72 research outputs found

    KI-Gesundheitssystem-Netzwerke: FĂŒr eine strategische Neubestimmung des Informed Consent

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    Die Ära der Anwendung von KĂŒnstlicher Intelligenz (KI) in der Medizin beginnt gerade erst. Sie wird begleitet von großen Hoffnungen fĂŒr Fortschritte in der medizinischen Versorgung, die sich auf neue Formen der Behandlung genauso beziehen wie auf den besseren Zugang zu therapeutischen Angeboten. Die KomplexitĂ€t von KI-Gesundheitssystem-Netzwerken und die Dynamik der Datenzirkulation innerhalb dieser Netzwerke sind jedoch selbst von etablierten Expertinnen und Experten auf diesem Gebiet kaum zu erfassen. Allein die Frage, wo die Grenzen zwischen Behandlung, medizinischer Forschung, Technikentwicklung und Kommerzialisierung verlaufen, ist schwer zu entscheiden. Die UnĂŒbersichtlichkeit von KI-Anwendungen und -Effekten in der Medizin droht auch das Patientinnen-/ Patientenrecht auf einen Informed Consent zu unterminieren, demgemĂ€ĂŸ ĂŒber eine Behandlung informiert und aufgeklĂ€rt werden muss, bevor ein Behandlungsauftrag ergeht. In diesem Artikel wird anhand der methodisch kontrollierten Kartierung von Patientinnen-/Patientendaten gezeigt, inwiefern es möglich und lohnenswert ist, neue Formen der AufklĂ€rung zu etablieren. Die These ist, dass eine Strategie, die das Ziel von DatensouverĂ€nitĂ€t in KIGesundheitssystem-Netzwerken verfolgt, nicht auf uninformierter Freigabe von Patientinnen-/Patientendaten grĂŒnden sollte. Vielmehr ist die Neubestimmung des Informed Consent notwendig – und möglich.The era of applied Artificial Intelligence (AI) in medicine is just beginning. It is accompanied by great hopes for advances in medical care, in terms of both new forms of treatment and better access to therapeutic services. The complexity of AI health system networks and the dynamics of data circulation within these networks can hardly be grasped even by established experts in this field. The very question of what differentiates treatment, medical research, technological development and commercialisation is difficult to determine. The complexity of AI in medicine threatens to undermine the patients’ rights to informed consent, which implies an adequate explanation of the process, treatment, risks and rights preceding the patient’s agreement thereto. In this article, a methodologically controlled mapping of patient data is used to show the extent to which it is worthwhile establishing new forms of informed consent. The argument is that a strategy aiming for data sovereignty within AI health should not be based on uninformed release of patient data. Instead, the redefinition of informed consent is necessary – and possible

    Validation of a proxy‐reported SARC‐F questionnaire for current and retrospective screening of sarcopenia‐related functional impairments

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    BACKGROUND: The strength, assistance walking, rise from a chair, climb stairs, and falls (SARC‐F) questionnaire is a well‐established instrument for screening of sarcopenia and sarcopenia‐related functional impairments. As it is based on self‐reporting, its use precludes patients who are unable to answer the questionnaire as a consequence of severe acute diseases or cognitive impairment. Therefore, we aimed to validate a proxy‐reported version of the SARC‐F for both ad‐hoc as well as retrospective screening for severe sarcopenia‐related functional impairments. METHODS: Patients aged ≄60 years completed the SARC‐F and performed the short physical performance battery (SPPB) at baseline (T1). Proxies in Cohort A gave a simultaneous assessment of the patients' functional status with the proxy‐reported SARC‐F at T1 and again, retrospectively, after 3 months (T2). Proxies in Cohort B only completed the SARC‐F retrospectively at T2. The questionnaires' performances were assessed through sensitivity/specificity analyses and receiver operating characteristic (ROC) curves. For non‐inferiority analyses, results of both the patient‐reported and proxy‐reported SARC‐F were correlated with the SPPB total score as well as the results of the chair‐rise test subcategory; the respective correlation coefficients were tested against each other. RESULTS: One hundred and four patients and 135 proxies participated. Using a SPPB score < 9 points as the reference standard, the proxy‐reported SARC‐F identified patients at high risk for sarcopenia‐related functional impairment with a sensitivity of 0.81 (ad‐hoc), 0.88 (retrospective Cohort A), and 0.87 (retrospective Cohort B) as well as a specificity of 0.89 (ad‐hoc), 0.78 (retrospective Cohort A), and 0.64 (retrospective Cohort B). Areas under the ROC curves were ≄ 0.9 for the ad‐hoc proxy‐reported SARC‐F and the retrospective proxy‐reported SARC‐F in both cohorts. The proxy‐reported SARC‐F showed a non‐inferior correlation with the SPPB compared with the patient‐reported SARC‐F for ad‐hoc (P = <0.001) as well as retrospective screening for severe sarcopenia‐related functional impairment in both Cohorts A (P = 0.007) and B (P = 0.026). CONCLUSIONS: Proxy‐reported SARC‐F is a valid instrument for both ad‐hoc as well as retrospective screening for sarcopenia‐related functional impairment and could become the standard tool for evaluating this risk in older adults with severe acute disease, for example, in patients with quickly evolving haematological conditions

    PSMA-RLT in Patients with Metastatic Hormone-Sensitive Prostate Cancer : A Retrospective Study

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    Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a novel treatment for patients with castration-resistant prostate cancer (CRPC). Given the mode of action, patients in an earlier disease stage, such as hormone-sensitive prostate cancer (HSPC), are also likely to benefit from [177Lu]Lu-PSMA- (177Lu-PSMA) or [225Ac]Ac-PSMA-radioligand treatment (225Ac-PSMA). In this retrospective study, we analyzed the safety and efficacy of PSMARLT in early-stage and hormone-sensitive metastatic prostate cancer patients. Methods: A retrospective study was performed in patients who received 177Lu-PSMA and/or 225Ac-PSMA with early-stage metastatic prostate cancer. The primary outcome parameter evaluated in this study was the progression-free survival (PFS) after PSMA-RLT and toxicity according to the Common Terminology Criteria for Adverse Events. Secondary outcome parameters were prostate-specific antigen (PSA) response and the date of onset of CRPC state. Results: In total, 20 patients were included of which 18 patients received 177Lu-PSMA radioligand and two patients received tandem treatment with both 177Lu-PSMA and 225Ac-PSMA radioligands. Patients received a median of 2 treatment cycles (range 1–6) and a median activity of 6.2 GBq 177Lu-PSMA per cycle (interquartile range (IQR) 5.2–7.4 GBq). PSMA-RLT was overall well-tolerated. The most common grade 1–2 side effects were xerostomia (n = 6) and fatigue (n = 8), which were only temporarily reported. One patient that received 225Ac-PSMA developed grade 3–4 bone marrow toxicity. The median PFS was 12 months (95% confidence interval (CI), 4.09–19.9 months). Seventeen (85%) patients had a ≄50% PSA response following PSMA-RLT. One patient developed CRPC 9 months following PSMA-RLT. Conclusions: In this small cohort study, PSMA-RLT appeared safe and showed encouraging efficacy for (metastasized) early-stage and hormone-sensitive prostate cancer patients. Prospective studies are awaited and should include long-term follow-up

    Aspirin use and bleeding events during thrombocytopenia after autologous stem-cell transplantation for multiple myeloma

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    BackgroundIn patients with cardiovascular (CV) comorbidities that necessitate antiplatelet therapy (APT), its optimal management during chemotherapy-induced thrombocytopenia remains elusive, as the risk of bleeding has to be balanced against the risk of CV events. The purpose of this study was to assess the risk for bleeding with APT during thrombocytopenia in patients with multiple myeloma undergoing high-dose chemotherapy and subsequent autologous stem-cell transplantation (ASCT) with and without acetylsalicylic acid (ASA) as comedication.MethodsWe assessed patients who underwent ASCT at the Heidelberg University Hospital between 2011 and 2020 for bleeding events, management strategies for ASA intake during thrombocytopenia, transfusion requirements, and the occurrence of CV events.ResultsThere were 57/1,113 patients who continued ASA until at least 1 day after ASCT; thus, a continuous platelet inhibition during thrombocytopenia was assumed. Most of the patients (41/57) continued ASA until they had a platelet count of 20–50/nl. This range reflects the kinetics of thrombocytopenia and nondaily measurements of platelets during ASCT. A tendency toward a higher risk for bleeding events in the ASA group was demonstrated (1.9% (control group) vs. 5.3% (ASA), p = 0.082). The risk factors for bleeding in multivariate analysis were the duration of thrombocytopenia &lt; 50/nl, a history of gastrointestinal bleeding, and diarrhea. The factors predicting the duration of thrombocytopenia were age &gt;60 years, a hematopoietic stem-cell transplantation comorbidity index ≄3, and an impaired bone marrow reserve at admission. CV events occurred in three patients; none of them took ASA or had an indication for APT.ConclusionsThe intake of ASA until thrombocytopenia with a platelet count of 20–50/nl appears safe, although an elevated risk cannot be excluded. If ASA is indicated for the secondary prevention of CV events, the evaluation of risk factors for bleeding and a prolonged time of thrombocytopenia before conditioning is crucial to adapt the strategy for ASA intake during thrombocytopenia

    Clonal hematopoiesis with <i>DNMT3A</i> and <i>PPM1D</i> mutations impairs regeneration in autologous stem cell transplant recipients

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    Clonal hematopoiesis (CH) is an age-related condition driven by stem and progenitor cells harboring recurrent mutations linked to myeloid neoplasms. Currently, potential effects on hematopoiesis, stem cell function and regenerative potential under stress conditions are unknown. We performed targeted DNA sequencing of 457 hematopoietic stem cell grafts collected for autologous stem cell transplantation (ASCT) in myeloma patients and correlated our findings with high-dimensional longitudinal clinical and laboratory data (26,510 data points for blood cell counts/serum values in 25 days around transplantation). We detected CHrelated mutations in 152 patients (33.3%). Since many patients (n=54) harbored multiple CH mutations in one or more genes, we applied a non-negative matrix factorization (NMF) clustering algorithm to identify genes that are commonly co-mutated in an unbiased approach. Patients with CH were assigned to one of three clusters (C1-C3) and compared to patients without CH (C0) in a gene specific manner. To study the dynamics of blood cell regeneration following ASCT, we developed a time-dependent linear mixed effect model to validate differences in blood cell count trajectories amongst different clusters. The results demonstrated that C2, composed of patients with DNMT3A and PPM1D single and co-mutated CH, correlated with reduced stem cell yields and delayed platelet count recovery following ASCT. Also, the benefit of maintenance therapy was particularly strong in C2 patients. Taken together, these data indicate an impaired regenerative potential of hematopoietic stem cell grafts harboring CH with DNMT3A and PPM1D mutations

    A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection

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    Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3–7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6+ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6+ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12–22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP–PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase–cAMP–PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase–cAMP–PKA axis in an immune rheostat-like fashion.</p

    EUNIS Habitat Classification: Expert system, characteristic species combinations and distribution maps of European habitats

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    Aim: The EUNIS Habitat Classification is a widely used reference framework for European habitat types (habitats), but it lacks formal definitions of individual habitats that would enable their unequivocal identification. Our goal was to develop a tool for assigning vegetation‐plot records to the habitats of the EUNIS system, use it to classify a European vegetation‐plot database, and compile statistically‐derived characteristic species combinations and distribution maps for these habitats. Location: Europe. Methods: We developed the classification expert system EUNIS‐ESy, which contains definitions of individual EUNIS habitats based on their species composition and geographic location. Each habitat was formally defined as a formula in a computer language combining algebraic and set‐theoretic concepts with formal logical operators. We applied this expert system to classify 1,261,373 vegetation plots from the European Vegetation Archive (EVA) and other databases. Then we determined diagnostic, constant and dominant species for each habitat by calculating species‐to‐habitat fidelity and constancy (occurrence frequency) in the classified data set. Finally, we mapped the plot locations for each habitat. Results: Formal definitions were developed for 199 habitats at Level 3 of the EUNIS hierarchy, including 25 coastal, 18 wetland, 55 grassland, 43 shrubland, 46 forest and 12 man‐made habitats. The expert system classified 1,125,121 vegetation plots to these habitat groups and 73,188 to other habitats, while 63,064 plots remained unclassified or were classified to more than one habitat. Data on each habitat were summarized in factsheets containing habitat description, distribution map, corresponding syntaxa and characteristic species combination. Conclusions: EUNIS habitats were characterized for the first time in terms of their species composition and distribution, based on a classification of a European database of vegetation plots using the newly developed electronic expert system EUNIS‐ESy. The data provided and the expert system have considerable potential for future use in European nature conservation planning, monitoring and assessment

    Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

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    Funder: laura and john arnold foundationBACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care

    Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

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    A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements
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