Non-communicable Diseases, Big Data and Artificial Intelligence

This reprint includes 15 articles in the field of non-communicable Diseases, big data, and artificial intelligence, overviewing the most recent advances in the field of AI and their application potential in 3P medicine

Assessing Risk For Right Heart Failure After Left Ventricular Assist Device Implantation

The lives of more than six million people in the United States are negatively impacted by the diagnosis of Advanced Heart Failure. Financial burden, repeated hospitalizations, and declining quality of life account for poor outcomes. Implantation of a left ventricular assist device (LVAD) has offered the promise of improved financial, clinical, and functional outcomes for those awaiting or ineligible for heart transplantation. Right Heart Failure (RHF), however, threatens positive outcomes as it remains the leading cause of mortality and morbidity following LVAD placement. Despite extensive research, there is no comprehensive tool for RHF risk assessment and stratification for this population. The D.N.P. project aimed to adapt and implement a scoring tool for such assessment. Providers rated the assessment tool to be feasible and useful in practice. Though limited by a small number of LVAD patients, RHF risk was found to fluctuate for each patient throughout the phases of care, and no single parameter consistently trended in the same direction as the combined score. This pilot project should inspire future projects aimed at identifying risk for RHF which can offer opportunities for preventative care and realization of all positive outcomes for LVAD recipients

Tehohoitopotilaiden neuromonitorointi

In critical illness the risk of neurological insults is high, whether because of the illness itself, or as a treatment complication. As a result, the length of hospital stay and the risk of both further morbidity and mortality are all roughly doubled. One of the major challenges is the inability to monitor a sedated, mechanically ventilated patient’s neurological symptoms during intensive care treatment, due to a lack of reliable methods. The aims of this thesis research were to identify and test potential non-invasive methods, which would be predictive of neurological outcome, showing potential as neuromonitoring methods of critical care patients unable to self-report. As a guiding theme, all tested methods could be applied to actual critical care with relative ease. Patients were included from two groups with a notably high incidence of neurological complications, namely acute liver failure patients with hepatic encephalopathy (I), and aortic surgery patients operated during hypothermic circulatory arrest (II). The first group included 20 patients, and the latter 30 patients. Late mortality and quality of life was assessed for the aortic surgery patients (III), and the postoperative development of certain blood biomarkers (IV). The tested non-invasive neuromonitoring methods included electroencephalogram (EEG) variables from frontal or fronto-temporal abbreviated monitoring, frontal near-infrared spectroscopy, transcranial Doppler ultrasound measurements of the intracranial blood flow, and finally biomarkers. The last included established biomarkers with an association with neurological complications, namely neuron-specific enolase, and protein S100β, and several interesting biomarkers normally associated with tumours and pancreatitis. Of the tested methods, the frontal EEG variables showed greatest promise, but the addition of the temporal channels did not increase sensitivity. Spectral EEG variables were predictive of the stage of hepatic encephalopathy (I), while a novel EEG variable called wavelet subband entropy was predictive of neurological outcome (I). The hemispheric asymmetry of frontal EEG was reasonably predictive of neurological outcome after aortic surgery (II). None of the other tested methods were predictive of outcome (I, II, IV), except protein S100β, which was significantly higher in the poor outcome group 48 to 72 hours after hypothermic circulatory arrest (II). The quality of life of aortic surgery patients was good after 5 to 8 years, and comparable with the general population of chronically ill patients (III). The aim of this explorative research was to identify and test non-invasive neuromonitoring methods, suitable for use in critical care. Based on the results, frontal EEG variables are promising and predict the grade of hepatic encephalopathy and neurological outcome. The other tested methods were not predictive of neurological outcome. The long-term quality of life of aortic surgery patients is very good, despite the high risk for neurological complications.Kriittisissä sairauksissa neurologisen komplikaation riski on suuri, sekä itse kriittisen sairauden että varsinaisen hoidon seurauksena. Haittatapahtuman johdosta sairaalahoidon kesto sekä sairastuvuuden ja kuolleisuuden riskit kaksinkertaistuvat. Yksi suurimmista haasteista on luotettavien menetelmien puute, joilla voitaisiin arvioida mekaanisen hengitystuen varassa olevan ja rauhoittavia lääkkeitä saavan potilaan neurologisia oireita tehohoidon aikana. Tämän väitöskirjatyön tarkoituksena oli tunnistaa ja testata lupaavia ei-kajoavia menetelmiä, jotka ennustaisivat neurologista lopputulosta, ja jotka soveltuisivat kriittisesti sairaan tehohoitopotilaan neuromonitorointiin. Kantavana teemana kaikki testatut menetelmät voitaisiin soveltaa kliiniseen työhön suhteellisen helposti. Potilaita kerättiin kahteen ryhmään, joissa neurologisten komplikaatioiden esiintyvyys on huomattavan suuri. Ensimmäinen ryhmä käsitti akuuttia maksan vajaatoimintaa ja hepaattista enkefalopatiaa sairastavat potilaat (I), toinen hypotermisen verenkierron pysäytyksen aikana rinta-aortan leikkauksen läpikäyvät potilaat (II). Ensimmäiseen ryhmään kuului 20 potilasta, jälkimmäiseen 30 potilasta. Aorttaleikatuilta potilailta arvioitiin myös elämänlaatua sekä myöhäiskuolleisuutta (III), lisäksi tiettyjen biomerkkiaineiden aorttaleikkauksen jälkeistä kehitystä ja soveltuvuutta neuromonitorointiin arvioitiin yhdessä osatyössä (IV). Tutkimuksessa arvioituihin ei-kajoaviin neuromonitorointimenetelmiin lukeutuivat otsa- ja ohimolohkon elektroenkefalografia (EEG), lähi-infrapunaspektroskopia, transkraniaalinen Doppler-ultraäänimittaus sekä verestä mitattavat biomerkkiaineet. Biomerkkiaineet kattoivat sekä vakiintuneita aivovauriota heijastavia merkkiaineita (hermostoperäinen enolaasi, proteiini S100β) että useita mielenkiintoisia merkkiaineita, jotka liittyvät kasvaintauteihin ja haimatulehdukseen. Testatuista menetelmistä otsalohkon EEG muuttujat olivat lupaavia, mutta ohimolohkon EEG lisääminen ei parantanut menetelmien herkkyyttä. EEG spektrimuuttujat ennustivat hepaattisen enkefalopatian astetta (I) luotettavasti, kun taas kokeellinen EEG-muuttuja (aalloke-alitaajuuden entropia) ennusti luotettavasti neurologista lopputulosta akuutin maksan vajaatoimintaa sairastavilla potilailla (I). Otsalohkon aivopuoliskojen EEG-rekisteröinnin hetkellinen epäsymmetria ennusti kohtalaisella tarkkuudella neurologisten päätetapahtumien esiintymisen aorttaleikatuilla potilailla (II). Muut testatut menetelmät eivät ennustaneet neurologista lopputulemaa (I, II, IV), paitsi proteiini S100β, joka oli merkittävästi korkeampi 48–72 tuntia leikkauksen jälkeen niillä potilailla, joiden neurologinen toipuminen oli huono (IV). Aorttaleikattujen potilaiden elämänlaatu oli hyvä 5–8 vuotta leikkauksen jälkeen ja verrattavissa kroonisesti sairaan väestön elämänlaatuun (III). Tämän kartoittavan tutkimuksen tarkoituksena oli tunnistaa ja testata ei-kajoavia neuromonitorointimenetelmiä, jotka soveltuvat tehohoitoon. Tulosten perusteella otsalohkon EEG-muuttujat ennustavat hepaattisen enkefalopatian astetta sekä potilaan neurologista toipumista. Muut testatut menetelmät eivät ennustaneet neurologista toipumista luotettavasti. Aorttaleikattujen potilaiden pitkäaikainen (5–8 vuoden) terveyteen liittyvä elämänlaatu on erittäin hyvä, vaikka leikkaukseen liittyy korkea aivovaurion riski

Mechanical Circulatory Support in High-Risk Percutaneous Coronary Intervention

The use of mechanical circulatory devices to support high-risk elective percutaneous coronary intervention (PCI) has become more common as the group of patients considered inoperable or high risk for surgical revascularization has grown. Most of the data examining outcomes in high-risk PCI are observational and retrospective. Limited prospective randomized studies have been unable to show improved clinical outcomes with routine mechanical circulatory support (MCS) in patients with a high burden of coronary artery disease and reduced ejection fraction. The role for MCS in high-risk PCI continues to evolve as understanding of the appropriate groups for this therapy evolves

Cohort profile: rationale and methods of UK Biobank repeat imaging study eye measures to study dementia

PURPOSE: The retina provides biomarkers of neuronal and vascular health that offer promising insights into cognitive ageing, mild cognitive impairment and dementia. This article described the rationale and methodology of eye and vision assessments with the aim of supporting the study of dementia in the UK Biobank Repeat Imaging study. PARTICIPANTS: UK Biobank is a large-scale, multicentre, prospective cohort containing in-depth genetic, lifestyle, environmental and health information from half a million participants aged 40-69 enrolled in 2006-2010 across the UK. A subset (up to 60 000 participants) of the cohort will be invited to the UK Biobank Repeat Imaging Study to collect repeated brain, cardiac and abdominal MRI scans, whole-body dual-energy X-ray absorptiometry, carotid ultrasound, as well as retinal optical coherence tomography (OCT) and colour fundus photographs. FINDINGS TO DATE: UK Biobank has helped make significant advances in understanding risk factors for many common diseases, including for dementia and cognitive decline. Ophthalmic genetic and epidemiology studies have also benefited from the unparalleled combination of very large numbers of participants, deep phenotyping and longitudinal follow-up of the cohort, with comprehensive health data linkage to disease outcomes. In addition, we have used UK Biobank data to describe the relationship between retinal structures, cognitive function and brain MRI-derived phenotypes. FUTURE PLANS: The collection of eye-related data (eg, OCT), as part of the UK Biobank Repeat Imaging study, will take place in 2022-2028. The depth and breadth and longitudinal nature of this dataset, coupled with its open-access policy, will create a major new resource for dementia diagnostic discovery and to better understand its association with comorbid diseases. In addition, the broad and diverse data available in this study will support research into ophthalmic diseases and various other health outcomes beyond dementia

Aspects of circulatory failure in respiratory extracorporeal membrane oxygenation

Extracorporeal Membrane Oxygenation (ECMO) was developed in the seventies for the intended use of supporting respiratory failure. Today ECMO has become a well-established treatment for patients with both respiratory and circulatory failure where conventional intensive care is inadequate. The conventional way of treating adults with respiratory failure has been venovenous ECMO (VV ECMO) and for cardiogenic failure venoarterial (VA ECMO). However, since the respiratory system is an intrinsic part of the cardiocirculatory system and these systems exist in conjunction with each other, a respiratory failure may also inflict impairment on the circulation. Furthermore, a distributive shock differs from a cardiogenic shock. Therefore, it also remains to be clarified if, and to what extent vasoplegic (distributive) circulatory failure in conjunction with respiratory failure benefits from ECMO support, and which mode (VV or VA) should be preferred. Furthermore, if VA ECMO is instituted in a patient with a respiratory failure there are several issues that needs to be addressed that differ from the VA patient with single organ cardiogenic failure. AIMS The first aim of this thesis was to describe if ECMO and more specifically VA ECMO has a positive effect on survival in adult patients with septic shock (Study 1). In Study 2 we investigated the incidence, indication and outcome in patients who were converted from VV to VA ECMO to clarify whether conversion has an impact on mortality. Furthermore, since patients on peripheral VA ECMO will have parallel circulations with ensuing differential hypoxemia (DH), we went on with investigating patients with signs of DH. Thus, in Study 3 we investigated the impact on oxygen saturation in the upper body by change of drainage position from the inferior vena cava (IVC) to the superior vena cava (SVC). Since septic shock on ECMO can lead to prolonged ECMO with significant lung parenchymal damage we continued in study 4 to investigate if pulmonary blood flow (PBF) measured with echocardiography may assist in assessment of the extent of pulmonary damage, and if echocardiography and CT findings were associated with patient outcome. METHODS All studies are retrospective, originating from a high-volume ECMO centre. Patients who were not treated at our unit during the whole ECMO run, and patients with ongoing cardiopulmonary resuscitation (CPR) at the time of ECMO initiation were excluded in all studies. In Study 1 all patients treated for septic shock between 2012 and 2017 with an age >18 years, fulfilling septic shock criteria according to Sepsis-3, and a vasoactive- inotropic support equivalent to a Vasoactive inotropic score (VIS) >50 to reach a mean arterial pressure >65 mmHg despite adequate fluid resuscitation, were included. In Study 2 all patients >18 years old who were commenced on VV ECMO between 2005 and 2018 were included. Patients who were converted to VA ECMO within the first six hours after ECMO treatment was commenced were excluded. In Study 3 all patients from the age of 15 years between 2009 and 2020 identified with differential hypoxemia were included. Patients were included if there had been a state of fulminant differential hypoxemia (FDH) leading to a repositioning or change of the drainage cannula. FDH was defined as a higher saturation in the lower part of the body compared to the upper part of the body or a saturation of the upper body below or equal to 60%. In Study 4, all patients from the age of 15 between 2011 and 2017 were screened. Patients with septic shock (according to Sepsis 2) originating from pneumonia and treated for >28 days were eligible for inclusion. RESULTS In Study 1, thirty-seven patients were included. Twenty-seven patients were submitted to VA and 10 patients to VV ECMO. Hospital survival was 90% in septic shock with left ventricular failure, and 65% in patients with distributive vasoplegic shock. In Study 2, 219 VV ECMO patients were evaluated, 21% (n=46) were converted to VA ECMO. The two main reasons for conversion were right ventricular failure (RVF) or cardiogenic shock. In the converted patients, there was a significant increase in Sequential Organ Failure Assessment (SOFA) scores between admission 12 (IQR 9-13) and conversion 15 (IQR 13-17), p<0.001. The converted patients had a higher mortality rate compared to the non-converted patients (62 vs. 16%, p<0.001). These patients also scored lower at admission on the Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score (2 (0–4) versus −2.5 (−4–1), p<0.001). Mortality among RVF patients was 67% compared to 50% in converted patients with circulatory shock. In Study 3, 472 patients were screened and seven were identified with FDH. The mean peripheral capillary saturation increased from 54(±6.6) to 86(±6.6) %, (p=<0.001) after repositioning of the cannula from the IVC to the SVC. Pre-oxygenator saturation increased from 62(±8.9) % to 74(±3.7) %, (p=0.016) after repositioning. In Study 4, CT failed to indicate any differences in viable lung parenchyma between survivors and non-survivors at any time over the course of ECMO treatment. A mixed effects model with time, survivors and non-survivors and the interaction between time and the two groups as independent variables, showed that the interaction was significant (p=0.004) with different coefficient slopes between the two groups regarding PBF. CONCLUSIONS Study 1 supported the use of VA ECMO for distributive septic shock. Study 2 indicated that VA ECMO should be considered as the first mode of choice in patients with respiratory failure combined with a compromised circulation. Study 3 elucidated DH in a clinical patient setting which has never been presented previously, showing that moving the drainage zone into the upper part of the body had a marked positive effect on upper body saturation. Finally in Study 4 we presented results demonstrating that CT was supported as a prognostic tool in prolonged respiratory ECMO. However, we found that PBF may possibly assist in the prediction of pulmonary recovery

Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas

Platinum drug-resistance in ovarian cancers is a major factor contributing to chemotherapeutic resistance of recurrent disease. Members of the Bcl-2 family such as the anti-apoptotic protein Bcl-XL have been shown to play a role in this resistance. Consequently, concurrent inhibition of Bcl-XL in combination with standard chemotherapy may improve treatment outcomes for ovarian cancer patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-XL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo\ud experimental data, wherein tumor xenografts were established in mice and treated with ABT-737 and carboplatin on a fixed periodic schedule, alone or in combination, and tumor sizes recorded regularly. We show that the validated model can be used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the time of infusion of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin administered each week combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. We also investigate the potential of ABT-737 co-therapy with carboplatin to prevent or delay the onset of carboplatin-resistance under two scenarios. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, the model is used to identify drug delivery schedules that induce tumor remission with even low doses of combination therapy. When resistance is intrinsic, due to a pre-existing cohort of resistant cells, tumor remission is no longer feasible, but our model can be used to identify dosing strategies that extend disease-free survival periods. These results underscore the potential of our model to accelerate the development of novel therapeutics such as ABT-737, by predicting optimal treatment strategies when these drugs are given in combination with currently approved cancer medications