The rise of taxon-specific epitope predictors.

Computational predictors of immunogenic peptides, or epitopes, are traditionally built based on data from a broad range of pathogens without consideration for taxonomic information. While this approach may be reasonable if one aims to develop one-size-fits-all models, it may be counterproductive if the proteins for which the model is expected to generalize are known to come from a specific subset of phylogenetically related pathogens. There is mounting evidence that, for these cases, taxon-specific models can outperform generalist ones, even when trained with substantially smaller amounts of data. In this comment, we provide some perspective on the current state of taxon-specific modelling for the prediction of linear B-cell epitopes, and the challenges faced when building and deploying these predictors.

Non-invasive technology for brain monitoring: definition and meaning of the principal parameters for the International PRactice On TEChnology neuro-moniToring group (I-PROTECT).

Technologies for monitoring organ function are rapidly advancing, aiding physicians in the care of patients in both operating rooms (ORs) and intensive care units (ICUs). Some of these emerging, minimally or non-invasive technologies focus on monitoring brain function and ensuring the integrity of its physiology. Generally, the central nervous system is the least monitored system compared to others, such as the respiratory, cardiovascular, and renal systems, even though it is a primary target in most therapeutic strategies. Frequently, the effects of sedatives, hypnotics, and analgesics are entirely unpredictable, especially in critically ill patients with multiple organ failure. This unpredictability exposes them to the risks of inadequate or excessive sedation/hypnosis, potentially leading to complications and long-term negative outcomes. The International PRactice On TEChnology neuro-moniToring group (I-PROTECT), comprised of experts from various fields of clinical neuromonitoring, presents this document with the aim of reviewing and standardizing the primary non-invasive tools for brain monitoring in anesthesia and intensive care practices. The focus is particularly on standardizing the nomenclature of different parameters generated by these tools. The document addresses processed electroencephalography, continuous/quantitative electroencephalography, brain oxygenation through near-infrared spectroscopy, transcranial Doppler, and automated pupillometry. The clinical utility of the key parameters available in each of these tools is summarized and explained. This comprehensive review was conducted by a panel of experts who deliberated on the included topics until a consensus was reached. Images and tables are utilized to clarify and enhance the understanding of the clinical significance of non-invasive neuromonitoring devices within these medical settings.

Electroencephalographic guided propofol-remifentanil TCI anesthesia with and without dexmedetomidine in a geriatric population: electroencephalographic signatures and clinical evaluation.

Elderly and multimorbid patients are at high risk for developing unfavorable postoperative neurocognitive outcomes; however, well-adjusted and EEG-guided anesthesia may help titrate anesthesia and improve postoperative outcomes. Over the last decade, dexmedetomidine has been increasingly used as an adjunct in the perioperative setting. Its synergistic effect with propofol decreases the dose of propofol needed to induce and maintain general anesthesia. In this pilot study, we evaluate two highly standardized anesthetic regimens for their potential to prevent burst suppression and postoperative neurocognitive dysfunction in a high-risk population. Prospective, randomized clinical trial with non-blinded intervention. Operating room and post anesthesia care unit at Hospital Base San José, Osorno/Universidad Austral, Valdivia, Chile. 23 patients with scheduled non-neurologic, non-cardiac surgeries with age > 69 years and a planned intervention time > 60 min. Patients were randomly assigned to receive either a propofol-remifentanil based anesthesia or an anesthetic regimen with dexmedetomidine-propofol-remifentanil. All patients underwent a slow titrated induction, followed by a target controlled infusion (TCI) of propofol and remifentanil (n = 10) or propofol, remifentanil and continuous dexmedetomidine infusion (n = 13). We compared the perioperative EEG signatures, drug-induced changes, and neurocognitive outcomes between two anesthetic regimens in geriatric patients. We conducted a pre- and postoperative Montreal Cognitive Assessment (MoCa) test and measured the level of alertness postoperatively using a sedation agitation scale to assess neurocognitive status. During slow induction, maintenance, and emergence, burst suppression was not observed in either group; however, EEG signatures differed significantly between the two groups. In general, EEG activity in the propofol group was dominated by faster rhythms than in the dexmedetomidine group. Time to responsiveness was not significantly different between the two groups (p = 0.352). Finally, no significant differences were found in postoperative cognitive outcomes evaluated by the MoCa test nor sedation agitation scale up to one hour after extubation. This pilot study demonstrates that the two proposed anesthetic regimens can be safely used to slowly induce anesthesia and avoid EEG burst suppression patterns. Despite the patients being elderly and at high risk, we did not observe postoperative neurocognitive deficits. The reduced alpha power in the dexmedetomidine-treated group was not associated with adverse neurocognitive outcomes.

Divergent immune microenvironments in two tumor nodules from a patient with mismatch repair-deficient prostate cancer.

Patients with prostate cancer (PC) generally do not respond favorably to immune checkpoint inhibitors, which may be due to a low abundance of tumor-infiltrating lymphocytes even when mutational load is high. Here, we identified a patient who presented with high-grade primary prostate cancer with two adjacent tumor nodules. While both nodules were mismatch repair-deficient (MMRd), exhibited pathogenic MSH2 and MSH6 alterations, had a high tumor mutational burden (TMB), and demonstrated high microsatellite instability (MSI), they had markedly distinct immune phenotypes. The first displayed a dense infiltrate of lymphocytes ("hot nodule"), while the second displayed significantly fewer infiltrating lymphocytes ("cold nodule"). Whole-exome DNA analysis found that both nodules shared many identical mutations, indicating that they were derived from a single clone. However, the cold nodule appeared to be sub-clonal relative to the hot nodule, suggesting divergent evolution of the cold nodule from the hot nodule. Whole-transcriptome RNA analysis found that the cold nodule demonstrated lower expression of genes related to antigen presentation (HLA) and, paradoxically, classical tumor immune tolerance markers such as PD-L1 (CD274) and CTLA-4. Immune cell deconvolution suggested that the hot nodule was enriched not only in CD8+ and CD4 + T lymphocytes, but also in M1 macrophages, activated NK cells, and γδ T cells compared to the cold nodule. This case highlights that MMRd/TMB-high PC can evolve to minimize an anti-tumor immune response, and nominates downregulation of antigen presentation machinery (HLA loss) as a potential mechanism of adaptive immune evasion in PC.

Changes in motor evoked potentials after erector spinae block in scoliosis surgery-when to take pre-incision baseline recordings?

Multimodal intraoperative neurophysiological monitoring (IONM) is highly valuable in scoliosis surgeries for monitoring spinal cord function, particularly during instrumentation. Accurate timing of baseline recordings of TcMEP and SSEP is crucial, as any changes observed during surgery and instrumentation are compared to these baseline recordings. However, the impact of ultrasound-guided erector spinae block (USG-ESPB) on SSEP and TcMEP is not well-studied in scoliosis surgery. In this report, we present two cases of scoliosis surgery where bilateral two-level USG-ESPB using different concentrations of ropivacaine (0.375% and 0.2%) resulted in a transient and significant deterioration of TcMEP, occurring 3 minutes after the block and lasting for 20 minutes. Remarkably, SSEPs remained unchanged during this period. These findings suggest that USG-ESPB may produce TcMEP changes, highlighting the importance of carefully considering the timing of baseline TcMEP acquisition in scoliosis surgery.

Factors influencing the need for emergent conversion to general anesthesia during mechanical thrombectomy in acute anterior circulation stroke - A retrospective observational study.

BACKGROUND: Endovascular mechanical thrombectomy (EMT) for acute ischemic stroke can be conducted under conscious sedation (CS) or general anesthesia (GA). Emergency conversion from CS to GA during the procedure can occur, but its predictors and impact on clinical outcomes are not fully understood. METHODS: A single centre retrospective analysis was conducted on 226 patients who underwent EMT for anterior circulation stroke. Two groups were identified: patients who completed the procedure under CS and those requiring emergency conversion to GA. The predictors of emergency conversion to GA and its impact on clinical outcomes were analyzed. RESULTS: Forty-five patients (19.9%) required conversion to GA. Atrial fibrillation (OR 2.38; CI 1.09-5.22; p = 0.03) and prolonged duration of procedure (OR 1.02; CI 1.01-1.04; p < 0.001) were identified as the independent predictors of emergency conversion to GA. CONCLUSION: Patients with atrial fibrillation and prolonged duration of procedure especially when utilizing combined aspiration-stent retriever or angioplasty/stenting techniques, had a higher likelihood of requiring emergency conversion to general anesthesia (GA).

CALANGO: A phylogeny-aware comparative genomics tool for discovering quantitative genotype-phenotype associations across species.

Living species vary significantly in phenotype and genomic content. Sophisticated statistical methods linking genes with phenotypes within a species have led to breakthroughs in complex genetic diseases and genetic breeding. Despite the abundance of genomic and phenotypic data available for thousands of species, finding genotype-phenotype associations across species is challenging due to the non-independence of species data resulting from common ancestry. To address this, we present CALANGO (comparative analysis with annotation-based genomic components), a phylogeny-aware comparative genomics tool to find homologous regions and biological roles associated with quantitative phenotypes across species. In two case studies, CALANGO identified both known and previously unidentified genotype-phenotype associations. The first study revealed unknown aspects of the ecological interaction between Escherichia coli, its integrated bacteriophages, and the pathogenicity phenotype. The second identified an association between maximum height in angiosperms and the expansion of a reproductive mechanism that prevents inbreeding and increases genetic diversity, with implications for conservation biology and agriculture.

Why are some plants taller? Researchers on the unveiling of genetic variation associated with complex quantitative phenotypes.

Francisco Pereira Lobo, Giovanni Marques de Castro, and Felipe Campelo are part of an international team of collaborators that developed CALANGO, a comparative genomics tool to investigate quantitative genotype-phenotype relationships. Their Patterns article highlights how the tool integrates species-centric data to perform genome-wide search and detect genes potentially involved in the emergence of complex quantitative traits across species. Here, they talk about their view of data science, their experience with interdisciplinary research, and the potential applications of their tool.

Mpox vaccine and infection-driven human immune signatures: an immunological analysis of an observational study.

BACKGROUND: Monkeypox virus has recently infected more than 88 000 people, raising concerns about our preparedness against this emerging viral pathogen. Licensed and approved for mpox, the JYNNEOS vaccine has fewer side-effects than previous smallpox vaccines and has shown immunogenicity against monkeypox in animal models. This study aims to elucidate human immune responses to JYNNEOS vaccination compared with mpox-induced immunity. METHODS: Peripheral blood mononuclear cells and sera were obtained from ten individuals vaccinated with one or two doses of JYNNEOS and six individuals diagnosed with monkeypox virus infection. Samples were obtained from seven individuals before vaccination to serve as a baseline. We examined the polyclonal serum (ELISA) and single B-cell (heavy chain gene and transcriptome data) antibody repertoires and T-cell responses (activation-induced marker and intracellular cytokine staining assays) induced by the JYNNEOS vaccine versus monkeypox virus infection. FINDINGS: All participants were men between the ages of 21 and 60 years, except for one woman in the group of mpox-convalescent individuals, and none had previous orthopoxvirus exposure. All mpox cases were mild. Vaccinee samples were collected 6-33 days after the first dose and 5-40 days after the second dose. Mpox-convalescent samples were collected 20-102 days after infection. In vaccine recipients, gene-level plasmablast and antibody responses were negligible and sera displayed moderate binding to recombinant orthopoxviral proteins (A29L, A35R, E8L, A30L, A27L, A33R, B18R, and L1R) and native proteins from the 2022 monkeypox outbreak strain. By contrast, recent monkeypox virus infection (within 20-102 days) induced robust serum antibody responses to monkeypox virus proteins and to native monkeypox virus proteins from a viral isolate obtained during the 2022 outbreak. JYNNEOS vaccine recipients presented robust orthopoxviral CD4+ and CD8+ T-cell responses. INTERPRETATION: Infection with monkeypox virus resulted in robust B-cell and T-cell responses, whereas immunisation with JYNNEOS elicited more robust T-cell responses. These data can help to inform vaccine design and policies for preventing mpox in humans. FUNDING: National Cancer Institute (National Institutes of Health), National Institute of Allergy and Infectious Diseases (National Institutes of Health), and Icahn School of Medicine.

Chronic ethanol exposure impairs alveolar leukocyte infiltration during pneumococcal pneumonia, leading to an increased bacterial burden despite increased CXCL1 and nitric oxide levels.

Ethanol abuse is a risk factor for the development of pneumonia caused by Streptococcus pneumoniae, a critical pathogen for public health. The aim of this article was to investigate the inflammatory mechanisms involved in pneumococcal pneumonia that may be associated with chronic ethanol exposure. Male C57BL6/J-Unib mice were exposed to 20% (v/v) ethanol for twelve weeks and intranasally infected with 5x104 CFU of S. pneumoniae. Twenty-four hours after infection, lungs, bronchoalveolar lavage and blood samples were obtained to assess the consequences of chronic ethanol exposure during infection. Alcohol-fed mice showed increased production of nitric oxide and CXCL1 in alveoli and plasma during pneumococcal pneumonia. Beside this, ethanol-treated mice exhibited a decrease in leukocyte infiltration into the alveoli and reduced frequency of severe lung inflammation, which was associated with an increase in bacterial load. Curiously, no changes were observed in survival after infection. Taken together, these results demonstrate that chronic ethanol exposure alters the inflammatory response during S. pneumoniae lung infection in mice with a reduction in the inflammatory infiltrate even in the presence of higher levels of the chemoattractant CXCL1.

Irreversible Geometrothermodynamics of Open Systems in Modified Gravity.

In this work, we explore the formalism of the irreversible thermodynamics of open systems and the possibility of gravitationally generated particle production in modified gravity. More specifically, we consider the scalar-tensor representation of f(R,T) gravity, in which the matter energy-momentum tensor is not conserved due to a nonminimal curvature-matter coupling. In the context of the irreversible thermodynamics of open systems, this non-conservation of the energy-momentum tensor can be interpreted as an irreversible flow of energy from the gravitational sector to the matter sector, which, in general, could result in particle creation. We obtain and discuss the expressions for the particle creation rate, the creation pressure, and the entropy and temperature evolutions. Applied together with the modified field equations of scalar-tensor f(R,T) gravity, the thermodynamics of open systems lead to a generalization of the ΛCDM cosmological paradigm, in which the particle creation rate and pressure are considered effectively as components of the cosmological fluid energy-momentum tensor. Thus, generally, modified theories of gravity in which these two quantities do not vanish provide a macroscopic phenomenological description of particle production in the cosmological fluid filling the Universe and also lead to the possibility of cosmological models that start from empty conditions and gradually build up matter and entropy.

Linear thinking does not reflect the newer 21st-century anesthesia concepts. A narrative review.

The brain constitutes a good example of a chaotic, nonlinear biological system where large neuronal networks operate chaotically with random connectivity. This critical state is significantly affected by the anesthetic loss of consciousness induced by drugs whose pharmacological behavior has been classically based on linear kinetics and dynamics. Recent developments in pharmacology and brain monitoring during anesthesia suggest a different view that we tried to explore in this article. The concepts of effect-site for hypnotic drugs modeling a maximum effect, electroencephalographic dynamics during induction, maintenance, and recovery from anesthesia are discussed, integrated into this alternative view, and how it may be applied in daily clinical practice.

The importance of monitoring cerebral oxygenation in non brain injured patients.

Over the past few years, the use of non-invasive neuromonitoring in non-brain injured patients has increased, as a result of the recognition that many of these patients are at risk of brain injury in a wide number of clinical scenarios and therefore may benefit from its application which allows interventions to prevent injury and improve outcome. Among these, are post cardiac arrest syndrome, sepsis, liver failure, acute respiratory failure, and the perioperative settings where in the absence of a primary brain injury, certain groups of patients have high risk of neurological complications. While there are many neuromonitoring modalities utilized in brain injured patients, the majority of those are either invasive such as intracranial pressure monitoring, require special skill such as transcranial Doppler ultrasonography, or intermittent such as pupillometry and therefore unable to provide continuous monitoring. Cerebral oximetry using Near infrared Spectroscopy, is a simple non invasive continuous measure of cerebral oxygenation that has been shown to be useful in preventing cerebral hypoxemia both within the intensive care unit and the perioperative settings. At present, current recommendations for standard monitoring during anesthesia or in the general intensive care concentrate mainly on hemodynamic and respiratory monitoring without specific indications regarding the brain, and in particular, brain oximetry. The aim of this manuscript is to provide an up-to-date overview of the pathophysiology and applications of cerebral oxygenation in non brain injured patients as part of non-invasive multimodal neuromonitoring in the early identification and treatment of neurological complications in this population.

Oxygen Reserve Index and Arterial Partial Pressure of Oxygen: Relationship in Open Heart Surgery.

BACKGROUND: Mild to moderate hyperoxia is potentially beneficial to patients undergoing open heart surgery. Oxygen Reserve Index (ORI) is a novel parameter that correlates to arterial oxygen tension (PaO2) in the hyperoxic range. This prospective study aimed to assess whether the relationship between ORI and PaO2 remains intact in the setting of open-heart surgery. METHODS: This study included patients undergoing valve, aortic arch and coronary artery bypass grafting (CABG) surgeries, on and off pump, between September 1st 2019 and August 31st 2021. Enrolled patients had arterial blood gas samples collected and analyzed after induction of anesthesia and increases in FiO2 in steps of 0.08 with ORI being recorded at the time of sample collection for cross reference and analysis. RESULTS: ORI values showed a statistically significant correlation with PaO2 values in the 100-200 mmHg range (r = 0.8193, p < 0.001). Additionally, there was a significant correlation between ORI and SpO2 values in the range of 95% and 100% (r = 0.529, p < 0.05). CONCLUSIONS: The preserved relationship between ORI and PaO2 in the mild and moderate hyperoxic range can allow more precise titration of oxygen therapy to guide therapy targeting normoxia, mildly and moderately hyperoxia. Additionally, it could have a potential use as an early warning system for impeding hypoxia.

Inhalational versus Intravenous General Anesthesia for mechanical thrombectomy for stroke: A single centre retrospective study.

BACKGROUND: When general anesthesia is used for endovascular thrombectomy (EVT) for acute ischemic stroke (AIS), the choice of anesthetic agents for maintenance remains inconclusive. The different effects of intravenous anesthetic and volatiles agents on cerebral hemodynamics are known and may explain differences in outcomes of patients with cerebral pathologies exposed to the different anesthetic modalities. In this single institutional retrospective study, we assessed the impact of total intravenous (TIVA) and inhalational anesthesia on outcomes after EVT. METHODS: We conducted a retrospective analysis of all patients ≥ 18 years who underwent EVT for AIS of the anterior or posterior circulation under general anesthesia. Baseline patient characteristics, anesthetic agents, intra operative hemodynamics, stroke characteristics, time intervals and clinical outcome data were collected and analyzed. RESULTS: The study cohort consisted of 191 patients. After excluding 76 patients who were lost to follow up at 90 days, 51 patients received inhalational anesthesia and 64 patients who received TIVA were analyzed. The clinical characteristics between the groups were comparable. Multivariate logistic regression analysis of outcome measures for TIVA versus inhalational anesthesia showed significantly increased odds of good functional outcome (mRS 0-2) at 90 days (adjusted odds ratio, 3.24; 95% CI, 1.25-8.36; p = 0.015) and a non-significant trend towards decreased mortality (adjusted odds ratio, 0.73; CI, 0.15-3.6; p = 0.70). CONCLUSION: Patients who had TIVA for mechanical thrombectomy had significantly increased odds of good functional outcome at 90 days and a non-significant trend towards decrease in mortality. These findings warrant further investigation with large randomized, prospective trials.

Mpox vaccine and infection-driven human immune signatures.

Background: Mpox (formerly known as monkeypox) outbreaks outside endemic areas peaked in July 2022, infecting > 85,000 people and raising concerns about our preparedness against this emerging viral pathogen. Licensed and approved for mpox, the JYNNEOS vaccine has fewer side effects than previous smallpox vaccines and demonstrated efficacy against mpox infection in humans. Comparing JYNNEOS vaccine- and mpox-induced immunity is imperative to evaluate JYNNEOS' immunogenicity and inform vaccine administration and design. Methods: We examined the polyclonal serum (ELISA) and single B cell (heavy chain gene and transcriptome data) antibody repertoires and T cells (AIM and ICS assays) induced by the JYNNEOS vaccine as well as mpox infection. Findings: Gene-level plasmablast and antibody responses were negligible and JYNNEOS vaccinee sera displayed minimal binding to recombinant mpox proteins and native proteins from the 2022 outbreak strain. In contrast, recent mpox infection (within 20-102 days) induced robust serum antibody responses to A29L, A35R, A33R, B18R, and A30L, and to native mpox proteins, compared to vaccinees. JYNNEOS vaccine recipients presented comparable CD4 and CD8 T cell responses against orthopox peptides to those observed after mpox infection. Interpretation: JYNNEOS immunization does not elicit a robust B cell response, and its immunogenicity may be mediated by T cells. Funding: Research reported in this publication was supported, in part, by the National Cancer Institute of the National Institutes of Health under Award Number U54CA267776, U19AI168631(VS), as well as institutional funds from the Icahn School of Medicine.