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Anna-Leena Vuorinen,1 Mika Lehto,2,3 Mikko Niemi,4,5 Kari Harno,6 Juha Pajula,1 Mark van Gils,1 Jaakko Lähteenmäki7 1VTT Technical Research Centre of Finland, Tampere, Finland; 2Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland; 3University of Helsinki, Helsinki, Finland; 4Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland; 5Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland; 6Department of Health and Social Management, University of Eastern Finland, Kuopio, Finland; 7VTT Technical Research Centre of Finland, Espoo, FinlandCorrespondence: Anna-Leena VuorinenVTT Technical Research Centre of Finland, P.O. Box 1300, Tampere, 33101, FinlandTel +358 40 8485966Email anna-leena.vuorinen@vtt.fiPurpose: To assess the association between VKORC1 and CYP2C9 variants and the incidence of adverse drug reactions in warfarin-treated patients in a real-world setting.Materials and Methods: This was a register-based cohort study (PreMed) linking data from Finnish biobanks, national health registries and patient records between January 1st 2007 and June 30th 2018. The inclusion criteria were: 1) ≥ 18 years of age, 2) CYP2C9 and VKORC1 genotype information available, 3) a diagnosis of a cardiovascular disease, 4) at least one warfarin purchase, 5) regular INR tests. Eligible individuals were divided into two warfarin sensitivity groups; normal responders, and sensitive and highly sensitive responders based on their VKORC1 and CYP2C9 genotypes. The incidences of clinical events were compared between the groups using Cox regression models.Results: The cohort consisted of 2508 participants (45% women, mean age of 69 years), of whom 65% were categorized as normal responders and 35% sensitive or highly sensitive responders. Compared to normal responders, sensitive and highly sensitive responders had fewer INR tests below 2 (median: 33.3% vs 43.8%, 95% CI: − 13.3%, − 10.0%) and more above 3 (median: 18.2% vs 6.7%, 95% Cl: 8.3%, 10.8%). The incidence (per 100 patient-years) of bleeding outcomes was 5.4 for normal responders and 5.6 for the sensitive and highly sensitive responder group (HR=1.03, 95% CI: 0.74, 1.44). The incidence of thromboembolic outcomes was 4.9 and 7.8, respectively (HR=1.48, 95% CI: 1.08, 2.03).Conclusion: In a real-world setting, genetically sensitive and highly sensitive responders to warfarin had more high INR tests and required a lower daily dose of warfarin than normal responders. However, the risk for bleeding events was not increased in sensitive and highly sensitive responders. Interestingly, the risk of thromboembolic outcomes was lower in normal responders compared to the sensitive and highly sensitive responders.Trial Registration: NCT04001166.Keywords: pharmacogenomics, warfarin, bleeding, INR, CYP2C9, VKORC1

Abstract Background Paramedics are often involved in treating palliative care patients with difficulties regarding symptom control. They report minimal training in palliative care and find decision-making difficult. This often leads to overtreatment and unnecessary transportation to the emergency department. The study’s objective is to determine how much palliative patients use emergency services, how well are they recognized by paramedics and how paramedics choose care in terms of treatment and transportation. Methods This study is a retrospective cohort study based in the Finnish Tampere University Hospital area. We included patients with a palliative care decision setting the goal of therapy as palliative intent between 1 August 2021 and 31 December 2021 and who died before 1 April 2022. From these patients, records of nurse paramedic visits were retrieved. Descriptive statistics were used to describe the data. Results Paramedics visited 69 patients in 97 callouts. These callouts comprised 0.26% of the total dispatches in the study area. The most common reasons for callouts were general weakness, breathing difficulty and pain. The paramedics provided treatment in 40% of the missions. 55% of the patients were transported to the emergency department. A palliative care plan was recognized by the paramedics in 42 of the 97 callouts. A total of 38 patients were recognized as palliative care patients by the paramedics while in the cases of 31 patients, palliative care was not recognized in any dispatch. Conclusion Patients in palliative care cause only a minimal load on the emergency medical services, but the paramedics do not necessarily recognize them as such. This leads to the risk of overtreatment and a high transportation rate to the emergency department, which is not an ethical choice. Recognition and treatment provided to palliative care patients by the paramedics could be improved with additional training and greater availability of patient records.

Abstract Background In Finland, the yearly number of mechanical thrombectomies for acute stroke is increasing and more patients are transported over 100 km to the comprehensive stroke centre (CSC) for definitive care. This leaves the rural townships without immediate emergency medical services (EMS) for hours. In this study we compare the EMS’ estimated return times to own station after the handover of a thrombectomy candidate between two transport methods: (1) using ground transportation with an ambulance to the CSC or (2) using a hydrid strategy starting the transportation with an ambulance and continuing by air with a helicopter emergency medical services unit (HEMS). Methods We reviewed retrospectively all thrombectomy candidates’ transportations from the hospital district of South Ostrobothnia to definitive care at the nearest CSC, Tampere University Hospital from June 2020 to October 2022. The dispatch protocol stated that a thrombectomy candidate’s transport begins immediately with an ambulance and if the local HEMS unit is available the patient is handed over to them at a rendezvous. If not, the patient is transported to the CSC by ground. Transport times and locations of the patient handovers were reviewed from the CSC’s EMS database and the driving time back to ambulance station was estimated using Google maps. The HEMS unit’s pilot’s log was reviewed to assess their mission engagement time. Results The median distance from the CSC to the ambulances’ stations was 188 km (IQR 149–204 km) and from the rendezvous with the HEMS unit 70 km (IQR 51–91 km, p

OBJECTIVES:. Anemia has been associated with an increased risk of both cardiac arrest and stroke, frequent complications of COVID-19. The effect of hemoglobin level at ICU admission on a composite outcome of cardiac arrest or stroke in an international cohort of COVID-19 patients was investigated. DESIGN:. Retrospective analysis of prospectively collected database. SETTING:. A registry of COVID-19 patients admitted to ICUs at over 370 international sites was reviewed for patients diagnosed with cardiac arrest or stroke up to 30 days after ICU admission. Anemia was defined as: normal (hemoglobin ≥ 12.0 g/dL for women, ≥ 13.5 g/dL for men), mild (hemoglobin 10.0–11.9 g/dL for women, 10.0–13.4 g/dL for men), moderate (hemoglobin ≥ 8.0 and < 10.0 g/dL for women and men), and severe (hemoglobin < 8.0 g/dL for women and men). PATIENTS:. Patients older than 18 years with acute COVID-19 infection in the ICU. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Of 6926 patients (median age = 59 yr, male = 65%), 760 patients (11.0%) experienced stroke (2.0%) and/or cardiac arrest (9.4%). Cardiac arrest or stroke was more common in patients with low hemoglobin, occurring in 12.8% of patients with normal hemoglobin, 13.3% of patients with mild anemia, and 16.7% of patients with moderate/severe anemia. Time to stroke or cardiac arrest by anemia status was analyzed using Cox proportional hazards regression with death as a competing risk. Covariates selected through clinical knowledge were age, sex, comorbidities (diabetes, hypertension, obesity, and cardiac or neurologic conditions), pandemic era, country income, mechanical ventilation, and extracorporeal membrane oxygenation. Moderate/severe anemia was associated with a higher risk of cardiac arrest or stroke (hazard ratio, 1.32; 95% CI, 1.05–1.67). CONCLUSIONS:. In an international registry of ICU patients with COVID-19, moderate/severe anemia was associated with increased hazard of cardiac arrest or stroke.

Abstract Background Mechanical thrombectomy is the treatment of choice for large vessel occlusion strokes done only in comprehensive stroke centres (CSC). We investigated whether the transportation time of thrombectomy candidates from another hospital district could be reduced by using an ambulance and a helicopter and how this affected their recovery. Methods We prospectively gathered the time points of thrombectomy candidates referred to the Tampere University Hospital from the hospital district of Southern Ostrobothnia. Primary and secondary transports were included. In Hybrid transport, the helicopter emergency medical services (HEMS) unit flew from an airport near the CSC to meet the patient during transport and continued the transport to definitive care. Ground transport was chosen only when the weather prevented flying, or the HEMS crew was occupied in another emergency. We contacted the patients treated with mechanical thrombectomy 90 days after the intervention and rated their recovery with the modified Rankin Scale (mRS). Favourable recovery was considered mRS 0–2. Results During the study, 72 patients were referred to the CSC, 71% of which were first diagnosed at the PSC. Hybrid transport (n = 34) decreased the median time from the start of transport from the PSC to the computed tomography (CT) at the CSC when compared to Ground (n = 17) transport (84 min, IQR 82–86 min vs. 109 min, IQR 104–116 min, p

In this proceedings contribution, we discuss recent developments in the perturbative determination of the Equation of State of dense quark matter, relevant for the microscopic description of neutron star cores. First, we introduce the current state of the art in the problem, both at zero and small temperatures, and then present results from two recent perturbative studies that pave the way towards extending the EoS to higher orders in perturbation theory.

Introduction & Background Food retailers’ transaction data are increasingly used for research. Unlike many other digital footprints, the representativeness of automatically accumulating food purchase data as such is less biased as food is consumed by all individuals. However, the process of obtaining individual/household level data requires consents from the consumers and, thus, may create selection bias. Objectives & Approach The aim of this work is to describe the recruitment process and participant characteristics in the Finnish LoCard study to evaluate the selection mechanism. The Finnish LoCard study comprises two cohorts collected in 2018 and 2023 with 47,066 and 42,340 participants, respectively, who have consented to release their food purchase data for research. The study collaborates with S group, the leading retailer in Finland with 47% market share. Members from their loyalty card program were invited to consent to their purchase data being used for research and voluntarily respond to a background questionnaire. Relevance to Digital Footprints Our analyses may provide further insights into the selectivity of consumers who are willing to share their purchase data for research purposes. Results For both LoCard cohorts, all loyalty card holders (n~2.3M) were considered. In LoCard I, the invitations were sent to 1.1M primary card holders with confirmed email addresses, of whom 47,066 (3.9%) participated and consented to their purchase data being used for research. In this cohort, women, middle-aged individuals, individuals with higher education, and employed individuals were overrepresented whereas the retired individuals, those with lower education and individuals with children were underrepresented. In the LoCard II, loyalty card holders (n ~2.24M) with an email address were invited. Of these, 852,009 (37.7%) opened the invitation link, and a further 42,340 provided the consent, resulting in response rate of 1.9% from the original population and 4.9% from those reacting to the email invitation. Data on the characteristics of LoCard II participants are not available yet but will be presented in the conference presentation. Conclusions & Implications This work investigates selection mechanisms in the Finnish LoCard study and evaluates the feasibility of reaching underrepresented groups in health studies, such as socioeconomically disadvantaged groups or young men, through a combination of loyalty card program and email invitations.

Background Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level.Methods Here we establish a patient-derived explant culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+T cell cytotoxic activity.Results We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax+metformin drug combination ex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+T cells and thus facilitating antitumor immunity.Conclusions Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.

Abstract Neutron-star cores contain matter at the highest densities in our Universe. This highly compressed matter may undergo a phase transition where nuclear matter melts into deconfined quark matter, liberating its constituent quarks and gluons. Quark matter exhibits an approximate conformal symmetry, predicting a specific form for its equation of state (EoS), but it is currently unknown whether the transition takes place inside at least some physical neutron stars. Here, we quantify this likelihood by combining information from astrophysical observations and theoretical calculations. Using Bayesian inference, we demonstrate that in the cores of maximally massive stars, the EoS is consistent with quark matter. We do this by establishing approximate conformal symmetry restoration with high credence at the highest densities probed and demonstrating that the number of active degrees of freedom is consistent with deconfined matter. The remaining likelihood is observed to correspond to EoSs exhibiting phase-transition-like behavior, treated as arbitrarily rapid crossovers in our framework.

Abstract As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide (TMZ) before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. We also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression.

Although electronic reading of fiction has become mainstream, little is known about how electronic texts are read, and whether this behavior is connected to readers’ motivation or experience reading electronically. To address this gap, sixty undergraduate students’ reading behavior was tracked while reading a 15-page short story. A novel method was used to study participants’ frequency of task-switching, their reading speed, and navigational patterns unobtrusively, outside of the lab. Reading behavior was analyzed by two multilevel models to assess (1) whether variance in behavior could be predicted by the task context, such as location in text or timing of reading sessions, and (2) whether behavior was connected to participants’ situational motivation to read the short story, their contextual motivation toward reading as an activity, or their task-relevant electronic experience. Our results showed that highly experienced and avid readers reacted to text difficulty more adaptively, indicating that motivation and electronic experience may have a key role in supporting comprehension. In contrast, situational motivation was not associated with reading behavior, contrary to our expectations. These findings provide a significant contribution to our understanding of e-reading, which can be used as a foundation to support recreational reading engagement on digital devices.

Collisionless shock waves, ubiquitous in the Universe, are crucial for particle acceleration in various astrophysical systems. Currently, the heliosphere is the only natural environment available for their in situ study. In this work, we showcase the collective acceleration of electrons and ions by one of the fastest in situ shocks ever recorded, observed by the pioneering Parker Solar Probe at only 34.5 million km from the Sun. Our analysis of this unprecedented, near-parallel shock shows electron acceleration up to 6 MeV amidst intense multiscale electromagnetic wave emissions. We also present evidence of a variable shock structure capable of injecting and accelerating ions from the solar wind to high energies through a self-consistent process. The exceptional capability of the probe’s instruments to measure electromagnetic fields in a shock traveling at 1% the speed of light has enabled us, for the first time, to confirm that the structure of a strong heliospheric shock aligns with theoretical models of strong shocks observed in astrophysical environments. This alignment offers viable avenues for understanding astrophysical shock processes and the self-consistent acceleration of charged particles.

Background and objectivesThe objectives of this study were to investigate the prognostic value of primary symptoms and leading symptoms in adult patients with diffuse infiltrating glioma and to provide a clinical perspective for evaluating survival.MethodsThis study included a retrospective cohort from two tertiary university hospitals (n = 604, 2006–2013, Tampere University Hospital and Turku University Hospital) and a prospective cohort (n = 156, 2014–2018, Tampere University Hospital). Preoperative symptoms were divided into primary and leading symptoms. Results were validated with the newer WHO 2021 classification criteria.ResultsThe most common primary symptoms were epileptic seizure (30.8% retrospective, 28.2% prospective), cognitive disorder (13.2% retrospective, 16.0% prospective), headache (8.6% retrospective, 12.8% prospective), and motor paresis (7.0% retrospective, 7.1% prospective). Symptoms that predicted better survival were epileptic seizure and visual or other sense-affecting symptom in the retrospective cohort and epileptic seizure and headache in the prospective cohort. Predictors of poor survival were cognitive disorder, motor dysfunction, sensory symptom, tumor hemorrhage, speech disorder and dizziness in the retrospective cohort and cognitive disorder, motor dysfunction, sensory symptom, and dizziness in the prospective cohort. Motor dysfunction served as an independent predictor of survival in a multivariate model (OR = 1.636).ConclusionPrimary and leading symptoms in diffuse gliomas are associated with prognoses in retrospective and prospective settings. Motor paresis was an independent prognostic factor for poor survival in multivariate analysis for grade 2-4 diffuse gliomas, especially in glioblastomas.

Widespread enterovirus D68 (EV-D68) epidemics occurred in the United States and in other parts of the world in 2014, 2016, and 2018 (2,2). Low-level EV-D68 detection was reported in the [...]

Abstract Both nonzero temperature and chemical potentials break the Lorentz symmetry present in vacuum quantum field theory by singling out the rest frame of the heat bath. This leads to complications in the application of thermal perturbation theory, including the appearance of novel infrared divergences in loop integrals and an apparent absence of four-dimensional integration-by-parts (IBP) identities, vital for high-order computations. Here, we propose a new strategy that enables the use of IBP techniques in the evaluation of Feynman integrals, in particular vacuum or bubble diagrams, in the limit of vanishing temperature T but nonzero chemical potentials μ. The central elements of the new setup include a contour representation for the temporal momentum integral, the use of a small but nonzero T as an IR regulator, and the systematic application of both temporal and spatial differential operators in the generation of linear relations among the loop integrals of interest. The relations we derive contain novel inhomogeneous terms featuring differentiated Fermi-Dirac distribution functions, which severely complicate calculations at nonzero temperature, but are shown to reduce to solvable lower-dimensional objects as T tends to zero. Pedagogical example computations are kept at the one- and two-loop levels, but the application of the new method to higher-order calculations is discussed in some detail.