Ambulatory blood pressure monitoring. Current status and future perspectives. / Monitorización ambulatoria de la presión arterial. Situación actual y perspectivas futuras.

Ambulatory Blood Pressure Monitoring (ABPM) is considered the best method for obtaining a reliable estimation of the true blood pressure. Average values obtained during the whole 24-hour period, or during daytime and nighttime periods are better correlated with the risk of mortality and cardiovascular disease compared to clinic or office blood pressure. Indeed, nighttime blood pressure, a measure only obtained through ABPM, is the most powerful risk predictor. ABPM is complementary to clinic blood pressure measurement and allows the definition of blood pressure phenotypes, such as "white-coat or masked hypertension, when clinic and ABPM measurements show discrepancy in normal values. Additional potentially relevant features include blood pressure variability, such as nocturnal blood pressure decline, morning surge or short-term variability, as determined by standard deviation or the coefficient of variation.

Shepherding the past: High-resolution data on Neolithic Southern Iberian livestock management at Cueva de El Toro (Antequera, Málaga).

The feeding strategies of the first domesticated herds had to manage the risks arising from the novelty of livestock practices in territories often distant from the animals' primary habitats. The Iberian Peninsula is characterised by a great diversity of environments, which undoubtedly influenced these dynamics. At the beginning of the Neolithic period these led the possibility to combine diverse livestock farming practices based on different animal feeding habits. This variability is also consistent with the rythms of adoption of domesticated animals, being later on the northern area. In order to address this issue, this work focuses on the dietary regimes of early sheep herds from southern Iberia, an area for which information is currently scarce. This study utilises high-resolution radiocarbon dating and stable isotope data on teeth to investigate sheep husbandry management strategies in Cueva de El Toro (Antequera, Málaga). The radiocarbon dates on the analysed remains evidenced they were deposited at the site over a short period, supporting the recurrent use of the cave. The sequential analysis of oxygen and carbon isotopes in tooth enamel reveals distinct livestock management strategies, reproduction patterns, feeding habits, and mobility during this short period. This variability demonstrates that livestock management practices in the western Mediterranean are more diverse than previously considered. Furthermore, these findings support the hypothesis that early Neolithic communities in the southern Iberian Peninsula were able to adopt different feeding strategies within the same herd, depending on their ecological and productive needs.

Artificial Intelligence-Derived Risk Prediction: A Novel Risk Calculator Using Office and Ambulatory Blood Pressure.

BACKGROUND: Quantification of total cardiovascular risk is essential for individualizing hypertension treatment. This study aimed to develop and validate a novel, machine-learning-derived model to predict cardiovascular mortality risk using office blood pressure (OBP) and ambulatory blood pressure (ABP). METHODS: The performance of the novel risk score was compared with existing risk scores, and the possibility of predicting ABP phenotypes utilizing clinical variables was assessed. Using data from 59 124 patients enrolled in the Spanish ABP Monitoring registry, machine-learning approaches (logistic regression, gradient-boosted decision trees, and deep neural networks) and stepwise forward feature selection were used. RESULTS: For the prediction of cardiovascular mortality, deep neural networks yielded the highest clinical performance. The novel mortality prediction models using OBP and ABP outperformed other risk scores. The area under the curve achieved by the novel approach, already when using OBP variables, was significantly higher when compared with the area under the curve of the Framingham risk score, Systemic Coronary Risk Estimation 2, and Atherosclerotic Cardiovascular Disease score. However, the prediction of cardiovascular mortality with ABP instead of OBP data significantly increased the area under the curve (0.870 versus 0.865; P=3.61×10-28), accuracy, and specificity, respectively. The prediction of ABP phenotypes (ie, white-coat, ambulatory, and masked hypertension) using clinical characteristics was limited. CONCLUSIONS: The receiver operating characteristic curves for cardiovascular mortality using ABP and OBP with deep neural network models outperformed all other risk metrics, indicating the potential for improving current risk scores by applying state-of-the-art machine learning approaches. The prediction of cardiovascular mortality using ABP data led to a significant increase in area under the curve and performance metrics.

Assessment and management of exaggerated blood pressure response to standing and orthostatic hypertension: consensus statement by the European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability.

Recent evidence suggests that an exaggerated blood pressure (BP) response to standing (ERTS) is associated with an increased risk of adverse outcomes, both in young and old individuals. In addition, ERTS has been shown to be an independent predictor of masked hypertension. In the vast majority of studies reporting on the prognostic value of orthostatic hypertension (OHT), the definition was based only on systolic office BP measurements. This consensus statement provides recommendations on the assessment and management of individuals with ERTS and/or OHT. ERTS is defined as an orthostatic increase in SBP at least 20 mmHg and OHT as an ERTS with standing SBP at least 140 mmHg. This statement recommends a standardized methodology to assess ERTS, by considering body and arm position, and the number and timing of BP measurements. ERTS/OHT should be confirmed in a second visit, to account for its limited reproducibility. The second assessment should evaluate BP changes from the supine to the standing posture. Ambulatory BP monitoring is recommended in most individuals with ERTS/OHT, especially if they have high-normal seated office BP. Implementation of lifestyle changes and close follow-up are recommended in individuals with ERTS/OHT. Whether specific antihypertensive treatment should be administered in hypertensive patients with ERTS/OHT is unknown. Thus, they should be managed as any other hypertensive patient. Standardized standing BP measurement should be implemented in future epidemiological and interventional studies.

Cardio-ankle vascular index for predicting cardiovascular morbimortality and determinants for its progression in the prospective advanced approach to arterial stiffness (TRIPLE-A-Stiffness) study.

BACKGROUND: The cardio-ankle vascular index (CAVI) measure of arterial stiffness is associated with prevalent cardiovascular risk factors, while its predictive value for cardiovascular events remains to be established. The aim was to determine associations of CAVI with cardiovascular morbimortality (primary outcome) and all-cause mortality (secondary outcome), and to establish the determinants of CAVI progression. METHODS: TRIPLE-A-Stiffness, an international multicentre prospective longitudinal study, enrolled >2000 subjects ≥40 years old at 32 centres from 18 European countries. Of these, 1250 subjects (55% women) were followed for a median of 3.82 (2.81-4.69) years. FINDINGS: Unadjusted cumulative incidence rates of outcomes according to CAVI stratification were higher in highest stratum (CAVI > 9). Cox regression with adjustment for age, sex, and cardiovascular risk factors revealed that CAVI was associated with increased cardiovascular morbimortality (HR 1.25 per 1 increase; 95% confidence interval, CI: 1.03-1.51) and all-cause mortality (HR 1.37 per 1 increase; 95% CI: 1.10-1.70) risk in subjects ≥60 years. In ROC analyses, CAVI optimal threshold was 9.25 (c-index 0.598; 0.542-0.654) and 8.30 (c-index 0.565; 0.512-0.618) in subjects ≥ or <60 years, respectively, to predict increased CV morbimortality. Finally, age, mean arterial blood pressure, anti-diabetic and lipid-lowering treatment were independent predictors of yearly CAVI progression adjusted for baseline CAVI. INTERPRETATION: The present study identified additional value for CAVI to predict outcomes after adjustment for CV risk factors, in particular for subjects ≥60 years. CAVI progression may represent a modifiable risk factor by treatments. FUNDING: International Society of Vascular Health (ISVH) and Fukuda Denshi, Japan.

A blunted nocturnal blood pressure decline is associated with all-cause and cardiovascular mortality.

OBJECTIVE: It has been suggested that a blunted nocturnal blood pressure (BP) decline is associated with a poor prognosis. Nevertheless, it remains unclear if an abnormal dipping is deleterious per se or it merely reflects an elevated BP during sleep. We aimed to assess the prognostic value of nocturnal BP decline, with or without concomitant elevated nocturnal BP. METHODS: Vital status and cause of death were obtained from death certificates in 59 124 patients, enrolled in the Spanish ABPM Registry between 2004 and 2014 (median follow-up: 10 years). The association between night-to-day ratio (NDR) and dipping patterns (extreme dippers, dippers, reduced dippers, and risers) with all-cause and cardiovascular mortality were evaluated by Cox-proportional models adjusted for clinical confounders and 24 h blood pressure. RESULTS: NDR was associated with all-cause mortality [hazard ratio for 1SD change: 1.15; 95% confidence interval (CI) 1.13-1.17]. Reduced dippers (1.13; 1.06-1.20) and risers (1.41; 1.32-1.51) were associated with an increased risk of all-cause death, whereas extreme dippers (0.90; 0.79-1.02) were not. Elevated NDR (≥0.9) in the absence of elevated night SBP (<120 mmHg) was associated with an increased risk of death (1.13; 1.04-1.22), as well as elevated night SBP but normal NDR (1.38; 1.26-1.50), and the combination of both abnormalities (1.56; 1.46-1.66). Similar results were obtained for cardiovascular mortality. CONCLUSION: Abnormalities in the circadian pattern are associated with an increased risk of all-cause and cardiovascular mortality. This is maintained even in the absence of nocturnal BP elevation.

Prognostic Relevance of Short-Term Blood Pressure Variability. The Spanish ABPM Registry.

BACKGROUND: The prognostic relevance of short-term blood pressure (BP) variability in hypertension is not clearly established. We aimed to evaluate the association of short-term BP variability, with all-cause and cardiovascular mortality in a large cohort of patients with hypertension. METHODS: We selected 59 124 patients from the Spanish Ambulatory Blood Pressure Monitoring Registry from 2004 to 2014 (median follow-up: 9.7 years). Systolic and diastolic BP SD and coefficient of variation from daytime and nighttime, weighted SD, weighted coefficient of variation, average real variability (mean of differences between consecutive readings), and BP variability ratio (ratio between systolic and diastolic 24-hour SD) were calculated through baseline 24-hour ambulatory BP monitoring. Association with all-cause and cardiovascular mortality were assessed by Cox regression models adjusted for clinical confounders and BP. RESULTS: Patients who died during follow-up had higher values of BP variability compared with those remaining alive. In adjusted models systolic and diastolic daytime and weighted SD and coefficient of variation, average real variability, as well as systolic nighttime SD and BP variability ratio were all significantly associated with all-cause and cardiovascular mortality. Hazard ratios for 1-SD increase in the systolic components ranged from 1.05 to 1.12 for all-cause mortality and from 1.07 to 1.17 for cardiovascular mortality. A daytime SD≥13 mm Hg, a nighttime and a weighted SD≥12 mm Hg, and an average real variability ≥10 mm Hg, all systolic, were independently associated with mortality. CONCLUSIONS: Short-term blood pressure variability shows a relatively weak but significant association with all-cause and cardiovascular mortality in patients with hypertension.

Impact of timing of antihypertensive treatment on mortality: an observational study from the Spanish Ambulatory Blood Pressure Monitoring Registry.

BACKGROUND AND AIMS: Whether bedtime versus morning administration of antihypertensive therapy is beneficial on outcomes is controversial. We evaluated the risk of total and cardiovascular mortality in a very large observational cohort of treated hypertensive patients, according to the timing of their usual treatment administration (morning versus evening). METHODS: Vital status and cause of death were obtained from death certificates of 28 406 treated hypertensive patients (mean age 62 years, 53% male individuals), enrolled in the Spanish Ambulatory Blood Pressure Monitoring (ABPM) Registry between 2004 and 2014. Among the 28 406 patients, most (86%) received their medication exclusively in the morning; whilst 13% were treated exclusively in the evening or at bedtime. Follow-up was for a median of 9.7 years and 4345 deaths occurred, of which 1478 were cardiovascular deaths. RESULTS: Using Cox-models adjusted for clinical confounders and 24-h SBP, and compared with patients treated in the morning (reference group), all-cause mortality [hazard ratio 1.01; 95% CI 0.93-1.09) and cardiovascular mortality (hazard ratio 1.04; 95% CI 0.91-1.19) was not significantly different in those receiving evening medication dosing. The results were consistent in all the subgroups of patients analysed. CONCLUSION: In this very large observational study, morning versus bedtime dosing of antihypertensive medication made no difference to the subsequent risk of all-cause or cardiovascular mortality. These findings are in accordance with results from a recent randomized controlled trial and do not support the hypothesis of a specific beneficial effect of night-time antihypertensive treatment dosing on risk of all-cause or cardiovascular death.

Effect of salivary fluid characteristics on the physical features of in vitro bread bolus: From the absence of saliva to artificially simulated hypersalivation.

Saliva facilitates food oral processing, bolus formation, swallowing, and sensory perception, in addition to contributing to oral health and phonation. Ageing, health affections, and polymedication are among many causes altering salivary production, modifying the mastication process, the food impregnation ratio, and in turn altering the characteristics of the bolus, swallowing, and digestion. In this in vitro work, using the AM2 masticator apparatus, which replicates the mechanical actions taking place while chewing solid foods and produces realistic food bolus in various oral conditions, we investigated the effect of salivary fluid characteristics, i.e., composition, quantity (from absence to hypersalivation), temperature, and enzymatic action, on the physical characteristics (i.e., particle size distribution (PSD), bolus mass, salivary fluid content) of in vitro boluses of Traditional French baguette. A ready-to-swallow bolus of baguette displayed on average a d50 value (median particle size by mass) of 4.1 ± 0.4 mm, with saliva fluid constituting âˆ¼ 35 % of the final bolus mass. The absence of saliva in mouth led to a deficient oral processing, forming bread boluses constituted by extremely big particles (ca. 80 % of particles had a size > 7.1 mm) that likely cannot be swallowed safely. On the contrary, an excess of saliva favoured an excessive breaking down of bread, leading to bread boluses constituted by smaller particles than those formed under healthy salivary conditions (d50 decreased from 4.1 mm to 3.1 mm), having a higher salivary fluid content (+10 %). On the other hand, the salivary fluid temperature did not affect PSD, d50, bolus mass, or salivary fluid content of in vitro bread boluses, however, the addition of human salivary α-amylase did, favouring particle size reduction (d50 decreased to 2.6 mm). Therefore, beyond the correlation between bolus hydration by saliva and food properties such as hardness and moisture content, our findings indicate that the quantity of salivary fluid present in the oral cavity and the enzymatic activity of salivary α-amylase during bread mastication significantly influence both the particle size distribution and the fluid content of bread boluses, ultimately determining the physical properties of the bolus and, therefore, potentially impacting the subsequent swallowing process.

From molecular mechanisms of prostate cancer to translational applications: based on multi-omics fusion analysis and intelligent medicine.

Prostate cancer is the most common cancer in men worldwide and has a high mortality rate. The complex and heterogeneous development of prostate cancer has become a core obstacle in the treatment of prostate cancer. Simultaneously, the issues of overtreatment in early-stage diagnosis, oligometastasis and dormant tumor recognition, as well as personalized drug utilization, are also specific concerns that require attention in the clinical management of prostate cancer. Some typical genetic mutations have been proved to be associated with prostate cancer's initiation and progression. However, single-omic studies usually are not able to explain the causal relationship between molecular alterations and clinical phenotypes. Exploration from a systems genetics perspective is also lacking in this field, that is, the impact of gene network, the environmental factors, and even lifestyle behaviors on disease progression. At the meantime, current trend emphasizes the utilization of artificial intelligence (AI) and machine learning techniques to process extensive multidimensional data, including multi-omics. These technologies unveil the potential patterns, correlations, and insights related to diseases, thereby aiding the interpretable clinical decision making and applications, namely intelligent medicine. Therefore, there is a pressing need to integrate multidimensional data for identification of molecular subtypes, prediction of cancer progression and aggressiveness, along with perosonalized treatment performing. In this review, we systematically elaborated the landscape from molecular mechanism discovery of prostate cancer to clinical translational applications. We discussed the molecular profiles and clinical manifestations of prostate cancer heterogeneity, the identification of different states of prostate cancer, as well as corresponding precision medicine practices. Taking multi-omics fusion, systems genetics, and intelligence medicine as the main perspectives, the current research results and knowledge-driven research path of prostate cancer were summarized.

Benchmarking of a microgel-reinforced hydrogel-based aqueous lubricant against commercial saliva substitutes.

Xerostomia, the subjective sensation of 'dry mouth' affecting at least 1 in 10 adults, predominantly elders, increases life-threatening infections, adversely impacting nutritional status and quality of life. A patented, microgel-reinforced hydrogel-based aqueous lubricant, prepared using either dairy or plant-based proteins, has been demonstrated to offer substantially enhanced lubricity comparable to real human saliva in in vitro experiments. Herein, we present the benchmarking of in vitro lubrication performance of this aqueous lubricant, both in its dairy and vegan formulation against a range of widely available and employed commercial saliva substitutes, latter classified based on their shear rheology into "liquids", "viscous liquids" and "gels", and also had varying extensional properties. Strikingly, the fabricated dairy-based aqueous lubricant offers up to 41-99% more effective boundary lubrication against liquids and viscous liquids, irrespective of topography of the tested dry mouth-mimicking tribological surfaces. Such high lubricity of the fabricated lubricants might be attributed to their limited real-time desorption (7%) from a dry-mouth mimicking hydrophobic surface unlike the tested commercial products including gels (23-58% desorption). This comprehensive benchmarking study therefore paves the way for employing these microgel-based aqueous lubricant formulations as a novel topical platform for dry mouth therapy.

Blood Pressure Variability as a Risk Factor for Cardiovascular Disease: Which Antihypertensive Agents Are More Effective?

Blood pressure oscillations during different time scales, known as blood pressure variability (BPV), have become a focus of growing scientific interest. BPV can be measured at long-term (seasonal variability or visit-to-visit), at mid-term (differences in consecutive days or weeks) or at short-term (day-night differences or changes induced by other daily activities and conditions). An increased BPV, either at long, mid or short-term is associated with a poor cardiovascular prognosis independently of the amount of blood pressure elevation. There is scarce evidence on the effect of different antihypertensive treatments on BPV, but some observational and interventional studies suggest that calcium channel blockers in general, and particularly amlodipine, either in monotherapy or combined with renin-angiotensin system blockers, can reduce BPV more efficiently than other antihypertensive drugs or combinations. Nevertheless, there are several aspects of the relationship between BPV, antihypertensive treatment, and clinical outcomes that are still unknown, and more work should be performed before considering BPV as a therapeutical target in clinical practice.

Altered sleep and neurovascular dysfunction in alpha-synucleinopathies: the perfect storm for glymphatic failure.

Clinical and cognitive progression in alpha-synucleinopathies is highly heterogeneous. While some patients remain stable over long periods of time, other suffer early dementia or fast motor deterioration. Sleep disturbances and nocturnal blood pressure abnormalities have been identified as independent risk factors for clinical progression but a mechanistic explanation linking both aspects is lacking. We hypothesize that impaired glymphatic system might play a key role on clinical progression. Glymphatic system clears brain waste during specific sleep stages, being blood pressure the motive force that propels the interstitial fluid through brain tissue to remove protein waste. Thus, the combination of severe sleep alterations, such as REM sleep behavioral disorder, and lack of the physiological nocturnal decrease of blood pressure due to severe dysautonomia may constitute the perfect storm for glymphatic failure, causing increased abnormal protein aggregation and spreading. In Lewy body disorders (Parkinson's disease and dementia with Lewy bodies) the increment of intraneuronal alpha-synuclein and extracellular amyloid-ß would lead to cognitive deterioration, while in multisystemic atrophy, increased pathology in oligodendroglia would relate to the faster and malignant motor progression. We present a research model that may help in developing studies aiming to elucidate the role of glymphatic function and associated factors mainly in alpha-synucleinopathies, but that could be relevant also for other protein accumulation-related neurodegenerative diseases. If the model is proven to be useful could open new lines for treatments targeting glymphatic function (for example through control of nocturnal blood pressure) with the objective to ameliorate cognitive and motor progression in alpha-synucleinopathies.

European Society of Hypertension recommendations for the validation of cuffless blood pressure measuring devices: European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability.

BACKGROUND: There is intense effort to develop cuffless blood pressure (BP) measuring devices, and several are already on the market claiming that they provide accurate measurements. These devices are heterogeneous in measurement principle, intended use, functions, and calibration, and have special accuracy issues requiring different validation than classic cuff BP monitors. To date, there are no generally accepted protocols for their validation to ensure adequate accuracy for clinical use. OBJECTIVE: This statement by the European Society of Hypertension (ESH) Working Group on BP Monitoring and Cardiovascular Variability recommends procedures for validating intermittent cuffless BP devices (providing measurements every >30 sec and usually 30-60 min, or upon user initiation), which are most common. VALIDATION PROCEDURES: Six validation tests are defined for evaluating different aspects of intermittent cuffless devices: static test (absolute BP accuracy); device position test (hydrostatic pressure effect robustness); treatment test (BP decrease accuracy); awake/asleep test (BP change accuracy); exercise test (BP increase accuracy); and recalibration test (cuff calibration stability over time). Not all these tests are required for a given device. The necessary tests depend on whether the device requires individual user calibration, measures automatically or manually, and takes measurements in more than one position. CONCLUSION: The validation of cuffless BP devices is complex and needs to be tailored according to their functions and calibration. These ESH recommendations present specific, clinically meaningful, and pragmatic validation procedures for different types of intermittent cuffless devices to ensure that only accurate devices will be used in the evaluation and management of hypertension.

Requirements for design and function of blood pressure measuring devices used for the management of hypertension: Consensus Statement by the European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability and STRIDE BP.

OBJECTIVE: To develop scientific consensus recommendations for the optimal design and functions of different types of blood pressure (BP) measuring devices used in clinical practice for the detection, management, and long-term follow-up of hypertension. METHODS: A scientific consensus meeting was performed by the European Society of Hypertension (ESH) Working Group on BP Monitoring and Cardiovascular Variability and STRIDE BP (Science and Technology for Regional Innovation and Development in Europe) during the 2022 Scientific Meeting of the ESH in Athens, Greece. Manufacturers were also invited to provide their feedback on BP device design and development. Thirty-one international experts in clinical hypertension and BP monitoring contributed to the development of consensus recommendations on the optimal design of BP devices. STATEMENT: International consensus was reached on the requirements for the design and features of five types of BP monitors, including office (or clinic) BP monitors, ambulatory BP monitors, home BP monitors, home BP telemonitors, and kiosk BP monitors for public spaces. For each device type "essential" requirements (must have), and "optional" ones (may have) are presented, as well as additional comments on the optimal device design and features. CONCLUSIONS: These consensus recommendations aim at providing manufacturers of BP devices with the requirements that are considered mandatory, or optional, by clinical experts involved in the detection and management of hypertension. They are also directed to administrative healthcare personnel involved in the provision and purchase of BP devices so that they can recommend the most appropriate ones.

Relationship between clinic and ambulatory blood pressure and mortality: an observational cohort study in 59 124 patients.

BACKGROUND: Ambulatory blood pressure provides a more comprehensive assessment than clinic blood pressure, and has been reported to better predict health outcomes than clinic or home pressure. We aimed to examine associations of clinic and 24-h ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of primary care patients referred for assessment of hypertension. METHODS: We did an observational cohort study using clinic and ambulatory blood pressure data obtained from March 1, 2004, to Dec 31, 2014, from the Spanish Ambulatory Blood Pressure Registry. This registry included patients from 223 primary care centres from the Spanish National Health System in all 17 regions of Spain. Mortality data (date and cause) were ascertained by a computerised search of the vital registry of the Spanish National Institute of Statistics. Complete data were available for age, sex, all blood pressure measures, and BMI. For each study participant, follow-up was from the date of their recruitment to the date of death or Dec 31, 2019, whichever occurred first. Cox models were used to estimate associations between usual clinic or ambulatory blood pressure and mortality, adjusted for confounders and additionally for alternative measures of blood pressure. For each measure of blood pressure, we created five groups (ie, fifths) defined by quintiles of that measure among those who subsequently died. FINDINGS: During a median follow-up of 9·7 years, 7174 (12·1%) of 59 124 patients died, including 2361 (4·0%) from cardiovascular causes. J-shaped associations were observed for several blood pressure measures. Among the top four baseline-defined fifths, 24-h systolic blood pressure was more strongly associated with all-cause death (hazard ratio [HR] 1·41 per 1 - SD increment [95% CI 1·36-1·47]) than clinic systolic blood pressure (1·18 [1·13-1·23]). After adjustment for clinic blood pressure, 24-h blood pressure remained strongly associated with all-cause deaths (HR 1·43 [95% CI 1·37-1·49]), but the association between clinic blood pressure and all-cause death was attenuated when adjusted for 24-h blood pressure (1·04 [1·00-1·09]). Compared with the informativeness of clinic systolic blood pressure (100%), night-time systolic blood pressure was most informative about risk of all-cause death (591%) and cardiovascular death (604%). Relative to blood pressure within the normal range, elevated all-cause mortality risks were observed for masked hypertension (HR 1·24 [95% CI 1·12-1·37]) and sustained hypertension (1·24 [1·15-1·32]), but not white-coat hypertension, and elevated cardiovascular mortality risks were observed for masked hypertension (1·37 [1·15-1·63]) and sustained hypertension (1·38 [1·22-1·55]), but not white-coat hypertension. INTERPRETATION: Ambulatory blood pressure, particularly night-time blood pressure, was more informative about the risk of all-cause death and cardiovascular death than clinic blood pressure. FUNDING: Spanish Society of Hypertension, Lacer Laboratories, UK Medical Research Council, Health Data Research UK, National Institute for Health and Care Research Biomedical Research Centres (Oxford and University College London Hospitals), and British Heart Foundation Centre for Research Excellence.

Specific identification of Mycobacterium bovis by Loop-Mediated Isothermal Amplification (LAMP) targeting the Region of Difference 12 (RD12) of the M. tuberculosis complex.

Bovine tuberculosis is a prevalent zoonotic disease that causes high risks for production animals, dairy producers and consumers, together with significant economic losses. Thus, methods for easy, fast and specific detection of Mycobacterium bovis in small and medium-sized livestock under field conditions are very required. In this work, a Loop-Mediated Isothermal Amplification LAMP-PCR targeting the Region of Difference 12 (RD12) of M. bovis genome was designed for the purpose of identification. A set of six primers designed for the isothermal amplification of five different genomic fragments led to the specific identification of M. bovis from other mycobacterial species. A basic colorimetric reaction was clearly observed at first sight under natural light, indicating positive identification of M. bovis in a maximum of 30 min of isothermal amplification at 65 °C. The limit of detection was near 50 fg of M. bovis genomic DNA, corresponding approximately to 10 copies of the genome. •The proposed LAMP-PCR amplification of M. bovis genomic DNA might be performed by untrained laboratory personnel.•Specific identification of M. bovis LAMP is possible in 30 min at 65.. C using a simple water bath.•The basic colorimetric reaction for M. bovis identification could be observed with the naked eye under natural light.

Paediatric solid oral dosage forms for combination products: Improving in vitro swallowability of minitablets using binary mixtures with pellets.

There is a growing interest in enhancing the acceptability of paediatric pharmaceutical formulations. Solid oral dosage forms (SODF), especially multiparticulates, are being considered as an alternative to liquid formulations, but they may compromise palatability when large volumes are required for dosing. We hypothesised that a binary mixture of multiparticulates for paediatric use, designed to increase the formulation maximum packing fraction, could reduce the viscosity of the mixture in soft food and facilitate swallowing. Using the Paediatric Soft Robotic Tongue (PSRT) - an in vitro device inspired by the anatomy and physiology of 2-year-old children - we investigated the oral phase of swallowing for multi-particulate formulations, i.e., pellets (350 and 700 µm particles), minitablets (MTs, 1.8 mm), and their binary mixtures (BM), by evaluating oral swallowing time, the percentage of particles swallowed, and post-swallow residues. We also conducted a systematic analysis of the effect of the administration method, bolus volume, carrier type, particle size, and particle volume fraction on pellets swallowability. The results demonstrated that the introduction of pellets affected the flowing ability of the carriers, increasing shear viscosity. The size of the pellets did not appear to influence particle swallowability but raising the particle volume fraction (v.f.) above 10% resulted in a decrease in the percentage of particles swallowed. At v.f. 0.4, pellets were easier to swallow (+ 13.1%) than MTs, being the administration method used highly dependent on the characteristics of the multi-particulate formulation under consideration. Finally, mixing MTs with only 24% of pellets improved particle swallowability, achieving swallowing levels similar to those of pellets alone. Thus, combining SODF, i.e., MTs and pellets, improves MT swallowability, and offers new possibilities for adjusting product palatability, being particularly attractive for combination products.