood pressure. Long-term follow-up is required to determine whether the relationship persists over time, and clinical trials are needed to assess the cardiovascular benefits of early interventions to block aldosterone.

Background: The strong relationship between blood pressure (BP) and age is well known. Limited evidence suggests that a steeper age-BP slope may be associated with an increased risk of adverse outcomes. The May Measurement Month campaign enables an investigation of geographic, socioeconomic, and sex differences in age-related BP gradients and their association with public-health outcomes., Methods: Cross-sectional, annual global BP May Measurement Month screening data were analyzed. Average systolic BP and age-related BP slopes across different age groups were calculated to assess regional, socioeconomic, and sex-stratified variations. The association of BP slopes derived from adjusted linear regression models with country-level health metrics was investigated., Results: Age-related systolic BP gradients differed distinctly across global geographic regions, income levels, and between sexes. The steepest age gradients of BP were observed in populations from Africa and Europe. Women had lower BP levels than men at younger ages (20s and 30s) but subsequently experienced more pronounced age-related BP gradients. Geographically divergent age-related BP gradients were significantly associated with major national public health indicators. Globally, steeper age-related BP slopes were associated with poor BP control, increased disability-adjusted life years, and death rates. A steeper population age-BP slope of 1 mm Hg per 10 years was associated with a decrease in life expectancy of 3.3 years in this population (95% CI, -5.1 to -1.4; P =0.0007)., Conclusions: Age-related BP gradients vary considerably across global populations and are associated with variability in BP-related risks and adverse outcomes across regions. Effective public health strategies may require region-specific targeting of adverse BP gradients to improve health outcomes., Competing Interests: A.E. Schutte has received speaker fees from Omron, Medtronic, Aktiia, Servier, Sanofi, and Novartis and is an advisory board member for Skylabs, Medtronic, and Abbott. M.P. Schlaich has received research support from Medtronic, Abbott, and Servier Australia. He serves on scientific advisory boards for Abbott, Boehringer Ingelheim, Servier, Novartis, and Medtronic and has received travel/speaker honoraria from Abbott, Medtronic, Lilly, and AstraZeneca. G.S. Stergiou has received speaker fees from AstraZeneca, Menarini, Omron, and Servier and consulting fees from Huawei, InBody, Microlife, Sanofi-Aventis, Skylabs, Sonion, and Viatris. The other authors report no conflicts.

Background: Guideline-recommended hyperkalaemia management includes dietary potassium (K + ) restriction, bicarbonate correction, diuretics and K + binders with dose reduction of renin-angiotensin-aldosterone system inhibitors as a last resort. The extent to which these recommendations are implemented is uncertain, as real-world data on hyperkalaemia management are limited. The Tracking Treatment Pathways in Adult Patients with Hyperkalemia (TRACK) study is a multinational, prospective, longitudinal study that is being conducted to address this knowledge gap. We report the design and baseline cohort characteristics of this real-world study of hyperkalaemia management decision-making., Methods: This study enrolled participants within 21 days of an episode of hyperkalaemia in four European countries (UK, Spain, Germany, Italy) and the USA. During the 12-month follow up, data collected will include participant and healthcare provider characteristics (specialty and practice setting), hyperkalaemia treatment objectives and strategies, rationale for management decisions and indicators of response and patient-reported perceptions of their hyperkalaemia treatment., Results: The enrolled cohort includes 1330 participants, mean age 68 years, of whom 31% were women. At baseline, 6% reported heart failure, 55% chronic kidney disease, 29% both and 9% neither. Most participants (57%) were taking an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker or angiotensin receptor/neprilysin inhibitor at baseline. Mineralocorticoid receptor antagonist use was lower (14%)., Conclusions: The prospective TRACK study will shed light on practitioners' hyperkalaemia management decision-making and assess the impact of their decisions on hyperkalaemia recurrence. Understanding practitioners' underlying thought processes will facilitate efforts to improve hyperkalaemia management.ClinicalTrials.gov: NCT05408039., Competing Interests: J.H. and M.P.B. receive salary support from CPC, a non-profit academic research organization affiliated with the University of Colorado, which receives research grant/consulting funding from Agios Pharmaceuticals, Alexion Pharma Good Kaisha, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca Pharma India, AstraZeneca Pharmaceuticals, AstraZeneca UK, AstraZeneca, Produtos Farmaceuticos, Atentiv, Bayer, Bayer (Proprietary) Limited, Bayer Aktiengesellschaft, Bayer Pharma, Beth Israel Deaconess Medical Center, Better Therapeutics, Bionest Partners, Boston Clinical Research Institute, BMS, CellResearch, Cleerly, Colorado Department of Public Health and Environment, Cook Regentec, CSL Behring, Eidos Therapeutics, EPG Communication Holdings, Esperion Therapeutics, Faraday Pharmaceuticals, HeartFlow, Hummingbird Bioscience, Insmed, Ionis Pharmaceuticals, IQVIA, Janssen Pharmaceuticals, Janssen Research & Development, Janssen Scientific Affairs, Lexicon Pharmaceuticals, LSG, MedImmune, Medpace, Medscape, Merck Sharp & Dohme, Northwell Health, Novartis Pharmaceuticals, Novo Nordisk, Osiris Therapeutics, Pfizer, PPD Development, Prothena Biosciences, Regeneron, Regents of the University of Colorado, Sanifit Therapeutics, Sanofi, Silence Therapeutics, Stanford University, Stealth BioTherapeutics, Brigham & Women's Hospital, Thrombosis Research Institute, UCD iC42 Lab, University of Colorado Denver, University of Pittsburgh, VarmX and WraSer. J.H. also reports owning AstraZeneca stock. N.S., M.B., H.C. and A.-K.S. own AstraZeneca stock. A.B. has received consultant fees and grant/other support from Abbott, Association of the British Pharmaceutical Industry, Accentus Medical, Amgen, Amore Health, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Closer Still Media, Daiichi Sankyo, Health Smart, Janssen, Lattice Point, Lilly, Medtronic, McKinsey, MSD, Napp, Novartis, Novo Nordisk, Pfizer, Remedica, Sanofi Aventis and AirEmail. J.Bover received advisory and/or lecture fees and/or congress travel expenses from AbbVie, Amgen, AstraZeneca, Bayer, CSL-Vifor, GSK, Menarini, Rubió, Sanofi and Theramex. J.Butler has received consultant fees from Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, BMS, Cardiac Dimension, Cardiocell, Cardior, CSL Behring, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Levator, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Pulnovo, Regeneron, Renibus, Roche, Salamandra, Salubris, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor and Zoll. P.M.F. has received consultant fees and grant/other support from Allena Pharmaceuticals, Alnylam, Amgen, AstraZeneca, Bayer, Gilead, Novo Nordisk, Otsuka Pharmaceuticals, Rocchetta and Vifor Fresenius and royalties as an author for UpToDate. L.F. serves on data safety monitoring boards for Novo Nordisk and Regeneron and owns Amgen stock. M.P.S. has received advisory board fees and honoraria from AstraZeneca, Bayer, Vifor Pharma Group and Boehringer Ingelheim/Lilly. N.T. has received grants/research support from the Canadian Institutes of Health Research, National Institutes of Health, Kidney Foundation of Canada, Bayer, AstraZeneca, Boehringer Ingelheim, Janssen Pharmaceuticals, Research Manitoba, Otsuka Pharmaceutical, Tricida and Lilly; honoraria or consultation fees from AstraZeneca, Bayer, Boehringer Ingelheim, GSK, Janssen Pharmaceuticals, Otsuka Pharmaceutical, Prokidney, Roche, Tricida and Lilly; and owns stock in ClinPredict, Klinrisk, Quanta, Marizyme, Mesentech, Renibus Therapeutics, PulseData and Tricida. W.C.W. has received consultant fees from Akebia, Anthos, Ardelyx, AstraZeneca, Bayer Boehringer Ingelheim, Cadrenal, GSK, Merck, Natera, Novartis, Pharmacosmos, Unicycive, Vera and Zydus., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

As hyperpolarized (HP) carbon-13 ( 13 C) metabolic imaging is clinically translated, there is a need for easy-to-implement, fast, and robust imaging techniques. However, achieving high temporal resolution without decreasing spatial and/or spectral resolution, whilst maintaining the usability of the imaging sequence is challenging. Therefore, this study looked to accelerate HP 13 C MRI by combining a well-established and robust sequence called two-dimensional Chemical Shift Imaging (2D CSI) with prospective under sampling and SENSitivity Encoding (SENSE) reconstruction. Due to the low natural abundance of 13 C, the sensitivity maps cannot be pre-acquired for the reconstruction. As such, the implementation of sodium ( 23 Na) sensitivity maps for SENSE reconstructed 13 C CSI was demonstrated in a phantom and in vivo in the pig kidney. Results showed that SENSE reconstruction using 23 Na sensitivity maps corrected aliased images with a four-fold acceleration. With high temporal resolution, the kidney spectra produced a detailed metabolic arrival and decay curve, useful for further metabolite kinetic modelling or denoising. Metabolic ratio maps were produced in three pigs demonstrating the technique's ability for repeat metabolic measurements. In cases with unknown metabolite spectra or limited HP MRI specialist knowledge, this robust acceleration method ensures comprehensive capture of metabolic signals, mitigating the risk of missing spectral data., (© 2024. The Author(s).)

Background/objectives: Artificial intelligence can assist with ocular image analysis for screening and diagnosis, but it is not yet capable of autonomous full-spectrum screening. Hypothetically, false-positive results may have unrealized screening potential arising from signals persisting despite training and/or ambiguous signals such as from biomarker overlap or high comorbidity. The study aimed to explore the potential to detect clinically useful incidental ocular biomarkers by screening fundus photographs of hypertensive adults using diabetic deep learning algorithms., Subjects/methods: Patients referred for treatment-resistant hypertension were imaged at a hospital unit in Perth, Australia, between 2016 and 2022. The same 45° colour fundus photograph selected for each of the 433 participants imaged was processed by three deep learning algorithms. Two expert retinal specialists graded all false-positive results for diabetic retinopathy in non-diabetic participants., Results: Of the 29 non-diabetic participants misclassified as positive for diabetic retinopathy, 28 (97%) had clinically useful retinal biomarkers. The models designed to screen for fewer diseases captured more incidental disease. All three algorithms showed a positive correlation between severity of hypertensive retinopathy and misclassified diabetic retinopathy., Conclusions: The results suggest that diabetic deep learning models may be responsive to hypertensive and other clinically useful retinal biomarkers within an at-risk, hypertensive cohort. Observing that models trained for fewer diseases captured more incidental pathology increases confidence in signalling hypotheses aligned with using self-supervised learning to develop autonomous comprehensive screening. Meanwhile, non-referable and false-positive outputs of other deep learning screening models could be explored for immediate clinical use in other populations., (© 2024. The Author(s).)

Hypertension is often linked with metabolic risk factors that share common pathophysiological pathways. Despite wide-spread availability of multiple drug classes, optimal blood pressure (BP) control remains challenging. Increased central sympathetic outflow is frequently neglected as a critical regulator of both circulatory and metabolic pathways and often remains unopposed therapeutically. Selective imidazoline receptor agonists (SIRAs) effectively reduce BP with a favorable side effect profile compared with older centrally acting antihypertensive drugs. Hard outcome data in hypertension, such as prevention of stroke, heart and kidney diseases, are not available with SIRAs. However, in direct comparisons, SIRAs were as effective as angiotensin-converting enzyme inhibitors, β-blockers, calcium channel blockers, and diuretics in lowering BP. Other beneficial effects on metabolic parameters in hypertensive patients with concomitant overweight and obesity have been documented with SIRAs. Here we review the existing evidence on the safety and efficacy of moxonidine, a widely available SIRA, compared with common antihypertensive agents and provide a consensus position statement based on inputs from 12 experts from Europe and Australia on SIRAs in hypertension management., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Single-pill combinations of 3 or more low-dose blood pressure (BP)-lowering drugs hold promise for initial or early treatment of hypertension., Objectives: We conducted a placebo-controlled trial of a new single-pill combination containing low doses of telmisartan, amlodipine, and indapamide in 2 dose options to assess efficacy and safety., Methods: This international, randomized, double-blind, placebo-controlled, parallel-group trial enrolled adults with hypertension receiving 0 to 1 BP-lowering drugs. After a 2-week placebo run-in during which any BP-lowering medication was stopped, participants were eligible if home systolic BP (SBP) was 130 to 154 mm Hg. Participants were randomized in a 2:2:1 ratio to GMRx2 ¼ dose (telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg), GMRx2 ½ dose (telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg), or placebo. The primary efficacy outcome was difference in change in home SBP from randomization to week 4, and primary safety outcome was treatment discontinuation due to an adverse event., Results: From June 14, 2021 to October 18, 2023, a total of 295 participants (mean age: 51 years; 56% female) were randomized and 96% completed the trial. Baseline mean home BP was 139/86 mm Hg and clinic BP was 138/86 mm Hg after placebo run-in. The placebo-corrected least square mean differences in home SBP at Week 4 were -7.3 mm Hg (95% CI: -4.5 to -10.2) for GMRx2 ¼ dose and -8.2 mm Hg (95% CI: -5.2 to -11.3) for GMRx2 ½ dose; reductions for clinic BP were 8.0/4.0 and 9.5/4.9 mm Hg. At Week 4, clinic BP control (<140/90 mm Hg) was 37%, 65%, and 70% for placebo, GMRx2 ¼ dose, and GMRx2 ½ dose, respectively (both doses P < 0.001 vs placebo). Placebo, GMRx2-triple ¼, and GMRx2 ½ treatment discontinuation due to an adverse event occurred in 1 (1.6%), 0, and 6 (5.1%), respectively; out of normal range serum sodium or potassium was observed in 4 (6.3%), 12 (10.6%), and 12 (10.1%), respectively, but no participant had a serum sodium <130/>150 mmol/L or potassium <3.0/>6.0 mmol/L. Serious adverse events were reported by 2 participants in the placebo and GMRx2 ½ groups and none in the GMRx2 ¼ group., Conclusions: In a population with mild-to-moderate BP elevation, both dose versions of the novel low-dose triple single-pill combination showed good tolerability and clinically relevant BP reductions compared with placebo. (Efficacy and Safety of GRMx2 Compared to Placebo for the Treatment of Hypertension: NCT04518306)., Competing Interests: Funding Support and Author Disclosures This trial was funded by George Medicines Pty Ltd (GM). The trial was designed by The Steering Committee, who were responsible for the study protocol. The funder of the study consulted with the U.S. Food and Drug Administration to ensure the trial design was suitable to inform an application for regulatory approval; the funder GM provided comments on a draft of the publication. The Steering Committee had full access to all the data, wrote and had final responsibility for the publication. Prof Rodgers, Dr Salam, Prof Schutte, C. ianacas, M. Shanthakumar, Dr Liu, and Dr Wang are employed at The George Institute for Global Health (TGI), which holds an interest in GM via its social enterprise arm, George Institute Ventures. None of the TGI staff have any personal financial interest in GM. Prof Rodgers is seconded part-time to GM. TGI holds patents for ultra -low-dose fixed-dose combination products for the treatment of hypertension and diabetes, and Prof Rodgers is listed as one of the inventors (granted: U.S. 10,369,156; U.S. 10,799,487; U.S. 10,322,117; U.S. 11,033,544; U.S. 11,478,462; pending: U.S. 17/932,982; U.S. 18/446,268; U.S. 17/ 598,122; U.S. 17/317,614; U.S. 17/527,084; U.S. 17/527,085; U.S. 17/ 527,087). Prof Rodgers does not have a financial interest in these patents. None of the other authors have a financial interest in GM or have received funding for their independent contribution to the GMRx2 program. Dr Schutte has received consulting fees and/or speaker honoraria from Omron Healthcare, Aktiia, Medtronic, Servier, Abbott, Sanofi, Sun Pharmaceuticals, Novartis, and Skylabs; is co-chair of the National Hypertension Taskforce of Australia; is a board member of Hypertension Australia, and Australian Cardiovascular Alliance; and is supported by an investigator grant from the National Health and Medical Research Council of Australia (GNT 2017504). Dr Ojji has received speaker honoraria from Novartis, AstraZeneca, Servier, Swipha, and Boehringer Ingelheim for speaking at educational meetings. Dr Narkiewicz has received speaker and consulting honoraria from Bausch Health, Berlin-Chemie/Menarini, Egis, Gedeon Richter, Gilead, Idorsia, Janssen, Krka, Novo Nordisk, Polpharma, Recordati, Sandoz, Servier, and Zentiva. Dr Schlaich has received consulting fees, and/or travel fees and research support from Medtronic, Abbott, ReCor, Novartis, Servier, Pfizer, and Boehringer Ingelheim; and is the current president of Hypertension Australia and Treasurer of the World Hypertension League. Dr Cushman has received institutional grants from Recor Medical and George Medicines; and has received consulting fees from Alnylam Pharmaceuticals. Dr Poulter has received financial support from several pharmaceutical companies that manufacture BP-lowering agents; has received consultancy fees from Servier and Aktiia; has received consultancy fees for research projects and staff from Servier and Pfizer; has received consultancy fees for arranging and speaking at educational meetings from AstraZeneca, Lri Therapharma, Napi, Servier, Sanofi, Eva Pharma, Pfizer, Emcure India, Dr Reddy's Laboratories, and Zydus; and has received support from the National Institute for Health Research Senior Investigator Awards, Biomedical Research Centre funding, and the British Heart Foundation Research Centre Excellence Award. Dr Wright has received support from NIH, Ohio Department of Medicaid, Agency for Health Care Research and Quality, Medtronic, Inc, and the Northeast Ohio Neighborhood Health Center Community Board of Directors. Dr Grobbee receives funding to his department as part of the EU Horizon Hypermarker project. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aimed to compare the outcomes of robotic-assisted rectal resection with conventional laparoscopic and open approaches, focusing on complication rates, conversion rates, length of hospital stay, and oncologic outcomes., Methods: A retrospective single-center cohort study included 106 patients with non-metastatic rectal cancer (UICC stages I-III) who underwent rectal resection from January 2013 to December 2023. Patients were assigned to open surgery (n = 23), conventional laparoscopic surgery (n = 55), or robotic-assisted surgery (n = 28)., Results: Robotic surgery demonstrated significantly lower conversion rates compared to minimal-invasive surgeries (p = 0.047) and shorter hospital stays (11.5 ± 8 days) compared to open (17.91 ± 12 days) and laparoscopic (17.2 ± 14 days) surgeries (p = 0.001). The quality of the specimen was significantly better (Score 1) in robotic (85.71%) and open (89.09%) cases compared to laparoscopic approaches (47.83%) (p < 0.001). Laparoscopic surgery was identified as a risk factor for worse specimen quality (p < 0.001). Older patients (> 63 years) had a higher risk for conversion in univariate analysis (p = 0.049). Morbidity was comparable between the groups (p = 0.131), and the anastomotic leakage rate did not differ significantly (laparoscopic: 18.18%, open: 13.04%, robotic: 17.86%). Kaplan-Meier survival curves showed no significant differences in overall survival probabilities among the groups., Conclusion: Robotic-assisted rectal resection provides significant advantages in terms of lower conversion rates, better specimen quality, and shorter hospital stays while maintaining comparable complication rates and oncologic outcomes to conventional laparoscopic and open approaches. These findings support robotic surgery as a standard treatment option for rectal cancer., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To test the hypothesis that an abiotic Earth and its inert atmosphere could form chemically reactive carbon- and nitrogen-containing compounds, we designed a plasma electrochemical setup to mimic lightning-induced electrochemistry under steady-state conditions of the early Earth. Air-gap electrochemical reactions at air-water-ground interfaces lead to remarkable yields, with up to 40 moles of carbon dioxide being reduced into carbon monoxide and formic acid, and 3 moles of gaseous nitrogen being fixed into nitrate, nitrite, and ammonium ions, per mole of transmitted electrons. Interfaces enable reactants (e.g., minerals) that may have been on land, in lakes, and in oceans to participate in radical and redox reactions, leading to higher yields compared to gas-phase-only reactions. Cloud-to-ground lightning strikes could have generated high concentrations of reactive molecules locally, establishing diverse feedstocks for early life to emerge and survive globally., Competing Interests: Competing interests statement:Harvard University has filed patent applications PCT/US2023/077332 and PCT/US2024/017763.

Mammalian cells replicate ~ 3 × 10 9 base pairs per cell cycle. One of the key molecules that slows down the cell cycle and prevents excessive DNA damage upon DNA replication stress is the checkpoint kinase ataxia-telangiectasia-and-RAD3-related (ATR). Proteolysis-targeting-chimeras (PROTACs) are an innovative pharmacological invention to molecularly dissect, biologically understand, and therapeutically assess catalytic and non-catalytic functions of enzymes. This work defines the first-in-class ATR PROTAC, Abd110/Ramotac-1. It is derived from the ATR inhibitor VE-821 and recruits the E3 ubiquitin-ligase component cereblon to ATR. Abd110 eliminates ATR rapidly in human leukemic cells. This mechanism provokes DNA replication catastrophe and augments anti-leukemic effects of the clinically used ribonucleotide reductase-2 inhibitor hydroxyurea. Moreover, Abd110 is more effective than VE-821 against human primary leukemic cells but spares normal primary immune cells. CRISPR-Cas9 screens show that ATR is a dependency factor in 116 myeloid and lymphoid leukemia cells. Treatment of wild-type but not of cereblon knockout cells with Abd110 stalls their proliferation which verifies that ATR elimination is the primary mechanism of Abd110. Altogether, our findings demonstrate specific anti-leukemic effects of an ATR PROTAC., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

May Measurement Month (MMM) is a global and national blood pressure (BP) screening campaign initiated by the International Society of Hypertension to improve awareness of BP worldwide. This study reports on the findings of the MMM21 campaign in Australia. Adult participants (≥18 years) were screened through opportunistic sampling across Australia between 1 May and 30 November 2021. Trained volunteers recorded standardized BP measurements from community volunteer participants along with demographic data, lifestyle factors, comorbidities, and history of COVID-19 infection and vaccination. Hypertension was defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg and/or taking antihypertensive medication. Data were collated and analysed centrally using the current MMM protocol and presented after the imputation of missing BP readings. A total of 1307 participants were screened in 2021, comprising 652 (49.9%) females and 654 (50.0%) males with a mean age of 48 years (SD 20.1). Of all 1307 participants, 524 (40.1%) had hypertension. Of participants with hypertension, 65.4% were aware and 59.3% were on antihypertensive medication. Of 311 participants on antihypertensive medication, 54.7% had controlled BP. Of all 524 participants with hypertension, 32.5% had controlled BP. The current 2021 data may indicate some progress in creating BP awareness; however, consecutive Australian data obtained since 2017 demonstrated stagnating treatment, and control rates compared with global rates and those in other high-income countries. Concerted efforts from all stakeholders will be required to further improve BP awareness, treatment, and control rates in Australia., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Conflict of interest: none declared.

The hyperactivation of the sympathetic nervous system (SNS) is linked to obesity, hypertension, and type 2 diabetes, which are characterized by elevated norepinephrine (NE) levels. Previous research has shown increased sodium-dependent glucose cotransporter 1 (SGLT1) protein levels in kidneys of hypertensive rodents, prompting investigation into the expression of SGLT1 in various tissues, such as skeletal muscle. This study aimed to assess (i) whether skeletal muscle cells and tissue express SGLT1 and SGLT2 proteins; (ii) if NE increases SGLT1 levels in skeletal muscle cells, and (iii) whether the skeletal muscle of neurogenically hypertensive mice exhibits increased SGLT1 expression. We found that (i) skeletal muscle cells and tissue are a novel source of the SGLT2 protein and that (ii) NE significantly elevated SGLT1 levels in skeletal muscle cells. As SGLT2 inhibition (SGLT2i) with Empagliflozin increased SGLT1 levels, in vivo studies with the dual inhibitor SGLT1/2i, Sotagliflozin were warranted. The treatment of neurogenically hypertensive mice using Sotagliflozin significantly reduced blood pressure. Our findings suggest that SNS activity upregulates the therapeutic target, SGLT1, in skeletal muscle, potentially worsening cardiometabolic control. As clinical trial data suggest cardiorenal benefits from SGLT2i, future studies should aim to utilize SGLT1i by itself, which may offer a therapeutic strategy for conditions with heightened SNS activity, such as hypertension, diabetes, and obesity.

Background: Salt intake in CKD patients can affect cardiovascular risk and kidney disease progression. Twenty-four hour (24h) urine collections are often used to investigate salt metabolism but are cumbersome to perform. We assessed urinary sodium (U-Na) concentration in spot urine samples and investigated the correlation with 24h U-Na excretion and concentration in CKD patients under nephrological care. Further, we studied the role of CKD stage and diuretics and evaluated the performance of commonly used formulas for the prediction of 24h U-Na excretion from spot urine samples., Methods: One hundred eight patients of the German Chronic Kidney Disease (GCKD) study were included. Each participant collected a 24h urine and two spot urine samples within the same period. The first spot urine sample (AM) was part of the second morning urine. The second urine sample was collected before dinner (PM). Patients were advised to take their medication as usual without changing dietary habits. U-Na concentrations in the two spot urine samples and their average ((AM + PM)/2) were correlated with U-Na concentration and total Na excretion in the 24h urine collections. Correlations were subsequently studied after stratification by CKD stage and diuretic intake. The usefulness of three commonly applied equations to estimate 24h U-Na excretion from spot urine samples (Kawasaki, Tanaka and Intersalt) was determined using Bland-Altman plots, analyses of sensitivity, specificity, as well as positive (PPV) and negative predictive values (NPV)., Results: Participants (42 women, 66 men) were on average (± SD) 62.2 (± 11.9) years old, with a mean serum creatinine of 1.6 (± 0.5) mg/dl. 95% had arterial hypertension, 37% diabetes mellitus and 55% were on diuretics. The best correlation with 24h U-Na total excretion was found for the PM spot U-Na sample. We also found strong correlations when comparing spot and 24h urine U-Na concentration. Correction of spot U-Na for U-creatinine did not improve strength of correlations. Neither CKD stage, nor intake of diuretics had significant impact on these correlations. All examined formulas revealed a significant mean bias. The lowest mean bias and the strongest correlation between estimated and measured U-Na excretion in 24h were obtained using the Tanaka-formula. Also, application of the Tanaka-formula with PM U-Na provided best sensitivity, specificity, PPV and NPV to estimate U-Na excretion > 4g/d corresponding to a salt consumption > 10g/d., Conclusion: U-Na concentration of spot urine samples correlated with 24h U-Na excretion especially when PM spot U-Na was used. However, correlation coefficients were relatively low. Neither CKD stage nor intake of diuretics appeared to have an influence on these correlations. There was a significant bias for all tested formulas with the Tanaka-formula providing the strongest correlation with measured 24h U-Na excretion. In summary, using spot urine samples together with the Tanaka-formula in epidemiological studies appears feasible to determine associations between approximate salt intake and outcomes in CKD patients. However, the usefulness of spot-urine samples to guide and monitor salt consumption in individual patients remains limited., (© 2024. The Author(s).)

One-dimensional dissolution of a layered compound in a nonpolar organic solvent is reported for the first time. A high-aspect ratio fluorohectorite modified with a cationic surfactant (dioctadecyldimethylammonium) showed spontaneous delamination into monolayer nanosheets in chloroform.

Purpose: Customised individually made (CIM) total knee arthroplasty (TKA) with personalised alignment is relatively new and evidence is limited. The aim of this study was to compare patient-reported outcome measures between CIM and off-the-shelf (OTS) TKA patients in a matched-pair analysis with a 2-year follow-up., Methods: In this single-centre, prospective cohort study, propensity score matching was performed on 51 CIM and 51 OTS TKA. Data were measured at baseline, at 4 months, 1 and 2 years and included the Forgotten Joint Score (FJS-12), the High Activity Arthroplasty Score (HAAS), the Knee injury and Osteoarthritis Outcome Score (KOOS), the EQ-5D-3L, the EQ-Visual Analogue Scale, satisfaction, overall knee improvement, willingness to undergo the surgery again and the Knee Society Score., Results: At 2 years follow-up, the FJS-12 (77 vs. 67, p = .058), HAAS (13 vs. 11, p < .001), KOOS daily living (92 vs. 86, p = .029), KOOS sport (76 vs. 65, p = .019), KOOS quality of life (81 vs. 71, p = .028) and the EQ-5D (.95 vs. .90, p = .030) were higher for CIM TKA compared to OTS TKA. Satisfaction rate was 92% for CIM TKA and 84% for OTS TKA (p = .357). Most patients reported an improvement in the overall knee state (94% CIM and 90% OTS, p = .487) and almost all patients would undergo the surgery again (96% CIM and 98% OTS, p = .999)., Conclusion: The current study found that CIM TKA patients had better functional outcomes at 2 years. Patient satisfaction was high and not statistically significantly different from OTS TKA patients., Level of Evidence: Level II prospective cohort study., (© 2024 The Author(s). Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: Renal denervation is a recognized adjunct therapy for hypertension with clinically significant blood pressure (BP)-lowering effects. Long-term follow-up data are critical to ascertain durability of the effect and safety. Aside from the 36-month follow-up data available from randomized control trials, recent cohort analyses extended follow-up out to 10 years. We sought to analyze study-level data and quantify the ambulatory BP reduction of renal denervation across contemporary randomized sham-controlled trials and available long-term follow-up data up to 10 years from observational studies., Methods: A systematic review was performed with data from 4 observational studies with follow-up out to 10 years and 2 randomized controlled trials meeting search and inclusion criteria with follow-up data out to 36 months. Study-level data were extracted and compared statistically., Results: In 2 contemporary randomized controlled trials with 36-month follow-up, an average sham-adjusted ambulatory systolic BP reduction of -12.7±4.5 mm Hg from baseline was observed ( P =0.05). Likewise, a -14.8±3.4 mm Hg ambulatory systolic BP reduction was found across observational studies with a mean long-term follow-up of 7.7±2.8 years (range, 3.5-9.4 years; P =0.0051). The observed reduction in estimated glomerular filtration rate across the long-term follow-up was in line with the predicted age-related decline. Antihypertensive drug burden was similar at baseline and follow-up., Conclusions: Renal denervation is associated with a significant and clinically meaningful reduction in ambulatory systolic BP in both contemporary randomized sham-controlled trials up to 36 months and observational cohort studies up to 10 years without adverse consequences on renal function., Competing Interests: Disclosures M.P. Schlaich has received support from a National Health and Medical Research Council Research Fellowship and research support from Medtronic, Abbott, and Servier Australia. He serves on scientific advisory boards for Abbott, Boehringer Ingelheim, Servier, Novartis, and Medtronic. A. Walton is a Proctor for Medtronic and Abbott, is on the Medical Advisory Board of Medtronic, and receives grant support from Medtronic, Abbott, and Edwards. M.D. Esler and G.W. Lambert have received consulting fees and travel and research support from Medtronic. The other authors report no conflicts.

Single-pill combination therapy containing four quarter-dose medications for high blood pressure improves BP control compared to monotherapy, however patient-reported acceptance of the quadpill as a treatment strategy remains undescribed. We collected within-trial feedback and interviewed participants from the quadruple ultra-low-dose treatment for hypertension (QUARTET) trial to characterise patient attitudes to this intervention. All trial participants were asked about ease and preference for the quadpill and provided an opportunity to give further comments on the trial at 12 weeks (trial primary endpoint) and 52 weeks extended follow-up. Separately, we used purposive and quota sampling for the semi-structured telephone interviews, with the resultant verbatim transcripts analysed using an inductive thematic analysis approach. Themes were re-evaluated after each successive interview, and at suspected data saturation, an additional interview conducted for confirmation. At 12 weeks follow-up, 502 of 591 (85%) participants responded to acceptability questions, and 359 of 417 (86%) responded at week 52. Most reported the trial capsule easy or very easy to take. From eight sites, 16 participants were interviewed between 5 August 2020 and 19 November 2020. All described a positive experience, preferred once-daily morning dosing and found routine facilitated adherence. Participants valued individual responsibility for adherence, and involvement of the general practitioner in blood-pressure management. Most reported capsule size did not deter adherence but desired a smaller capsule. Participants described a preference for minimising number and dosage of medications, reduced capsule size, and once-daily morning dosing. These findings suggest a preference for single-pill combination therapy for blood pressure lowering., (© 2024. The Author(s).)

Introduction: The effort adolescents make determines the risk for dropping out of vocational education and training (VET) early and their chances of graduating upper secondary education. Studies have shown that adolescents' efforts decrease during the transition to upper secondary general education and increases for the transition to VET. In this study, we examined adolescent self-efficacy in lower secondary education, adolescent-instructor relationship (AIR) in VET and general education, and perceived person-environment fit (PEF) as predictors of adolescent effort., Method: We calculated two longitudinal multigroup structural equation models. Group 1 comprised 1266 (mean age in T 1  = 15.7 years; female: 44%) lower secondary education graduates who moved on to VET with two learning contexts, company and vocational school in Switzerland. Group 2 included 517 (mean age in T 1  = 15.7 years; female: 44%) lower secondary education graduates who moved on to upper secondary general education and thus stayed in a school. Adolescents' survey data was collected in 2016 and 2017., Results: Self-efficacy in lower secondary education and AIR in upper secondary education indirectly predicted effort in upper secondary education via PEF, controlling for effort in lower secondary education. Findings were similar for general education and vocational school. However, the effects differed between company and general education (moderation). The positive effect of AIR on PEF was statistically significantly weaker for adolescents in general education than for adolescents in VET and their company learning context., Conclusion: We discuss strategies to enhance adolescents' efforts in upper secondary education., (© 2024 The Authors. Journal of Adolescence published by Wiley Periodicals LLC on behalf of Foundation for Professionals in Services to Adolescents.)

The importance of the sympathetic nervous system in essential hypertension has been recognized in 2 eras. The first was in early decades of the 20 th century, through to the 1960s. Here, the sympathetic nervous system was identified as a target for the treatment of hypertension, and an extensive range of antiadrenergic therapies were developed. Then, after a period of lapsed interest, in a second era from 1985 on, the development of precise measures of human sympathetic nerve firing and transmitter release allowed demonstration of the importance of neural mechanisms in the initiation and maintenance of the arterial blood pressure elevation in hypertension. This led to the development of a device treatment of hypertension, catheter-based renal denervation, which we will discuss., Competing Interests: Disclosures M.D. Esler and J.W. Osborn have received consulting fees and travel and research support from Medtronic. M.P. Schlaich has received research support from Medtronic, Abbott, and Servier Australia. He serves on scientific advisory boards for Abbott, BI, Servier, Novartis, and Medtronic.

Background: A combination of four ultra-low-dose blood pressure (BP) medications lowered office BP more effectively than initial monotherapy in the QUARTET trial. The effects on average ambulatory BP changes at 12 weeks have not yet been reported in detail., Methods: Adults with hypertension who were untreated or on monotherapy were eligible for participation. Overall, 591 participants were randomized to either the quadpill (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) or monotherapy control (irbesartan 150 mg). The difference in 24-h, daytime, and night-time systolic and diastolic ambulatory BP at 12 weeks along further metrics were predefined secondary outcomes., Results: Of 576 participants, 289 were randomized to the quadpill group and 287 to the monotherapy group. At 12 weeks, mean 24-h ambulatory SBP and DBP were 7.7 [95% confidence interval (95% CI) 9.6-5.8] and 5.3 (95% CI: 6.5-4.1) mmHg lower in the quadpill vs. monotherapy group ( P  < 0.001 for both). Similar reductions in the quadpill group were observed for daytime (8.1/5.7 mmHg lower) and night-time (6.3/4.0 mmHg lower) BP at 12 weeks (all P  < 0.001) compared to monotherapy. The rate of BP control (24-h average BP < 130/80 mmHg) at 12 weeks was higher in the quadpill group (77 vs. 50%; P  < 0.001). The reduction in BP load was also more pronounced with the quadpill., Conclusion: A quadruple quarter-dose combination compared with monotherapy resulted in greater ambulatory BP lowering across the entire 24-h period with higher ambulatory BP control rates and reduced BP variability at 12 weeks. These findings further substantiate the efficacy of an ultra-low-dose quadpill-based BP lowering strategy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The aim of this study was to evaluate the responsiveness of different patient-reported outcome measures in patients with primary total knee arthroplasty (TKA)., Methods: In this prospective observational study, we assessed patients with TKA before the surgery, after 4 months, after 1 year, and after 2 years. Measures were the objective Knee Society Score (KSS) and the following patient-reported outcome measures: Knee injury and Osteoarthritis Outcome Score (KOOS), KOOS-12, Forgotten Joint Score (FJS-12), High-Activity Arthroplasty Score, and EQ-5D-3L. Responsiveness was determined by effect size (ES), standardized response mean (SRM), area under the receiver operating characteristics curve, floor and ceiling effects, and hypothesis testing., Results: We analyzed data from 309 TKAs (272 patients, 56% female). The ES and SRM for the change in KSS, KOOS, KOOS-12, FJS-12, and EQ-5D-3L from baseline to each follow-up were large (>0.8). The largest responsiveness from baseline to follow-up was found for the KSS, KOOS/KOOS-12 quality of life, KOOS-12 summary, KOOS-12 pain, and FJS-12 (2.0 > ES <3.9, 1.4 > SRM <2.4). The area under the curve from baseline to each follow-up was ≥0.7 for KOOS, KOOS-12, and FJS-12 (range 0.71 to 0.95) and <0.7 for KSS and EQ-5D-3L (range 0.65 to 0.74). We found floor or ceiling effects in the KOOS, KOOS-12, and EQ-5D-3L, but not in the KSS, FJS-12, and High-Activity Arthroplasty Score., Conclusions: Our study demonstrated that responsiveness differed between the various measures. The KOOS-12 and FJS-12 showed the greatest internal and external responsiveness, although ceiling effects occurred in the KOOS-12., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Renal denervation (RDN) has been consistently shown in recent sham-controlled clinical trials to reduce blood pressure (BP). Salt sensitivity is a critical factor in hypertension pathogenesis, but cumbersome to assess by gold-standard methodology. Twenty-four-hour average heart rate (HR) and mean arterial pressure (MAP) dipping, taken by ambulatory blood pressure monitoring (ABPM), stratifies patients into high, moderate, and low salt sensitivity index (SSI) risk categories., Objectives: We aimed to assess whether ABPM-derived SSI risk could predict the systolic blood pressure reduction at long-term follow-up in a real-world RDN patient cohort., Methods: Sixty participants had repeat ABPM as part of a renal denervation long-term follow-up. Average time since RDN was 8.9 ± 1.2 years. Based on baseline ABPM, participants were stratified into low (HR < 70 bpm and MAP dipping > 10%), moderate (HR ≥70 bpm or MAP dipping ≤ 10%), and high (HR ≥ 70 bpm and MAP dipping ≤ 10%) SSI risk groups, respectively., Results: One-way ANOVA indicated a significant treatment effect ( P  = 0.03) between low ( n  = 15), moderate ( n  = 35), and high ( n  = 10) SSI risk with systolic BP reduction of 9.6 ± 3.7 mmHg, 8.4 ± 3.5 mmHg, and 28.2 ± 9.6 mmHg, respectively. Baseline BP was not significantly different between SSI Risk groups ( P  = 0.18). High SSI risk independently correlated with systolic BP reduction ( P  = 0.02)., Conclusions: Our investigation indicates that SSI risk may be a simple and accessible measure for predicting the BP response to RDN. However, the influence of pharmacological therapy on these participants is an important extraneous variable requiring testing in prospective or drug naive RDN cohorts., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Low-dose combinations are a promising intervention for improving blood pressure (BP) control but their effects on therapeutic inertia are uncertain., Methods: Analysis of 591 patients randomized to an ultra-low-dose quadruple pill or initial monotherapy. The episode of therapeutic inertia was defined as a patient visit with a BP of >140/90 mm Hg without intensification of antihypertensive treatment. We compared the frequency of therapeutic inertia episodes between Quadpill and initial monotherapy as a proportion of the total population (intention-to-treat analysis with the denominator being all participants randomized) and as a proportion of people with uncontrolled BP (with the denominator being participants with uncontrolled BP)., Results: Therapeutic inertia occurred in fewer participants randomized to Quadpill compared with monotherapy. For example, among the 390 participants with a 6-month follow-up, therapeutic inertia according to unattended BP was 21/192 (11%) versus 45/192 (23%), P =0.002. There were similar rates of therapeutic inertia among those with uncontrolled unattended BP in each group (all P >0.4). Consistent observations were seen with the use of attended office BP measures. The major determinants of not intensifying treatment during follow-up were BP readings that were close to target and large improvements in BP compared with the previous visit., Conclusions: Among all treated individuals, low-dose Quadpill reduced the number of therapeutic inertia episodes compared with initial monotherapy. After the first follow-up visit, most high BP values did not lead to treatment intensification in both groups. Education is needed about the importance of treatment intensification despite a significant improvement in BP or BP being close to target., Registration: URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12616001144404; Unique identifier: ACTRN12616001144404., Competing Interests: Disclosures The George Institute for Global Health (TGI) has submitted patent applications in respect of low fixed-dose combination products for the treatment of cardiovascular or cardiometabolic disease. A. Rodgers and C. Chow are listed as inventors. A. Rodgers is employed by TGI and seconded part-time to George Medicines Pty Ltd (GM). George Health Enterprises Pty Ltd (GHE) and its subsidiary, GM, have received investment funds to develop fixed-dose combination products, including combinations of blood pressure-lowering drugs. GHE is the social enterprise arm of TGI. A. Rodgers and C. Chow do not have direct financial interests in these patent applications or investments. The other authors report no conflicts.

The Baltic Sea is home to a genetically isolated and morphologically distinct grey seal population. This population has been the subject of 120-years of careful documentation, from detailed records of bounty statistics to annual monitoring of health and abundance. It has also been exposed to a range of well-documented stressors, including hunting, pollution and climate change. To investigate the vulnerability of marine mammal populations to multiple stressors, data series relating to the Baltic grey seal population size, hunt and health were compiled, vital demographic rates were estimated, and a detailed population model was constructed. The Baltic grey seal population fell from approximately 90,000 to as few as 3000 individuals during the 1900s as the result of hunting and pollution. Subsequently, the population has recovered to approximately 55,000 individuals. Fertility levels for mature females have increased from 9% in the 1970s to 86% at present. The recovery of the population has led to demands for increased hunting, resulting in a sudden increase in annual quotas from a few hundred to 3550 in 2020. Simultaneously, environmental changes, such as warmer winters and reduced prey availability due to overfishing, are likely impacting fecundity and health. Future population development is projected for a range of hunting and environmental stress scenarios, illustrating how hunting, in combination with environmental degradation, can lead to population collapse. The current combined hunting quotas of all Baltic Nations caused a 10% population decline within three generations in 100% of simulations. To enable continued recovery of the population, combined annual quotas of less than 1900 are needed, although this quota should be re-evaluated annually as monitoring of population size and seal health continues. Sustainable management of long-lived slowly growing species requires an understanding of the drivers of population growth and the repercussions of management decisions over many decades. The case of the Baltic grey seal illustrates how long-term ecological time series are pivotal in establishing historical baselines in population abundance and demography to inform sustainable management., (© 2024 The Authors. Journal of Animal Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society.)

Background: One of five patients is dissatisfied with the outcome of TKA. With the increasing number of TKAs, this affects many patients. It has been suggested that high expectations may influence satisfaction, but the relationship between preoperative patient expectations and postoperative patient satisfaction remains poorly understood., Questions/purposes: (1) Are preoperative patient expectations correlated with postoperative satisfaction? (2) Are expectations correlated with patient characteristics or patient-reported outcome measures (PROMs)? (3) Is satisfaction correlated with patient characteristics or PROMs? (4) Do patients report specific items as more relevant to their expectations?, Methods: This was a single-center, observational, retrospective, comparative study involving patients who underwent TKA. Between December 2020 and June 2022, three senior surgeons performed 306 TKAs. Of these, 76% (234) had the preoperative PROMs required for this study, and of these, 82% (193) had completed PROMs at the 12-month follow-up interval and were analyzed. Of the 193 included patients, 53% (102) were women; the mean age was 68 ± 9 years. Data were collected at baseline, 4 months, and 12 months. Twelve months of follow-up has been shown to be adequate in studies with PROMs. Patient expectations were measured using the validated Hospital for Special Surgery Knee Replacement Expectation Survey on a scale from 0 to 100, with higher scores indicating higher expectations. We also assessed patient satisfaction, the Knee injury and Osteoarthritis Outcome Score, Forgotten Joint Score, High-Activity Arthroplasty Score, EQ-5D-3L, and the objective Knee Society Score. Bivariate linear correlations were analyzed using the Pearson or Spearman test., Results: Preoperative patient expectations did not correlate with postoperative satisfaction. The mean Hospital for Special Surgery Knee Replacement Expectation Survey score was 82 ±16 points and did not correlate with satisfaction at either 4 months (r = -0.061; p = 0.42) or 12 months (r = -0.126; p = 0.11). Expectations did not correlate with patient characteristics or any of the preoperative or postoperative PROMs or the Knee Society Score. Patient satisfaction was 88% (158 of 179) at 4 months and 83% (160 of 193) at 12 months and did not correlate with patient characteristics or any of the preoperative PROMs or Knee Society Score. Patient satisfaction was medium to strongly correlated with postoperative PROMs and Knee Society Score. The Hospital for Special Surgery Knee Replacement Expectation Survey items with the most frequent expected improvement were "ability to walk" (99% [192 of 193]), "go downstairs" (99% [191 of 192]), and "go upstairs" (99% [192 of 193])., Conclusion: Preoperative expectations were not correlated with postoperative satisfaction or PROMs. Surgeons should be aware that patients have high expectations. However, these expectations appear to be less relevant in determining postoperative satisfaction., Level of Evidence: Level III, therapeutic study., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2024 by the Association of Bone and Joint Surgeons.)

Background and Hypothesis: Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality, and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study., Methods: The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60 mL/min/1.73m2 and an overt proteinuria. Cardio-, cerebro- and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology., Results: Over a median of 6.5 years, 10 271 events occurred in total and 680 participants (13.0%) died while 2947 participants (56.5%) experienced any event. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology, and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney), and 66.0 (infection). Participants with diabetic kidney disease and men were more prone to experiencing events., Conclusion: This comprehensive explorative tool to visualize adverse events (https://gckd.diz.uk-erlangen.de/), their combination, mortality, and multimorbidity among persons with CKD may manifest as a valuable resource for patient care, identification of high-risk groups, health services, and public health policy planning., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Human microglia are critically involved in Alzheimer's disease (AD) progression, as shown by genetic and molecular studies. However, their role in tau pathology progression in human brain has not been well described. Here, we characterized 32 human donors along progression of AD pathology, both in time-from early to late pathology-and in space-from entorhinal cortex (EC), inferior temporal gyrus (ITG), prefrontal cortex (PFC) to visual cortex (V2 and V1)-with biochemistry, immunohistochemistry, and single nuclei-RNA-sequencing, profiling a total of 337,512 brain myeloid cells, including microglia. While the majority of microglia are similar across brain regions, we identified a specific subset unique to EC which may contribute to the early tau pathology present in this region. We calculated conversion of microglia subtypes to diseased states and compared conversion patterns to those from AD animal models. Targeting genes implicated in this conversion, or their upstream/downstream pathways, could halt gene programs initiated by early tau progression. We used expression patterns of early tau progression to identify genes whose expression is reversed along spreading of spatial tau pathology (EC > ITG > PFC > V2 > V1) and identified their potential involvement in microglia subtype conversion to a diseased state. This study provides a data resource that builds on our knowledge of myeloid cell contribution to AD by defining the heterogeneity of microglia and brain macrophages during both temporal and regional pathology aspects of AD progression at an unprecedented resolution., (© 2024. The Author(s).)

Two recent large trials showed the potential of single pill combinations (SPCs) with ≥3 low-dose components among people with hypertension who were untreated or receiving monotherapy. In both trials, these 'hypertension polypills' were superior to usual care, achieving >80% BP control without increasing withdrawal due to side effects. However, there are no such products available for prescribers. To address this unmet need, George Medicines developed GMRx2 with telmisartan/amlodipine/indapamide in three strengths (mg): 10/1.25/0.625, 20/2.5/1.25; 40/5/2.5. Two pivotal trials are ongoing to support FDA submission for the treatment of hypertension, including initial treatment. These assess efficacy and safety of GMRx2 compared to: placebo, and each of the three possible dual combinations. Regulatory submissions are planned for 2024, with the aim of providing access to GMRx2 in developed and developing regions. Wider implementation of GMRx2-based treatment strategies will be guided by further research to inform access and appropriate scale up., Competing Interests: Authors Anthony Rodgers, Abdul Salam, Sonali Gnanenthiran and Aletta E Schutte are employed at TGI, which holds an interest in GMRx2 via its ownership of George Health Enterprises. None of the TGI staff have a personal financial interest in GM. Professor Rodgers is seconded part-time to GM. TGI holds patents for ultra-low-dose fixed-dose combination products for the treatment of hypertension and diabetes, and Professor Rodgers is listed as one of the inventors (Granted: US 10,369,15; US 10,799,487; US 10,322,117; US 11,033,544; US 11,478,462; Pending: US 17/932,982; US 18/446,268; US 17/598,122; US 17/317,614; US 17/527,084; US 17/527,085; US 17/527,087). Professor Rodgers does not have a financial interest in these patents. None of the other authors have a financial interest in GM or have received funding for their independent contribution to the GMRx2 program. Aletta E Schutte has received consulting fees and/or speaker honoraria from Omron Healthcare, Aktiia, Medtronic, Servier, Abbott, Sanofi, Sun Pharmaceuticals, Novartis. She is supported by a Fellowship of the National Health and Medical Research Council of Australia (ID 2017504). Dike B. Ojji has received speaker honoraria from Novartis, AstraZeneca, Servier, Swipha and Boehringer for speaking at educational meetings. Krzysztof Narkiewicz has received speaker and consulting honoraria from Bausch Health, Berlin-Chemie/Menarini, Egis, Idorsia, Gedeon Richter, Gilead, Krka, Novo Nordisk, Polpharma, Recordati, Sandoz and Servier. Markus Schlaich has received consulting fees, and/or travel and research support from Medtronic, Abbott, ReCor, Novartis, Servier, Pfizer, and Boehringer-Ingelheim. He is the current president of Hypertension Australia and Treasurer of the World Hypertension League., (Copyright: © 2024 The Author(s).)

Efforts to limit the impact of the coronavirus disease (COVID-19) pandemic led to the implementation of public health measures and reallocation of health resources. To investigate trends in blood pressure (BP), hypertension and BMI in the Australian population during the COVID-19 pandemic, data from publicly accessible health stations were analyzed. Average BP and BMI measured by the SiSU Health Station network in Australia in over 1.6 million health screenings were compared between the years 2018 and 2021. Additionally, paired trajectories for BP and BMI development before and during the COVID-19 pandemic were calculated. Comparisons between pre-COVID years and post-COVID years of 2018 versus 2020, 2019 versus 2020, 2018 versus 2021, and 2019 versus 2021 showed increases in average adjusted systolic BP of 2.0, 1.7, 2.6, and 2.3 mmHg, respectively. Paired analysis of longitudinal data showed an overall increase in the trajectory of systolic BP of 3.2 mmHg between pre- and post-COVID years. The prevalence of hypertension in users of the health stations increased by approximately 25% in the years 2020-2021. Similar trends were seen for BMI. Data from public Australian health stations indicated a strong trend toward higher BP during the COVID-19 pandemic. At the population level, BP increments have been shown to markedly increase cardiovascular disease risk. Anti-pandemic measures need to be carefully evaluated in terms of secondary public health effects and health support systems extended to effectively target cardiovascular risk., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Resistant hypertension is associated with an exceedingly high cardiovascular risk and there remains an unmet therapeutic need driven by pathophysiologic pathways unaddressed by guideline-recommended therapy. While spironolactone is widely considered as the preferable fourth-line drug, its broad application is limited by its side effect profile, especially off-target steroid receptor-mediated effects and hyperkalaemia in at-risk subpopulations. Recent landmark trials have reported promising safety and efficacy results for a number of novel compounds targeting relevant pathophysiologic pathways that remain unopposed by contemporary drugs. These include the dual endothelin receptor antagonist, aprocitentan, the aldosterone synthase inhibitor, baxdrostat and the nonsteroidal mineralocorticoid receptor antagonist finerenone. Furthermore, the evidence base for consideration of catheter-based renal denervation as a safe and effective adjunct therapeutic approach across the clinical spectrum of hypertension has been further substantiated. This review will summarise the recently published evidence on novel antihypertensive drugs and renal denervation in the context of resistant hypertension., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Resistant hypertension is characterized by the inability of guideline-recommended triple combination therapy to control blood pressure (BP) to target. It is associated with a significantly increased risk of adverse outcomes. Despite abundant preclinical evidence supporting the critical role of the endothelin pathway in resistant hypertension (RH), clinical implementation of endothelin antagonists for the treatment of hypertension was hindered by various factors. Recently, the novel dual endothelin-receptor antagonist aprocitentan was tested in individuals with resistant hypertension in the PRECISION trial and provided compelling evidence supporting both short and longer-term safety and clinically meaningful and sustained BP lowering efficacy. These findings resulted in the recent regulatory approval of aprocitentan by the FDA. Aprocitentan may be a particularly useful antihypertensive option for individuals with advanced age, chronic kidney disease, and albuminuria.

Background: Despite the prognostic relevance of cachexia in pancreatic cancer, individual body composition has not been routinely integrated into treatment planning. In this multicenter study, we investigated the prognostic value of sarcopenia and myosteatosis automatically extracted from routine computed tomography (CT) scans of patients with advanced pancreatic ductal adenocarcinoma (PDAC)., Patients and Methods: We retrospectively analyzed clinical imaging data of 601 patients from three German cancer centers. We applied a deep learning approach to assess sarcopenia by the abdominal muscle-to-bone ratio (MBR) and myosteatosis by the ratio of abdominal inter- and intramuscular fat to muscle volume. In the pooled cohort, univariable and multivariable analyses were carried out to analyze the association between body composition markers and overall survival (OS). We analyzed the relationship between body composition markers and laboratory values during the first year of therapy in a subgroup using linear regression analysis adjusted for age, sex, and American Joint Committee on Cancer (AJCC) stage., Results: Deep learning-derived MBR [hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.47-0.77, P < 0.005] and myosteatosis (HR 3.73, 95% CI 1.66-8.39, P < 0.005) were significantly associated with OS in univariable analysis. In multivariable analysis, MBR (P = 0.019) and myosteatosis (P = 0.02) were associated with OS independent of age, sex, and AJCC stage. In a subgroup, MBR and myosteatosis were associated with albumin and C-reactive protein levels after initiation of therapy. Additionally, MBR was also associated with hemoglobin and total protein levels., Conclusions: Our work demonstrates that deep learning can be applied across cancer centers to automatically assess sarcopenia and myosteatosis from routine CT scans. We highlight the prognostic role of our proposed markers and show a strong relationship with protein levels, inflammation, and anemia. In clinical practice, automated body composition analysis holds the potential to further personalize cancer treatment., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Customised individually made (CIM) total knee arthroplasty (TKA) was introduced to potentially improve patient satisfaction and other patient-reported outcome measures (PROMs). The purpose of this study was to compare PROMs, especially patient satisfaction, of patients with CIM and OTS TKA in a matched-pair analysis with a 2-year follow-up., Methods: This is a prospective cohort study with a propensity score matching of 85 CIM and 85 off-the-shelf (OTS) TKA. Follow-up was at 4 months, 1 year and 2 years. The primary outcome was patient satisfaction. Secondary outcomes were as follows: overall improvement, willingness to undergo the surgery again, Knee injury and Osteoarthritis Outcome Score (KOOS), Forgotten Joint Score (FJS-12), High-Activity Arthroplasty Score (HAAS), EQ-5D-3L, EQ-VAS, Knee Society Score (KSS) and surgeon satisfaction., Results: Patient satisfaction ranged from 86 to 90% and did not differ between CIM and OTS TKA. The EQ-VAS after 4 months and the HAAS after 1 year and 2 years were higher for CIM TKA. KOOS, FJS-12 and EQ-5D-3L were not different at follow-up. The changes in KOOS symptoms, pain and daily living were higher for OTS TKA. The KSS was higher for patients with CIM TKA. Surgeon satisfaction was high throughout both groups. Patients who were satisfied after 2 years did not differ preoperatively from those who were not satisfied. Postoperatively, all PROMs were better for satisfied patients. Patient satisfaction was not correlated with patient characteristics, implant or preoperative PROMs, and medium to strongly correlated with postoperative PROMs., Conclusion: Patient satisfaction was high with no differences between patients with CIM and OTS TKA. Both implant systems improved function, pain and health-related quality of life. Patients with CIM TKA showed superior results in demanding activities as measured by the HAAS., Level of Evidence: II, prospective cohort study., (© 2023. The Author(s).)

Herein, we review interventional peripheral neuromodulatory approaches to reduce blood pressure (BP), specifically focusing on catheter-based renal denervation (RDN), as well as the latest data from recent clinical trials underpinning its clinical use. Given the apparent failure of established lifestyle measures and pharmacologic BP-lowering approaches to improve hypertension (HTN) control rates, the past decade has seen remarkable scientific efforts to explore the utility of interventional strategies for BP management. Experimental studies and human clinical trials have demonstrated the crucial role of the sympathetic nervous system in the development and mainenance of HTN - consequently, most recent interventional technologies aimed primarily at modulating neural pathways. Advanced approaches that were rigorously tested in human studies include RDN, endovascular baroreflex amplification, baroreflex activation therapy and cardiac neuromodulation stimulation.Amongst these, RDN is by far the most established technology. With recent robust evidence from clinical trials and real-world data showing the safety and efficacy of both ultrasound and radiofrequency-based approaches, a recent clinical consensus statement of the European Society of Cardiology Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions concludes that RDN represents an ancillary therapeutic option in patients with uncontrolled resistant HTN confirmed by ambulatory blood pressure measurement and in spite of attention to lifestyle changes and optimised pharmacological treatment. Furthermore, RDN could alos be considered for patienst unlikley to adhere to or tolerate long-term antihypertensive drug treatment. Very recent data indicate long-term safety and efficacy up to 10 years. Appropriate implementation of RDN into clinical practice is now warranted.For all other interventions additional data from adequately designed human studies are required to establish their safety and clinical utility for potential future use in routine practice., Competing Interests: Competing interests: MGK has received consulting fees and/or travel and research support from Medtronic. RC is supported by the Australian National Heart Foundation post doc fellowship. CES and SS have been involved in renal denervation studies supported by Medtronic. SS has received consulting fees and/or travel and research support from Medtronic. MS has received consulting fees, and/or travel and research support from Medtronic, Abbott, Novartis, Servier, Pfizer and Boehringer-Ingelheim., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

There is great potential for the use of terrestrial laser scanning (TLS) to quantify aspects of habitat structure in the study of animal ecology and behaviour. Viewsheds-the area visible from a given position-influence an animal's perception of risk and ability to respond to potential danger. The management and conservation of large herbivores and their habitats can benefit greatly from understanding how vegetation structure shapes viewsheds and influences animal activity patterns and foraging behaviour. This study aimed to identify how woodland understory structure influenced horizontal viewsheds at deer eye height. Mobile TLS was used in August 2020 to quantify horizontal visibility-in the form of Viewshed Coefficients (VC)-and understory leaf area index (LAI) of 71 circular sample plots (15-m radius) across 10 woodland sites in North Wales (UK) where fallow deer ( Dama dama ) are present. The plots were also surveyed in summer for woody plant size structure, stem density and bramble ( Rubus fruticosus agg.). Eight plots were re-scanned twice in winter to compare seasonal VC values and assess scan consistency. Sample plots with higher densities of small stems had significantly reduced VC 1 m from the ground. Other stem size classes, mean percentage bramble cover and understory LAI did not significantly affect VC. There was no difference in VC between summer and winter scans, or between repeated winter scans. The density of small stems influenced viewsheds at deer eye height and may alter behavioural responses to perceived risk. This study demonstrates how TLS technology can be applied to address questions in large herbivore ecology and conservation., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Background: Renal denervation (RDN) reduces blood pressure (BP) in patients with uncontrolled hypertension in the absence of antihypertensive medications., Objectives: This trial assessed the safety and efficacy of RDN in the presence of antihypertensive medications., Methods: SPYRAL HTN-ON MED is a prospective, randomized, sham-controlled, patient- and assessor-blinded trial enrolling patients from 56 clinical centers worldwide. Patients were prescribed 1 to 3 antihypertensive medications. Patients were randomized to radiofrequency RDN or sham control procedure. The primary efficacy endpoint was the baseline-adjusted change in mean 24-hour ambulatory systolic BP at 6 months between groups using a Bayesian trial design and analysis., Results: The treatment difference in the mean 24-hour ambulatory systolic BP from baseline to 6 months between the RDN group (n = 206; -6.5 ± 10.7 mm Hg) and sham control group (n = 131; -4.5 ± 10.3 mm Hg) was -1.9 mm Hg (95% CI: -4.4 to 0.5 mm Hg; P = 0.12). There was no significant difference between groups in the primary efficacy analysis with a posterior probability of superiority of 0.51 (Bayesian treatment difference: -0.03 mm Hg [95% CI: -2.82 to 2.77 mm Hg]). However, there were changes and increases in medication intensity among sham control patients. RDN was associated with a reduction in office systolic BP compared with sham control at 6 months (adjusted treatment difference: -4.9 mm Hg; P = 0.0015). Night-time BP reductions and win ratio analysis also favored RDN. There was 1 adverse safety event among 253 assessed patients., Conclusions: There was no significant difference between groups in the primary analysis. However, multiple secondary endpoint analyses favored RDN over sham control. (SPYRAL HTN-ON MED Study [Global Clinical Study of Renal Denervation With the Symplicity Spyral Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications]; NCT02439775)., Competing Interests: Funding Support and Author Disclosures This study was funded by Medtronic. Dr Kandzari has received institutional research/grant support from Biotronik, Boston Scientific, Cardiovascular Systems, Inc, Orbus Neich, Teleflex, Medtronic, and Ablative Solutions; and has received personal consulting honoraria from Cardiovascular Systems, Inc, Medtronic, and Abbott Vascular. Dr Townsend is a consultant for Medtronic, Cytel, and Janssen. Dr Kario has received personal fees from Medtronic during the conduct of the study; has received grants from A&D Company, Omron Healthcare, Fukuda Denshi, CureApp, Sanwa Kagaku Kenkyusho, Teijin Pharma, Boehringer Ingelheim Japan, and Fukuda Lifetec; has received consulting fees from A&D Company, JIMRO, Omron Healthcare, CureApp, Terumo, and Fukuda Denshi; has received honoraria from Otsuka Pharmaceuticals and Omron Healthcare; and has participated on the Advisory Board of Fukuda Denshi, outside of the submitted work. Dr Mahfoud is supported by Deutsche Gesellschaft für Kardiologie (DGK), Deutsche Forschungsgemeinschaft (SFB TRR219), and Deutsche Herzstiftung; has received scientific support from Ablative Solutions, Medtronic, and ReCor Medical; and has received speaker honoraria/consulting fees from Ablative Solutions, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, ReCor Medical, Servier, and Terumo. Dr Weber has received consulting fees from Medtronic, ReCor, Ablative Solutions, Johnson and Johnson, and Urovant. Dr Schmieder has received grants and personal fees from Medtronic, Recor, and Ablative Solutions. Dr Pocock has received personal fees from Medtronic outside of the submitted work. Dr Tsioufis has received institutional research/grant support from Medtronic and ReCor Medical; and has received personal consulting honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, ReCor Medical, SERVIER, WinMedica, and ELPEN. Dr Konstantinidis receives payments from Medtronic for work as research center secondary investigator. Dr Choi has received consulting fees from Medtronic, outside of the submitted work. Dr East has received consulting fees from Medtronic. Dr Lauder has received speaker fees and honoraria from Medtronic and ReCor Medical. Dr Cohen has received research support and consultant fees from Medtronic and ReCor; and receives fees from Metavention, outside of the submitted work. Dr Kobayashi is on the advisory board and Speakers Bureau for Medtronic and ReCor Medical. Dr Lee has received grants from and serves on the advisory board for Medtronic, outside of the submitted work. Dr Weil has received support from Medtronic, Recor Medical, Novartis, and AstraZeneca. Dr Agdirlioglu receives speaker honoraria from AstraZeneca, Boehringer Ingelheim, and Novartis, outside of the submitted work. Dr Schlaich has received consulting fees and/or travel and research support from Medtronic, Abbott, Novartis, Servier, Pfizer, and Boehringer Ingelheim. Dr Shetty has received consulting and speaker fees from Medtronic. Dr Devireddy has received personal fees from Edwards Lifesciences, Medtronic, ReCor Medical, and Shockwave Medical, outside of the submitted work. Dr Sharp has received personal fees from Medtronic, Boston Scientific, Recor Medical, and Philips, outside the submitted work. Dr Anderson has received speaker fees from Shockwave Medical, Edwards Lifesciences, and Medtronic. Mr Fahy, Mrs DeBruin, and Dr Brar are employees of Medtronic. Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, ReCor, Servier, and Vifor during the conduct of the study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Pelvic anatomy is critical in challenging rectal resections. This study investigated how pelvic anatomy relates to total mesorectal excision (TME) quality, anastomotic leakage rate, and long-term oncological outcomes., Methods: Patients undergoing elective rectal cancer resection from 2008 to 2017 in an Austrian institution were retrospectively reviewed regardless of the surgical approach. CT scans were analysed for pelvic measurements and volumes. The primary outcomes of interest were the correlation between pelvic dimensions and the TME quality and anastomotic leakage. Subanalysis was done by surgical approach (open, laparoscopic, transanal TME). Secondary outcomes were overall and disease-free survivals., Results: Among 154 eligible patients, 112 were included. The angle between pubic symphysis and promontory significantly correlated with worse TME grades (TME grade 1: mean(s.d.) 102.7(5.7)°; TME grade 2: 92.0(4.4)°; TME grade 3: 91.4(3.6)°; P < 0.001). A significantly lower distance between tumour and circumferential resection margin (CRM) was observed in grade 3 resections, whereas no difference appeared in grade 1 and grade 2 resection (TME grade 1: mean(s.d.) 11.92(9.4) mm; TME grade 2: 10.8(8.1) mm; TME grade 3: 3.1(4.1) mm; P = 0.003). The anastomotic leakage rate was significantly higher in case of a lower CRM (patients with anastomotic leakage: mean(s.d.) 6.8(5.8) mm versus others: 12.6(9.8) mm, P = 0.027), but not associated with pelvimetry measurements. The transanal TME (TaTME) subgroup displayed a wider angle between the pubic symphysis and promontory, younger age and improved TME quality compared to others (respectively, mean TME grades in TaTME versus open versus laparoscopic: 1.0 ± 0.0, 1.5 ± 0.7 and 1.3 ± 0.5, P = 0.013). Finally, oncological survival was not impacted by pelvic measurements or worse TME quality., Conclusion: The angle between the pubic symphysis and promontory and the distance between tumour and CRM were associated with worse TME grades. The anastomotic leakage was associated with a lower CRM but not with pelvimetric measures., (© Crown copyright 2023.)

Purpose: Patients with BRAF V600E -mutant metastatic colorectal cancer (mCRC) have a dismal prognosis. The best strategies in these patients remain elusive. Against this background, we report the clinical course of patients with BRAF V600E -mutant mCRC to retrieve the best treatment strategy., Patients and Methods: Clinico-pathological data were extracted from the electronic health records. Kaplan-Meier method was used to estimate overall (OS) and progression-free survival (PFS). Objective response rate (ORR) was assessed according to RECIST 1.1., Results: In total, 51 patients were enrolled. FOLFOXIRI was administered to 12 patients; 29 patients received FOLFOX or FOLFIRI as first-line treatment. Median OS was 17.6 months. Median PFS with FOLFOXIRI (13.0 months) was significantly prolonged (HR 0.325) as compared to FOLFOX/FOLFIRI (4.3 months). However, this failed to translate into an OS benefit (p = 0.433). Interestingly, addition of a monoclonal antibody to chemotherapy associated with superior OS (HR 0.523). A total of 64.7% patients received further-line therapy, which included a BRAF inhibitor in 17 patients. Targeted therapy associated with very favourable OS (25.1 months)., Conclusion: Patients with BRAF V600E -mutated mCRC benefit from the addition of an antibody to first-line chemotherapy. Further-line treatment including a BRAF inhibitor has a dramatic impact on survival., (© 2023. The Author(s).)

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30-60 mL·min -1 per 1.73 m 2 or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters (n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35-2.30), CV death (HR 2.18, 95% CI: 1.50-3.16), MACE (HR 1.38, 95% CI: 1.12-1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56-2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality., (© 2023. West China School of Stomatology Sichuan University.)

Externalized histones erupt from the nucleus as extracellular traps, are associated with several acute and chronic lung disorders, but their implications in the molecular pathogenesis of interstitial lung disease are incompletely defined. To investigate the role and molecular mechanisms of externalized histones within the immunologic networks of pulmonary fibrosis, we studied externalized histones in human and animal bronchoalveolar lavage (BAL) samples of lung fibrosis. Neutralizing anti-histone antibodies were administered in bleomycin-induced fibrosis of C57BL/6 J mice, and subsequent studies used conditional/constitutive knockout mouse strains for TGFβ and IL-27 signaling along with isolated platelets and cultured macrophages. We found that externalized histones (citH3) were significantly ( P < 0.01) increased in cell-free BAL fluids of patients with idiopathic pulmonary fibrosis (IPF; n = 29) as compared to healthy controls ( n = 10). The pulmonary sources of externalized histones were Ly6G + CD11b + neutrophils and nonhematopoietic cells after bleomycin in mice. Neutralizing monoclonal anti-histone H2A/H4 antibodies reduced the pulmonary collagen accumulation and hydroxyproline concentration. Histones activated platelets to release TGFβ1, which signaled through the TGFbRI/TGFbRII receptor complex on LysM + cells to antagonize macrophage-derived IL-27 production. TGFβ1 evoked multiple downstream mechanisms in macrophages, including p38 MAPK, tristetraprolin, IL-10, and binding of SMAD3 to the IL-27 promotor regions. IL-27RA-deficient mice displayed more severe collagen depositions suggesting that intact IL-27 signaling limits fibrosis. In conclusion, externalized histones inactivate a safety switch of antifibrotic, macrophage-derived IL-27 by boosting platelet-derived TGFβ1. Externalized histones are accessible to neutralizing antibodies for improving the severity of experimental pulmonary fibrosis.

Background: 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., Aims: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2022 Royal Australasian College of Physicians.)

PURPOSE OF REVIEW: Resistant hypertension (RH) defined as uncontrolled blood pressure despite the use of a combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic at maximally tolerated doses is associated with a substantially increased risk of cardiovascular and renal events. Despite targeting relevant pathophysiological pathways contributing to elevated blood pressure, approximately 10-15% of hypertensive patients remain above recommended blood pressure targets. Further optimization of blood pressure control is particularly challenging in patient populations who frequently present with RH such as elderly and patients with chronic kidney disease, due to the unfavorable safety profile of the recommended fourth-line therapy with mineralocorticoid receptor antagonists. This review explores the potential role of endothelin antagonists as an alternative fourth-line therapy. RECENT FINDINGS: Despite the well-described role of the endothelin pathway in the pathogenesis of hypertension, it is currently not targeted therapeutically. Recently however, main outcome data from the PRECISION study, a randomized placebo-controlled phase 3 trial, in patients with RH on guideline-recommended standardized single-pill background therapy convincingly demonstrated the safety and blood pressure-lowering efficacy of the dual endothelin antagonist Aprocitentan. Findings from the phase 3 PRECISION study could signify a turning point in the utilization of endothelin receptor antagonists as a standard treatment for patients with RH., (© 2023. The Author(s).)

Chronic Kidney Disease (CKD) and Cardiovascular Disease (CVD) are two devastating diseases that may occur in nondiabetics or individuals with diabetes and, when combined, it is referred to as cardiorenal disease. The impact of cardiorenal disease on society, the economy and the healthcare system is enormous. Although there are numerous therapies for cardiorenal disease, one therapy showing a great deal of promise is sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors. The SGLT family member, SGLT2, is often implicated in the pathogenesis of a range of diseases, and the dysregulation of the activity of SGLT2 markedly effects the transport of glucose and sodium across the luminal membrane of renal cells. Inhibitors of SGLT2 were developed based on the antidiabetic action initiated by inhibiting renal glucose reabsorption, thereby increasing glucosuria. Of great medical significance, large-scale clinical trials utilizing a range of SGLT2 inhibitors have demonstrated both metabolic and biochemical benefits via numerous novel mechanisms, such as sympathoinhibition, which will be discussed in this review. In summary, SGLT2 inhibitors clearly exert cardio-renal protection in people with and without diabetes in both preclinical and clinical settings. This exciting class of inhibitors improve hyperglycemia, high blood pressure, hyperlipidemia and diabetic retinopathy via multiple mechanisms, of which many are yet to be elucidated.