Background: We investigated delirium prevalence and potential effects of long-term sedation in critically ill COVID-19 patients; to identify opportunities for improving sedation practices and delirium prevention. Methods: This prospective, single-center, observational cohort study was conducted from April-June 2020. Adult COVID-19 patients were eligible if admitted to an ICU with mechanical ventilation/intravenous sedation; or a general care unit with brain monitoring due to altered mental status. Patients were evaluated daily until discharge using the Richmond Agitation-Sedation Scale, Confusion Assessment Method for the ICU, and CAM-Severity. Cumulative doses of sedation and paralytic medications were recorded. At three months post-enrollment, cognition, mood, and quality of life were measured by the Telephone Interview for Cognitive Status (TICS), Center for Epidemiologic Studies Depression Scale 10-item (CES-10), and EuroQol 5-Dimension-3 Level (EQ-5D-3L), respectively. Results: 67 patients were enrolled, with a mean (SD) age of 59 (12) years, 30 (45%) Hispanic, 43 (64%) developing acute respiratory distress syndrome, 55 (82%) mechanically ventilated (mean duration of 22.9 days), and 5 comatose for the entire study. Of the 62 patients assessed for delirium, 61 (98%) had delirium at least once, with a mean (SD) of 12.7 (13.0) days. >90% of patients received opioids, benzodiazepines, or propofol at least once; median (IQR) total dose of 37.4 (78.9) mg (fentanyl equivalents), 52.5 (813.3) mg (midazolam equivalents), and 46 (53) g (propofol), respectively. At follow-up, 40 (60%) patients were reached, while 16 (24%) were deceased/comfort measures. Patients showed reductions in cognition, mood, and quality of life with median (IQR) scores for TICS (0-41): 30 (26-33); CES-D-10 (0-30): 6 (4-12); EQ-5D-3L (1-3): 2 (mobility, self-care, usual activities, pain/discomfort). Conclusion: Critically and acutely ill patients with COVID-19 early in the pandemic experienced a high rate of delirium and sedation. Large doses of sedatives may contribute to greater delirium burden during hospitalization, and lead to poor clinical outcomes. ### Competing Interest Statement Dr. Westover is a co-founder, serves as a scientific advisor and consultant, and has a personal equity interest in Beacon Biosignals. ### Funding Statement MBW was supported by the Glenn Foundation for Medical Research and American Federation for Aging Research (Breakthroughs in Gerontology Grant); American Academy of Sleep Medicine (AASM Foundation Strategic Research Award); Football Players Health Study (FPHS) at Harvard University; Department of Defense through a subcontract from Moberg ICU Solutions, Inc; and NIH (1R01NS102190, 1R01NS102574, 1R01NS107291, 1RF1AG064312, RF1NS120947, R01AG073410 R01HL161253, R01NS126282, R01AG073598), and NSF (2014431). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: According to the Partners Human Research Committee, it qualified for an exemption from formal oversight by the Mass General Brigham Institutional Review Board and met the criteria for a waiver of informed consent. The study was performed in compliance with the ethical principles outlined in the 1964 Declaration of Helsinki, its subsequent amendments, and comparable ethical standards. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data supporting the findings reported in this article, including text, tables, and figures, are available from the corresponding author upon reasonable request.

Background: Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma (NHL). Several treatment options are approved by the US Food and Drug Administration for second- or later-line FL therapy, including rituximab + lenalidomide (R 2). However, advanced-stage FL remains incurable and new treatment options for relapsed or refractory (R/R) disease are needed. Epcoritamab, a subcutaneously administered, bispecific antibody that binds CD3 on T lymphocytes and CD20 on B cells, induces potent and selective T-cell-mediated killing of malignant CD20 + B cells (van der Horst et al, Blood Cancer J 2021). In the first-in-human, phase 1/2 EPCORE NHL-1 trial (NCT03625037) in heavily pretreated patients with B-cell NHL (N=68), epcoritamab showed manageable safety and promising single-agent anti-tumor activity (Hutchings et al, Lancet 2021). Among 10 patients with R/R FL, objective response rate (ORR) was 90% (95% CI: 55-100) and complete response (CR) rate was 50%. In the ongoing phase 1b/2 trial evaluating epcoritamab + R 2 for R/R FL (EPCORE NHL-2 arms 2a and 2b; NCT04663347), ORR was 98% among 104 efficacy-evaluable patients, with a complete metabolic response in 87%. Most cytokine release syndrome (CRS) events were low grade (n=111; grade 1-2, 46%; grade 3, 2%) and occurred in cycle 1; all CRS events resolved with routine management. These encouraging data, and the distinct mechanisms of action of epcoritamab and R 2, support ongoing evaluation of this combination for its potential to improve clinical outcomes in patients with R/R FL. The phase 3 EPCORE FL-1 trial was designed to evaluate epcoritamab in combination with R 2 vs R 2 alone in patients with R/R FL with ≥1 prior line of anti-lymphoma therapy. We present an updated protocol, reflecting recent developments and revisions implemented in this study. Study Design and Methods: EPCORE FL-1 (NCT05409066) is a global, randomized, open-label, multicenter phase 3 trial designed to evaluate efficacy and safety of epcoritamab in combination with R 2 vs R 2 alone in patients with R/R FL. Adult patients must have histologically confirmed classic FL (previously grades 1 to 3a FL) stage II, III, or IV with a CD20 + tumor on a representative biopsy based on local pathology report and no evidence of histologic transformation. Patients must have R/R disease after ≥1 prior anti-lymphoma regimen that contained an anti-CD20 monoclonal antibody in combination with chemotherapy; patients receiving only prior anti-CD20 monoclonal antibody monotherapy and/or radiation are not eligible. Other key eligibility criteria include Eastern Cooperative Oncology Group performance status 0 to 2, fluorodeoxyglucose positron emission tomography-avid disease, and ≥1 measurable disease site per Lugano 2014 criteria. Lenalidomide-refractory FL (best response to lenalidomide of stable or progressive disease or progressive disease within 6 months of completion of lenalidomide) is excluded. Approximately 520 patients will be enrolled and randomized 1:1 to receive a full dose of epcoritamab in combination with R 2 or R 2 alone ( Figure); the trial is currently enrolling in 2 arms, Arms A & C. Based on emerging safety and efficacy data, Arm B has been closed to enrollment and the recommended dose of epcoritamab in combination with R 2 is 48 mg. Epcoritamab will be subcutaneously administered using a step-up dosing regimen to full dose in cycle 1 (28 days/cycle). Full dose of epcoritamab will be administered weekly in cycles 2-3 and monthly from cycle 4 onward for up to 12 cycles of treatment. Patients will be serially assessed for disease progression at prespecified intervals. The primary endpoint is progression-free survival assessed by independent review committee (IRC) per Lugano criteria. Key secondary efficacy endpoints include CR rate (by IRC per Lugano criteria), overall survival, and minimal residual disease negativity. Other efficacy endpoints include best overall response, duration of response, duration of complete response, time to progression, event-free survival, time to next anti-lymphoma treatment, and patient-reported outcomes. Safety endpoints include incidence and severity of treatment-emergent adverse events and adverse events of special interest. Exploratory endpoints include assessments of pharmacodynamic and pharmacokinetic data. The study opened for enrollment in 2022 in North America, South America, Europe, Africa, Asia, and Australia.

Abstract Objective To develop an automated, physiologic metric of immune effector cell‐associated neurotoxicity syndrome among patients undergoing chimeric antigen receptor‐T cell therapy. Methods We conducted a retrospective observational cohort study from 2016 to 2020 at two tertiary care centers among patients receiving chimeric antigen receptor‐T cell therapy with a CD19 or B‐cell maturation antigen ligand. We determined the daily neurotoxicity grade for each patient during EEG monitoring via chart review and extracted clinical variables and outcomes from the electronic health records. Using quantitative EEG features, we developed a machine learning model to detect the presence and severity of neurotoxicity, known as the EEG immune effector cell‐associated neurotoxicity syndrome score. Results The EEG immune effector cell‐associated neurotoxicity syndrome score significantly correlated with the grade of neurotoxicity with a median Spearman's R2 of 0.69 (95% CI of 0.59–0.77). The mean area under receiving operator curve was greater than 0.85 for each binary discrimination level. The score also showed significant correlations with maximum ferritin (R2 0.24, p = 0.008), minimum platelets (R2 –0.29, p = 0.001), and dexamethasone usage (R2 0.42, p < 0.0001). The score significantly correlated with duration of neurotoxicity (R2 0.31, p < 0.0001). Interpretation The EEG immune effector cell‐associated neurotoxicity syndrome score possesses high criterion, construct, and predictive validity, which substantiates its use as a physiologic method to detect the presence and severity of neurotoxicity among patients undergoing chimeric antigen receptor T‐cell therapy.

Intensive care units (ICUs) may disrupt sleep. Quantitative ICU studies of concurrent and continuous sound and light levels and timings remain sparse in part due to the lack of ICU equipment that monitors sound and light. Here, we describe sound and light levels across three adult ICUs in a large urban United States tertiary care hospital using a novel sensor. The novel sound and light sensor is composed of a Gravity Sound Level Meter for sound level measurements and an Adafruit TSL2561 digital luminosity sensor for light levels. Sound and light levels were continuously monitored in the room of 136 patients (mean age = 67.0 (8.7) years, 44.9% female) enrolled in the Investigation of Sleep in the Intensive Care Unit study (ICU-SLEEP; Clinicaltrials.gov: #NCT03355053), at the Massachusetts General Hospital. The hours of available sound and light data ranged from 24.0 to 72.2 hours. Average sound and light levels oscillated throughout the day and night. On average, the loudest hour was 17:00 and the quietest hour was 02:00. Average light levels were brightest at 09:00 and dimmest at 04:00. For all participants, average nightly sound levels exceeded the WHO guideline of < 35 decibels. Similarly, mean nightly light levels varied across participants (minimum: 1.00 lux, maximum: 577.05 lux). Sound and light events were more frequent between 08:00 and 20:00 than between 20:00 and 08:00 and were largely similar on weekdays and weekend days. Peaks in distinct alarm frequencies (Alarm 1) occurred at 01:00, 06:00, and at 20:00. Alarms at other frequencies (Alarm 2) were relatively consistent throughout the day and night, with a small peak at 20:00. In conclusion, we present a sound and light data collection method and results from a cohort of critically ill patients, demonstrating excess sound and light levels across multiple ICUs in a large tertiary care hospital in the United States. ClinicalTrials.gov, #NCT03355053. Registered 28 November 2017, .

Background: Follicular lymphoma (FL) is a heterogeneous disease. Early progression after initial treatment with chemoimmunotherapy, or POD24, occurs in approximately 20% of patients and is a strong predictor of poor outcomes. There is no standard treatment approach for patients with high-risk, relapsed or refractory (R/R) FL, including those with disease that is primary refractory, double refractory, or refractory to prior anti-CD20 treatment and those with POD24. In these patients with a high unmet need, novel options are needed to improve efficacy. Epcoritamab, a subcutaneous T-cell–engaging bispecific antibody, demonstrated impressive single-agent antitumor activity and a manageable safety profile in R/R FL (Hutchings et al, Lancet 2021) and shows promise combined with standards of care. Aims: To present pooled analyses from cohorts 2a and 2b of the ongoing phase 1/2 EPCORE™ NHL-2 trial (NCT04663347) of epcoritamab + R2 in R/R FL. Methods: Patients with R/R CD20+ FL received subcutaneous epcoritamab + R2 for 12 cycles (28 d each). Epcoritamab was dosed QW in cycles 1–3, Q2W in cycles 4–9, and Q4W in cycles ≥10 (2a) or QW in cycles 1–2 and Q4W in cycles ≥3 (2b) for ≤2 y. Informed consent was obtained. Results: As of October 31, 2022, 109 R/R FL patients had received epcoritamab 48 mg + R2 in 2a and 2b. Median age was 65 y, 56% of patients had FLIPI 3–5, 61% had stage IV disease, and 59% had only 1 prior line of treatment. Most had received alkylating agents (92%) or anthracyclines (62%); 2 had prior CAR T. At a median follow-up of 8.8 mo (range, 1.2–18.5), 82% were still on treatment. The most common treatment-emergent AEs were CRS and neutropenia (48% each), injection-site reactions (38%), and fatigue (33%). CRS events were mostly low grade (G; 46% G1–2, 2% G3) and mostly occurred following the first full dose (cycle 1, day 15); all resolved and none led to discontinuation. ICANS occurred in 2 patients (G1, G2) and resolved. In 101 efficacy-evaluable patients, overall response rate (ORR) was 97%, with complete metabolic response (CMR) in 86%. Median time to any response and CMR was 1.4 mo. Estimated 6-mo progression-free survival was 93%. Notably, patients achieved higher ORR/CMR rates with epcoritamab + R2 vs their immediate prior therapy (ORR, 97% vs 85%; CMR, 86% vs 60%; Figure). High ORR/CMR rates were consistent across high-risk subgroups: POD24 (progression within 2 y of first-line treatment with chemoimmunotherapy, n=38; Figure), 95%/82%; subset of POD24 patients that received epcoritamab in second line (n=20), 95%/90%; double refractory (refractory to anti-CD20 and an alkylating agent, n=39; Figure), 92%/79%; refractory to last line of therapy (no response or relapse within 6 mo after last line of therapy, n=40; Figure), 93%/80%; primary refractory (no response or relapse within 6 mo after first-line treatment, n=39), 97%/87%; refractory to prior anti-CD20 treatment (n=49), 94%/84%. Additional data with longer follow-up will be presented. Summary/Conclusion: Epcoritamab + R2 showed potent antitumor activity and a manageable safety profile in a large R/R FL population. Encouraging responses were seen in patients with high-risk disease, suggesting subcutaneous epcoritamab may abrogate negative effects of high-risk features. A separate POD24 cohort is planned, and epcoritamab + R2 is being studied in the phase 3 EPCORE FL-1 trial (NCT05409066).Keywords: Hematological malignancy, Bispecific, Follicular lymphoma

Basilar artery occlusion (BAO) is associated with high morbidity and mortality. Endovascular therapy (EVT) has been shown to be beneficial in acute BAO patients. This retrospective observational study used the National Inpatient Sample (NIS) database to identify BAO patients using the International Classification of Diseases (ICD). Multivariable models were used to evaluate the association of risk factors, comorbidities, length of stay (LOS) in hospital, total cost, disposition, and transfer status. A total of 1120 (447 females, 39.95%) patients were identified, with a higher proportion of White individuals (66.8% vs. 57.6%), atrial fibrillation (31.5% vs. 17.2%; p < 0.0001), and peripheral vascular disease (21.2% vs. 13.7%; p = 0.009). A lower proportion of individuals with diabetes mellitus (32.1% vs. 39.5%; p = 0.05) was found in the EVT group. Majority of the patients (924/1120, 82.5%) were treated at the urban teaching facility, which also performed most of the EVT procedures (164, 89.13%), followed by non-academic urban (166, 14.8%) and rural (30, 2.7%) hospitals. Most patients (19/30, 63%) admitted to rural hospitals were transferred to other facilities. Urban academic hospitals also had the highest median LOS (8.9 days), cost of hospitalization (USD 117,261), and disposition to home (32.6%). This study observed distinct patterns and geographical disparities in the acute treatment of BAO patients. There is a need for national- and state-level strategies to improve access to stroke care.

Objective: To elucidate the role of inflammatory cytokines in Acute Ischemic Stroke patients Background: Acute ischemic stroke (AIS) is one of the leading causes of mortality and long-term disability. Ischemic changes results in inflammatory process characterized by various molecules and cytokines. There is limited data on the early changes and interaction in these cytokines. The aim of this study is to characterize the inflammatory response and explore the interaction of multiple cytokines and molecules among acute ischemic stroke (AIS) patients. Design/Methods: This is a prospective study of AIS patients presented to a tertiary care hospital within 24 hours from the symptom onset. Patients with prior history of stroke, autoimmune diseases, and neurodegenerative diseases were excluded. Plasma samples were collected on admission and at 24 hours. Cytokines and molecules were analyzed using enzyme-linked immunosorbent assay (ELISA). R-software was used for evaluating the differences among the molecules. Results: A total of 100 patients (males: 54; females: 46) from Caucasian, Hispanic, and Native American descent were included. Cytokine quantification observed a significant increase in PDGF, MPO, and MMP-9 among cases as compared to the controls at admission and 24 hours. Moreover, the levels of IL-33, IL-36, PDGF, MMP-9, and TNF-α decreases over time. Furthermore, IL-1 and IL-23 were negatively corelated with NIHSS, while the levels of IL-6 were positively corelated with infarct volume. Conclusions: Our results characterize the trends in inflammatory molecules over time and their correlation with stroke severity. These observations help to better understand the inflammatory response and identify molecular biomarkers and relevant targets for subsequent modulating therapeutic interventions in AIS patients. Disclosure: Dr. Farooqui has nothing to disclose. sajid suriya has nothing to disclose. Dr. Ikram has nothing to disclose. Dr. Qaryouti has nothing to disclose. Dr. Quadri has nothing to disclose. The institution of Dr. Paul has received research support from NIH/NINDS. Dr. Zafar has nothing to disclose.

Introduction Recently, evidence has been accumulating that both smoking and mental health disorders are continuously increasing among adolescents. This systematic review elucidates the research into evidence of the direction of the association and risk factors influencing the relationship between smoking and depression. We also highlight recent studies on the effects of electronic cigarettes and developments on the association between depression and smoking. Methods A literature search was conducted on databases including PubMed, Ovid Medline, EMBASE, and PsycINFO and in relevant neurology and psychiatry journals. Terms used for electronic searches included smoking, tobacco, cigarettes; depression; adolescent, youth; direction. Relevant information was then utilized to synthesize findings on the association between smoking and depression among adolescent population. Results The initial database searches yielded 2,738 related articles. After screening and cross-referencing, duplicate articles, articles published in languages other than English, and studies on animals, social and lifestyle factors, mood disorders, and substance use were excluded. Of these, a total of 122 publications only focusing on smoking and depression in the adolescent population were selected for synthesis in this qualitative systemic review. These include 110 original research articles, eight meta-analyses and reviews, and four reports and websites. Conclusion The relationship between smoking and depression in the literature does not reflect the cause-effect relationship. The lack of evidence on the direction of the association may reflect futile study designs, confounding factors and/or use of indirect measures of depression and quantification of smoking. Future prospective randomized studies should target elucidation of the causal association.

7506 Background: Follicular lymphoma (FL) is a heterogeneous disease. Early progression after initial treatment (tx) with chemoimmunotherapy (CIT), POD24, occurs in around 20% of patients (pts) and strongly predicts poor outcomes. There is no standard tx approach for high-risk, relapsed or refractory (R/R) FL (high-risk subgroups in Table). Novel options are needed to improve efficacy in pts with high unmet need. Epcoritamab, a subcutaneous (SC) T-cell–engaging bispecific antibody, demonstrated impressive single-agent antitumor activity and a manageable safety profile in R/R FL (Hutchings et al, Lancet 2021) and shows promise combined with standards of care. Here we present pooled analyses from cohorts 2a and 2b of the ongoing phase 1/2 EPCORE NHL-2 trial (NCT04663347) of epcoritamab with rituximab + lenalidomide (R 2 ). Methods: Pts with R/R CD20 + FL received epcoritamab SC + R 2 for 12 cycles (Cs; 28 d each). Epcoritamab was dosed QW in C1–3, Q2W in C4–9, and Q4W in C≥10 (2a) or QW in C1–2 and Q4W in C≥3 (2b) for ≤2 y. Results: As of Oct 31, 2022, 109 R/R FL pts had received epcoritamab 48 mg + R 2 in 2a and 2b. Median age was 65 y, 56% of pts had FLIPI 3–5, 61% had stage IV disease, and 59% had only 1 prior tx. Most had received alkylating agents (92%) or anthracyclines (62%); 2 had prior CAR T. At a median follow-up of 8.8 mo (range, 1.2–18.5), 82% were still on tx. The most common tx-emergent AEs were: CRS and neutropenia, 48% each; injection-site reactions, 38%; and fatigue, 33%. CRS events were mostly low grade (G; 46% G1–2, 2% G3) and mostly occurred following the first full dose on C1D15; all resolved and none led to discontinuation. ICANS occurred in 2 pts (G1, G2) and resolved. In 101 efficacy-evaluable pts, overall response rate (ORR) was 97%, with complete metabolic response (CMR) in 86%. Notably, pts achieved higher ORR/CMR rates with epcoritamab + R 2 vs their immediate prior tx line (ORR, 97% vs 85%; CMR, 86% vs 60%). Estimated 6-mo progression-free survival was 93%. In second-line (2L) pts with POD24, ORR/CMR rates were 95%/90% (additional high-risk subgroup data in Table). Additional data with longer follow-up will be presented. Conclusions: Epcoritamab + R 2 showed potent antitumor activity and a manageable safety profile in a large R/R FL population. Encouraging responses were seen in pts with high-risk disease, suggesting epcoritamab SC may abrogate negative effects of high-risk features. A separate POD24 cohort is planned, and epcoritamab + R 2 is being studied in the phase 3 EPCORE FL-1 trial (NCT05409066). Clinical trial information: NCT04663347 . [Table: see text]

Neurologic disability level at hospital discharge is an important outcome in many clinical research studies. Outside of clinical trials, neurologic outcomes must typically be extracted by labor intensive manual review of clinical notes in the electronic health record (EHR). To overcome this challenge, we set out to develop a natural language processing (NLP) approach that automatically reads clinical notes to determine neurologic outcomes, to make it possible to conduct larger scale neurologic outcomes studies. We obtained 7314 notes from 3632 patients hospitalized at two large Boston hospitals between January 2012 and June 2020, including discharge summaries (3485), occupational therapy (1472) and physical therapy (2357) notes. Fourteen clinical experts reviewed notes to assign scores on the Glasgow Outcome Scale (GOS) with 4 classes, namely 'good recovery', 'moderate disability', 'severe disability', and 'death' and on the Modified Rankin Scale (mRS), with 7 classes, namely 'no symptoms', 'no significant disability', 'slight disability', 'moderate disability', 'moderately severe disability', 'severe disability', and 'death'. For 428 patients' notes, 2 experts scored the cases generating interrater reliability estimates for GOS and mRS. After preprocessing and extracting features from the notes, we trained a multiclass logistic regression model using LASSO regularization and 5-fold cross validation for hyperparameter tuning. The model performed well on the test set, achieving a micro average area under the receiver operating characteristic and F-score of 0.94 (95% CI 0.93-0.95) and 0.77 (0.75-0.80) for GOS, and 0.90 (0.89-0.91) and 0.59 (0.57-0.62) for mRS, respectively. Our work demonstrates that an NLP algorithm can accurately assign neurologic outcomes based on free text clinical notes. This algorithm increases the scale of research on neurological outcomes that is possible with EHR data.

Introduction: To measure sleep in the intensive care unit (ICU), full polysomnography is impractical, while activity monitoring and subjective assessments are severely confounded. However, sleep is an intensely networked state, and reflected in numerous signals. Here, we explore the feasibility of estimating conventional sleep indices in the ICU with heart rate variability (HRV) and respiration signals using artificial intelligence methods Methods: We used deep learning models to stage sleep with HRV (through electrocardiogram) and respiratory effort (through a wearable belt) signals in critically ill adult patients admitted to surgical and medical ICUs, and in age and sex-matched sleep laboratory patients Results: We studied 102 adult patients in the ICU across multiple days and nights, and 220 patients in a clinical sleep laboratory. We found that sleep stages predicted by HRV- and breathing-based models showed agreement in 60% of the ICU data and in 81% of the sleep laboratory data. In the ICU, deep NREM (N2 + N3) proportion of total sleep duration was reduced (ICU 39%, sleep laboratory 57%, p < 0.01), REM proportion showed heavy-tailed distribution, and the number of wake transitions per hour of sleep (median 3.6) was comparable to sleep laboratory patients with sleep-disordered breathing (median 3.9). Sleep in the ICU was also fragmented, with 38% of sleep occurring during daytime hours. Finally, patients in the ICU showed faster and less variable breathing patterns compared to sleep laboratory patients Conclusion: The cardiovascular and respiratory networks encode sleep state information, which, together with artificial intelligence methods, can be utilized to measure sleep state in the ICU

Tribulus terrestris and Withania somnifera have been used in Indian medicine for a long time to treat a variety of diseases. The Present study evaluates anticancer activities of methanolic and aqueous extracts of W. somnifera and T. terrestris against breast cancer cell lines (MCF-7) were tested using MTT assay In-vitro, concentrations ranging of extracts from 2.5µg/ml to 25µg/ml.The results showed that all the plant extracts inhibited breast cancer cells' growth in dose-dependent. Methanolic and aqueous extracts of W. somnifera showing higher anticancer activity whit IC50 14.20 and 17.00µg/ml, respectively. The results of this study give direction for more pharmacological evaluation of these plants and isolation of their active compounds that may be tested and developed into new drugs for the treatment of the cancer.

Background: Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) and the most common indolent NHL. Rituximab-based therapy has been a mainstay in FL treatment, improving response rates, time to progression, and overall survival. Despite these improvements, most patients with FL will still relapse after frontline therapy, and therapies with curative potential are still elusive. Patients who relapse will experience poorer outcomes than those who do not and will continue to progress through successive lines of therapy (LOTs). The approval of treatments (eg, obinutuzumab and lenalidomide) may offer patients novel therapeutic options with the goal of improving outcomes in relapsed/refractory (R/R) FL. In this analysis, changes in treatment patterns and outcomes were assessed for the time periods from 2015 to 2017 compared with 2018 to 2021 to understand the impact of these new therapies on R/R FL. Methods: This retrospective, observational study used US patient electronic medical records (EMRs) and claims data from Optum Market Clarity. Inclusion criteria were ≥ 1 diagnosis of FL between January 1, 2015, and December 31, 2021, from EMRs or ≥ 2 diagnoses of FL from claims (index date = first diagnosis); no FL or other primary cancer diagnosis 12 months prior to the index date (except unspecified NHL and benign prostate cancer); ≥ 12 months prior enrollment/clinical activity, without a diagnosis of diffuse large B-cell lymphoma after first diagnosis of FL; at least 1 LOT after the index date; and ≥ 6 months of follow-up. Treatment regimen utilization and overall survival (OS; defined as the time from initiation of an LOT to death) was analyzed using the Kaplan-Meier method, and patients were censored at the end of enrollment period/last clinical activity. Log-rank tests were used to evaluate survival differences stratified by time period for each LOT. Results: A total of 2042 patients had 1 LOT, and 283 progressed to ≥ 2 LOTs between 2015 and 2017. For the 2018 to 2021 period, 2152 patients had 1 LOT and 441 progressed to ≥ 2 LOTs. The most prevalent first-line (1L) treatments across both time periods were rituximab-based therapies (2015-2017 vs 2018-2021: rituximab monotherapy [31.7% vs 30.0%], rituximab and bendamustine [41.1% vs 36.6%], and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [12.4% vs 12.2%]). Rituximab and bendamustine and rituximab monotherapy were also the most frequently used in second-line (2L) therapy and later during both time periods. Comparing the periods 2018 to 2021 with 2015 to 2017, increased utilization was observed for obinutuzumab-based therapies (1L: obinutuzumab and bendamustine [6.8% vs 0.8%]; ≥ 2L: obinutuzumab monotherapy [3.2% vs 0%]) and rituximab and lenalidomide (≥ 2L: 8.4% vs 3.9%). PI3K inhibitor utilization remained low across both time periods (1.1% [2018-2021] vs 0.7% [2015-2017]). Despite the introduction of new therapies, 2-year OS rates were similar across both time periods for patients receiving 1L and ≥ 2L therapy (Figures 1 and 2). Limitations: Optum Market Clarity does not have physician-assessed progression events; thus, LOT advancement in this analysis was based on treatment-regimen change and may not necessarily indicate disease progression. With all real-world studies, there are inherent limitations due to unmeasured confounders and censoring because of loss to follow-up; however, these limitations are likely to similarly apply to the results from both time periods in this analysis. Conclusions: This real-world analysis suggests that no clear standard of care exists in the frontline or R/R FL setting despite the approval of novel agents. In addition, 2-year OS outcomes in the frontline and R/R settings appear to have remained similar in the periods of 2015 to 2017 and 2018 to 2021, substantiating the continued need for and increased utilization of novel therapies that might offer improvement in patient outcomes across LOTs for FL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CAR-T cell therapy is an effective cancer therapy for multiple refractory/relapsed hematologic malignancies but is associated with substantial toxicity, including Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS). Improved detection and assessment of ICANS could improve management and allow greater utilization of CAR-T cell therapy, however, an objective, specific biomarker has not been identified. We hypothesized that the severity of ICANS can be quantified based on patterns of abnormal brain activity seen in electroencephalography (EEG) signals. We conducted a retrospective observational study of 120 CAR-T cell therapy patients who had received EEG monitoring. We determined a daily ICANS grade for each patient through chart review. We used visually assessed EEG features and machine learning techniques to develop the Visual EEG-Immune Effector Cell Associated Neurotoxicity Syndrome (VE-ICANS) score and assessed the association between VE-ICANS and ICANS. We also used it to determine the significance and relative importance of the EEG features. We developed the Visual EEG-ICANS (VE-ICANS) grading scale, a grading scale with a physiological basis that has a strong correlation to ICANS severity (R = 0.58 [0.47–0.66]) and excellent discrimination measured via area under the receiver operator curve (AUC = 0.91 for ICANS ≥ 2). This scale shows promise as a biomarker for ICANS which could help to improve clinical care through greater accuracy in assessing ICANS severity.

Coronavirus disease 2019 (COVID-19) is an illness caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Mutations in the genetic coding and the variations in the spike proteins are critical for the virus's mechanism of facilitating fusion with the human host, making the disease more severe. Recent research indicates that comorbidities including diabetes, hypertension, renal disease, heart failure, and atherosclerosis play a significant role in the severity and high mortality rates of (COVID-19), suggesting that perhaps the metabolic syndrome and its components are associated with COVID-19 morbidity. Primarily, angiotensin-converting enzyme 2 (ACE2) receptor is identified as the entrance receptor of SARS-CoV-2. Increased ACE2 expression, endothelial dysfunction plays a vital role in the progression and severity of complications developed due to COVID-19. In this review, we will discuss the association and management of cardiorenal disease and COVID-19.

Background Immune effector cell-associated neurotoxicity syndrome (ICANS) is a clinical and neuropsychiatric syndrome that can occur days to weeks following administration chimeric antigen receptor (CAR) T-cell therapy. Manifestations of ICANS range from encephalopathy and aphasia to cerebral edema and death. Because the onset and time course of ICANS is currently unpredictable, prolonged hospitalization for close monitoring following CAR T-cell infusion is a frequent standard of care. Methods This study was conducted at Brigham and Women’s Hospital from April 2015 to February 2020. A cohort of 199 hospitalized patients treated with CAR T-cell therapy was used to develop a combined hidden Markov model and lasso-penalized logistic regression model to forecast the course of ICANS. Model development was done using leave-one-patient-out cross validation. Results Among the 199 patients included in the analysis 133 were male (66.8%), and the mean (SD) age was 59.5 (11.8) years. 97 patients (48.7%) developed ICANS, of which 59 (29.6%) experienced severe grades 3–4 ICANS. Median time of ICANS onset was day 9. Selected clinical predictors included maximum daily temperature, C reactive protein, IL-6, and procalcitonin. The model correctly predicted which patients developed ICANS and severe ICANS, respectively, with area under the curve of 96.7% and 93.2% when predicting 5 days ahead, and area under the curve of 93.2% and 80.6% when predicting the entire future risk trajectory looking forward from day 5. Forecasting performance was also evaluated over time horizons ranging from 1 to 7 days, using metrics of forecast bias, mean absolute deviation, and weighted average percentage error. Conclusion The forecasting model accurately predicts risk of ICANS following CAR T-cell infusion and the time course ICANS follows once it has begun.Cite Now

The origin of the high pathogenicity of an emerging avian influenza H5N1 due to the -RRRKK- insertion at the cleavage loop of the hemagglutinin H5, was studied using the molecular dynamics technique, in comparison with those of the noninserted H5 and H3 bound to the furin (FR) active site. The cleavage loop of the highly pathogenic H5 was found to bind strongly to the FR cavity, serving as a conformation suitable for the proteolytic reaction. With this configuration, the appropriate interatomic distances were found for all three reaction centers of the enzyme-substrate complex: the arrangement of the catalytic triad, attachment of the catalytic Ser(368) to the reactive S1-Arg, and formation of the oxyanion hole. Experimentally, the--RRRKK--insertion was also found to increase in cleavage of hemagglutinin by FR. The simulated data provide a clear answer to the question of why inserted H5 is better cleaved by FR than the other subtypes, explaining the high pathogenicity of avian influenza H5N1.

OBJECTIVES:Delirium is a common and frequently underdiagnosed complication in acutely hospitalized patients, and its severity is associated with worse clinical outcomes. We propose a physiologically based method to quantify delirium severity as a tool that can help close this diagnostic gap: the Electroencephalographic Confusion Assessment Method Severity Score (E-CAM-S).DESIGN:Retrospective cohort study.SETTING:Single-center tertiary academic medical center.PATIENTS:Three-hundred seventy-three adult patients undergoing electroencephalography to evaluate altered mental status between August 2015 and December 2019.INTERVENTIONS:None.MEASUREMENTS AND MAIN RESULTS:We developed the E-CAM-S based on a learning-to-rank machine learning model of forehead electroencephalography signals. Clinical delirium severity was assessed using the Confusion Assessment Method Severity (CAM-S). We compared associations of E-CAM-S and CAM-S with hospital length of stay and inhospital mortality. E-CAM-S correlated with clinical CAM-S (R = 0.67; p < 0.0001). For the overall cohort, E-CAM-S and CAM-S were similar in their strength of association with hospital length of stay (correlation = 0.31 vs 0.41, respectively; p = 0.082) and inhospital mortality (area under the curve = 0.77 vs 0.81; p = 0.310). Even when restricted to noncomatose patients, E-CAM-S remained statistically similar to CAM-S in its association with length of stay (correlation = 0.37 vs 0.42, respectively; p = 0.188) and inhospital mortality (area under the curve = 0.83 vs 0.74; p = 0.112). In addition to previously appreciated spectral features, the machine learning framework identified variability in multiple measures over time as important features in electroencephalography-based prediction of delirium severity.CONCLUSIONS:The E-CAM-S is an automated, physiologic measure of delirium severity that predicts clinical outcomes with a level of performance comparable to conventional interview-based clinical assessment.