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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.

Osmolytes are well known to protect the protein structure against different chemical and physical denaturants. Since their actions with protein surfaces are mechanistically complicated and context dependent, the underlying molecular mechanism is not fully understood. Here, we combined single-molecule magnetic tweezers and molecular dynamics (MD) simulation to explore the mechanical role of osmolytes from two different classes, trimethylamine N -oxide (TMAO) and trehalose, as mechanical stabilizers of protein structure. We observed that these osmolytes increase the protein L mechanical stability by decreasing unfolding kinetics while accelerating the refolding kinetics under force, eventually shifting the energy landscape toward the folded state. These osmolytes mechanically stabilize the protein L and plausibly guide them to more thermodynamically robust states. Finally, we observed that osmolyte-modulated protein folding increases mechanical work output up to twofold, allowing the protein to fold under a higher force regime and providing a significant implication for folding-induced structural stability in proteins.

Active nematics undergo spontaneous symmetry breaking and show phase separation instability. Within the prevailing notion that macroscopic properties depend only on symmetries and conservation laws, different microscopic models are used out of convenience. Here, we test this notion carefully by analyzing three different microscopic models of apolar active nematics. They share the same symmetry but differ in implementing reciprocal or non-reciprocal interactions, including a Vicsek-like implementation. We show how such subtle differences in microscopic realization determine if the ordering transition is continuous or first order. Despite the difference in the type of phase transition, all three models exhibit fluctuation-dominated phase separation and quasi-long-range order in the nematic phase.

Acute respiratory failure (ARF) strikes an estimated two million people in the United States each year, with care exceeding US$50 billion. The hallmark of ARF is a heterogeneous injury, with normal tissue intermingled with a large volume of low compliance and collapsed tissue. Mechanical ventilation is necessary to oxygenate and ventilate patients with ARF, but if set inappropriately, it can cause an unintended ventilator-induced lung injury (VILI). The mechanism of VILI is believed to be overdistension of the remaining normal tissue known as the 'baby' lung, causing volutrauma, repetitive collapse and reopening of lung tissue with each breath, causing atelectrauma, and inflammation secondary to this mechanical damage, causing biotrauma. To avoid VILI, extracorporeal membrane oxygenation (ECMO) can temporally replace the pulmonary function of gas exchange without requiring high tidal volumes (V T ) or airway pressures. In theory, the lower V T and airway pressure will minimize all three VILI mechanisms, allowing the lung to 'rest' and heal in the collapsed state. The optimal method of mechanical ventilation for the patient on ECMO is unknown. The ARDSNetwork Acute Respiratory Management Approach (ARMA) is a Rest Lung Approach (RLA) that attempts to reduce the excessive stress and strain on the remaining normal lung tissue and buys time for the lung to heal in the collapsed state. Theoretically, excessive tissue stress and strain can also be avoided if the lung is fully open, as long as the alveolar re-collapse is prevented during expiration, an approach known as the Open Lung Approach (OLA). A third lung-protective strategy is the Stabilize Lung Approach (SLA), in which the lung is initially stabilized and gradually reopened over time. This review will analyze the physiologic efficacy and pathophysiologic potential of the above lung-protective approaches., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To perform a systematic review and meta-analysis to assess the efficacy and safety of corticosteroids in patients with sepsis., Data Sources: We searched PubMed, Embase, and the Cochrane Library, up to January 10, 2023., Study Selection: We included randomized controlled trials (RCTs) comparing corticosteroids with placebo or standard care with sepsis., Data Extraction: The critical outcomes of interest included mortality, shock reversal, length of stay in the ICU, and adverse events., Data Analysis: We performed both a pairwise and dose-response meta-analysis to evaluate the effect of different corticosteroid doses on outcomes. We used Grading of Recommendations Assessment, Development and Evaluation to assess certainty in pooled estimates., Data Synthesis: We included 45 RCTs involving 9563 patients. Corticosteroids probably reduce short-term mortality (risk ratio [RR], 0.93; 95% CI, 0.88-0.99; moderate certainty) and increase shock reversal at 7 days (RR, 1.24; 95% CI, 1.11-1.38; high certainty). Corticosteroids may have no important effect on duration of ICU stay (mean difference, -0.6 fewer days; 95% CI, 1.48 fewer to 0.27 more; low certainty); however, probably increase the risk of hyperglycemia (RR, 1.13; 95% CI, 1.08-1.18; moderate certainty) and hypernatremia (RR, 1.64; 95% CI, 1.32-2.03; moderate certainty) and may increase the risk of neuromuscular weakness (RR, 1.21; 95% CI, 1.01-1.45; low certainty). The dose-response analysis showed a reduction in mortality with corticosteroids with optimal dosing of approximately 260 mg/d of hydrocortisone (RR, 0.90; 95% CI, 0.83-0.98) or equivalent., Conclusions: We found that corticosteroids may reduce mortality and increase shock reversal but they may also increase the risk of hyperglycemia, hypernatremia, and neuromuscular weakness. The dose-response analysis indicates optimal dosing is around 260 mg/d of hydrocortisone or equivalent., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare.

The chromosome of a bacterium consists of a mega-base pair-long circular DNA, which self-organizes within the micron-sized bacterial cell volume, compacting itself by three orders of magnitude. Unlike eukaryotic chromosomes, it lacks a nuclear membrane and freely floats in the cytosol confined by the cell membrane. It is believed that strong confinement, cross-linking by associated proteins, and molecular crowding all contribute to determine chromosome size and morphology. Modelling the chromosome simply as a circular polymer decorated with closed side loops in a cylindrical confining volume has been shown to already recapture some of the salient properties observed experimentally. Here we describe how a computer simulation can be set up to study structure and dynamics of bacterial chromosomes using this model., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This document updates previously published Clinical Practice Guidelines for the management of patients with acute respiratory distress syndrome (ARDS), incorporating new evidence addressing the use of corticosteroids, venovenous extracorporeal membrane oxygenation, neuromuscular blocking agents, and positive end-expiratory pressure (PEEP). Methods: We summarized evidence addressing four "PICO questions" (patient, intervention, comparison, and outcome). A multidisciplinary panel with expertise in ARDS used the Grading of Recommendations, Assessment, Development, and Evaluation framework to develop clinical recommendations. Results: We suggest the use of: 1 ) corticosteroids for patients with ARDS (conditional recommendation, moderate certainty of evidence), 2 ) venovenous extracorporeal membrane oxygenation in selected patients with severe ARDS (conditional recommendation, low certainty of evidence), 3 ) neuromuscular blockers in patients with early severe ARDS (conditional recommendation, low certainty of evidence), and 4 ) higher PEEP without lung recruitment maneuvers as opposed to lower PEEP in patients with moderate to severe ARDS (conditional recommendation, low to moderate certainty), and 5 ) we recommend against using prolonged lung recruitment maneuvers in patients with moderate to severe ARDS (strong recommendation, moderate certainty). Conclusions: We provide updated evidence-based recommendations for the management of ARDS. Individual patient and illness characteristics should be factored into clinical decision making and implementation of these recommendations while additional evidence is generated from much-needed clinical trials.

Purpose: We sought to understand the beliefs and practices of Canadian intensivists regarding their use of ketamine as a sedative in critically ill patients and to gauge their interest in a randomized controlled trial (RCT) examining its use in the intensive care unit (ICU)., Methods: We designed and validated an electronic self-administered survey examining the use of ketamine as a sedative infusion for ICU patients. We surveyed 400 physician members of the Canadian Critical Care Society (CCCS) via email between February and April 2022 and sent three reminders at two-week intervals. The survey was redistributed in January 2023 to improve the response rate., Results: We received 87/400 (22%) completed questionnaires. Most respondents reported they rarely use ketamine as a continuous infusion for sedation or analgesia in the ICU (52/87, 58%). Physicians reported the following conditions would make them more likely to use ketamine: asthma exacerbation (73/87, 82%), tolerance to opioids (68/87, 77%), status epilepticus (44/87, 50%), and severe acute respiratory distress syndrome (33/87, 38%). Concern for side-effects that limited respondents' use of ketamine include adverse psychotropic effects (61/87, 69%) and delirium (47/87, 53%). The majority of respondents agreed there is need for an RCT to evaluate ketamine as a sedative infusion in the ICU (62/87, 71%)., Conclusion: This survey of Canadian intensivists illustrates that use of ketamine as a continuous infusion for sedation is limited, and is at least partly driven by concerns of adverse psychotropic effects. Canadian physicians endorse the need for a trial investigating the safety and efficacy of ketamine as a sedative for critically ill patients., (© 2023. Canadian Anesthesiologists' Society.)

Nipah virus, a zoonotic virus from the family Paramyxoviridae has led to significant loss of lives till date with the most recent outbreak in India reported in Kerala. The virus has a considerably high mortality rate along with lack of characteristic symptoms which results in the delay of the virus detection. No specific vaccine is available for the virus although monoclonal antibody treatment has been seen to be effective along with favipiravir. The high mortality and complications caused by the virus underscores the necessity to develop alternative modes of vaccination. One such method has been designed in this study using peptide cocktail consisting of the immunologically important epitopes for use as vaccine. The human leucocytic antigens that are used for the study were analyzed for their presence in various ethnic Indian populations. This study may serve as a new avenue for development of more efficient peptide cocktail vaccines in recent future based on the population genetics and ethnicity., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aims: Postoperative pain for patients having hip arthroplasty ranges from moderate to severe. Many regional anaesthesia procedures treat postoperative pain to improve functional ability and quality of life. Evidence comparing the analgesic effects of the pericapsular nerve group (PENG) block and fascia iliaca compartment block (FICB) remains unclear. The analgesic efficacies of PENG and FICB in hip arthroplasty were compared to determine which technique is associated with superior analgesia., Methods: The electronic databases (PubMed, Cochrane Library, Google Scholar and Web of Sciences) were searched for published randomised controlled trials (RCTs) till 5 April 2023 comparing PENG block vs. FICB following hip arthroplasty. The primary outcome was pain scores [numerical rating scale (NRS) or visual analogue scale (VAS)] between 0 and 10 at rest and during movement at 24 h. Secondary outcomes included pain scores at rest and during movement within 30 min, at 6 h and 12 h, time to first rescue analgesia and cumulative postoperative opioid use in 24 h. We assessed the risk of bias using the Cochrane Collaboration Risk-of-Bias 2 tool. Using Grading of Recommendations Assessment, Development, and Evaluation (GRADE), the certainty of the evidence was assessed. Subgroup analysis was performed to explore the source of heterogeneity., Results: We included 12 RCTs examining 644 patients. Pain scores at rest at 24 h (standardised mean differences (SMDs): 0.17; 95% confidence interval (CI): -0.90 to 1.23; P = 0.76, moderate certainty) and during movement at 24 h (SMD: -0.58, 95% CI: -1.53 to 0.38, P = 0.24, moderate certainty) were not different in both PENG block and FICB. Pain scores at rest and during movement within 30 min may be lower with PENG block than FICB. However, the pain score at rest and during movement at 6 h and the time to first rescue analgesia were not different between the two treatment arms. The mean opioid consumption in oral morphine equivalents (mg) in 24 h may be lower with PENG than FICB., Conclusion: We observed no difference between the PENG block and the FICB at 24 h for pain at rest and movement with a moderate degree of certainty. However, PENG block showed improved analgesia within 30 min at rest and during movement, and reduce postoperative opioid consumption in 24 h with moderate certainty of evidence. Further large-scale and high-quality RCTs are required to supplement the present findings., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Anaesthesia.)

Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare.

While mitochondria oxidative phosphorylation is broadly regulated, the impact of mitochondrial Ca2+ on substrate flux under both physiological and pathological conditions is increasingly being recognized. Under physiologic conditions, mitochondrial Ca2+ enters through the mitochondrial Ca2+ uniporter and boosts ATP production. However, maintaining Ca2+ homeostasis is crucial as too little Ca2+ inhibits adaptation to stress and Ca2+ overload can trigger cell death. In this review, we discuss new insights obtained over the past several years expanding the relationship between mitochondrial Ca2+ and oxidative phosphorylation, with most data obtained from heart, liver, or skeletal muscle. Two new themes are emerging. First, beyond boosting ATP synthesis, Ca2+ appears to be a critical determinant of fuel substrate choice between glucose and fatty acids. Second, Ca2+ exerts local effects on the electron transport chain indirectly, not via traditional allosteric mechanisms. These depend critically on the transporters involved, such as the uniporter or the Na+-Ca2+ exchanger. Alteration of these new relationships during disease can be either compensatory or harmful and suggest that targeting mitochondrial Ca2+ may be of therapeutic benefit during diseases featuring impairments in oxidative phosphorylation., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

The CXCR4 chemokine is a key molecular regulator of many biological functions controlling leukocyte functions during inflammation and immunity, and during embryonic development. Overexpression of CXCR4 is also associated with many types of cancer where its activation promotes angiogenesis, tumor growth/survival, and metastasis. In addition, CXCR4 is involved in HIV replication, working as a co-receptor for viral entry, making CXCR4 a very attractive target for developing novel therapeutic agents. Here we report the pharmacokinetic profile in rats of a potent CXCR4 antagonist cyclotide, MCo-CVX-5c, previously developed in our group that displayed a remarkable in vivo resistance to biological degradation in serum. This bioactive cyclotide, however, was rapidly eliminated through renal clearance. Several lipidated versions of cyclotide MCo-CVX-5c showed a significant increase in the half-life when compared to the unlipidated form. The palmitoylated version of cyclotide MCo-CVX-5c displayed similar CXCR4 antagonistic activity as the unlipidated cyclotide, while the cyclotide modified with octadecanedioic (18-oxo-octadecanoic) acid exhibited a remarkable decrease in its ability to antagonize CXCR4. Similar results were also obtained when tested for its ability to inhibit growth in two cancer cell lines and HIV infection in cells. These results show that the half-life of cyclotides can be improved by lipidation although it can also affect their biological activity depending on the lipid employed., Competing Interests: Declaration of Competing Interest The author has no other relevant affiliations or financial involvement with any organization or entity with financial interest in or financial conflict with the subject matter or materials discussed in the manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Competing Interests: The authors have no conflicts of interest to declare.

Salmonella, a stealthy facultative intracellular pathogen, utilises an array of host immune evasion strategies. This facilitates successful survival via replicative niche establishment in otherwise hostile environments such as macrophages. Salmonella survives in and utilises macrophages for effective dissemination, ultimately leading to systemic infection. Bacterial xenophagy or macro-autophagy is an important host defense mechanism in macrophages. Here, we report for the first time that the Salmonella pathogenicity island-1 (SPI-1) effector SopB is involved in subverting host autophagy via dual mechanisms. SopB is a phosphoinositide phosphatase capable of altering the phosphoinositide dynamics of the host cell. Here, we demonstrate that SopB mediates escape from autophagy by inhibiting the terminal fusion of Salmonella-containing vacuoles (SCVs) with lysosomes and/or autophagosomes. We also report that SopB downregulates overall lysosomal biogenesis by modulating the Akt-transcription factor EB (TFEB) axis via restricting the latter's nuclear localisation. TFEB is a master regulator of lysosomal biogenesis and autophagy. This reduces the overall lysosome content inside host macrophages, further facilitating the survival of Salmonella in macrophages and systemic dissemination of Salmonella., (Copyright © 2023 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

While opioids are part of usual care for analgesia in the ICU, there are concerns regarding excess use. This is a systematic review of nonsteroidal anti-inflammatory drugs (NSAIDs) use in postoperative critical care adult patients., Data Sources: We searched Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, trial registries, Google Scholar, and relevant systematic reviews through March 2023., Study Selection: Titles, abstracts, and full texts were reviewed independently and induplicate by two investigators to identify eligible studies. We included randomized control trials (RCTs) that compared NSAIDs alone or as an adjunct to opioids for systemic analgesia. The primary outcome was opioid utilization., Data Extraction: In duplicate, investigators independently extracted study characteristics, patient demographics, intervention details, and outcomes of interest using predefined abstraction forms. Statistical analyses were conducted using Review Manager software Version 5.4. (The Cochrane Collaboration, Copenhagen, Denmark)., Data Synthesis: We included 15 RCTs ( n = 1,621 patients) for admission to the ICU for postoperative management after elective procedures. Adjunctive NSAID therapy to opioids reduced 24-hour oral morphine equivalent consumption by 21.4 mg (95% CI, 11.8-31.0 mg reduction; high certainty) and probably reduced pain scores (measured by Visual Analog Scale) by 6.1 mm (95% CI, 12.2 decrease to 0.1 increase; moderate certainty). Adjunctive NSAID therapy probably had no impact on the duration of mechanical ventilation (1.6 hr reduction; 95% CI, 0.4 hr to 2.7 reduction; moderate certainty) and may have no impact on ICU length of stay (2.1 hr reduction; 95% CI, 6.1 hr reduction to 2.0 hr increase; low certainty). Variability in reporting adverse outcomes (e.g., gastrointestinal bleeding, acute kidney injury) precluded their meta-analysis., Conclusions: In postoperative critical care adult patients, systemic NSAIDs reduced opioid use and probably reduced pain scores. However, the evidence is uncertain for the duration of mechanical ventilation or ICU length of stay. Further research is required to characterize the prevalence of NSAID-related adverse outcomes., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

This study aimed to systematically review the available data on major depressive disorder (MDD) and provide insight into how it may affect stroke risk and mortality. We conducted this systematic review drawing upon research published between July 2002 and July 2022 from the following databases: PubMed, ScienceDirect, and Google Scholar. After eliminating duplicates, screening the title and abstract, determining eligibility, and quality assessment, eight articles were left for utilization in this systematic review (one meta-analysis and seven non-randomized studies). There was a potentially significant association between MDD and stroke risk and mortality. The apparent connection between MDD and stroke has medical and public health relevance, given the high incidence, prevalence, and financial burden of MDD and stroke in the general populace. Therefore, it is imperative that further studies are conducted to confirm and validate this association between MDD and stroke while also elucidating the mechanism involved, investigating potential variables influencing this association, and contrasting MDD with conventional stroke risk factors to determine its predictive usefulness in comparison to traditional risk factors. This will have a significant effect on clinical practice since the information provided by such research will help guide essential targets for stroke prevention., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Khan et al.)

In a generation where advancements in research and understanding have led to remarkable achievements in medicine, it is still unfathomable that, after more than a century, the cause of schizophrenia is still a mystery. While antipsychotics, without a doubt, have brought on an exemplary revolution in the way psychiatric disorders are now treated, there are still imperative deficits that need to be addressed to ultimately enable individuals with schizophrenia to function normally in society. However, without a definite cause of schizophrenia, even though speculation has been made on its inflammatory and neurodegenerative nature, it has provided an unnecessary hindrance to finding further potential treatment modalities for these patients. Nevertheless, some trials are investigating potential adjunctive treatment regimens to antipsychotics, which can help achieve complete remission. Exploring these drugs will have significant implications for managing schizophrenia in future clinical practices. This systematic review was conducted between January 2012 to July 2022 according to Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines to evaluate the safety and efficacy of ondansetron and simvastatin as adjunctive treatment to antipsychotics in adult patients with schizophrenia. This review included nine randomized controlled trials. Overall, both simvastatin and ondansetron, when used as adjunctive treatment in schizophrenia, appear to be safe. Ondansetron showed promising results, with all studies on this drug showing positive overall results on schizophrenia symptoms. On the other hand, simvastatin demonstrated mixed results, which can be attributed to the limited participants in the studies and the shorter duration of the trials. However, more extensive trials with uniform assessment tools are needed to demonstrate concrete evidence of the effectiveness of these drugs, whether alone or in combination with each other or perhaps another drug such as aspirin in schizophrenia., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Khan et al.)

In myelodysplastic syndrome (MDS), neoplastic cells originate in hematopoietic stem cells of the bone marrow, causing dysplasia in multiple cell lines. This may ultimately lead to cytopenia and anemia. MDS generally occurs in patients aged over 60 years, and if left unchecked, it can lead to secondary acute myeloid leukemia (AML), which has a worse prognosis than de novo AML. Hence, it is important to find methods to treat and manage MDS and prevent secondary AML. This review tries to point out the best methods to find out the best possible treatment for MDS, which can lead to its remission or possibly cure and prevent it from progressing into AML. In order to do this, the pathogenesis of MDS is taken into account, and it is clear that the various molecular mutations that lead to the hematologic neoplasms directly affect the different chemotherapy agents that can be used. The different common mutations leading to MDS and secondary AML have been reviewed along with the drugs best inclined to target them. Some mutations lead to a worse prognosis than others, and ongoing mutations can lead to drug-resistant neoplasms. Thus, drugs targeting the mutations need to be used. The feasibility of an allogeneic stem cell transplant is also taken into account, as this can lead to a total cure of MDS. Methods of decreasing post-transplant recovery time and complications have been looked into, and more studies need to be done on the matter. Currently, it is clear that a more personalized approach to each individual case with its own set of drug combinations is the best approach to treating MDS and secondary leukemia and increasing the overall survival (OS)., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Chaudhuri et al.)

Nef is a small accessory protein pivotal in the HIV-1 viral replication cycle. It is a multifunctional protein and its interactions with kinases in host cells have been well characterized through many in vitro and structural studies. Nef forms a homodimer to activate the kinases and subsequently the phosphorylation pathways. The disruption of its homodimerization represents a valuable approach in the search for novel classes of antiretroviral. However, this research avenue is still underdeveloped as just a few Nef inhibitors have been reported so far, with very limited structural information about their mechanism of action. To address this issue, we have employed an in silico structure-based drug design strategy that combines de novo ligand design with molecular docking and extensive molecular dynamics simulations. Since the Nef pocket involved in homodimerization has high lipophilicity, the initial de novo-designed structures displayed poor drug-likeness and solubility. Taking information from the hydration sites within the homodimerization pocket, structural modifications in the initial lead compound have been introduced to improve the solubility and drug-likeness, without affecting the binding profile. We propose lead compounds that can be the starting point for further optimizations to deliver long-awaited, rationally designed Nef inhibitors., 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 © 2023 Elsevier Ltd. All rights reserved.)

SMYD1, a striated muscle-specific lysine methyltransferase, was originally shown to play a key role in embryonic cardiac development but more recently we demonstrated that loss of Smyd1 in the murine adult heart leads to cardiac hypertrophy and failure. However, the effects of SMYD1 overexpression in the heart and its molecular function in the cardiomyocyte in response to ischemic stress are unknown. In this study, we show that inducible, cardiomyocyte-specific overexpression of SMYD1a in mice protects the heart from ischemic injury as seen by a > 50% reduction in infarct size and decreased myocyte cell death. We also demonstrate that attenuated pathological remodeling is a result of enhanced mitochondrial respiration efficiency, which is driven by increased mitochondrial cristae formation and stabilization of respiratory chain supercomplexes within the cristae. These morphological changes occur concomitant with increased OPA1 expression, a known driver of cristae morphology and supercomplex formation. Together, these analyses identify OPA1 as a novel downstream target of SMYD1a whereby cardiomyocytes upregulate energy efficiency to dynamically adapt to the energy demands of the cell. In addition, these findings highlight a new epigenetic mechanism by which SMYD1a regulates mitochondrial energetics and functions to protect the heart from ischemic injury., (© 2023. The Author(s).)

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder that affects approximately 2% of the human population. Traditional treatment of OCD includes selective serotonin reuptake inhibitor (SSRI) or serotonin reuptake inhibitor (SRI) treatment along with cognitive behavioral therapy (CBT). Nearly 25%-30% of OCD patients do not respond to SSRIs. Glutamatergic agents are currently being studied for the treatment of OCD due to the glutamatergic pathway in the brain, related to OCD, and the role of the cortico-striato-thalamic circuit (CSTC). This review assesses the clinical effectiveness of N-methyl-D-aspartate (NMDA) antagonists, ketamine/esketamine, memantine, and amantadine, for adult patients with OCD. Inclusion criteria include human studies published within the last 15 years, with patients diagnosed with OCD, aged over 18 years, with only psychiatric comorbidities, and full-text articles. Papers that included interventions other than CBT, exposure with response prevention (ERP), and SSRI/SRI were excluded. Articles were searched for using PubMed, PubMed Central, Medical Literature Analysis and Retrieval System Online, GeorgiA LIbrary LEarning Online, EBSCO Information Services, OpenAthens, Multidisciplinary Digital Publishing Institute, and Google Scholar databases, last searched on December 2, 2022. The risk of bias was assessed using Cochrane Risk of Bias tools, the Scale for the Assessment of Narrative Review Articles (SANRA) checklist for literature reviews, and the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for quasi-experimental studies. Results were presented and synthesized by Excel spreadsheet analysis. The database search yielded 4,221 articles, which was cut down to 18 articles by inclusion/exclusion criteria, including duplications. 80% of the ketamine studies resulted in a significant reduction of obsessions and compulsions based on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and each of the memantine and amantadine studies displayed clinical effectiveness, also. Limitations include the small number of amantadine studies and the limited availability of other NMDA receptor (NMDAR) antagonist-focused studies. This systematic review shows that ketamine is an effective drug for the treatment of non-refractory, mild to moderate OCD, and memantine and amantadine are effective augmentation agents for the treatment of mild to severe OCD., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ferguson et al.)

Dengue virus, an arbovirus, is one of the most prevalent diseases in the tropical environment and leads to huge number of casualties every year. No therapeutics are available till date against the viral disease and the only medications provide symptomatic relief. In this study, we have focused on utilizing conventional nanobodies and repurposing them for Dengue. Computationally affinity matured, best binding nanobodies tagged with constant antibody regions, could be proposed as therapeutics. These could also be applied for drug delivery purposes due to their high specificity against the viral Capsid. Another application of these nanobodies has been thought to utilize them for diagnostic purposes, to use the nanobodies for viral detection from patient samples at the earliest stage using ELISA. This study may open a new avenue for immunologic study in foreseeable future with the usage of the same molecules for multiple purposes. HighlightsNatural nanobodies against viruses were modified for use against Dengue virus Capsid conserved regions.Computational affinity maturation was performed making use of change in binding affinities upon mutating various residues in the complementary determining regions.Docking studies performed to inspect the docking groove, interface analysis and energy calculations.MM/GBSA calculations done to calculate binding free energy of the complex to determine stability of the complex.Communicated by Ramaswamy H. Sarma.

To evaluate the efficacy and cost-effectiveness of high-flow nasal cannula (HFNC) when compared with noninvasive positive pressure ventilation (NIPPV) in patients with acute hypoxic respiratory failure (AHRF)., Data Sources: We performed a comprehensive search of MEDLINE, Embase, CINAHL, the Cochrane library, and the international Health Technology Assessment database from inception to September 14, 2022., Study Selection: We included randomized control studies that compared HFNC to NIPPV in adult patients with AHRF. For clinical outcomes, we included only parallel group and crossover randomized control trials (RCTs). For economic outcomes, we included any study design that evaluated cost-effectiveness, cost-utility, or cost benefit analyses., Data Extraction: Clinical outcomes of interest included intubation, mortality, ICU and hospital length of stay (LOS), and patient-reported dyspnea. Economic outcomes of interest included costs, cost-effectiveness, and cost-utility., Data Synthesis: We included nine RCTs ( n = 1,539 patients) and one cost-effectiveness study. Compared with NIPPV, HFNC may have no effect on the need for intubation (relative risk [RR], 0.93; 95% CI, 0.69-1.27; low certainty) and an uncertain effect on mortality (RR, 0.84; 95% CI, 0.59-1.21; very low certainty). In subgroup analysis, NIPPV delivered through the helmet interface-as opposed to the facemask interface-may reduce intubation compared with HFNC ( p = 0.006; moderate credibility of subgroup effect). There was no difference in ICU or hospital LOS (both low certainty) and an uncertain effect on patient-reported dyspnea (very low certainty). We could make no conclusions regarding the cost-effectiveness of HFNC compared with NIPPV., Conclusions: HFNC and NIPPV may be similarly effective at reducing the need for intubation with an uncertain effect on mortality in hospitalized patients with hypoxemic respiratory failure. More research evaluating different interfaces in varying clinical contexts is needed to improve generalizability and precision of findings., Competing Interests: Dr. Rochwerg is supported by a McMaster Department of Medicine Mid-Career Research Award. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

We consider the dynamics of a bio-filament under the collective drive of motor proteins. They are attached irreversibly to a substrate and undergo stochastic attachment-detachment with the filament to produce a directed force on it. We establish the dependence of the mean directed force and force correlations on the parameters describing the individual motor proteins using analytical theory and direct numerical simulations. The effective Langevin description for the filament motion gives mean-squared displacement, asymptotic diffusion constant, and mobility leading to an effective temperature. Finally, we show how competition between motor protein extensions generates a self-load, describable in terms of the effective temperature, affecting the filament motion.

During aging, environmental stressors and mutations along with reduced DNA repair cause germ cell aneuploidy and genome instability, which limits fertility and embryo development. Benevolent commensal microbiota and dietary plants secrete indoles, which improve healthspan and reproductive success, suggesting regulation of germ cell quality. We show that indoles prevent aneuploidy and promote DNA repair and embryo viability, which depends on age and genotoxic stress levels and affects embryo quality across generations. In young animals or with low doses of radiation, indoles promote DNA repair and embryo viability; however, in older animals or with high doses of radiation, indoles promote death of the embryo. These studies reveal a previously unknown quality control mechanism by which indole integrates DNA repair and cell death responses to preclude germ cell aneuploidy and ensure transgenerational genome integrity. Such regulation affects healthy aging, reproductive senescence, cancer, and the evolution of genetic diversity in invertebrates and vertebrates.

Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of adenosine triphosphate (ATP) synthase. Here, we provide evidence that phosphatidylethanolamine (PE) modulates UCP1-dependent proton conductance across the IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist-induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PE-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.

Purpose: The helmet is a novel interface for delivering non-invasive ventilation (NIV). We conducted a case series to characterize introduction of the helmet interface in both COVID and non-COVID patients at two-centres., Methods: We enrolled all patients with respiratory failure admitted to the Juravinski Hospital (Hamilton, Canada) and St. Joseph's Health Center (Syracuse, New York) between November 1, 2020 and June 30, 2021 who used the helmet interface (Intersurgical StarMed) as part of this introduction into clinical practice. We collected patient demographics, reason for respiratory failure, NIV settings, device-related complications and outcomes. We report respiratory therapist's initial experiences with the helmet using descriptive results., Results: We included 16 patients with a mean age of 64.3 ± 10.9 years. The most common etiology for respiratory failure was pneumonia (81.3%). The median duration of NIV during the ICU admission was 67.5 (15.3, 80.8) hours, with a mean maximum PS of 13.9 ± 6.6 cm H2O and a mean maximum PEEP of 10.4 ± 5.1 cm H20. Three patients (18.7%) did not tolerate the helmet. Ten (62.5%) patients ultimately required intubation, and 7 (43.4%) patients died while in the ICU. The most common reason for intubation was worsening hypoxia (70%). No adverse events related to the helmet were recorded., Conclusion: Over the 8-month period of this study, we found that the helmet was well tolerated in over 80% of patients, although, more than half ultimately required intubation. Randomized controlled trials with this device are required to fully assess the efficacy of this interface., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chaudhuri, Sharma, Burns, Piticaru, Cook and Rochwerg.)

The HAK (High-affinity K+ ) family members mediate K+ transport that confers normal plant growth and resistance against unfavourable environmental conditions. Rice (Oryza sativa L.) HAK transporters have been extensively investigated for phylogenetic analyses with other plants species with very few of them functionally characterised. But very little information is known about their evolutionary aspects, overall structural, functional characterisation, and global expression pattern of the complete HAK family members in response to salt stress. In this study, 27 rice transporters were phylogenetically clustered with different dicot and monocot family members. Subsequently, the exon-intron structural patterns, conserved motif analyses, evolutionary divergence based different substitution matrix, orthologous-paralogous relationships were studied elaborately. Structural characterisations included a comparative study of secondary and tertiary structure, post-translational modifications, correspondence analyses, normal mode analyses, K+ /Na+ binding affinities of each of the OsHAK gene members. Global expression profile under salt stress showed clade-specific expression pattern of the proteins. Additionally, five OsHAK genes were chosen for further expression analyses in root and shoot tissues of two rice varieties during short-term salinity in the presence and absence of exogenous spermidine. All the information can be used as first-hand data for dissecting the administrative role of rice HAK transporters under various abiotic stresses.

Understanding the role of solvent in translating molecular anisotropy to supramolecular polymers is in the early stages. A solvent's influence on the strength of different noncovalent interactions can explain anisotropic growth in some cases, but its effect on cooperative processes, particularly in mixed solvents, remains obscure. We report the self-assembly of a series of chiral perylene bisimides in water-cosolvent mixtures, and the results highlight the fascinating influence of solvent-solute interactions on supramolecular anisotropy, both chiral and morphological. The initial assembly is agnostic to solvent composition, resulting in weakly chiral, spherical nanostructures. In an extremely narrow solvent composition range, the nanospheres transform into long, prominently chiral supramolecular polymers. Further, chirality can be fully reversed by changing the good (achiral) cosolvent. We elucidate how solvent modulates specific noncovalent interactions and governs the kinetics and thermodynamics of key processes, such as spontaneous phase segregation, secondary nucleation, and cooperative growth. In the context of supramolecular polymerization, our results encourage one to steer the focus away from the physical attributes of a solvent (polarity, phase diagram, etc.) and toward the complexities of solvent-solute interactions.

Background: Post-cardiac arrest, outcomes for most patients are poor, regardless of setting. Many patients who do achieve spontaneous return of circulation require vasopressor therapy to maintain organ perfusion. There is some evidence to support the use of corticosteroids in cardiac arrest., Research Question: Assess the efficacy and safety of corticosteroids in patients following in- and out-of-hospital cardiac arrest., Study Design and Methods: We searched databases CINAHL, EMBASE, LILACS, MEDLINE, Web of Science, CENTRAL, ClinicalTrails.gov, and ICTRP. We included randomized controlled trials (RCTs) that examined the efficacy and safety of corticosteroids, as compared to placebo or usual care in patients post-cardiac arrest. We pooled estimates of effect size using random effects meta-analysis and report relative risk (RR) with 95% confidence intervals (CIs). We assessed risk of bias (ROB) for the included trials using the modified Cochrane ROB tool and rated the certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation methodology., Results: We included 8 RCTs (n = 2213 patients). Corticosteroids administered post-cardiac arrest had an uncertain effect on mortality measured at the longest point of follow-up (RR 0.96, 95% CI 0.90-1.02, very low certainty, required information size not met using trial sequential analysis). Corticosteroids probably increase return of spontaneous circulation (ROSC) (RR 1.32, 95% CI 1.18-1.47, moderate certainty) and may increase the likelihood of survival with good functional outcome (RR 1.49, 95% CI 0.87-2.54, low certainty). Corticosteroids may decrease the risk of ventilator associated pneumonia (RR 0.76, 95% CI 0.46-1.09, low certainty), may increase renal failure (RR 1.29, 95% CI 0.84-1.99, low certainty), and have an uncertain effect on bleeding (RR 2.04, 95% CI 0.53-7.84, very low certainty) and peritonitis (RR 10.54, 95% CI 2.99-37.19, very low certainty)., Conclusions: In patients during or after cardiac arrest, corticosteroids have an uncertain effect on mortality but probably increase ROSC and may increase the likelihood of survival with good functional outcome at hospital discharge. Corticosteroids may decrease ventilator associated pneumonia, may increase renal failure, and have an uncertain effect on bleeding and peritonitis. However, the pooled evidence examining these outcomes was sparse and imprecision contributed to low or very low certainty of evidence., (© 2023. The Author(s).)

HIV-1, the causative agent of AIDS leads to many deaths worldwide though few options are available as therapeutics. To deal with the continuous mutation in the virus genome, requirement of new drugs is always there. Subtype variation plays a crucial role in case of HIV-1 therapeutics development. In this study, we want to investigate some pre examined molecules that can be effective for HIV-1 VPR. Inhibition of several protein-protein interactions with the small molecules will lead to identify some molecules as therapeutics other than the conventional drugs. We retrieved the sequences of different subtypes from the database and representative sequences were identified. Representative structures were modelled and validated using MD simulations. Forty molecules, showing anti Vpr activity in vitro were identified from literature survey and those were docked with each subtype representative structures. Two molecules a stable Hematoxylin Derivative (SHD) and Damnacanthal (D3), these were shown to be bind more effectively for all the subtypes. The stability of the protein and those two small molecule complexes were identified again with MD simulation followed by the binding energy calculation. Thus, these molecules can be thought as any option other than the conventional drug targeting HIV-1 Vpr.Communicated by Ramaswamy H. Sarma.

Design concepts for organic light emitting diode (OLED) emitters, which exhibit thermally activated delayed fluorescence (TADF) and thereby achieve quantum yields exceeding 25%, depend on singlet-triplet splitting energies of order kT to allow reverse intersystem crossing at ambient temperatures. Simulation methods for these systems must be able to treat relatively large organic molecules, as well as predict their excited state energies, transition energies, singlet-triplet splittings, and absorption and emission cross sections with reasonable accuracy, in order to prove useful in the design process. Here we compare predictions of TDDFT with M06-2X and ωB97X-D exchange-correlation functionals and a G o @HF/BSE, and TDDFT/ωB97X-D and M06-2X methods in which the former method favors local exciton (LE) states while the latter favors DA CT states and ωB97X-D makes intermediate predictions. W o @HF/BSE method for these quantities in the well-studied DPTZ-DBTO2 TADF emitter molecule. Geometry optimization is performed for ground state (GS) and lowest donor-acceptor charge transfer (CT) state for each functional. Optical absorption and emission cross sections and energies are calculated at these geometries. Relaxation energies are on the order of 0.5 eV, and the importance of obtaining excited state equilibrium geometries in predicting delayed fluorescence is demonstrated. There are clear trends in predictions of G o W o @HF/BSE, and TDDFT/ωB97X-D and M06-2X methods in which the former method favors local exciton (LE) states while the latter favors DA CT states and ωB97X-D makes intermediate predictions. G o W o @HF/BSE suffers from triplet instability for LE states but not CT states relevant for TADF. Shifts in HOMO and LUMO levels on adding a conductor-like polarizable continuum model dielectric background are used to estimate changes in excitation energies on going from the gas phase to a solvated molecule.

Vasovagal syncope (VVS) is a transient, sudden loss of consciousness followed by complete resolution, usually due to a paradoxical autonomic reaction that results in hypotension and/or bradycardia. In this study, we assessed the correlation between VVS and a patient's psychiatric status, as well as if this association could be a target in the treatment of those patients. We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched the available literature using the following databases: PubMed, Google Scholar, and ScienceDirect, with last access on July 21, 2022. The search resulted in 1691 articles, and inclusion and exclusion criteria were applied to nine remaining articles, all of which were accepted after using the quality assessment tools, four observational and four randomized controlled trials (RCTs). Four of the included studies assessed the correlation among vasovagal syncope, psychosocial impairment, and quality of life. We found a consistent correlation among VVS, psychosocial impairment, and quality of life (QoL), meaning that VVS patients usually have some degree of psychosocial impairment, especially in the form of anxiety and depression, and a poorer QoL in comparison to their healthy counterparts. The use of psychotherapy and antidepressants was proven to be effective in VVS in RCTs, but further evidence is needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Abuzainah et al.)

This systematic review paper aimed to assess and analyze the prevalence of maternal colonization of Staphylococcus aureus ( S. aureus ) also known as m ethicillin-sensitive Staphylococcus aureus ( MSSA ) and m ethicillin-resistant Staphylococcus aureus ( MRSA ) in the peripartum period and its significance on vertical transmission to the neonate and if it is a potential threat to the health of newborns. For this, multiple databases, such as PubMed, MEDLINE, ScienceDirect, and the database of Elsevier, were used to scout for relevant articles, and results were reported adhering to the principles set by Preferred Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines 2020. A specific medical subject headings (MeSH) criterion was designed to search for relevant publications on PubMed. A total of 26 articles were finally selected after a meticulous screening process, including detailed inclusion and exclusion criteria, manual reading of titles and abstracts, and availability of accessible full-text articles. A few articles were also selected after going through the citations section of the initially selected papers. Quality appraisal was done on the selected publications. Maternal colonization of S. aureus is determined to be highly prevalent with the hypothesis that nasal colonization had higher rates than recto-vaginal sites. Increasing maternal age, history of vaginitis, and multiparity were the most common risk factors for MRSA and MSSA colonization. Premature babies were at the highest risk of MRSA colonization. Breast milk is also a risk factor for neonatal MRSA transmission. Through this systematic review, we concluded that although the rate of vertical transmission of MRSA is lower than that of MSSA, we felt that it held significance as neonates with the bug have poor outcomes due to skin and soft tissue infections and there is spread of MRSA to other neonates in the wards and spread to siblings in cases of triplets and quadruplets and even death due to potential MRSA sepsis. Women in Africa and China had high prevalence rates of MRSA and S. aureus which can probably be attributed to a lack of access to adequate healthcare facilities. We recommend screening with regular recto-vaginal swabs and nasal swabs especially in regions with a high burden of MRSA to be performed at regular intervals after confirmation of pregnancy, as prevention and screening are effective to avoid serious complications., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Allakky et al.)