Valve-in-Valve Transcatheter Aortic Valve Replacement Versus Redo-Surgical Aortic Valve Replacement in Patients With Aortic Stenosis: A Systematic Review and Meta-analysis.

Aortic stenosis is a common and significant valve condition requiring bioprosthetic heart valves with transcatheter aortic valve replacement (TAVR) being strongly recommended for high-risk patients or patients over 75 years. This meta-analysis aimed to pool existing data on postprocedural clinical as well as echocardiographic outcomes comparing valve-in-valve (ViV)-TAVR to redo-surgical aortic valve replacement to assess the short-term and medium-term outcomes for both treatment methods. A systematic literature search on Cochrane Central, Scopus, and Medline (PubMed interface) electronic databases from inception to August 2023. We used odds ratios (OR) for dichotomous outcomes and mean differences (MD) for continuous outcomes. Twenty-four studies (25,216 patients) were pooled with a mean follow-up of 16.4 months. The analysis revealed that ViV-TAVR group showed a significant reduction in 30-day mortality (OR 0.50, 95% confidence interval [CI] 0.43 to 0.58, p <0.00001), new-onset atrial fibrillation (OR 0.34, 95% CI 0.17 to 0.67, p = 0.002), major bleeding event (OR 0.28, 95% CI 0.17 to 0.45, p <0.00001) and lower rate of device success (OR 0.25, 95% CI 0.12 to 0.53, p = 0.0003). There were no significant differences between either group when assessing 1-year mortality, stroke, myocardial infarction, postoperative left ventricular ejection fraction, and effective orifice area. ViV-TAVR cohort showed a significantly increased incidence of paravalvular leaks, aortic regurgitation, and increased mean aortic valve gradient. ViV-TAVR is a viable short-term option for elderly patients with high co-morbidities and operative risks, reducing perioperative complications and improving 30-day mortality with no significant cardiovascular adverse events. However, both treatment methods present similar results on short-term to medium-term complications assessment.

Evaluating the efficacy and safety of nivolumab and ipilimumab combination therapy compared to nivolumab monotherapy in advanced cancers (excluding melanoma): a systemic review and meta-analysis.

BACKGROUND: Nivolumab (Nivo) and ipilimumab (Ipi) have revolutionized cancer treatment by targeting different pathways. Their combination shows promising results in various cancers, including melanoma, but not all studies have demonstrated significant benefits. A meta-analysis was performed to assess the effectiveness and safety of Nivo-Ipi compared to Nivo alone in advanced cancer types (excluding melanoma). METHODS: Following PRISMA guidelines, we conducted a meta-analysis up to September 30, 2023, searching databases for randomized controlled trials (RCTs). We focused on advanced solid malignancies (excluding melanoma) with specific Nivo and Ipi dosing. Primary outcomes were overall survival (OS), progression-free survival (PFS), grades 3-4 adverse events (AEs), and treatment-related discontinuations. Secondary outcomes included specific adverse events. Statistical analysis in Review Manager included hazard ratio (HR) and risk ratio (RR), assessing heterogeneity (Higgins I2). RESULTS: Nine RCTs, involving 2152 patients covering various malignancies, were analyzed. The Nivo plus Ipi group exhibited a median OS of 12.3 months and a median PFS of 3.73 months, compared to monotherapy with 11.67 months and 3.98 months, respectively. OS showed no significant difference between Nivo and Ipi combination and Nivo alone (HR = 0.97, 95% CI: 0.88 to 1.08, p = 0.61). PFS had a slight improvement with combination therapy (HR = 0.91, 95% CI: 0.82 to 1.00, p = 0.04). Treatment-related cumulative grades 3-4 adverse events were higher with Nivo and Ipi (RR = 1.52, 95% CI: 1.30 to 1.78, p < 0.00001), as were treatment-related discontinuations (RR = 1.99, 95% CI: 1.46 to 2.70, p < 0.0001). Hepatotoxicity (RR = 2.42, 95% CI: 1.39 to 4.24, p = 0.002), GI toxicity (RR = 2.84, 95% CI: 1.44 to 5.59, p = 0.002), pneumonitis (RR = 2.29, 95% CI: 1.24 to 2.23, p = 0.008), dermatitis (RR = 2.96, 95% CI: 1.08 to 8.14, p = 0.04), and endocrine dysfunction (RR = 6.22, 95% CI: 2.31 to 16.71, p = 0.0003) were more frequent with Nivo and Ipi. CONCLUSIONS: Combining nivolumab and ipilimumab did not significantly improve overall survival compared to nivolumab alone in advanced cancers (except melanoma). However, it did show slightly better PFS at the cost of increased toxicity, particularly grades 3-4 adverse events. Specific AEs occurred more frequently in the combination group. Further trials are needed to fully assess this combination in treating advanced cancers.

Computational Insights into Schottky Barrier Heights: Graphene and Borophene Interfaces with H- and H́-XSi2N4 (X = Mo, W) Monolayers.

The two-dimensional (2D) semiconducting family of XSi2N4 (X = Mo and W), an emergent class of air-stable monolayers, has recently gained attention due to its distinctive structural, mechanical, transport, and optical properties. However, the electrical contact between XSi2N4 and metals remains a mystery. In this study, we inspect the electronic and transport properties, specifically the Schottky barrier height (SBH) and tunneling probability, of XSi2N4-based van der Waals contacts by means of first-principles calculations. Our findings reveal that the electrical contacts of XSi2N4 with metals can serve as the foundation for nanoelectronic devices with ultralow SBHs. We further analyzed the tunneling probability of different metal contacts with XSi2N4. We found that the H-phase XSi2N4/metal contact shows superior tunneling probability compared to that of H́-based metal contacts. Our results suggest that heterostructures at interfaces can potentially enable efficient tunneling barrier modulation in metal contacts, particularly in the case of MoSi2N4/borophene compared to MoSi2N4/graphene and WSi2N4/graphene in transport-efficient electronic devices. Among the studied heterostructures, tunneling efficiency is highest at the H and H́-MoSi2N4/borophene interfaces, with barrier heights of 2.1 and 1.52 eV, respectively, and barrier widths of 1.04 and 0.8 Å. Furthermore, the tunneling probability for these interfaces was identified to be 21.3 and 36.4%, indicating a good efficiency of carrier injection. Thus, our study highlights the potential of MoSi2N4/borophene contact in designing power-efficient Ohmic devices.

Assessing global good agricultural practices standard adoption: insights from fruit and vegetable farmers in Pakistan.

This study examines the challenges Pakistani farmers face in adopting global good agricultural practices (GGAP) and highlights the limitations in infrastructure and cost-based clauses. A questionnaire based on GGAP's fruit and vegetable module version 5.0 was developed and validated by the Department of Environmental Sciences, Government College University, Faisalabad. This was a survey-based study of 15 farmers divided into 5 groups according to their annual farm turnover. The findings of the study indicated that, although the basic paperwork requirements of GGAP were implementable, clauses related to capital investment and technical record-keeping were not. Results showed that 90-100% of farmers considered risk assessments, training, and documentation on their farms. However, 42-56% of clauses related to record-keeping, installation, visual presentation, and infrastructure development, and 24-37% of clauses related to external testing, health, safety, and hygiene were declared not implementable. The study revealed a need for adapting GGAP standards to Pakistan's unique agricultural conditions, suggesting the development of localized standards for more practical implementation. The study's findings highlight crucial insights for policymakers and stakeholders in the agriculture sector and suggest the need for target strategies to overcome implementation barriers and optimize the adaptation of Global GAP in Pakistan that would help to increase exports of agricultural commodities.

Synthesis of new class of non-sulfonamide bis-benzimidazoles as antitumor agents by inhibiting carbonic anhydrase-IX enzyme.

In several types of cancers, the expression of carbonic anhydrase-IX (CA-IX) enzyme is elevated than its normal level which ultimately plays a key role in the tumor growth of epithelial cells in breast and lung cancer by acidifying tumor microenvironment, therefore, inhibition of this target is important in antitumor therapy. We have synthesized bis-benzimidazole derivatives (1-25) by using 3,3'-diaminobenzidine and various aromatic aldehydes and characterized by various spectroscopic methods (UV/Visible, 1HNMR, 13CNMR, and mass spectrometry). Their inhibitory potential for human CA-IX (hCA-IX) was evaluated in-vitro, where several synthesized derivatives showed potent inhibition of hCA-IX (IC50 values in range of 5.23 ± 1.05 to 40.10 ± 1.78 µM) and compounds 3-5, 7-8, 13-16, 21 and 23 showed superior activity than the standard drug "acetazolamide" (IC50 = 18.24 ± 1.43 µM). Furthermore, all these compounds showed no toxicity on human fibroblast cell lines (BJ cell lines). Moreover, molecular docking was carried out to predict their binding modes in the active site of CA-IX and revealed a significant role of imidazole ring of synthesized entities in their effective binding with the specific residues of CA-IX. The obtained results paved the way for further in vivo and other pharmacological studies for the optimization of these molecules as possible anti-cancer agents.

Analyzing safety and effectiveness of Mavacamten in comparison with placebo for managing hypertrophic cardiomyopathy: a systemic review and meta-analysis.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a hereditary myocardial disorder, often due to sarcomere gene mutations, characterized by the left ventricular hypertrophy. Current treatments offer symptomatic relief but lack specificity. Mavacamten, an allosteric inhibitor, has shown significant improvements in HCM patients in trials, reducing the requirement for invasive treatments. This meta-analysis assesses Mavacamten's efficacy and safety as a targeted HCM intervention. METHODS: This study examined four randomized controlled trials comparing Mavacamten to placebo in HCM patients. Each trial had a unique primary endpoint, and secondary outcomes included improvements in NYHA-FC, eligibility for septal reduction therapy (SRT) or undergoing it, adverse events (serious and treatment-related), atrial fibrillation, and non-sustained ventricular tachycardia. Statistical analysis involved calculating risk ratios (RRs) and assessing heterogeneity. RESULTS: The four included studies showed minimal risk of bias and involved 503 patients with HCM (273 Mavacamten and 230 placebo). Mavacamten significantly increased the primary endpoint (RR 2.15, 95% CI 1.20-3.86, P = 0.01) and ≥ 1 NYHA-FC class (RR 2.21, 95% CI 1.48-3.3, P = 0.0001). Mavacamten group had lower rates of SRT compared to those receiving placebo (RR, 0.30, 95% CI 0.22-0.40; P < 0.00001). No significant differences existed in rates adverse events between the Mavacamten and placebo groups. CONCLUSIONS: Our study suggests that Mavacamten may have therapeutic benefits for HCM patients, as indicated by its positive impact on certain endpoints. Further research with larger samples, longer follow-up, and comprehensive analysis is needed to understand Mavacamten's safety and efficacy in HCM patients.

Evaluating Glycemic Control Efficacy and Safety of the Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist Danuglipron in Type 2 Diabetes Patients: A Systemic Review and Meta-Analysis.

Introduction: Diabetes Mellitus (DM) is a significant global health concern, with Type 2 DM (T2DM) being highly prevalent. Glucagon-Like Peptide 1 receptor agonists (GLP-1RA), such as Danuglipron, offer potential benefits in T2DM management. This meta-analysis examines the safety and efficacy of Danuglipron, focusing on adverse outcomes and glycemic parameters. Methods: A systematic search was conducted in PubMed, Scopus, and Cochrane Library for RCTs involving Danuglipron till August 2023, following PRISMA guidelines. The Cochrane risk-of-bias tool was used for quality assessment. Adverse outcomes (diarrhea, nausea, vomiting, headache, decreased appetite, dyspepsia, dizziness) and glycemic parameters like changes in HbA1C, fasting plasma glucose (FPG), and body weight were analyzed. Results: Four RCTs published from 2021 to 2023 were included. Both doses of Danuglipron were associated with diarrhea (RR=2.66, 90% CI: 1.32 to 5.35, p=0.02), nausea (RR=5.5, 90% CI: 3.4 to 8.88, p<0.00001), and vomiting (RR=5.98, 90% CI: 2.93 to 12.23, p=0.0001). The 120mg dose showed decreased appetite (RR=3.46, 90% CI: 1.57 to 7.62, p=0.01), dyspepsia (RR=4.04, 90% CI: 1.93 to 8.43, p=0.002), and dizziness (RR=5.08, 90% CI: 1.45 to 17.82, p=0.03). Reductions in HbA1C (SMD -1.09, 90% CI -1.39 to -0.8, p < 0.00001), FPG (SMD -1.10, 90% CI -1.46 to -0.75, p < 0.00001), and body weight (SMD -1.08, 90% CI -1.42 to -0.74, p < 0.00001) were observed for both doses. Conclusion: Danuglipron demonstrates potential for glycemic control and weight reduction in T2DM. Adverse outcomes include diarrhea, nausea, vomiting, and decreased appetite, with dose-related effects. Clinicians must weigh benefits against side effects when considering Danuglipron for T2DM management.

Assessment Precision of CT Perfusion Imaging in the Detection of Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

Stroke, a prevalent medical emergency, comprises ischemic and hemorrhagic subtypes, with acute ischemic stroke (AIS) being a predominant type. The application of computed tomography perfusion (CTP) imaging has gained prominence due to its rapidity and accessibility in stroke evaluation. This study systematically reviews and conducts a meta-analysis of existing literature to assess the diagnostic accuracy of CTP in detecting AIS and predicting hemorrhagic transformation (HT). Employing Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, an extensive search was conducted across electronic databases and relevant radiology journals. Studies conducted between 2007 and 2023 that fulfilled predetermined inclusion criteria underwent quality assessment using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS 2) tool. Cochrane diagnostic accuracy tools were used for data extraction. Thirteen studies involving a total of 1014 patients were included in the analysis. The diagnostic performance of CTP in predicting HT demonstrated high sensitivity (86.7%) and moderate specificity (77.8%), resulting in an overall accuracy of 79.1%. The negative predictive value (NPV) was notably high (92.9%), signifying its efficacy in excluding patients at risk of HT. The positive predictive value (PPV) was comparatively lower (60.3%), highlighting the need for clinical context when making thrombolysis decisions. The false positive rate was 16.2%, while the false negative rate was minimal (9.8%). Subgroup analysis underscored consistent sensitivity and specificity across diverse imaging metrics. The findings of this study emphasize the promising diagnostic accuracy of CTP imaging in predicting HT subsequent to AIS. This non-invasive technique can aid treatment decisions and patient management strategies. By effectively assessing perfusion status and offering predictive insights, CTP imaging improves stroke intervention choices, especially in identifying patients with a lower risk of HT.

Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.

Metabolic reprogramming is one of the hallmarks of tumorigenesis. Here, we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. NM1 directly affects mitochondrial oxidative phosphorylation (OXPHOS) by regulating mitochondrial transcription factors TFAM and PGC1α, and its deletion leads to underdeveloped mitochondria inner cristae and mitochondrial redistribution within the cell. These changes are associated with reduced OXPHOS gene expression, decreased mitochondrial DNA copy number, and deregulated mitochondrial dynamics, which lead to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis.This, in turn, is associated with a metabolomic profile typical for cancer cells, namely increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. NM1 KO cells form solid tumors in a mouse model, suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient carcinogenic signal. We suggest that NM1 plays a role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the onset of tumorigenesis.

In vitro and in vivo antimicrobial potential of lithium complex against multi-drug resistant Acinetobacter baumannii.

IMPORTANCE: Multi-drug resistance (MDR) by virtue of evolving resistance and virulence mechanisms among A. baumannii is a global concern which is responsible for lethal hospital-acquired infections. Therefore, it is crucial to develop new therapeutics against it. Metal complexes are compact structures with diverse mechanisms that the pathogens cannot evade easily which make them a strong drug candidate. In this study, we assessed the in vitro and in vivo efficacy of lithium complex {[Li(phen)2 sal]} against biofilm-forming MDR A. baumannii. The lithium complex displayed strong antimicrobial activity and reduced the pre-formed mature biofilm which is key barrier for antimicrobial action. Moreover, it employs oxidative stress as one of its mode of actions and causes cellular rupturing. Lithium complex was non-toxic and was significantly effective to overcome pneumonia in mice model. These results highlight the untapped potential of metal complexes that can be explored and utilized for combating notorious A. baumannii infections.

Microarray needles comprised of arginine-modified chitosan/PVA hydrogel for enhanced antibacterial and wound healing potential of curcumin.

Wound healing is a multifaceted and complex process that includes inflammation, hemostasis, remodeling, and granulation. Failures in any link may cause the healing process to be delayed. As a result, wound healing has always been a main research focus across the entire medical field, posing significant challenges and financial burdens. Hence, the current investigation focused on the design and development of arginine-modified chitosan/PVA hydrogel-based microneedles (MNs) as a curcumin (CUR) delivery system for improved wound healing and antibacterial activity. The substrate possesses exceptional swelling capabilities that allow tissue fluid from the wound to be absorbed, speeding up wound closure. The antibacterial activity of MNs was investigated against S. aureus and E. coli. The results revealed that the developed CUR-loaded MNs had increased antioxidant activity and sustained drug release behavior. Furthermore, after being loaded in the developed MNs, it revealed improved antibacterial activity of CUR. Wound healing potential was assessed by histopathological analysis and wound closure%. The observed results suggest that the CUR-loaded MNs greatly improved wound healing potential via tissue regeneration and collagen deposition, demonstrating the potential of developed MNs patches to be used as an effective carrier for wound healing in healthcare settings.

A Novel Experience Of Ultrasound-Guided Erector Spinae Plane Block With Sedation In Breast Cancer Surgery: A Case Report.

We report the anaesthetic management of a breast cancer patient, at a high risk for undergoing general anaesthesia, using a single-shot ultrasound-guided Erector Spinae Plane Block (ESPB) with monitored sedation. Targetted at T4, 20 mL of 0.375% bupivacaine provided complete surgical anaesthesia in 15 minutes. Concurrent sedation was administered with target controlled infusion of propofol with entropy monitoring throughout the procedure. The surgery lasted 90 minutes and the patient remained pain free and haemodynamically stable throughout. At the end of the surgery, the patient received 1 g of paracetamol intravenously, and did not require any further analgesics other than routinely administered paracetamol until her discharge from the hospital. On top of the successful execution of our plan, this case was especially interesting as her postoperative analgesia remained completely opioid-free.

Biological Implications of MicroRNAs as Regulators and Biomarkers of Therapeutic Toxicities in Breast Cancer.

Contemporary breast cancer management includes surgical resection combined with a multimodal approach, including chemotherapy, radiotherapy, endocrine therapy, and targeted therapies. Breast cancer treatment is now personalised in accordance with disease and host factors, which has translated to enhanced outcomes for the vast majority of patients. Unfortunately, the treatment of the disease involves patients developing treatment-induced toxicities, with cardiovascular and metabolic side effects having negative implications for long-term quality-of-life metrics. MicroRNAs (miRNAs) are a class of small non-coding ribonucleic acids that are 17 to 25 nucleotides in length, which have utility in modifying genetic expression by working at a post-transcriptional cellular level. miRNAs have involvement in modulating breast cancer development, which is well described, with these biomarkers acting as important regulators of disease, as well as potential diagnostic and therapeutic biomarkers. This review focuses on highlighting the role of miRNAs as regulators and biomarkers of disease, particularly in breast cancer management, with a specific mention of the potential value of miRNAs in predicting treatment-related cardiovascular toxicity.

Proceeding the categorization of microplastics through deep learning-based image segmentation.

Microplastics (MPs) have been recognized as prominent anthropogenic pollutants that inflict significant harm to marine ecosystems. Various approaches have been proposed to mitigate the risks posed by MPs. Gaining an understanding of the morphology of plastic particles can provide valuable insights into the source and their interaction with marine organisms, which can assist the development of response measures. In this study, we present an automated technique for identifying MPs through segmentation of MPs in microscopic images using a deep convolutional neural network (DCNN) based on a shape classification nomenclature framework. We used MP images from diverse samples to train a Mask Region Convolutional Neural Network (Mask R-CNN) based model for classification. Erosion and dilation operations were added to the model to improve segmentation results. On the testing dataset, the mean F1-score (F1) of segmentation and shape classification was 0.7601 and 0.617, respectively. These results demonstrate the potential of proposed method for the automatic segmentation and shape classification of MPs. Furthermore, by adopting a specific nomenclature, our approach represents a practical step towards the global standardization of MPs categorization criteria. This work also identifies future research directions to improve accuracy and further explore the possibilities of using DCNN for MPs identification.

Free carrier-mediated ferromagnetism in nonmagnetic ion (Bi-Li) codoped ZnO nanowires.

Non-magnetic dopants and p-type materials are attractive choices to explore the mechanism and origin of room-temperature defect-based ferromagnetism in metal oxide-based DMSs. In this study, we performed comprehensive transport, magnetic, structural, optical, and compositional as well as DFT studies of pristine, Li-doped, and Bi-Li codoped vertically aligned ZnO NW films to explore the mechanism and origin of ferromagnetism. We used a simple solution process to synthesize a wurtzite structure and vertically aligned ZnO NWs on a Si substrate. The doping, high crystallinity, and vertical alignment along the 002 planes were evidenced through HRTEM, FESEM, and XRD measurements. The XPS analysis confirmed the +1 and +3 states of Li and Bi, respectively. Moreover, Raman analysis also depicted the characteristic peaks of ZnO NWs at 98.31 cm-1 and 437.71 cm-1. The PL studies of doped NWs showed a typical NBE peak of ZnO at ∼395 nm along with a sub-gap defect-related broad peak at ∼504 nm indicating the presence of defects due to doping. The pure ZnO NW samples showed negligible saturation magnetization (Ms) at room temperature while the saturation magnetization was observed to increase with Li-doping and reduced with Bi-Li codoping. According to the Hall studies the pure ZnO NW film showed n-type conductivity, while all doped and codoped samples showed p-type conductivity. The hole concentration was observed to increase with Li-doping and decrease with Bi-Li codoping showing similar behavior to that of the Ms value, thereby suggesting a direct correlation between Ms and carrier concentration. The I-V properties showed a similar trend to that of carrier concentration and Ms. Our DFT studies showed that magnetization increased by Li doping and reduced by Li-Bi codoping in defective ZnO crystals by replacing Zn with Li and Bi atoms at the Zn site. Overall, our studies highlight the immense potential of hole-mediated Bi-Li codoped ZnO NW devices which are expected to play a pivotal role in developing spintronic devices.

ß-actin mediated H3K27ac changes demonstrate the link between compartment switching and enhancer-dependent transcriptional regulation.

BACKGROUND: Recent work has demonstrated that three-dimensional genome organization is directly affected by changes in the levels of nuclear cytoskeletal proteins such as ß-actin. The mechanisms which translate changes in 3D genome structure into changes in transcription, however, are not fully understood. Here, we use a comprehensive genomic analysis of cells lacking nuclear ß-actin to investigate the mechanistic links between compartment organization, enhancer activity, and gene expression. RESULTS: Using HiC-Seq, ATAC-Seq, and RNA-Seq, we first demonstrate that transcriptional and chromatin accessibility changes observed upon ß-actin loss are highly enriched in compartment-switching regions. Accessibility changes within compartment switching genes, however, are mainly observed in non-promoter regions which potentially represent distal regulatory elements. Our results also show that ß-actin loss induces widespread accumulation of the enhancer-specific epigenetic mark H3K27ac. Using the ABC model of enhancer annotation, we then establish that these epigenetic changes have a direct impact on enhancer activity and underlie transcriptional changes observed upon compartment switching. A complementary analysis of fibroblasts undergoing reprogramming into pluripotent stem cells further confirms that this relationship between compartment switching and enhancer-dependent transcriptional change is not specific to ß-actin knockout cells but represents a general mechanism linking compartment-level genome organization to gene expression. CONCLUSIONS: We demonstrate that enhancer-dependent transcriptional regulation plays a crucial role in driving gene expression changes observed upon compartment-switching. Our results also reveal a novel function of nuclear ß-actin in regulating enhancer function by influencing H3K27 acetylation levels.

The Impact of Inflammation and General Anesthesia on Memory and Executive Function in Mice.

BACKGROUND: Perioperative neurocognitive disorders (PNDs) are complex, multifactorial conditions that are associated with poor long-term outcomes. Inflammation and exposure to general anesthetic drugs are likely contributing factors; however, the relative impact of each factor alone versus the combination of these factors remains poorly understood. The goal of this study was to compare the relative impact of inflammation, general anesthesia, and the combination of both factors on memory and executive function. METHODS: To induce neuroinflammation at the time of exposure to an anesthetic drug, adult male mice were treated with lipopolysaccharide (LPS) or vehicle. One day later, they were anesthetized with etomidate (or vehicle). Levels of proinflammatory cytokines were measured in the hippocampus and cortex 24 hours after LPS treatment. Recognition memory and executive function were assessed starting 24 hours after anesthesia using the novel object recognition assay and the puzzle box, respectively. Data are expressed as mean (or median) differences (95% confidence interval). RESULTS: LPS induced neuroinflammation, as indicated by elevated levels of proinflammatory cytokines, including interleukin-1ß (LPS versus control, hippocampus: 3.49 pg/mg [2.06-4.92], P < .001; cortex: 2.60 pg/mg [0.83-4.40], P = .010) and tumor necrosis factor-α (hippocampus: 3.50 pg/mg [0.83-11.82], P = .002; cortex: 2.38 pg/mg [0.44-4.31], P = .021). Recognition memory was impaired in mice treated with LPS, as evinced by a lack of preference for the novel object (novel versus familiar: 1.03 seconds [-1.25 to 3.30], P = .689), but not in mice treated with etomidate alone (novel versus familiar: 2.38 seconds [0.15-4.60], P = .031). Mice cotreated with both LPS and etomidate also exhibited memory deficits (novel versus familiar: 1.40 seconds [-0.83 to 3.62], P = .383). In the puzzle box, mice treated with either LPS or etomidate alone showed no deficits. However, the combination of LPS and etomidate caused deficits in problem-solving tasks (door open task: -0.21 seconds [-0.40 to -0.01], P = .037; plug task: -0.30 seconds [-0.50 to -0.10], P < .001; log values versus control), indicating impaired executive function. CONCLUSIONS: Impairments in recognition memory were driven by inflammation. Deficits in executive function were only observed in mice cotreated with LPS and etomidate. Thus, an interplay between inflammation and etomidate anesthesia led to cognitive deficits that were not observed with either factor alone. These findings suggest that inflammation and anesthetic drugs may interact synergistically, or their combination may unmask covert or latent deficits induced by each factor alone, leading to PNDs.

Clinical Application of Detecting COVID-19 Risks: A Natural Language Processing Approach.

The clinical application of detecting COVID-19 factors is a challenging task. The existing named entity recognition models are usually trained on a limited set of named entities. Besides clinical, the non-clinical factors, such as social determinant of health (SDoH), are also important to study the infectious disease. In this paper, we propose a generalizable machine learning approach that improves on previous efforts by recognizing a large number of clinical risk factors and SDoH. The novelty of the proposed method lies in the subtle combination of a number of deep neural networks, including the BiLSTM-CNN-CRF method and a transformer-based embedding layer. Experimental results on a cohort of COVID-19 data prepared from PubMed articles show the superiority of the proposed approach. When compared to other methods, the proposed approach achieves a performance gain of about 1-5% in terms of macro- and micro-average F1 scores. Clinical practitioners and researchers can use this approach to obtain accurate information regarding clinical risks and SDoH factors, and use this pipeline as a tool to end the pandemic or to prepare for future pandemics.