| 1. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 2. |
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| 4. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 5. |
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| 6. |
- Dankiewicz, Josef, et al.
(author)
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Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest
- 2021
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In: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 384:24, s. 2283-2294
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Journal article (peer-reviewed)abstract
- Hypothermia or Normothermia after Cardiac Arrest This trial randomly assigned patients with coma after out-of-hospital cardiac arrest to undergo targeted hypothermia at 33 degrees C or normothermia with treatment of fever. At 6 months, there were no significant between-group differences regarding death or functional outcomes. Background Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. Methods In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33 degrees C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, >= 37.8 degrees C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. Results A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P=0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score >= 4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. Conclusions In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, .)
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| 7. |
- Barragan, O., et al.
(author)
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The young HD 73583 (TOI-560) planetary system: two 10-M-circle plus mini-Neptunes transiting a 500-Myr-old, bright, and active K dwarf
- 2022
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In: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 514:2, s. 1606-1627
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Journal article (peer-reviewed)abstract
- We present the discovery and characterization of two transiting planets observed by TESS in the light curves of the young and bright (V = 9.67) star HD73583 (TOI-560). We perform an intensive spectroscopic and photometric space- and ground-based follow-up in order to confirm and characterize the system. We found that HD73583 is a young (similar to 500 Myr) active star with a rotational period of 12.08 +/- 0.11 d, and a mass and radius of 0.73 +/- 0.02 M-circle dot and 0.65 +/- 0.02 R-circle dot, respectively. HD 73583 b (P-b = 6.3980420(-0.0000062)(+0.0000067 )d) has a mass and radius of 10.2(-3.1)(+3.4) M-circle plus and 2.79 +/- 0.10 R-circle plus, respectively, which gives a density of 2.58(-0.81)(+0.95) g cm(-3). HD 73583 c (P-c = 18.87974(-0.00074)(+0.00086) d) has a mass and radius of 9.7(-1.7)(+1.8) M-circle plus and 2.39(-0.09)(+0.10) R-circle plus, respectively, which translates to a density of 3.88(-0.80)(+0.91) g cm(-3). Both planets are consistent with worlds made of a solid core surrounded by a volatile envelope. Because of their youth and host star brightness, they both are excellent candidates to perform transmission spectroscopy studies. We expect ongoing atmospheric mass-loss for both planets caused by stellar irradiation. We estimate that the detection of evaporating signatures on H and He would be challenging, but doable with present and future instruments.
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| 8. |
- Dankiewicz, Josef, et al.
(author)
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Targeted hypothermia versus targeted Normothermia after out-of-hospital cardiac arrest (TTM2): A randomized clinical trial - Rationale and design
- 2019
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In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 217, s. 23-31
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Journal article (peer-reviewed)abstract
- Background: Less than 500 participants have been included in randomized trials comparing hypothermia with regular care for out-of-hospital cardiac arrest patients, and many of these trials were small and at a high risk of bias. Consequently, the accrued data on this potentially beneficial intervention resembles that of a drug following small phase II trials. A large confirmatory trial is therefore warranted. Methods: The TTM2-trial is an international, multicenter, parallel group, investigator-initiated, randomized, superiority trial in which a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and early treatment of fever (≥37.8°C). Participants will be randomized within 3 hours of return of spontaneous circulation with the intervention period lasting 40 hours in both groups. Sedation will be mandatory for all patients throughout the intervention period. The clinical team involved with direct patient care will not be blinded to allocation group due to the inherent difficulty in blinding the intervention. Prognosticators, outcome-assessors, the steering group, the trial coordinating team, and trial statistician will be blinded. The primary outcome will be all-cause mortality at 180 days after randomization. We estimate a 55% mortality in the control group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The main secondary neurological outcome will be poor functional outcome (modified Rankin Scale 4–6) at 180 days after arrest. Discussion: The TTM2-trial will compare hypothermia to 33°C with normothermia and early treatment of fever (≥37.8°C) after out-of-hospital cardiac arrest. © 2019
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| 9. |
- Chesnut, Randall M., et al.
(author)
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Perceived Utility of Intracranial Pressure Monitoring in Traumatic Brain Injury : A Seattle International Brain Injury Consensus Conference Consensus-Based Analysis and Recommendations
- 2023
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In: Neurosurgery. - : Oxford University Press. - 0148-396X .- 1524-4040. ; 93:2, s. 399-408
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Journal article (peer-reviewed)abstract
- BACKGROUND: Intracranial pressure (ICP) monitoring is widely practiced, but the indications are incompletely developed, and guidelines are poorly followed. OBJECTIVE: To study the monitoring practices of an established expert panel (the clinical working group from the Seattle International Brain Injury Consensus Conference effort) to examine the match between monitoring guidelines and their clinical decision-making and offer guidance for clinicians considering monitor insertion.METHODS: We polled the 42 Seattle International Brain Injury Consensus Conference panel members' ICP monitoring decisions for virtual patients, using matrices of presenting signs (Glasgow Coma Scale [GCS] total or GCS motor, pupillary examination, and computed tomography diagnosis). Monitor insertion decisions were yes, no, or unsure (traffic light approach). We analyzed their responses for weighting of the presenting signs in decision-making using univariate regression.RESULTS: Heatmaps constructed from the choices of 41 panel members revealed wider ICP monitor use than predicted by guidelines. Clinical examination (GCS) was by far the most important characteristic and differed from guidelines in being nonlinear. The modified Marshall computed tomography classification was second and pupils third. We constructed a heatmap and listed the main clinical determinants representing 80% ICP monitor insertion consensus for our recommendations.CONCLUSION: Candidacy for ICP monitoring exceeds published indicators for monitor insertion, suggesting the clinical perception that the value of ICP data is greater than simply detecting and monitoring severe intracranial hypertension. Monitor insertion heatmaps are offered as potential guidance for ICP monitor insertion and to stimulate research into what actually drives monitor insertion in unconstrained, real-world conditions.
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| 10. |
- Graham, N. S. N., et al.
(author)
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Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury
- 2021
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:613
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Journal article (peer-reviewed)abstract
- Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.
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| 11. |
- Oddo, Dominic, et al.
(author)
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Characterization of a Set of Small Planets with TESS and CHEOPS and an Analysis of Photometric Performance
- 2023
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In: Astronomical Journal. - : American Astronomical Society. - 0004-6256 .- 1538-3881. ; 165:3
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Journal article (peer-reviewed)abstract
- The radius valley carries implications for how the atmospheres of small planets form and evolve, but this feature is visible only with highly precise characterizations of many small planets. We present the characterization of nine planets and one planet candidate with both NASA TESS and ESA CHEOPS observations, which adds to the overall population of planets bordering the radius valley. While five of our planets—TOI 118 b, TOI 262 b, TOI 455 b, TOI 560 b, and TOI 562 b—have already been published, we vet and validate transit signals as planetary using follow-up observations for four new TESS planets, including TOI 198 b, TOI 244 b, TOI 444 b, and TOI 470 b. While a three times increase in primary mirror size should mean that one CHEOPS transit yields an equivalent model uncertainty in transit depth as about nine TESS transits in the case that the star is equally as bright in both bands, we find that our CHEOPS transits typically yield uncertainties equivalent to between two and 12 TESS transits, averaging 5.9 equivalent transits. Therefore, we find that while our fits to CHEOPS transits provide overall lower uncertainties on transit depth and better precision relative to fits to TESS transits, our uncertainties for these fits do not always match expected predictions given photon-limited noise. We find no correlations between number of equivalent transits and any physical parameters, indicating that this behavior is not strictly systematic, but rather might be due to other factors such as in-transit gaps during CHEOPS visits or nonhomogeneous detrending of CHEOPS light curves.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Kamps, M. J. A., et al.
(author)
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Prognostication of neurologic outcome in cardiac arrest patients after mild therapeutic hypothermia: a meta-analysis of the current literature
- 2013
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In: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 39:10, s. 1671-1682
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Research review (peer-reviewed)abstract
- To assess the sensitivity and false positive rate (FPR) of neurological examination and somatosensory evoked potentials (SSEPs) to predict poor outcome in adult patients treated with therapeutic hypothermia after cardiopulmonary resuscitation (CPR). MEDLINE and EMBASE were searched for cohort studies describing the association of clinical neurological examination or SSEPs after return of spontaneous circulation with neurological outcome. Poor outcome was defined as severe disability, vegetative state and death. Sensitivity and FPR were determined. A total of 1,153 patients from ten studies were included. The FPR of a bilaterally absent cortical N20 response of the SSEP could be calculated from nine studies including 492 patients. The SSEP had an FPR of 0.007 (confidence interval, CI, 0.001-0.047) to predict poor outcome. The Glasgow coma score (GCS) motor response was assessed in 811 patients from nine studies. A GCS motor score of 1-2 at 72 h had a high FPR of 0.21 (CI 0.08-0.43). Corneal reflex and pupillary reactivity at 72 h after the arrest were available in 429 and 566 patients, respectively. Bilaterally absent corneal reflexes had an FPR of 0.02 (CI 0.002-0.13). Bilaterally absent pupillary reflexes had an FPR of 0.004 (CI 0.001-0.03). At 72 h after the arrest the motor response to painful stimuli and the corneal reflexes are not a reliable tool for the early prediction of poor outcome in patients treated with hypothermia. The reliability of the pupillary response to light and the SSEP is comparable to that in patients not treated with hypothermia.
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| 16. |
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| 17. |
- Ackerley, Rochelle, 1980, et al.
(author)
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Insights and Perspectives on Sensory-Motor Integration and Rehabilitation
- 2016
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In: Multisensory Research. - : Brill. - 2213-4794 .- 2213-4808. ; 29:6-7, s. 607-633
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Journal article (peer-reviewed)abstract
- The present review focuses on the flow and interaction of somatosensory-motor signals in the central and peripheral nervous system. Specifically, where incoming sensory signals from the periphery are processed and interpreted to initiate behaviors, and how ongoing behaviors produce sensory consequences encoded and used to fine-tune subsequent actions. We describe the structure-function relations of this loop, how these relations can be modeled and aspects of somatosensory-motor rehabilitation. The work reviewed here shows that it is imperative to understand the fundamental mechanisms of the somatosensory-motor system to restore accurate motor abilities and appropriate somatosensory feedback. Knowledge of the salient neural mechanisms of sensory-motor integration has begun to generate innovative approaches to improve rehabilitation training following neurological impairments such as stroke. The present work supports the integration of basic science principles of sensory-motor integration into rehabilitation procedures to create new solutions for sensory-motor disorders.
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| 18. |
- Graham, N., et al.
(author)
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Alzheimer's disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI
- 2024
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In: Journal of Neurology Neurosurgery and Psychiatry. - 0022-3050. ; 95:4, s. 356-359
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Journal article (peer-reviewed)abstract
- BackgroundTraumatic brain injury (TBI) is associated with the tauopathies Alzheimer's disease and chronic traumatic encephalopathy. Advanced immunoassays show significant elevations in plasma total tau (t-tau) early post-TBI, but concentrations subsequently normalise rapidly. Tau phosphorylated at serine-181 (p-tau181) is a well-validated Alzheimer's disease marker that could potentially seed progressive neurodegeneration. We tested whether post-traumatic p-tau181 concentrations are elevated and relate to progressive brain atrophy.MethodsPlasma p-tau181 and other post-traumatic biomarkers, including total-tau (t-tau), neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), were assessed after moderate-to-severe TBI in the BIO-AX-TBI cohort (first sample mean 2.7 days, second sample within 10 days, then 6 weeks, 6 months and 12 months, n=42). Brain atrophy rates were assessed in aligned serial MRI (n=40). Concentrations were compared patients with and without Alzheimer's disease, with healthy controls.ResultsPlasma p-tau181 concentrations were significantly raised in patients with Alzheimer's disease but not after TBI, where concentrations were non-elevated, and remained stable over one year. P-tau181 after TBI was not predictive of brain atrophy rates in either grey or white matter. In contrast, substantial trauma-associated elevations in t-tau, NfL, GFAP and UCH-L1 were seen, with concentrations of NfL and t-tau predictive of brain atrophy rates.ConclusionsPlasma p-tau181 is not significantly elevated during the first year after moderate-to-severe TBI and levels do not relate to neuroimaging measures of neurodegeneration.
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| 19. |
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| 20. |
- Hawryluk, Gregory W. J., et al.
(author)
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A management algorithm for patients with intracranial pressure monitoring : the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC)
- 2019
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In: Intensive Care Medicine. - : Springer. - 0342-4642 .- 1432-1238. ; 45:12, s. 1783-1794
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Journal article (peer-reviewed)abstract
- Background: Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation's sTBI Management Guidelines, as they were not evidence-based.Methods: We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists' decision tendencies were the focus of recommendations.Results: We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination.Conclusions: Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.
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| 21. |
- Oddo, Calogero M., et al.
(author)
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Artificial spatiotemporal touch inputs reveal complementary decoding in neocortical neurons
- 2017
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Journal article (peer-reviewed)abstract
- Investigations of the mechanisms of touch perception and decoding has been hampered by difficulties in achieving invariant patterns of skin sensor activation. To obtain reproducible spatiotemporal patterns of activation of sensory afferents, we used an artificial fingertip equipped with an array of neuromorphic sensors. The artificial fingertip was used to transduce real-world haptic stimuli into spatiotemporal patterns of spikes. These spike patterns were delivered to the skin afferents of the second digit of rats via an array of stimulation electrodes. Combined with low-noise intra-and extracellular recordings from neocortical neurons in vivo, this approach provided a previously inaccessible high resolution analysis of the representation of tactile information in the neocortical neuronal circuitry. The results indicate high information content in individual neurons and reveal multiple novel neuronal tactile coding features such as heterogeneous and complementary spatiotemporal input selectivity also between neighboring neurons. Such neuronal heterogeneity and complementariness can potentially support a very high decoding capacity in a limited population of neurons. Our results also indicate a potential neuroprosthetic approach to communicate with the brain at a very high resolution and provide a potential novel solution for evaluating the degree or state of neurological disease in animal models.
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| 22. |
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| 23. |
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| 24. |
- Bernini, A., et al.
(author)
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Cerebral Metabolic Dysfunction at the Acute Phase of Traumatic Brain Injury Correlates with Long-Term Tissue Loss
- 2023
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 40:5-6, s. 472-481
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Journal article (peer-reviewed)abstract
- Following traumatic brain injury (TBI), cerebral metabolic dysfunction, characterized by an elevated cerebral microdialysis (CMD) lactate/pyruvate (LP) ratio, is associated with poor outcome. However, the exact pathophysiological mechanisms underlying this association are not entirely established. In this pre-planned analysis of the BIOmarkers of AXonal injury after Traumatic Brain Injury (BIO-AX-TBI) prospective study, we investigated any associations of LP ratio with brain structure volume change rates at 1 year. Fourteen subjects underwent acute-phase (0-96 h post-TBI) CMD monitoring and had longitudinal magnetic resonance imaging (MRI) quantification of brain volume loss between the subacute phase (14 days to 6 weeks) and 1 year after TBI, recalculated as an annual rate. On average, CMD showed an elevated (>25) LP ratio (31 [interquartile range (IQR) 24-34]), indicating acute cerebral metabolic dysfunction. Annualized whole brain and total gray matter (GM) volume change rates were abnormally reduced (-3.2% [-9.3 to -2.2] and -1.9% [-4.4 to 1.7], respectively). Reduced annualized total GM volume correlated significantly with elevated CMD LP ratio (Spearman's rho = -0.68, p-value = 0.01) and low CMD glucose (rho = 0.66, p-value = 0.01). After adjusting for age, admission Glasgow Coma Scale (GCS) score and CT Marshall score, CMD LP ratio remained strongly associated with 1-year total GM volume change rate (p < 0.001; multi-variable analysis). No relationship was found between WM volume changes and CMD metabolites. We demonstrate a strong association between acute post-traumatic cerebral metabolic dysfunction and 1-year gray matter atrophy, reinforcing the role of CMD LP ratio as an early biomarker of poor long-term recovery after TBI.
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| 25. |
- Chesnut, Randall, et al.
(author)
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A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring : the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC)
- 2020
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In: Intensive Care Medicine. - : Springer. - 0342-4642 .- 1432-1238. ; 46:5, s. 919-929
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Journal article (peer-reviewed)abstract
- Background: Current guidelines for the treatment of adult severe traumatic brain injury (sTBI) consist of high-quality evidence reports, but they are no longer accompanied by management protocols, as these require expert opinion to bridge the gap between published evidence and patient care. We aimed to establish a modern sTBI protocol for adult patients with both intracranial pressure (ICP) and brain oxygen monitors in place.Methods: Our consensus working group consisted of 42 experienced and actively practicing sTBI opinion leaders from six continents. Having previously established a protocol for the treatment of patients with ICP monitoring alone, we addressed patients who have a brain oxygen monitor in addition to an ICP monitor. The management protocols were developed through a Delphi-method-based consensus approach and were finalized at an in-person meeting.Results: We established three distinct treatment protocols, each with three tiers whereby higher tiers involve therapies with higher risk. One protocol addresses the management of ICP elevation when brain oxygenation is normal. A second addresses management of brain hypoxia with normal ICP. The third protocol addresses the situation when both intracranial hypertension and brain hypoxia are present. The panel considered issues pertaining to blood transfusion and ventilator management when designing the different algorithms.Conclusions: These protocols are intended to assist clinicians in the management of patients with both ICP and brain oxygen monitors but they do not reflect either a standard-of-care or a substitute for thoughtful individualized management. These protocols should be used in conjunction with recommendations for basic care, management of critical neuroworsening and weaning treatment recently published in conjunction with the Seattle International Brain Injury Consensus Conference.
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| 26. |
- Enander, Jonas M.D., et al.
(author)
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Ubiquitous neocortical decoding of tactile input patterns
- 2019
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In: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 13
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Journal article (peer-reviewed)abstract
- Whereas functional localization historically has been a key concept in neuroscience, direct neuronal recordings show that input of a particular modality can be recorded well outside its primary receiving areas in the neocortex. Here, we wanted to explore if such spatially unbounded inputs potentially contain any information about the quality of the input received. We utilized a recently introduced approach to study the neuronal decoding capacity at a high resolution by delivering a set of electrical, highly reproducible spatiotemporal tactile afferent activation patterns to the skin of the contralateral second digit of the forepaw of the anesthetized rat. Surprisingly, we found that neurons in all areas recorded from, across all cortical depths tested, could decode the tactile input patterns, including neurons of the primary visual cortex. Within both somatosensory and visual cortical areas, the combined decoding accuracy of a population of neurons was higher than for the best performing single neuron within the respective area. Such cooperative decoding indicates that not only did individual neurons decode the input, they also did so by generating responses with different temporal profiles compared to other neurons, which suggests that each neuron could have unique contributions to the tactile information processing. These findings suggest that tactile processing in principle could be globally distributed in the neocortex, possibly for comparison with internal expectations and disambiguation processes relying on other modalities.
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| 27. |
- Genna, Clara, et al.
(author)
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Bilateral tactile input patterns decoded at comparable levels but different time scales in neocortical neurons
- 2018
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In: The Journal of Neuroscience. - 0270-6474. ; 38:15, s. 3669-3679
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Journal article (peer-reviewed)abstract
- The presence of contralateral tactile input can profoundly affect ipsilateral tactile perception, and unilateral stroke in somatosensory areas can result in bilateral tactile deficits, suggesting that bilateral tactile integration is an important part of brain function. Although previous studies have shown that bilateral tactile inputs exist and that there are neural interactions between inputs from the two sides, no previous study explored to what extent the local neuronal circuitry processing contains detailed information about the nature of the tactile input from the two sides. To address this question, we used a recently introduced approach to deliver a set of electrical, reproducible, tactile afferent, spatiotemporal activation patterns, which permits a high-resolution analysis of the neuronal decoding capacity, to the skin of the second forepaw digits of the anesthetized male rat. Surprisingly, we found that individual neurons of the primary somatosensory can decode contralateral and ipsilateral input patterns to comparable extents. Although the contralateral input was stronger and more rapidly decoded, given sufficient poststimulus processing time, ipsilateral decoding levels essentially caught up to contralateral levels. Moreover, there was a weak but significant correlation for neurons with high decoding performance for contralateral tactile input to also perform well on decoding ipsilateral input. Our findings shed new light on the brain mechanisms underlying bimanual haptic integration.
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| 28. |
- Genna, Clara, et al.
(author)
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Spatiotemporal Dynamics of the Cortical Responses Induced by a Prolonged Tactile Stimulation of the Human Fingertips
- 2017
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In: Brain Topography. - : Springer Science and Business Media LLC. - 0896-0267 .- 1573-6792. ; 30:4, s. 473-485
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Journal article (peer-reviewed)abstract
- The sense of touch is fundamental for daily behavior. The aim of this work is to understand the neural network responsible for touch processing during a prolonged tactile stimulation, delivered by means of a mechatronic platform by passively sliding a ridged surface under the subject’s fingertip while recording the electroencephalogram (EEG). We then analyzed: (i) the temporal features of the Somatosensory Evoked Potentials and their topographical distribution bilaterally across the cortex; (ii) the associated temporal modulation of the EEG frequency bands. Long-latency SEP were identified with the following physiological sequence P100—N140—P240. P100 and N140 were bilateral potentials with higher amplitude in the contralateral hemisphere and with delayed latency in the ipsilateral side. Moreover, we found a late potential elicited around 200 ms after the stimulation was stopped, which likely encoded the end of tactile input. The analysis of cortical oscillations indicated an initial increase in the power of theta band (4–7 Hz) for 500 ms after the stimulus onset followed a decrease in the power of the alpha band (8–15 Hz) that lasted for the remainder of stimulation. This decrease was prominent in the somatosensory cortex and equally distributed in both contralateral and ipsilateral hemispheres. This study shows that prolonged stimulation of the human fingertip engages the cortex in widespread bilateral processing of tactile information, with different modulations of the theta and alpha bands across time.
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| 29. |
- Graham, Neil Samuel Nyholm, et al.
(author)
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Multicentre longitudinal study of fluid and neuroimaging BIOmarkers of AXonal injury after traumatic brain injury: the BIO-AX-TBI study protocol.
- 2020
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In: BMJ open. - : BMJ. - 2044-6055. ; 10:11
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Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) often results in persistent disability, due particularly to cognitive impairments. Outcomes remain difficult to predict but appear to relate to axonal injury. Several new approaches involving fluid and neuroimaging biomarkers show promise to sensitively quantify axonal injury. By assessing these longitudinally in a large cohort, we aim both to improve our understanding of the pathophysiology of TBI, and provide better tools to predict clinical outcome.BIOmarkers of AXonal injury after TBI is a prospective longitudinal study of fluid and neuroimaging biomarkers of axonal injury after moderate-to-severe TBI, currently being conducted across multiple European centres. We will provide a detailed characterisation of axonal injury after TBI, using fluid (such as plasma/microdialysate neurofilament light) and neuroimaging biomarkers (including diffusion tensor MRI), which will then be related to detailed clinical, cognitive and functional outcome measures. We aim to recruit at least 250 patients, including 40 with cerebral microdialysis performed, with serial assessments performed twice in the first 10 days after injury, subacutely at 10 days to 6weeks, at 6 and 12 months after injury.The relevant ethical approvals have been granted by the following ethics committees: in London, by the Camberwell St Giles Research Ethics Committee; in Policlinico (Milan), by the Comitato Etico Milano Area 2; in Niguarda (Milan), by the Comitato Etico Milano Area 3; in Careggi (Florence), by the Comitato Etico Regionale per la Sperimentazione Clinica della Regione Toscana, Sezione area vasta centro; in Trento, by the Trento Comitato Etico per le Sperimentazioni Cliniche, Azienda Provinciale per i Servizi Sanitari della Provincia autonoma di Trento; in Lausanne, by the Commission cantonale d'éthique de la recherche sur l'être humain; in Ljubljana, by the National Medical Ethics Committee at the Ministry of Health of the Republic of Slovenia. The study findings will be disseminated to patients, healthcare professionals, academics and policy-makers including through presentation at conferences and peer-reviewed publications. Data will be shared with approved researchers to provide further insights for patient benefit.NCT03534154.
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| 30. |
- Holgersson, Johan, et al.
(author)
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Hypothermic versus Normothermic Temperature Control after Cardiac Arrest
- 2022
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In: NEJM Evidence. - 2766-5526. ; 1:11, s. 1-13
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Journal article (peer-reviewed)abstract
- BACKGROUNDThe evidence for temperature control for comatose survivors of cardiac arrest is inconclusive. Controversy exists as to whether the effects of hypothermia differ per the circumstances of the cardiac arrest or patient characteristics.METHODSAn individual patient data meta-analysis of the Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest (TTM) and Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trials was conducted. The intervention was hypothermia at 33°C and the comparator was normothermia. The primary outcome was all-cause mortality at 6 months. Secondary outcomes included poor functional outcome (modified Rankin scale score of 4 to 6) at 6 months. Predefined subgroups based on the design variables in the original trials were tested for interaction with the intervention as follows: age (older or younger than the median), sex (female or male), initial cardiac rhythm (shockable or nonshockable), time to return of spontaneous circulation (above or below the median), and circulatory shock on admission (presence or absence).RESULTSThe primary analyses included 2800 patients, with 1403 assigned to hypothermia and 1397 to normothermia. Death occurred for 691 of 1398 participants (49.4%) in the hypothermia group and 666 of 1391 participants (47.9%) in the normothermia group (relative risk with hypothermia, 1.03; 95% confidence interval [CI], 0.96 to 1.11; P=0.41). A poor functional outcome occurred for 733 of 1350 participants (54.3%) in the hypothermia group and 718 of 1330 participants (54.0%) in the normothermia group (relative risk with hypothermia, 1.01; 95% CI, 0.94 to 1.08; P=0.88). Outcomes were consistent in the predefined subgroups.CONCLUSIONSHypothermia at 33°C did not decrease 6-month mortality compared with normothermia after out-of-hospital cardiac arrest. (Funded by Vetenskapsrådet; ClinicalTrials.gov numbers NCT02908308 and NCT01020916.)
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| 31. |
- Lilja, Gisela, et al.
(author)
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Protocol for outcome reporting and follow-up in the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest trial (TTM2)
- 2020
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In: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 150, s. 104-112
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Journal article (peer-reviewed)abstract
- Aims: The TTM2-trial is a multi-centre randomised clinical trial where targeted temperature management (TTM) at 33 °C will be compared with normothermia and early treatment of fever (≥37.8 °C) after Out-of-Hospital Cardiac Arrest (OHCA). This paper presents the design and rationale of the TTM2-trial follow-up, where information on secondary and exploratory outcomes will be collected. We also present the explorative outcome analyses which will focus on neurocognitive function and societal participation in OHCA-survivors. Methods: Blinded outcome-assessors will perform follow-up at 30-days after the OHCA with a telephone interview, including the modified Rankin Scale (mRS) and the Glasgow Outcome Scale Extended (GOSE). Face-to-face meetings will be performed at 6 and 24-months, and include reports on outcome from several sources of information: clinician-reported: mRS, GOSE; patient-reported: EuroQol-5 Dimensions-5 Level responses version (EQ-5D-5L), Life satisfaction, Two Simple Questions; observer-reported: Informant Questionnaire on Cognitive Decline in the Elderly-Cardiac Arrest version (IQCODE-CA) and neurocognitive performance measures: Montreal Cognitive Assessment, (MoCA), Symbol Digit Modalities Test (SDMT). Exploratory analyses will be performed with an emphasis on brain injury in the survivors, where the two intervention groups will be compared for potential differences in neuro-cognitive function (MoCA, SDMT) and societal participation (GOSE). Strategies to increase inter-rater reliability and decrease missing data are described. Discussion: The TTM2-trial follow-up is a pragmatic yet detailed pre-planned and standardised assessment of patient's outcome designed to ensure data-quality, decrease missing data and provide optimal conditions to investigate clinically relevant effects of TTM, including OHCA-survivors’ neurocognitive function and societal participation.
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| 32. |
- Rongala, Udaya B., et al.
(author)
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Cuneate spiking neural network learning to classify naturalistic texture stimuli under varying sensing conditions
- 2020
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In: Neural Networks. - : Elsevier BV. - 0893-6080. ; 123, s. 273-287
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Journal article (peer-reviewed)abstract
- We implemented a functional neuronal network that was able to learn and discriminate haptic features from biomimetic tactile sensor inputs using a two-layer spiking neuron model and homeostatic synaptic learning mechanism. The first order neuron model was used to emulate biological tactile afferents and the second order neuron model was used to emulate biological cuneate neurons. We have evaluated 10 naturalistic textures using a passive touch protocol, under varying sensing conditions. Tactile sensor data acquired with five textures under five sensing conditions were used for a synaptic learning process, to tune the synaptic weights between tactile afferents and cuneate neurons. Using post-learning synaptic weights, we evaluated the individual and population cuneate neuron responses by decoding across 10 stimuli, under varying sensing conditions. This resulted in a high decoding performance. We further validated the decoding performance across stimuli, irrespective of sensing velocities using a set of 25 cuneate neuron responses. This resulted in a median decoding performance of 96% across the set of cuneate neurons. Being able to learn and perform generalized discrimination across tactile stimuli, makes this functional spiking tactile system effective and suitable for further robotic applications.
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| 33. |
- Rongala, Udaya B., et al.
(author)
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Intracellular dynamics in cuneate nucleus neurons support self-stabilizing learning of generalizable tactile representations
- 2018
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In: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 12
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Journal article (peer-reviewed)abstract
- How the brain represents the external world is an unresolved issue for neuroscience, which could provide fundamental insights into brain circuitry operation and solutions for artificial intelligence and robotics. The neurons of the cuneate nucleus form the first interface for the sense of touch in the brain. They were previously shown to have a highly skewed synaptic weight distribution for tactile primary afferent inputs, suggesting that their connectivity is strongly shaped by learning. Here we first characterized the intracellular dynamics and inhibitory synaptic inputs of cuneate neurons in vivo and modeled their integration of tactile sensory inputs. We then replaced the tactile inputs with input from a sensorized bionic fingertip and modeled the learning-induced representations that emerged from varied sensory experiences. The model reproduced both the intrinsic membrane dynamics and the synaptic weight distributions observed in cuneate neurons in vivo. In terms of higher level model properties, individual cuneate neurons learnt to identify specific sets of correlated sensors, which at the population level resulted in a decomposition of the sensor space into its recurring high-dimensional components. Such vector components could be applied to identify both past and novel sensory experiences and likely correspond to the fundamental haptic input features these neurons encode in vivo. In addition, we show that the cuneate learning architecture is robust to a wide range of intrinsic parameter settings due to the neuronal intrinsic dynamics. Therefore, the architecture is a potentially generic solution for forming versatile representations of the external world in different sensor systems.
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| 34. |
- Sarigul, Buse, et al.
(author)
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Prognostication and Goals of Care Decisions in Severe Traumatic Brain Injury : A Survey of The Seattle International Severe Traumatic Brain Injury Consensus Conference Working Group
- 2023
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 40:15-16, s. 1707-1717
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Journal article (peer-reviewed)abstract
- Best practice guidelines have advanced severe traumatic brain injury (TBI) care; however, there is little that currently informs goals of care decisions and processes despite their importance and frequency. Panelists from the Seattle International severe traumatic Brain Injury Consensus Conference (SIBICC) participated in a survey consisting of 24 questions. Questions queried use of prognostic calculators, variability in and responsibility for goals of care decisions, and acceptability of neurological outcomes, as well as putative means of improving decisions that might limit care. A total of 97.6% of the 42 SIBICC panelists completed the survey. Responses to most questions were highly variable. Overall, panelists reported infrequent use of prognostic calculators, and observed variability in patient prognostication and goals of care decisions. They felt that it would be beneficial for physicians to improve consensus on what constitutes an acceptable neurological outcome as well as what chance of achieving that outcome is acceptable. Panelists felt that the public should help to define what constitutes a good outcome and expressed some support for a "nihilism guard." More than 50% of panelists felt that if it was certain to be permanent, a vegetative state or lower severe disability would justify a withdrawal of care decision, whereas 15% felt that upper severe disability justified such a decision. Whether conceptualizing an ideal or existing prognostic calculator to predict death or an unacceptable outcome, on average a 64-69% chance of a poor outcome was felt to justify treatment withdrawal. These results demonstrate important variability in goals of care decision making and a desire to reduce this variability. Our panel of recognized TBI experts opined on the neurological outcomes and chances of those outcomes that might prompt consideration of care withdrawal; however, imprecision of prognostication and existing prognostication tools is a significant impediment to standardizing the approach to care-limiting decisions.
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