Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.

BACKGROUND: The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS). METHODS: In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort). RESULTS: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. CONCLUSIONS: In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

Protective Effects of Lovastatin in a Population-Based ALS Study and Mouse Model.

OBJECTIVE: The objective of this study was to use a novel combined pharmacoepidemiologic and amyotrophic lateral sclerosis (ALS) mouse model approach to identify potential motor neuron protective medications. METHODS: We constructed a large, population-based case-control study to investigate motor neuron disease (MND) among US Medicare beneficiaries aged 66 to 90 in 2009. We included 1,128 incident MND cases and 56,400 age, sex, race, and ethnicity matched controls. We calculated MND relative risk for >1,000 active ingredients represented in Part D (pharmacy) claims in 2006 to 2007 (>1 year before diagnosis/reference). We then applied a comprehensive screening approach to select medications for testing in SOD1G93A mice: sulfasalazine, telmisartan, and lovastatin. We treated mice with the human dose equivalent of the medication or vehicle via subcutaneous osmotic pump before onset of weakness. We then assessed weight, gait, and survival. In additional mice, we conducted histological studies. RESULTS: We observed previously established medical associations for MND and an inverse dose-response association between lovastatin and MND, with 28% reduced risk at 40 mg/day. In SOD1G93A mouse studies, sulfasalazine and telmisartan conferred no benefit, whereas lovastatin treatment delayed onset and prolonged survival. Lovastatin treated mice also had less microgliosis, misfolded SOD1, and spinal motor neuron loss in the ventral horn. INTERPRETATION: Lovastatin reduced the risk of ALS in humans, which was confirmed in an ALS mouse model by delayed symptom onset, prolonged survival, and preservation of motor neurons. Although further studies to understand the mechanism are required, lovastatin may represent a potential neuroprotective therapy for patients with ALS. These data demonstrate the utility of a combined pharmacoepidemiologic and mouse model approach. ANN NEUROL 2023;93:881-892.

Optimising multiplex immunofluorescence staining for characterising the tumour immune micro-environment.

Exploring the tumour microenvironment provides insight into the unique interaction between the host and tumour. Ultimately, its study improves understanding of how an individual mounts and achieves an anti-tumour immune response. In the context of colorectal cancer, immune biomarkers within the tumour microenvironment outperform traditional histopathological staging in predicting disease recurrence. Multiplex immunofluorescence enables simultaneous assessment of multiple markers to provide a highly accurate classification of immune cells and their spatial characterisation relative to tumour tissue. Further, automated slide staining provides staining consistency and reduces labour costs. Image acquisition using a non-spectral scanner allows more researchers to utilise multiplexed immunofluorescence for translational research. Herein we describe the optimisation process of conducting automated staining using a five-colour, tyramide signal amplification-based multiplex immunofluorescence panel. Using antibodies against CD3, CD8, CD103 and cytokeratin, the panel characterises T cell populations within human colorectal adenocarcinoma tissue. We provide an overview of primary antibody titration and the development of tyramide signal amplification immunofluorescence monoplex assays. We detail the processes of antibody stripping and the role of exogenous horseradish peroxidase inhibition to facilitate multiplexing. An account of determining the staining sequence and fluorophore assignment is provided. We describe image acquisition using a standard fluorescence microscope slide scanner and the management of spectral crosstalk using this system. Finally, we briefly document the digital image analysis required to characterise cells and determine their spatial distribution within the colorectal tumour microenvironment.

Acute Trem2 reduction triggers increased microglial phagocytosis, slowing amyloid deposition in mice.

Heterozygous genetic variants within the TREM2 gene show a strong association with increased Alzheimer's disease (AD) risk. Amyloid beta-depositing mouse models haploinsufficient or null for Trem2 have identified important relationships among TREM2, microglia, and AD pathology; however, results are challenging to interpret in the context of varying microglial phenotypes and disease progression. We hypothesized that acute Trem2 reduction may alter amyloid pathology and microglial responses independent of genetic Trem2 deletion in mouse models. We developed antisense oligonucleotides (ASOs) that potently but transiently lower Trem2 messenger RNA throughout the brain and administered them to APP/PS1 mice at varying stages of plaque pathology. Late-stage ASO-mediated Trem2 knockdown significantly reduced plaque deposition and attenuated microglial association around plaque deposits when evaluated 1 mo after ASO injection. Changes in microglial gene signatures 1 wk after ASO administration and phagocytosis measured in ASO-treated cells together indicate that microglia may be activated with short-term Trem2 reduction. These results suggest a time- and/or dose-dependent role for TREM2 in mediating plaque deposition and microglial responses in which loss of TREM2 function may be beneficial for microglial activation and plaque removal in an acute context.

Moving Biosurveillance Beyond Coded Data Using AI for Symptom Detection From Physician Notes: Retrospective Cohort Study.

BACKGROUND: Real-time surveillance of emerging infectious diseases necessitates a dynamically evolving, computable case definition, which frequently incorporates symptom-related criteria. For symptom detection, both population health monitoring platforms and research initiatives primarily depend on structured data extracted from electronic health records. OBJECTIVE: This study sought to validate and test an artificial intelligence (AI)-based natural language processing (NLP) pipeline for detecting COVID-19 symptoms from physician notes in pediatric patients. We specifically study patients presenting to the emergency department (ED) who can be sentinel cases in an outbreak. METHODS: Subjects in this retrospective cohort study are patients who are 21 years of age and younger, who presented to a pediatric ED at a large academic children's hospital between March 1, 2020, and May 31, 2022. The ED notes for all patients were processed with an NLP pipeline tuned to detect the mention of 11 COVID-19 symptoms based on Centers for Disease Control and Prevention (CDC) criteria. For a gold standard, 3 subject matter experts labeled 226 ED notes and had strong agreement (F1-score=0.986; positive predictive value [PPV]=0.972; and sensitivity=1.0). F1-score, PPV, and sensitivity were used to compare the performance of both NLP and the International Classification of Diseases, 10th Revision (ICD-10) coding to the gold standard chart review. As a formative use case, variations in symptom patterns were measured across SARS-CoV-2 variant eras. RESULTS: There were 85,678 ED encounters during the study period, including 4% (n=3420) with patients with COVID-19. NLP was more accurate at identifying encounters with patients that had any of the COVID-19 symptoms (F1-score=0.796) than ICD-10 codes (F1-score =0.451). NLP accuracy was higher for positive symptoms (sensitivity=0.930) than ICD-10 (sensitivity=0.300). However, ICD-10 accuracy was higher for negative symptoms (specificity=0.994) than NLP (specificity=0.917). Congestion or runny nose showed the highest accuracy difference (NLP: F1-score=0.828 and ICD-10: F1-score=0.042). For encounters with patients with COVID-19, prevalence estimates of each NLP symptom differed across variant eras. Patients with COVID-19 were more likely to have each NLP symptom detected than patients without this disease. Effect sizes (odds ratios) varied across pandemic eras. CONCLUSIONS: This study establishes the value of AI-based NLP as a highly effective tool for real-time COVID-19 symptom detection in pediatric patients, outperforming traditional ICD-10 methods. It also reveals the evolving nature of symptom prevalence across different virus variants, underscoring the need for dynamic, technology-driven approaches in infectious disease surveillance.

The BAND score: A simple model for upfront prediction of poor outcomes despite successful stroke thrombectomy.

BACKGROUND: While endovascular thrombectomy (EVT) is beneficial for patients with acute large vessel occlusion ischemic strokes, a significant portion of patients still do poorly despite successful recanalization. Identifying patients at high risk for poor outcomes can be helpful for future clinical trial design and optimizing acute stroke triage. METHODS: Consecutive EVT patients were identified from 2016 to 2021 at a Comprehensive Stroke Center, and clinical information was recorded. Poor outcome was defined as a 90-day modified Rankin Scale (mRS) of 4 or greater despite achieving a modified thrombolysis in cerebral infarction (mTICI) score of 2b or greater. Multivariable regression analyses were used to identify risk factors for poor outcomes, and a scoring system was constructed. RESULTS: 483 patients with successful recanalization were identified. From a randomly selected training cohort (n = 357), the 10-point BAND score was constructed from independent risk factors for poor outcomes: baseline disability (1 point: baseline mRS ≥ 2), age (1 point: 60-69 years, 2 points: 70-79 years, 3 points: 80-84 years, 4 points: 85 years or older), NIHSS (2 points: 13-17, 3 points: 18-22, and 4 points: ≥ 23), and delay from last known normal (1 point: ≥ 6 h). The BAND score was significantly associated with rates of poor outcomes (p < 0.001), and it achieved an area under the receiver-operating characteristic curve (AUC) of 0.80 (95 %CI 0.76-0.85) in our training cohort and 0.78 (95 %CI 0.70-0.86) in our validation cohort (n = 126). Overall, the BAND score had a significantly higher AUC value than the widely validated THRIVE score and the THRIVE-EVT calculation (p = 0.001 and 0.029, respectively). Among patients with high BAND scores (7 or higher), 88.2 % had poor outcomes. CONCLUSION: The BAND score is a simple tool to predict poor outcomes despite successful recanalization. Future studies are needed to confirm the BAND score's external validity.

Novel low-grade renal spindle cell neoplasm with HEY1::NCOA2 fusion that is distinct from mesenchymal chondrosarcoma.

HEY1-NCOA2 fusion is most described in mesenchymal chondrosarcoma. This is the first case report of a primary renal spindle cell neoplasm of uncertain malignant potential with a HEY1::NCOA2 fusion identified by Fusionplex RNA-sequencing that is histologically distinct from mesenchymal chondrosarcoma. The neoplasm was identified in a 33-year-old woman without significant past medical history who underwent partial nephrectomy for an incidentally discovered renal mass. The histologic features of the mass included spindle cells with variable cellularity and monotonous bland cytology forming vague fascicles and storiform architecture within a myxoedematous and collagenous stroma with areas of calcification. The morphologic and immunophenotypic features were not specific for any entity but were most similar to low-grade fibromyxoid sarcoma. To date, the patient has not had recurrence, and the malignant potential of the neoplasm is uncertain.

Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.

BACKGROUND: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations. METHODS: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured. RESULTS: A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose. CONCLUSIONS: In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).

Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).

Lumbar punctures are safe in patients with ALS and have a risk profile similar to that in the non-ALS population.

INTRODUCTION/AIMS: Analysis of biofluids, especially cerebrospinal fluid (CSF), is critically important for amyotrophic lateral sclerosis (ALS) research. Collection of CSF is typically performed by lumbar puncture (LP). Previous studies have demonstrated the safety of LPs in patients with other neurodegenerative diseases, such as Alzheimer's disease, although there are no published studies of the safety of LPs in patients with ALS. We performed a retrospective analysis of complications resulting from LPs. METHODS: This is a retrospective study of LPs performed between 2015 and 2021 on a total of 233 participants (healthy controls [n = 63], ALS [n = 154], and disease controls [n = 16]) as part of clinical research studies at the Washington University ALS Center. We used bivariate logistical analyses looking for associations between participant characteristics and adverse events (AEs), and likelihood ratio tests were used for significance testing. RESULTS: We found an overall AE rate of 21.03%. AEs included headache, back pain, vasovagal syncope, and severe headache requiring epidural blood patch. Participants with ALS were not more likely to experience post-LP AEs compared to controls (odds ratio [OR] 0.61 [0.32-1.18]). Post-LP headaches were significantly less likely in participants with ALS (OR 0.36 [0.15-0.83]). DISCUSSION: Our findings demonstrate that LP is a safe procedure for participants with ALS, with a similar or lower rate of AEs than in participants without ALS.

Specific RNA interactions promote TDP-43 multivalent phase separation and maintain liquid properties.

TDP-43 is an RNA-binding protein that forms ribonucleoprotein condensates via liquid-liquid phase separation (LLPS) and regulates gene expression through specific RNA interactions. Loss of TDP-43 protein homeostasis and dysfunction are tied to neurodegenerative disorders, mainly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Alterations of TDP-43 LLPS properties may be linked to protein aggregation. However, the mechanisms regulating TDP-43 LLPS are ill-defined, particularly how TDP-43 association with specific RNA targets regulates TDP-43 condensation remains unclear. We show that RNA binding strongly promotes TDP-43 LLPS through sequence-specific interactions. RNA-driven condensation increases with the number of adjacent TDP-43-binding sites and is also mediated by multivalent interactions involving the amino and carboxy-terminal TDP-43 domains. The physiological relevance of RNA-driven TDP-43 condensation is supported by similar observations in mammalian cellular lysate. Importantly, we find that TDP-43-RNA association maintains liquid-like properties of the condensates, which are disrupted in the presence of ALS-linked TDP-43 mutations. Altogether, RNA binding plays a central role in modulating TDP-43 condensation while maintaining protein solubility, and defects in this RNA-mediated activity may underpin TDP-43-associated pathogenesis.

Progress Note Understanding - Assessment and Plan Reasoning: Overview of the 2022 N2C2 Track 3 shared task.

Daily progress notes are a common note type in the electronic health record (EHR) where healthcare providers document the patient's daily progress and treatment plans. The EHR is designed to document all the care provided to patients, but it also enables note bloat with extraneous information that distracts from the diagnoses and treatment plans. Applications of natural language processing (NLP) in the EHR is a growing field with the majority of methods in information extraction. Few tasks use NLP methods for downstream diagnostic decision support. We introduced the 2022 National NLP Clinical Challenge (N2C2) Track 3: Progress Note Understanding - Assessment and Plan Reasoning as one step towards a new suite of tasks. The Assessment and Plan Reasoning task focuses on the most critical components of progress notes, Assessment and Plan subsections where health problems and diagnoses are contained. The goal of the task was to develop and evaluate NLP systems that automatically predict causal relations between the overall status of the patient contained in the Assessment section and its relation to each component of the Plan section which contains the diagnoses and treatment plans. The goal of the task was to identify and prioritize diagnoses as the first steps in diagnostic decision support to find the most relevant information in long documents like daily progress notes. We present the results of the 2022 N2C2 Track 3 and provide a description of the data, evaluation, participation and system performance.

DR.BENCH: Diagnostic Reasoning Benchmark for Clinical Natural Language Processing.

The meaningful use of electronic health records (EHR) continues to progress in the digital era with clinical decision support systems augmented by artificial intelligence. A priority in improving provider experience is to overcome information overload and reduce the cognitive burden so fewer medical errors and cognitive biases are introduced during patient care. One major type of medical error is diagnostic error due to systematic or predictable errors in judgement that rely on heuristics. The potential for clinical natural language processing (cNLP) to model diagnostic reasoning in humans with forward reasoning from data to diagnosis and potentially reduce cognitive burden and medical error has not been investigated. Existing tasks to advance the science in cNLP have largely focused on information extraction and named entity recognition through classification tasks. We introduce a novel suite of tasks coined as Diagnostic Reasoning Benchmarks, Dr.Bench, as a new benchmark for developing and evaluating cNLP models with clinical diagnostic reasoning ability. The suite includes six tasks from ten publicly available datasets addressing clinical text understanding, medical knowledge reasoning, and diagnosis generation. DR.BENCH is the first clinical suite of tasks designed to be a natural language generation framework to evaluate pre-trained language models for diagnostic reasoning. The goal of DR. BENCH is to advance the science in cNLP to support downstream applications in computerized diagnostic decision support and improve the efficiency and accuracy of healthcare providers during patient care. We fine-tune and evaluate the state-of-the-art generative models on DR.BENCH. Experiments show that with domain adaptation pre-training on medical knowledge, the model demonstrated opportunities for improvement when evaluated in DR. BENCH. We share DR. BENCH as a publicly available GitLab repository with a systematic approach to load and evaluate models for the cNLP community. We also discuss the carbon footprint produced during the experiments and encourage future work on DR.BENCH to report the carbon footprint.

Representing and utilizing clinical textual data for real world studies: An OHDSI approach.

Clinical documentation in electronic health records contains crucial narratives and details about patients and their care. Natural language processing (NLP) can unlock the information conveyed in clinical notes and reports, and thus plays a critical role in real-world studies. The NLP Working Group at the Observational Health Data Sciences and Informatics (OHDSI) consortium was established to develop methods and tools to promote the use of textual data and NLP in real-world observational studies. In this paper, we describe a framework for representing and utilizing textual data in real-world evidence generation, including representations of information from clinical text in the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM), the workflow and tools that were developed to extract, transform and load (ETL) data from clinical notes into tables in OMOP CDM, as well as current applications and specific use cases of the proposed OHDSI NLP solution at large consortia and individual institutions with English textual data. Challenges faced and lessons learned during the process are also discussed to provide valuable insights for researchers who are planning to implement NLP solutions in real-world studies.

Systematic reviews and consensus definitions for the Standardised Endpoints in Perioperative Medicine (StEP) initiative: mortality, morbidity, and organ failure.

BACKGROUND: Mortality, morbidity, and organ failure are important and common serious harms after surgery. However, there are many candidate measures to describe these outcome domains. Definitions of these measures are highly variable, and validity is often unclear. As part of the International Standardised Endpoints in Perioperative Medicine (StEP) initiative, this study aimed to derive a set of standardised and valid measures of mortality, morbidity, and organ failure for use in perioperative clinical trials. METHODS: Three domains of endpoints (mortality, morbidity, and organ failure) were explored through systematic literature review and a three-stage Delphi consensus process using methods consistently applied across the StEP initiative. Reliability, feasibility, and patient-centredness were assessed in round 3 of the consensus process. RESULTS: A high level of consensus was achieved for two mortality time points, 30-day and 1-yr mortality, and these two measures are recommended. No organ failure endpoints achieved threshold criteria for consensus recommendation. The Clavien-Dindo classification of complications achieved threshold criteria for consensus in round 2 of the Delphi process but did not achieve the threshold criteria in round 3 where it scored equivalently to the Post Operative Morbidity Survey. Clavien-Dindo therefore received conditional endorsement as the most widely used measure. No composite measures of organ failure achieved an acceptable level of consensus. CONCLUSIONS: Both 30-day and 1-yr mortality measures are recommended. No measure is recommended for organ failure. One measure (Clavien-Dindo) is conditionally endorsed for postoperative morbidity, but our findings suggest that no single endpoint offers a reliable and valid measure to describe perioperative morbidity that is not dependent on the quality of deli-vered care. Further refinement of current measures, or development of novel measures, of postoperative morbidity might improve consensus in this area.

Clinical practice guidelines for enhanced recovery after colon and rectal surgery from the American Society of Colon and Rectal Surgeons and the Society of American Gastrointestinal and Endoscopic Surgeons.

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.

Spinal Cord Infarction With Prolonged Femoral Venoarterial Extracorporeal Membrane Oxygenation.

OBJECTIVES: There have been sporadic reports of ischemic spinal cord injury (SCI) during venoarterial extracorporeal membrane oxygenation (VA-ECMO) support. The authors observed a troubling pattern of this catastrophic complication and evaluated the potential mechanisms of SCI related to ECMO. DESIGN: This study was a case series. SETTING: This study was performed at a single institution in a University setting. PARTICIPANTS: Patients requiring prolonged VA-ECMO were included. INTERVENTIONS: No interventions were done. This was an observational study. MEASUREMENTS AND MAIN RESULTS: Four hypotheses of etiology were considered: (1) hypercoagulable state/thromboembolism, (2) regional hypoxia/hypocarbia, (3) hyperperfusion and spinal cord edema, and (4) mechanical coverage of spinal arteries. The SCI involved the lower thoracic (T7-T12 level) spinal cord to the cauda equina in all patients. Seven out of 132 (5.3%) patients with prolonged VA-ECMO support developed SCI. The median time from ECMO cannulation to SCI was 7 (range: 6-17) days.There was no evidence of embolic SCI or extended regional hypoxia or hypocarbia. A unilateral, internal iliac artery was covered by the arterial cannula in 6/7 86%) patients, but flow into the internal iliac was demonstrated on imaging in all available patients. The median total flow (ECMO + intrinsic cardiac output) was 8.5 L/min (LPM), and indexed flow was 4.1 LPM/m2. The median central venous oxygen saturation was 88%, and intracranial pressure was measured at 30 mmHg in one patient, suggestive of hyperperfusion and spinal cord edema. CONCLUSIONS: An SCI is a serious complication of extended peripheral VA-ECMO support. Its etiology remains uncertain, but the authors' preliminary data suggested that spinal cord edema from hyperperfusion or venous congestion could contribute.

A viral toolkit for recording transcription factor-DNA interactions in live mouse tissues.

Transcription factors (TFs) enact precise regulation of gene expression through site-specific, genome-wide binding. Common methods for TF-occupancy profiling, such as chromatin immunoprecipitation, are limited by requirement of TF-specific antibodies and provide only end-point snapshots of TF binding. Alternatively, TF-tagging techniques, in which a TF is fused to a DNA-modifying enzyme that marks TF-binding events across the genome as they occur, do not require TF-specific antibodies and offer the potential for unique applications, such as recording of TF occupancy over time and cell type specificity through conditional expression of the TF-enzyme fusion. Here, we create a viral toolkit for one such method, calling cards, and demonstrate that these reagents can be delivered to the live mouse brain and used to report TF occupancy. Further, we establish a Cre-dependent calling cards system and, in proof-of-principle experiments, show utility in defining cell type-specific TF profiles and recording and integrating TF-binding events across time. This versatile approach will enable unique studies of TF-mediated gene regulation in live animal models.

Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial.

BACKGROUND: Coformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS). OBJECTIVE: Determine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial. METHODS: Adults 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. RESULTS: Risk 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. CONCLUSIONS: Early PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS. TRIAL REGISTRATION NUMBER: NCT03127514; NCT03488524.

Incidence of amyotrophic lateral sclerosis in older adults.

INTRODUCTION/AIMS: We investigated the age- and sex-specific incidence and survival of Medicare beneficiaries with amyotrophic lateral sclerosis (ALS) in patients 66 to 90 years of age. METHODS: We identified all incident ALS cases within a population-based sample of Medicare beneficiaries in 2009 (total: 22 000 177 person-years at risk for ALS). We calculated age- and sex-specific incidence in 2009 according to multiple, progressively more stringent case definitions. Our most inclusive definition required one ALS code, whereas the most restrictive definition required at least one additional ALS code more than 6 months after the first code, including one from a neurologist. We identified associated imaging studies and electrodiagnostic testing and followed all cases through the end of 2014 to determine survival. RESULTS: The overall incidence for our most inclusive definition was 22.84 per 100 000 person-years for men and 16.05 per 100 000 person-years for women. The overall incidence was 5.72 per 100 000 person-years for men and 3.99 per 100 000 person-years for women for our most restrictive definition. For our most inclusive definition, fewer than 39.7% of cases ever had an ALS diagnosis from a neurologist, more than 50% had an electrodiagnostic test or imaging study, and 40.1% survived less than 1 year after diagnosis, with 25.5% of these cases surviving no more than 6 months. Cases not meeting the most restrictive definition were more likely than those who did meet the restrictive definition to be older, black, or Asian. DISCUSSION: The oldest and marginalized Medicare beneficiaries diagnosed with ALS are less likely to be included in epidemiological studies with restrictive definitions, but future studies will need to assess the accuracy of diagnosis.