A systematic review and meta-analysis of placebo effect in clinical trials on chronic prostatitis/chronic pelvic pain syndrome.

BACKGROUND: It is a common practice to control efficacy of pharmacological treatment with a placebo group. However, placebo itself may affect subjective and even objective results. The purpose of this study was to evaluate the placebo effect on symptoms of CP/CPPS to improve future clinical trials. METHODS: A search at three databases (Scopus, MEDLINE, and Web of Science) was conducted to identify double-blind placebo-controlled clinical trials on the treatment of CP/CPPS published until April 2021. The primary outcome - National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score. SECONDARY OUTCOMES: Qmax, PVR, IPSS, and prostate volume. RESULTS: A total of 3502 studies were identified. Placebo arms of 42 articles (5512 patients, median 31 patients) were included in the systematic review. Systematic review identified positive changes in the primary endpoint, meta-analysis of 10 articles found that NIH-CPSI total score results were significantly influenced by placebo, mean difference -4.2 (95% confidence interval [CI]: -6.31, -2.09). Mean difference of NIH-CPSI pain domain was -2.31 (95% CI: -3.4, -1.21), urinary domain -1.12 (95% CI: -1.62, -0.62), quality of life domain -1.67 (95% CI: -2.38, -0.96); p < 0.001 for all. In case of the objective indicator - Qmax, there were three articles included in the meta-analysis. Qmax mean change from baseline was 0.68 (95% CI: -0.85, 2.22, p = 0.38). Systematic review showed no significant changes in pain, measured by VAS or other scores, IPSS and PVR. CONCLUSIONS: Placebo significantly affected the subjective parameters (NIH-CPSI) and limitedly affected various other measurements of pain (visual analog scale, McGill pain questionnaire). There was no long-term effect on IPSS and objective measurements (Qmax, PVR). This study can be used in further clinical trials to develop general rules of CPPS treatment assessment.

Comparative performance of MRI-derived PRECISE scores and delta-radiomics models for the prediction of prostate cancer progression in patients on active surveillance.

OBJECTIVES: To compare the performance of the PRECISE scoring system against several MRI-derived delta-radiomics models for predicting histopathological prostate cancer (PCa) progression in patients on active surveillance (AS). METHODS: The study included AS patients with biopsy-proven PCa with a minimum follow-up of 2 years and at least one repeat targeted biopsy. Histopathological progression was defined as grade group progression from diagnostic biopsy. The control group included patients with both radiologically and histopathologically stable disease. PRECISE scores were applied prospectively by four uro-radiologists with 5-16 years' experience. T2WI- and ADC-derived delta-radiomics features were computed using baseline and latest available MRI scans, with the predictive modelling performed using the parenclitic networks (PN), least absolute shrinkage and selection operator (LASSO) logistic regression, and random forests (RF) algorithms. Standard measures of discrimination and areas under the ROC curve (AUCs) were calculated, with AUCs compared using DeLong's test. RESULTS: The study included 64 patients (27 progressors and 37 non-progressors) with a median follow-up of 46 months. PRECISE scores had the highest specificity (94.7%) and positive predictive value (90.9%), whilst RF had the highest sensitivity (92.6%) and negative predictive value (92.6%) for predicting disease progression. The AUC for PRECISE (84.4%) was non-significantly higher than AUCs of 81.5%, 78.0%, and 80.9% for PN, LASSO regression, and RF, respectively (p = 0.64, 0.43, and 0.57, respectively). No significant differences were observed between AUCs of the three delta-radiomics models (p-value range 0.34-0.77). CONCLUSIONS: PRECISE and delta-radiomics models achieved comparably good performance for predicting PCa progression in AS patients. KEY POINTS: • The observed high specificity and PPV of PRECISE are complemented by the high sensitivity and NPV of delta-radiomics, suggesting a possible synergy between the two image assessment approaches. • The comparable performance of delta-radiomics to PRECISE scores applied by expert readers highlights the prospective use of the former as an objective and standardisable quantitative tool for MRI-guided AS follow-up. • The marginally superior performance of parenclitic networks compared to conventional machine learning algorithms warrants its further use in radiomics research.

Cuffless Blood Pressure Measurement Using a Smartphone-Case Based ECG Monitor with Photoplethysmography in Hypertensive Patients.

The availability of simple, accurate, and affordable cuffless blood pressure (BP) devices has the potential to greatly increase the compliance with measurement recommendations and the utilization of BP measurements for BP telemonitoring. The aim of this study is to evaluate the correlation between findings from routine BP measurements using a conventional sphygmomanometer with the results from a portable ECG monitor combined with photoplethysmography (PPG) for pulse wave registration in patients with arterial hypertension. METHODS: The study included 500 patients aged 32-88 years (mean 64 ± 7.9 years). Mean values from three routine BP measurements by a sphygmomanometer with cuff were selected for comparison; within one minute after the last measurement, an electrocardiogram (ECG) was recorded for 3 min in the standard lead I using a smartphone-case based single-channel ECG monitor (CardioQVARK®-limited responsibility company "L-CARD", Moscow, Russia) simultaneously with a PPG pulse wave recording. Using a combination of the heart signal with the PPG, levels of systolic and diastolic BP were determined based on machine learning using a previously developed and validated algorithm and were compared with sphygmomanometer results. RESULTS: According to the Bland-Altman analysis, SD for systolic BP was 3.63, and bias was 0.32 for systolic BP. SD was 2.95 and bias was 0.61 for diastolic BP. The correlation between the results from the sphygmomanometer and the cuffless method was 0.89 (p = 0.001) for systolic and 0.87 (p = 0.002) for diastolic BP. CONCLUSION: Blood pressure measurements on a smartphone-case without a cuff are encouraging. However, further research is needed to improve the accuracy and reliability of clinical use in the majority of patients.

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.

BACKGROUND: Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. METHODS: We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. RESULTS: Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life. CONCLUSIONS: In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).

Carfilzomib, lenalidomide, and dexamethasone in patients with relapsed multiple myeloma categorised by age: secondary analysis from the phase 3 ASPIRE study.

A primary analysis of the ASPIRE study found that the addition of carfilzomib to lenalidomide and dexamethasone (carfilzomib group) significantly improved progression-free survival (PFS) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma (RMM). This post hoc analysis examined outcomes from ASPIRE in patients categorised by age. In the carfilzomib group, 103/396 patients were ≥70 years old, and in the control group, 115/396 patients were ≥70 years old. Median PFS for patients <70 years old was 28·6 months for the carfilzomib group versus 17·6 months for the control group [hazard ratio (HR), 0·701]. Median PFS for patients ≥70 years old was 23·8 months for the carfilzomib group versus 16·0 months for the control group (HR, 0·753). For patients <70 years the overall response rate (ORR) was 86·0% (carfilzomib group) and 66·9% (control group); for patients ≥70 years old the ORR was 90·3% (carfilzomib group) and 66·1% (control group). Within the carfilzomib group, grade ≥3 cardiovascular adverse events occurred more frequently among patients ≥70 years old compared with patients <70 years old. Carfilzomib-lenalidomide-dexamethasone has a favourable benefit-risk profile for patients with RMM, including elderly patients ≥70 years old. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01080391.

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study.

BACKGROUND: Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. METHODS: In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m(2) on days 1 and 2 of cycle 1; 56 mg/m(2) thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m(2); intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. FINDINGS: Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6-not estimable) in the carfilzomib group versus 9·4 months (8·4-10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44-0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). INTERPRETATION: For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. FUNDING: Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Contrast-enhanced ultrasound (CEUS) as a follow-up method after the focal treatment of renal tumors: systematic review and meta-analysis.

CONTEXT: Contrast-enhanced ultrasound (CEUS) is a cost-effective radiation-free diagnostic method that can be used for renal tumor postoperative visualization after ablative treatment. OBJECTIVE: To assess CEUS diagnostic accuracy comparing with CT and MRI as a follow-up method in short-term and long-term postoperative periods after renal tumor ablation. MATERIALS AND METHODS: A systematic review and meta-analysis were performed in Scopus and Medline databases using the query "(kidney OR rena* OR RCC) AND (ablation OR RFA OR MWA OR cryo*) AND CEUS". The endpoint of the study was the evaluation of the overall accuracy of CEUS. RESULTS: Twelve trials were included in the review. With CT or MRI as a reference, for a short-term group (< 6 weeks after ablation) pooled sensitivity was 90.2%, I2 = 0%; pooled specificity was 99.3%, I2 = 0%; pooled NPV was 98.6%, I2 = 0%; pooled PPV was 94.6%, I2 = 0%; the AUC on the SROC curve was 0.971. For the long-term group (> 6 weeks after ablation), pooled sensitivity was 95.3%, I2 = 0%; pooled specificity was 97.6%, I2 = 0%; PPV was 74.2%, I2 = 4%; NPV was 99.4%, I2 = 5%; AUC = 0.93. CONCLUSION: CEUS has high sensitivity and specificity in ruling out the presence of local recurrence after renal tumor ablation with a higher risk of false-positive results within follow-up > 6 weeks compared with that for CT or MRI. Further studies with a unified protocol and morphological control of local renal tumor recurrence after ablation are needed.

The Blood Plasma Lipidomic Profile in Atherosclerosis of the Brachiocephalic Arteries.

According to the World Health Organization, ischemic stroke is the second leading cause of death in the world. Frequently, it is caused by brachiocephalic artery (BCA) atherosclerosis. Timely detection of atherosclerosis and its unstable course can allow for a timely response to potentially dangerous changes and reduce the risk of vascular complications. Omics technologies allow us to identify new biomarkers that we can use in diagnosing diseases. This research included 90 blood plasma samples. The study group comprised 52 patients with severe atherosclerotic lesions BCA, and the control group comprised 38 patients with no BCA atherosclerosis. Targeted and panoramic lipidomic profiling of their blood plasma was carried out. There was a statistically significant difference (p < 0.05) in the values of the indices saturated fatty acids (FAs), unsaturated FAs, monounsaturated FAs, omega-3, and omega-6. Based on the results on the blood plasma lipidome, we formed models that have a fairly good ability to determine atherosclerotic lesions of the brachiocephalic arteries, as well as a model for identifying unstable atherosclerotic plaques. According only to the panoramic lipidome data, divided into groups according to stable and unstable atherosclerotic plaques, a significant difference was taken into account: p value < 0.05 and abs (fold change) > 2. Unfortunately, we did not observe significant differences according to the established plasma panoramic lipidome criteria between patients with stable and unstable plaques. Omics technologies allow us to obtain data about any changes in the body. According to our data, statistically significant differences in lipidomic profiling were obtained when comparing groups with or without BCA atherosclerosis.

Exhaled breath analysis in adult patients with cystic fibrosis by real-time proton mass spectrometry.

BACKGROUND: Proton-transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS) is a promising tool for a rapid online determination of exhaled volatile organic compounds (eVOCs) profiles in patients with cystic fibrosis (CF). OBJECTIVE: To detect VOC breath signatures specific to adult patients with CF compared with controls using PTR-TOF-MS. METHODS: 102 CF patients (54 M/48, mean age 25.6 ± 7.8 yrs) and 97 healthy controls (56 M/41F, mean age 25.8 ± 6.0 yrs) were examined. Samples from normal quiet breathing and forced expiratory maneuvers were analyzed with PTR-TOF-MS (Ionicon, Austria) to obtain VOC profiles listed as ions at various mass-to-charge ratios (m/z). RESULTS: PTR-TOF-MS analysis was able to detect 167 features in exhaled breath from CF patients and healthy controls. According to cluster analysis and LASSO regression, patients with CF and controls were separated. The most significant VOCs for CF were indole, phenol, dimethyl sulfide, and not indicated: m/z = 297.0720 ([C12H13N2O7 and C17H13O5]H + ), m/z = 281.0534 ([C19H7NO2, C12H11NO7 and C16H9O5]H + ) during five-fold cross-validation both in forced expiratory maneuver and in normal quiet breathing. CONCLUSION: PTR-TOF-MS is a promising method for determining the molecular composition of exhaled air specific to CF.

Short-term and medium-term clinical outcomes of multisystem inflammatory syndrome in children: a prospective observational cohort study.

BACKGROUND: Even though the incidence of Multisystem Inflammatory Syndrome in children (MIS-C) is decreasing cases are still reported across the world. Studying the consequences of MIS-C enhances our understanding of the disease's prognosis. The objective of this study was to assess short- and medium-term clinical outcomes of MIS-C. METHODS: Prospective observational cohort study at Municipal Children's Hospital Morozovskaya, Moscow, Russia. All children meeting the Royal College of Paediatrics and Child Health (RCPCH), Centers for Disease Control and Prevention (CDC), or the World Health Organization (WHO) MIS-C case definition admitted to the hospital between 17 May and 26 October 2020 were included in the study. All survivors were invited to attend a clinic at 2 and 6 weeks after hospital discharge. RESULTS: 37 children median age 6 years (interquartile range [IQR] 3.3-9.4), 59.5% (22/37) boys were included in the study. 48.6% (18/37) of patients required ICU care. One child died. All children had increased levels of systemic inflammatory markers during the acute event. Echocardiographic investigations identified abnormal findings in 35.1% (13/37) of children. 5.6% (2/36) of children were presenting with any symptoms six weeks after discharge. By six weeks the inflammatory markers were within the reference norms in all children. The echocardiographic evaluation showed persistent coronary dilatation in one child. CONCLUSIONS: Despite the severity of their acute MIS-C, the majority of children in our cohort fully recovered with none having elevated laboratory markers of inflammation at 6 weeks, few (< 10%) reporting persistent symptoms at 6 weeks, and only one with persistent echocardiographic abnormalities.

Meta-analysis on the Efficacy of Platelet-rich Plasma in Patients with Androgenetic Alopecia.

Platelet-rich plasma (PRP) is an autologous platelet concentrate in plasma enriched with growth factors that may stimulate tissue regeneration, collagen formation, re-epithelization, and angiogenesis. PRP is widely used as an androgenetic alopecia treatment option. The present work aims to test the efficacy of various PRP methods, including those with single-spin and double-spin centrifugation. We performed a review of articles published from 2011 to 2021 in PubMed and ScienceDirect. The studies vary in the preparation procedure, dose, number, intervals between the procedures, and the injection technique because of low standardization of PRP preparation, complicating the evaluation of the clinical efficacy of the method. Based on the conducted statistical analysis, we came to the conclusion that the double-spin PRP preparation method was superior to the single-spin technique, which may be taken into account for AGA management.

Safety and Efficacy of Different Anticoagulant Doses for Patients with COVID-19 in the ICU: A Systematic Review and Meta-Analysis.

Critically ill COVID-19 patients have a high incidence of thromboembolic events, which significantly influence the risk of mortality. Anticoagulant therapy is generally recommended to these patients but the optimal dosing regimens require further investigations. The objective of this systematic review and meta-analysis was to assess the efficacy and safety of prophylactic, intermediate and therapeutic dose anticoagulation in COVID-19 patients admitted to the ICU. A systematic search for original prospective observational studies and clinical trials was performed in online databases from 2020 to 2022. A total of 13 studies (3239 patients) were included. The type of anticoagulant dosing showed no significant influence on short-term mortality (p = 0.84), deep vein thrombosis (p = 0.66), arterial thrombosis (p = 0.44), major bleeding (p = 0.35) and minor bleeding incidence (p = 0.46). An anticoagulation regimen significantly influenced pulmonary embolism occurrence (16% for prophylactic dose vs. 4% for therapeutic dose, p = 0.02), but the number of studies in the analysis was relatively low. In conclusion, the results of this meta-analysis suggest that critically ill COVID-19 patients admitted in the ICU have no benefit from therapeutic doses of anticoagulants and that all three thromboprophylaxis regimes have a comparable effect on short term mortality and venous thromboembolism incidence but for pulmonary embolism, for which the results were inconclusive.

Thermal ablation vs. active surveillance for renal masses: a systematic review and network meta-analysis.

INTRODUCTION: Partial nephrectomy, thermal ablation and active surveillance are acceptable options for T1 stage renal tumor management. Currently, we lack sufficient information to make an accurate comparison of thermal ablation with active surveillance. The study objectives were to compare thermal ablation with active surveillance indirectly using partial nephrectomy as a reference. EVIDENCE ACQUISITION: We performed a systematic literature search using two databases (Scopus and Medline). The detailed search strategy is available at Prospero, CRD42021290055. The primary outcome was cancer-specific survival. Secondary outcomes included overall survival and metastasis-free survival. EVIDENCE SYNTHESIS: The final sample comprised 33 articles. They included the ones that compare: partial nephrectomy to ablation (29 studies), partial nephrectomy to active surveillance (2 studies), and partial nephrectomy vs. active surveillance vs. ablation (2 articles). We assessed 3-year and 5-year cancer-specific survival, and 3-, 5- and 7-year overall survival. The surface under the cumulative ranking curve (SUCRA) treatment benefit ranking was: cancer-specific survival - 48.6% for thermal ablation and 1.6% for active surveillance (5-year follow-up); overall survival - 52% for thermal ablation and 0.6% for active surveillance (7-year follow-up). The results demonstrated a significantly higher 3-year cancer-specific survival (RR 1.55, P=0.02) and 3- and 7-year follow-up overall survival (RR 1.85, P=0.03) in thermal ablation compared to active surveillance. At 5-year follow-up, cancer-specific survival and overall survival were in favor of thermal ablation while no statistically significant difference was reported. CONCLUSIONS: Thermal ablation offers a significantly higher cancer-specific survival and overall survival at mid-term follow-up in the management of T1 renal tumors compared to active surveillance. However, it is necessary to conduct further prospective randomized studies to validate the data.

Colchicine in patients with heart failure and preserved left ventricular ejection fraction: rationale and design of a prospective, randomised, open-label, crossover clinical trial.

INTRODUCTION: Systemic low-grade inflammation is a fundamental pathophysiological mechanism of heart failure with preserved left ventricular ejection fraction (HFpEF). The efficacy of anti-inflammatory therapy in HFpEF is largely understudied. The aim of the study is to assess the anti-inflammatory effect of colchicine in HFpEF by looking at inflammatory biomarkers: high-sensitivity C reactive protein (hsCRP) and soluble suppression of tumorigenicity 2 (sST2). METHODS AND ANALYSIS: This is a single-centre, prospective, randomised controlled, open-label, blinded-endpoint crossover clinical trial of stable but symptomatic patients with HFpEF. Patients will be randomised to either colchicine treatment 0.5 mg two times per day or usual care for 12 weeks followed by a 2-week washout period and crossover to 12 weeks of treatment with the alternate therapy. The primary objective is to investigate if administration of colchicine compared with usual care reduces inflammation in patients with HFpEF measured by primary endpoint sST2 and co-primary endpoint hsCRP at baseline and 12-week follow-up. Secondary objective is to determine if treatment with colchicine influences N-terminal pro-B-type natriuretic peptide levels, left ventricular diastolic function and remodelling, right ventricular systolic function and left atrial volumetric characteristics. We are aiming to enrol a total of 40 participants. This trial will answer the question if colchicine treatment reduces systemic low-grade inflammation and influences left ventricular diastolic function and remodelling with patients with HFpEF. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Ethics Committee of Sechenov University (reference: 03-22). TRIAL REGISTRATION NUMBER: NCT05637398.

Practical Application of a New Cuffless Blood Pressure Measurement Method.

It would be useful to develop a reliable method for the cuffless measurement of blood pressure (BP), as such a method could be made available anytime and anywhere for the effective screening and monitoring of arterial hypertension. The purpose of this study is to evaluate blood pressure measurements through a CardioQVARK device in clinical practice in different patient groups. METHODS: This study involved 167 patients aged 31 to 88 years (mean 64.2 ± 7.8 years) with normal blood pressure, high blood pressure, and compensated high blood pressure. During each session, three routine blood pressure measurements with intervals of 30 s were taken using a sphygmomanometer with an appropriate cuff size, and the mean value was selected for comparison. The measurements were carried out by two observers trained at the same time with a reference sphygmomanometer using a Y-shaped connector. In the minute following the last cuff-based measurements, an electrocardiogram (ECG) with an I-lead and a photoplethysmocardiogram were recorded simultaneously for 3 min with the CardioQVARK device. We compared the systolic and diastolic BP obtained from a cuff-based mercury sphygmomanometer and smartphone-case-based BP device: the CardioQVARK monitor. A statistical analysis plan was developed using the IEEE Standard for Wearable Cuffless Blood Pressure Devices. Bland-Altman plots were used to estimate the precision of cuffless measurements. RESULTS: The mean difference between the values defined by CardioQVARK and the cuff-based sphygmomanometer for systolic blood pressure (SBP) was 0.31 ± 3.61, while that for diastolic blood pressure (DBP) was 0.44 ± 3.76. The mean absolute difference (MAD) for SBP was 3.44 ± 2.5 mm Hg, and that for DBP was 3.21 ± 2.82 mm Hg. In the subgroups, the smallest error (less than 3 mm Hg) was observed in the prehypertension group, with a slightly larger error (up to 4 mm Hg) found among patients with a normal blood pressure and stage 1 hypertension. The largest error was found in the stage 2 hypertension group (4-5.5 mm Hg). The largest error was 4.2 mm Hg in the high blood pressure group. We, therefore, did not record an error in excess of 7 mmHg, the upper boundary considered acceptable in the IEEE recommendations. We also did not reach a mean error of 5 mmHg, the upper boundary considered acceptable according to the very recent ESH recommendations. At the same time, in all groups of patients, the systolic blood pressure was determined with an error of less than 5 mm Hg in more than 80% of patients. While this study shows that the CardioQVARK device meets the standards of IEEE, the Bland-Altman analysis indicates that the cuffless measurement of diastolic blood pressure has significant bias. The difference was very small and unlikely to be of clinical relevance for the individual patient, but it may well have epidemiological relevance on a population level. Therefore, the CardioQVARK device, while being worthwhile for monitoring patients over time, may not be suitable for screening purposes. Cuffless blood pressure measurement devices are emerging as a convenient and tolerable alternative to cuff-based devices. However, there are several limitations to cuffless blood pressure measurement devices that should be considered. For instance, this study showed a high proportion of measurements with a measurement error of <5 mmHg, while detecting a small, although statistically significant, bias in the measurement of diastolic blood pressure. This suggests that this device may not be suitable for screening purposes. However, its value for monitoring BP over time is confirmed. Furthermore, and most importantly, the easy measurement method and the device portability (integrated in a smartphone) may increase the self-awareness of hypertensive patients and, potentially, lead to an improved adherence to their treatment. CONCLUSION: The cuffless blood pressure technology developed in this study was tested in accordance with the IEEE protocol and showed great precision in patient groups with different blood pressure ranges. This approach, therefore, has the potential to be applied in clinical practice.

Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial.

BACKGROUND: Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. METHODS: This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187. FINDINGS: Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8-28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8-6·7). The most common grade 3-4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study. INTERPRETATION: Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited. FUNDING: CTI BioPharma Corp.