OBJECTIVE: Endovascular therapy (EVT) is the most successful treatment for patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) in the anterior circulation. However, futile recanalization (FR) seriously affects the prognosis of these patients. The aim of this study was to investigate predictors of FR after EVT in patients with AIS.
METHODS: Patients diagnosed with AIS due to anterior circulation LVO and receiving EVT between June 2020 and October 2022 were prospectively enrolled. FR after EVT was defined as a poor 90-day prognosis (modified Rankin Scale [mRS] score ≥ 3) despite achieving successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] classification of 2b-3). All included patients were categorized into control group (mRS score < 3) and FR group (mRS score ≥ 3). Demographic characteristics, comorbidities (hypertension, diabetes, atrial fibrillation, smoking, etc.), stroke-specific data (NIHSS score, ASPECT score and site of occlusion), procedure data (treatment type [direct thrombectomy vs. bridging thrombectomy], degree of vascular recanalization [mTICI], procedure duration time and onset-recanalization time), laboratory indicators (lymphocytes count, neutrophils count, monocytes count, C-reactive protein, neutrophil-to-lymphocyte ratio [NLR], monocyte-to-high-density lipoprotein ratio [MHR], lymphocyte-to-monocyte ratio [LMR], lymphocyte-to-C-reactive protein ratio [LCR], lymphocyte-to-high-density lipoprotein ratio[LHR], total cholesterol and triglycerides.) were compared between the two groups. Multivariate logistic regression analysis was performed to explore independent predictors of FR after EVT.
RESULTS: A total of 196 patients were included in this study, among which 57 patients were included in the control group and 139 patients were included in the FR group. Age, proportion of patients with hypertension and diabetes mellitus, median NIHSS score, CRP level, procedure duration time, neutrophil count and NLR were higher in the FR group than in the control group. Lymphocyte count, LMR, and LCR were lower in the FR group than in the control group. There were no significant differences in platelet count, monocytes count, total cholesterol, triglycerides, HDL, LDL, gender, smoking, atrial fibrillation, percentage of occluded sites, onset-recanalization time, ASPECT score and type of treatment between the two groups. Multivariate logistic regression analysis demonstrated that NLR was independently associated with FR after EVT (OR = 1.37, 95%CI = 1.005-1.86, P = 0.046).
CONCLUSIONS: This study demonstrated that high NLR was associated with a risk of FR in patients with AIS due to anterior circulation LVO. These findings may help clinicians determine which patients with AIS are at higher risk of FR after EVT. Our study can provide a theoretical basis for interventions in the aforementioned population.

To investigate if a prospective feedback loop that flags older patients at risk of death can reduce non-beneficial treatment at end of life.
Prospective stepped-wedge cluster randomised trial with usual care and intervention phases.
Three large tertiary public hospitals in south-east Queensland, Australia.
14 clinical teams were recruited across the three hospitals. Teams were recruited based on a consistent history of admitting patients aged 75+ years, and needed a nominated lead specialist consultant. Under the care of these teams, there were 4,268 patients (median age 84 years) who were potentially near the end of life and flagged at risk of non-beneficial treatment.
The intervention notified clinicians of patients under their care determined as at-risk of non-beneficial treatment. There were two notification flags: a real-time notification and an email sent to clinicians about the at-risk patients at the end of each screening day. The nudge intervention ran for 16-35 weeks across the three hospitals.
The primary outcome was the proportion of patients with one or more intensive care unit (ICU) admissions. The secondary outcomes examined times from patients being flagged at-risk.
There was no improvement in the primary outcome of reduced ICU admissions (mean probability difference [intervention minus usual care] = -0.01, 95% confidence interval -0.08 to 0.01). There were no differences for the times to death, discharge, or medical emergency call. There was a reduction in the probability of re-admission to hospital during the intervention phase (mean probability difference -0.08, 95% confidence interval -0.13 to -0.03).
This nudge intervention was not sufficient to reduce the trial\'s non-beneficial treatment outcomes in older hospital patients.
Australia New Zealand Clinical Trial Registry, ACTRN12619000675123 (registered 6 May 2019).

BACKGROUND: Clinical trials often involve some form of interim monitoring to determine futility before planned trial completion. While many options for interim monitoring exist (e.g., alpha-spending, conditional power), nonparametric based interim monitoring methods are also needed to account for more complex trial designs and analyses. The upstrap is one recently proposed nonparametric method that may be applied for interim monitoring.
METHODS: Upstrapping is motivated by the case resampling bootstrap and involves repeatedly sampling with replacement from the interim data to simulate thousands of fully enrolled trials. The p-value is calculated for each upstrapped trial and the proportion of upstrapped trials for which the p-value criteria are met is compared with a pre-specified decision threshold. To evaluate the potential utility for upstrapping as a form of interim futility monitoring, we conducted a simulation study considering different sample sizes with several different proposed calibration strategies for the upstrap. We first compared trial rejection rates across a selection of threshold combinations to validate the upstrapping method. Then, we applied upstrapping methods to simulated clinical trial data, directly comparing their performance with more traditional alpha-spending and conditional power interim monitoring methods for futility.
RESULTS: The method validation demonstrated that upstrapping is much more likely to find evidence of futility in the null scenario than the alternative across a variety of simulations settings. Our three proposed approaches for calibration of the upstrap had different strengths depending on the stopping rules used. Compared to O\'Brien-Fleming group sequential methods, upstrapped approaches had type I error rates that differed by at most 1.7% and expected sample size was 2-22% lower in the null scenario, while in the alternative scenario power fluctuated between 15.7% lower and 0.2% higher and expected sample size was 0-15% lower.
CONCLUSIONS: In this proof-of-concept simulation study, we evaluated the potential for upstrapping as a resampling-based method for futility monitoring in clinical trials. The trade-offs in expected sample size, power, and type I error rate control indicate that the upstrap can be calibrated to implement futility monitoring with varying degrees of aggressiveness and that performance similarities can be identified relative to considered alpha-spending and conditional power futility monitoring methods.

Pediatric surgeons need to learn to give as much importance to the ethical approach as they have been giving to the systemic methodology in their clinical approach all along. The law of the land and the governmental rules also need to be kept in mind before deciding the final solution. They need to always put medical problems in the background of ethical context, reach a few solutions keeping in mind the available resources, and apply the best solution in the interest of their pediatric patients.

BACKGROUND: Advance Directive documents allow citizens to choose the treatments they want for end-of-life care without considering therapeutic futility.
OBJECTIVE: To analyze patients\' and caregivers\' answers to Advance Directives and understand their expectations regarding their decisions.
METHODS: This study analyzed participants\' answers to a previously published trial, conceived to test the document\'s efficacy as a communication tool.
METHODS: Sixty palliative patients and 60 caregivers (n = 120) registered their preferences in the Advance Directive document and expressed their expectations regarding whether to receive the chosen treatments.
RESULTS: In the patient and caregiver groups, 30% and 23.3% wanted to receive cardiorespiratory resuscitation; 23.3% and 25% wanted to receive artificial organ support; and 40% and 35% chose to receive artificial feeding and hydration, respectively. The participants ignored the concept of therapeutic futility and expected to receive invasive treatments. The concept of therapeutic futility should be addressed and discussed with both the patients and caregivers. Legal Advanced Directive documents should be made clear to reduce misinterpretations and potential legal conflicts.
CONCLUSIONS: The authors suggest that all citizens should be clarified regarding the futility concept before filling out the Advance Directives and propose a grammatical change in the document, replacing the phrase \"Health Care to Receive / Not to Receive\" with the sentence \"Health Care to Accept / Refuse\" so that patients cannot demand treatments, but instead accept or refuse the proposed therapeutic plans.
BACKGROUND: ClinicalTrials.gov ID NCT05090072.
UNASSIGNED: https://clinicaltrials.gov/ct2/show/NCT05090072.

The rise in intensive care treatment procedures is accompanied by an increase in the complexity of decisions regarding the selection, administration and duration of treatment measures. Whether a treatment goal is desirable in an individual case and the treatment plan required to achieve it is acceptable for the patient depends on the patient\'s preferences, values and life plans. There is often uncertainty as to whether a patient-centered treatment goal can be achieved. The use of a time-limited treatment trial (TLT) as a binding agreement between the intensive care unit (ICU) team and the patient or their legal representative on a treatment concept over a defined period of time in the ICU can be helpful to reduce uncertainties and to ensure the continuation of intensive care measures in the patients\' best interest.
UNASSIGNED: Die Zunahme der intensivmedizinischen Behandlungsverfahren ist mit einer Steigerung der Komplexität der Entscheidungen über Auswahl, Anwendung und Dauer der Therapiemaßnahmen verbunden. Ob im individuellen Fall ein Behandlungsziel erstrebenswert und der dafür notwendige Behandlungsweg akzeptabel ist, hängt von den persönlichen Wünschen, Werthaltungen und Lebensentwürfen der Patientinnen und Patienten ab. Häufig bestehen Unsicherheiten darüber, ob ein patientenzentriertes Behandlungsziel erreicht werden kann. Der Einsatz eines zeitlich begrenzten Therapieversuches (TLT) als eine verbindliche Übereinkunft zwischen dem Behandlungsteam und der Patientin/dem Patienten bzw. dem juristischen Stellvertretenden zu einem Behandlungskonzept über einen definierten Zeitraum auf der Intensivstation kann hilfreich sein, um Unsicherheiten zu reduzieren und die Fortführung intensivmedizinischer Maßnahmen im Sinne des/der Patient/in besser einordnen und rechtfertigen zu können.

UNASSIGNED: Potentially inappropriate treatment in critically ill adults is associated with healthcare provider distress and burnout. Knowledge regarding perceived potentially inappropriate treatment amongst pediatric healthcare providers is limited.
UNASSIGNED: Determine the frequency and factors associated with potentially inappropriate treatment in critically ill children as perceived by providers, and describe the factors that providers report contribute to the distress they experience when providing treatment perceived as potentially inappropriate.
UNASSIGNED: Prospective observational mixed-methods study in a single tertiary level PICU conducted between March 2 and September 14, 2018. Patients 0-17 years inclusive with: (1) ≥1 organ system dysfunction (2) moderate to severe mental and physical disabilities, or (3) baseline dependence on medical technology were enrolled if they remained admitted to the PICU for ≥48 h, and were not medically fit for transfer/discharge. The frequency of perceived potentially inappropriate treatment was stratified into three groups based on degree of consensus (1, 2 or 3 providers) regarding the appropriateness of ongoing active treatment per enrolled patient. Distress was self-reported using a 100-point scale.
UNASSIGNED: Of 374 patients admitted during the study, 133 satisfied the inclusion-exclusion criteria. Eighteen patients (unanimous - 3 patients, 2 providers - 7 patients; single provider - 8 patients) were perceived as receiving potentially inappropriate treatment; unanimous consensus was associated with 100% mortality on 3-month follow up post PICU discharge. Fifty-three percent of providers experienced distress secondary to providing treatment perceived as potentially inappropriate. Qualitative thematic analysis revealed five themes regarding factors associated with provider distress: (1) suffering including a sense of causing harm, (2) conflict, (3) quality of life, (4) resource utilization, and (5) uncertainty.
UNASSIGNED: While treatment perceived as potentially inappropriate was infrequent, provider distress was commonly observed. By identifying specific factor(s) contributing to perceived potentially inappropriate treatment and any associated provider distress, organizations can design, implement and assess targeted interventions.

Seamless phase 2/3 design has become increasingly popular in clinical trials with a single endpoint. Trials that define success based on the achievement of all co-primary endpoints (CPEs) encounter the challenge of inflated type 2 error rates, often leading to an overly large sample size. To tackle this challenge, we introduced a seamless phase 2/3 design strategy that employs Bayesian predictive power (BPP) for futility monitoring and sample size re-estimation at interim analysis. The correlations among multiple CPEs are incorporated using a Dirichlet-multinomial distribution. An alternative approach based on conditional power (CP) was also discussed for comparison. A seamless phase 2/3 vaccine trial employing four binary endpoints under the non-inferior hypothesis serves as an example. Our results spotlight that, in scenarios with relatively small phase 2 sample sizes (e.g., 50 or 100 subjects), the BPP approach either outperforms or matches the CP approach in terms of overall power. Particularly, with n1 = 50 and ρ = 0, BPP showcases an overall power advantage over CP by as much as 8.54%. Furthermore, when the phase 2 stage enrolled more subjects (e.g., 150 or 200), especially with a phase 2 sample size of 200 and ρ = 0, the BPP approach evidences a peak difference of 5.76% in early stop probability over the CP approach, emphasizing its better efficiency in terminating futile trials. It\'s noteworthy that both BPP and CP methodologies maintained type 1 error rates under 2.5%. In conclusion, the integration of the Dirichlet-Multinominal model with the BPP approach offers improvement in certain scenarios over the CP approach for seamless phase 2/3 trials with multiple CPEs.

TP 53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are among the most lethal malignancies, characterized by dismal outcomes with currently available therapies. Allogeneic hematopoietic cell transplantation (allo-HCT) is widely thought to be the only treatment option to offer durable disease control. However, outcomes with allo-HCT in this context are quite poor, calling into question the utility of transplantation. In this review, we summarize the latest data on allo-HCT outcomes in this subgroup, evaluating the limitations of available evidence; we review the molecular heterogeneity of this disease, delineating outcomes based on distinct biological features to aid in patient selection; and we critically examine whether allo-HCT should be routinely applied in this disease on the basis of currently available data. We propose that the exceptionally poor outcomes of patients with TP53-mutated MDS/AML with biallelic loss and/or adverse-risk cytogenetics should motivate randomized-controlled trials of HCT vs non-HCT to determine whether transplantation can prolong survival and/or positively impact other clinically relevant outcomes such as patient-reported outcomes or healthcare resource utilization in this disease subset. Without dedicated prospective randomized trials, selecting who may actually derive benefit from allo-HCT for TP53-mutated MDS/AML can be described as ambiguous guesswork and must be carefully contemplated.

Under the Global Methane Pledge, Canada is developing oil and gas sector methane regulations targeting 75% reductions from 2012 levels by 2030. Without measured baselines and inventories, such policies are ultimately unverifiable and unenforceable. Using the major oil and gas producing province of Saskatchewan as a case study, we derive first-ever measurement-based methane inventories for the region and comprehensively model previous emissions back to the 2012 baseline. Although relative reductions of 23-69% have likely occurred, the dispersion of modeled possibilities and the high emissions from continuing production illustrate the limits of this approach as a meaningful policy metric. Moreover, nearly 90% of apparent reductions are explained by decreased production at heavy oil facilities, suggesting emissions have potential to rebound if production resumes. By contrast, derived measurement-based methane emissions intensities facilitate quantitative assessment and show that despite any past reductions, Saskatchewan\'s 0.41 ± 0.03 g/MJ intensity remains among the highest in North America. This highlights how relative reduction targets absent measured baselines and inventories are inherently futile and risk rewarding high emitters while obscuring ongoing mitigation potential. Ultimately, required global methane reductions will only be achieved by adopting objectively and independently verifiable emission metrics while measuring and tracking progress toward a net zero future.