| 1. |
- Arndt, D. S., et al.
(författare)
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STATE OF THE CLIMATE IN 2017
- 2018
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 99:8, s. S1-S310
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Forskningsöversikt (refereegranskat)
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| 2. |
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| 3. |
- van Es, Michael A, et al.
(författare)
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Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis
- 2009
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:10, s. 1083-1087
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.
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| 4. |
- Blauw, Hylke M, et al.
(författare)
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A large genome scan for rare CNVs in amyotrophic lateral sclerosis
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford Journals. - 0964-6906 .- 1460-2083. ; 19:20, s. 4091-4099
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
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| 5. |
- Borges, Joao Batista, et al.
(författare)
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Real-time effects of PEEP and tidal volume on regional ventilation and perfusion in experimental lung injury
- 2020
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Ingår i: Intensive Care Medicine Experimental. - : SPRINGEROPEN. - 2197-425X. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Real-time bedside information on regional ventilation and perfusion during mechanical ventilation (MV) may help to elucidate the physiological and pathophysiological effects of MV settings in healthy and injured lungs. We aimed to study the effects of positive end-expiratory pressure (PEEP) and tidal volume (V-T) on the distributions of regional ventilation and perfusion by electrical impedance tomography (EIT) in healthy and injured lungs. Methods One-hit acute lung injury model was established in 6 piglets by repeated lung lavages (injured group). Four ventilated piglets served as the control group. A randomized sequence of any possible combination of three V-T (7, 10, and 15 ml/kg) and four levels of PEEP (5, 8, 10, and 12 cmH(2)O) was performed in all animals. Ventilation and perfusion distributions were computed by EIT within three regions-of-interest (ROIs): nondependent, middle, dependent. A mixed design with one between-subjects factor (group: intervention or control), and two within-subjects factors (PEEP and V-T) was used, with a three-way mixed analysis of variance (ANOVA). Results Two-way interactions between PEEP and group, and V-T and group, were observed for the dependent ROI (p = 0.035 and 0.012, respectively), indicating that the increase in the dependent ROI ventilation was greater at higher PEEP and V-T in the injured group than in the control group. A two-way interaction between PEEP and V-T was observed for perfusion distribution in each ROI: nondependent (p = 0.030), middle (p = 0.006), and dependent (p = 0.001); no interaction was observed between injured and control groups. Conclusions Large PEEP and V-T levels were associated with greater pulmonary ventilation of the dependent lung region in experimental lung injury, whereas they affected pulmonary perfusion of all lung regions both in the control and in the experimental lung injury groups.
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| 6. |
- Crockett, Douglas C., et al.
(författare)
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Validating the inspired sinewave technique to measure the volume of the 'baby lung' in a porcine lung-injury model
- 2020
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Ingår i: British Journal of Anaesthesia. - : ELSEVIER SCI LTD. - 0007-0912 .- 1471-6771. ; 124:3, s. 345-353
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bedside lung volume measurement could personalise ventilation and reduce driving pressure in patients with acute respiratory distress syndrome (ARDS). We investigated a modified gas-dilution method, the inspired sinewave technique (IST), to measure the effective lung volume (ELV) in pigs with uninjured lungs and in an ARDS model. Methods: Anaesthetised mechanically ventilated pigs were studied before and after surfactant depletion by saline lavage. Changes in PEEP were used to change ELV. Paired measurements of absolute ELV were taken with IST (ELVIST) and compared with gold-standard measures (sulphur hexafluoride wash in/washout [ELVSF6] and computed tomography (CT) [ELVCT]). Measured volumes were used to calculate changes in ELV (Delta ELV) between PEEP levels for each method (Delta ELVIST, Delta ELVSF6, and Delta ELVCT). Results: The coefficient of variation was <5% for repeated ELVIST measurements (n=13 pigs). There was a strong linear relationship between ELVIST and ELVSF6 in uninjured lungs (r(2)=0.97), and with both ELVSF6 and ELVCT in the ARDS model (r(2)=0.87 and 0.92, respectively). ELVIST had a mean bias of -12 to 13% (95% limits=+/- 17 - 25%) compared with ELVSF6 and ELVCT. Delta ELVIST was concordant with Delta ELVSF6 and Delta ELVCT in 98-100% of measurements, and had a mean bias of -73 to -77 ml (95% limits=+/- 128 - 186 ml) compared with Delta ELVSF6 and -1 ml (95% limits +/- 333 ml) compared with Delta ELVCT. Conclusions: IST provides a repeatable measure of absolute ELV and shows minimal bias when tracking PEEP-induced changes in lung volume compared with CT in a saline-lavage model of ARDS.
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| 7. |
- Cronin, John N, et al.
(författare)
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Dynamic single-slice CT estimates whole-lung dual-energy CT variables in pigs with and without experimental lung injury
- 2019
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Ingår i: Intensive Care Medicine Experimental. - : Springer. - 2197-425X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dynamic single-slice CT (dCT) is increasingly used to examine the intra-tidal, physiological variation in aeration and lung density in experimental lung injury. The ability of dCT to predict whole-lung values is unclear, especially for dual-energy CT (DECT) variables. Additionally, the effect of inspiration-related lung movement on CT variables has not yet been quantified.METHODS: Eight domestic pigs were studied under general anaesthesia, including four following saline-lavage surfactant depletion (lung injury model). DECT, dCT and whole-lung images were collected at 12 ventilatory settings. Whole-lung single energy scans images were collected during expiratory and inspiratory apnoeas at positive end-expiratory pressures from 0 to 20 cmH2O. Means and distributions of CT variables were calculated for both dCT and whole-lung images. The cranio-caudal displacement of the anatomical slice was measured from whole-lung images.RESULTS: Mean CT density and volume fractions of soft tissue, gas, iodinated blood, atelectasis, poor aeration, normal aeration and overdistension correlated between dCT and the whole lung (r2 0.75-0.94) with agreement between CT density distributions (r 0.89-0.97). Inspiration increased the matching between dCT and whole-lung values and was associated with a movement of 32% (SD 15%) of the imaged slice out of the scanner field-of-view. This effect introduced an artefactual increase in dCT mean CT density during inspiration, opposite to that caused by the underlying physiology.CONCLUSIONS: Overall, dCT closely approximates whole-lung aeration and density. This approximation is improved by inspiration where a decrease in CT density and atelectasis can be interpreted as physiological rather than artefactual.
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| 8. |
- Cronin, John N., et al.
(författare)
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Intra-tidal PaO2 oscillations associated with mechanical ventilation : a pilot study to identify discrete morphologies in a porcine model
- 2023
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Ingår i: Intensive Care Medicine Experimental. - : Springer Nature. - 2197-425X. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Within-breath oscillations in arterial oxygen tension (PaO2) can be detected using fast responding intra-arterial oxygen sensors in animal models. These PaO2 signals, which rise in inspiration and fall in expiration, may represent cyclical recruitment/derecruitment and, therefore, a potential clinical monitor to allow titration of ventilator settings in lung injury. However, in hypovolaemia models, these oscillations have the potential to become inverted, such that they decline, rather than rise, in inspiration. This inversion suggests multiple aetiologies may underlie these oscillations. A correct interpretation of the various PaO2 oscillation morphologies is essential to translate this signal into a monitoring tool for clinical practice. We present a pilot study to demonstrate the feasibility of a new analysis method to identify these morphologies.Methods Seven domestic pigs (average weight 31.1 kg) were studied under general anaesthesia with muscle relaxation and mechanical ventilation. Three underwent saline-lavage lung injury and four were uninjured. Variations in PEEP, tidal volume and presence/absence of lung injury were used to induce different morphologies of PaO2 oscillation. Functional principal component analysis and k-means clustering were employed to separate PaO2 oscillations into distinct morphologies, and the cardiorespiratory physiology associated with these PaO2 morphologies was compared.Results PaO2 oscillations from 73 ventilatory conditions were included. Five functional principal components were sufficient to explain = 95% of the variance of the recorded PaO2 signals. From these, five unique morphologies of PaO2 oscillation were identified, ranging from those which increased in inspiration and decreased in expiration, through to those which decreased in inspiration and increased in expiration. This progression was associated with the estimates of the first functional principal component (P < 0.001, R-2 = 0.88). Intermediate morphologies demonstrated waveforms with two peaks and troughs per breath. The progression towards inverted oscillations was associated with increased pulse pressure variation (P = 0.03).Conclusions Functional principal component analysis and k-means clustering are appropriate to identify unique morphologies of PaO2 waveform associated with distinct cardiorespiratory physiology. We demonstrated novel intermediate morphologies of PaO2 waveform, which may represent a development of zone 2 physiologies within the lung. Future studies of PaO2 oscillations and modelling should aim to understand the aetiologies of these morphologies.
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| 9. |
- Cronin, John N., et al.
(författare)
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Mechanical Ventilation Redistributes Blood to Poorly Ventilated Areas in Experimental Lung Injury*
- 2020
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Ingår i: Critical Care Medicine. - : LIPPINCOTT WILLIAMS & WILKINS. - 0090-3493 .- 1530-0293. ; 48:3, s. E200-E208
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Determine the intra-tidal regional gas and blood volume distributions at different levels of atelectasis in experimental lung injury. Test the hypotheses that pulmonary aeration and blood volume matching is reduced during inspiration in the setting of minimal tidal recruitment/derecruitment and that this mismatching is an important determinant of hypoxemia.Design: Preclinical study.Setting: Research laboratory.Subjects: Seven anesthetized pigs 28.7 kg (sd, 2.1 kg).Interventions: All animals received a saline-lavage surfactant depletion lung injury model. Positive end-expiratory pressure was varied between 0 and 20 cm H2O to induce different levels of atelectasis.Measurements and Main Results: Dynamic dual-energy CT images of a juxtadiaphragmatic slice were obtained, gas and blood volume fractions within three gravitational regions calculated and normalized to lung tissue mass (normalized gas volume and normalized blood volume, respectively). Ventilatory conditions were grouped based upon the fractional atelectatic mass in expiration (< 20%, 20-40%, and >= 40%). Tidal recruitment/derecruitment with fractional atelectatic mass in expiration greater than or equal to 40% was less than 7% of lung mass. In this group, inspiration-related increase in normalized gas volume was greater in the nondependent (818 mu L/g [95% CI, 729-908 mu L/g]) than the dependent region (149 mu L/g [120-178 mu L/g]). Normalized blood volume decreased in inspiration in the nondependent region (29 mu L/g [12-46 mu L/g]) and increased in the dependent region (39 mu L/g [30-48 mu L/g]). Inspiration-related changes in normalized gas volume and normalized blood volume were negatively correlated in fractional atelectatic mass in expiration greater than or equal to 40% and 20-40% groups (r(2) = 0.56 and 0.40), but not in fractional atelectatic mass in expiration less than 20% group (r(2) = 0.01). Both the increase in normalized blood volume in the dependent region and fractional atelectatic mass in expiration negatively correlated with Pao(2)/Fio(2) ratio (rho = -0.77 and -0.93, respectively).Conclusions: In experimental atelectasis with minimal tidal recruitment/derecruitment, mechanical inspiratory breaths redistributed blood volume away from well-ventilated areas, worsening Pao(2)/Fio(2).
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| 10. |
- Formenti, Federico, et al.
(författare)
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Respiratory oscillations in alveolar oxygen tension measured in arterial blood.
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Arterial oxygen partial pressure can increase during inspiration and decrease during expiration in the presence of a variable shunt fraction, such as with cyclical atelectasis, but it is generally presumed to remain constant within a respiratory cycle in the healthy lung. We measured arterial oxygen partial pressure continuously with a fast intra-vascular sensor in the carotid artery of anaesthetized, mechanically ventilated pigs, without lung injury. Here we demonstrate that arterial oxygen partial pressure shows respiratory oscillations in the uninjured pig lung, in the absence of cyclical atelectasis (as determined with dynamic computed tomography), with oscillation amplitudes that exceeded 50 mmHg, depending on the conditions of mechanical ventilation. These arterial oxygen partial pressure respiratory oscillations can be modelled from a single alveolar compartment and a constant oxygen uptake, without the requirement for an increased shunt fraction during expiration. Our results are likely to contribute to the interpretation of arterial oxygen respiratory oscillations observed during mechanical ventilation in the acute respiratory distress syndrome.
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