Fall prediction in hypertensive patients via short-term HRV analysis

Falls are a major problem of later life having severe consequences on quality of life and a significant burden in occidental countries. Many technological solutions have been proposed to assess the risk or to predict falls and the majority is based on accelerometers and gyroscopes. However, very little was done for identifying first time fallers, which are very difficult to recognise. This paper presents a meta-model predicting falls using short term Heart Rate Variability (HRV) analysis acquired at the baseline. 170 hypertensive patients (age: 72 ± 8 years, 56 female) were investigated, of which 34 fell once in the 3 months after the baseline assessment. This study is focused on hypertensive patients, which were considered as convenient pragmatic sample, as they undergo regular outpatient visits, during which short term ECG can be easily recorded without significant increase of healthcare costs. For each subject, 11 consecutive excerpts of 5 minutes each (55 min) were extracted from ECGs recorded between 10:30 and 12:30 and analysed. Linear and nonlinear HRV features were extracted and averaged among the 11 excerpts, which were, then, considered for the statistical and data mining analysis. The best predictive meta-model was based on Multinomial Naïve Bayes, which enabled to predict first-time fallers with sensitivity, specificity and accuracy rates of 72%, 61%, 68% respectively

Classification tree for risk assessment in patients suffering from congestive heart failure via long-term heart rate variability

This study aims to develop an automatic classifier for risk assessment in patients suffering from congestive heart failure (CHF). The proposed classifier separates lower risk patients from higher risk ones, using standard long-term heart rate variability (HRV) measures. Patients are labeled as lower or higher risk according to the New York Heart Association classification (NYHA). A retrospective analysis on two public Holter databases was performed, analyzing the data of 12 patients suffering from mild CHF (NYHA I and II), labeled as lower risk, and 32 suffering from severe CHF (NYHA III and IV), labeled as higher risk. Only patients with a fraction of total heartbeats intervals (RR) classified as normal-to-normal (NN) intervals (NN/RR) higher than 80% were selected as eligible in order to have a satisfactory signal quality. Classification and regression tree (CART) was employed to develop the classifiers. A total of 30 higher risk and 11 lower risk patients were included in the analysis. The proposed classification trees achieved a sensitivity and a specificity rate of 93.3% and 63.6%, respectively, in identifying higher risk patients. Finally, the rules obtained by CART are comprehensible and consistent with the consensus showed by previous studies that depressed HRV is a useful tool for risk assessment in patients suffering from CHF

Heart rate variability and target organ damage in hypertensive patients

Background: We evaluated the association between linear standard Heart Rate Variability (HRV) measures and vascular, renal and cardiac target organ damage (TOD). Methods: A retrospective analysis was performed including 200 patients registered in the Regione Campania network (aged 62.4 ± 12, male 64%). HRV analysis was performed by 24-h holter ECG. Renal damage was assessed by estimated glomerular filtration rate (eGFR), vascular damage by carotid intima-media thickness (IMT), and cardiac damage by left ventricular mass index. Results: Significantly lower values of the ratio of low to high frequency power (LF/HF) were found in the patients with moderate or severe eGFR (p-value < 0.001). Similarly, depressed values of indexes of the overall autonomic modulation on heart were found in patients with plaque compared to those with a normal IMT (p-value <0.05). These associations remained significant after adjustment for other factors known to contribute to the development of target organ damage, such as age. Moreover, depressed LF/HF was found also in patients with left ventricular hypertrophy but this association was not significant after adjustment for other factors. Conclusions: Depressed HRV appeared to be associated with vascular and renal TOD, suggesting the involvement of autonomic imbalance in the TOD. However, as the mechanisms by which abnormal autonomic balance may lead to TOD, and, particularly, to renal organ damage are not clearly known, further prospective studies with longitudinal design are needed to determine the association between HRV and the development of TOD

Multicenter Observational Retrospective Study on Febrile Events in Patients with Acute Myeloid Leukemia Treated with Cpx-351 in "Real-Life": The SEIFEM Experience

: In the present study, we aimed to evaluate the absolute risk of infection in the real-life setting of AML patients treated with CPX-351. The study included all patients with AML from 30 Italian hematology centers of the SEIFEM group who received CPX-351 from July 2018 to June 2021. There were 200 patients included. Overall, 336 CPX-351 courses were counted: all 200 patients received the first induction cycle, 18 patients (5%) received a second CPX-351 induction, while 86 patients (26%) proceeded with the first CPX-351 consolidation cycle, and 32 patients (10%) received a second CPX-351 consolidation. A total of 249 febrile events were recorded: 193 during the first or second induction, and 56 after the first or second consolidation. After the diagnostic work-up, 92 events (37%) were classified as febrile neutropenia of unknown origin (FUO), 118 (47%) were classifiable as microbiologically documented infections, and 39 (17%) were classifiable as clinically documented infections. The overall 30-day mortality rate was 14% (28/200). The attributable mortality-infection rate was 6% (15/249). A lack of response to the CPX-351 treatment was the only factor significantly associated with mortality in the multivariate analysis [p-value: 0.004, OR 0.05, 95% CI 0.01-0.39]. Our study confirms the good safety profile of CPX-351 in a real-life setting, with an incidence of infectious complications comparable to that of the pivotal studies; despite prolonged neutropenia, the incidence of fungal infections was low, as was infection-related mortality

Pregnancy during COVID-19: social contact patterns and vaccine coverage of pregnant women from CoMix in 19 European countries

CoMix Europe Working Group: Daniela Paolotti, André Karch, Veronika Jäger, Joaquin Baruch, Tanya Melillo, Henrieta Hudeckova, Magdalena Rosinska, Marta Niedzwiedzka-Stadnik, Krista Fischer, Sigrid Vorobjov, Hanna Sõnajalg, Christian Althaus, Nicola Low, Martina Reichmuth, Kari Auranen, Markku Nurhonen, Goranka Petrović, Zvjezdana Lovric Makaric, Sónia Namorado, Constantino Caetano, Ana João Santos, Gergely Röst, Beatrix Oroszi, Márton Karsai, Mario Fafangel, Petra Klepac, Natalija Kranjec, Cristina Vilaplana, Jordi Casabona.CoMix Europe Working Group: Sónia Namorado, Constantino Caetano, and Ana João Santos (Department of Epidemiology, National Institute of Health Dr Ricardo Jorge, Portugal)Background: Evidence and advice for pregnant women evolved during the COVID-19 pandemic. We studied social contact behaviour and vaccine uptake in pregnant women between March 2020 and September 2021 in 19 European countries. Methods: In each country, repeated online survey data were collected from a panel of nationally-representative participants. We calculated the adjusted mean number of contacts reported with an individual-level generalized additive mixed model, modelled using the negative binomial distribution and a log link function. Mean proportion of people in isolation or quarantine, and vaccination coverage by pregnancy status and gender were calculated using a clustered bootstrap. Findings: We recorded 4,129 observations from 1,041 pregnant women, and 115,359 observations from 29,860 non-pregnant individuals aged 18-49. Pregnant women made slightly fewer contacts (3.6, 95%CI = 3.5-3.7) than non-pregnant women (4.0, 95%CI = 3.9-4.0), driven by fewer work contacts but marginally more contacts in non-essential social settings. Approximately 15-20% pregnant and 5% of non-pregnant individuals reported to be in isolation and quarantine for large parts of the study period. COVID-19 vaccine coverage was higher in pregnant women than in non-pregnant women between January and April 2021. Since May 2021, vaccination in non-pregnant women began to increase and surpassed that in pregnant women. Interpretation: Limited social contact to avoid pathogen exposure during the COVID-19 pandemic has been a challenge to many, especially women going through pregnancy. More recognition of maternal social support desire is needed in the ongoing pandemic. As COVID-19 vaccination continues to remain an important pillar of outbreak response, strategies to promote correct information can provide reassurance and facilitate informed pregnancy vaccine decisions in this vulnerable group.HPRU in Modelling & Health Economics,NIHR200908,European Union’s Horizon 2020 research and innovation programme,EpiPose 101003688,TransMID 682540,TransMID 682540,TransMID 682540,EpiPose 101003688,Wellcome Trust,213589/Z/18/Z,National Institute for Health Research,CV220-088—COMIX,CV220-088—COMIX,CV220-088— COMIX,Global Challenges Research Fund,ES/P010873/1,Medical Research Council,MC_PC_19065,NIHR,PR-OD-1017-20002 HPRU in Modelling & Health Economics (NIHR200908: KLMW); European Union Horizon 2020 research and innovation programme – (EpiPose 101,003,688: AG, WJE). Wellcome Trust (213,589/Z/18/Z: ESP). European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (TransMID 682,540: CF, PN, NH). This research was partly funded by the Global Challenges Research Fund (GCRF) project RECAP managed through RCUK and ESRC (ES/P010873/1: CIJ). NIHR (PR-OD-1017–20,002: WJE) UK MRC (MC_PC_19065—Covid 19: Understanding the dynamics and drivers of the COVID-19 epidemic using real-time outbreak analytics: WJE).info:eu-repo/semantics/publishedVersio

Social contact patterns during the COVID-19 pandemic in 21 European countries - evidence from a two-year study

CoMix Europe Working Group: Daniela Paolotti, Michele Tizzani, Ciro Cattuto, Andrea Schmidt, Gerald Gredinger, Sophie Stumpfl, Joaquin Baruch, Tanya Melillo, Henrieta Hudeckova, Jana Zibolenova, Zuzana Chladna, Magdalena Rosinska, Marta Niedzwiedzka-Stadnik, Krista Fischer, Sigrid Vorobjov, Hanna Sõnajalg, Christian Althaus, Nicola Low, Martina Reichmuth, Kari Auranen, Markku Nurhonen, Goranka Petrović, Zvjezdana Lovric Makaric, Sónia Namorado, Constantino Caetano, Ana João Santos, Gergely Röst, Beatrix Oroszi, Márton Karsai, Mario Fafangel, Petra Klepac, Natalija Kranjec, Cristina Vilaplana, Jordi Casabona.Sónia Namorado, Constantino Caetano, and Ana João Santos (Department of Epidemiology, National Institute of Health Dr Ricardo Jorge, Portugal).Background: Most countries have enacted some restrictions to reduce social contacts to slow down disease transmission during the COVID-19 pandemic. For nearly two years, individuals likely also adopted new behaviours to avoid pathogen exposure based on personal circumstances. We aimed to understand the way in which different factors affect social contacts - a critical step to improving future pandemic responses. Methods: The analysis was based on repeated cross-sectional contact survey data collected in a standardized international study from 21 European countries between March 2020 and March 2022. We calculated the mean daily contacts reported using a clustered bootstrap by country and by settings (at home, at work, or in other settings). Where data were available, contact rates during the study period were compared with rates recorded prior to the pandemic. We fitted censored individual-level generalized additive mixed models to examine the effects of various factors on the number of social contacts. Results: The survey recorded 463,336 observations from 96,456 participants. In all countries where comparison data were available, contact rates over the previous two years were substantially lower than those seen prior to the pandemic (approximately from over 10 to < 5), predominantly due to fewer contacts outside the home. Government restrictions imposed immediate effect on contacts, and these effects lingered after the restrictions were lifted. Across countries, the relationships between national policy, individual perceptions, or personal circumstances determining contacts varied. Conclusions: Our study, coordinated at the regional level, provides important insights into the understanding of the factors associated with social contacts to support future infectious disease outbreak responses.The following funding sources are acknowledged as providing funding for the named authors. HPRU in Modelling & Health Economics (NIHR200908: KLMW); European Union Horizon 2020 research and innovation programme (EpiPose 101003688: AG, WJE); European Research Council under the European Union Horizon 2020 research and innovation programme (TransMID 682540: CF, PB, NH) This research was partly funded by the Global Challenges Research Fund (GCRF) project RECAP managed through RCUK and ESRC (ES/P010873/1: CIJ) NIHR (PR_OD_1017_20002: WJE) UK MRC (MC_PC_19065—Covid 19: Under standing the dynamics and drivers of the COVID-19 epidemic using real-time outbreak analytics: WJE). In Belgium, CoMix data collection in Belgium was made possible with fnancial support of Janssen Pharmaceuticals and the national public health institute of Belgium, Sciensano. In Germany, the COVIMOD project is funded by intramural funds of the Institute of Epidemiology and Social Medicine, University of Münster, and of the Institute of Medical Epidemiology, Biometry and Informatics, Martin Luther University Halle-Wittenberg, as well as by funds provided by the Robert Koch Institute, Berlin, the Helmholtz-Gemeinschaft Deutscher Forschungszentren e.V. via the HZEpiAdHoc "The Helmholtz Epidemiologic Response against the COVID-19 Pandemic" project, the Saxonian COVID-19 Research Consortium SaxoCOV (co-fnanced with tax funds on the basis of the budget passed by the Saxon state parliament), the Federal Ministry of Education and Research (BMBF) as part of the Network University Medicine (NUM) via the egePan Unimed project (funding code: 01KX2021) and the Deutsche Forschungsge meinschaft (DFG, German Research Foundation, project number 458526380)info:eu-repo/semantics/publishedVersio

The future of sensitivity analysis: an essential discipline for systems modeling and policy support

Sensitivity analysis (SA) is en route to becoming an integral part of mathematical modeling. The tremendous potential benefits of SA are, however, yet to be fully realized, both for advancing mechanistic and data-driven modeling of human and natural systems, and in support of decision making. In this perspective paper, a multidisciplinary group of researchers and practitioners revisit the current status of SA, and outline research challenges in regard to both theoretical frameworks and their applications to solve real-world problems. Six areas are discussed that warrant further attention, including (1) structuring and standardizing SA as a discipline, (2) realizing the untapped potential of SA for systems modeling, (3) addressing the computational burden of SA, (4) progressing SA in the context of machine learning, (5) clarifying the relationship and role of SA to uncertainty quantification, and (6) evolving the use of SA in support of decision making. An outlook for the future of SA is provided that underlines how SA must underpin a wide variety of activities to better serve science and society

Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug&ndash;Drug Interactions in Rats

Gadoxetate, a magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 and multidrug resistance-associated protein 2. Six drugs, with varying degrees of transporter inhibition, were used to assess gadoxetate dynamic contrast enhanced MRI biomarkers for transporter inhibition in rats. Prospective prediction of changes in gadoxetate systemic and liver AUC (AUCR), resulting from transporter modulation, were performed by physiologically-based pharmacokinetic (PBPK) modelling. A tracer-kinetic model was used to estimate rate constants for hepatic uptake (khe), and biliary excretion (kbh). The observed median fold-decreases in gadoxetate liver AUC were 3.8- and 1.5-fold for ciclosporin and rifampicin, respectively. Ketoconazole unexpectedly decreased systemic and liver gadoxetate AUCs; the remaining drugs investigated (asunaprevir, bosentan, and pioglitazone) caused marginal changes. Ciclosporin decreased gadoxetate khe and kbh by 3.78 and 0.09 mL/min/mL, while decreases for rifampicin were 7.20 and 0.07 mL/min/mL, respectively. The relative decrease in khe (e.g., 96% for ciclosporin) was similar to PBPK-predicted inhibition of uptake (97&ndash;98%). PBPK modelling correctly predicted changes in gadoxetate systemic AUCR, whereas underprediction of decreases in liver AUCs was evident. The current study illustrates the modelling framework and integration of liver imaging data, PBPK, and tracer-kinetic models for prospective quantification of hepatic transporter-mediated DDI in humans