| 1. |
- Ahmed, Laeeq, et al.
(författare)
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Predicting target profiles with confidence as a service using docking scores
- 2020
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Ingår i: Journal of Cheminformatics. - : Springer Nature. - 1758-2946. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Identifying and assessing ligand-target binding is a core component in early drug discovery as one or more unwanted interactions may be associated with safety issues. Contributions: We present an open-source, extendable web service for predicting target profiles with confidence using machine learning for a panel of 7 targets, where models are trained on molecular docking scores from a large virtual library. The method uses conformal prediction to produce valid measures of prediction efficiency for a particular confidence level. The service also offers the possibility to dock chemical structures to the panel of targets with QuickVina on individual compound basis. Results: The docking procedure and resulting models were validated by docking well-known inhibitors for each of the 7 targets using QuickVina. The model predictions showed comparable performance to molecular docking scores against an external validation set. The implementation as publicly available microservices on Kubernetes ensures resilience, scalability, and extensibility.
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| 2. |
- Holzgraefe, Bernhard, et al.
(författare)
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Does extracorporeal membrane oxygenation attenuate hypoxic pulmonary vasoconstriction in a porcine model of global alveolar hypoxia?
- 2020
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 64:7, s. 992-1001
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Tidskriftsartikel (refereegranskat)abstract
- Background During severe respiratory failure, hypoxic pulmonary vasoconstriction (HPV) is partly suppressed, but may still play a role in increasing pulmonary vascular resistance (PVR). Experimental studies suggest that the degree of HPV during severe respiratory failure is dependent on pulmonary oxygen tension (PvO(2)). Therefore, it has been suggested that increasing PvO(2) by veno-venous extracorporeal membrane oxygenation (V-V ECMO) would adequately reduce PVR in V-V ECMO patients. Objective Whether increased PvO(2) by V-V ECMO decreases PVR in global alveolar hypoxia. Methods Nine landrace pigs were ventilated with a mixture of oxygen and nitrogen. After 15 minutes of stable ventilation and hemodynamics, the animals were cannulated for V-V ECMO. Starting with alveolar normoxia, the fraction of inspiratory oxygen (FIO2) was stepwise reduced to establish different degrees of alveolar hypoxia. PvO(2) was increased by V-V ECMO. Results V-V ECMO decreased PVR (from 5.5 [4.5-7.1] to 3.4 [2.6-3.9] mm Hg L-1 min, P = .006) (median (interquartile range),) during ventilation with FIO2 of 0.15. At lower FIO2, PVR increased; at FIO2 0.10 to 4.9 [4.2-7.0], P = .036, at FIO2 0.05 to 6.0 [4.3-8.6], P = .002, and at FIO2 0 to 5.4 [3.5 - 7.0] mm Hg L-1 min, P = .05. Conclusions The effect of increased PvO(2) by V-V ECMO on PVR depended highly on the degree of alveolar hypoxia. Our results partly explain why V-V ECMO does not always reduce right ventricular afterload at severe alveolar hypoxia.
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| 3. |
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| 4. |
- Höstman, Staffan, et al.
(författare)
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Intensive buffering can keep pH above 7.2 for over 4 h during apnea : an experimental porcine study
- 2013
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 57:1, s. 63-70
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Ventilation with low tidal volumes reduces mortality in acute respiratory distress syndrome. A further reduction of tidal volumes might be beneficial, and it is known that apneic oxygenation (no tidal volumes) with arteriovenous CO(2) removal can keep acid-base balance and oxygenation normal for at least 7 h in an acute lung injury model. We hypothesized that adequate buffering might be another approach and tested whether tris-hydroxymethyl aminomethane (THAM) alone could keep pH at a physiological level during apneic oxygenation for 4 h.METHODS:Six pigs were anesthetized, muscle relaxed, and normoventilated. The lungs were recruited, and apneic oxygenation as well as administration of THAM, 20 mmol/kg/h, was initiated. The experiment ended after 270 min, except one that was studied for 6 h.RESULTS:Two animals died before the end of the experiment. Arterial pH and arterial carbon dioxide tension (PaCO(2) ) changed from 7.5 (7.5, 7.5) to 7.3 (7.2, 7.3) kPa, P < 0.001 at 270 min, and from 4.5 (4.3, 4.7) to 25 (22, 28) kPa, P < 0.001, respectively. Base excess increased from 5 (3, 6) to 54 (51, 57) mM, P < 0.001. Cardiac output and arterial pressure were well maintained. The pig, which was studied for 6 h, had pH 7.27 and PaCO(2) 27 kPa at that time.CONCLUSION:With intensive buffering using THAM, pH can be kept in a physiologically acceptable range for 4 h during apnea.
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| 5. |
- Höstman, Staffan, 1979-
(författare)
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Minimal volume ventilation in lung injury : With special reference to apnea and buffer treatment
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A fairly large portion of patients receiving surgical or intensive care will need mechanical ventilation at some point. The potential ventilator-induced lung injury (VILI) is thus of interest. One of the main causal factors in VILI is the cyclic energy shifts, i.e. tidal volumes, in the lung during mechanical ventilation. The problem can be approached in two ways. Firstly, one can utilize apneic oxygenation and thus not cause any tidal injuries at all. Secondly, and more traditionally, one can simply lower the tidal volumes and respiratory rates used. The following describes a series of animal experiments exploring these options.In the first two papers, I explored and improved upon the methodology of apneic oxygenation. There is a generally held belief that it is only possible to perform apneic oxygenation by prior denitrogenation and by using 100% oxygen during the apnea. As 100% oxygen is toxic, this has prevented apneic oxygenation from more widespread use. The first paper proves that it is indeed possible to perform apneic oxygenation with less than 100% oxygen. I also calculated the alveolar nitrogen concentration which would conversely give the alveolar oxygen concentration. The second paper addresses the second large limitation of apneic oxygenation, i.e. hypercapnia. Using a high dose infusion of tris(hydroxymethyl)aminomethane (THAM) buffer, a pH > 7.2 could be maintained during apneic oxygenation for more than 4.5 hours.In the last two papers, THAM’s properties as a proton acceptor are explored during respiratory acidosis caused by very low volume ventilation. In paper III, I found that THAM does not, in the long term, affect pH in respiratory acidosis after stopping the THAM infusion. It does, however, lower PVR, even though the PaCO2 of THAM-treated animals had rebounded to levels higher than that of the controls. In the last experiment, I used volumetric capnography to confirm our hypothesis that carbon dioxide elimination through the lungs was lower during the THAM infusion. Again, the PaCO2 rebounded after the THAM infusion had stopped and I concluded that renal elimination of protonated THAM was not sufficient.
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| 6. |
- Höstman, Staffan, et al.
(författare)
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Non-toxic alveolar oxygen concentration without hypoxemia during apnoeic oxygenation : an experimental study
- 2011
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 55:9, s. 1078-1084
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Tidskriftsartikel (refereegranskat)abstract
- Background: Oxygenation without tidal breathing, i.e. apnoeic oxygenation in combination with extracorporeal carbon dioxide removal, might be an option in the treatment of acute respiratory failure. However, ventilation with 100% O(2), which is potentially toxic, is considered a prerequisite to ensure acceptable oxygenation. We hypothesized that trapping nitrogen (N(2)) in the lungs before the start of apnoeic oxygenation would keep the alveolar O(2) at a non-toxic level and still maintain normoxaemia. The aim was to test whether a predicted N(2) concentration would agree with a measured concentration at the end of an apnoeic period. Methods: Seven anaesthetized, muscle relaxed, endotracheally intubated pigs (22-27 kg) were ventilated in a randomized order with an inspired fraction of O(2) 0.6 and 0.8 at two positive end-expiratory pressure levels (5 cm and 10 cm H(2)O) before being connected to continuous positive airway pressure using 100% O(2) for apnoeic oxygenation. N(2) was measured before the start of and at the end of the 10-min apnoeic period. The predicted N(2) concentration was calculated from the initial N(2) concentration, the end-expiratory lung volume, and the anatomical dead space. Results: The mean difference and standard deviation between measured and predicted N(2) concentration was -0.5 +/- 2%, P = 0.587. No significant difference in the agreement between measured and predicted N(2) concentrations was seen in the four settings. Conclusions: This study indicates that it is possible to predict and keep alveolar N(2) concentration at a desired level and, thus, alveolar O(2) concentration at a non-toxic level during apnoeic oxygenation.
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| 7. |
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| 8. |
- Höstman, Staffan, et al.
(författare)
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THAM administration reduces pulmonary carbon dioxide elimination in hypercapnia : an experimental porcine study
- 2018
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 62:6, s. 820-828
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Tidskriftsartikel (refereegranskat)abstract
- Background: In a previous study, we found a rebound of arterial carbon dioxide tension (PaCO2) after stopping THAM buffer administration. We hypothesized that this was due to reduced pulmonary CO2 elimination during THAM administration. The aim of this study was to investigate this hypothesis in an experimental porcine hypercapnic model.Methods: In seven, initially normoventilated, anesthetized pigs (22-27 kg) minute ventilation was reduced by 66% for 7 h. Two hours after commencing hypoventilation, THAM was infused IV for 3 h in a dose targeting a pH of 7.35 followed by a 2 h observation period. Acid-base status, blood-gas content and exhaled CO2 were measured.Results: THAM raised pH (7.07 0.04 to 7.41 +/- 0.04, P < 0.05) and lowered PaCO2 (15.2 +/- 1.4 to 12.2 +/- 1.1 kPa, P < 0.05). After the infusion, pH decreased and PaCO2 increased again. At the end of the observation period, pH and PaCO2 were 7.24 +/- 0.03 and 16.6 +/- 1.2 kPa, respectively (P < 0.05). Pulmonary CO2 excretion decreased from 109 +/- 12 to 74 +/- 12 ml/min (P < 0.05) during the THAM infusion but returned at the end of the observation period to 111 +/- 15 ml/min (P < 0.05). The estimated reduction of pulmonary CO2 elimination during the infusion was 5800 ml.Conclusions: In this respiratory acidosis model, THAM reduced PaCO2, but seemed not to increase the total CO2 elimination due to decreased pulmonary CO2 excretion(,) suggesting only cautious use of THAM in hypercapnic acidosis.
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| 9. |
- Höstman, Staffan, et al.
(författare)
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THAM reduces CO2-associated increase in pulmonary vascular resistance : an experimental study in lung-injured piglets
- 2015
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Ingår i: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535 .- 1466-609X. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Low tidal volume (VT) ventilation is recommended in patients with acute respiratory distress syndrome (ARDS). This may increase arterial carbon dioxide tension (PaCO2), decrease pH, and augment pulmonary vascular resistance (PVR). We hypothesized that Tris(hydroxymethyl)aminomethane (THAM), a pure proton acceptor, would dampen these effects, preventing the increase in PVR.METHODS: A one-hit injury ARDS model was established by repeated lung lavages in 18 piglets. After ventilation with VT of 6 ml/kg to maintain normocapnia, VT was reduced to 3 ml/kg to induce hypercapnia. Six animals received THAM for 1 h, six for 3 h, and six serving as controls received no THAM. In all, the experiment continued for 6 h. The THAM dosage was calculated to normalize pH and exhibit a lasting effect. Gas exchange, pulmonary, and systemic hemodynamics were tracked. Inflammatory markers were obtained at the end of the experiment.RESULTS: In the controls, the decrease in VT from 6 to 3 ml/kg increased PaCO2 from 6.0±0.5 to 13.8±1.5 kPa and lowered pH from 7.40±0.01 to 7.12±0.06, whereas base excess (BE) remained stable at 2.7±2.3 mEq/L to 3.4±3.2 mEq/L. In the THAM groups, PaCO2 decreased and pH increased above 7.4 during the infusions. After discontinuing the infusions, PaCO2 increased above the corresponding level of the controls (15.2±1.7 kPa and 22.6±3.3 kPa for 1-h and 3-h THAM infusions, respectively). Despite a marked increase in BE (13.8±3.5 and 31.2±2.2 for 1-h and 3-h THAM infusions, respectively), pH became similar to the corresponding levels of the controls. PVR was lower in the THAM groups (at 6 h, 329±77 dyn∙s/m(5) and 255±43 dyn∙s/m(5) in the 1-h and 3-h groups, respectively, compared with 450±141 dyn∙s/m(5) in the controls), as were pulmonary arterial pressures.CONCLUSIONS: The pH in the THAM groups was similar to pH in the controls at 6 h, despite a marked increase in BE. This was due to an increase in PaCO2 after stopping the THAM infusion, possibly by intracellular release of CO2. Pulmonary arterial pressure and PVR were lower in the THAM-treated animals, indicating that THAM may be an option to reduce PVR in acute hypercapnia.
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