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Background: There have been conflicting results on the association of asthma with the severity of coronavirus disease 2019 (COVID-19). Poor metabolic health has been previously associated with both severe COVID-19 and inflammation in asthma., Objectives: To examine the association between asthma and COVID-19 outcomes and whether these associations are modified by metabolic syndrome., Methods: We performed an international, observational cohort study of adult patients hospitalized for COVID-19 from February 2020 through October 2021. The primary outcome was hospital mortality., Results: The study included 27,660 patients from 164 hospitals, 12,114 (44%) female, with a median (interquartile range) age of 63 years (51-75). After adjusting for age, sex, smoking, race, ethnicity, geographic region, and Elixhauser comorbidity index, we found that patients with asthma were not at greater risk of hospital death when compared with patients with no chronic pulmonary disease (controls) (adjusted odds ratio [aOR], 0.97; 95% CI, 0.90-1.04; P = .40). Patients with asthma, when compared with controls, required higher respiratory support identified by the need for supplemental oxygen (aOR, 1.07; 95% CI, 1.01-1.14; P = .02), high-flow nasal cannula or noninvasive mechanical ventilation (aOR, 1.06; 95% CI, 1.00-1.13; P = .04), and invasive mechanical ventilation (aOR, 1.09; 95% CI, 1.03-1.16; P = .003). Metabolic syndrome increased the risk of death in patients with asthma, but the magnitude of observed association was similar to controls in stratified analysis (interaction P value .24)., Conclusions: In this international cohort of hospitalized COVID-19 patients, asthma was not associated with mortality but was associated with increased need for respiratory support. Although metabolic dysfunction was associated with increased risks in COVID-19, these risks were similar for patients with or without asthma., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Laparoscopy in gallbladder cancer (GBC) has a possible role in staging, radical cure, and palliation in gallbladder cancer. However, a few studies have advocated the use of laparoscopic approach and concluded the safety of this approach. This present study was undertaken to determine the safety and feasibility between open and laparoscopic cholecystectomy in patients with the non-metastatic GBC., Materials and Methods: A systematic database search was performed in MEDLINE, Embase, and Google Scholar for relevant articles. As a result, a list of such studies, clinical trials, published in English up to May 2021, was obtained,14 studies were included and statistical analysis was conducted using RevMan software 5.3 (The Nordic Cochrane Centre)., Results: The 5-year survival rate was reported in 13 out of 14 studies (1388 patients), and all compared laparoscopic and open approach. There was no significant heterogeneity in between the studies (chi-square, 10.66; df, 12; I 2 , 0%). There was significant higher overall survival in open group (389/850 vs 194/538 or 1.45, 95% CI (1.12-1.88), P value, 0.005). There was no significant difference in recurrence rate, operative time, blood loss, lymph node yield, and postoperative complication in between open and laparoscopic groups., Conclusions: Our present study demonstrates that overall survival is significantly increased with open approach when compared with laparoscopic approach. There is no difference in recurrence rate, operative time, blood loss, lymph node yield, and postoperative complications between the open and laparoscopic cholecystectomy groups., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Indian Association of Surgical Oncology 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Importance: Early prognostication of patients hospitalized with COVID-19 who may require mechanical ventilation and have worse outcomes within 30 days of admission is useful for delivering appropriate clinical care and optimizing resource allocation., Objective: To develop machine learning models to predict COVID-19 severity at the time of the hospital admission based on a single institution data., Design, Setting, and Participants: We established a retrospective cohort of patients with COVID-19 from University of Texas Southwestern Medical Center from May 2020 to March 2022. Easily accessible objective markers including basic laboratory variables and initial respiratory status were assessed using Random Forest's feature importance score to create a predictive risk score. Twenty-five significant variables were identified to be used in classification models. The best predictive models were selected with repeated tenfold cross-validation methods., Main Outcomes and Measures: Among patients with COVID-19 admitted to the hospital, severity was defined by 30-day mortality (30DM) rates and need for mechanical ventilation., Results: This was a large, single institution COVID-19 cohort including total of 1795 patients. The average age was 59.7 years old with diverse heterogeneity. 236 (13%) required mechanical ventilation and 156 patients (8.6%) died within 30 days of hospitalization. Predictive accuracy of each predictive model was validated with the 10-CV method. Random Forest classifier for 30DM model had 192 sub-trees, and obtained 0.72 sensitivity and 0.78 specificity, and 0.82 AUC. The model used to predict MV has 64 sub-trees and returned obtained 0.75 sensitivity and 0.75 specificity, and 0.81 AUC. Our scoring tool can be accessed at https://faculty.tamuc.edu/mmete/covid-risk.html ., Conclusions and Relevance: In this study, we developed a risk score based on objective variables of COVID-19 patients within six hours of admission to the hospital, therefore helping predict a patient's risk of developing critical illness secondary to COVID-19., (© 2023. The Author(s).)

Tumor-associated macrophages (TAMs) constitute the most prolific resident of the tumor microenvironment (TME) that regulate its TME into tumor suppressive or progressive milieu by utilizing immunoediting machinery. Here, the tumor cells construct an immunosuppressive microenvironment that educates TAMs to polarize from anti-tumor TAM-M1 to pro-tumor TAM-M2 phenotype consequently contributing to tumor progression. In colorectal cancer (CRC), the TME displays a prominent pro-tumorigenic immune profile with elevated expression of immune-checkpoint molecules notably PD-1, CTLA4, etc., in both MSI and ultra-mutated MSS tumors. This authenticated immune-checkpoint inhibition (ICI) immunotherapy as a pre-requisite for clinical benefit in CRC. However, in response to ICI, specifically, the MSI hi tumors evolved to produce novel immune escape variants thus undermining ICI. Lately, TAM-directed therapies extending from macrophage depletion to repolarization have enabled TME alteration. While TAM accrual implicates clinical benefit in CRC, sustained inflammatory insult may program TAMs to shift from M1 to M2 phenotype. Their ability to oscillate on both facets of the spectrum represents macrophage repolarization immunotherapy as an effective approach to treating CRC. In this review, we briefly discuss the differentiation heterogeneity of colonic macrophages that partake in macrophage-directed immunoediting mechanisms in CRC progression and its employment in macrophage re-polarization immunotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: A novel, sensitive and specific LC-MS/MS technique was developed and validated for the quantification of fostemsavir in human plasma and its pharmacokinetic application in rabbits., Methods: Chromatographic separation of the fostemsavir and fosamprenavir (internal standard) were achieved on Zorbax C18 (50 mm × 2 mm × 5 μm) column with 0.80 mL/min flow rate and coupled with API6000 triple quadrupole MS in multi reaction monitoring mode by applying mass transitions m/z 584.16/105.03 for fostemsavir and m/z 586.19/57.07 for the internal standard., Results: The calibration curve exhibited linearity in concentration range of 58.5-2340.0 ng/mL for fostemsavir. The LLOQ was 58.5 ng/mL. The validated LC-MS/MS process was effectively applied for the analysis of plasma in healthy rabbits for determinations of Fostemsavir. From the pharmacokinetic data, the mean of C max and T max were 198.19 ± 5.85 ng/mL and 2.42 ± 0.13, respectively. Plasma concentration reduced with t 1/2 of 7.02 ± 0.14. AUC 0→Last value obtained was 2374.87 ± 29.75 ng. h/ml, respectively., Conclusion: In summary, the developed method has been successfully validated and pharmacokinetic parameters were demonstrated after oral administration of Fostemsavir to healthy rabbits., Competing Interests: Declaration of Competing Interest No, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aortic aneurysms-both abdominal and thoracic-are a significant cause of death and disability in the United States. Endovascular aneurysm repair has since become the preferred operative treatment of most thoracic and abdominal aneurysms because of a lower rate of complications and better outcomes compared with the open approach. Patients who present for endovascular aneurysm repair often have comorbid conditions related to their aortic pathology. These conditions should be evaluated and optimized before the procedure., Competing Interests: Disclosure Dr S. Cheruku is supported by the Society of Critical Care Medicine VIRUS Automation Grant and the Society of Critical Care Medicine VIRUS CURE-ID Grant., (Copyright © 2022 Elsevier Inc. All rights reserved.)

While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.

Irinotecan-loaded solid lipid nanoparticles (IRI-SLNs) was formulated and tested for its potential activity against colon cancer. IRI-SLNs were prepared by applying the principles of DoE. Nanoparticles were further surface modified using chitosan. Characterizations such as size, poly-dispersity, surface charge, morphology, entrapment, drug release pattern, cytotoxicity were conducted. In-vivo studies in male Wistar rats were carried to ascertain distribution pattern of SLNs and their acute toxicity on various vital organs. Lastly, stability of the SLNs were evaluated. Particles had a size, polydispersity and zeta potential of 430.77 ± 8.69 nm, 0.36 ± 0.02 and -40.06 ± 0.61 mV, respectively. Entrapment of IRI was 62.24 ± 2.90% in IRI-SLNs. Sustained drug release was achieved at a colonic pH and long-term stability of NPs was seen. Cytotoxicity assay results showed that SLNs exhibited toxicity on HCT-116 cells. Biodistribution studies confirmed higher concentration of drug in the colon after surface modification. An acute toxicity study conducted for 7 days showed no severe toxic effects on major organs. Thus, we picture that the developed SLNs may benefit in delivering IRI to the tumour cells, therefore decreasing the dose and dose-associated toxicities., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Studies indicate that the recovery from coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome may be slower than other viral pneumonia. There are limited data to guide decisions among patients who need extracorporeal membrane oxygenation (ECMO) support, especially the expected time of recovery and considering lung transplantation (LT)., Methods: This was a retrospective chart review of patients with COVID-19-associated acute respiratory distress syndrome placed on ECMO between March 1, 2020, and September 15, 2021 (n = 20; median age, 44 y; range, 22-62 y; male:female, 15:5). We contrasted the baseline variables and clinical course of patients with and without the need for ECMO support >30 d (ECMO long haulers, n = 10)., Results: Ten patients met the criteria for ECMO long haulers (median duration of ECMO, 86 d; range, 42-201 d). The long haulers were healthier at baseline with fewer comorbidities but had worse pulmonary compliance and higher partial pressure of CO2. They had a significantly higher number of membrane oxygenator failures, changes to their cannulation sites, and suffer more complications on ECMO. One of the long hauler was bridged to LT while another 6 patients recovered and were discharged. Overall survival was better among the ECMO long haulers (70% versus 20%; 9.3, 1.2-73; P = 0.03)., Conclusions: Despite worse pulmonary physiology, frequent complications, and a tortuous hospital course that may appear to portend a poor prognosis, ECMO long haulers have the potential to recover and be weaned off ECMO without the need for LT. A customized approach comprising a more conservative timeline for the consideration of LT may be prudent among these patients., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) course may be affected by environmental factors. Ecological studies previously suggested a link between climatological factors and COVID-19 fatality rates. However, individual-level impact of these factors has not been thoroughly evaluated yet., Aim: To study the association of climatological factors related to patient location with unfavorable outcomes in patients., Methods: In this observational analysis of the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: COVID-19 Registry cohort, the latitudes and altitudes of hospitals were examined as a covariate for mortality within 28 d of admission and the length of hospital stay. Adjusting for baseline parameters and admission date, multivariable regression modeling was utilized. Generalized estimating equations were used to fit the models., Results: Twenty-two thousand one hundred eight patients from over 20 countries were evaluated. The median age was 62 (interquartile range: 49-74) years, and 54% of the included patients were males. The median age increased with increasing latitude as well as the frequency of comorbidities. Contrarily, the percentage of comorbidities was lower in elevated altitudes. Mortality within 28 d of hospital admission was found to be 25%. The median hospital-free days among all included patients was 20 d. Despite the significant linear relationship between mortality and hospital-free days (adjusted odds ratio (aOR) = 1.39 (1.04, 1.86), P = 0.025 for mortality within 28 d of admission; aOR = -1.47 (-2.60, -0.33), P = 0.011 for hospital-free days), suggesting that adverse patient outcomes were more common in locations further away from the Equator; the results were no longer significant when adjusted for baseline differences (aOR = 1.32 (1.00, 1.74), P = 0.051 for 28-day mortality; aOR = -1.07 (-2.13, -0.01), P = 0.050 for hospital-free days). When we looked at the altitude's effect, we discovered that it demonstrated a non-linear association with mortality within 28 d of hospital admission (aOR = 0.96 (0.62, 1.47), 1.04 (0.92, 1.19), 0.49 (0.22, 0.90), and 0.51 (0.27, 0.98), for the altitude points of 75 MASL, 125 MASL, 400 MASL, and 600 MASL, in comparison to the reference altitude of 148 m.a.s.l, respectively. P = 0.001). We detected an association between latitude and 28-day mortality as well as hospital-free days in this worldwide study. When the baseline features were taken into account, however, this did not stay significant., Conclusion: Our findings suggest that differences observed in previous epidemiological studies may be due to ecological fallacy rather than implying a causal relationship at the patient level., Competing Interests: Conflict-of-interest statement: None of the authors have any conflict of interest to disclose., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Importance: Even with its proclivity for older age, coronavirus disease 2019 has been shown to affect all age groups. However, there remains a lack of research focused primarily on the young adult population., Objectives: To describe the epidemiology and outcomes of coronavirus disease 2019 and identify the risk factors associated with critical illness and mortality in hospitalized young adults., Design Settings and Participants: A retrospective cohort study of the Society of Critical Care Medicine's Viral Infection and Respiratory Illness Universal Study registry. Patients 18-40 years old, hospitalized from coronavirus disease 2019 from March 2020 to April 2021, were included in the analysis., Main Outcomes and Measures: Critical illness was defined as a composite of mortality and 21 predefined interventions and complications. Multivariable logistic regression was used to assess associations with critical illness and mortality., Results: Data from 4,005 patients (152 centers, 19 countries, 18.6% non-U.S. patients) were analyzed. The median age was 32 years (interquartile range, 27-37 yr); 51% were female, 29.4% Hispanic, and 42.9% had obesity. Most patients (63.2%) had comorbidities, the most common being hypertension (14.5%) and diabetes (13.7%). Hospital and ICU mortality were 3.2% (129/4,005) and 8.3% (109/1,313), respectively. Critical illness occurred in 25% ( n = 996), and 34.3% ( n = 1,376) were admitted to the ICU. Older age ( p = 0.03), male sex (adjusted odds ratio, 1.83 [95% CI, 1.2-2.6]), and obesity (adjusted odds ratio, 1.6 [95% CI, 1.1-2.4]) were associated with hospital mortality. In addition to the above factors, the presence of any comorbidity was associated with critical illness from coronavirus disease 2019. Multiple sensitivity analyses, including analysis with U.S. patients only and patients admitted to high-volume sites, showed similar risk factors., Conclusions: Among hospitalized young adults, obese males with comorbidities are at higher risk of developing critical illness or dying from coronavirus disease 2019., Competing Interests: Dr. Kumar is currently funded by funding the Gordon and Betty Moore Foundation, Centers for Disease Control and Prevention Foundation through the University of Washington, and Janssen Research & Development, LLC. Dr. Khanna is currently funded by a Clinical and Translational Science Institute National Institutes of Health (NIH)/National Center for Advancing Translational Science KL2 TR001421 award for a trial on continuous postoperative hemodynamic and saturation monitoring and is a site principal investigator (PI) (institutional funding) for a randomized trial of cytokine filtration in severe coronavirus disease 2019 (COVID-19) and a prospective observational trial of blood volume assessment and capillary permeability in COVID-19. He is funded for his position on the steering committee for the SILtuximab in Viral Acute Respiratory distress syndrome study. His institution also received funding for the Society of Critical Care Medicine (SCCM) Viral Infection and Respiratory Illness Universal Study (VIRUS) Electronic Medical Records (EMR) automation pilot. Dr. Bhalala is currently funded by the NIH (Site-PI for Stress Hydrocortisone in Pediatric Septic Shock—R01HD096901), The Children’s Hospital of Philadelphia (Site PI for Pediatric Resuscitation Quality Collaborative), Voelcker Pilot Grant (PI for the project on Prearrest Electrocardiographic Changes), The Children’s Hospital of San Antonio Endowed Chair Funds for ancillary projects related to SCCM VIRUS (COVID-19) Registry, and SCCM VIRUS EMR automation pilot. Dr. Kashyap receives funding from the NIH/National Heart, Lung and Blood Institute: R01HL 130881, UG3/UH3HL 141722; Gordon and Betty Moore Foundation and Janssen Research & Development, LLC; and royalties from Ambient Clinical Analytics. Inc. Dr. Gajic receives funding from the Agency of Healthcare Research and Quality R18HS 26609-2, NIH/National Heart, Lung and Blood Institute: R01HL 130881, UG3/UH3HL 141722; Department of Defense DOD W81XWH; American Heart Association Rapid Response Grant—COVID-19; and royalties from Ambient Clinical Analytics. Inc. Dr. Walkey currently receives funding from the NIH/National Heart, Lung and Blood Institute grants R01HL151607, R01HL139751, R01HL136660, Agency of Healthcare Research and Quality, R01HS026485, Boston Biomedical Innovation Center/NIH/NHLBI 5U54HL119145-07, and royalties from UpToDate. The remaining authors have disclosed that they do not have any conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Carbonylation of (hetero)aryl iodides/bromides with highly deactivated 2-aminopyridines using Pd-Co(CO) 4 bimetallic catalysis is accomplished. The use of Co 2 (CO) 8 as a solid CO(g) source enhanced reaction rates observed when compared to CO(g), and excellent yields highlight the versatility of the developed protocol. A wide range of electronically and sterically demanding heterocyclic amines and (hetero)aryl iodides/bromides employed for this study resulted in excellent yields of amino carbonylated products. The developed methodology was further extended to synthesize Trypanosome brucie and luciferase inhibitors.

Objectives: The inability to identify landmarks is an absolute contraindication for intraosseous access. The feasibility of landmark identification using ultrasound (US) has been demonstrated on human cadavers. We aimed to study the feasibility of point-of-care US in identifying proximal humerus landmarks in living human patients., Methods: This was a prospective cohort study conducted from May 3 to June 7, 2017, after approval from the Institutional Review Board at the Cleveland Clinic. Sixty upper extremities of 30 consenting participants across 3 distinct body mass index (BMI) groups (normal, obese, and morbidly obese) were alternately examined with a 12 L-RS linear US transducer (GE Healthcare, Chicago, IL) by 2 investigators. Six anatomic landmarks were identified: the humeral shaft, the surgical neck of the humerus, the lesser tubercle, the greater tubercle, the inter tubercular sulcus, and the target site for needle insertion on the greater tubercle. Rates of successful identification of all 6 landmarks as defined by independent agreement between the investigators were reported as estimated incidence rates with 95% bootstrap confidence interval (CI) sampling at the participant level., Results: Ultrasound had an overall success rate of 0.87 (95% CI, 0.78-0.95) in identifying all 6 landmarks with slight variability among various BMI groups. After excluding the surgical neck, the overall success rate improved to 0.93 (95% CI, 0.87-0.98), with minimum variability across BMI groups and no change in the ability to identify the target site., Conclusions: Ultrasound is reliable in identifying proximal humerus intraosseous landmarks, with reasonable accuracy across various BMI groups., (© 2020 American Institute of Ultrasound in Medicine.)

Objectives: To describe the outcomes of hospitalized patients in a multicenter, international coronavirus disease 2019 registry., Design: Cross-sectional observational study including coronavirus disease 2019 patients hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection between February 15, 2020, and November 30, 2020, according to age and type of organ support therapies., Setting: About 168 hospitals in 16 countries within the Society of Critical Care Medicine's Discovery Viral Infection and Respiratory Illness University Study coronavirus disease 2019 registry., Patients: Adult hospitalized coronavirus disease 2019 patients who did and did not require various types and combinations of organ support (mechanical ventilation, renal replacement therapy, vasopressors, and extracorporeal membrane oxygenation)., Interventions: None., Measurements and Main Results: Primary outcome was hospital mortality. Secondary outcomes were discharge home with or without assistance and hospital length of stay. Risk-adjusted variation in hospital mortality for patients receiving invasive mechanical ventilation was assessed by using multilevel models with hospitals as a random effect, adjusted for age, race/ethnicity, sex, and comorbidities. Among 20,608 patients with coronavirus disease 2019, the mean (± sd) age was 60.5 (±17), 11,1887 (54.3%) were men, 8,745 (42.4%) were admitted to the ICU, and 3,906 (19%) died in the hospital. Hospital mortality was 8.2% for patients receiving no organ support (n = 15,001). The most common organ support therapy was invasive mechanical ventilation (n = 5,005; 24.3%), with a hospital mortality of 49.8%. Mortality ranged from 40.8% among patients receiving only invasive mechanical ventilation (n =1,749) to 71.6% for patients receiving invasive mechanical ventilation, vasoactive drugs, and new renal replacement therapy (n = 655). Mortality was 39% for patients receiving extracorporeal membrane oxygenation (n = 389). Rates of discharge home ranged from 73.5% for patients who did not require organ support therapies to 29.8% for patients who only received invasive mechanical ventilation, and 8.8% for invasive mechanical ventilation, vasoactive drugs, and renal replacement; 10.8% of patients older than 74 years who received invasive mechanical ventilation were discharged home. Median hospital length of stay for patients on mechanical ventilation was 17.1 days (9.7-28 d). Adjusted interhospital variation in mortality among patients receiving invasive mechanical ventilation was large (median odds ratio 1.69)., Conclusions: Coronavirus disease 2019 prognosis varies by age and level of organ support. Interhospital variation in mortality of mechanically ventilated patients was not explained by patient characteristics and requires further evaluation., Competing Interests: Drs. Kumar’s, Denson’s, Walkey’s, and Kashyap’s institutions received funding from the Gordon and Betty Moore Foundation. Drs. Kumar’s and Kashyap’s institutions received funding from Janssen Research & Development, LLC. Drs. Kaufman’s and Denson’s institutions received funding from the Society of Critical Care Medicine. Dr. Banner-Goodspeed received partial salary support through her home institution from multiple federal research grants (including from the National Institutes of Health [NIH] and Department of Defense) as key personnel, not the principal investigator. Dr. Anderson III disclosed he is an Advisory Board member for Gift of Life Michigan. Dr. Denson received other support from American Diabetes Association Grant #7-20-COVID-53. Dr. Gajic received support for article research from Gordon and Betty Moore Foundation. Dr. Walkey receives funding from the NIH/National Heart, Lung and Blood Institute grants R01HL151607, R01HL139751, and R01HL136660, Agency of Healthcare Research and Quality, R01HS026485, Boston Biomedical Innovation Center/NIH/NHLBI 5U54HL119145-07, and royalties from UptoDate. They had no influence on acquisition, analysis, interpretation, and reporting of pooled data for this article. Dr. Harhay’s institution receives funding from the NIH/National Heart, Lung and Blood Institute grant R00 HL141678, and he received support for article research from the NIH. They had no influence on acquisition, analysis, interpretation, and reporting of pooled data for this article. Dr. Gajic receives funding from the Agency of Healthcare Research and Quality R18HS 26609-2, NIH/National Heart, Lung and Blood Institute: R01HL 130881 and UG3/UH3HL 141722; Department of Defense W81XWH; American Heart Association Rapid Response Grant—coronavirus disease 2019 (COVID-19); and royalties from Ambient Clinical Analytics. They had no influence on acquisition, analysis, interpretation, and reporting of pooled data for this article. Dr. Kashyap receives funding from the NIH/National Heart, Lung and Blood Institute: R01HL 130881 and UG3/UH3HL 141722; Gordon and Betty Moore Foundation, and Janssen Research & Development, LLC; and royalties from Ambient Clinical Analytics. They had no influence on acquisition, analysis, interpretation, and reporting of pooled data for this article. Dr. St. Hill receives funding from the Minnesota Department of Health. They had no influence on acquisition, analysis, interpretation, and reporting of pooled data for this article. Dr. Denson receives funding for COVID-19 research from the American Diabetes Association grant #7-20-COVID-053, Centers for Disease Control and Prevention BroadAgency Announcement 75D301-20-R-67897, and National Institute of General Medical Sciences/NIH award U54 GM104940, which funds the Louisiana Clinical and Translational Science Center. They had no influence on acquisition, analysis, interpretation, and reporting of pooled data for this article. Dr. Martin receives funding from the Biomedical Advanced Research and Development Authority and NIH through the National Institute of Biomedical Imaging and Bioengineering U54 EB-027690, the National Heart, Lung and Blood Institute: U54 HL-143541-02S2, the National Institute for General Medical Sciences R01 GM-104323, and the Office of the Director OT2 OD-026551; as well as funding from Genentech for clinical trial monitoring. They had no influence on acquisition, analysis, interpretation, and reporting of pooled data for this article. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Cardiopulmonary resuscitation (CPR) in patients with severe acute respiratory syndrome coronavirus-2-associated disease (coronavirus disease 2019) poses a unique challenge to health- care providers due to the risk of viral aerosolization and disease transmission. This has caused some centers to modify existing CPR procedures, limit the duration of CPR, or consider avoiding CPR altogether. In this review, the authors propose a procedure for CPR in the intensive care unit that minimizes the number of personnel in the immediate vicinity of the patient and conserves the use of scarce personal protective equipment. Highlighting the low likelihood of successful resuscitation in high-risk patients may prompt patients to decline CPR. The authors recommend the preemptive placement of central venous lines in high-risk patients with intravenous tubing extensions that allow for medication delivery from outside the patients' rooms. During CPR, this practice can be used to deliver critical medications without delay. The use of a mechanical compression system for CPR further reduces the risk of infectious exposure to health- care providers. Extracorporeal membrane oxygenation should be reserved for patients with few comorbidities and a single failing organ system. Reliable teleconferencing tools are essential to facilitate communication between providers inside and outside the patients' rooms. General principles regarding the ethics and peri-resuscitative management of coronavirus 2019 patients also are discussed., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Combined thoracic-abdominal organ transplants are infrequently performed procedures indicated for patients with failure of two or more transplantable organs. In this review, we discuss recipient selection, surgical considerations, anesthetic management, and outcomes associated with common combinations of thoracic-abdominal transplant operations. General principles regarding the postoperative care of these patients are also discussed. These procedures present a unique challenge requiring specialized knowledge, technical expertise, and leadership from the anesthesiology team throughout the perioperative period.

Thoracic endovascular aneurysm repair (TEVAR) is fast becoming the primary treatment of thoracic aortic aneurysms, thoracic aortic dissections, acute aortic injuries, and other conditions affecting the thoracic aorta. Patients scheduled for TEVAR tend to have a host of comorbid conditions, including coronary artery disease, diabetes, and chronic obstructive pulmonary disease. Intraoperative management should optimize end-organ perfusion, facilitate neuromonitoring, and adjust hemodynamic management. Complications include spinal cord injury, peripheral vascular injury, contrast-induced nephropathy, postimplantation syndrome, and endoleaks. Patients who undergo TEVAR require care in a postoperative environment where these complications can be rapidly detected and aggressively treated., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Conjugated polymer nanoparticles exhibit very interesting properties for use as bio-imaging agents. In this paper, we report the synthesis of PCDTBT (poly([9-(1'-octylnonyl)-9H-carbazole-2,7-diyl]-2,5-thiophenediyl-2,1,3-benzothiadiazole-4,7-diyl-2,5-thiophene-diyl)) nanoparticles of varying sizes using the mini-emulsion and emulsion/solvent evaporation approach. The effect of the size of the particles on the optical properties is investigated using UV-Vis absorption and fluorescence emission spectroscopy. It is shown that PCDTBT nanoparticles have a fluorescence emission maximum around 710 nm, within the biological near-infrared "optical window". The photoluminescence quantum yield shows a characteristic trend as a function of size. The particles are not cytotoxic and are taken up successfully by human lung cancer carcinoma A549 cells. Irrespective of the size, all particles show excellent fluorescent brightness for bioimaging. The fidelity of the particles as fluorescent probes to study particle dynamics in situ is shown as a proof of concept by performing raster image correlation spectroscopy. Combined, these results show that PCDTBT is an excellent candidate to serve as a fluorescent probe for near-infrared bio-imaging.

Fluorescent conjugated polymers formulated in nanoparticles show attractive properties to be used as bioimaging probes. However, their fluorescence brightness is generally limited by quenching phenomena due to interchain aggregation in the confined nanoparticle space. In this work, branched conjugated polymer networks are investigated as a way to enhance the photoluminescence quantum yield of the resulting conjugated polymer nanoparticles (CPNs). 1,3,5-Tribromobenzene and 2,2',7,7'-tetrabromo-9,9'-spirobifluorene are chosen as branching moieties and are added in 3 or 5 mol % to the poly( p -phenylene ethynylene) (PPE) conjugated polymer synthesis. Nanoparticles of all samples are prepared via the combined miniemulsion/solvent evaporation technique. The optical properties of the branched polymers in solution and in nanoparticle form are then compared to those of the linear PPE counterpart. The fluorescence quantum yield of the CPNs increases from 5 to 11% for the samples containing 1,3,5-tribromobenzene. Furthermore, when 5 mol % of either branching molecule is used, the one-photon fluorescence brightness doubles. The nanoparticles show low cytotoxicity in A549 human lung carcinoma cells up to a concentration of 100 μg/mL for 24 h. They also exhibit good particle uptake into cells and compatibility with two-photon imaging.

In this study, methanolic extract of Saraca asoca bark was evaluated for its aphrodisiac potential using male and female Wistar albino rats. Male rats were dosed daily for 54 days at a dose of 100 mg/kg p.o. Sexual activity of male rats was assessed after 14, 28, 42 and 54 days of the study. Male rats were placed in a glass chamber lit with a dim red light (10W) followed by the introduction of sexually receptive female rats in a ratio of 1:1. Improvement in sexual behaviour of male rats was characterised by an increase in both mount frequency and intromission frequency and decrease or reduction in mount latency and intromission latency compared to normal control. After completion of the study, the effect of the S. asoca extract on sperm count, sperm motility and sperm morphology was also assessed. The extract of S. asoca bark was found to be safe as it did not affect these sperm parameters. From this study, it was found that methanolic extract of S. asoca bark plays a role in enhancing sexual behaviour and potential without causing reproductive toxicity., (© 2018 Blackwell Verlag GmbH.)

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N -methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 ( 6 ) and its active parent molecule BMS-986169 ( 5 ), which demonstrated high binding affinity for the GluN2B allosteric site ( K i = 4.0 nM) and selective inhibition of GluN2B receptor function (IC 50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5 , 6 , or the major circulating metabolites met-1 and met-2 . The prodrug BMS-986163 ( 6 ) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder., Competing Interests: The authors declare no competing financial interest.

During the last decade, conjugated polymers have emerged as an interesting class of fluorescence imaging probes since they generally show high fluorescence brightness, high photostability, fast emission rates, non-blinking behavior and low cytotoxicity. The main concern related to most conjugated polymers is their lack of hydrophilicity and thereby poor bio-availability. This can, however, be overcome by the formulation of conjugated polymer nanoparticles in aqueous medium. This review provides an overview of the different techniques employed for the preparation of conjugated polymer nanoparticles, together with methods to improve their photoluminescence quantum yields. For selective targeting of specific cells, dedicated surface functionalization protocols have been developed, using different functional groups for ligand immobilization. Finally, conjugated polymer nanoparticles have recently also been employed for theranostic applications, wherein the particles are simultaneously used as fluorescent probes and carriers for anti-tumor drugs., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Conjugated polymers are versatile bio-imaging probes as their optical properties can be readily fine-tuned. In this manuscript, fluorescent conjugated polymer nanoparticles are fabricated using three different poly(p-phenylene ethynylene) (PPE) derivatives. The polymers have the same backbone but carry different side chains, i.e. regular octyloxy substituents, half of the octyloxy chains azide terminated, or azide functionalized tetraethylene glycol (TEG) moieties. The azide groups are specifically chosen to allow coupling of (bio)molecules to the surface of the particles using straightforward azide-alkyne click reactions, enabling different bioconjugation and targeting strategies. The influence of the functionalization pattern on the size and optical properties of the nanoparticles is studied using transmission electron microscopy, dynamic light scattering, UV-Vis absorption and fluorescence spectroscopy. The polymer containing the azide functionalized TEG chains affords larger particles, which can be attributed to hydration of the outer layer of the more hydrophilic polymer particles. However, this does not impact the fluorescence quantum yield. The two azide functionalized PPE particles exhibit the highest quantum yields (13%). Despite the presence of azide groups on two of the three materials, all particles are biocompatible and taken up by A549 human lung carcinoma cells. A proof of concept click reaction was performed as well., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Aortic surgeries requiring hypothermic circulatory arrest evoke systemic inflammatory responses that often manifest as vasoplegia and hypotension. Because mast cells can rapidly release vasoactive and proinflammatory effectors, we investigated their role in intraoperative hypotension., Methods: We studied 31 patients undergoing proximal aortic repair with hypothermic circulatory arrest between June 2013 and April 2015 at Duke University Medical Center. Plasma samples were obtained at different intraoperative time points to quantify chymase, interleukin-6, interleukin-8, tumor necrosis factor alpha, and white blood cell CD11b expression. Hypotension was defined as the area (minutes × millimeters mercury) below a mean arterial pressure of 55 mm Hg. Biomarker responses and their association with intraoperative hypotension were analyzed by 2-sample t test and Wilcoxon rank sum test. Multivariable logistic regression analysis was used to examine the association between clinical variables and elevated chymase levels., Results: Mast cell-specific chymase increased from a median 0.97 pg/mg (interquartile range [IQR], 0.01-1.84 pg/mg) plasma protein at baseline to 5.74 pg/mg (IQR, 2.91-9.48 pg/mg) plasma protein after instituting cardiopulmonary bypass, 6.16 pg/mg (IQR, 3.60-9.41 pg/mg) plasma protein after completing circulatory arrest, and 7.64 pg/mg (IQR, 4.63-12.71 pg/mg) plasma protein after weaning from cardiopulmonary bypass (each P value < .0001 vs baseline). Chymase was the only biomarker associated with hypotension during (P = .0255) and after (P = .0221) cardiopulmonary bypass. Increased temperatures at circulatory arrest and low presurgical hemoglobin levels were independent predictors of increased chymase responses., Conclusions: Mast cell activation occurs in cardiac surgery requiring cardiopulmonary bypass and hypothermic circulatory arrest and is associated with intraoperative hypotension., Competing Interests: The authors declare no conflict of interest., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

A series of novel 4-amino-6-(1,3,4-oxadiazolo/1,3,4-thiadiazolo)-pyrimidine derivatives of biological interest were prepared by sequential amination, hydrazide formation, and hydrazine carbothioamidination followed by cyclization. All the synthesized compounds (6a-6h and 7a-7f) were screened for antibacterial and antifungal activity. From this group, compound 7f (MIC (μg/mL μg/mL )/Inhibition (mm): 6.25/23-30) showed good antibacterial and antifungal activity. Reagents and conditions: (a) Ethyl acetoacetate, 60% NaH, 1,4-dioxane, 60°C, 6 h; (b) DIPEA, 1,4-dioxane, 100°C, 14 h; (c) NH2NH2 ⋅ H2O, EtOH, reflux, 14 h; (d) Tolyl isothiocyanatobenzene, DMF, RT, 2 h; (e) (if X = O) EDC⋅ HCl, TEA, DMF, RT, 14 h; (f) (if X = S) Conc. H2O4, RT, 14h.

The pH dependent reactivity of an analog methanobactin peptide (amb) with the sequence acetyl-His1-Cys2-Gly3-Pro4-His5-Cys6 (Mw = 694.79 Da) was investigated for its binding ability for a series of biologically active metal ions using ion mobility-mass spectrometry. Cu(II), Zn(II) and, to a lesser extent, Ni(II) were observed to form complexes with amb from 1 : 1 molar equivalent amb:metal(II) solutions at pH > 6, indicating the deprotonation of the imidazole N of His (pKa = 6.0) must occur to allow the initial anchoring of the metal(II) ion. The amb-metal(II) complexes were observed as both positive and negative ions, although the Zn(II) complexes preferred forming an overall negative ion complex which is consistent with the two thiolate groups of Cys2 and Cys6 being involved in Zn(II) coordination. The Cu(II) addition, however, always resulted in a Cys-Cys disulfide bridge in both Cu-free amb and Cu-bound amb, which excluded thiolate coordination to Cu(II). Collision cross- section measurements showed the Zn(II) and Cu(II) negative ion complexes were smaller than the positive ion complexes, suggesting Zn(II) binds most compactly via the imidazole N of His and the thiolate groups of Cys, whereas Cu(II) binds most compactly via the imidazole N of His and two deprotonated N of two amide groups on the peptide backbone. The lowest energy structures from the B3LYP/LanL2DZ level of theory showed the functional groups of His5, Cys2 and Cys6 coordinated to Zn(II), whereas the His1 and the amide nitrogens of Cys2 and Gly3 coordinated to Cu(II), producing an overall negative charged complex. The positive ion complexes of Zn(II) and Cu(II) were both shown to coordinate via the two imidazole nitrogens of His1 and His5 and either the oxygen of the backbone carbonyl of Cys6 or the oxygen of the C-terminal, respectively.

We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl]phenyl}acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs alpha1-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.

Purpose: The value of MRI and ultrasound in quantifying hepatic steatosis is assessed and the results compared with those obtained by liver biopsies., Methods: A total of 38 patients undergoing hepatic biopsy for a variety of liver diseases were recruited for this study. Hepatic fat morphology and severity were assessed visually in each biopsy specimen. Steatosis pattern included macrovesicular, microvesicular, or mixed. The severity of hepatic steatosis was assessed by MRI through chemical shift imaging (n = 38) and by ultrasound through echogenicity (n = 31)., Results: MRI had a better correlation than ultrasound for microscopic fat content (r = 0.77, P < 0.001 vs. r = 0.41, P < 0.05). In macrovesicular steatosis, MRI and ultrasound both correlated well with microscopic fat content (r = 0.92, P < 0.001 vs. r = 0.90, P < 0.001). In nonalcoholic fatty liver disease, ultrasound revealed severe steatosis in all instances, but MRI fat content ranged greatly (19%-40%). In diagnoses excluding nonalcoholic fatty liver disease, increasing ultrasound severity did not correspond to advanced MRI fat content., Conclusion: Hepatic MRI and ultrasound are both useful in identifying heavy fat accumulation associated with nonalcoholic fatty liver disease. MRI is superior to ultrasound in detecting and quantifying minor degrees of fatty metamorphosis in the liver.

To better develop N-[4-(benzoylamino)phenylsulfonyl]glycine (BAPSG), a potent and selective aldose reductase inhibitor capable of delaying the progression of ocular diabetic complications, the objective of this study was to assess its pharmacokinetics. The plasma pharmacokinetics of BASPG was assessed in male Sprague-Dawley rats following intravenous, intraperitoneal and oral routes of administration and its distribution to various tissues including those of the eye was studied following intraperitoneal administration. In addition, rat plasma protein binding of BAPSG was studied using ultracentrifugation method and its ocular tissue disposition was assessed following topical administration in rabbits. Plasma and tissue levels of BAPSG were analysed using an HPLC assay. BAPSG exhibited dose-proportionate AUC0 --> infinity (area under the plasma concentration-time curve) following both intravenous and intraperitoneal administration over the dose range (5-50 mg kg(-1)) studied and an erratic oral absorption profile with low oral bioavailability. The fraction bioavailability following oral and intraperitoneal administration was 0.06 and 0.7-1, respectively. BAPSG exhibited short plasma elimination half-lives in the range 0.5-1.5 h. BAPSG was bound to rat plasma proteins and the percent protein binding ranged from 83 to 99.8%. BAPSG was better distributed to cornea, lens and retina than to brain, following intraperitoneal administration in rats. However, the distribution was lower compared with kidney and liver. Following topical administration in rabbits, BAPSG delivery to the surface ocular tissues, cornea and conjunctiva was higher compared with intraocular tissues, aqueous humour, iris-ciliary body and lens. Thus, BAPSG was distributed to ocular tissues following systemic and topical modes of administration.

Insulin resistance and altered maternal metabolism in gestational diabetes mellitus (GDM) may impair fetal arachidonic acid (AA) and docosahexaenoic acid (DHA) status. The objectives were to test the hypothesis that fetal polyunsaturated fatty acids would be altered with GDM and identify factors related to fetal phospholipid (PL) AA and DHA. Maternal and cord vein erythrocyte PL fatty acids were determined in GDM (n = 13) and healthy pregnant women (controls, n = 12). Cord vein erythrocyte PL AA and DHA concentrations were significantly lower in GDM vs. controls. Maternal blood hemoglobin A1C was inversely correlated to fetal erythrocyte PL DHA and AA in controls and GDM (n = 25). Pregravid body mass index was negatively associated with fetal PL DHA. The data support the hypothesis that there is impairment in fetal accretion of DHA and AA in GDM.