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IMPORTANCE: International guidelines recommend body temperature control below 37.8 °C in unconscious patients with out-of-hospital cardiac arrest (OHCA); however, a target temperature of 33 °C might lead to better outcomes when the initial rhythm is nonshockable. OBJECTIVE: To assess whether hypothermia at 33 °C increases survival and improves function when compared with controlled normothermia in unconscious adults resuscitated from OHCA with initial nonshockable rhythm. DATA SOURCES: Individual patient data meta-analysis of 2 multicenter, randomized clinical trials (Targeted Normothermia after Out-of-Hospital Cardiac Arrest [TTM2; NCT02908308] and HYPERION [NCT01994772]) with blinded outcome assessors. Unconscious patients with OHCA and an initial nonshockable rhythm were eligible for the final analysis. STUDY SELECTION: The study cohorts had similar inclusion and exclusion criteria. Patients were randomized to hypothermia (target temperature 33 °C) or normothermia (target temperature 36.5 to 37.7 °C), according to different study protocols, for at least 24 hours. Additional analyses of mortality and unfavorable functional outcome were performed according to age, sex, initial rhythm, presence or absence of shock on admission, time to return of spontaneous circulation, lactate levels on admission, and the cardiac arrest hospital prognosis score. DATA EXTRACTION AND SYNTHESIS: Only patients who experienced OHCA and had a nonshockable rhythm with all causes of cardiac arrest were included. Variables from the 2 studies were available from the original data sets and pooled into a unique database and analyzed. Clinical outcomes were harmonized into a single file, which was checked for accuracy of numbers, distributions, and categories. The last day of follow-up from arrest was recorded for each patient. Adjustment for primary outcome and functional outcome was performed using age, gender, time to return of spontaneous circulation, and bystander cardiopulmonary resuscitation. MAIN OUTCOMES AND MEASURES: The primary outcome was mortality at 3 months; secondary outcomes included unfavorable functional outcome at 3 to 6 months, defined as a Cerebral Performance Category score of 3 to 5. RESULTS: A total of 912 patients were included, 490 from the TTM2 trial and 422 from the HYPERION trial. Of those, 442 had been assigned to hypothermia (48.4%; mean age, 65.5 years; 287 males [64.9%]) and 470 to normothermia (51.6%; mean age, 65.6 years; 327 males [69.6%]); 571 patients had a first monitored rhythm of asystole (62.6%) and 503 a presumed noncardiac cause of arrest (55.2%). At 3 months, 354 of 442 patients in the hypothermia group (80.1%) and 386 of 470 patients in the normothermia group (82.1%) had died (relative risk [RR] with hypothermia, 1.04; 95% CI, 0.89-1.20; P = .63). On the last day of follow-up, 386 of 429 in the hypothermia group (90.0%) and 413 of 463 in the normothermia group (89.2%) had an unfavorable functional outcome (RR with hypothermia, 0.99; 95% CI, 0.87-1.15; P = .97). The association of hypothermia with death and functional outcome was consistent across the prespecified subgroups. CONCLUSIONS AND RELEVANCE: In this individual patient data meta-analysis, including unconscious survivors from OHCA with an initial nonshockable rhythm, hypothermia at 33 °C did not significantly improve survival or functional outcome.

IMPORTANCE: The Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens. OBJECTIVES: To investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA. DESIGN, SETTING, AND PARTICIPANTS: This study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing. INTERVENTIONS: Randomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher). MAIN OUTCOMES AND MEASURES: Functional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes. RESULTS: At 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P = .46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,−0.33 to 1.05; P = .37) and SDMT (mean difference, 0.06; 95% CI,−0.16 to 0.27; P = .62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%). CONCLUSIONS: In this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02908308

IMPORTANCE: Blood phosphorylated tau (p-tau) and amyloid-β peptides (Aβ) are promising peripheral biomarkers of Alzheimer disease (AD) pathology. However, their potential alterations due to alternative mechanisms, such as hypoxia in patients resuscitated from cardiac arrest, are not known. OBJECTIVE: To evaluate whether the levels and trajectories of blood p-tau, Aβ42, and Aβ40 following cardiac arrest, in comparison with neural injury markers neurofilament light (NfL) and total tau (t-tau), can be used for neurological prognostication following cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS: This prospective clinical biobank study used data from the randomized Target Temperature Management After Out-of-Hospital Cardiac Arrest (TTM) trial. Unconscious patients with cardiac arrest of presumed cardiac origin were included between November 11, 2010, and January 10, 2013, from 29 international sites. Serum analysis for serum NfL and t-tau were performed between August 1 and August 23, 2017. Serum p-tau, Aβ42, and Aβ40 were analyzed between July 1 and July 15, 2021, and between May 13 and May 25, 2022. A total of 717 participants from the TTM cohort were examined: an initial discovery subset (n = 80) and a validation subset. Both subsets were evenly distributed for good and poor neurological outcome after cardiac arrest. EXPOSURES: Serum p-tau, Aβ42, and Aβ40 concentrations using single molecule array technology. Serum levels of NfL and t-tau were included as comparators. MAIN OUTCOMES AND MEASURES: Blood biomarker levels at 24 hours, 48 hours, and 72 hours after cardiac arrest. Poor neurologic outcome at 6-month follow-up, defined according to the cerebral performance category scale as category 3 (severe cerebral disability), 4 (coma), or 5 (brain death). RESULTS: This study included 717 participants (137 [19.1%] female and 580 male [80.9%]; mean [SD] age, 63.9 [13.5] years) who experienced out-of-hospital cardiac arrest. Significantly elevated serum p-tau levels were observed at 24 hours, 48 hours, and 72 hours in cardiac arrest patients with poor neurological outcome. The magnitude and prognostication of the change was greater at 24 hours (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI, 0.95-0.97), which was similar to NfL (AUC, 0.94; 95% CI, 0.92-0.96). However, at later time points, p-tau levels decreased and were weakly associated with neurological outcome. In contrast, NfL and t-tau maintained high diagnostic accuracies, even 72 hours after cardiac arrest. Serum Aβ42 and Aβ40 concentrations increased over time in most patients but were only weakly associated with neurological outcome. CONCLUSIONS AND RELEVANCE: In this case-control study, blood biomarkers indicative of AD pathology demonstrated different dynamics of change after cardiac arrest. The increase of p-tau at 24 hours after cardiac arrest suggests a rapid secretion from the interstitial fluid following hypoxic-ischemic brain injury rather than ongoing neuronal injury like NfL or t-tau. In contrast, delayed increases of Aβ peptides after cardiac arrest indicate activation of amyloidogenic processing in response to ischemia.

Graphical AbstractMiR-9-3p a novel predictor of neurological outcome following cardiac arrest.

Background:Targeted therapeutic mild hypercapnia may attenuate brain injury in comatose adults resuscitated from out-of-hospital cardiac arrest.

Targeted temperature management (TTM) exerts substantial impact on hemodynamic function in out-of-hospital cardiac arrest (OHCA) patients. Whole-body oxygen consumption (VO2) and delivery (DO2) have not previously been investigated in a clinical setting during TTM at different levels of temperature after OHCA. A substudy of 151 patients randomized at a single center in the TTM-trial, where patients were randomly assigned TTM at 33°C (TTM33) or 36°C (TTM36) for 24 hours. We calculated VO2according to the principle of Fick (VO2= cardiac output*arteriovenous oxygen content difference). DO2was calculated as cardiac output*arterial oxygen content. Cardiac output was measured by pulmonary artery catheter with thermodilution. Arteriovenous oxygen content difference was calculated from arterial and mixed venous oxygen saturation and hemoglobin. Oxygen extraction ratio = VO2/DO2. At 24 hours, the VO2was 169 ± 59 mL O2per minute in TTM33 and 217 ± 53 mL O2per minute in TTM36 (p< 0.0001). During 24 hours of TTM, the overall difference was 53 mL O2minute (95% confidence interval [CI]: 31–74, pgroup< 0.0001). After rewarming at 36 and 48 hours, there was no difference in VO2between the groups. DO2was overall 277 mL O2per minute (95% CI: 175–379, pgroup< 0.0001) higher in the TTM36-group during TTM. Oxygen extraction ratio during TTM was not significantly different between the two groups (2% [95% CI: −0.1 to 5, pgroup= 0.09]). VO2during the first 36 hours after OHCA correlated significantly with temperature, and VO2was 19 mL O2per minute lower per degree reduction in temperature (95% CI: 15–22), p< 0.0001. TTM at 33°C compared to 36°C after OHCA is associated with significantly lower VO2and DO2, however, oxygen extraction ratio was not significantly different. For each degree lower body temperature, the VO2fell by 19 mL O2per minute.

Objectives: During targeted temperature management after out-of-hospital cardiac arrest infusion of vasoactive drugs is often needed to ensure cerebral perfusion pressure. This study investigated mean arterial pressure after out-of-hospital cardiac arrest and the association with brain injury and long-term cognitive function.Methods: Post-hoc analysis of patients surviving at least 48 hours in the biobank substudy of the targeted temperature management trial with available blood pressure data. Patients were stratified in three groups according to mean arterial pressure during targeted temperature management (4–28 hours after admission; <70 mmHg, 70–80 mmHg, >80 mmHg). A biomarker of brain injury, neuron-specific enolase, was measured and impaired cognitive function was defined as a mini-mental state examination score below 27 in 6-month survivors.Results: Of the 657 patients included in the present analysis, 154 (23%) had mean arterial pressure less than 70 mmHg, 288 (44%) had mean arterial pressure between 70 and 80 mmHg and 215 (33%) had mean arterial pressure greater than 80 mmHg. There were no statistically significant differences in survival (P=0.35) or neuron-specific enolase levels (P=0.12) between the groups. The level of target temperature did not statistically significantly interact with mean arterial pressure regarding neuron-specific enolase (Pinteraction_MAP*TTM=0.58). In the subgroup of survivors with impaired cognitive function (n=132) (35%) mean arterial pressure during targeted temperature management was significantly higher (Pgroup=0.03).Conclusions: In a large cohort of comatose out-of-hospital cardiac arrest patients, low mean arterial pressure during targeted temperature management was not associated with higher neuron-specific enolase regardless of the level of target temperature (33°C or 36°C for 24 hours). In survivors with impaired cognitive function, mean arterial pressure during targeted temperature management was significantly higher.

Neuroimaging with magnetic resonance imaging (MRI) may assist clinicians in evaluating brain injury and optimising care in comatose adults resuscitated after out-of-hospital cardiac arrest (OHCA). However, contemporary international data on its use are lacking.

After resuscitation from out-of-hospital cardiac arrest (OHCA), renal injury and hemodynamic instability are common. We aimed to assess the association between low cardiac output during targeted temperature management (TTM) and acute kidney injury (AKI) after OHCA.

AbstractBackground:Anoxic brain injury is the primary cause of death after resuscitation from out-of-hospital cardiac arrest (OHCA) and prognostication is challenging. The aim of this study was to evaluate the potential of two fragments of tau as serum biomarkers for neurological outcome.Methods:Single-center sub-study of 171 patients included in the Target Temperature Management (TTM) Trial randomly assigned to TTM at 33 °C or TTM at 36 °C for 24 h after OHCA. Fragments (tau-A and tau-C) of the neuronal protein tau were measured in serum 24, 48 and 72 h after OHCA. The primary endpoint was neurological outcome.Results:Median (quartile 1 – quartile 3) tau-A (ng/ml) values were 58 (43–71) versus 51 (43–67), 72 (57–84) versus 71 (59–82) and 76 (61–92) versus 75 (64–89) for good versus unfavourable outcome at 24, 48 and 72 h, respectively (pgroup= 0.95). Median tau C (ng/ml) values were 38 (29–50) versus 36 (29–49), 49 (38–58) versus 48 (33–59) and 48 (39–59) versus 48 (36–62) (pgroup= 0.95). Tau-A and tau-C did not predict neurological outcome (area under the receiver-operating curve at 48 h; tau-A: 0.51 and tau-C: 0.51).Conclusions:Serum levels of tau fragments were unable to predict neurological outcome after OHCA.Trial registration:ClinicalTrials.gov identifier: NCT01020916.

This study investigates the association between mean arterial pressure (MAP) and renal function after out-of-hospital cardiac arrest (OHCA).

IMPORTANCE: Prognostication of neurologic outcome after cardiac arrest is an important but challenging aspect of patient therapy management in critical care units. OBJECTIVE: To determine whether serum neurofilament light chain (NFL) levels can be used for prognostication of neurologic outcome after cardiac arrest. DESIGN, SETTING AND PARTICIPANTS: Prospective clinical biobank study of data from the randomized Target Temperature Management After Cardiac Arrest trial, an international, multicenter study with 29 participating sites. Patients were included between November 11, 2010, and January 10, 2013. Serum NFL levels were analyzed between August 1 and August 23, 2017, after trial completion. A total of 782 unconscious patients with out-of-hospital cardiac arrest of presumed cardiac origin were eligible. EXPOSURES: Serum NFL concentrations analyzed at 24, 48, and 72 hours after cardiac arrest with an ultrasensitive immunoassay. MAIN OUTCOMES AND MEASURES: Poor neurologic outcome at 6-month follow-up, defined according to the Cerebral Performance Category Scale as cerebral performance category 3 (severe cerebral disability), 4 (coma), or 5 (brain death). RESULTS: Of 782 eligible patients, 65 patients (8.3%) were excluded because of issues with aliquoting, missing sampling, missing outcome, or transport problems of samples. Of the 717 patients included (91.7%), 580 were men (80.9%) and median (interquartile range [IQR]) age was 65 (56-73) years. A total of 360 patients (50.2%) had poor neurologic outcome at 6 months. Median (IQR) serum NFL level was significantly increased in the patients with poor outcome vs good outcome at 24 hours (1426 [299-3577] vs 37 [20-70] pg/mL), 48 hours (3240 [623-8271] vs 46 [26-101] pg/mL), and 72 hours (3344 [845-7838] vs 54 [30-122] pg/mL) (P &lt; .001 at all time points), with high overall performance (area under the curve, 0.94-0.95) and high sensitivities at high specificities (eg, 69% sensitivity with 98% specificity at 24 hours). Serum NFL levels had significantly greater performance than the other biochemical serum markers (ie, tau, neuron-specific enolase, and S100). At comparable specificities, serum NFL levels had greater sensitivity for poor outcome compared with routine electroencephalogram, somatosensory-evoked potentials, head computed tomography, and both pupillary and corneal reflexes (ranging from 29.2% to 49.0% greater for serum NFL level). CONCLUSIONS AND RELEVANCE: Findings from this study suggest that the serum NFL level is a highly predictive marker of long-term poor neurologic outcome at 24 hours after cardiac arrest and may be a useful complement to currently available neurologic prognostication methods.

Supplemental Digital Content is available in the text.

Background:Two major cardiac arrest trials are evaluating different strategies that may potentially mitigate neurological injury after cardiac arrest and are allowing co-enrolment. However, one trial will target hypothermia and the other will target mild hypercapnia, in which the carbon dioxide (CO2) measurement may be influenced by the choice of temperature adjustment during arterial blood gases (ABGs) measurement. The trials have agreed to standardise assessment by the α-stat method.

IMPORTANCE: The value of microRNAs (miRNAs) as biomarkers has been investigated in various clinical contexts. Initial small-scale studies suggested that miRNAs might be useful indicators of outcome after cardiac arrest. OBJECTIVE: To address the prognostic value of circulating miRNAs in a large cohort of comatose patients with out-of-hospital cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS: This substudy of the Target Temperature Management After Cardiac Arrest (TTM) trial, a multicenter randomized, parallel-group, assessor-blinded clinical trial, compared the 6-month neurologic outcomes and survival of patients with cardiac arrest after targeted temperature management at 33°C or 36°C. Five hundred seventy-nine patients who survived the first 24 hours after the return of spontaneous circulation and who had blood samples available for miRNA assessment were enrolled from 29 intensive care units in 9 countries from November 11, 2010, to January 10, 2013. Final follow-up was completed on July 3, 2013, and data were assessed from February 1, 2014, to February 1, 2016. INTERVENTIONS: Blood sampling at 48 hours after the return of spontaneous circulation. MAIN OUTCOMES AND MEASURES: The primary end point was poor neurologic outcome at 6 months (cerebral performance category score, 3 [severe neurologic sequelae], 4 [coma], or 5 [death]). The secondary end point was survival until the end of the trial. Circulating levels of miRNAs were measured by sequencing and polymerase chain reaction. RESULTS: Of the 579 patients (265 men [80.3%]; mean [SD] age, 63 [12] years), 304 patients (52.5%) had a poor neurologic outcome at 6 months. In the discovery phase with short RNA sequencing in 50 patients, the brain-enriched miR-124-3p level was identified as a candidate prognostic variable for neurologic outcomes. In the validation cohort of 529 patients, mean (SD) levels of miR-124-3p were higher in patients with a poor outcome (8408 [12 465] copies/µL) compared with patients with a good outcome (1842 [3025] copies/μL; P &lt; .001). The miR-124-3p level was significantly associated with neurologic outcomes in the univariable analysis (odds ratio, 6.72; 95% CI, 4.53-9.97). In multivariable analyses using logistic regression, miR-124-3p levels were independently associated with neurologic outcomes (odds ratio, 1.62; 95% CI, 1.13-2.32). In Cox proportional hazards models, higher levels of miR-124-3p were significantly associated with lower survival (hazard ratio, 1.63; 95% CI, 1.37-1.93). CONCLUSIONS AND RELEVANCE: Levels of miR-124-3p can be used as prognostication tools for neurologic outcome and survival after out-of-hospital cardiac arrest. Thus, miRNA levels may aid in tailoring health care for patients with cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01020916

To explore if the brain biomarker neuron-specific enolase (NSE) in combination with a biomarker for stress; CT-proAVP (copeptin), oxidation; peroxiredoxin 4 (Prx4), inflammation; procalcitonin (PCT), or with biomarkers from the heart; midregional proatrial natriuretic peptide (MR-proANP), or troponin T (TnT) can improve the prognostic accuracy of long-term outcome after out-of-hospital cardiac arrest (OHCA). Serum samples from cardiac arrest patients, treated at 33°C for 24 hours, were collected serially at 12, 24, and 48 hours after cardiac arrest. The concentration of the investigated biomarkers was measured using stored samples, and long-term outcome was evaluated by the cerebral performance category (CPC) at 6 months. Poor outcome was defined as CPC 3–5. Sixty-two patients with OHCA of presumed cardiac cause were included. NSE had best prognostic accuracy for poor outcome at 48 hours with a receiver operating characteristic area under curve (AUC) of 0.94 (95% confidence interval [CI] 0.87–1). The combination of NSE with TnT, both at 48 hours, increased the AUC to 0.98 (95% CI 0.95–1, likelihood ratio [LR] test p-value 0.07, net reclassification index [NRI] <0.001); NSE and MR-proANP, both at 12 hours, yielded an AUC of 0.91 (95% CI 0.80–1, LR test p-value 0.0014, NRI p-value 0.003); NSE at 48 hours with MR-proANP at 12 hours yielded an AUC of 0.97 (95% CI 0.92–1, LR test p-value 0.055, NRI p-value 0.04). This pilot study suggests that a combination of biomarkers with NSE could be beneficial for improving early prognostication of long-term outcome following OHCA.

Targeted Temperature Management (TTM) following shockable out-of-hospital cardiac arrest (OHCA) has been recommended. The effect of different targeted temperatures on the human metabolome has not been compared. Elevated levels of metabolites from the Krebs cycle have recently been associated with a poor outcome in OHCA patients. Similarly, decreased levels of the amino acids valine and leucine have been linked with a poor outcome in septic shock patients.Method:From a single center in the randomized clinical TTM trial, we analyzed blood samples from resuscitated unconscious OHCA patients at two timepoints (hospital arrival and 48 hours later) using ultra-performance liquid mass-spectrometry. Patients were randomized to either 33°C or 36°C hypothermia for the first 28 hours. Sixty-one metabolites of the ~3000 compounds detected were prespecified for quantification and analyzed in the current study. Differences (95% CI) in metabolite concentrations from a constrained linear mixed model are reported, and p-values from the interaction term timepoint x TTM arm.Results:Of the 146 patients, 70 (48 %) were randomized to TTM 33°C. The baseline characteristics (age, gender, shockable rhythm, time to return of spontaneous circulation) and outcome (180 days mortality) were similar in the TTM groups. After 48 hours, approx. 24 hours from the cessation of TTM, fourteen metabolites differed significantly between the two groups. Among these, lactate acid (190 μM (74-305 μM), p<0.001), pyruvic acid (26 μM (8-44 μM), p<0.01), 2-oxoglutaric acid (2.7 μM (1.0-4.4 μM), p<0.01) and prostaglandin E2 (0.60 nM (0.24-1.0 nM), p<0.01) were increased in the TTM 33 °C arm whereas valine (25 μM (15-35 μM), p<0.001) and leucine (14 μM (8.3 - 20 μM), p<0.001) were decreased.Conclusion:TTM at 33°C for 24 hours after OHCA results in a prognostically poorer metabolome even 24 hours later compared with TTM at 36°C.

We study the effect of gravitational focusing of the Earth on dark matter. We find that the effect can produce a detectable diurnal modulation in the dark matter signal for part of the parameter space which for high dark matter masses is larger than the diurnal modulation induced by the fluctuations in the flux of dark matter particles due to the rotation of the Earth around its own axis. The two sources of diurnal modulation have different phases and can be distinguished from each other. We demonstrate that the diurnal modulation can potentially check the self-consistency of experiments that observe annual modulated signals that can be attributed to dark matter. Failing to discover a daily varying signal can result conclusively in the falsification of the hypothesis that the annual modulation is due to dark matter. We also suggest that null result experiments should check for a daily modulation of their rejected background signal with specific phases. A potential discovery could mean that dark matter collisions have been vetoed out. [ABSTRACT FROM AUTHOR]

We study the possibility of asymmetric dark matter with self-interactions forming compact stable objects. We solve the Tolman-Oppenheimer-Volkoff equation and find the mass-radius relation of such "dark stars," their density profile and their Chandrasekhar mass limit. We consider fermionic asymmetric dark matter with Yukawa-type self-interactions appropriate for solving the well-known problems of the collisionless dark matter paradigm. We find that in several cases the relativistic effects are significant. [ABSTRACT FROM AUTHOR]

Temperature management for patients comatose after cardiac arrest has been an integral component of postcardiac arrest care for the last decade. In this review, we present recent findings and discuss implications for future trials.

IMPORTANCE: Brain injury affects neurologic function and quality of life in survivors after cardiac arrest. OBJECTIVE: To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939. INTERVENTIONS: Targeted temperature management at 33°C vs 36°C. MAIN OUTCOMES AND MEASURES: Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2. RESULTS: In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33°C group (interquartile range [IQR], 0-28) vs 17 in the 36°C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33°C and 36°C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33°C group median, 28; IQR, 26-30; vs 36°C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33°C group median, 79.5; IQR, 78.0-85.9; vs 36°C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33°C group vs 61.8% in the 36°C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm. CONCLUSIONS AND RELEVANCE: Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33°C or 36°C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales. TRIAL REGISTRATION: ClinicalTrials.gov NCT01020916

We investigate models in which inflation is driven by an ultraviolet safe and interacting scalar sector stemming from a new class of nonsupersymmetric gauge field theories. These new theories, differently from generic scalar models, are well defined to arbitrary short distances because of the existence of a controllable ultraviolet interacting fixed point. The scalar couplings at the ultraviolet fixed point and their overall running are predicted by the geometric structure of the underlying theory. We analyse the minimal and non-minimal coupling to gravity of these theories and the consequences for inflation. In the minimal coupling case the theory requires large non-perturbative quantum corrections to the quantum potential for the theory to agree with data, while in the non- minimal coupling case the perturbative regime in the couplings of the theory is preferred. Requiring the theory to reproduce the observed amplitude of density perturbations constrain the geometric data of the theory such as the number of colors and flavors for generic values of the non-minimal coupling. [ABSTRACT FROM AUTHOR]

Studies have found higher survival rates after out-of-hospital cardiac arrest and admission to tertiary heart centers. The aim was to examine the level-of-care at tertiary centers compared with nontertiary hospitals and the association with outcome after out-of-hospital cardiac arrest.

Supplemental Digital Content is available in the text.

ObjectiveTo investigate the effects of fever therapy compared with no fever therapy in a wide population of febrile adults.DesignSystematic review with meta-analyses and trial sequential analyses of randomised clinical trials.Data sourcesCENTRAL, BIOSIS, CINAHL, MEDLINE, Embase, LILACS, Scopus, and Web of Science Core Collection, searched from their inception to 2 July 2021.Eligibility criteriaRandomised clinical trials in adults diagnosed as having fever of any origin. Included experimental interventions were any fever therapy, and the control intervention had to be no fever therapy (with or without placebo/sham).Data extraction and synthesisTwo authors independently selected studies, extracted data, and assessed the risk of bias. Primary outcomes were all cause mortality and serious adverse events. Secondary outcomes were quality of life and non-serious adverse events. Aggregate data were synthesised with meta-analyses, subgroup analyses, and trial sequential analyses, and the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.ResultsForty two trials assessing 5140 participants were included. Twenty three trials assessed 11 different antipyretic drugs, 11 trials assessed physical cooling, and eight trials assessed a combination of antipyretic drugs and physical cooling. Of the participants, 3007 were critically ill, 1892 were non-critically ill, 3277 had infectious fever, and 1139 had non-infectious fever. All trials were assessed as being at high risk of bias. Meta-analysis and trial sequential analysis showed that the hypothesis that fever therapy reduces the risk of death (risk ratio 1.04, 95% confidence interval 0.90 to 1.19; I2=0%; P=0.62; 16 trials; high certainty evidence) and the risk of serious adverse events (risk ratio 1.02, 0.89 to 1.17; I2=0%; P=0.78; 16 trials; high certainty evidence) could be rejected. One trial assessing quality of life was included, showing no difference between fever therapy and control. Meta-analysis and trial sequential analysis showed that the hypothesis that fever therapy reduces the risk of non-serious adverse events could be neither confirmed nor rejected (risk ratio 0.92, 0.67 to 1.25; I2=66.5%; P=0.58; four trials; very low certainty evidence).ConclusionsFever therapy does not seem to affect the risk of death and serious adverse events.Systematic review registrationPROSPERO CRD42019134006

Particles in a yet unexplored dark sector with sufficiently large mass and small gauge coupling may form purely gravitational atoms (quantum gravitational bound states) with a rich phenomenology. In particular, we investigate the possibility of having an observable signal of gravitational waves or ultrahigh-energy cosmic rays from the decay of gravitational atoms. We show that, if ordinary Einstein gravity holds up to the Planck scale, then within the Lambda-cold dark matter model (ΛCDM), the frequency of the gravitational wave signal produced by the decays is always higher than 1013 Hz. An observable signal of gravitational waves with smaller frequency from such decays, in addition to probing near Planckian dark physics, would also imply a departure from Einstein gravity near the Planck scale or an early epoch of nonstandard cosmology. As an example, we consider an early universe cosmology with a matter-dominated phase, violating our assumption that the Universe is radiation dominated after reheating, which gives a signal in an interesting frequency range for near-Planckian bound states. We also show how gravitational atoms arise in the minimal Planckian interacting dark matter scenario and compute their gravitational wave signature. [ABSTRACT FROM AUTHOR]

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Sub-GeV halo dark matter that enters the Sun can potentially scatter off hot solar nuclei and be ejected much faster than its incoming velocity. We derive an expression for the rate and velocity distribution of these reflected particles, taking into account the Sun's temperature and opacity. We further demonstrate that future direct-detection experiments could use these energetic reflected particles to probe light dark matter in parameter space that cannot be accessed via ordinary halo dark matter. [ABSTRACT FROM AUTHOR]

Theoretical models of self-interacting dark matter represent a promising answer to a series of open problems within the so-called collisionless cold dark matter paradigm. In case of asymmetric dark matter, self-interactions might facilitate gravitational collapse and potentially lead to the formation of compact objects predominantly made of dark matter. Considering both fermionic and bosonic (scalar ϕ4) equations of state, we construct the equilibrium structure of rotating dark stars, focusing on their bulk properties and comparing them with baryonic neutron stars. We also show that these dark objects admit the I-Love-Q universal relations, which link their moments of inertia, tidal deformabilities, and quadrupole moments. Finally, we prove that stars built with a dark matter equation of state are not compact enough to mimic black holes in general relativity, thus making them distinguishable in potential events of gravitational interferometers. [ABSTRACT FROM AUTHOR]