Electrocardiogram-based mortality prediction in patients with COVID-19 using machine learning.

BACKGROUND AND PURPOSE: The electrocardiogram (ECG) is frequently obtained in the work-up of COVID-19 patients. So far, no study has evaluated whether ECG-based machine learning models have added value to predict in-hospital mortality specifically in COVID-19 patients. METHODS: Using data from the CAPACITY-COVID registry, we studied 882 patients admitted with COVID-19 across seven hospitals in the Netherlands. Raw format 12-lead ECGs recorded within 72 h of admission were studied. With data from five hospitals (n = 634), three models were developed: (a) a logistic regression baseline model using age and sex, (b) a least absolute shrinkage and selection operator (LASSO) model using age, sex and human annotated ECG features, and (c) a pre-trained deep neural network (DNN) using age, sex and the raw ECG waveforms. Data from two hospitals (n = 248) was used for external validation. RESULTS: Performances for models a, b and c were comparable with an area under the receiver operating curve of 0.73 (95% confidence interval [CI] 0.65-0.79), 0.76 (95% CI 0.68-0.82) and 0.77 (95% CI 0.70-0.83) respectively. Predictors of mortality in the LASSO model were age, low QRS voltage, ST depression, premature atrial complexes, sex, increased ventricular rate, and right bundle branch block. CONCLUSION: This study shows that the ECG-based prediction models could be helpful for the initial risk stratification of patients diagnosed with COVID-19, and that several ECG abnormalities are associated with in-hospital all-cause mortality of COVID-19 patients. Moreover, this proof-of-principle study shows that the use of pre-trained DNNs for ECG analysis does not underperform compared with time-consuming manual annotation of ECG features.

Computational screening of transition metal/p-block hybrid electrocatalysts for CO2 reduction.

Among all the pollutants in the atmosphere, CO2 has the highest impact on global warming, and with the rising levels of this pollutant, studies on developing various technologies to convert CO2 into carbon-neutral fuels and chemicals have become more valuable. In this work, we present a detailed computational study of electrochemical reduction of CO2 reaction (the CO2 RR) to methane and/or methanol over different transition metal-p block catalysts using density functional theory calculations. In addition to the catalyst structure, we studied reaction mechanisms using free energy diagrams that explain the product selectivity with respect to the competing hydrogen evolution reaction. Furthermore, we developed scaling relations between all the active C bound intermediate species with ΔG(CO*) and O bound species with ΔG(OH*) The limiting potential lines with ΔG(OH*) as the descriptor are much less negative compared to UL lines with ΔG(CO*) as the descriptor indicating that catalyst materials following pathways via OH- bound intermediate species require more negative potentials than CO*→ HCO* and CO2 → COOH* steps to convert into products. We developed thermodynamic volcano plots with two descriptors; the CO* and OH* binding free energies and determined the best catalyst material among the initially investigated catalyst materials expecting this plot will provide guidance to the future work on improving the activity of transition metal-p block catalysts for this important reduction reaction.

Novel use of repolarization parameters in electrocardiographic imaging to uncover arrhythmogenic substrate.

BACKGROUND: Measuring repolarization characteristics is challenging and has been reserved for experienced physicians. In electrocardiographic imaging (ECGI), activation-recovery interval (ARI) is used as a measure of local cardiac repolarization duration. We hypothesized that repolarization characteristics, such as local electrogram morphology and local and global dispersion of repolarization timing and duration could be of significance in ECGI. OBJECTIVE: To further explore their potential in arrhythmic risk stratification we investigated the use of novel repolarization parameters in ECGI. MATERIALS AND METHODS: We developed and compared methods for T-peak and T-end detection in reconstructed potentials. All methods were validated on annotated reconstructed electrograms (EGMs). Characteristics of the reconstructed EGMs and epicardial substrate maps in IVF patients were analyzed by using data recorded during sinus rhythm. The ECGI data were analyzed for EGM morphology, conduction, and repolarization. RESULTS: We acquired ECGI data from 8 subjects for this study. In all patients we evaluated four repolarization parameters: Repolarization time, T-wave area, Tpeak-Tend interval, and T-wave alternans. Most prominent findings were steep repolarization time gradients in regions with flat EGMs. These regions were also characterized by low T-wave area and large differences in Tpeak-Tend interval. CONCLUSIONS: Measuring novel repolarization parameters in reconstructed electrograms acquired with ECGI is feasible, can be done in a fully automated manner and may provide additional information on underlying arrhythmogenic substrate for risk stratification. Further studies are needed to investigate their potential use and clinical application.

The role of initial clinical presentation, comorbidity and treatment in multiple myeloma patients on survival: a detailed population-based cohort study.

PURPOSE: This prospective, observational population-based cohort study was performed to determine overall survival (OS) in multiple myeloma (MM) patients in Friesland, the Netherlands, in the era of novel agents and to analyse the influence of first-line treatment, MM-related end-organ damage and comorbidities at initial presentation on OS. METHODS: Detailed clinical information was obtained from the population-based registry 'HemoBase' during the period January 2005 to January 2013, with a follow-up to January 2014. RESULTS: Overall, the symptomatic MM patients (n = 225) had a median OS of 40 months. In the age categories <65, 65-75 and ≥75 years, 99, 94 and 87% of the patients received treatment, with a median OS of 92, 42 and 31 months, respectively. OS for patients with or without treatment was 43 and 3 months, respectively. In multivariable analysis, risk factors for worse OS were increasing age (<65: reference; 65-75: HRadj. = 2.2 (95% CI 1.3-3.7) and ≥75: HRadj. = 2.8 (95% CI 1.7-4.8); P < 0.001), not receiving initial treatment (HRadj. = 4.0 (95% CI 2.1-7.7); P < 0.001), hypercalcaemia (P < 0.001, HRadj. = 1.7 (95% CI 1.2-2.6), P = 0.006) and impaired renal function (HRadj. = 2.6 (95% CI 1.7-4.0); P < 0.001). CONCLUSIONS: Increasing age, not receiving initial treatment, hypercalcaemia and impaired renal function at initial presentation were independent risk factors for worse OS. Comorbidity according to Charlson comorbidity index score was not an independent variable predicting OS.

Influence of euthanasia method on blood and gill variables in normoxic and hypoxic Gulf killifish Fundulus grandis.

In many experiments, euthanasia, or humane killing, of animals is necessary. Some methods of euthanasia cause death through cessation of respiratory or cardiovascular systems, causing oxygen levels of blood and tissues to drop. For experiments where the goal is to measure the effects of environmental low oxygen (hypoxia), the choice of euthanasia technique, therefore, may confound the results. This study examined the effects of four euthanasia methods commonly used in fish biology (overdose of MS-222, overdose of clove oil, rapid cooling and blunt trauma to the head) on variables known to be altered during hypoxia (haematocrit, plasma cortisol, blood lactate and blood glucose) or reflecting gill damage (trypan blue exclusion) and energetic status (ATP, ADP and ATP:ADP) in Gulf killifish Fundulus grandis after 24 h exposure to well-aerated conditions (normoxia, 7·93 mg O2 l-1 , c. 150 mm Hg or c. 20 kPa) or reduced oxygen levels (0·86 mg O2 l-1 , c. 17 mm Hg or c. 2·2 kPa). Regardless of oxygen treatment, fish euthanized by an overdose of MS-222 had higher haematocrit and lower gill ATP:ADP than fish euthanized by other methods. The effects of 24 h hypoxic exposure on these and other variables, however, were equivalent among methods of euthanasia (i.e. there were no significant interactions between euthanasia method and oxygen treatment). The choice of an appropriate euthanasia method, therefore, will depend upon the magnitude of the treatment effects (e.g. hypoxia) relative to potential artefacts caused by euthanasia on the variables of interest.

Elucidation of Pathways for NO Electroreduction on Pt(111) from First Principles.

The mechanism of nitric oxide electroreduction on Pt(111) is investigated using a combination of first principles calculations and electrokinetic rate theories. Barriers for chemical cleavage of N-O bonds on Pt(111) are found to be inaccessibly high at room temperature, implying that explicit electrochemical steps, along with the aqueous environment, play important roles in the experimentally observed formation of ammonia. Use of explicit water models, and associated determination of potential-dependent barriers based on Bulter-Volmer kinetics, demonstrate that ammonia is produced through a series of water-assisted protonation and bond dissociation steps at modest voltages (<0.3 V). In addition, the analysis sheds light on the poorly understood formation mechanism of nitrous oxide (N2 O) at higher potentials, which suggests that N2 O is not produced through a Langmuir-Hinshelwood mechanism; rather, its formation is facilitated through an Eley-Rideal-type process.

Trends in methanol decomposition on transition metal alloy clusters from scaling and Brønsted-Evans-Polanyi relationships.

A combination of first principles Density Functional Theory calculations and thermochemical scaling relationships are employed to estimate the thermochemistry and kinetics of methanol decomposition on unsupported subnanometer metal clusters. The approach uses binding energies of various atomic and molecular species, determined on the pure metal clusters, to develop scaling relationships that are then further used to estimate the methanol decomposition thermodynamics for a series of pure and bimetallic clusters with four atoms per cluster. Additionally, activation energy barriers are estimated from Brønsted-Evans-Polanyi plots relating transition and final state energies on these clusters. The energetic results are combined with a simple, microkinetically-inspired rate expression to estimate reaction rates as a function of important catalytic descriptors, including the carbon and atomic oxygen binding energies to the clusters. Based on these analyses, several alloy clusters are identified as promising candidates for the methanol decomposition reaction.

Temporal dynamics in growth and white skeletal muscle composition of the mummichog Fundulus heteroclitus during chronic hypoxia and hyperoxia.

Specific growth rate (G(S) ) and white skeletal muscle composition were measured in the mummichog Fundulus heteroclitus over a period of 28 days at four levels of dissolved oxygen (DO): severe hypoxia (c. 1.2 mg O(2) l(-1) ), moderate hypoxia (3.0 mg O(2) l(-1) ), normoxia (7.1 mg O(2) l(-1) ) and hyperoxia (10.6 mg O(2) l(-1) ). The G(S) was calculated over 0-8, 0-14, 0-28 and 14-28 days, and muscle protein, lactate dehydrogenase (LDH), DNA, RNA and water were measured at 0, 8, 14 and 28 days. Exposure of fish to severe hypoxia was associated with significantly reduced G(S) , lower muscle protein content and lower RNA:DNA compared with other DO treatments. When calculated over the first and second half of the 28 day exposure, however, G(S) of fish in severe hypoxia increased significantly during the second two-week interval, to the same rate as that of normoxic fish. Muscle LDH activity and water content were not significantly affected by DO level. Neither moderate hypoxia nor hyperoxia significantly affected G(S) or any biochemical variable. The results demonstrate that F. heteroclitus can tolerate wide variation in ambient oxygen concentration and, during prolonged exposure to severe hypoxia, shows significant compensation for the initial negative effects on growth. The capacity of F. heteroclitus to grow over a wide range of DO probably contributes to its ability to exploit habitats characterized by marked variation in oxygen availability.

Lipegfilgrastim for prophylaxis of chemotherapy-induced neutropenia in Dutch patients.

BACKGROUND: Chemotherapy (CT)-induced neutropenia and febrile neutropenia (FN) can lead to changes in the treatment plan, potentially worsening the cancer outcome. This study evaluated the effect of the glycopegylated granulocyte-colony stimulating factor lipegfilgrastim, used as primary (PP) or secondary prophylaxis (SP), on treatment modifications in adult patients receiving cytotoxic CT with or without biological/targeted therapy (BT) for solid and haematological tumours. METHODS: This phase 4, prospective, observational study was conducted in eight centres in the Netherlands, in 2015-2017. Other study objectives were to characterise the population of cancer patients receiving lipegfilgrastim, to evaluate the incidence of CT-induced neutropenic events, and to assess safety. RESULTS: Of 142 patients, 73.94% had breast cancer and 55.63% received CT in the adjuvant setting. Most patients received lipegfilgrastim as PP (74.65%) and were at low (34.51%) or high risk (39.44%) of FN. CT dose delays were recorded for 22.64% and 36.11% of patients receiving lipegfilgrastim for PP and SP, respectively. CT dose reductions were recorded for 2.11% of patients; no CT dose omissions and one BT dose omission occurred. FN and grade III/IV neutropenia were reported for 5.63% and 9.86% of patients, respectively; associated hospitalisations were rare. The most frequently lipegfilgrastimrelated adverse events (AE) were myalgia, bone pain, and back pain. Serious AEs (55) were reported for 30 (21.13%) patients. There were two deaths, unrelated to lipegfilgrastim administration. CONCLUSION: Administration of lipegfilgrastim in routine clinical practice in the Netherlands results in limited CT/BT dose modifications and low incidence of neutropenic events, with no new safety concerns.

A conformation of cyclosporin A in aqueous environment revealed by the X-ray structure of a cyclosporin-Fab complex.

The conformation of the immunosuppressive drug cyclosporin A (CsA) in a complex with a Fab molecule has been established by crystallographic analysis to 2.65 angstrom resolution. This conformation of CsA is similar to that recently observed in the complex with the rotamase cyclophilin, its binding protein in vivo, and totally different from its conformation in an isolated form as determined from x-ray and nuclear magnetic resonance analysis. Because the surfaces of CsA interacting with cyclophilin or with the Fab are not identical, these results suggest that the conformation of CsA observed in the bound form preexists in aqueous solution and is not produced by interaction with the proteins.

Class II aminoacyl transfer RNA synthetases: crystal structure of yeast aspartyl-tRNA synthetase complexed with tRNA(Asp).

The crystal structure of the binary complex tRNA(Asp)-aspartyl tRNA synthetase from yeast was solved with the use of multiple isomorphous replacement to 3 angstrom resolution. The dimeric synthetase, a member of class II aminoacyl tRNA synthetases (aaRS's) exhibits the characteristic signature motifs conserved in eight aaRS's. These three sequence motifs are contained in the catalytic site domain, built around an antiparallel beta sheet, and flanked by three alpha helices that form the pocket in which adenosine triphosphate (ATP) and the CCA end of tRNA bind. The tRNA(Asp) molecule approaches the synthetase from the variable loop side. The two major contact areas are with the acceptor end and the anticodon stem and loop. In both sites the protein interacts with the tRNA from the major groove side. The correlation between aaRS class II and the initial site of aminoacylation at 3'-OH can be explained by the structure. The molecular association leads to the following features: (i) the backbone of the GCCA single-stranded portion of the acceptor end exhibits a regular helical conformation; (ii) the loop between residues 320 and 342 in motif 2 interacts with the acceptor stem in the major groove and is in contact with the discriminator base G and the first base pair UA; and (iii) the anticodon loop undergoes a large conformational change in order to bind the protein. The conformation of the tRNA molecule in the complex is dictated more by the interaction with the protein than by its own sequence.

Exercise- and hypoxia-induced anaerobic metabolism and recovery: a student laboratory exercise using teleost fish.

Anaerobic metabolism is recruited in vertebrates under conditions of intense exercise or lowered environmental oxygen availability (hypoxia), typically resulting in the accumulation of lactate in blood and tissues. Lactate will be cleared over time after the reoxygenation of tissues, eventually returning to control levels. Here, we present a laboratory exercise developed as part of an upper-level vertebrate physiology class that demonstrates the effects of exercise and hypoxia exposure on blood lactate in fish and the subsequent decrease in lactate during recovery. Typically, the results obtained by students demonstrate that both treatments cause significant increases in blood lactate concentrations (two to three times higher than control values) that decrease back to normal values within 3 h of recovery under normoxia. The procedures described are generally applicable to other fish species and provide an alternative to using humans or other mammalian species to investigate anaerobic metabolism.

Similarities and differences for atomic and diatomic molecule adsorption on the B-5 type sites of the HCP(101Ì 6) surfaces of Co, Os, and Ru from DFT calculations.

The differences in relative adsorption energies for mono-atomic and diatomic prototype species (C,N,O,S,H,CO,NO,SO,CH,NH,H2,O2) relevant to catalytic processes such as Fischer-Tropsch and Ammonia Synthesis chemistry are investigated on the previously un-studied ( 10 1 ¯ 6 ) surface(s) of Co, Os, and Ru. Recent work in the literature has confirmed that catalytically relevant nanoparticles of HCP elements such as Co, Os, and Ru typically possess highly active 'B5' sites; unfortunately many early and extant theory and model-ing treatments of "stepped HCP surfaces" use ad-hoc created steps via manual deletion of atoms from an ideal HCP(0001) slab model. To date the differences in adsorption energies at various B5 step edge types, and any possible trends across the same type of B5 sites on various HCP catalyst species has not been thoroughly characterized. Our work in this manuscript uses the low energy ( 10 1 ¯ 6 ) Miller Index surface of Co, Os, and Ru which exposes 2 distinct and strongly adsorbing step edge sites, the B5B and B5A step edge which have been reported as relevant in the literature for Cobalt nanoparticle catalysis applications. Results from this study should be used to help further understand atomistic processes on the stepped surfaces of catalytically active HCP elements.

Size, Composition, and Support-Doping Effects on Oxygen Reduction Activity of Platinum-Alloy and on Non-platinum Metal-Decorated-Graphene Nanocatalysts.

Recent investigations reported in the open literature concerning the functionalization of graphene as a support material for transition metal nanoparticle catalysts have examined isolated systems for their potential Oxygen Reduction Reaction (ORR) activity. In this work we present results which characterize the ability to use functionalized graphene (via dopants B, N) to upshift and downshift the adsorption energy of mono-atomic oxygen, O* (the ORR activity descriptor on ORR Volcano Plots), for various compositions of 4-atom, 7-atom, and 19-atom sub-nanometer binary alloy/intermetallic transition metal nanoparticle catalysts on graphene (TMNP-MDG). Our results show several important and interesting features: (1) that the combination of geometric and electronic effects makes development of simple linear mixing rules for size/composition difficult; (2) that the transition from 4- to 7- to 19-atom TMNP on MDG has pronounced effects on ORR activity for all compositions; (3) that the use of B and N as dopants to modulate the graphene-TMNP electronic structure interaction can cause shifts in the oxygen adsorption energy of 0.5 eV or more; (4) that it might be possible to make specific doped-graphene-Ni x Cu y TMNP systems which fall close to the Volcano Peak for ORR. Our results point to systems which should be investigated experimentally and may improve the viability of future fuel cell or other ORR applications, and provide new paths for future investigations of more detail for TMNP-MDG screening.

Vertebrate osmoregulation: a student laboratory exercise using teleost fish.

Here, we describe a laboratory experiment as part of an upper-level vertebrate physiology course for biology majors to investigate the physiological response of vertebrates to osmoregulatory challenges. The experiment involves measuring plasma osmolality and Na+-K+-ATPase activity in gill tissue of teleost fish acclimated to water of differing salinity. We describe results obtained using the widely available goldfish (Carassius auratus) and a common baitfish, the Gulf killifish (Fundulus grandis). The procedures described are generally applicable to other fish species, and they provide an alternative to the experimental use of humans or other mammalian species to investigate osmoregulation mechanisms. In addition to reenforcing the conceptual material covered in lecture, this laboratory exercise trains students in a wide range of laboratory and analytical skills, such as calculating and performing dilutions, pipetting, tissue sampling and homogenizing, preparing standard curves, conducting enzymatic assays, and analyzing and interpreting results. Typical student results are presented and discussed, as are common experimental and conceptual mistakes made by students.

Mutations in DNA mismatch repair genes are not responsible for microsatellite instability in most sporadic endometrial carcinomas.

Endometrial carcinoma is the second most common tumor type in women with hereditary nonpolyposis colorectal carcinoma. Microsatellite instability (MI) has been observed in the inherited (hereditary nonpolyposis colorectal carcinoma-associated) form of endometrial carcinoma as well as in approximately 20% of presumably sporadic cases. Recent studies suggest that MI in many cell lines or xenografts derived from sporadic colorectal carcinomas is not attributable to mutations in four known human DNA mismatch repair (MMR) genes (hMSH2, hMLH1, hPMS1, and hPMS2). Mutational analyses of these four MMR genes in endometrial carcinomas have not been previously reported. We analyzed nine sporadic MI-positive primary endometrial carcinomas for mutations in the above four MMR genes. Mutations were detected in two tumors (in hMSH2), and both of the mutations were acquired somatically. Immunohistochemical staining revealed a lack of expression of hMSH2 protein in the two tumors containing hMSH2 mutations. Our data suggest that mutations in these four known DNA MMR genes are not responsible for MI in the majority of sporadic endometrial carcinomas displaying this phenotype.

PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma.

The two most common types of genetic alterations yet identified in uterine endometrioid carcinoma (UEC) are PTEN mutations and microsatellite instability (MI). Furthermore, MI-positive UECs (defined as tumors with detectable alterations at two or more different microsatellite loci) are significantly more likely to contain PTEN mutations than are MI-negative UECs. To determine whether PTEN inactivation is a relatively early event in endometrial tumorigenesis, we evaluated complex atypical hyperplasia (CAH), the direct precursor to UEC, for the presence of PTEN mutations. Mutations were present in 3 of 11 (27%) CAHs with synchronous UEC and in 4 of 18 (22%) CAHs that were not associated with invasive carcinoma. One case with synchronous CAH and UEC contained a germ-line PTEN mutation. In addition, we evaluated the same series of CAHs for MI. We identified four MI-positive CAHs with synchronous UEC but did not detect the MI phenotype in any CAHs without associated invasive carcinoma. A PTEN-mutant (germ-line mutation) MI-negative CAH was synchronous with a PTEN-mutant MI-positive UEC. These results suggest that mutation of PTEN can be an early event in the pathogenesis of UEC and may precede the development of the MI phenotype in a subset of cases.

Hughes Abdominal Repair Trial (HART) - Abdominal wall closure techniques to reduce the incidence of incisional hernias: study protocol for a randomised controlled trial.

BACKGROUND: Incisional hernias are common complications of midline closure following abdominal surgery and cause significant morbidity, impaired quality of life and increased health care costs. The 'Hughes Repair' combines a standard mass closure with a series of horizontal and two vertical mattress sutures within a single suture. This theoretically distributes the load along the incision length as well as across it. There is evidence to suggest that this technique is as effective as mesh repair for the operative management of incisional hernias; however, no trials have compared the Hughes Repair with standard mass closure for the prevention of incisional hernia formation following a midline incision. METHODS/DESIGN: This is a 1:1 randomised controlled trial comparing two suture techniques for the closure of the midline abdominal wound following surgery for colorectal cancer. Full ethical approval has been gained (Wales REC 3, MREC 12/WA/0374). Eight hundred patients will be randomised from approximately 20 general surgical units within the United Kingdom. Patients undergoing open or laparoscopic (more than a 5-cm midline incision) surgery for colorectal cancer, elective or emergency, are eligible. Patients under the age of 18 years, those having mesh inserted or undergoing musculofascial flap closure of the perineal defect in abdominoperineal wound closure, and those unable to give informed consent will be excluded. Patients will be randomised intraoperatively to either the Hughes Repair or standard mass closure. The primary outcome measure is the incidence of incisional hernias at 1 year as assessed by standardised clinical examination. The secondary outcomes include quality of life patient-reported outcome measures, cost-utility analysis, incidence of complete abdominal wound dehiscence and C-POSSUM scores. The incidence of incisional hernia at 1 year, assessed by computerised tomography, will form a tertiary outcome. DISCUSSION: A feasibility phase has been completed. The results of the study will be used to inform current and future practice and potentially reduce the risk of incisional hernia formation following midline incisions. TRIAL REGISTRATION NUMBER: ISRCTN 25616490 . Registered on 1 January 2012.

X-ray structure at 1.55 A of toxin gamma, a cardiotoxin from Naja nigricollis venom. Crystal packing reveals a model for insertion into membranes.

The crystal structure of toxin gamma from Naja nigricollis has been solved and refined to 1.55 A resolution. The final R-factor, computed with all X-ray data available, is 17.9%. The three-dimensional structure is characterized by a core formed by two beta-sheets organized in three extended loops. It is similar to that of cardiotoxin V4II from Naja mossambica mossambica, with the exception of the hydrophobic loop I. The flexibility and variability of the loops contrast sharply with the rigidity of the molecular core and its high degree of structural conservation among the cardiotoxin family. The most flexible loop II adopts different conformations in the three monomers forming the crystal asymmetric unit. These monomers form a trimer around an approximate 3-fold axis, with conserved hydrophobic side-chains on the outside and hydrophilic residues in the central channel or involved in interactions with the other molecules. The trimer thus resembles a membrane protein with a central channel that could allow the passage of small ions. It is proposed as a model for the insertion of cardiotoxin into a membrane.