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Purpose: To compare the oncologic outcomes of patients with nonmetastatic muscle-invasive bladder cancer (MIBC) undergoing complete versus incomplete transurethral tumor resection (TURBT) before radiation therapy., Methods and Materials: Patients with nonmetastatic MIBC who underwent curative-intent radiation therapy between 2002 and 2018 at 10 Canadian institutions were retrospectively evaluated. Inverse probability of treatment weighting was performed using baseline characteristics. Differences in survival outcomes by complete and incomplete TURBT were analyzed., Results: Of the 757 patients included, 66% (498) had documentation of a complete and 34% (259) an incomplete TURBT. Before adjustment, 121 (47%) and 45 (9%) patients who underwent incomplete and complete TURBT, respectively, were diagnosed with cT3-4 tumor (P <.001). After weight-adjustment, all baseline cohort characteristics were balanced (absolute standardized differences < 0.1). The adjusted median follow-up was 27 months. Adjusted survival analyses showed no significant difference in 5-year overall survival (48% vs 52%, 1.03 [0.82-1.29]; P = .8), cancer-specific survival (64% vs 61%, 0.93 [0.70-1.25]; P = .7), metastasis-free survival (43% vs 46%, 0.97 [0.79-1.19]; P = .8), and disease-free survival (32% vs 35%, 0.95 [0.79-1.15]; P = .7) between the 2 groups., Conclusions: Complete TURBT may be associated with clinical organ-confined disease. Extent of TURBT was not independently associated with oncologic outcomes in patients with MIBC treated with radiation therapy., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The value of pelvic lymph node irradiation is debated for patients with muscle-invasive bladder cancer (MIBC) undergoing curative-intent radiation therapy (RT). We sought to compare the oncologic outcomes between bladder-only (BO)-RT and whole-pelvis (WP)-RT using a large Canadian multicenter collaborative database., Patients and Methods: The study cohort consisted of 809 patients with MIBC (cT2-4aN0-2M0) who underwent curative RT at academic centers across Canada. Patients were divided into two groups on the basis of the RT volume: WP-RT versus BO-RT. Inverse probability of treatment weighting (IPTW) and absolute standardized differences (ASDs) were used to balance covariates across treatment groups. Regression models were used to assess the effect of the RT volume on the rates of complete response (CR), cancer-specific survival (CSS), and overall survival (OS)., Results: After exclusion criteria, 599 patients were included, of whom 369 (61.6%) underwent WP-RT. Patients receiving WP-RT were younger (ASD, 0.41) and more likely to have an Eastern Cooperative Oncology Group performance status of 0-1 (ASD, 0.21), clinical node-positive disease (ASD, 0.40), and lymphovascular invasion (ASD, 0.25). In addition, WP-RT patients were more commonly treated with neoadjuvant chemotherapy (ASD, 0.29) and concurrent chemotherapy (ASD, 0.44). In the IPTW cohort, BO-RT and WP-RT groups were well balanced (all pretreatment parameters with an ASD <0.10). In multivariable analysis, WP-RT was not associated with CR rates post-RT (odds ratio, 1.14 [95 CI, 0.76 to 1.72]; P = .526) but was associated with both CSS (hazard ratio [HR], 0.66 [95% CI, 0.47 to 0.93]; P = .016) and OS (HR, 0.68 [95% CI, 0.54 to 0.87]; P = .002), independent of other prognostic factors., Conclusion: Our study demonstrated that WP radiation was associated with better survival compared with bladder radiation alone after adjusted analysis. Additional randomized controlled trials are needed to confirm our findings.

Background: The optimal target for partial pressure of arterial carbon dioxide (PaCO₂) remains uncertain in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) following out-of-hospital cardiac arrest (OHCA)., Research Question: Are PaCO₂ levels associated with functional outcomes in patients receiving VA-ECMO after OHCA?, Study Design: and Methods: This multicenter, registry-based observational study, conducted from 2014 to 2020, included non-traumatic adult OHCA patients on VA-ECMO with PaCO₂ levels measured within six hours of initiation (initial PaCO₂ set) and at 18-30 hours post-initiation (24-hour PaCO₂ set). PaCO₂ levels were categorized into five groups: hypocapnia (<30 mmHg), low normocapnia (30-<40 mmHg), high normocapnia (40-<50 mmHg), mild hypercapnia (50-<60 mmHg), and moderate to severe hypercapnia (≥60 mmHg). The primary outcome was the favorable functional outcome at 30 days, analyzed using multivariable logistic regression. PaCO₂ trajectories from initial to 24-hour levels were also explored., Results: A total of 1,454 and 572 patients were analyzed in the initial and 24-hour PaCO₂ sets, respectively. Compared to high normocapnia, low normocapnia was associated with worse functional outcomes in both initial and 24-hour PaCO₂ analyses, with adjusted odds ratios of 0.59 (95% CI, 0.38-0.89) for initial low normocapnia and 0.56 (95% CI, 0.33-0.95) for 24-hour low normocapnia. Other categories were similarly associated with worse functional outcomes in both PaCO₂ analyses. In exploratory analyses, trajectories ending in high normocapnia demonstrated higher proportions of the favorable functional outcome than those ending in low normocapnia, regardless of initial PaCO₂ levels., Interpretation: In non-traumatic adult OHCA patients on VA-ECMO, high normocapnia was associated with better functional outcomes than low normocapnia in both initial and 24-hour PaCO₂ analyses. These findings suggest a hypothesis that maintaining high normocapnia levels, irrespective of initial PaCO 2 , may improve functional outcomes for patients on VA-ECMO after OHCA., (Copyright © 2025. Published by Elsevier Inc.)

Pain perception is not solely determined by noxious stimuli, but also varies due to other factors, such as beliefs about pain and its uncertainty. A widely accepted theory posits that the brain integrates prediction of pain with noxious stimuli, to estimate pain intensity. This theory assumes that the estimated pain value is adjusted to minimize surprise, mathematically defined as errors between predictions and outcomes. However, it is still unclear whether the represented surprise directly influences pain perception or merely serves to update this estimate. In this study, we empirically examined this question using virtual reality. In the task, participants reported felt pain via VAS after their arm was stimulated by noxious heat and thrusted into by a virtual knife actively. To manipulate surprise level, the visual threat suddenly disappeared randomly, and noxious heat was presented in the on- or post-action phases. We observed that a transphysical surprising event, created by sudden disappearance of a visual threat cue combined with delayed noxious heat, amplified pain intensity. Subsequent model-based analysis using Bayesian theory revealed significant modulation of pain by the Bayesian surprise value. These results illustrated a real-time computational process for pain perception during a single task trial, suggesting that the brain anticipates pain using an efference copy of actions, integrates it with multimodal stimuli, and perceives it as a surprise., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2025. Published by Elsevier B.V.)

Background: Neoadjuvant chemotherapy (NAC) improves survival for patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. Studies on the potential benefit of NAC before radiation-based therapy (RT) are conflicting., Objective: To evaluate the effect of NAC on patients with MIBC treated with curative-intent RT in a real-world setting., Design, Setting, and Participants: The study cohort consisted of 785 patients with MIBC (cT2-4aN0-2M0) who underwent RT at academic centers across Canada. Patients were classified into two treatment groups based on the administration of NAC before RT (NAC vs no NAC)., Outcome Measurements and Statistical Analysis: The inverse probability of treatment weighting (IPTW) with absolute standardized differences (ASDs) was used to balance covariates across treatment groups. The impact of NAC on complete response, overall, and cancer-specific survival (CSS) after RT in the weighted cohort was analyzed., Results and Limitations: After applying the exclusion criteria, 586 patients were included; 102 (17%) received NAC before RT. Patients in the NAC subgroup were younger (mean age 65 vs 77 yr; ASD 1.20); more likely to have Eastern Cooperative Oncology Group performance status 0-1 (87% vs 78%; ASD 0.28), lymphovascular invasion (32% vs 20%; ASD 0.27), higher cT stage (cT3-4 in 29% vs 20%; ASD 0.21), and higher cN stage (cN1-2 in 32% vs 4%; ASD 0.81); and more commonly treated with concurrent chemotherapy (79% vs 67%; ASD 0.28). After IPTW, NAC versus no NAC cohorts were well balanced (ASD <0.20) for all included covariates. NAC was significantly associated with improved CSS (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.14-0.56; p < 0.001) and overall survival (HR 0.56; 95% CI 0.38-0.84; p = 0.005). This study was limited by potential occult imbalances across treatment groups., Conclusions: If tolerated, NAC might be associated with improved survival and should be considered for eligible patients with MIBC planning to undergo bladder preservation with RT. Prospective trials are warranted., Patient Summary: In this study, we showed that neoadjuvant chemotherapy might be associated with improved survival in patients with muscle-invasive bladder cancer who elect for curative-intent radiation-based therapy., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Importance: Among cancer surgeries, patients requiring open radical cystectomy have the highest risk of red blood cell (RBC) transfusion. Prophylactic tranexamic acid (TXA) reduces blood loss during cardiac and orthopedic surgery, and it is possible that similar effects of TXA would be observed during radical cystectomy., Objective: To determine whether TXA, administered before incision and for the duration of radical cystectomy, reduced the number of RBC transfusions received by patients up to 30 days after surgery., Design, Setting, and Participants: The Tranexamic Acid During Cystectomy Trial (TACT) was a double-blind, placebo-controlled, randomized clinical trial with enrollment between June 2013 and January 2021. This multicenter trial was conducted in 10 academic centers. A consecutive sample of patients was eligible if the patients had a planned open radical cystectomy for the treatment of bladder cancer., Intervention: Before incision, patients in the intervention arm received a loading dose of intravenous TXA, 10 mg/kg, followed by a maintenance infusion of 5 mg/kg per hour for the duration of the surgery. In the control arm, patients received indistinguishable matching placebo., Main Outcomes and Measures: The primary outcome was receipt of RBC transfusion up to 30 days after surgery., Results: A total of 386 patients were assessed for eligibility, and 33 did not meet eligibility. Of 353 randomized patients (median [IQR] age, 69 [62-75] years; 263 male [74.5%]), 344 were included in the intention-to-treat analysis. RBC transfusion up to 30 days occurred in 64 of 173 patients (37.0%) in the TXA group and 64 of 171 patients (37.4%) in the placebo group (relative risk, 0.99; 95% CI, 0.83-1.18). There were no differences in secondary outcomes among the TXA group vs placebo group including mean (SD) number of RBC units transfused (0.9 [1.5] U vs 1.1 [1.8] U; P = .43), estimated blood loss (927 [733] mL vs 963 [624] mL; P = .52), intraoperative transfusion (28.3% [49 of 173] vs 24.0% [41 of 171]; P = .08), or venous thromboembolic events (3.5% [6 of 173] vs 2.9% [5 of 171]; P = .57). Non-transfusion-related adverse events were similar between groups., Conclusions and Relevance: Results of this randomized clinical trial reveal that TXA did not reduce blood transfusion in patients undergoing open radical cystectomy for bladder cancer. Based on this trial, routine use of TXA during open radical cystectomy is not recommended., Trial Registration: ClinicalTrials.gov Identifier: NCT01869413.

Meta-learning enables us to learn how to learn the same or similar tasks more efficiently. Decision-making literature theorizes that a prefrontal network, including the orbitofrontal and anterior cingulate cortices, underlies meta-learning of decision making by reinforcement learning. Recently, computationally similar meta-learning has been theorized and empirically demonstrated in motor adaptation. However, it remains unclear whether meta-learning of motor adaptation also relies on a prefrontal network. Considering hierarchical information flow from the prefrontal to motor cortices, this study explores whether meta-learning is processed in the dorsolateral prefrontal cortex (DLPFC) or in the dorsal premotor cortex (PMd), which is situated upstream of the primary motor cortex, but downstream of the DLPFC. Transcranial magnetic stimulation (TMS) was delivered to either PMd or DLPFC during a motor meta-learning task, in which human participants were trained to regulate the rate and retention of motor adaptation to maximize rewards. While motor adaptation itself was intact, TMS to PMd, but not DLPFC, attenuated meta-learning, impairing the ability to regulate motor adaptation to maximize rewards. Further analyses revealed that TMS to PMd attenuated meta-learning of memory retention. These results suggest that meta-learning of motor adaptation relies more on the premotor area than on a prefrontal network. Thus, while PMd is traditionally viewed as crucial for planning motor actions, this study suggests that PMd is also crucial for meta-learning of motor adaptation, processing goal-directed planning of how long motor memory should be retained to fit the long-term goal of motor adaptation., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Meta-learning is a metacognitive function for successful, efficient learning in various tasks. While it is possible that meta-learning is linked to functional recovery in stroke, it has not been investigated in previous clinical research on metacognition., Aim: Examine if individual meta-learning ability is associated with functional outcomes., Design: Cohort study., Settings: Rehabilitation ward in Fujita Health University Hospital., Population: Twenty-nine hemiparetic people after stroke., Methods: The study measured individual sensorimotor adaptation rate, meta-learning (acceleration of adaptation through training), and Functional Independence Measure (FIM) motor effectiveness, an index of functional outcome measuring improvement in proficiency of activity of daily living (ADL). Participants performed visuomotor adaptation training sessions with their less-affected arm. They made arm-reaching movements to hit a target with cursor feedback, which was occasionally rotated with regard to their hand positions, requiring them to change the movement direction accordingly. Initial adaptation rate and meta-learning were quantified from pre- and post-training tests. The relationship between these indices of adaptation ability and FIM motor effectiveness was examined by multiple linear regression analyses., Results: One participant was excluded before data collection in the motor task. In the remaining 28 individuals, the regression analyses revealed that FIM motor effectiveness positively correlated with meta-learning (µ=0.90, P=0.008), which was attenuated by age (µ=-0.015, P=0.005), but not with initial adaptation rate (P=0.08). Control analyses suggested that this observed association between FIM motor effectiveness and meta-learning was not mediated by patients' demographics or stroke characteristics., Conclusions: This study demonstrates that those who can accelerate adaptation through training are likely to improve ADL, suggesting that meta-learning may be linked with functional outcomes in some stroke individuals. Meta-learning may enable the brain to keep (re-)learning motor skills when motor functions change abruptly due to stroke and neural recovery, thereby associated with improvement in ADL., Clinical Rehabilitation Impact: Meta-learning is part of metacognitive functions that is positively associated with functional outcomes.

Importance: For pediatric out-of-hospital cardiac arrest (OHCA), emergency medical services (EMS) may elect to transport to the hospital during active cardiopulmonary resuscitation (CPR) (ie, intra-arrest transport) or to continue on-scene CPR for the entirety of the resuscitative effort. The comparative effectiveness of these strategies is unclear., Objective: To evaluate the association between intra-arrest transport compared with continued on-scene CPR and survival after pediatric OHCA, and to determine whether this association differs based on the timing of intra-arrest transport., Design, Setting, and Participants: This cohort study included pediatric patients aged younger than 18 years with EMS-treated OHCA between December 1, 2005 and June 30, 2015. Data were collected from the Resuscitation Outcomes Consortium Epidemiologic Registry, a prospective 10-site OHCA registry in the US and Canada. Data analysis was performed from May 2022 to February 2024., Exposures: Intra-arrest transport, defined as an initiation of transport prior to the return of spontaneous circulation, and the interval between EMS arrival and intra-arrest transport., Main Outcomes and Measures: The primary outcome was survival to hospital discharge. Patients who underwent intra-arrest transport at any given minute after EMS arrival were compared with patients who were at risk of undergoing intra-arrest transport within the same minute using time-dependent propensity scores calculated from patient demographics, arrest characteristics, and EMS interventions. We examined subgroups based on age (<1 year vs ≥1 year)., Results: Of 2854 eligible pediatric patients (median [IQR] age, 1 [0-9] years); 1691 males [59.3%]) who experienced OHCA between December 2005 and June 2015, 1892 children (66.3%) were treated with intra-arrest transport and 962 children (33.7%) received continued on-scene CPR. The median (IQR) time between EMS arrival and intra-arrest transport was 15 (9-22) minutes. In the propensity score-matched cohort (3680 matched cases), there was no significant difference in survival to hospital discharge between the intra-arrest transport group and the continued on-scene CPR group (87 of 1840 patients [4.7%] vs 95 of 1840 patients [5.2%]; risk ratio [RR], 0.81 [95% CI, 0.59-1.10]). Survival to hospital discharge was not modified by the timing of intra-arrest transport (P value for the interaction between intra-arrest transport and time to matching = .10). Among patients aged younger than 1 year, intra-arrest transport was associated with lower survival to hospital discharge (RR, 0.52; 95% CI, 0.33-0.83) but there was no association for children aged 1 year or older (RR, 1.22; 95% CI, 0.77-1.93)., Conclusions and Relevance: In this cohort study of a North American OHCA registry, intra-arrest transport compared with continued on-scene CPR was not associated with survival to hospital discharge among children with OHCA. However, intra-arrest transport was associated with a lower likelihood of survival to hospital discharge among children aged younger than 1 year.

Although the role of aerobic glycolysis in activated T cells has been well characterized, whether and how fatty acids (FAs) contribute to donor T cell function in allogeneic hematopoietic stem cell transplantation is unclear. Using xenogeneic graft-versus-host disease (GVHD) models, this study demonstrated that exogenous FAs serve as a crucial source of mitochondrial respiration in donor T cells in humans. By comparing human T cells isolated from wild-type NOD/Shi-scid-IL2rγnull (NOG) mice with those from MHC class I/II-deficient NOG mice, we found that donor T cells increased extracellular FA uptake, the extent of which correlates with their proliferation, and continued to increase FA uptake during effector differentiation. Gene expression analysis showed the upregulation of a wide range of lipid metabolism-related genes, including lipid hydrolysis, mitochondrial FA transport, and FA oxidation. Extracellular flux analysis demonstrated that mitochondrial FA transport was required to fully achieve the mitochondrial maximal respiration rate and spare respiratory capacity, whereas the substantial disruption of glucose supply by either glucose deprivation or mitochondrial pyruvate transport blockade did not impair oxidative phosphorylation. Taken together, FA-driven mitochondrial respiration is a hallmark that differentiates TCR-dependent T cell activation from TCR-independent immune response after hematopoietic stem cell transplant., (Copyright © 2024 The Authors.)

Importance: While epinephrine and advanced airway management (AAM) (supraglottic airway insertion and endotracheal intubation) are commonly used for out-of-hospital cardiac arrest (OHCA), the optimal sequence of these interventions remains unclear., Objective: To evaluate the association of the sequence of epinephrine administration and AAM with patient outcomes after OHCA., Design, Setting, and Participants: This cohort study analyzed the nationwide, population-based OHCA registry in Japan and included adults (aged ≥18 years) with OHCA for whom emergency medical services personnel administered epinephrine and/or placed an advanced airway between January 1, 2014, and December 31, 2019. The data analysis was performed between October 1, 2022, and May 12, 2023., Exposure: The sequence of intravenous epinephrine administration and AAM., Main Outcomes and Measures: The primary outcome was 1-month survival. Secondary outcomes were 1-month survival with favorable functional status and prehospital return of spontaneous circulation. To control imbalances in measured patient demographics, cardiac arrest characteristics, and bystander and prehospital interventions, propensity scores and inverse probability of treatment weighting (IPTW) were performed for shockable and nonshockable initial rhythm subcohorts., Results: Of 259 237 eligible patients (median [IQR] age, 79 [69-86] years), 152 289 (58.7%) were male. A total of 21 592 patients (8.3%) had an initial shockable rhythm, and 237 645 (91.7%) had an initial nonshockable rhythm. Using IPTW, all covariates between the epinephrine-first and AAM-first groups were well balanced, with all standardized mean differences less than 0.100. After IPTW, the epinephrine-first group had a higher likelihood of 1-month survival for both shockable (odds ratio [OR], 1.19; 95% CI, 1.09-1.30) and nonshockable (OR, 1.28; 95% CI, 1.19-1.37) rhythms compared with the AAM-first group. For the secondary outcomes, the epinephrine-first group experienced an increased likelihood of favorable functional status and prehospital return of spontaneous circulation for both shockable and nonshockable rhythms compared with the AAM-first group., Conclusions and Relevance: These findings suggest that for patients with OHCA, administration of epinephrine before placement of an advanced airway may be the optimal treatment sequence for improved patient outcomes.

Recent evidence indicates that specific types of nuclear acids, including guanosine and its derivatives, act as natural ligands for TLR7. This led us to hypothesize that purine nucleoside phosphorylase inhibitors not only can induce apoptosis of T cells but also can lead to TLR7 activation by accumulation of guanine nucleosides, in particular under systemic inflammation, where damaged tissues release a large amount of nucleotides. We demonstrate in the present study that a purine nucleoside phosphorylase inhibitor, forodesine, can reduce the disease severity and prolong the survival in a xenogeneic mouse model of graft-versus-host disease (GVHD). Guanine nucleosides were undetectable in mice during GVHD but increased significantly following forodesine treatment. Our in vitro experiments showed that forodesine enhanced guanosine-mediated cytokine production from APCs, including alveolar macrophages and plasmacytoid dendritic cells, through TLR7 signaling. Forodesine also enhanced Ag-presenting capacity, as demonstrated by increased CD8+ T cell proliferation and higher secretion of IFN-γ and IL-12p40 in an MLR with plasmacytoid dendritic cells. Furthermore, forodesine stimulated IFN-γ production from activated T cells in the presence of a low concentration of guanosine while inhibiting their proliferation and inducing apoptotic cell death. Although forodesine ameliorated GVHD severity, mice treated with forodesine showed significantly higher levels of multiple proinflammatory cytokines and chemokines in plasma, suggesting in vivo upregulation of TLR7 signaling. Our study suggests that forodesine may activate a wide range of immune cells, including T cells, through TLR7 stimulation while inhibiting GVHD by inducing apoptosis of T cells, after allogeneic hematopoietic stem cell transplant., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Objective: To assess if estimated glomerular filtration rate (eGFR) can replace measured GFR (mGFR) in partial nephrectomy (PN) trials, using data from a randomised clinical trial., Patients and Methods: We conducted a post hoc analysis of the renal hypothermia trial. Patients underwent mGFR with diethylenetriaminepentaacetic acid (DTPA) plasma clearance preoperatively and 1 year after PN. The eGFR was calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equations incorporating age and sex, with and without race: 2009 eGFRcr(ASR) and 2009 eGFRcr(AS), and the 2021 equation that only incorporates age and sex: 2021 eGFRcr(AS). Performance was evaluated by determining the median bias, precision (interquartile range [IQR] of median bias), and accuracy (percentage of eGFR within 30% of mGFR)., Results: Overall, 183 patients were included. Pre- and postoperative median bias and precision were similar between the 2009 eGFRcr(ASR) (-0.2 mL/min/1.73 m 2 , 95% confidence interval [CI] -2.2 to 1.7, IQR 18.8; and -2.9, 95% CI -5.1 to -1.5, IQR 15, respectively) and 2009 eGFRcr(AS) (-0.3 mL/min/1.73 m 2 , 95% CI -2.4 to 1.5, IQR 18.8; and -3.0, 95% CI -5.7 to -1.7, IQR 15.0, respectively). Bias and precision were worse for the 2021 eGFRcr(AS) (-8.8 mL/min/1.73 m 2 , 95% CI -10.9 to -6.3, IQR 24.7; and -12.0, 95% CI -15.8 to -8.9, IQR 23.5, respectively). Similarly, pre- and postoperative accuracy was >90% for the 2009 eGFRcr(ASR) and 2009 eGFRcr(AS) equations . Accuracy was 78.6% preoperatively and 66.5% postoperatively for 2021 eGFRcr(AS)., Conclusion: The 2009 eGFRcr(AS) can accurately estimate GFR in PN trials and could be used instead of mGFR to reduce cost and patient burden., (© 2023 BJU International.)

Background: Intrarenal venous flow (IRVF) patterns assessed using Doppler renal ultrasonography are real-time bedside visualizations of renal vein hemodynamics. Although this technique has the potential to detect renal congestion during sepsis resuscitation, there have been few studies on this method. We aimed to examine the relationship between IRVF patterns, clinical parameters, and outcomes in critically ill adult patients with sepsis. We hypothesized that discontinuous IRVF was associated with elevated central venous pressure (CVP) and subsequent acute kidney injury (AKI) or death., Methods: We conducted a prospective observational study in two tertiary-care hospitals, enrolling adult patients with sepsis who stayed in the intensive care unit for at least 24 h, had central venous catheters placed, and received invasive mechanical ventilation. Renal ultrasonography was performed at a single time point at the bedside after sepsis resuscitation, and IRVF patterns (discontinuous vs. continuous) were confirmed by a blinded assessor. The primary outcome was CVP obtained at the time of renal ultrasonography. We also repeatedly assessed a composite of Kidney Disease Improving Global Outcomes of Stage 3 AKI or death over the course of a week as a secondary outcome. The association of IRVF patterns with CVP was examined using Student's t-test (primary analysis) and that with composite outcomes was assessed using a generalized estimating equation analysis, to account for intra-individual correlations. A sample size of 32 was set in order to detect a 5-mmHg difference in CVP between IRVF patterns., Results: Of the 38 patients who met the eligibility criteria, 22 (57.9%) showed discontinuous IRVF patterns that suggested blunted renal venous flow. IRVF patterns were not associated with CVP (discontinuous flow group: mean 9.24 cm H 2 O [standard deviation: 3.19], continuous flow group: 10.65 cm H 2 O [standard deviation: 2.53], p = 0.154). By contrast, the composite outcome incidence was significantly higher in the discontinuous IRVF pattern group (odds ratio: 9.67; 95% confidence interval: 2.13-44.03, p = 0.003)., Conclusions: IRVF patterns were not associated with CVP but were associated with subsequent AKI in critically ill adult patients with sepsis. IRVF may be useful for capturing renal congestion at the bedside that is related to clinical patient outcomes., (© 2023. The Author(s).)

Humans and animals develop learning-to-learn strategies throughout their lives to accelerate learning. One theory suggests that this is achieved by a metacognitive process of controlling and monitoring learning. Although such learning-to-learn is also observed in motor learning, the metacognitive aspect of learning regulation has not been considered in classical theories of motor learning. Here, we formulated a minimal mechanism of this process as reinforcement learning of motor learning properties, which regulates a policy for memory update in response to sensory prediction error while monitoring its performance. This theory was confirmed in human motor learning experiments, in which the subjective sense of learning-outcome association determined the direction of up- and down-regulation of both learning speed and memory retention. Thus, it provides a simple, unifying account for variations in learning speeds, where the reinforcement learning mechanism monitors and controls the motor learning process., (© 2023. The Author(s).)

Background: Collecting blood cultures from indwelling arterial catheters is an attractive option in critically ill adult patients when peripheral venipuncture is difficult. However, whether the contamination proportion of blood cultures from arterial catheters is acceptable compared with that from venipuncture is inconclusive., Research Question: Is contamination of blood cultures from arterial catheters noninferior to that from venipuncture in critically ill adult patients with suspected bloodstream infection?, Study Design and Methods: In this multicenter prospective diagnostic study conducted at five hospitals, we enrolled episodes of paired blood culture collection, each set consisting of blood drawn from an arterial catheter and another by venipuncture, were obtained from critically ill adult patients with cilinical indication. The primary measure was the proportion of contamination, defined as the number of false-positive results relative to the total number of procedures done. The reference standard for true bloodstream infection was blinded assessment by infectious disease specialists. We examined the noninferiority hypothesis that the contamination proportion of blood cultures from arterial catheters did not exceed that from venipuncture by 2.0%., Results: Of 1,655 episodes of blood culture from December 2018 to July 2021, 590 paired blood culture episodes were enrolled, and 41 of the 590 episodes (6.9%) produced a true bloodstream infection. In blood cultures from arterial catheters, 33 of 590 (6.0%) were positive, and two of 590 (0.3%) were contaminated; in venipuncture, 36 of 590 (6.1%) were positive, and four of 590 (0.7%) were contaminated. The estimated difference in contamination proportion (arterial catheter - venipuncture) was -0.3% (upper limit of one-sided 95% CI, +0.3%). The upper limit of the 95% CI did not exceed the predefined margin of +2.0%, establishing noninferiority (P for noninferiority < .001)., Interpretation: Obtaining blood cultures from arterial catheters is an acceptable alternative to venipuncture in critically ill patients., Clinical Trial Registration: University Hospital Medical Information Network Center (UMIN-CTR); No.: UMIN000035392; URL: https://center6.umin.ac.jp/., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The purpose of the study was to investigate the accuracy of mainstream EtCO 2 measurements on the Y-piece (filtered) side of the heat and moisture exchanger filter (HMEF) in adult critically ill patients, compared to that on the patient (unfiltered) side of HMEF. We conducted a prospective observational method comparison study between July 2019 and December 2019. Critically ill adult patients receiving mechanical ventilation with HMEF were included. We performed a noninferiority comparison of the accuracy of EtCO 2 measurements on the two sides of HMEF. The accuracy was measured by the absolute difference between PaCO 2 and EtCO 2 . We set the non-inferiority margin at + 1 mmHg in accuracy difference between the two sides of HMEF. We also assessed the agreement between PaCO 2 and EtCO 2 using Bland-Altman analysis. Among thirty-seven patients, the accuracy difference was - 0.14 mmHg (two-sided 90% CI - 0.58 to 0.29), and the upper limit of the CI did not exceed the predefined margin of + 1 mmHg, establishing non-inferiority of EtCO 2 on the Y-piece side of HMEF (P for non-inferiority < 0.001). In the Bland-Altman analyses, 95% limits of agreement between PaCO 2 and EtCO 2 were similar on both sides of HMEF (Y-piece side, - 8.67 to  + 10.65 mmHg; patient side, - 8.93 to  + 10.67 mmHg). The accuracy of mainstream EtCO 2 measurements on the Y-piece side of HMEF was noninferior to that on the patient side in critically ill adults. Mechanically ventilated adult patients could be accurately monitored with mainstream EtCO 2 on the Y-piece side of the HMEF unless their tidal volume was extremely low., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: We aimed to investigate the association between blood urea nitrogen to creatinine ratio (BCR) and survival with favourable neurological outcomes in patients with out-of-hospital cardiac arrest (OHCA)., Methods: This prospective, multicentre, observational study conducted in Osaka, Japan enrolled consecutive OHCA patients transported to 16 participating institutions from 2012 through 2019. We included adult patients with non-traumatic OHCA who achieved a return of spontaneous circulation and whose blood urea nitrogen and creatinine levels on hospital arrival were available. Based on BCR values, they were divided into: 'low BCR' (BCR <10), 'normal BCR' (10 ≤ BCR < 20), 'high BCR' (20 ≤ BCR < 30), and 'very high BCR' (BCR ≥ 30). We evaluated the association between BCR values and neurologically favourable outcomes, defined as cerebral performance category score of 1 or 2 at one month after OHCA., Results: Among 4415 eligible patients, the 'normal BCR' group had the highest favourable neurological outcome [19.4 % (461/2372)], followed by 'high BCR' [12.5 % (141/1127)], 'low BCR' [11.2 % (50/445)], and 'very high BCR' groups [6.6 % (31/471)]. In the multivariable analysis, adjusted odds ratios for 'low BCR', 'high BCR', and 'very high BCR' compared with 'normal BCR' for favourable neurological outcomes were 0.58 [95 % confidence interval (CI 0.37-0.91)], 0.70 (95 % CI 0.49-0.99), and 0.40 (95 % CI 0.21-0.76), respectively. Cubic spline analysis indicated that the association between BCR and favourable neurological outcomes was non-linear (p for non-linearity = 0.003). In subgroup analysis, there was an interaction between the aetiology of arrest and BCR in neurological outcome (p for interaction <0.001); favourable neurological outcome of cardiogenic OHCA patients was lower when the BCR was higher or lower, but not in non-cardiogenic OHCA patients., Conclusions: Both higher and lower BCR were associated with poor neurological outcomes compared to normal BCR, especially in cardiogenic OHCA patients., Competing Interests: Declaration of competing interest All the authors declare that they have no potential conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Importance: While epinephrine has been widely used in prehospital resuscitation for pediatric patients with out-of-hospital cardiac arrest (OHCA), the benefit and optimal timing of epinephrine administration have not been fully investigated., Objectives: To evaluate the association between epinephrine administration and patient outcomes and to ascertain whether the timing of epinephrine administration was associated with patient outcomes after pediatric OHCA., Design, Setting, and Participants: This cohort study included pediatric patients (<18 years) with OHCA treated by emergency medical services (EMS) from April 2011 to June 2015. Eligible patients were identified from the Resuscitation Outcomes Consortium Epidemiologic Registry, a prospective OHCA registry at 10 sites in the US and Canada. Data analysis was performed from May 2021 to January 2023., Exposures: The main exposures were prehospital intravenous or intraosseous epinephrine administration and the interval between arrival of an advanced life support (ALS)-capable EMS clinician (ALS arrival) and the first administration of epinephrine., Main Outcomes and Measures: The primary outcome was survival to hospital discharge. Patients who received epinephrine at any given minute after ALS arrival were matched with patients who were at risk of receiving epinephrine within the same minute using time-dependent propensity scores calculated from patient demographics, arrest characteristics, and EMS interventions., Results: Of 1032 eligible individuals (median [IQR] age, 1 [0-10] years), 625 (60.6%) were male. 765 patients (74.1%) received epinephrine and 267 (25.9%) did not. The median (IQR) time interval between ALS arrival and epinephrine administration was 9 (6.2-12.1) minutes. In the propensity score-matched cohort (1432 patients), survival to hospital discharge was higher in the epinephrine group compared with the at-risk group (epinephrine: 45 of 716 [6.3%] vs at-risk: 29 of 716 [4.1%]; risk ratio, 2.09; 95% CI, 1.29-3.40). The timing of epinephrine administration was also not associated with survival to hospital discharge after ALS arrival (P for the interaction between epinephrine administration and time to matching = .34)., Conclusions and Relevance: In this study of pediatric patients with OHCA in the US and Canada, epinephrine administration was associated with survival to hospital discharge, while timing of the administration was not associated with survival.

Purpose: There are conflicting reports regarding radical cystectomy complication risk from obesity subcategories, and a BMI threshold below which complication risk is notably reduced is undefined. A BMI threshold may be helpful in prehabilitation to aid patient counseling and inform weight loss strategies to potentially mitigate obesity-associated complication risk. This study aims to identify such a threshold and further investigate the association between BMI subcategories and perioperative complications from radical cystectomy., Materials and Methods: Data were extracted from the Canadian Bladder Cancer Information System, a prospective registry across 14 academic centers. Five hundred and eighty-nine patients were analyzed. Perioperative (≤90 days) complications were compared between BMI subcategories. Unconditional multivariable logistic regression and cubic spline analysis were performed to determine the association between BMI and complication risk and identify a BMI threshold., Results: Perioperative complications were reported in 51 (30%), 97 (43%), and 85 (43%) normal, overweight, and obese patients ( P = . 02). BMI was independently associated with developing any complication (OR 1.04 95% CI 1.01, 1.07). Predicted complication risk began to rise consistently above a BMI threshold of 34 kg/m 2 . Both overweight (OR 2.00 95% CI 1.26-3.17) and obese (OR 1.98 95% CI 1.24-3.18) patients had increased risk of complications compared to normal BMI patients., Conclusions: Complication risk from radical cystectomy is independently associated with BMI. Both overweight and obese patients are at increased risk compared to normal BMI patients. A BMI threshold of 34 kg/m 2 has been identified, which may inform prehabilitation treatment strategies.

Background: Tranexamic acid is frequently reported to reduce bleeding-related complications in major surgery and trauma. We aimed to investigate whether tranexamic acid reduced hematoma size after percutaneous kidney biopsy., Methods: We conducted a double-blind, parallel three-group, randomized placebo-controlled trial at a teaching hospital in Japan between January 2016 and July 2018. Adult patients with clinical indication for ultrasound-guided percutaneous biopsy of a native kidney were included. Participants were randomly assigned into three groups: high-dose tranexamic acid (1,000 mg in total), low-dose tranexamic acid (500 mg in total), or placebo (counterpart saline). Intervention drugs were intravenously administered twice, as a bolus just before the biopsy and as a continuous infusion initiated just after the biopsy. Primary outcome was post-biopsy perirenal hematoma size as measured by ultrasound on the morning after the biopsy., Results: We assessed 90 adult patients for study eligibility, of whom 56 were randomly allocated into the three groups: 20 for high-dose tranexamic acid, 19 for low-dose tranexamic acid, and 17 for placebo. The median size of perirenal hematoma was 200 mm2 (interquartile range, 21-650) in the high-dose tranexamic acid group, 52 mm2 (0-139) in the low-dose tranexamic acid group, and 0 mm2 (0-339) in the placebo group (p = 0.048 for high-dose tranexamic acid vs. placebo)., Conclusion: In this trial, the median size of post-kidney biopsy hematoma was unexpectedly larger in the high-dose tranexamic acid group than in the placebo group. Although our results do not support the routine use of tranexamic acid in percutaneous kidney biopsy at present, further studies are needed to confirm the results., (© 2022 S. Karger AG, Basel.)

Background: True recovery, in which a stroke patient regains the same precise motor skills observed in prestroke conditions, is the fundamental goal of rehabilitation training. However, a transient drop in task performance during rehabilitation training after stroke, observed in human clinical outcome as well as in both macaque and squirrel monkey retrieval data, might prevent smooth transitions during recovery. This drop, i.e., recovery valley, often occurs during the transition from compensatory skill to precision skill. Here, we sought computational mechanisms behind such transitions and recovery. Analogous to motor skill learning, we considered that the motor recovery process is composed of spontaneous recovery and training-induced recovery. Specifically, we hypothesized that the interaction of these multiple skill update processes might determine profiles of the recovery valley., Methods: A computational model of motor recovery was developed based on a state-space model of motor learning that incorporates a retention factor and interaction terms for training-induced recovery and spontaneous recovery. The model was fit to previously reported macaque motor recovery data where the monkey practiced precision grip skills after a lesion in the sensorimotor area in the cortex. Multiple computational models and the effects of each parameter were examined by model comparisons based on information criteria and sensitivity analyses of each parameter., Result: Both training-induced and spontaneous recoveries were necessary to explain the behavioral data. Since these two factors contributed following logarithmic function, the training-induced recovery were effective only after spontaneous biological recovery had developed. In the training-induced recovery component, the practice of the compensation also contributed to recovery of the precision grip skill as if there is a significant generalization effect of learning between these two skills. In addition, a retention factor was critical to explain the recovery profiles., Conclusions: We found that spontaneous recovery, training-induced recovery, retention factors, and interaction terms are crucial to explain recovery and recovery valley profiles. This simulation-based examination of the model parameters provides suggestions for effective rehabilitation methods to prevent the recovery valley, such as plasticity-promoting medications, brain stimulation, and robotic rehabilitation technologies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Izawa, Higo and Murata.)

Background: An association between post-arrest hyperoxaemia and worse outcomes has been reported for out-of-hospital cardiac arrest (OHCA) patients, but little is known about the relationship between intra-arrest hyperoxaemia and clinically relevant outcomes. This study aimed to investigate the association between intra-arrest hyperoxaemia and outcomes for OHCA patients., Methods: This was an observational study using a registry database of OHCA cases that occurred between 2014 and 2017 in Japan. We included adult, non-traumatic OHCA patients who were in cardiac arrest at the time of hospital arrival and for whom partial pressure of arterial oxygen (PaO 2 ) levels was measured during resuscitation. Main exposure was intra-arrest PaO 2 level, which was divided into three categories: hypoxaemia, PaO 2  < 60 mmHg; normoxaemia, 60-300; or hyperoxaemia, ≥300. Primary outcome was favourable functional survival at one month or at hospital discharge. Multivariable logistic regression was performed to adjust for clinically relevant variables., Results: Among 16,013 patients who met the eligibility criteria, the proportion of favourable functional survival increased as the PaO 2 categories became higher: 0.5 % (57/11,484) in hypoxaemia, 1.1 % (48/4243) in normoxaemia, and 5.2 % (15/286) in hyperoxaemia (p-value for trend < 0.001). Higher PaO 2 categories were associated with favourable functional survival and the adjusted odds ratios increased as the PaO 2 categories became higher: 2.09 (95 % CI: 1.39-3.14) in normoxaemia and 5.04 (95 % CI: 2.62-9.70) in hyperoxaemia when compared to hypoxaemia as a reference., Conclusion: In this observational study of adult OHCA patients, intra-arrest normoxaemia and hyperoxaemia were associated with better functional survival, compared to hypoxaemia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Cardiac surgery is performed worldwide. Most types of cardiac surgery are performed using cardiopulmonary bypass (CPB). Cardiac surgery performed with CPB is associated with morbidities. CPB needs an extracorporeal circulation that replaces the heart and lungs, and performs circulation, ventilation, and oxygenation of the blood. The lower limit of mean blood pressure to maintain blood flow to vital organs increases in people with chronic hypertension. Because people undergoing cardiac surgery commonly have chronic hypertension, we hypothesised that maintaining a relatively high blood pressure improves desirable outcomes among the people undergoing cardiac surgery with CPB., Objectives: To evaluate the benefits and harms of higher versus lower blood pressure targets during cardiac surgery with CPB., Search Methods: We used standard, extensive Cochrane search methods. The latest search of databases was November 2021 and trials registries in January 2020., Selection Criteria: We included randomised controlled trials (RCTs) comparing a higher blood pressure target (mean arterial pressure 65 mmHg or greater) with a lower blood pressure target (mean arterial pressure less than 65 mmHg) in adults undergoing cardiac surgery with CPB., Data Collection and Analysis: We used standard Cochrane methods. Primary outcomes were 1. acute kidney injury, 2. cognitive deterioration, and 3. all-cause mortality. Secondary outcomes were 4. quality of life, 5. acute ischaemic stroke, 6. haemorrhagic stroke, 7. length of hospital stay, 8. renal replacement therapy, 9. delirium, 10. perioperative transfusion of blood products, and 11. perioperative myocardial infarction. We used GRADE to assess certainty of evidence., Main Results: We included three RCTs with 737 people compared a higher blood pressure target with a lower blood pressure target during cardiac surgery with CPB. A high blood pressure target may result in little to no difference in acute kidney injury (risk ratio (RR) 1.30, 95% confidence interval (CI) 0.81 to 2.08; I² = 72%; 2 studies, 487 participants; low-certainty evidence), cognitive deterioration (RR 0.82, 95% CI 0.45 to 1.50; I² = 0%; 2 studies, 389 participants; low-certainty evidence), and all-cause mortality (RR 1.33, 95% CI 0.30 to 5.90; I² = 49%; 3 studies, 737 participants; low-certainty evidence). No study reported haemorrhagic stroke. Although a high blood pressure target may increase the length of hospital stay slightly, we found no differences between a higher and a lower blood pressure target for the other secondary outcomes. We also identified one ongoing RCT which is comparing a higher versus a lower blood pressure target among the people who undergo cardiac surgery with CPB., Authors' Conclusions: A high blood pressure target may result in little to no difference in patient outcomes including acute kidney injury and mortality. Given the wide CIs, further studies are needed to confirm the efficacy of a higher blood pressure target among those who undergo cardiac surgery with CPB., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

The premotor cortex is traditionally known to be involved in motor preparation and execution. More recently, evidence from neuroscience research shows that the dorsal premotor cortex (PMd) is also involved in sensory error-based motor adaptation and that invasive brain stimulation on PMd can attenuate adaptation in monkeys. The present study examines if adaptation can be modulated noninvasively in humans. Twenty-five healthy volunteers participated in a motor task in which rapid arm-reaching movements were made to hit a target, whereas the online cursor feedback about the hand position was visually rotated, inducing sensory error that drove motor adaptation. Transcranial magnetic stimulation (TMS) was delivered to PMd just before experiencing a sensory error, as in the previous study on monkeys. The degree of motor adaptation was measured as the change in the hand direction in response to the experienced error. TMS was found to increase adaptation compared with control conditions. Interestingly, the direction of modulation was opposite to the previous study on monkeys, which might originate from different methods and parameters of stimulation. The effect was also location-specific and was not a mere artifact of applying TMS because the facilitatory modulation occurred when stimulating PMd but not when stimulating the ventral premotor cortex, which was known for different roles and networks from PMd. Since noninvasive neuromodulation is a promising tool for research and clinical practice, the present study demonstrates that PMd is a feasible target region of neuromodulation to understand human motor adaptation and improve motor rehabilitation., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Model-based reinforcement learning enables an agent to learn in variable environments and tasks by optimizing its actions based on the predicted states and outcomes. This mechanism has also been considered in the brain. However, exactly how the brain selects an appropriate model for confronting environments has remained unclear. Here, we investigated the model selection algorithm in the human brain during a reinforcement learning task. One primary theory of model selection in the brain is based on sensory prediction errors. Here, we compared this theory with an alternative possibility of internal model selection with reward prediction errors. To compare these two theories, we devised a switching experiment from a first-order Markov decision process to a second-order Markov decision process that provides either reward- or sensory prediction error regarding environmental change. We tested two representative computational models driven by different prediction errors. One is the sensory prediction-error-driven Bayesian algorithm, which has been discussed as a representative internal model selection algorithm in the animal reinforcement learning task. The other is the reward-prediction-error-driven policy gradient algorithm. We compared the simulation results of these two computational models with human reinforcement learning behaviors. The model fitting result supports that the policy gradient algorithm is preferable to the Bayesian algorithm. This suggests that the human brain employs the reward prediction error to select an appropriate internal model in the reinforcement learning task., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Elevated perioperative heart rate potentially causes perioperative myocardial injury because of imbalance in oxygen supply and demand. However, large multicenter studies evaluating early postoperative heart rate and major adverse cardiac and cerebrovascular events (MACCEs) are lacking., Objective: To assess the associations of 4 postoperative heart rate assessment methods with in-hospital MACCEs after elective coronary artery bypass grafting (CABG)., Methods: Using data from the eICU Collaborative Research Database in the United States from 2014 to 2015, the study evaluated postoperative heart rate measured during hospitalization within 24 hours after intensive care unit admission. Four heart rate assessment methods were evaluated: maximum heart rate, duration above heart rate 100/min, area above heart rate 100/min, and time-weighted average heart rate. The outcome was in-hospital MACCEs, defined as a composite of in-hospital death, myocardial infarction, angina, arrhythmia, heart failure, stroke, cardiac arrest, or repeat revascularization., Results: Among 2585 patients, the crude rate of in-hospital MACCEs was 6.2%. In multivariable logistic regression analysis, the adjusted odds ratios (95% CI) for in-hospital MAC-CEs assessed by maximum heart rate in each heart rate category (beats per minute: >100-110, >110-120, >120-130, and >130) were 1.43 (0.95-2.15), 0.98 (0.56-1.64), 1.47 (0.76-2.69), and 1.71 (0.80-3.35), respectively. Similarly, none of the other 3 methods were associated with MACCEs., Conclusions: More research is needed to assess the usefulness of heart rate measurement in patients after CABG., (©2022 American Association of Critical-Care Nurses.)

The redundancy inherent to the human body is a central problem that must be solved by the brain when acquiring new motor skills. The problem of redundancy becomes particularly critical when learning a new motor policy from scratch in a novel environment and task (i.e., de novo learning). It has been proposed that motor variability could be leveraged to explore and identify task-potent motor commands, and recent results indicated a possible role of motor exploration in error-based motor learning, including in de novo learning tasks. However, the precise computational mechanisms underlying this role remain poorly understood. A new controller in a de novo motor task can potentially be learned by first using motor exploration to learn a sensitivity derivative, which can transform observed task errors into motor corrections, enabling the error-based learning of the controller. Although this approach has been discussed, the computational properties of exploration and how this mechanism can explain recent reports of motor exploration in error-based de-novo learning have not been thoroughly examined. Here, we used this approach to simulate the tasks used in several recent studies of human motor learning tasks in which motor exploration was observed, and replicating their main results. Analyses of the proposed learning mechanism using equations and simulations suggested that exploring the entire motor command space leads to the training of an efficient sensitivity derivative, enabling rapid learning of the controller, in visuomotor adaptation and de novo tasks. The successful replication of previous experimental results elucidated the role of motor exploration in motor learning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Little is known about the effect of prehospital epinephrine administration in out-of-hospital cardiac arrest (OHCA) patients with refractory shockable rhythm, for whom initial defibrillation was unsuccessful., Methods and Results: This study using Japanese nationwide population-based registry included all adult OHCA patients aged ≥18 years with refractory shockable rhythm between January 2014 and December 2017. Patients with or without epinephrine during cardiac arrest were sequentially matched using a risk set matching based on the time-dependent propensity scores within the same minute. The primary outcome was 1-month survival. The secondary outcomes included 1-month survival with favourable neurological outcome (cerebral performance category scale: 1 or 2) and prehospital return of spontaneous circulation (ROSC). Of the 499 944 patients registered in the database during the study period, 22 877 were included. Among them, 8467 (37.0%) received epinephrine. After time-dependent propensity score-sequential matching, 16 798 patients were included in the matched cohort. In the matched cohort, positive associations were observed between epinephrine and 1-month survival [epinephrine: 17.3% (1454/8399) vs. no epinephrine: 14.6% (1224/8399); RR 1.22 (95% confidence interval, CI: 1.13-1.32)] and prehospital ROSC [epinephrine: 22.2% (1868/8399) vs. no epinephrine: 10.7% (900/8399); RR 2.07 (95% CI: 1.91-2.25)]. No significant positive association was observed between epinephrine and favourable neurological outcome [epinephrine: 7.8% (654/8399) vs. no epinephrine: 7.1% (611/8399); RR 1.13 (95% CI 0.998-1.27)]., Conclusion: Using the nationwide population-based registry with time-dependent propensity score-sequential matching analysis, prehospital epinephrine administration in adult OHCA patients with refractory shockable rhythm was positively associated with 1-month survival and prehospital ROSC., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021.)

Study Objective: While often prioritized in the resuscitation of patients with out-of-hospital cardiac arrest, the optimal timing of advanced airway insertion is unknown. We evaluated the association between the timing of advanced airway (laryngeal tube and endotracheal intubation) insertion attempt and survival to hospital discharge in adult out-of-hospital cardiac arrest., Methods: We performed a secondary analysis of the Pragmatic Airway Resuscitation Trial (PART), a clinical trial comparing the effects of laryngeal tube and endotracheal intubation on outcomes after adult out-of-hospital cardiac arrest. We stratified the cohort by randomized airway strategy (laryngeal tube or endotracheal intubation). Within each subset, we defined a time-dependent propensity score using patients, arrest, and emergency medical services systems characteristics. Using the propensity score, we matched each patient receiving an initial attempt of laryngeal tube or endotracheal intubation with a patient at risk of receiving laryngeal tube or endotracheal intubation attempt within the same minute., Results: Of 2,146 eligible patients, 1,091 (50.8%) and 1,055 (49.2%) were assigned to initial laryngeal tube and endotracheal intubation strategies, respectively. In the propensity score-matched cohort, timing of laryngeal tube insertion attempt was not associated with survival to hospital discharge: 0 to lesser than 5 minutes (risk ratio [RR]=1.35, 95% confidence interval [CI] 0.53 to 3.44); 5 to lesser than10 minutes (RR=1.07, 95% CI 0.66 to 1.73); 10 to lesser than 15 minutes (RR=1.17, 95% CI 0.60 to 2.31); or 15 to lesser than 20 minutes (RR=2.09, 95% CI 0.35 to 12.47) after advanced life support arrival. Timing of endotracheal intubation attempt was also not associated with survival: 0 to lesser than 5 minutes (RR=0.50, 95% CI 0.05 to 4.87); 5 to lesser than10 minutes (RR=1.20, 95% CI 0.51 to 2.81); 10 to lesser than15 minutes (RR=1.03, 95% CI 0.49 to 2.14); 15 to lesser than 20 minutes (RR=0.85, 95% CI 0.30 to 2.42); or more than/equal to 20 minutes (RR=0.71, 95% CI 0.07 to 7.14)., Conclusion: In the PART, timing of advanced airway insertion attempt was not associated with survival to hospital discharge., (Copyright © 2021 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)