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The fusion of thermal and visible images acts as an important device for target detection. The quality of the spectral content of the fused image improves with wavelet-based image fusion. However, compared to PCA-based fusion, most wavelet-based methods provide results with a lower spatial resolution. The outcome gets better when the two approaches are combined, but they may still be refined. Compared to wavelets, the curvelet transforms more accurately depict the edges in the image. Enhancing the edges is a smart way to improve spatial resolution and the edges are crucial for interpreting the images. The fusion technique that utilizes curvelets enables the provision of additional data in both spectral and spatial areas concurrently. In this paper, we employ an amalgamation of Curvelet Transform and a Bounded PCA (CTBPCA) method to fuse thermal and visible images. To evidence the enhanced efficiency of our proposed technique, multiple evaluation metrics and comparisons with existing image merging methods are employed. Our approach outperforms others in both qualitative and quantitative analysis, except for runtime performance. Future Enhancement-The study will be based on using the fused image for target recognition. Future work should also focus on this method's continued improvement and optimization for real-time video processing. [ABSTRACT FROM AUTHOR]

We explore the dynamics of a tracer in an active particle harmonic chain, investigating the influence of interactions. Our analysis involves calculating mean-squared displacements (MSDs) and space-time correlations through Green's function techniques and numerical simulations. Depending on chain characteristics, i.e. , different time scales determined by interaction stiffness and persistence of activity, tagged-particle MSDs exhibit ballistic, diffusive, and single-file diffusion (SFD) scaling over time, with crossovers explained by our analytic expressions. Our results reveal transitions in bulk particle displacement distributions from an early-time bimodal to late-time Gaussian, passing through regimes of unimodal distributions with finite support and negative excess kurtosis and longer-tailed distributions with positive excess kurtosis. The distributions exhibit data collapse, aligning with ballistic, diffusive, and SFD scaling in the appropriate time regimes. However, at much longer times, the distributions become Gaussian. Finally, we derive analytic expressions for steady-state static and dynamic two-point displacement correlations. We verify these from simulations and highlight the differences from the equilibrium results.

Using the Lebwohl-Lasher interaction for reciprocal local alignment, we present a comprehensive phase diagram for a dry, apolar, active nematic system using its stochastic off-lattice dynamics. The nematic-isotropic transition in this system is first-order and occurs alongside a fluctuation-dominated phase separation. Our phase diagram identifies three distinct regions based on activity and orientational noise relative to alignment strength: a homogeneous isotropic phase, a nematic phase with giant density fluctuations, and a coexistence region. Using mean-field analysis and hydrodynamic theory, we demonstrate that reciprocal interactions lead to a density fluctuation-induced first-order transition and derive a phase boundary consistent with numerical results. Quenching from the isotropic to nematic phase reveals coarsening dynamics where nematic ordering precedes particle clustering. Both the nematic and density fields exhibit similar scaling behaviors, exhibiting dynamic exponents z S ≈ 2.5 and z ρ ≈ 2.34, consistently falling within the range of 2 and 3.

Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using 13 C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/ Slc16a1 ). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions., Competing Interests: Disclosures S.G.D. serves as a consultant for Abbott Laboratories and Pfizer. S.G.D and J.R have received research support from Novartis and Merck. The remaining authors declare no competing interests or financial relationships.

Background: The incidence of nosocomial meningitis, and utility of lumbar puncture, is unclear in hospitalized patients without preceding neurosurgery or head trauma., Aim: We planned for a systematic review and meta-analysis to evaluate accuracy of clinical features and diagnostic utility of lumbar puncture in nosocomial meningitis., Methods: We searched MEDLINE, MEDLINE In-Process/ePubs, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science from inception until June 5, 2024. We included studies evaluating utility of clinical features, or lumbar puncture, to rule out nosocomial meningitis in patients without preceding neurosurgery or head trauma. We excluded studies examining community acquired meningitis, outbreaks, HIV positive individuals, and case reports. Outcomes included incidence, risk factors and diagnostic accuracy of clinical features for nosocomial meningitis, and lumbar puncture complications. Given few included studies and heterogeneity, we could only summarize incidence of nosocomial meningitis., Findings: Of 13,302 citations, we reviewed 197 manuscripts and included 6. There were 23 of 333 (6.9%, very low certainty) positive lumbar punctures among individuals who underwent lumbar puncture to rule out nosocomial meningitis., Conclusions: There were insufficient data to evaluate the diagnostic accuracy of lumbar puncture in nosocomial meningitis in patients without preceding neurosurgery or head trauma. Very low certainty evidence indicates the incidence of nosocomial meningitis is low in this population. Given complications and costs associated with lumbar puncture, future studies should evaluate its utility in nosocomial meningitis. In the meantime, it may be reasonable to reserve lumbar puncture to instances of high suspicion., (© 2024 The Authors.)

Dengue virus, an arbovirus of genus Flavivirus, is an infectious disease causing organisms in the tropical environment leading to numerous deaths every year. No therapeutic is available against the virus till date with only symptomatic relief available. Here, we have tried to design therapeutic compounds from scratch by fragment based method followed by pharmacophore based modelling to find suitable similar structure molecules and validated the same by MD simulation, followed by binding energy calculations and ADMET analysis. The receptor binding region of the dengue envelope protein was considered as the target for prevention of viral host cell entry and thus infection. This resulted in the final selection of kanamycin as a stable binding molecule against the Dengue virus envelope protein receptor binding domain. This study results in selection of a single molecule having high binding energy and prominent stable interactions as determined by post simulation analyses. This study aims to provide a direction for development of small molecule therapeutics against the dengue virus in order to control infection. This study may open a new avenue in the arena of structure based and fragment based therapeutic design to obtain novel molecules with therapeutic potential., Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00262-9., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024. Springer Nature or its licensor (e.g. a society or other partner) 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.)

Oxidative phosphorylation is regulated by mitochondrial calcium (Ca 2+ ) in health and disease. In physiological states, Ca 2+ enters via the mitochondrial Ca 2+ uniporter and rapidly enhances NADH and ATP production. However, maintaining Ca 2+ homeostasis is critical: insufficient Ca 2+ impairs stress adaptation, and Ca 2+ overload can trigger cell death. In this review, we delve into recent insights further defining the relationship between mitochondrial Ca 2+ dynamics and oxidative phosphorylation. Our focus is on how such regulation affects cardiac function in health and disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, mitochondrial cardiomyopathies, Barth syndrome, and Friedreich's ataxia. Several themes emerge from recent data. First, mitochondrial Ca 2+ regulation is critical for fuel substrate selection, metabolite import, and matching of ATP supply to demand. Second, mitochondrial Ca 2+ regulates both the production and response to reactive oxygen species (ROS), and the balance between its pro- and antioxidant effects is key to how it contributes to physiological and pathological states. Third, Ca 2+ exerts localized effects on the electron transport chain (ETC), not through traditional allosteric mechanisms but rather indirectly. These effects hinge on specific transporters, such as the uniporter or the Na + /Ca 2+ exchanger, and may not be noticeable acutely, contributing differently to phenotypes depending on whether Ca 2+ transporters are acutely or chronically modified. Perturbations in these novel relationships during disease states may either serve as compensatory mechanisms or exacerbate impairments in oxidative phosphorylation. Consequently, targeting mitochondrial Ca 2+ holds promise as a therapeutic strategy for a variety of cardiac diseases characterized by contractile failure or arrhythmias.

Mpox virus is the latest member of the Poxviridae family of which small pox virus is a member. Monekypox virus has led to thousands of infections across the globe. Poxvirus gains entry into the cell making use of glycosaminoglycans like chondroitin sulphate and heparan sulphate. The interaction of the Mpox virus protein E8L also called cell surface binding protein is crucial for host cell attachment, membrane fusion and viral entry into the host cell leading to establishment of infection thus making this protein a very attractive therapeutic target. In this study we have tried to utilize the chondroitin sulphate binding groove present in the protein and identify molecules which are structurally similar to chondroitin sulphate. These molecules can thus occupy the same pocket but with a better binding affinity than chondroitin sulphate in order to outcompete the latter molecule from binding to the E8L protein and thus prevent it from performing its function. This study may pave the way for development of highly efficient therapeutics against the Mpox virus and further curb its infective potential.Communicated by Ramaswamy H. Sarma.

We consider a two-dimensional, tangentially active, semi-flexible, self-avoiding polymer to find a dynamical re-entrant transition between motile open chains and spinning achiral spirals with increasing activity. Utilizing probability distributions of the turning number, we ascertain the comparative stability of the spiral structure and present a detailed phase diagram within the activity inertia plane. The onset of spiral formation at low activity levels is governed by a torque balance and is independent of inertia. At higher activities, however, inertial effects lead to spiral destabilization, an effect absent in the overdamped limit. We further delineate alterations in size and shape by analyzing the end-to-end distance distribution and the radius of gyration tensor. The Kullback-Leibler divergence from equilibrium distributions exhibits a non-monotonic relationship with activity, reaching a peak at the most compact spirals characterized by the most persistent spinning. As inertia increases, this divergence from equilibrium diminishes.

Dengue fever is a serious health hazard on a global scale and its primary causative agent is the dengue virus (DENV). The non-structural protein 1 (NS1) of DENV plays a pivotal role in pathogenesis. It is associated with several autoimmune events, endothelial cell apoptosis, and vascular leakage, which increase mainly during the critical phase of infection. In this study, important residues of the oligomerization domain of NS1 protein were identified by literature searches. Virtual screening has been conducted using the entire dataset of the DrugBank database and the potential small-molecule inhibitors against the NS1 protein have been chosen on the basis of binding energy values. This is succeeded by molecular dynamics (MD) simulations of the shortlisted compounds, ultimately giving rise to five compounds. These five compounds were further subjected to RAMD simulations by applying a random direction force of specific magnitude on the ligand center of mass in order to push the ligand out of the protein-binding pocket, for the quantitative estimation of their binding energy values to determine the interaction strength between protein and ligand which prevents ligand unbinding from its binding site, ultimately leading to the selection of three major compounds, DB00826 (Natamycin), DB11274 (Dihydro-alphaergocryptine), and DB11275 (Epicriptine), with the DB11274 having a role against idiopathic Parkinson's disease, and thus may have possible important roles in the prevention of dengue-associated Parkinsonism. These compounds may act as prospective drugs against dengue, by preventing the oligomerization of the NS1 protein, thereby preventing disease progression and pathogenesis., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The therapeutic application of CRISPR-Cas9 is limited due to its off-target activity. To have a better understanding of this off-target effect, we focused on its mismatch-prone PAM distal end. The off-target activity of SpCas9 depends directly on the nature of mismatches, which in turn results in deviation of the active site of SpCas9 due to structural instability in the RNA-DNA duplex strand. In order to test the hypothesis, we designed an array of mismatched target sites at the PAM distal end and performed in vitro and cell line-based experiments, which showed a strong correlation for Cas9 activity. We found that target sites having multiple mismatches in the 18th to 15th position upstream of the PAM showed no to little activity. For further mechanistic validation, Molecular Dynamics simulations were performed, which revealed that certain mismatches showed elevated root mean square deviation values that can be attributed to conformational instability within the RNA-DNA duplex. Therefore, for successful prediction of the off-target effect of SpCas9, along with complementation-derived energy, the RNA-DNA duplex stability should be taken into account., Competing Interests: Conflict of 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To conduct a systematic review and meta-analysis assessing whether the use of antipsychotic medications in critically ill adult patients with delirium impacts patient-important outcomes., Data Sources: A medical librarian searched Ovid MEDLINE, EMBASE, APA PsycInfo, and Wiley's Cochrane Library as well as clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform up to November 2023., Study Selection: Independently and in duplicate, reviewers screened abstracts and titles for eligibility, then full text of qualifying studies. We included parallel-group randomized controlled trials (RCTs) that included critically ill adult patients with delirium. The intervention group was required to receive antipsychotic medications at any dose, whereas the control group received usual care or placebo., Data Extraction: Reviewers extracted data independently and in duplicate using a piloted abstraction form. Statistical analyses were conducted using RevMan software (version 5.4)., Data Synthesis: Five RCTs ( n = 1750) met eligibility criteria. The use of antipsychotic medications compared with placebo did not increase the number of delirium- or coma-free days (mean difference 0.90 d; 95% CI, -0.32 to 2.12; moderate certainty), nor did it result in a difference in mortality, duration of mechanical ventilation, ICU, or hospital length of stay. The use of antipsychotics did not result in an increased risk of adverse events (risk ratio 1.27; 95% CI, 0.71-2.30; high certainty). Subgroup analysis of typical versus atypical antipsychotics did not identify any subgroup effect for any outcome., Conclusions: In conclusion, our systematic review and meta-analysis demonstrated with moderate certainty that there is no difference in delirium- or coma-free days when delirious critically ill adults are treated with antipsychotic medications. Further studies in the subset of patients with hyperactive delirium may be of benefit., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Dengue virus (DENV) is the leading cause of numerous deaths every year due to its high infectivity. In this study we have tried to target the DENV envelope protein receptor binding domain, the region crucial for binding to host receptors which leads to membrane fusion and entry of the viral genome into the human host cell. We have taken 13 known FDA approved antiviral therapeutic antibodies from therapeutic antibody database and tried to repurpose them against the DENV envelope protein. Based on the humanness analysis, 10 antibodies were selected against the DENV envelope protein. Computational affinity maturation of the 10 selected antibodies was performed to increase their binding affinity and specificity against the DENV envelope protein which ultimately led to 8 mutant antibodies having better binding affinity than the native ones. Molecular Dynamics (MD) simulation shows that, the stability of the complexes involving both the native and mutant antibodies were found to be the same although the binding energy between the protein and the respective antibodies was seen to improve upon computational affinity maturation. Contact analyses show similar robustness of the interaction for both the mutant and native antibodies during complex formation with the DENV envelope protein. This has led to the selection of total 18 antibodies including 10 natural and 8 affinity matured mutants which have a high probability of interacting with the DENV envelope protein. Finally, based on all these analyses along with heated MD simulation, Bamlanivimab, Etesivimab and Tixagevimab with a mutation of residue 100 of the heavy chain from serine to tyrosine were selected as prospective therapeutic antibodies to combat DENV infection. This study may open a new avenue in designing therapeutics to combat Dengue viral infection., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The spontaneous breathing trial (SBT) technique that best balance successful extubation with the risk for reintubation is unknown. We sought to determine the comparative efficacy and safety of alternative SBT techniques., Methods: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to February 2023 for randomized or quasi-randomized trials comparing SBT techniques in critically ill adults and children and reported initial SBT success, successful extubation, reintubation (primary outcomes) and mortality (ICU, hospital, most protracted; secondary outcome) rates. Two reviewers screened, reviewed full-texts, and abstracted data. We performed frequentist random-effects network meta-analysis., Results: We included 40 RCTs (6716 patients). Pressure Support (PS) versus T-piece SBTs was the most common comparison. Initial successful SBT rates were increased with PS [risk ratio (RR) 1.08, 95% confidence interval (CI) (1.05-1.11)], PS/automatic tube compensation (ATC) [1.12 (1.01 -1.25), high flow nasal cannulae (HFNC) [1.07 (1.00-1.13) (all moderate certainty), and ATC [RR 1.11, (1.03-1.20); low certainty] SBTs compared to T-piece SBTs. Similarly, initial successful SBT rates were increased with PS, ATC, and PS/ATC SBTs compared to continuous positive airway pressure (CPAP) SBTs. Successful extubation rates were increased with PS [RR 1.06, (1.03-1.09); high certainty], ATC [RR 1.13, (1.05-1.21); moderate certainty], and HFNC [RR 1.06, (1.02-1.11); high certainty] SBTs, compared to T-piece SBTs. There was little to no difference in reintubation rates with PS (vs. T-piece) SBTs [RR 1.05, (0.91-1.21); low certainty], but increased reintubation rates with PS [RR 2.84, (1.61-5.03); moderate certainty] and ATC [RR 2.95 (1.57-5.56); moderate certainty] SBTs compared to HFNC SBTs., Conclusions: SBTs conducted with pressure augmentation (PS, ATC, PS/ATC) versus without (T-piece, CPAP) increased initial successful SBT and successful extubation rates. Although SBTs conducted with PS or ATC versus HFNC increased reintubation rates, this was not the case for PS versus T-piece SBTs., (© 2024. The Author(s).)

Metastasis of non-small cell lung carcinoma (NSCLC) is a rare cause of cardiac metastatic tumors (CMT). We present a case of NSCLC infiltrating the apical left ventricle mimicking cardiac aneurysm and tamponade. The patient, who had a history of NSCLC, presented with acute shortness of breath and an echocardiogram concerning for ruptured left ventricular aneurysm. A neoplastic mass found at the cardiac apex suggested CMT leading to ventricular wall rupture and cardiac tamponade. Transthoracic echocardiography is the most ubiquitous imaging modality for CMT diagnosis, with cardiac magnetic resonance imaging offering a more detailed assessment. CMT from NSCLC can cause dangerous cardiac tamponade, warranting consideration in patients with suspected metastases., Competing Interests: The authors report no funding or conflicts of interest. The patient’s family provided permission to publish the case., (Copyright © 2024 Baylor University Medical Center.)

Hepatitis C virus, a member of the Flaviviridae family and genus Hepacivirus, is an enveloped, positively single stranded RNA virus. Its surface consists of a heterodimer of E1 and E2 proteins which play a crucial role in receptor binding and membrane fusion. In this study we have used in silico virtual screening by utilizing ensemble docking on the approved drugs. These drugs can bind with high efficiency to the 36 prominent conformations of the CD81 binding site clustered from a total of 3 µs MD simulation data on the E2 protein. We started with 9213 compounds from the FDA list of drugs and progressively came down to 5 compounds which have been seen to bind with very high efficiency to not only all the conformations but also the two predicted druggable pockets that encompass the CD81 binding site. MM/PBSA binding energy calculations also point to the highly stable interaction of the compounds to the E2 protein. This study may in future broaden the arsenal of therapeutics for use against HCV infection and lead to more effective care against the virus., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To characterise sex and gender-based analysis (SGBA) and diversity metric reporting, representation of female/women participants in acute care trials and temporal changes in reporting before and after publication of the 2016 Sex and Gender Equity in Research guideline., Design: Systematic review., Data Sources: We searched MEDLINE for trials published in five leading medical journals in 2014, 2018 and 2020., Study Selection: Trials that enrolled acutely ill adults, compared two or more interventions and reported at least one clinical outcome., Data Abstraction and Synthesis: 4 reviewers screened citations and 22 reviewers abstracted data, in duplicate. We compared reporting differences between intensive care unit (ICU) and cardiology trials., Results: We included 88 trials (75 (85.2%) ICU and 13 (14.8%) cardiology) (n=111 428; 38 140 (34.2%) females/women). Of 23 (26.1%) trials that reported an SGBA, most used a forest plot (22 (95.7%)), were prespecified (21 (91.3%)) and reported a sex-by-intervention interaction with a significance test (19 (82.6%)). Discordant sex and gender terminology were found between headings and subheadings within baseline characteristics tables (17/32 (53.1%)) and between baseline characteristics tables and SGBA (4/23 (17.4%)). Only 25 acute care trials (28.4%) reported race or ethnicity. Participants were predominantly white (78.8%) and male/men (65.8%). No trial reported gendered-social factors. SGBA reporting and female/women representation did not improve temporally. Compared with ICU trials, cardiology trials reported significantly more SGBA (15/75 (20%) vs 8/13 (61.5%) p=0.005)., Conclusions: Acute care trials in leading medical journals infrequently included SGBA, female/women and non-white trial participants, reported race or ethnicity and never reported gender-related factors. Substantial opportunity exists to improve SGBA and diversity metric reporting and recruitment of female/women participants in acute care trials., Prospero Registration Number: CRD42022282565., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/. EB-C has received investigator-initiated grant funding from Bayer, BMS-Pfizer and Roche Diagnostics and consulting honoraria from Trimedic Therapeutics, which were unrelated to the current work. JR is a co-methodologist on the Society of Critical Care Medicine Guideline Committee–End of Life Care in the ICU Guidelines. VP is a member of the Canadian Critical Care Society–Equity, Diversity, Decolonisation and Inclusion Committee. KEAB is President of the Canadian Critical Care Society and an Ex-officio member of the Canadian Critical Care Trials Group Executive Committee. There are no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: New evidence is available examining the use of corticosteroids in sepsis, acute respiratory distress syndrome (ARDS) and community-acquired pneumonia (CAP), warranting a focused update of the 2017 guideline on critical illness-related corticosteroid insufficiency., Objectives: To develop evidence-based recommendations for use of corticosteroids in hospitalized adults and children with sepsis, ARDS, and CAP., Panel Design: The 22-member panel included diverse representation from medicine, including adult and pediatric intensivists, pulmonologists, endocrinologists, nurses, pharmacists, and clinician-methodologists with expertise in developing evidence-based Clinical Practice Guidelines. We followed Society of Critical Care Medicine conflict of interest policies in all phases of the guideline development, including task force selection and voting., Methods: After development of five focused Population, Intervention, Control, and Outcomes (PICO) questions, we conducted systematic reviews to identify the best available evidence addressing each question. We evaluated the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach and formulated recommendations using the evidence-to-decision framework., Results: In response to the five PICOs, the panel issued four recommendations addressing the use of corticosteroids in patients with sepsis, ARDS, and CAP. These included a conditional recommendation to administer corticosteroids for patients with septic shock and critically ill patients with ARDS and a strong recommendation for use in hospitalized patients with severe CAP. The panel also recommended against high dose/short duration administration of corticosteroids for septic shock. In response to the final PICO regarding type of corticosteroid molecule in ARDS, the panel was unable to provide specific recommendations addressing corticosteroid molecule, dose, and duration of therapy, based on currently available evidence., Conclusions: The panel provided updated recommendations based on current evidence to inform clinicians, patients, and other stakeholders on the use of corticosteroids for sepsis, ARDS, and CAP., Competing Interests: Dr. Balk received funding from Dompe Pharmaceuticals, Merck, and BioMerieux. Dr. Sarwal’s institution receives funding from Biogen, Bard, Novartis, CVR Global, Lung Pacer, the National Institute on Aging (R01 AG066910-01), Shaltout, and Butterfly. Dr. Gershengorn disclosed that she served as an advisory board member for Gilead Sciences. Dr. Menon received funding from the Canadian Institutes of Health Research. Dr. Jayaprakash disclosed that she was the site principal investigator for sponsored trials through Abbott Laboratories and BioCogniV. Dr. Russell reports patents owned by the University of British Columbia (UBC) that are related to the use of PCSK9 inhibitor(s) in sepsis and related to the use of vasopressin in septic shock and a patent owned by Ferring for use of selepressin in septic shock. Dr. Russell is an inventor of these patents. Dr. Russell was a founder, Director and shareholder in Cyon Therapeutics and is a shareholder in Molecular You Corp. Dr. Russell is no longer actively consulting for any industry. Dr. Russell reports receiving consulting fees in the last 3 years from: 1) SIB Therapeutics LLC (developing a sepsis drug). 2) Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin). 3) Dr. Russell was a funded member of the Data and Safety Monitoring Board of a National Institutes of Health-sponsored trial of plasma in COVID-19 (PASS-IT-ON) (2020–2021). 4) PAR Pharma (sells prepared bags of vasopressin). Dr. Russell reports having received an investigator-initiated grant from Grifols (entitled “Is HBP a mechanism of albumin’s efficacy in human septic shock?”) that was provided to and administered by UBC. Dr. Russell was a nonfunded Science Advisor and member of the Government of Canada COVID-19 Therapeutics Task Force (June 2020 to 2021). Dr. Asehnoune received funding from LFB and Edwards Lifesciences Baxter. Dr. Spencer-Segal received funding from Camurus AB, Chiasma, and Recordati Rare Diseases. Dr. Esper received funding from Honeywell. Dr. Annane has been involved with research relating to this guideline, in particular with multiple randomized control trials examining the use of corticosteroids in sepsis. He participated in the discussion for corticosteroids in sepsis but abstained from voting on final recommendations pertaining to corticosteroids in sepsis and septic shock. Dr. Menon is funded by a Canadian Institute of Health Research grant for The Stress Hydrocortisone in Pediatric Septic Shock trial. The remaining authors have disclosed that they do not have any potential conflicts of interest. The 22-member panel included diverse representation from medicine, including adult and pediatric intensivists, pulmonologists, endocrinologists, nurses, pharmacists, and clinician-methodologists with expertise in developing evidence-based Clinical Practice Guidelines. We followed Society of Critical Care Medicine conflict of interest policies in all phases of the guideline development, including task force selection and voting., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Competing Interests: Dr. Balk received funding from Dompe Pharmaceuticals, Merck, and BioMerieux. Dr. Sarwal’s institution receives funding from Biogen, Bard, Novartis, CVR Global, Lung Pacer, the National Institute on Aging (R01 AG066910-01), Shaltout, and Butterfly. Dr. Gershengorn disclosed that she served as an advisory board member for Gilead Sciences. Dr. Menon received funding from the Canadian Institutes of Health Research. Dr. Jayaprakash disclosed that she was the site principle investigator for sponsored trials through Abott Laboratories and BioCogniV. Dr. Russell reports patents owned by the University of British Columbia (UBC) that are related to the use of PCSK9 inhibitor(s) in sepsis and related to the use of vasopressin in septic shock and a patent owned by Ferring for use of selepressin in septic shock. Dr. Russell is an inventor on these patents. Dr. Russell was a founder, Director and shareholder in Cyon Therapeutics and is a shareholder in Molecular You Corp. Dr. Russell is no longer actively consulting for any industry. Dr. Russell reports receiving consulting fees in the last 3 years from: 1) SIB Therapeutics LLC (developing a sepsis drug). 2) Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin). 3) Dr. Russell was a funded member of the Data and Safety Monitoring Board of an NIH-sponsored trial of plasma in COVID-19 (PASS-IT-ON) (2020–2021). 4) PAR Pharma (sells prepared bags of vasopressin). Dr. Russell reports having received an investigator-initiated grant from Grifols (entitled “Is HBP a mechanism of albumin’s efficacy in human septic shock?”) that was provided to and administered by UBC. Dr. Russell was a nonfunded Science Advisor and member, Government of Canada COVID-19 Therapeutics Task Force (June 2020 to 2021). Dr. Asehnoune received funding from LFB and Edwards Lifecience Baxter. Dr. Spencer-Segal received funding from Camurus AB, Chiasma, and Recordati Rare Diseases. Dr. Esper received funding from Honeywell. The remaining authors have disclosed that they do not have any potential conflicts of interest.

The key to any controlled supramolecular polymerization (CSP) process lies in controlling the nucleation step, which is typically achieved by sequestering monomers in a kinetically trapped state. However, kinetic traps that are shallow cannot prevent spontaneous nucleation, thus limiting the applicability of the CSP in such systems. We use a molecular additive to overcome this limitation by modifying the energy landscape of a competitive self-assembly process and increasing the kinetic stability of an otherwise short-lived trap state. The additive achieves this by simultaneously catalyzing OFF-pathway nucleation and inhibiting ON-pathway aggregation. In the process, it guides the molecular assembly exclusively toward the OFF-pathway aggregate analogue. The mechanisms of OFF-pathway catalysis and ON-pathway inhibition are elucidated. By specifically targeting the nucleation step, it was possible to achieve pathway selection at an extremely low additive-to-monomer ratio of 1:100. The generality of our approach is also demonstrated for other related molecular systems. Finally, removing the additive triggers the cross-nucleation of the ON-pathway aggregate on the surface of a less stable, OFF-pathway aggregate analogue. The resultant supramolecular polymer not only exhibits a more uniform morphology but more importantly, a marked improvement in the structural order that leads to an amplification of chiral asymmetry and a high absorption dissymmetry factor ( g Abs ) of ∼0.05.

HIV-1 Vpr is a multifunctional accessory protein consisting of 96 amino acids that play a critical role in viral pathogenesis. Among its diverse range of activities, Vpr can create a cation-selective ion channel within the plasma membrane. However, the oligomeric state of this channel has not yet been elucidated. In this study, we investigated the conformational dynamics of Vpr helices to model the ion channel topology. First, we employed a series of multiscale simulations to investigate the specific structure of monomeric Vpr in a membrane model. During the lipid bilayer self-assembly coarse grain simulation, the C-terminal helix (residues 56-77) effectively formed the transmembrane region, while the N-terminal helix exhibited an amphipathic nature by associating horizontally with a single leaflet. All-atom molecular dynamics (MD) simulations of full-length Vpr inside a phospholipid bilayer show that the C-terminal helix remains very stable inside the bilayer core in a vertical orientation. Subsequently, using the predicted C-terminal helix orientation and conformation, various oligomeric states (ranging from tetramer to heptamer) possibly forming the Vpr ion channel were built and further evaluated. Among these models, the pentameric form exhibited consistent stability in MD simulations and displayed a compatible conformation for a water-assisted ion transport mechanism. This study provides structural insights into the ion channel activity of the Vpr protein and the foundation for developing therapeutics against HIV-1 Vpr-related conditions.

The rodent-borne Arenavirus in humans has led to the emergence of regional endemic situations and has deeply emerged into pandemic-causing viruses. Arenavirus have a bisegmented ambisense RNA that produces four proteins: glycoprotein, nucleocapsid, RdRp and Z protein. The peptide-based vaccine targets the glycoprotein of the virus encountered by the immune system. Screening of B-Cell and T-Cell epitopes was done based on their immunological properties like antigenicity, allergenicity, toxicity and anti-inflammatory properties were performed. Selected epitopes were then clustered and epitopes were stitched using linker sequences. The immunological and physico-chemical properties of the vaccine construct was checked and modelled structure was validated by a 2-step MD simulation. The thermostability of the vaccine was checked followed by the immune simulation to test the immunogenicity of the vaccine upon introduction into the body over the course of the next 100 days and codon optimization was performed. Finally a 443 amino acid long peptide vaccine was designed which could provide protection against several members of the mammarenavirus family in a variety of population worldwide as denoted by the epitope conservancy and population coverage analysis. This study of designing a peptide vaccine targeting the glycoprotein of mammarenavirues may help develop novel therapeutics in near future., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Dengue virus, an arbovirus, leads to millions of infections every year ultimately leading to a high rate of mortality. Highly effective and specific therapeutic option is not available till date to combat viral infection. One of the first stages in the virus lifecycle encompasses the viral entry into the host cell which is mediated by the interaction between heparan sulphate and the Dengue virus envelope protein in turn leading to the interaction between the envelope protein receptor binding domain and host cell receptors. The heparan sulphate binding site on the envelope protein was established using literature survey and the result validated using ColDock simulations. We have performed virtual screening against the heparan sulphate binding site using DrugBank database and short-listed probable inhibitors based on binding energy calculation following Molecular Dynamics (MD) simulations in this study. Two compounds (PubChem IDS 448062 and 656615) were selected for further analyses on which RAMD simulations were performed to quantitate the binding stability of both the molecules in the protein binding pocket which ultimately led to the selection of ZK-806450 molecule as the final selected compound. Competitive binding MD simulation against dengue virus envelope protein was performed for this molecule and heparan sulphate in order to ascertain the efficiency of binding of this molecule to the dengue virus envelope protein in the presence of its natural ligand molecule and found that this molecule has a higher affinity for the dengue virus envelope protein GAG binding site than heparan sulphate. This study may help in the use of this inhibitor molecule to combat dengue virus infection in foreseeable future and open a new avenue for drug repurposing methodology using competitive binding MD simulation., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Adherence to antihypertensives is crucial for control of blood pressure. This study analyzed factors and interventions that could affect adherence to antihypertensives in the US. PubMed, Scopus, Web of Science, and Embase were searched on January 21, 2022 and December 25, 2023 for studies on the adherence to antihypertensives in the US. Nineteen studies and 23 545 747 patients were included in the analysis, which showed that adherence to antihypertensives was the highest among Whites (OR: 1.47, 95% CI 1.34-1.61 compared to African Americans). Employment status and sex were associated with insignificant differences in adherence rates. In contrast, marital status yielded a significant difference where unmarried patients demonstrated low adherence rates compared to married ones (OR: 0.8, 95% CI 0.67-0.95). On analysis of comorbidities, diabetic patients reported lower adherence to antihypertensives (OR: 0.95, 95% CI 0.92-0.97); furthermore, patients who did not have Alzheimer showed higher adherence rates. Different BMIs did not significantly affect the adherence rates. Patients without insurance reported significantly lower adherence rates than insured patients (OR: 3.93, 95% CI 3.43-4.51). Polypill users had higher adherence rates compared with the free-dose combination (OR: 1.21, 95% CI 1.2-1.21), while telepharmacy did not prove to be as effective. Lower adherence rates were seen among African Americans, uninsured, or younger patients. Accordingly, interventions such as fixed-dose combinations should be targeted at susceptible groups. Obesity and overweight did not affect the adherence to antihypertensives., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Objectives: We postulate that corticosteroid-related side effects in critically ill patients are similar across sepsis, acute respiratory distress syndrome (ARDS), and community-acquired pneumonia (CAP). By pooling data across all trials that have examined corticosteroids in these three acute conditions, we aim to examine the side effects of corticosteroid use in critical illness., Data Sources: We performed a comprehensive search of MEDLINE, Embase, Centers for Disease Control and Prevention library of COVID research, CINAHL, and Cochrane center for trials., Study Selection: We included randomized controlled trials (RCTs) that compared corticosteroids to no corticosteroids or placebo in patients with sepsis, ARDS, and CAP., Data Extraction: We summarized data addressing the most described side effects of corticosteroid use in critical care: gastrointestinal bleeding, hyperglycemia, hypernatremia, superinfections/secondary infections, neuropsychiatric effects, and neuromuscular weakness., Data Synthesis: We included 47 RCTs ( n = 13,893 patients). Corticosteroids probably have no effect on gastrointestinal bleeding (relative risk [RR], 1.08; 95% CI, 0.87-1.34; absolute risk increase [ARI], 0.3%; moderate certainty) or secondary infections (RR, 0.97; 95% CI, 0.89-1.05; absolute risk reduction, 0.5%; moderate certainty) and may have no effect on neuromuscular weakness (RR, 1.22; 95% CI, 1.03-1.45; ARI, 1.4%; low certainty) or neuropsychiatric events (RR, 1.19; 95% CI, 0.82-1.74; ARI, 0.5%; low certainty). Conversely, they increase the risk of hyperglycemia (RR, 1.21; 95% CI, 1.11-1.31; ARI, 5.4%; high certainty) and probably increase the risk of hypernatremia (RR, 1.59; 95% CI, 1.29-1.96; ARI, 2.3%; moderate certainty)., Conclusions: In ARDS, sepsis, and CAP, corticosteroids are associated with hyperglycemia and probably with hypernatremia but likely have no effect on gastrointestinal bleeding or secondary infections. More data examining effects of corticosteroids, particularly on neuropsychiatric outcomes and neuromuscular weakness, would clarify the safety of this class of drugs in critical illness., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Aspiration thrombectomy has gained popularity in patients with massive and sub-massive pulmonary embolism (PE) and having contraindications to thrombolysis., Methods: A meta-analysis was conducted including studies on aspiration thrombectomy in patients with high-risk and intermediate-risk PE. The pooled odds ratio for efficacy parameters, including change in heart rate, blood pressure and right ventricle/left ventricle (RV/LV) ratio, and safety parameters including major bleeding and stroke, was calculated using a random effects model., Results: The meta-analysis of 24 selected studies revealed that intermediate and high-risk pulmonary embolism (PE) patients demonstrated significant improvements: modified Miller score odds ratio of 10.60, mean pulmonary artery pressure reduction by 0.04 mm Hg, and an overall all-cause mortality odds ratio of 0.10. Considerable heterogeneity was observed in various outcomes., Conclusion: Aspiration thrombectomy has success rates in both high-risk and intermediate-risk PE, however, procedural risks, including bleeding, must be anticipated., 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 © 2024 Elsevier Inc. All rights reserved.)

Axonal transport in neurons is essential for cargo movement between the cell body and synapses. Caenorhabditis elegans UNC-104 and its homolog KIF1A are kinesin-3 motors that anterogradely transport precursors of synaptic vesicles (pre-SVs) and are degraded at synapses. However, in C. elegans, touch neuron-specific knockdown of the E1 ubiquitin-activating enzyme, uba-1, leads to UNC-104 accumulation at neuronal ends and synapses. Here, we performed an RNAi screen and identified that depletion of fbxb-65, which encodes an F-box protein, leads to UNC-104 accumulation at neuronal distal ends, and alters UNC-104 net anterograde movement and levels of UNC-104 on cargo without changing synaptic UNC-104 levels. Split fluorescence reconstitution showed that UNC-104 and FBXB-65 interact throughout the neuron. Our theoretical model suggests that UNC-104 might exhibit cooperative cargo binding that is regulated by FBXB-65. FBXB-65 regulates an unidentified post-translational modification (PTM) of UNC-104 in a region beside the cargo-binding PH domain. Both fbxb-65 and UNC-104, independently of FBXB-65, regulate axonal pre-SV distribution, transport of pre-SVs at branch points and organismal lifespan. FBXB-65 regulates a PTM of UNC-104 and the number of motors on the cargo surface, which can fine-tune cargo transport to the synapse., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Ambient stable solution processed n-channel organic field effect transistors (OFETs) are essential for next-generation low-cost organic electronic devices. Several molecular features, such as suitable orbital energy levels, easy synthetic steps, etc. , must be considered while designing efficient active layer materials. Here, we report a case of improved ambient stability of solution-processed n-type OFETs upon suitable end-groups substitution of the active layer materials. A pair of core-substituted napthalenediimide (NDIFCN 2 and EHNDICN 2 ) derivatives with alkyl and perfluorinated end groups are considered. The transistor devices made out of these two derivatives exhibited largely different ambient stability behavior. The superior device stability (more than 25 days under ambient conditions) of one of the derivatives (NDIFCN 2 ) was ascribed to the presence of fluorinated end groups that function as hydrophobic guard units inhibiting moisture infiltration into the active layer, thereby achieving ambient stability under humid conditions (>65% relative atmospheric humidity). Molecular level optical and electrochemical properties, thermal stability, and the solution-processed (spin coat and drop cast active layers) device characteristics are described in detail. Our findings highlight the requirement of hydrophobic end groups or sidechains for ambient stability of active layer materials, along with deep LUMO levels for ambient stability., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

We report the photophysical properties of a molecular folda-dimer system PDI-AnEt 2 -PDI , where the electron-donating N , N -diethylaniline (AnEt 2 ) moiety bridges two electron-accepting perylene diimide (PDI) chromophores. The conformationally flexible PDI-AnEt 2 -PDI adopts either an open (two PDIs far apart) or folded (two PDIs within π-stacking distance) conformation, depending on the solvent environment. We characterized the photoinduced charge separation dynamics of both open and folded forms in solvents of varying polarity. The open form undergoes charge separation to give PDI •- -AnEt 2 •+ -PDI (Bridge electron transfer) independent of solvent polarity. The folded form exhibits two charge separation photoproducts, yielding both PDI •- -AnEt 2 •+ -PDI and PDI •- -AnEt 2 -PDI •+ , the latter of which is formed via symmetry-breaking charge separation (SBCS) between the two π-stacked PDI chromophores. Our results further indicate that the conformational flexibility of the folda-dimer leads to unexpected excimer formation in some open form conditions. In contrast, no excimer formation is observed in the folded form, indicating that this geometry preferentially yields the SBCS instead. Our results provide insight into how conformationally flexible folda-dimer systems can be designed and built to tune competitive photophysical pathways.

Importance: Considerable controversy exists regarding the best spontaneous breathing trial (SBT) technique to use., Objective: To summarize trials comparing alternative SBTs., Data Sources: Several databases (MEDLINE [from inception to February 2023], the Cochrane Central Register of Controlled Trials [in February 2023], and Embase [from inception to February 2023] and 5 conference proceedings (from January 1990 to April 2023) were searched in this systematic review and meta-analysis., Study Selection: Randomized trials directly comparing SBT techniques in critically ill adults or children and reporting at least 1 clinical outcome were selected., Data Extraction and Synthesis: Paired reviewers independently screened citations, abstracted data, and assessed quality for the systematic review and meta-analysis using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA guidelines). Data were pooled using random-effects models., Main Outcomes and Measures: Primary outcomes included SBT success, extubation success, and reintubation., Results: The systematic review and meta-analysis identified 40 trials that included 6716 patients. Low-quality evidence (14 trials [n = 4459]) suggested that patients were not more likely to pass a pressure support (PS) compared with a T-piece SBT (risk ratio [RR], 1.04; 95% CI, 0.97-1.11; P = .31; I2 = 73%), unless 1 outlier trial accounting for all heterogeneity was excluded (RR, 1.09; 95% CI, 1.06-1.12; P < .001; I2 = 0% [13 trials; n = 3939]; moderate-quality evidence), but were significantly more likely to be successfully extubated (RR, 1.07; 95% CI, 1.04-1.10; P < .001; I2 = 0%; 16 trials [n = 4462]; moderate-quality evidence). Limited data (5 trials [n = 502]) revealed that patients who underwent automatic tube compensation/continuous positive airway pressure compared with PS SBTs had a significantly higher successful extubation rate (RR, 1.10; 95% CI, 1.00-1.21; P = .04; I2 = 0% [low-quality evidence]). Compared with T-piece SBTs, high-flow oxygen SBTs (3 trials [n = 386]) had significantly higher successful extubation (RR, 1.06; 95% CI, 1.00-1.11; P = .04; I2 = 0%) and lower reintubation (RR, 0.37; 95% CI, 0.21-0.65; P = <.001; I2 = 0% [both low-quality evidence]) rates. Credible subgroup effects were not found., Conclusions and Relevance: In this systematic review and meta-analysis, the findings suggest that patients undergoing PS compared with T-piece SBTs were more likely to be extubated successfully and more likely to pass an SBT, after exclusion of an outlier trial. Pressure support SBTs were not associated with increased risk of reintubation. Future trials should compare SBT techniques that maximize differences in inspiratory support.

Active scalar baths consisting of active Brownian particles are characterized by a non-Gaussian velocity distribution, a kinetic temperature, and a diffusion coefficient that scale with the square of the active velocity v&#95;{0}. While these results hold in overdamped active systems, inertial effects lead to normal velocity distributions, with kinetic temperature and diffusion coefficient increasing as ∼v&#95;{0}^{α} with 1<α<2. Remarkably, the late-time diffusivity and mobility decrease with mass. Moreover, we show that the equilibrium Einstein relation is asymptotically recovered with inertia. In summary, the inertial mass restores an equilibriumlike behavior.