Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. ...This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes.
A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported.
1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict "survival". Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients' age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy.
Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration "ClinicalTrials" (clinicaltrials.gov) under NCT04455451.
Background Cardiac surgery−related acute kidney injury (AKI) is a common postoperative complication that greatly increases morbidity and mortality. There are currently no effective interventions to ...prevent AKI associated with cardiac surgery. Experimental data have shown that administration of the mineralocorticoid receptor blocker spironolactone prevents renal injury induced by ischemia-reperfusion in rats. The objective of this study was to test whether short-term perioperative administration of oral spironolactone could reduce the incidence of AKI in cardiac surgical patients. Study Design Randomized, double-blinded, placebo-controlled trial. Setting & Participants Data were collected from April 2014 through July 2015 at the National Heart Institute in Mexico. 233 patients were included; 115 and 118 received spironolactone or placebo, respectively. Intervention Spironolactone or placebo once at a dose of 100 mg 12 to 24 hours before surgery and subsequently 3 further doses of 25 mg in postoperative days 0, 1, and 2 were administered. Outcomes Patients were followed up for 7 days or until discharge from the intensive care unit (ICU). The primary end point was AKI incidence defined by KDIGO criteria. Secondary end points included requirement of renal replacement therapy, ICU length of stay, and ICU mortality. Data were analyzed according to the intention-to-treat principle. Results Mean age was 53.2 ± 15 years, mean serum creatinine level was 0.9 ± 0.2 mg/dL, median Thakar score for estimation of AKI risk was 2 (IQR, 1-3), and 25% had diabetes. The incidence of AKI was higher for the spironolactone group (43% vs 29%; P = 0.02). No significant differences were found for secondary end points. Limitations Single center, AKI was mostly driven by AKI stage 1, planned sample size was not achieved, and there was no renin-angiotensin-aldosterone system washout period. Conclusions Our trial demonstrated that spironolactone was not protective for AKI associated with cardiac surgery and there may be a trend toward risk.
To identify mediators of glioblastoma antiangiogenic therapy resistance and target these mediators in xenografts.
We conducted microarray analysis comparing bevacizumab-resistant glioblastomas (BRG) ...with pretreatment tumors from the same patients. We established novel xenograft models of antiangiogenic therapy resistance to target candidate resistance mediator(s).
BRG microarray analysis revealed upregulation versus pretreatment of receptor tyrosine kinase c-Met, which underwent further investigation because of its prior biologic plausibility as a bevacizumab resistance mediator. BRGs exhibited increased hypoxia versus pretreatment in a manner correlating with their c-Met upregulation, increased c-Met phosphorylation, and increased phosphorylation of c-Met-activated focal adhesion kinase and STAT3. We developed 2 novel xenograft models of antiangiogenic therapy resistance. In the first model, serial bevacizumab treatment of an initially responsive xenograft generated a xenograft with acquired bevacizumab resistance, which exhibited upregulated c-Met expression versus pretreatment. In the second model, a BRG-derived xenograft maintained refractoriness to the MRI tumor vasculature alterations and survival-promoting effects of bevacizumab. Growth of this BRG-derived xenograft was inhibited by a c-Met inhibitor. Transducing these xenograft cells with c-Met short hairpin RNA inhibited their invasion and survival in hypoxia, disrupted their mesenchymal morphology, and converted them from bevacizumab-resistant to bevacizumab-responsive. Engineering bevacizumab-responsive cells to express constitutively active c-Met caused these cells to form bevacizumab-resistant xenografts.
These findings support the role of c-Met in survival in hypoxia and invasion, features associated with antiangiogenic therapy resistance, and growth and therapeutic resistance of xenografts resistant to antiangiogenic therapy. Therapeutically targeting c-Met could prevent or overcome antiangiogenic therapy resistance.
Large randomized trials are the best method to test the efficacy and safety of treatments expected to have moderate effects. We observed a significant decline in potential participants' response to ...mailed invitations to participate in such trials over a 10-year period and investigated possible reasons behind this and potential modifications to the invitation process to mitigate it.
Participants who declined to participate in the HPS2-THRIVE trial were asked to give a reason. Formal focus groups were conducted to explore the reasons that potential participants might have for not participating. In addition, two embedded randomized comparisons around the timing of provision of the full participant information leaflet (PIL) and its style were conducted during recruitment into this large randomized trial. HPS2-THRIVE is registered at ClinicalTrials.gov (NCT00461630).
The commonest reason given for declining invitations related to mobility and transportation (despite the offer of travel expenses). Both the focus groups and potential participants who declined their invitation indicated concern about side-effects of the treatment (as presented in the PIL) as a reason for declining the invitation. Neither delaying provision of the full PIL until the potential participant attended the trial clinic, nor modifying the style of the PIL improved the proportion of potential participants entering the trial: odds ratio (OR) 1.05 (95% confidence interval (CI) 0.94-1.17) and 1.10 (95% CI 0.94-1.28), respectively. However, modifying the style of the PIL did increase the proportion of participants attending screening appointments (OR 1.17, 95% CI 1.03-1.33).
Many reasons given for not participating in trials are not tractable to individual trials. However, modification of the PIL does show potential to modestly improve participation. If further trials could identify similar simple interventions that were beneficial, their net effects could substantially improve trial participation and facilitate recruitment into large trials.
Background
The relevance of vitamin D for prevention of cardiovascular disease is uncertain. The BEST‐D (Biochemical Efficacy and Safety Trial of vitamin D) trial previously reported effects of ...vitamin D on plasma markers of vitamin D status, and the present report describes the effects on blood pressure, heart rate, arterial stiffness, and cardiac function.
Methods and Results
This was a randomized, double‐blind, placebo‐controlled trial of 305 older people living in United Kingdom, who were allocated vitamin D 4000 IU (100 μg), vitamin D 2000 IU (50 μg), or placebo daily. Primary outcomes were plasma concentrations of 25‐hydroxy‐vitamin D and secondary outcomes were blood pressure, heart rate, and arterial stiffness in all participants at 6 and 12 months, plasma N‐terminal prohormone of brain natriuretic peptide levels in all participants at 12 months, and echocardiographic measures of cardiac function in a randomly selected subset (n=177) at 12 months. Mean (SE) plasma 25‐hydroxy‐vitamin D concentrations were 50 (SE 2) nmol/L at baseline and increased to 137 (2.4), 102 (2.4), and 53 (2.4) nmol/L after 12 months in those allocated 4000 IU/d, 2000 IU/d of vitamin D, or placebo, respectively. Allocation to vitamin D had no significant effect on mean levels of blood pressure, heart rate, or arterial stiffness at either 6 or 12 months, nor on any echocardiographic measures of cardiac function, or plasma N‐terminal prohormone of brain natriuretic peptide concentration at 12 months.
Conclusions
The absence of any significant effect of vitamin D on blood pressure, arterial stiffness, or cardiac function suggests that any beneficial effects of vitamin D on cardiovascular disease are unlikely to be mediated through these mechanisms.
Clinical Trial Registration
URL: https://www.clinicaltrialsregister.eu/ctr-search/search. Unique identifier: EudraCT number: 2011–005763‐24a
The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft ...models and patient specimens, we identified a c-Met/β1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/β1 complex formation through an engineered inducible heterodimerization system promoted features crucial to overcoming stressors during metastases or antiangiogenic therapy: migration in the primary site, survival under hypoxia, and extravasation out of circulation. c-Met/β1 complex formation was up-regulated by hypoxia, while VEGF binding VEGFR2 sequestered c-Met and β1 integrin, preventing their binding. Complex formation promoted ligand-independent receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing the c-Met/β1 complex to maintain the high-affinity β1 integrin conformation. Site-directed mutagenesis verified the necessity for c-Met/β1 binding of amino acids predicted by crystallography to mediate their extracellular interaction. Far-Western blotting and sequential immunoprecipitation revealed that c-Met displaced α5 integrin from β1 integrin, creating a complex with much greater affinity for fibronectin (FN) than α5β1. Thus, tumor cells adapt to microenvironmental stressors induced bymetastases or bevacizumab by coopting receptors, which normally promote both cell migration modes: chemotaxis, movement toward concentrations of environmental chemoattractants, and haptotaxis, movement controlled by the relative strengths of peripheral adhesions. Tumor cells then redirect these receptors away from their conventional binding partners, forming a powerful structural c-Met/β1 complex whose ligand-independent cross-activation and robust affinity for FN drive invasive oncologic processes.
Drug development in human chronic lymphocytic leukemia (CLL) has been limited by lack of a suitable animal model to adequately assess pharmacologic properties relevant to clinical application. A ...recently described TCL-1 transgenic mouse develops a chronic B-cell CD5+ leukemia that might be useful for such studies. Following confirmation of the natural history of this leukemia in the transgenic mice, we demonstrated that the transformed murine lymphocytes express relevant therapeutic targets (Bcl-2, Mcl-1, AKT, PDK1, and DNMT1), wild-type p53 status, and in vitro sensitivity to therapeutic agents relevant to the treatment of human CLL. We then demonstrated the in vivo clinical activity of low-dose fludarabine in transgenic TCL-1 mice with active leukemia. These studies demonstrated both early reduction in blood-lymphocyte count and spleen size and prolongation of survival (P = .046) compared with control mice. Similar to human CLL, an emergence of resistance was noted with fludarabine treatment in vivo. Overall, these studies suggest that the TCL-1 transgenic leukemia mouse model has similar clinical and therapeutic response properties to human CLL and may therefore serve as a useful in vivo tool to screen new drugs for subsequent development in CLL.
While anti-angiogenic therapy was initially greeted enthusiastically by the cancer community, initial successes with this therapeutic modality were tempered by the failure of angiogenesis inhibitors ...to produce sustained clinical responses in most patients, with resistance to the inhibitors frequently developing. We recently reported that hypoxia increases after the devascularization caused by anti-angiogenic therapy, consistent with the goals of these therapies, but that some tumor cells become resistant and survive the hypoxic insult elicited by anti-angiogenic therapy through autophagy by activating both AMPK and HIF1A pathways. These findings suggest that modulating the autophagy pathway may someday allow anti-angiogenic therapy to fulfill its therapeutic potential. However, further work will clearly be needed to develop more potent and specific autophagy inhibitors and to better understand the regulators of autophagy in malignant cells.
A multicenter, randomized trial involving participants with diabetes and no evident cardiovascular disease at trial entry showed that aspirin led to a lower risk of serious vascular events than ...placebo but also caused a higher risk of major bleeding.
In this trial involving patients with diabetes without evidence of cardiovascular disease, the risk of serious vascular events was similar in those who received n−3 fatty acid supplements and those ...who received placebo.
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