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BackgroundLarge vessel recanalization (LVR) before endovascular therapy (EVT) for acute large vessel ischemic strokes is a poorly understood phenomenon. Better understanding of predictors for LVR is important for optimizing stroke triage and patient selection for bridging thrombolysis.MethodsIn this retrospective cohort study, consecutive patients presenting to a comprehensive stroke center for EVT treatment were identified from 2018 to 2022. Demographic information, clinical characteristics, intravenous thrombolysis (IVT) use, and LVR before EVT were recorded. Factors independently associated with different rates of LVR were identified, and a prediction model for LVR was constructed.Results640 patients were identified. 57 (8.9%) patients had LVR before EVT. A minority (36.4%) of LVR patients had significant improvements in National Institutes of Health Stroke Scale. Independent predictors for LVR were identified and used to construct the 8-point HALT score: hyperlipidemia (1 point), atrial fibrillation (1 point), location of vascular occlusion (internal carotid: 0 points, M1: 1 point, M2: 2 points, vertebral/basilar: 3 points), and thrombolysis at least 1.5 hours before angiography (3 points). The HALT score had an area under the receiver-operating curve (AUC) of 0.85 (95% CI 0.81 to 0.90, P<0.001) for predicting LVR. LVR before EVT occurred in only 1 of 302 patients (0.3%) with low (0–2) HALT scores.ConclusionsIVT at least 1.5 hours before angiography, site of vascular occlusion, atrial fibrillation, and hyperlipidemia are independent predictors for LVR. The 8-point HALT score proposed in this study may be a valuable tool for predicting LVR before EVT.

Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in ALS–FTD, including in presymptomatic C9orf72mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS–FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS–FTD, including in presymptomatic C9orf72mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials.

Although many machine learning methods, especially from the field of deep learning, have been instrumental in addressing challenges within robotic applications, we cannot take full advantage of such methods before these can provide performance and safety guarantees. The lack of trust that impedes the use of these methods mainly stems from a lack of human understanding of what exactly machine learning models have learned, and how robust their behaviour is. This is the problem the field of explainable artificial intelligence aims to solve. Based on insights from the social sciences, we know that humans prefer contrastive explanations, i.e. explanations answering the hypothetical question “what if?”.In this paper, we show that linear model trees are capable of producing answers to such questions, so-called counterfactual explanations, for robotic systems, including in the case of multiple, continuous inputs and outputs. We demonstrate the use of this method to produce counterfactual explanations for two robotic applications. Additionally, we explore the issue of infeasibility, which is of particular interest in systems governed by the laws of physics.

BackgroundHigh levels of platelet inhibition have been associated with hemorrhagic complications following Pipeline embolization of intracranial aneurysms. We therefore titrate clopidogrel dosing to maintain a moderate level of platelet inhibition using the VerifyNow P2Y12 assay. However, many patients demonstrate dramatic increases in platelet inhibition following treatment despite being on a consistent antiplatelet regimen. We therefore elected to explore the incidence of this phenomenon and possible predisposing factors.MethodsAll successful Pipeline aneurysm treatments performed at our institution from 2011 to 2019 with moderate procedure-day platelet inhibition levels as indicated by a VerifyNow PRU of 60–235 were included. Patients who received glycoprotein IIb/IIIa inhibitors and those treated for ruptured/symptomatic lesions were excluded. The incidence of excessive platelet inhibition defined by a PRU<60 within 8 weeks of treatment was noted. Multivariable logistic regression was performed to determined independent predictors of the phenomenon.ResultsSome 190 treatments were performed in 178 qualifying patients. A post-procedure PRU <60 occurred following 79% of treatments, documented on average after 8.5 (range 1–47) days. A higher procedure day hematocrit level (P=0.003, OR 1.09, 95% CI 1.029 to 1.152) was an independent predictor of reaching a PRU <60, while intra-procedural midazolam exposure (P=0.044, OR 0.44, 95% CI 0.201 to 0.980) and a higher procedure-day PRU (P=0.047, OR 0.99, 95% CI 0.982 to 1.000) were associated with a reduced odds. Time-since-procedure and hematocrit levels were associated with excessive platelet inhibition when excluding patients who initially demonstrated hyperresponse.ConclusionElevations in platelet inhibition were frequently observed following flow diversion with Pipeline.

IMPORTANCE: Clinical trial activity in amyotrophic lateral sclerosis (ALS) is dramatically increasing; as a result, trial modifications have been introduced to improve efficiency, outcome measures have been reassessed, and considerable discussion about the level of data necessary to advance a drug to approval has occurred. This review discusses what recent pivotal studies can teach the community about these topics. OBSERVATIONS: By restricting inclusion and exclusion criteria, recent trials have enrolled populations distinct from previous studies. This has led to efficacy signals being observed in studies that are smaller and shorter than was thought feasible previously. However, such trials raise questions about generalizability of results. Small trials with equivocal clinical results also raise questions about the data necessary to lead to regulatory approval. The ALS Functional Rating Scale–Revised remains the most commonly used primary outcome measure; this review discusses innovations in its use. Blood neurofilament levels can predict prognosis in ALS and may be a sensitive indicator of biologic effect; current knowledge does not yet support its use as a primary outcome. CONCLUSIONS AND RELEVANCE: It is now possible to use specific inclusion criteria to recruit a homogeneous patient population progressing at a specific rate; this will likely impact trials in the future. Generalizability of results on limited populations remains a concern. Although clinical outcomes remain the most appropriate primary outcome measures, fluid markers reflecting biologically important processes will assume more importance as more is learned about the association between such markers and clinical end points. The benefit of use of analytic strategies, such as responder analyses, is still uncertain.

A public–private partnership managed by the FNIH aims to address biological, manufacturing and regulatory challenges to the development of gene therapies for rare diseases.

The American Society of Colon and Rectal Surgeons (ASCRS) and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) are dedicated to ensuring high-quality innovative patient care for surgical patients by advancing the science, prevention, and management of disorders and diseases of the colon, rectum, and anus as well as minimally invasive surgery. The ASCRS and SAGES society members involved in the creation of these guidelines were chosen because they have demonstrated expertise in the specialty of colon and rectal surgery and enhanced recovery. This consensus document was created to lead international efforts in defining quality care for conditions related to the colon, rectum, and anus and develop clinical practice guidelines based on the best available evidence. While not proscriptive, these guidelines provide information on which decisions can be made and do not dictate a specific form of treatment. These guidelines are intended for the use of all practitioners, healthcare workers, and patients who desire information about the management of the conditions addressed by the topics covered in these guidelines. These guidelines should not be deemed inclusive of all proper methods of care nor exclusive of methods of care reasonably directed toward obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all the circumstances presented by the individual patient. This clinical practice guideline represents a collaborative effort between the American Society of Colon and Rectal Surgeons (ASCRS) and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and was approved by both societies.

The peripheral nerve contains diverse cell types that support its proper function and maintenance. In this study, we analyzed multiple peripheral nerves using single-nuclei RNA sequencing, which allowed us to circumvent difficulties encountered in analyzing cells with complex morphologies via conventional single-cell methods. The resultant mouse peripheral nerve cell atlas highlights a diversity of cell types, including multiple subtypes of Schwann cells (SCs), immune cells and stromal cells. We identified a distinct myelinating SC subtype that expresses Cldn14, Adamtsl1and Pmp2and preferentially ensheathes motor axons. The number of these motor-associated Pmp2+SCs is reduced in both an amyotrophic lateral sclerosis (ALS) SOD1G93Amouse model and human ALS nerve samples. Our findings reveal the diversity of SCs and other cell types in peripheral nerve and serve as a reference for future studies of nerve biology and disease.

BackgroundCoformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).ObjectiveDetermine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.MethodsAdults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation.ResultsRisk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO.ConclusionsEarly PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.Trial registration numberNCT03127514; NCT03488524.

At the dawn of a new decade and in the wake of the COVID-19 pandemic, the role of the sports medicine specialist is rapidly changing. For the orthopedic team physician, in particular, it is essential to understand and accept the evolving responsibilities necessary to optimize treatment outcomes and maintain the trust of the athletes to whom we provide care.The role of orthopedic team physicians has evolved greatly over the past decade having been influenced by advances in sports science and performance, new surgical and biologic technologies, social media, medicolegal liability, marketing, and sexual misconduct cases by some team physicians. The great variety of events and sports that are covered from high school and collegiate to the Olympic and professional levels requires a myriad of skills outside of the traditional medical training curriculum. In the current climate of increasing media scrutiny from a 24-h news cycle it is imperative for orthopedic team physicians, whether operative or nonoperative, to continually adapt to the needs and expectations of athletes who also are patients. This is especially true in the wake of the COVID-19 pandemic. Orthopedic team physicians' responsibilities continue to evolve ensuring their relevance and necessity on the sidelines and in the training room as well as in the operative suite.

AbstractSeveral recent formulations of Rule Consequentialism (RC) have broken with the consensus that RC should be formulated in terms of code acceptance, claiming instead that RC should focus on the consequences of codes' being taught. I begin this article with an examination of the standard case for acceptance formulations. In addition to depending on the mistaken assumption that complianceand acceptanceformulations are the only options, the standard case claims advantages for acceptance formulations that, upon closer examination, favor teaching formulations. In the remainder of the article, I defend this new teaching-centered approach against some recent criticisms. I argue that preoccupation with the somewhat technical problem of identifying the best criterion for making choices under conditions of uncertainty has distracted rule consequentialists from paying more careful attention to the advantages and disadvantages that result from decisions concerning where they locate RC's stipulated assumptions within the theory.

BackgroundThere is a paucity of data regarding mechanical thrombectomy (MT) in distal arterial occlusions (DAO). We aim to evaluate the safety and efficacy of MT in patients with DAO and compare their outcomes with proximal arterial occlusion (PAO) strokes.MethodsThe Trevo Registry was a prospective open-label MT registry including 2008 patients from 76 sites across 12 countries. Patients were categorized into: PAO: intracranial ICA, and MCA–M1; and DAO: MCA–M2, MCA–M3, ACA, and PCA. Baseline and outcome variables were compared across the PAO vs DAO patients with pre-morbid mRS 0–2.ResultsAmong 407 DAOs including 350 (86.0%) M2, 25 (6.1%) M3, 10 (2.5%) ACA, and 22 (5.4%) PCA occlusions, there were 376 DAO with pre-morbid mRS 0–2 which were compared with 1268 PAO patients. The median baseline NIHSS score was lower in DAO (13 [8–18] vs 16 [12–20], P<0.001). There were no differences in terms of age, sex, IV-tPA use, co-morbidities, or time to treatment across DAO vs PAO. The rates of post-procedure reperfusion, symptomatic intracranial hemorrhage (sICH), and 90-mortality were comparable between both groups. DAO showed significantly higher rates of 90-day mRS 0–2 (68.3% vs 56.5%, P<0.001). After adjustment for potential confounders, the level of arterial occlusion was not associated with the chances of excellent outcome (DAO for 90-day mRS 0–1: OR; 1.18, 95% CI [0.90 to 1.54], P=0.225), successful reperfusion or SICH. However, DAO patients were more likely to be functionally independent (mRS 0–2: OR; 1.45, 95% CI [1,09 to 1.92], P=0.01) or dead (OR; 1.54, 95% CI [1.06 to 2.27], P=0.02) at 90 days.ConclusionEndovascular therapy in DAO appears to result in a comparable safety and technical success profile as in PAO. The potential benefits of DAO thrombectomy should be investigated in future randomized trials.

BackgroundCatheter retention and difficulty in retrieval have been observed during embolization of brain arteriovenous malformations (bAVMs) with the Onyx liquid embolic system (Onyx). The Apollo Onyx delivery microcatheter (Apollo) is a single lumen catheter designed for controlled delivery of Onyx into the neurovasculature, with a detachable distal tip to aid catheter retrieval. This study evaluates the safety of the Apollo for delivery of Onyx during embolization of bAVMs.MethodsThis was a prospective, non-randomized, single-arm, multicenter, post-market study of patients with a bAVM who underwent Onyx embolization with the Apollo between May 2015 and February 2018. The primary endpoint was any catheter-related adverse event (AE) at 30 days, such as unintentional tip detachment or malfunction with clinical sequelae, or retained catheter. Procedure-related AEs (untoward medical occurrence, disease, injury, or clinical signs) and serious AEs (life threatening illness or injury, permanent physiological impairment, hospitalization, or requiring intervention) were also recorded.ResultsA total of 112 patients were enrolled (mean age 44.1±17.6 years, 56.3% men), and 201 Apollo devices were used in 142 embolization procedures. The mean Spetzler–Martin grade was 2.38. The primary endpoint was not observed (0/112, 0%). The catheter tip detached during 83 (58.5%) procedures, of which 2 (2.4%) were unintentional and did not result in clinical sequelae. At 30 days, procedure related AEs occurred in 26 (23.2%) patients, and procedure-related serious AEs in 12 (10.7%). At 12 months, there were 3 (2.7%) mortalities, including 2 (1.8%) neurological deaths, none of which were device-related.ConclusionThis study demonstrates the safety of Apollo for Onyx embolization of bAVMs.Clinical trial registrationCNCT02378883.

Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.

Some neurological complications following surgery have been related to a mismatch in cerebral oxygen supply and demand that may either lead to more subtle changes of brain function or overt complications like stroke or coma. Discovery of a perioperative neurological complication may be outside the treatment window, thereby making prevention an important focus. Early commercial devices used differential spectroscopy to measure relative changes from baseline of 2 chromophores: oxy- and deoxyhemoglobin. It was the introduction of spatially resolved spectroscopy techniques that allowed near-infrared spectroscopy (NIRS)–based cerebral oximetry as we know it today. Modern cerebral oximeters measure the hemoglobin saturation of blood in a specific “optical field” containing arterial, capillary, and venous blood, not tissue oxygenation itself. Multiple cerebral oximeters are commercially available, all of which have technical differences that make them noninterchangeable. The mechanism and meaning of these measurements are likely not widely understood by many practicing physicians. Additionally, as with many clinically used monitors, there is a lack of high-quality evidence on which clinicians can base decisions in their effort to use cerebral oximetry to reduce neurocognitive complications after surgery. Therefore, the Sixth Perioperative Quality Initiative (POQI-6) consensus conference brought together an international team of multidisciplinary experts including anesthesiologists, surgeons, and critical care physicians to objectively survey the literature on cerebral oximetry and provide consensus, evidence-based recommendations for its use in accordance with the GRading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria for evaluating biomedical literature. The group produced the following consensus recommendations: (1) interpreting perioperative cerebral oximetry measurements in the context of a preinduction baseline value; (2) interpreting perioperative cerebral oximetry measurements in the context of the physiologic variables that affect them; (3) using caution in comparing cerebral oximetry values between different manufacturers; (4) using preoperative cerebral oximetry to identify patients at increased risk of adverse outcomes after cardiac surgery; (5) using intraoperative cerebral oximetry indexed to preinduction baseline to identify patients at increased risk of adverse outcomes after cardiac surgery; (6) using cerebral oximetry to identify and guide management of acute cerebral malperfusion during cardiac surgery; (7) using an intraoperative cerebral oximetry–guided interventional algorithm to reduce intensive care unit (ICU) length of stay after cardiac surgery. Additionally, there was agreement that (8) there is insufficient evidence to recommend using intraoperative cerebral oximetry to reduce mortality or organ-specific morbidity after cardiac surgery; (9) there is insufficient evidence to recommend using intraoperative cerebral oximetry to improve outcomes after noncardiac surgery.

Postoperative delirium is a geriatric syndrome that manifests as changes in cognition, attention, and levels of consciousness after surgery. It occurs in up to 50% of patients after major surgery and is associated with adverse outcomes, including increased hospital length of stay, higher cost of care, higher rates of institutionalization after discharge, and higher rates of readmission. Furthermore, it is associated with functional decline and cognitive impairments after surgery. As the age and medical complexity of our surgical population increases, practitioners need the skills to identify and prevent delirium in this high-risk population. Because delirium is a common and consequential postoperative complication, there has been an abundance of recent research focused on delirium, conducted by clinicians from a variety of specialties. There have also been several reviews and recommendation statements; however, these have not been based on robust evidence. The Sixth Perioperative Quality Initiative (POQI-6) consensus conference brought together a team of multidisciplinary experts to formally survey and evaluate the literature on postoperative delirium prevention and provide evidence-based recommendations using an iterative Delphi process and Grading of Recommendations Assessment, Development and Evaluation (GRADE) Criteria for evaluating biomedical literature.

Electroencephalographic (EEG) monitoring to indicate brain state during anesthesia has become widely available. It remains unclear whether EEG-guided anesthesia influences perioperative outcomes. The sixth Perioperative Quality Initiative (POQI-6) brought together an international team of multidisciplinary experts from anesthesiology, biomedical engineering, neurology, and surgery to review the current literature and to develop consensus recommendations on the utility of EEG monitoring during anesthesia. We retrieved a total of 1023 articles addressing the use of EEG monitoring during anesthesia and conducted meta-analyses from 15 trials to determine the effect of EEG-guided anesthesia on the rate of unintentional awareness, postoperative delirium, neurocognitive disorder, and long-term mortality after surgery. After considering current evidence, the working group recommends that EEG monitoring should be considered as part of the vital organ monitors to guide anesthetic management. In addition, we encourage anesthesiologists to be knowledgeable in basic EEG interpretation, such as raw waveform, spectrogram, and processed indices, when using these devices. Current evidence suggests that EEG-guided anesthesia reduces the rate of awareness during total intravenous anesthesia and has similar efficacy in preventing awareness as compared with end-tidal anesthetic gas monitoring. There is, however, insufficient evidence to recommend the use of EEG monitoring for preventing postoperative delirium, neurocognitive disorder, or postoperative mortality.

Introduction The Sofia 6-French PLUS catheter is a recently approved aspiration catheter for use in neuro-endovascular procedures. The description of Sofia 6-French PLUS use in acute ischemic stroke is limited.Objective The purpose of this article is to describe our initial experience with the new Sofia 6-French PLUS catheter for treatment of acute ischemic stroke and to report on its safety and efficacy.Methods We performed a retrospective study of 54 thrombectomy cases treated with the Sofia 6-French PLUS catheter. Mean patient age and admission National Institutes of Health Stroke Scale score were 65.30 (1.92) and 15.98 (0.89), respectively. The most common sites of vessel occlusion included the M1 segment (50%) and internal carotid artery (31%). Thrombectomy was performed using the direct aspiration first pass technique and/or aspiration in conjunction with a stent retriever.Results Successful navigation of the Sofia 6-French PLUS catheter to the site of thromboembolus was achieved in 94% of cases. Revascularization was achieved in a total of 47 cases (87%). Mean time from groin access to revascularization was 42.79 (3.23) min. There were no catheter-related complications. Final outcome data was available for 44 patients (81%). Of these patients, 41% achieved a good outcome (modified Rankin scale score of 0–2) at 60–90 day follow-up, 41% had a poor outcome (modified Rankin 3–5) and eight patients died (18%).Conclusions We demonstrate the safe and effective use of the Sofia 6-French PLUS catheter for treatment of acute ischemic stroke. Future studies in the form of a randomized clinical trial or multicenter registry are warranted to further evaluate its comparative safety and efficacy.