Performance of the Aktiia optical blood pressure measurement device in the elderly: a comparison with double blinded auscultation in different body positions.

BACKGROUND: Accurate blood pressure (BP) measurement is essential for the correct diagnosis and management of hypertension (HTN) especially in the elderly population. As with of all BP devices, the accuracy of cuffless devices must be verified. This study (NCT04027777) aimed to evaluate the performance of a wrist cuffless optical BP device in an elderly population cohort in different body positions with auscultation as the reference measurement. DESIGN AND METHODS: Patients aged 65-85 years with different BP categories but without diabetes were recruited. After an initial calibration based on auscultatory measurements, BP estimation from the Aktiia Bracelet (Aktiia SA, Switzerland) were compared to reference double-blinded auscultatory measurements in sitting, standing and lying positions on four separate visits distributed over one month. In the absence of a universal standard for cuffless BP device at the time of the study, modified ISO81060-2 criteria were used for performance analysis. RESULTS: Thirty-five participants were included in the analysis fulfilling the inclusion requirements of ISO 81060-2. A total of 469 paired measurements were obtained with overall 83% acceptance rate. Differences (mean ± SD)   between Aktiia Bracelet and auscultation for systolic BP were -0.26 ± 9.96 mmHg for all body positions aggregated (sitting 1.23 ± 7.88 mmHg, standing -1.81 ± 11.11 mmHg, lying -1.8 ± 9.96 mmHg). Similarly, differences for diastolic BP were -0.75 ± 7.0 mmHg (0.2 ± 5.55 mmHg, -5.35 ± 7.75 mmHg and -0.94 ± 7.47 mmHg, respectively). Standard deviation of the averaged differences per subject for systolic/diastolic BP was 3.8/2.5 mmHg in sitting and 4.4/3.7 mmHg for all body positions aggregated. CONCLUSIONS: Overall, this study demonstrates a similar performance of the Aktiia Bracelet compared to auscultation in an elderly population in body positions representative of daily activities. The use of more comfortable, non-invasive, and non-occlusive BP monitors during long periods may facilitate e-health and may contribute to better management of HTN, including diagnosis and treatment of HTN, in the elderly.

Accuracy of blood pressure measurements is essential in the diagnosis and the follow-up of patients with high blood pressure. As with any blood pressure measuring device, a validation is necessary. In this study including a elderly population, we compared values obtained by the cuffless Aktiia Bracelet (Aktiia SA, Switzerland) after an initial calibration with the reference auscultatory method during four separate study days distributed over one month. We show that the accuracy of the Aktiia Bracelet is similar to auscultation. The accuracy varies depending on the position in which the measurement is performed. Overall, the accuracy is not modified by a higher age category. The use of a cuffless device in the elderly population characterized by high prevalence of hypertension may facilitate the follow-up of blood pressure with more comfort and minimal constraints.

Selective inhibition of cyclooxygenase-2 by enflicoxib, its enantiomers and its main metabolites in vitro in canine blood.

Enflicoxib is approved for the treatment of pain and inflammation in canine osteoarthritis. The objective of this work was to assess the mechanistic basis of enflicoxib therapy investigating the COX inhibitory activity of enflicoxib (racemate), its enantiomers and its main metabolites using the canine whole blood assay. The (R)-(+)-Enflicoxib enantiomer and metabolite M8 (hydroxylated pyrazoline) did not induce significant COX inhibition. Enflicoxib and its (S)-(-)-Enflicoxib enantiomer inhibited COX-1 and COX-2 with variable degree of preferential isoform inhibition, but no significant therapeutic effect is anticipated in vivo. The pyrazol metabolite showed the highest COX-2 inhibition and was the most selective (IC50 COX-1/ COX-2 ratio: 19.45). As the pyrazol metabolite shows saturable binding to red blood cells, its in vivo concentrations in plasma are lower than in whole blood. Accordingly, when applying the red blood cell partitioning, the respective IC50 and IC80 for COX-2 inhibition decreased from 2.8 µM (1129 ng/ml) and 13.4 µM (5404 ng/ml) to 0.2 µM (80.7 ng/ml) and 1.2 µM (484 ng/ml) and the selectivity ratio increased to close to 55. The corrected pyrazol metabolite IC50 and IC80 are well within the plasma levels described in treated dogs.

Pharmacokinetics of enflicoxib in dogs: Effects of prandial state and repeated administration.

The pharmacokinetics of enflicoxib were evaluated in both a bioavailability study and a multi-dose safety study in Beagle dogs. When administered at 8 mg/kg, the oral bioavailability (F) of enflicoxib was 44.1% in fasted dogs, but F increased to 63.4% under post prandial conditions. Enflicoxib is rapidly metabolised. After the first 48 h, the plasma levels of its pyrazol metabolite were much higher and persistent than those of the parent compound. Following intravenous administration, the total body plasma clearance of enflicoxib was of 140 ml/h/kg and the volume of distribution based on the terminal phase was 4 L/kg. Plasma protein binding for both compounds was approximately 99%. The blood to plasma ratio for the pyrazol metabolite showed saturable kinetics with higher blood cell affinity at lower total blood concentrations which ranged from 2.49 to 0.95 for concentrations from 1 to 15 µg/ml. Enflicoxib and its pyrazol metabolite exhibited dose-proportional pharmacokinetics for single oral doses of 8-40 mg/kg and for multiple oral doses of 4-20 mg/kg. After 7 months of repeated weekly administrations, pre-dose plasma concentrations (Cmin,ss ) remained constant throughout the study, with no trend to any significant over-accumulation. The mean terminal elimination half-life (t½ ) was 20 h for enflicoxib and 17 days for the pyrazol metabolite. The pharmacokinetic profile of enflicoxib and its pyrazol metabolite in dogs supports the proposed dosing regimen in which doses are separated by 1 week.

Evaluation of a Novel Ear Pulse Oximeter: Towards Automated Oxygen Titration in Eyeglass Frames.

Current oxygen delivery modes lack monitoring and can be cumbersome for patients with chronic respiratory diseases. Integrating a pulse oximeter and nasal oxygen cannulas into eyeglasses would reduce the burden of current solutions. An ear pulse oximeter (OxyFrame) was evaluated on 16 healthy volunteers and 20 hypoxemic patients with chronic respiratory diseases undergoing a prespecified protocol simulating daily activities. Correlation, error, and accuracy root mean square error (ARMS) were calculated to compare SpO2 measured by OxyFrame, a standard pulse oximeter (MASIMO), and arterial blood gas analysis (aBGA). SpO2 measured by OxyFrame and MASIMO correlated strongly in volunteers, with low error and high accuracy (r = 0.85, error = 0.2 ± 2.9%, ARMS = 2.88%). Performances were similar in patients (r = 0.87, error 0 ± 2.5%, ARMS = 2.49% compared with MASIMO; and r = 0.93, error = 0.4 ± 1.9%, ARMS = 1.94% compared with aBGA). However, the percentage of rejected measurements was high (volunteers 77.2%, patients 46.9%). The OxyFrame cavum conchae pulse oximeter was successfully evaluated, and demonstrated accurate SpO2 measurements, compliant with ISO 80601-2-61:2017. Several reasons for the high rejection rate were identified, and potential solutions were proposed, which might be valuable for optimization of the sensor hardware.

Noninvasive measurement of stroke volume changes in critically ill patients by means of electrical impedance tomography.

Previous animal experiments have suggested that electrical impedance tomography (EIT) has the ability to noninvasively track changes in cardiac stroke volume (SV). The present study intended to reproduce these findings in patients during a fluid challenge. In a prospective observational study including critically ill patients on mechanical ventilation, SV was estimated via ECG-gated EIT before and after a fluid challenge and compared to transpulmonary thermodilution reference measurements. Relative changes in EIT-derived cardiosynchronous impedance changes in the heart ([Formula: see text]) and lung region ([Formula: see text]) were compared to changes in reference SV by assessing the concordance rate (CR) and Pearson's correlation coefficient (R). We compared 39 measurements of 20 patients. [Formula: see text] did not show to be a reliable estimate for tracking changes of SV (CR = 52.6% and R = 0.13 with P = 0.44). In contrast, [Formula: see text] showed an acceptable trending performance (CR = 94.4% and R = 0.72 with P < 0.0001). Our results indicate that ECG-gated EIT measurements of [Formula: see text] are able to noninvasively monitor changes in SV during a fluid challenge in critically ill patients. However, this was not possible using [Formula: see text]. The present approach is limited by the influences induced by ventilation, posture or changes in electrode-skin contact and requires further validation.

Stringent fluid management might help to prevent postoperative ileus after loop ileostomy closure.

PURPOSE: The present study aimed to analyze the impact of perioperative fluid management on postoperative ileus (POI) after loop ileostomy closure. METHODS: Consecutive loop ileostomy closures over a 6-year period (May 2011-May 2017) were included. Main outcomes were POI, defined as time to first stool beyond POD 3, and postoperative complications of any grade. Critical fluid management-related thresholds including postoperative weight gain were identified through receiver operator characteristics (ROC) analysis and tested in a multivariable analysis. RESULTS: Of 238 included patients, 33 (14%) presented with POI; overall complications occurred in 91 patients (38%). 1.7 L IV fluids at postoperative day (POD) 0 was determined a critical threshold for POI (area under ROC curve (AUROC), 0.64), yielding a negative predictive value (NPV) of 93%. Further, a critical cutoff for a postoperative weight gain of 1.2 kg at POD 2 was identified (AUROC, 0.65; NPV, 95%). Multivariable analysis confirmed POD 0 fluids of > 1.7 L (OR, 4.7; 95% CI, 1.4-15.3; p = 0.01) and POD 2 weight gain of > 1.2 kg (OR, 3.1; 95% CI, 1-9.4; p = 0.046) as independent predictors for POI. CONCLUSIONS: Perioperative fluid administration of > 1.7 L and POD 2 weight gain of > 1.2 kg represent critical thresholds for POI after loop ileostomy closure.

Postoperative urinary retention in colorectal surgery within an enhanced recovery pathway.

BACKGROUND: Enhanced recovery after surgery (ERAS) guidelines for colorectal surgery suggest routine transurethral bladder drainage with early removal to prevent urinary tract infection (UTI). The aim of this study was to identify risk factors for urinary retention (UR). METHODS: This retrospective analysis included all colorectal patients since ERAS implementation in May 2011-November 2014. From the prospective ERAS database, over 100 items related to demographics, surgery, compliance, and outcome were analyzed. Risk factors for UR were identified by multiple logistic regressions; then, UR was correlated to functional outcomes and UTI and acute kidney injury rates. RESULTS: The study cohort consisted of 513 consecutive patients. Of these, 73 patients (14%) presented with UR. Multivariate analysis identified male gender (odds ratio 1.4; 95% CI, 1-1.8; P = 0.045) and postoperative thoracic epidural analgesia (EDA; odds ratio 2.6; 95% CI, 1.6-4.3; P ≤ 0.001) as independent risk factors for postoperative UR. Functional recovery was impeded in patients with UR, who were less mobile (mobilization day 1 >4 h: 57% versus 70%, P = 0.024) and gained more weight (2.8 ± 2.5 kg versus 1.6 ±3 kg on day 1, P = 0.001) due to fluid overload. Furthermore, patients with urinary catheters reported more pain (visual analog scales day 3: 3.1 ± 2.5 versus 2.2 ± 2.4, P = 0.002) and depended longer on intravenous fluid administration (termination of intravenous fluids later than day 1: 53% versus 39%, P = 0.021). Ten of 73 patients (14%) developed UTI in patients with UR and 42 of 440 (10%) in patients without UR (P = 0.276). Six of 73 patients (8%) developed acute kidney injury in patients with UR and 36 of 440 (8%) in patients without UR (P = 0.991). CONCLUSIONS: Male gender and EDA were independent risk factors for postoperative UR which appeared to be a significant impediment for functional recovery.

Postoperative ileus in an enhanced recovery pathway-a retrospective cohort study.

PURPOSE: Enhanced recovery after surgery (ERAS) protocols advocate no nasogastric tubes after colorectal surgery, but postoperative ileus (POI) remains a challenging clinical reality. The aim of this study was to assess incidence and risk factors of POI. METHODS: This retrospective analysis included all consecutive colorectal surgical procedures since May 2011 until November 2014. Uni- and multivariate risk factors for POI were identified by multiple logistic regression and functional and surgical outcomes assessed. RESULTS: The study cohort consisted of 513 consecutive colorectal ERAS patients. One hundred twenty-eight patients (24.7%) needed postoperative reinsertion of nasogastric tube at the 3.9 ± 2.9 postoperative day. Multivariate analysis retained the American Society of Anesthesiologists group 3-4 (odds ratio (OR) 1.3; 95% CI 1-1.8, p = 0.043) and duration of surgery of >3 h (OR 1.3; 95% CI 1-1.7, p = 0.047) as independent risk factors for POI. Minimally invasive surgery (OR 0.6; 95% CI 0.5-0.8, p ≤ 0.001) and overall compliance of >70% to the ERAS protocol (OR 0.7; 95% CI 0.6-1, p = 0.031) represented independent protective factors. POI was associated with respiratory (23 vs. 5%, p ≤ 0.001) and cardiovascular (16 vs. 3%, p ≤ 0.001) complications. CONCLUSIONS: POI was frequent in the present study. Overall compliance to the ERAS protocol and minimally invasive surgery helped to prevent POI, which was significantly correlated with medical complications.

Enhanced Recovery After Surgery: Can We Rely on the Key Factors or Do We Need the Bel Ensemble?

BACKGROUND: The success of enhanced recovery (ERAS) pathways depends on the actual application of the intended protocol (adherence), but its full implementation remains challenging. In order to potentially streamline the pathway, it is indispensable to know the impact of individual items and the entire protocol on clinical outcomes. METHODS: Retrospective analysis including all consecutive colorectal ERAS patients since implementation (May 2011) until February 2014; demographics, adherence and outcomes were retrieved from a prospectively maintained database. Primary outcome was the impact of individual item and of the entire protocol on complications (overall and major) and length of hospital stay. Statistical analysis included logistic multivariate regression and adjustment for confounding factors. RESULTS: There were 328 patients with complete data sets analyzed. A minimally invasive approach [odd ratio (OR) 0.62; confidence interval (CI) 0.4-0.9] was significantly associated with less overall complications. In contrast, the use of prophylactic nasogastric tubes (OR 3.18; CI 1.4-7.4), prophylactic abdominal and pelvic drains (OR 1.96; 1.2-3.2) and intraoperative thoracic epidural analgesia (OR 1.76; CI 1.3-2.4) were associated with more overall complications. Minimal invasive approach was further associated with reduced hospital stay (OR 0.5; CI 0.4-0.7) and less major complications (OR 0.58; CI 0.4-0.8). Higher adherence to the entire ERAS protocol was associated with significantly less complications (P < 0.001) and shorter hospital stay (P < 0.001). CONCLUSIONS: Minimally invasive surgery was the single most important component of the ERAS pathway while nasogastric tubes, drains and epidurals should be avoided. Overall, increasing adherence with the protocol was associated with better outcomes and should be the goal.

Electrical impedance tomography (EIT) for quantification of pulmonary edema in acute lung injury.

BACKGROUND: Assessment of pulmonary edema is a key factor in monitoring and guidance of therapy in critically ill patients. To date, methods available at the bedside for estimating the physiologic correlate of pulmonary edema, extravascular lung water, often are unreliable or require invasive measurements. The aim of the present study was to develop a novel approach to reliably assess extravascular lung water by making use of the functional imaging capabilities of electrical impedance tomography. METHODS: Thirty domestic pigs were anesthetized and randomized to three different groups. Group 1 was a sham group with no lung injury. Group 2 had acute lung injury induced by saline lavage. Group 3 had vascular lung injury induced by intravenous injection of oleic acid. A novel, noninvasive technique using changes in thoracic electrical impedance with lateral body rotation was used to measure a new metric, the lung water ratioEIT, which reflects total extravascular lung water. The lung water ratioEIT was compared with postmortem gravimetric lung water analysis and transcardiopulmonary thermodilution measurements. RESULTS: A significant correlation was found between extravascular lung water as measured by postmortem gravimetric analysis and electrical impedance tomography (r = 0.80; p < 0.05). Significant changes after lung injury were found in groups 2 and 3 in extravascular lung water derived from transcardiopulmonary thermodilution as well as in measurements derived by lung water ratioEIT. CONCLUSIONS: Extravascular lung water could be determined noninvasively by assessing characteristic changes observed on electrical impedance tomograms during lateral body rotation. The novel lung water ratioEIT holds promise to become a noninvasive bedside measure of pulmonary edema.

Nutritional Status Deteriorates Postoperatively Despite Preoperative Nutritional Support.

BACKGROUND/AIMS: The aim of the current study was to assess the postoperative evolution of nutritional status and to relate it with postoperative outcomes. METHODS: Demographic, surgical and nutritional parameters were assessed 10 days preoperatively (d-10) and 30 days postoperatively (d30) in 146 patients. Risk factors responsible for perioperative (>5% between d-10 and d30) weight loss were identified. Overall, severe (Clavien 3-5) and infectious complications were compared in patients with and without perioperative weight loss (>5%). RESULTS: Nutritional status worsened beyond the postoperative period as reflected by decreasing weight (67 ± 13 kg at d-10 vs. 63 ± 13 kg at d30, p < 0.001), body mass index (23.4 ± 4 vs. 22.2 ± 4 kg/m2, p < 0.001) and mid upper-arm muscle circumference (MAMC, 241 ± 32 vs. 232 ± 30 mm, p < 0.001). Fifty-two patients (46%) lost >5% of their body weight between d-10 and d30. Patients who presented overall (63 vs. 36%, p = 0.004) and major (27 vs. 10%, p = 0.016) postoperative complications were at significantly higher risk to deteriorate postoperative nutritional status. Multivariate analysis identified low preoperative lean body mass (OR 3.2; 95% CI 1.2-8.9, p = 0.023) and low preoperative MAMC (OR 2.5; 95% CI 0.9-6.8, p = 0.066) as independent risk factors for perioperative weight loss. CONCLUSIONS: These data suggest continuing nutritional follow-up after the index hospitalization.

Variety of non-invasive continuous monitoring methodologies including electrical impedance tomography provides novel insights into the physiology of lung collapse and recruitment ­ case report of an anaesthetized horse.

INTRODUCTION: The use of alveolar recruitment maneuvers during general anaesthesia of horses is a potentially useful therapeutic option for the ventilatory management. While the routine application of recruitments would benefit from the availability of dedicated large animal ventilators their impact on ventilation and perfusion in the horse is not yet well documented nor completely understood. CASE HISTORY: A healthy 533 kg experimental horse underwent general anaesthesia in lateral recumbency. During intermittent positive pressure ventilation a stepwise alveolar recruitment maneuver was performed. MANAGEMENT: Anaesthesia was induced with ketamine and midazolam and maintained with isoflurane in oxygen using a large animal circle system. Mechanical ventilation was applied in pressure ventilation mode and an alveolar recruitment maneuver performed employing a sequence of ascending and descending positive end expiratory pressures. Next to the standard monitoring, which included spirometry, additionally three non-invasive monitoring techniques were used: electrical impedance tomography (EIT), volumetric capnography and respiratory ultrasonic plethysmography. The functional images continuously delivered by EIT initially showed markedly reduced ventilation in the dependent lung and allowed on-line monitoring of the dynamic changes in the distribution of ventilation during the recruitment maneuver. Furthermore, continuous monitoring of compliance, dead space fraction, tidal volumes and changes in end expiratory lung volume were possible without technical difficulties. FOLLOW: up The horse made an unremarkable recovery. CONCLUSION: The novel non-invasive monitoring technologies used in this study provided unprecedented insights into the physiology of lung collapse and recruitment. The synergic information of these techniques holds promise to be useful when developing and evaluating new ventilatory strategies in horses.

Validation of the Aktiia blood pressure cuff for clinical use according to the ANSI/AAMI/ISO 81060-2:2013 protocol.

OBJECTIVE: Assess the accuracy and precision of the Aktiia initialization oscillometric upper-arm cuff device (Aktiia SA, Neuchâtel, Switzerland) for home blood pressure (BP) monitoring in the general population according to the American National Standards Institute / Association for the Advancement of Medical Instrumentation/International Organization for Standardization (ANSI/AAMI/ISO) 81060-2:2013 standard. METHODS: Three trained observers validated BP measurements performed using the Aktiia cuff versus BP measurements performed using a standard mercury sphygmomanometer. Two ISO 81060-2 criteria were used to validate the Aktiia cuff. Criterion 1 evaluated, for both SBP and DBP, whether the mean error between BP readings performed by the Aktiia cuff and auscultation was ≤±5 mmHg, and whether the SD of the error was ≤8 mmHg. Criterion 2 assessed whether, for the SBP and DBP of each individual subject, the SD of the averaged paired determinations per subject of the Aktiia cuff and of the auscultation met the criteria listed in the table of Averaged Subject Data Acceptance. RESULTS: Mean differences between the Aktiia cuff and the standard mercury sphygmomanometer (criterion 1) were 1.3 ± 7.11 mmHg for SBP and -0.2 ± 5.46 mmHg for DBP. The SD of the averaged paired differences per subject (criterion 2) was 6.55 mmHg for SBP and 5.15 mmHg for DBP. CONCLUSION: Aktiia initialization cuff complies with the requirements of the ANSI/AAMI/ISO guidelines and can be safely recommended for BP measurements in the adult population.

Aktiia cuffless blood pressure monitor yields equivalent daytime blood pressure measurements compared to a 24-h ambulatory blood pressure monitor: Preliminary results from a prospective single-center study.

In this preliminary study, we compared daytime blood pressure (BP) measurements performed by a commercially available cuffless-and continual-BP monitor (Aktiia monitor, Neuchâtel, Switzerland) and a traditional ambulatory BP monitor (ABPM; Dyasis 3, Novacor, Paris, France) from 52 patients enrolled in a 12-week cardiac rehabilitation (CR) program (Neuchâtel, Switzerland). Daytime (9am-9pm) systolic (SBP) and diastolic (DBP) BP from 7-day averaged data from Aktiia monitor were compared to 1-day averaged BP data from ABPM. No significant differences were found between the Aktiia monitor and the ABPM for SBP (µ ± σ [95% confidence interval]: 1.6 ± 10.5 [-1.5, 4.6] mmHg, P = 0.306; correlation [R2]: 0.70; ± 10/ ± 15 mmHg agreements: 60%, 84%). Marginally non-significant bias was found for DBP (-2.2 ± 8.0 [-4.5, 0.1] mmHg, P = 0.058; R2: 0.66; ±10/±15 mmHg agreements: 78%, 96%). These intermediate results show that daytime BP measurements using the Aktiia monitor generate data comparable to that of an ABPM monitor.

In vitro evaluation of the interaction potential of irosustat with drug-metabolizing enzymes.

Irosustat is a first-generation, irreversible, steroid sulfatase inhibitor currently in development for hormone-dependent cancer therapy. To predict clinical drug-drug interactions between irosustat and possible concomitantly administered medications, the inhibition/induction potential of irosustat with the main drug-metabolizing enzymes was investigated in vitro. The interaction of aromatase inhibitors in the in vitro metabolism of irosustat was also studied. Irosustat inhibited CYP1A2 activity in human liver microsomes through the formation of its desulfamoylated degradation product and metabolite 667-coumarin. CYP1A2 inhibition by 667-coumarin was competitive, with a K(i) of 0.77 µM, a concentration exceeding by only 5-fold the maximal steady-state concentration of 667-coumarin in human plasma with the recommended dose of irosustat. In addition, 667-coumarin metabolites enhanced the inhibition of CYP1A2 activity. Additional clinical interaction studies of irosustat with CYP1A2 substrate drugs are strongly recommended. 667-Coumarin also appeared to be a competitive inhibitor of CYP2C19 (K(i) = 5.8 µM) in human liver microsomes, and this inhibition increased with assessment in human hepatocytes. Inhibition of CYP2C19 enzyme activity was not caused by repression of CYP2C19 gene expression. Therefore, additional mechanistic experiments or follow-up studies with clinical evaluation are recommended. Irosustat neither inhibited CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, or UDP-glucuronosyltransferase 1A1, 1A4, or 2B7 activities nor induced CYP1A2, CYP2C9, CYP2C19, or CYP3A4/5 at clinically relevant concentrations. Results from human liver microsomes indicated that no changes in irosustat pharmacokinetics in vivo are expected as a result of inhibition of irosustat metabolism in cases of concomitant medication administration or irosustat-aromatase inhibitor combination therapy with letrozole, anastrozole, or exemestane.

Guidance for the Interpretation of Continual Cuffless Blood Pressure Data for the Diagnosis and Management of Hypertension.

Hypertension remains the leading risk factor for death worldwide. Despite its prevalence, success of blood pressure (BP) management efforts remains elusive, and part of the difficulty lies in the tool still used to diagnose, measure, and treat hypertension: the sphygmomanometer introduced by Samuel Siegfried Karl von Basch in 1867. In recent years, there has been an explosion of devices attempting to provide estimates of BP without a cuff, overcoming many limitations of cuff-based BP monitors. Unfortunately, the differences in underlying technologies between traditional BP cuffs and newer cuffless devices, as well as hesitancy of changing a well-implemented standard, still generate understandable skepticism about and reluctance to adopt cuffless BP monitors in clinical practice. This guidance document aims to navigate the scientific and medical communities through the types of cuffless devices and present examples of robust BP data collection which are better representations of a person's true BP. It highlights the differences between data collected by cuffless and traditional cuff-based devices and provides an initial framework of interpretation of the new cuffless datasets using, as an example, a CE-marked continual cuffless BP device (Aktiia BP Monitor, Aktiia, Switzerland). Demonstration of novel BP metrics, which have the potential to change the paradigm of hypertension diagnosis and treatment, are now possible for the first time with cuffless BP monitors that provide continual readings over long periods. Widespread adoption of continual cuffless BP monitors in healthcare will require a collaborative and thoughtful process, acknowledging that the transition from a legacy to a novel medical technology will be slow. Finally, this guidance concludes with a call to action to international scientific and expert associations to include cuffless BP monitors in original scientific research and in future versions of guidelines and standards.

Heart-lung interactions measured by electrical impedance tomography.

OBJECTIVE: The clinical value of stroke volume variations to assess intravascular fluid status in critically ill patients is well known. Electrical impedance tomography is a noninvasive monitoring technology that has been primarily used to assess ventilation. We investigated the potential of electrical impedance tomography to measure left ventricular stroke volume variation as an expression of heart-lung interactions. The objective of this study was thus to determine in a set of different hemodynamic conditions whether stroke volume variation measured by electrical impedance tomography correlates with those derived from an aortic ultrasonic flow probe and arterial pulse contour analysis. DESIGN: Prospective animal study. SETTING: University animal research laboratory. SUBJECTS: Domestic pigs, 29-50 kg. INTERVENTIONS: A wide range of hemodynamic conditions were induced by mechanical ventilation at different levels of positive end-expiratory pressure (0-15 cm H2O) and with tidal volumes of 8 and 16 mL/kg of body weight and by hypovolemia due to blood withdrawal with subsequent retransfusion followed by infusions of hydroxyethyl starch. MEASUREMENTS AND MAIN RESULTS: In eight pigs, aortic stroke volume variations measured by electrical impedance tomography were measured and compared to those derived from an aortic ultrasonic flow probe and from arterial pulse contour analysis. Data for four animals were used to develop and train a novel frequency-domain electrical impedance tomography analysis algorithm, while data for the remaining four were used to test the performance of the novel methodology. Correlation of stroke volume variation measured by electrical impedance tomography and that derived from an aortic ultrasonic flow probe was significant (r = 0.69; p < .001), as was the correlation between stroke volume variation measured by electrical impedance tomography and that derived from arterial pulse contour analysis (r = 0.73; p < .001). Correlation of stroke volume variation derived from an aortic ultrasonic flow probe and that derived from arterial pulse contour analysis was significant too (r = 0.82; p < .001). Bland-Altman analysis comparing stroke volume variation measured by electrical impedance tomography and that derived from an aortic ultrasonic flow probe revealed an overall bias of 1.87% and limits of agreement of ± 7.02%; when comparing stroke volume variation measured by electrical impedance tomography and that derived from arterial pulse contour analysis, the overall bias was 0.49% and the limits of agreement were ± 5.85%. CONCLUSION: Stroke volume variation measured by electrical impedance tomography correlated with both the gold standard of direct aortic blood flow measurements of stroke volume variation and pulse contour analysis, marking an important step toward a completely noninvasive monitoring of heart-lung interactions.

In vitro metabolism of irosustat, a novel steroid sulfatase inhibitor: interspecies comparison, metabolite identification, and metabolic enzyme identification.

Irosustat is a novel steroid sulfatase inhibitor for hormone-dependent cancer therapy. Its structure is a tricyclic coumarin-based sulfamate that undergoes desulfamoylation in aqueous solution, yielding the sulfamoyl-free derivative, 667-coumarin. The aim of the present work was to study the in vitro metabolism of irosustat, including its metabolic profile in liver microsomes and hepatocytes, the potential species differences, and the identification of the main metabolites and of the enzymes participating in its metabolism. Irosustat was extensively metabolized in vitro, showing similar metabolite profiles among rat, dog, monkey, and humans (both sexes). In liver microsomes, the dog was the species that metabolized irosustat most similarly to metabolism in humans. Marked differences were found between liver microsomes and hepatocytes, meaning that phase I and phase II enzymes contribute to irosustat metabolism. Various monohydroxylated metabolites of irosustat and of 667-coumarin were found in liver microsomes, which mostly involved hydroxylations at the C8, C10, and C12 positions in the cycloheptane ring moiety. 667-Coumarin was formed by degradation but also by non-NADPH-dependent enzymatic hydrolysis, probably catalyzed by microsomal steroid sulfatase. The main metabolites formed by hepatocytes were glucuronide and sulfate conjugates of 667-coumarin and of some of its monohydroxylated metabolites. The major cytochrome P450 enzymes involved in the transformation of irosustat were CYP2C8, CYP2C9, CYP3A4/5, and CYP2E1. Moreover, various phase II enzymes (UDP-glucuronosyltransferases and sulfotransferases) were capable of conjugating many of the metabolites of irosustat and 667-coumarin; however, the clinically relevant isoforms could not be elucidated.

Drug interaction potential of toremifene and N-desmethyltoremifene with multiple cytochrome P450 isoforms.

Toremifene is an effective agent for the treatment of breast cancer in postmenopausal women and is being evaluated for its ability to prevent bone fractures in men with prostate cancer taking androgen deprivation therapy. Due to the potential for drug-drug interactions, the ability of toremifene and its primary circulating metabolite N-desmethyltoremifene (NDMT) to inhibit nine human cytochrome P450 (CYP) enzymes was determined using human liver microsomes. Induction of CYP1A2 and 3A4 by toremifene was also investigated in human hepatocytes. Toremifene did not significantly inhibit CYP1A2 or 2D6. However, toremifene is a competitive inhibitor of CYP3A4, non-competitive inhibitor of CYP2A6, 2C8, 2C9, 2C19 and 2E1 and mixed-type inhibitor of CYP2B6. CYP inhibition by NDMT was similar in magnitude to toremifene. Toremifene did not induce CYP1A2 but increased CYP3A4 monooxygenase activity and gene expression in drug-exposed human primary hepatocytes. Although clinical doses of toremifene produce steady state exposures to toremifene and NDMT that may be sufficient to cause pharmacokinetic drug-drug interactions with other drugs metabolised by CYP2B6, CYP2C8, CYP3A4, CYP2C9 and CYP2C19, these data indicate that toremifene is unlikely to play a role in clinical drug-drug interactions with substrate drugs of CYP1A2 and CYP2D6.

Validation of the optical Aktiia bracelet in different body positions for the persistent monitoring of blood pressure.

The diagnosis of hypertension and the adjustment of antihypertensive drugs are evolving from isolated measurements performed at the physician offices to the full phenotyping of patients in real-life conditions. Indeed, the strongest predictor of cardiovascular risk comes from night measurements. The aim of this study was to demonstrate that a wearable device (the Aktiia Bracelet) can accurately estimate BP in the most common body positions of daily life and thus become a candidate solution for the BP phenotyping of patients. We recruited 91 patients with BP ranging from low to hypertensive levels and compared BP values from the Aktiia Bracelet against auscultatory reference values for 4 weeks according to an extended ISO 81060-2 protocol. After initializing on day one, the observed means and standard deviations of differences for systolic BP were of 0.46 ± 7.75 mmHg in the sitting position, - 2.44 ± 10.15 mmHg in the lying, - 3.02 ± 6.10 mmHg in the sitting with the device on the lap, and - 0.62 ± 12.51 mmHg in the standing position. Differences for diastolic BP readings were respectively of 0.39 ± 6.86 mmHg, - 1.93 ± 7.65 mmHg, - 4.22 ± 6.56 mmHg and - 4.85 ± 9.11 mmHg. This study demonstrates that a wearable device can accurately estimate BP in the most common body positions compared to auscultation, although precision varies across positions. While wearable persistent BP monitors have the potential to facilitate the identification of individual BP phenotypes at scale, their prognostic value for cardiovascular events and its association with target organ damage will need cross-sectional and longitudinal studies. Deploying this technology at a community level may be also useful to drive public health interventions against the epidemy of hypertension.