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Medication adherence is a well-recognized problem in the management of patients with chronic diseases needing a long-term pharmacotherapy. While fighting against non-adherence, an important question frequently arises, i.e., how much adherence is enough to obtain the full treatment benefits? Most studies having attempted to answer this question have used large pharmacy records and health care databases to quantify the percentage of days covered by the prescribed treatment and hence deduce a threshold below which there appears to be fewer benefits from therapy. In the present paper, the use of data obtained using electronic monitoring of adherence is discussed as another means to assess adherence thresholds with a particular emphasis on hypertension. The data show that even with the use of electronic monitoring of adherence, which provides a comprehensive dosing history, it is extremely difficult to define an adherence threshold in hypertension. This is due to many factors that need to be taken into account, including not only the pattern of patients' adherence and their clinical and environmental characteristics, but also the pharmacological characteristics of the prescribed drugs, the severity of the disease and many others. To determine adherence cut-offs more precisely, specific protocols should be designed to answer the question in various clinical conditions. These protocols should be conducted in well-defined patients' groups, they should use the most reliable methods to measure adherence providing if possible a detailed dosing history perhaps combined with drugs levels in blood or urine. These studies should also choose the best methods to measure clinical endpoints, such as ambulatory blood pressure monitoring or home blood pressure in the case of hypertension. One important aspect is that datasets should be solid and large enough to be able to analyze adherence data as a continuous variable using newly developed mathematical models including new metrics catching the complexity of adherence. The rapid development of new technologies like devices, connectivity, and analytics, will probably provide new solutions to improve our ability to define valid and clinically useful adherence thresholds in various therapeutic areas.

Mobile health diagnostics have been shown to be effective and scalable for chronic disease detection and management. By maximizing the smartphones’ optics and computational power, they could allow assessment of physiological information from the morphology of pulse waves and thus estimate cuffless blood pressure (BP). We trained the parameters of an existing pulse wave analysis algorithm (oBPM), previously validated in anaesthesia on pulse oximeter signals, by collecting optical signals from 51 patients fingertips via a smartphone while simultaneously acquiring BP measurements through an arterial catheter. We then compared smartphone-based measurements obtained on 50 participants in an ambulatory setting via the OptiBP app against simultaneously acquired auscultatory systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP) measurements. Patients were normotensive (70.0% for SBP versus 61.4% for DBP), hypertensive (17.1% vs. 13.6%) or hypotensive (12.9% vs. 25.0%). The difference in BP (mean ± standard deviation) between both methods were within the ISO 81,060–2:2018 standard for SBP (− 0.7 ± 7.7 mmHg), DBP (− 0.4 ± 4.5 mmHg) and MBP (− 0.6 ± 5.2 mmHg). These results demonstrate that BP can be measured with accuracy at the finger using the OptiBP smartphone app. This may become an important tool to detect hypertension in various settings, for example in low-income countries, where the availability of smartphones is high but access to health care is low.

Experimentally renal tissue hypoxia appears to play an important role in the pathogenesis of chronic kidney disease (CKD) and arterial hypertension (AHT). In this study we measured renal tissue oxygenation and its determinants in humans using blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) under standardized hydration conditions. Four coronal slices were selected, and a multi gradient echo sequence was used to acquire T2* weighted images. The mean cortical and medullary R2* values ( = 1/T2*) were calculated before and after administration of IV furosemide, a low R2* indicating a high tissue oxygenation. We studied 195 subjects (95 CKD, 58 treated AHT, and 42 healthy controls). Mean cortical R2 and medullary R2* were not significantly different between the groups at baseline. In stimulated conditions (furosemide injection), the decrease in R2* was significantly blunted in patients with CKD and AHT. In multivariate linear regression analyses, neither cortical nor medullary R2* were associated with eGFR or blood pressure, but cortical R2* correlated positively with male gender, blood glucose and uric acid levels. In conclusion, our data show that kidney oxygenation is tightly regulated in CKD and hypertensive patients at rest. However, the metabolic response to acute changes in sodium transport is altered in CKD and in AHT, despite preserved renal function in the latter group. This suggests the presence of early renal metabolic alterations in hypertension. The correlations between cortical R2* values, male gender, glycemia and uric acid levels suggest that these factors interfere with the regulation of renal tissue oxygenation.

Myo -inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di- O -(methoxy-diethyleneglycol)- myo -inositol-1,2,3,5-tetrakis(phosphate), (OEG 2 ) 2 -IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG 2 ) 2 -IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG 2 ) 2 -IP4 disrupts the nucleation and growth of pathological calcification. Cardiovascular calcification is a serious pathology for which effective pharmacological treatments are lacking. Here the authors show that an optimized oligo(ethylene glycol) derivative of inositol phosphate interferes with calcium phosphate crystallization and inhibits soft tissue calcification in vivo following subcutaneous injection.

BackgroundNon-adherence to medication remains a persistent and significant challenge, with profound implications for patient outcomes and the long-term sustainability of healthcare systems. Two decades ago, the World Health Organization (WHO) dedicated its seminal report to adherence to long-term therapies, catalysing notable changes that advanced both research and practice in medication adherence. The aim of this paper was to identify the most important progress made over the last 2 decades in medication adherence management and to initiate a discussion on future objectives, suggesting priority targets for the next 20 years.MethodsThis research used the WHO adherence model as a theoretical framework, categorizing adherence factors into five dimensions: health system, therapy, condition, patient-related, and socioeconomic. Ten international experts, five from Europe and five from the United States, were assigned to these dimensions and participated in structured online discussions. Initially, based on their desk reviews, experts identified significant achievements and future targets. They then ranked these items and provided feedback through several rounds, ensuring anonymity to minimize bias, ultimately reaching a consensus. This iterative process allowed for the creation of top-ten lists of past achievements and future targets for medication adherence management over the next 20 years.ResultsAnalysis of the top-ranked achievements affirms that notable progress has been made in medication adherence research and practice over the past 20 years, with increased awareness and a surge in dedicated scientific publications. Despite these advancements, non-adherence remains a prevalent issue, underscoring the need for the ongoing implementation of innovative solutions identified in this work, such as novel digital health solutions. Interdisciplinary collaboration and a holistic understanding of patient behaviours and socio-economic factors are crucial.ConclusionWhile refraining from imposing a rigid “adherence Decalogue,” we are confident that this overview of recent achievements and the curated selection of future targets may provide a useful foundation for further discussions aimed at advancing medication adherence management. Our results call for a paradigm shift, advocating the repositioning of medication adherence on national agendas and underscoring the necessity for an adherence-supportive ecosystem that extends beyond mere patient support.

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10⁻¹¹). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Urinary steroid metabolomics by GC-MS is an established method in both clinical and research settings to describe steroidogenic disorders. However, population-based reference intervals for adults do not exist. We measured daytime and night time urinary excretion of 40 steroid metabolites by GC-MS in 1128 adult participants of European ancestry, aged 18 to 90 years, within a large population-based, multicentric, cross-sectional study. Age and sex-related patterns in adjacent daytime and night time urine collections over 24 hours were modelled for each steroid metabolite by multivariable linear mixed regression. We compared our results with those obtained through a systematic literature review on reference intervals of urinary steroid excretion. Flexible models were created for all urinary steroid metabolites thereby estimating sex- and age-related changes of the urinary steroid metabolome. Most urinary steroid metabolites showed an age-dependence with the exception of 6β-OH-cortisol, 18-OH-cortisol, and β-cortol. Reference intervals for all metabolites excreted during 24 hours were derived from the 2.5th and 97.5th percentile of modelled reference curves. The excretion rate per period of metabolites predominantly derived from the adrenals was mainly higher during the day than at night and the correlation between day and night time metabolite excretion was highly positive for most androgens and moderately positive for glucocorticoids. This study gives unprecedented new insights into sex- and age-specificity of the human adult steroid metabolome and provides further information on the day/night variation of urinary steroid hormone excretion. The population-based reference ranges for 40 GC-MS-measured metabolites will facilitate the interpretation of steroid profiles in clinical practice.

Background Men have larger kidneys than women, but it is unclear whether gender remains an independent predictor of kidney size (expressed as weight or length) after correction for body size. We analysed autopsy data to assess whether relative renal length and weight (e.g. corrected for body weight, height or body surface area (BSA)) are also larger in men. Assuming that kidney size is associated with nephron number, opposite findings could partly explain why women are less prone to the development and progression of chronic kidney disease than men. Methods All forensic autopsies performed between 2009 and 2015 at the local university hospital of Geneva in individuals of European descent aged ≥18 years without a known history of diabetes and/or kidney disease were examined. Individuals with putrefied or severely injured bodies were excluded. Relative renal weight and length were respectively defined as renal weight divided by body weight or BSA and renal length divided by body height or BSA. Results A total of 635 autopsies (68.7% men) were included in the analysis. Left kidneys were on average 8 g heavier and 2 mm longer than right kidneys (both: p  < 0.05). Absolute renal weight (165 ± 40 vs 122 ± 29 g) and length (12.0 ± 1.3 vs 11.4 ± 1.1 cm) were higher in men. Relative renal weight was also higher in men, but relative renal length was larger in women. In multivariable regression analysis, body height, body weight, the degree of blood congestion or depletion at autopsy and age were determinants of renal weight, whereas arterial hypertension and smoking were not. Percentile curves of renal weight and length according to sex and body height were constructed. Conclusion Absolute and relative renal weights were both smaller in women. This is in line with recent studies stating that nephron numbers are also lower in women. Relative renal length was longer in women, suggesting that female kidneys have a more elongated shape. In comparison with older autopsy studies, renal weight appears to be stable over time.

Introduction: The measurement of renal functional reserve (RFR) can unmask glomerular hyperfiltration in residual nephrons, but its determination is time-consuming. In this study, we assessed whether contrast-enhanced ultrasound (CEUS) is a valuable alternative to the gold standard inulin clearance and whether L-arginine or protein shakes lead to similar changes in glomerular filtration rate (GFR) as animal proteins in men and women. Methods: Changes in GFR and renal microperfusion were studied in 25 healthy subjects (8 men, 17 women) by simultaneously performing inulin clearance and CEUS (perfusion index, PI) before and 1 and 2 h after different protein loads (L-arginine, protein shake or meat). The Doppler parameters – renal resistive index (RRI) and pulsatility index (PuI) – were also measured. Results: None of the oral protein loads induced significant changes in CEUS-assessed PI. Only meat increased inulin clearance (from 111.2 ± 16.0 to 149.8 ± 27.2 mL/min, p < 0.05) and mobilized RFR, while L-arginine decreased GFR (106.7 ± 45.3 to 86.3 ± 42.6 mL/min, p < 0.05). Protein shakes had a neutral effect. There were no correlations between changes in inulin clearance and PI. At Doppler, RRI and PuI increased after meat intake (from 0.647 ± 0.029 to 0.694 ± 0.050 a.u., p < 0.05 and from 1.130 ± 0.087 to 1.318 ± 0.163 a.u., p < 0.05, respectively), but their changes also did not correlate with changes in inulin clearance. Results were similar in both sexes. Conclusions: CEUS is not a valuable alternative for inulin clearance to measure RFR. Meat ingestion leads to modest changes in renal Doppler parameters and to glomerular hyperfiltration in both women and men, while protein shakes and L-arginine do not.

Glomerular damage indicated by proteinuria is a main symptom in diabetic nephropathy. Mineralocorticoid receptor (MR) antagonists (MRAs) are beneficial irrespective of aldosterone availability. Thus, we hypothesized an alternatively activated MR to promote glomerular damage in proteinuric diabetic nephropathy. Specifically, we aimed first to demonstrate the presence of steroid hormones serving as alternative MR targets in type II diabetic patients with proteinuric kidney disease, second whether MR selectivity was modified, third to characterize MR and glucocorticoid receptor (GR) expression and activity in glomerular cell types exposed to eu- and hyperglycemic conditions, fourth to characterize the pro-fibrotic potential of primary human renal mesangial cells (HRMC) upon stimulation with aldosterone and cortisol, and fifth to specify the involvement of the MR and/or GR in pro-fibrotic signaling. Urinary steroid hormone profiles of patients with diabetic kidney disease were analyzed by gas chromatography-mass spectrometry and compared to an age and gender matched healthy control group taken out of a population study. In both cohorts, the activity of the MR pre-receptor enzyme 11[beta]-hydroxysteroid dehydrogenase type 2 (HSD11B2), which inactivates cortisol to prevent it from binding to the MR, was assessed to define a change in MR selectivity. Expression of HSD11B2, MR and GR was quantified in HRMC and primary human renal glomerular endothelial cells (HRGEC). Activity of MR and GR was explored in HRMC by measuring the MR/GR down-stream signal SGK1 and the pro-fibrotic genes TGFB1, FN1 and COL1A1 in normal and high glucose conditions with the MR/GR agonists aldosterone/cortisol and the MR/GR antagonists spironolactone/RU486. In patients with diabetic kidney disease alternative MR activation is conceivable as cortisol and cortisone metabolites are increased. Systemic availability of active metabolites is counteracted via an increased HSD11B2 activity. As this cortisol deactivation is absent in HRMC and HRGEC, cortisol binding to the MR is enabled. Both, cortisol and aldosterone stimulation led to an increased expression of pro-fibrotic genes in HRMC. This mechanism was related to the MR as well as the GR and more marked in high glucose conditions linking the benefit of MRAs in diabetic kidney disease to these findings.