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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.

The article focuses on improving Indiana's infrastructure through the I-69 project. Topics include up gradation of four-lane State Road 37 to the new I-69 by the I-69 Finish Line, describes all the improvements made in the construction such as construction of 39 new bridges, and project staff worked with local officials for construction of two large monuments at Martinsville's north and south entrances.

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.

'Engineering for Non-Engineers' discusses science and engineering principles associated with equipment, utilities, facilities, and associated GMP systems useful to practitioners in compliance and validation. Reader comments, questions, and suggestions are [...]

Welcome to 'Validation Strategy and Planning.' This column discusses various topics associated with validation strategy and planning useful to practitioners in validation and compliance. We intend this column to be [...]

Under the life-cycle saving model, population aging leads to an increased demand for life-cycle wealth. Changes in transfer systems create or destroy one component of life-cycle wealth--transfer wealth. The decline in the familial transfer system in Taiwan and reform of the US Social Security system are two examples of ways that transfer wealth is reduced. The combined effects of aging and changes in transfer systems are analyzed using simulation analysis. Rapid aging and radical decline in transfer systems lead to a large but transitory surge in aggregate saving. Capital per worker increases rapidly and remains at a high level. Keywords: Saving; capital; social security and public pensions; aging; intergenerational transfers JEL classification: E2; H55; J1

Objective: To evaluate the following: (1) the intramethod variability of impedance cardiography (ICG) cardiac output (CO) measurements via the latest generation monitor and thermodilution CO measurements (CO-TDs); (2) the intermethod [...]

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.

Objective. To quantify uncertainty in forecasts of health expenditures. Study Design. Stochastic time series models are estimated for historical variations in fertility, mortality, and health spending per capita in the United States, and used to generate stochastic simulations of the growth of Medicare expenditures. Individual health spending is modeled to depend on the number of years until death. Data Sources/Study Setting. A simple accounting model is developed for forecasting health expenditures, using the U.S. Medicare system as an example. Principal Findings. Medicare expenditures are projected to rise from 2.2 percent of GDP (gross domestic product) to about 8 percent of GDP by 2075. This increase is due in equal measure to increasing health spending per beneficiary and to population aging. The traditional projection method constructs high, medium, and low scenarios to assess uncertainty, an approach that has many problems. Using stochastic forecasting, we find a 95 percent probability that Medicare spending in 2075 will fall between 4 percent and 18 percent of GDP, indicating a wide band of uncertainty. Although there is substantial uncertainty about future mortality decline, it contributed little to uncertainty about future Medicare spending, since lower mortality both raises the number of elderly, tending to raise spending, and is associated with improved health of the elderly, tending to reduce spending. Uncertainty about fertility, by contrast, leads to great uncertainty about the future size of the labor force, and therefore adds importa ntly to uncertainty about the health-share of GDP. In the shorter term, the major source of uncertainty is health spending per capita. Conclusions. History is a valuable guide for quantifying our uncertainty about future health expenditures. The probabilistic model we present has several advantages over the high-low scenario approach to forecasting. It indicates great uncertainty about future Medicare expenditures relative to GDP. Key Words. Health expenditures, forecasting, demography, Medicare, The United States devoted 13.6 percent of its GDP (gross domestic product) to health care in 1998, more than any other OECD nation (Organization for Economic Cooperation and Development 2000). [...]

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.

This study investigated the degree to which statistical item selection is effective in reducing direction-of-wording effects in balanced affective measures developed from relatively small item pools. A pool of Likert-type loneliness items and their reversals was partitioned into balanced subsets by random and statistical item selection. Factor analyses of the alternate forms indicated that selection of items with high item-total correlations produced an instrument that showed the clearest direction-of-wording effects, with the positively and negatively keyed items loading on separate factors. The second factor was small in magnitude but clear and consistent. The clarity of the effects decreased as the internal consistency of the item subsets decreased. Possible explanations for these findings are discussed and directions for future research are suggested.

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.

Patellar tendinopathy is commonly encountered in orthopedic and sports medicine clinics. Ultrasound-guided (USG) percutaneous tendon scraping is well described for Achilles tendinopathy, but not patellar tendinopathy. This manuscript describes the technique and reports results from a case series of patients with patellar tendinopathy treated with USG percutaneous tendon scraping. A retrospective review of the medical record identified 6 patients who underwent tendon scraping for patellar tendinopathy. This was a retrospective case series performed by searching the medical record for patients who underwent tendon scraping for patellar tendinopathy. Six patients met the criteria for inclusion. Five had primary patellar tendinopathy and 1 had continued pain despite open debridement. There were 3 competitive athletes and 3 recreational athletes. No major adverse events were reported. All competitive athletes safely returned to the sport at 1 month. At an average follow-up of 13.5±6 months, mean improvement in the Victorian Institute of Sport Assessment-Patellar Tendon (VISA-P) score was 53±24.2 points. At the final follow-up, 83% of patients experienced a clinically significant improvement in symptoms. USG percutaneous patellar tendon scraping is a minimally invasive intervention that may improve symptoms and help patients safely return to sport/activity. Because the intervention is entirely outside of the tendon, it is low risk and may be useful for in-season athletes.

Supplemental Digital Content is available in the text.

The use of chemical functionalization of nanoparticles for controlled assembly relies on selective surface modification that promotes highly specific chemical transformations. It is often also important to control physical properties of the materials produced by this approach and in case of iron nanoparticles, magnetic properties are often the target of the applications. Here, iron nanoparticles are assembled using “click chemistry”, with two batches of iron nanoparticles functionalized with 5-hexynoic acid and 5-azidopentanoic acid, respectively. The functionalization process and the final assembly are followed by a combination of spectroscopic techniques, scanning electron microscopy, and density functional theory calculations. Most importantly, the magnetic properties of the material produced can be retained, as demonstrated by vibrating sample magnetometer measurements, with substantial changes in the morphology of the material. The observed changes are attributed to partial oxidation of the produced functionalized surfaces and the suggestions for further improvements are made.

Background Peri-procedural blood loss and hemodilution occur in patients undergoing mechanical thrombectomy (MT) for ischemic stroke; however, its relationships with thrombectomy passes, procedure times, and clinical outcomes are unknown.Methods Consecutive patients undergoing MT for anterior circulation large-vessel occlusion ischemic strokes were identified at a Comprehensive Stroke Center. Clinical information, modified treatment in cerebral ischemia (mTICI) scores, and modified Rankin Scores (mRS) at 90 days were prospectively collected from 2012 to 2021. Hemoglobin measurements before and after MTs were collected retrospectively via chart review, and changes were quantified. Patients with new-onset severe anemia (defined as post-MT hemoglobin less than 10g/dL) were identified. Modified Rankin scale (mRS) at 90 days was used to measure clinical outcomes.Results Four-hundred and forty-five patients were identified. Hemoglobin decreased 1.27 ± 1.05 g/dL after MT on average. Greater number of thrombectomy passes and longer procedure times were associated with larger decreases in hemoglobin (p< 0.001 and p= 0.002, respectively). 11.5% (51 of 445) of patients had new-onset severe anemia, and this incidence was significantly higher with more thrombectomy passes (6.4% for one pass, 11.9% for two passes, and 17.4% for three or more passes; p= 0.010). In multivariable analyses, new-onset severe anemia was associated with significantly higher odds of 90-day poor outcomes (mRS 3-6, OR 2.70 [95%CI 1.12–6.51], p= 0.027) and death (OR 2.73 [95%CI 1.06–7.04], p= 0.037) compared to mild post-MT anemia.Conclusions More thrombectomy passes and longer procedure times were significantly associated with larger peri-procedural decreases in hemoglobin. Patients with new-onset hemoglobin less than 10 g/dL are at risk of poor outcomes.

Objective: We sought to calculate the sensitivity, specificity, negative predictive value, and positive predictive value of a limited sinus computed tomographic (CT) scan for sinus disease. Methods: We conducted a [...]