Microbial exposure during early human development primes fetal immune cells.

The human fetal immune system begins to develop early during gestation; however, factors responsible for fetal immune-priming remain elusive. We explored potential exposure to microbial agents in utero and their contribution toward activation of memory T cells in fetal tissues. We profiled microbes across fetal organs using 16S rRNA gene sequencing and detected low but consistent microbial signal in fetal gut, skin, placenta, and lungs in the 2nd trimester of gestation. We identified several live bacterial strains including Staphylococcus and Lactobacillus in fetal tissues, which induced in vitro activation of memory T cells in fetal mesenteric lymph node, supporting the role of microbial exposure in fetal immune-priming. Finally, using SEM and RNA-ISH, we visualized discrete localization of bacteria-like structures and eubacterial-RNA within 14th weeks fetal gut lumen. These findings indicate selective presence of live microbes in fetal organs during the 2nd trimester of gestation and have broader implications toward the establishment of immune competency and priming before birth.

Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma.

We employed scRNA sequencing to extensively characterize the cellular landscape of human liver from development to disease. Analysis of ∼212,000 cells representing human fetal, hepatocellular carcinoma (HCC), and mouse liver revealed remarkable fetal-like reprogramming of the tumor microenvironment. Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including re-emergence of fetal-associated endothelial cells (PLVAP/VEGFR2) and fetal-like (FOLR2) tumor-associated macrophages. In a cross-species comparative analysis, we discovered remarkable similarity between mouse embryonic, fetal-liver, and tumor macrophages. Spatial transcriptomics further revealed a shared onco-fetal ecosystem between fetal liver and HCC. Furthermore, gene regulatory analysis, spatial transcriptomics, and in vitro functional assays implicated VEGF and NOTCH signaling in maintaining onco-fetal ecosystem. Taken together, we report a shared immunosuppressive onco-fetal ecosystem in fetal liver and HCC. Our results unravel a previously unexplored onco-fetal reprogramming of the tumor ecosystem, provide novel targets for therapeutic interventions in HCC, and open avenues for identifying similar paradigms in other cancers and disease.

Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease.

Mononuclear phagocytes (MNPs) encompass dendritic cells, monocytes, and macrophages (MoMac), which exhibit antimicrobial, homeostatic, and immunoregulatory functions. We integrated 178,651 MNPs from 13 tissues across 41 datasets to generate a MNP single-cell RNA compendium (MNP-VERSE), a publicly available tool to map MNPs and define conserved gene signatures of MNP populations. Next, we generated a MoMac-focused compendium that revealed an array of specialized cell subsets widely distributed across multiple tissues. Specific pathological forms were expanded in cancer and inflammation. All neoplastic tissues contained conserved tumor-associated macrophage populations. In particular, we focused on IL4I1+CD274(PD-L1)+IDO1+ macrophages, which accumulated in the tumor periphery in a T cell-dependent manner via interferon-γ (IFN-γ) and CD40/CD40L-induced maturation from IFN-primed monocytes. IL4I1_Macs exhibited immunosuppressive characteristics through tryptophan degradation and promoted the entry of regulatory T cell into tumors. This integrated analysis provides a robust online-available platform for uniform annotation and dissection of specific macrophage functions in healthy and pathological states.

A subset of Kupffer cells regulates metabolism through the expression of CD36.

Tissue macrophages are immune cells whose phenotypes and functions are dictated by origin and niches. However, tissues are complex environments, and macrophage heterogeneity within the same organ has been overlooked so far. Here, we used high-dimensional approaches to characterize macrophage populations in the murine liver. We identified two distinct populations among embryonically derived Kupffer cells (KCs) sharing a core signature while differentially expressing numerous genes and proteins: a major CD206loESAM- population (KC1) and a minor CD206hiESAM+ population (KC2). KC2 expressed genes involved in metabolic processes, including fatty acid metabolism both in steady-state and in diet-induced obesity and hepatic steatosis. Functional characterization by depletion of KC2 or targeted silencing of the fatty acid transporter Cd36 highlighted a crucial contribution of KC2 in the liver oxidative stress associated with obesity. In summary, our study reveals that KCs are more heterogeneous than anticipated, notably describing a subpopulation wired with metabolic functions.

NK cells modulate in vivo control of SARS-CoV-2 replication and suppression of lung damage.

Natural killer (NK) cells play a critical role in virus control. However, it has remained largely unclear whether NK cell mobilization in SARS-CoV-2 infections is beneficial or pathologic. To address this deficit, we employed a validated experimental NK cell depletion non-human primate (NHP) model with SARS-CoV-2 Delta variant B.1.617.2 challenge. Viral loads (VL), NK cell numbers, activation, proliferation, and functional measures were evaluated in blood and tissues. In non-depleted (control) animals, infection rapidly induced NK cell expansion, activation, and increased tissue trafficking associated with VL. Strikingly, we report that experimental NK cell depletion leads to higher VL, longer duration of viral shedding, significantly increased levels of pro-inflammatory cytokines in the lungs, and overt lung damage. Overall, we find the first significant and conclusive evidence for NK cell-mediated control of SARS-CoV-2 virus replication and disease pathology. These data indicate that adjunct therapies for infection could largely benefit from NK cell-targeted approaches.

Advances in cellular and tissue-based imaging techniques for sarcoid granulomas.

Sarcoidosis embodies a complex inflammatory disorder spanning multiple systems, with its origin remaining elusive. It manifests as the infiltration of inflammatory cells that coalesce into distinctive noncaseous granulomas within afflicted organs. Unraveling this disease necessitates the utilization of cellular or tissue-based imaging methods to both visualize and characterize the biochemistry of these sarcoid granulomas. Although hematoxylin and eosin stain, standard in routine use alongside cytological stains have found utility in diagnosis within clinical contexts, special stains such as Masson's trichrome, reticulin, methenamine silver, and Ziehl-Neelsen provide additional varied perspectives of sarcoid granuloma imaging. Immunohistochemistry aids in pinpointing specific proteins and gene expressions further characterizing these granulomas. Finally, recent advances in spatial transcriptomics promise to divulge profound insights into their spatial orientation and three-dimensional (3-D) molecular mapping. This review focuses on a range of preexisting imaging methods employed for visualizing sarcoid granulomas at the cellular level while also exploring the potential of the latest cutting-edge approaches like spatial transcriptomics and matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), with the overarching goal of shedding light on the trajectory of sarcoidosis research.

First Insight into the Phylogenetic Diversity of Bovicola caprae Infesting Goats of Different Agro-climatic Locations in India.

Bovicola caprae is an important obligate ectoparasite of goats worldwide including India. The present study aimed at the molecular confirmation, phylogenetics and population structure analyses of B. caprae infesting goats of three different agro-climatic locations in India, by targeting the mitochondrial cytochrome C oxidase subunit 1 (cox1) genetic marker. The phylogenetic tree exhibited the presence of two different lineages of B. caprae. The sequences generated herein clustered in lineage 2 along with the GenBank™ archived sequences from China and Iran. The sequences generated herein also showed the circulation of sub-lineages of B. caprae in India based on the analysis of pairwise genetic distances between sequences and median-joining haplotype network. The population structure analyses revealed low nucleotide (0.00353 ± 0.00291 and 0.02694 ± 0.00363) and high haplotype (0.667 ± 0.314 and 0.618 ± 0.104) diversities for the present study isolates as well as for the complete dataset, respectively, which evinced a recent demographic expansion. High genetic differentiation (FST value = 0.97826) and low gene flow (Nm = 0.00556) were also recorded in the different lineages/populations. In conclusion, the present study addressed the research gap and provided the first insight into the phylogenetics of the goat louse B. caprae and highlighted the circulation of sub-lineages of the ectoparasite in India.

Mentha aquatica (Water Mint) as a Source of Active Pharmaceutical and Cosmetic Ingredients: A Critical Review.

Mentha aquatica L., or water mint, is an important member of the Mentha genus, and has long been used in traditional medicine, mainly to treat respiratory diseases such as the common cold. Nevertheless, although over the years many studies have shown that it's potential grows beyond this use, a review that highlights M. aquatica L.'s true potential is still lacking. Thus, the main purpose of the present article is to provide a thorough and multidisciplinary critical review of M. aquatica L., including its phytochemical characterization, main bioactivities, and current marketed cosmetic products. Many compounds have been identified as part of M. aquatica L. composition, such as terpenes, phenolic acids, phenols, and terpenoids, which have been linked to a vast therapeutic potential, namely anti-inflammatory, antioxidant, antibacterial, antifungal, antiobesity, and hepatoprotection bioactivities, with additional anticancer potential for several types of tumors (breast, lung, and skin), and psycho and neuroactive potential in depression, or Alzheimer's or Parkinson's disease. Additionally, it has been proven to be suitable for cosmetic application since several cleansing, hydrating, protecting, and/or odor masking products containing it are already available, with the main functions attributed to M. aquatica including refreshing/cooling effects, calming/soothing/relaxing effects, and purifying effects, properties closely related to its anti-inflammatory and antioxidant bioactivities. Hence, M. aquatica is an extremely versatile plant, with its extracts and essential oils having great therapeutic and cosmetic potential. With many marketed cosmetic products, future studies should focus on this plant's medicinal aspects, so that 1 day it can be part of therapeutic regimens.

Lipoplexes' Structure, Preparation, and Role in Managing Different Diseases.

Lipid-based vectors are becoming promising alternatives to traditional therapies over the last 2 decades specially for managing life-threatening diseases like cancer. Cationic lipids are the most prevalent non-viral vectors utilized in gene delivery. The increasing number of clinical trials about lipoplex-based gene therapy demonstrates their potential as well-established technology that can provide robust gene transfection. In this regard, this review will summarize this important point. These vectors however have a modest transfection efficiency. This limitation can be partly addressed by using functional lipids that provide a plethora of options for investigating nucleic acid-lipid interactions as well as in vitro and in vivo nucleic acid delivery for biomedical applications. Despite their lower gene transfer efficiency, lipid-based vectors such as lipoplexes have several advantages over viral ones: they are less toxic and immunogenic, can be targeted, and are simple to produce on a large scale. Researchers are actively investigating the parameters that are essential for an effective lipoplex delivery method. These include factors that influence the structure, stability, internalization, and transfection of the lipoplex. Thorough understanding of the design principles will enable synthesis of customized lipoplex formulations for life-saving therapy.

Investigating the dynamic nature of landslide susceptibility in the Indian Himalayan region.

Landslide susceptibility zonation (LSZ) mapping is used to delineate areas prone to landslides and is critical for effective landslide hazard management. The existing methodologies for generating such maps tend to neglect the influence of dynamic environmental variables on landslide occurrences, which may lead to obsolete and erroneous estimates of landslide susceptibility (LS) for a concerned area. Although recent studies have started to report the effects of Land Use/ Land Cover (LULC) variation on LSZ mapping, variations in other dynamic variables like rainfall, soil moisture, and evapotranspiration apart from LULC may also influence slope stability in mountainous regions. The present study investigates the impact of variations in these four variables on the LS distribution, of a selected Indian Himalayan region between 2017 and 2021. Random Forest (RF) susceptibility models are utilized for evaluating the LS for the selected years and geospatial technologies are employed for LS change detection. The results indicate up to 19% variations in the spatial extent for some of the zones of the generated LSZ maps. The research findings of this study are crucial since they reveal the impact of dynamic behavior on LS, which has not been previously documented in the literature.

Author Response: Oxygen Delivery Devices in Postoperative Patients: Proper Selection of Patients Matters!

How to cite this article: Mishra S, Kothari N, Sharma A, Goyal S. Author Response: Oxygen Delivery Devices in Postoperative Patients: Proper Selection of Patients Matters! Indian J Crit Care Med 2024;28(8):803.

Comparison of Oxygen Delivery Devices in Postoperative Patients with Hypoxemia: An Open-labeled Randomized Controlled Study.

Background: Acute hypoxemic respiratory failure is among the more commonly occurring complications in postoperative patients. Supplemental oxygen and addressing the primary etiology form the basis of its treatment. Materials and methods: We conducted an open-labeled randomized control trial with 90 adult patients and compared three oxygen delivery vehicles (ODV), i.e., noninvasive ventilation (NIV), high-flow nasal cannula (HFNC), and venturi mask (VM) in postoperative hypoxemic patients. The primary outcome variable was a change in the P/F ratio after 2 hours of use of ODV. Results: It was observed that the change in P/F ratio after 2 hours was similar in all three ODV groups (p = 0.274). The mean values of the post-ODV P/F ratio were comparable with the pre-ODV P/F ratio in all three modalities. The P/F ratio after HFNC was 358.08 ± 117.95; after NIV was 357.60 ± 220.67; and after VM was 355.47 ± 101.90 (p = 0.997). Conclusion: Among HFNC, NIV, and VM, none of the devices proved superior to the other for use in postoperative hypoxemia. How to cite this article: Mishra S, Kothari N, Sharma A, Goyal S, Rathod D, Meshram T, et al. Comparison of Oxygen Delivery Devices in Postoperative Patients with Hypoxemia: An Open-labeled Randomized Controlled Study. Indian J Crit Care Med 2024;28(3):294-298.

Comparison of Modified ROX Index Score and ROX Index Score for Early Prediction of High Flow Nasal Oxygen Therapy Outcome in Patients with Acute Respiratory Failure: A Prospective Observational Cohort Study.

Background: We compared the modified ROX index and ROX index scores in earlier predictions of high-flow nasal oxygen (HFNO) therapy outcomes in patients with acute respiratory failure. Methods: We conducted a prospective observational study on 151 acute respiratory failure patients initiated on HFNO therapy. The primary objective of this research was to compare the modified ROX index and ROX index to investigate which score predicted HFNO treatment outcome earlier. Results: The modified ROX index score had better predictive power than the ROX score at different time points, especially one hour following the start of HFNO therapy (AUC 0.790; 95% CI: 0.717-0.863; p < 0.001). For the ROX Index at 1 hour, the ideal cut-off value for HFNO outcome was 4.36 (sensitivity: 72.6%, specificity: 53.9%), and for the modified ROX index at 1 hour, it was 4.63 (sensitivity: 74.2%, specificity: 69.7%). The presence of various comorbidities didn't show any change in ROX-HR cut-off values. Conclusion: The modified ROX index is a better predictor of the success of HFNO therapy than the ROX index. Furthermore, the presence of any comorbidities did not affect modified ROX index cut-off values or the outcome of HFNO therapy. How to cite this article: Sarkar AG, Sharma A, Kothari N, Goyal S, Meshram T, Kumari K, et al. Comparison of Modified ROX Index Score and ROX Index Score for Early Prediction of High Flow Nasal Oxygen Therapy Outcome in Patients with Acute Respiratory Failure: A Prospective Observational Cohort Study. Indian J Crit Care Med 2024;28(9):842-846.

Author Response: Beyond the Nasal Prongs: A Joust of Oxygen Delivery Methods in Post-op Hypoxemia.

How to cite this article: Mishra S, Kothari N, Sharma A, Goyal S, Rathod DK, Meshram T, et al. Author Response: Beyond the Nasal Prongs: A Joust of Oxygen Delivery Methods in Post-op Hypoxemia. Indian J Crit Care Med 2024;28(6):626-627.

Comparison of midpoint transverse process to pleura (MTP) block and erector spinae plane block (ESP) for postoperative analgesia in modified radical mastectomy patients: A double-blinded, randomized control trial.

Background and Aims: Modified radical mastectomy (MRM) is associated with moderate severity of postoperative pain. Besides intravenous (IV) analgesics, various nerve blocks are being described for pain relief of MRM patients. We compared erector spinae plane (ESP) block with midpoint transverse process to pleura (MTP) block in these patients for postoperative analgesia. Material and Methods: After receiving ethical committee approval from the institutional ethics committee (AIIMS, Jodhpur) and written informed consent from study participants, 66 patients who were assigned American Society of Anesthesiologists (ASA) physical status I and II, aged 18-75 years, and were scheduled to undergo MRM were enrolled and randomly allocated into two groups. Unilateral block was given before surgery at T3 or T4 level and with 15 ml of 0.5% ropivacaine in both the groups. Infusion of 0.5% ropivacaine (Neon laboratories limited, Mumbai, India) and 0.2% ropivacaine at a rate of 5 ml/h was maintained intraoperatively and postoperatively, respectively. Pain was assessed using the Visual Analogue Scale (VAS) for the next 24 hours. The total number of patients needing rescue analgesia, the total amount of rescue analgesics consumed in the next 24 hours, and patient satisfaction score were also compared between groups. Results: Demographics and baseline vitals were comparable in the groups. On comparing VAS scores in both the groups during rest and movement at different time intervals, there was no difference in pain scores during the initial two hours. From the third hour, there was a statistically significant difference (P < 0.001) in pain VAS scores in both groups. The ESP group had lower VAS scores compared to the MTP group when followed for the next 24 hours. There was a statistically significant difference in patient satisfaction. Conclusion: ESP block is more efficacious when compared to MTP block for postoperative analgesia in MRM patients.

Evaluation and comparison of sonographic difficult airway assessment parameters with clinical airway predictors.

Background and Aims: None of the clinical difficult airway predictors are 100% sensitive and specific. Ultrasound is being used for airway assessment, but there is still no established parameters or model to predict difficult laryngoscopy. This observational study was planned to determine the predictive ability of clinical and sonography-based airway assessment parameters for difficult laryngoscopy and intubation. Material and Methods: A total of 130 patients of 18-60 years of age undergoing elective intubation were included. The distribution of Cormack-Lehane (CL) grade and intubation difficulty scale (IDS) was correlated with the clinical and sonographic screening parameters for difficult airways. Results: The prevalence of difficult laryngoscopy and difficult intubation in our study was 17.6% and 11.5%, respectively. Mallampati grade (MMG), upper lip bite test (ULBT), neck circumference, hyomental distance ratio (HMDR), tongue thickness (TT), skin to epiglottis/epiglottis to vocal cord distance (SED/E-VC), and mandibular condylar mobility (MCM) had significant association with the difficult laryngoscopy and MMG, neck circumference, SED, SED/E-VC; MCM had significant association with the difficult intubation. The combination of these predictors showed better diagnostic ability for difficult airways. Model 1 based on ultrasound parameters showed an area under the curve (AUC) of 0.848 (CI- 0.748-0.947, P value < 0.0001) and model 2 based on combined clinical and ultrasound parameters showed an AUC of 0.755 (95% CI- 0.631-0.879, P value < 0.0001). Conclusions: Ultrasound-based airway predictors can help in predicting difficult laryngoscopy and intubation along with the clinical parameters. Individual sonographic predictors have moderately satisfactory diagnostic profiles. The models based on combined tests have better diagnostic value.

Immunosuppressive mechanisms of oncofetal reprogramming in the tumor microenvironment: implications in immunotherapy response.

Both fetal and tumor tissue microenvironments display immunosuppressive features characterized by the presence of specific immunomodulatory stromal and immune cell populations. Recently, we discovered shared microenvironments between hepatocellular carcinoma (HCC) and fetal tissues and described this phenomenon as an oncofetal ecosystem. This ecosystem includes fetal-like immune (macrophage) and stromal (endothelial) cells within the tumor microenvironment (TME). This discovery highlights reciprocal interactions between fetal-like macrophages and T cells which result in the orchestration of an immunosuppressive TME. Importantly, VEGF-A protein expression by tumor cells and fetal-like macrophages plays an important role in oncofetal reprogramming of the TME in HCCs. Interestingly, recent clinical data indicate that blocking VEGF-A or CTLA4 alongside PD-L1 is effective in treating advanced HCC. Consequently, some immunotherapies may target and rely on oncofetal cells for clinical responsiveness. This understanding provides exciting opportunities to utilize oncofetal niche characteristics as biomarkers of immunotherapy response in HCC and might also have validity for predicting responses to immunotherapy in other cancers. In this review, we explore the immunosuppressive mechanisms and interactions of oncofetal cells in the TME of HCC and their potential implications for immunotherapy response.

Plasmodium falciparum infection and disease in infancy associated with increased risk of malaria and anaemia in childhood.

BACKGROUND: Infants under 6 months of age are often excluded from malaria surveillance and observational studies. The impact of malaria during early infancy on health later in childhood remains unknown. METHODS: Infants from two birth cohorts in Malawi were monitored at quarterly intervals and whenever they were ill from birth through 24 months for Plasmodium falciparum infections and clinical malaria. Poisson regression and linear mixed effects models measured the effect of exposure to malaria in infancy on subsequent malaria incidence, weight-for-age z-scores (WAZ), and haemoglobin concentrations after 6 months. RESULTS: Infants with at least one P. falciparum infection during their first 6 months had increased incidence ratio (IRR) of P. falciparum infection (IRR = 1.27, 95% CI, 1.06-1.52) and clinical malaria (IRR = 2.37, 95% CI, 2.02-2.80) compared to infants without infection. Infants with clinical malaria had increased risk of P. falciparum infection incidence between 6 and 24 months (IRR = 1.64, 95% CI, 1.38-1.94) and clinical malaria (IRR = 1.85, 95% CI, 1.48-2.32). Exposure to malaria was associated with lower WAZ over time (p = 0.02) and lower haemoglobin levels than unexposed infants at every time interval (p = 0.02). CONCLUSIONS: Infants experiencing malaria infection or clinical malaria are at increased risk of subsequent infection and disease, have poorer growth, and lower haemoglobin concentrations.

Na2ZrFe(PO4)3─A Rhombohedral NASICON-Structured Material: Synthesis, Structure and Na-Intercalation Behavior.

A NASICON-structured earth-abundant mixed transition metal (TM) containing Na-TM-phosphate, viz., Na2ZrFe(PO4)3, has been prepared via a sol-gel route using a low-cost Fe3+-based precursor. The as-prepared material crystallizes in the desired rhombohedral NASICON structure (space group: R3̅c) at room temperature. Synchrotron X-ray diffraction (XRD), transmission electron microscopy, X-ray absorption spectroscopy, etc., have been performed to determine the crystal structure, associated details, composition, and electronic structures. In light of the structural features, as one of the possible functionalities of Na2FeZr(PO4)3, Na-intercalation/deintercalation has been examined, which indicates the occurrence of reversible electrochemical Na-insertion/extraction via Fe2+/Fe3+ redox at an average potential of ∼2.5 V. The electrochemical data and direct evidences from operando synchrotron XRD indicate that the rhombohedral structure is preserved during Na-insertion/extraction, albeit within a certain range of Na-content (i.e., ∼2-3 p.f.u.), beyond which rhombohedral → monoclinic transformation takes place. Within this range, Na-insertion/extraction takes place via solid-solution pathway, resulting in outstanding cyclic stability, higher Na-diffusivity, and good rate-capability. To the best of the authors' knowledge, this represents the first in-depth structural, compositional, and electrochemical studies with Na2ZrFe(PO4)3, along with the interplay between those, which provide insights into the design of similar low-cost materials for various applications, including sustainable electrochemical energy storage systems.

SpDamID: Marking DNA Bound by Protein Complexes Identifies Notch-Dimer Responsive Enhancers.

We developed Split DamID (SpDamID), a protein complementation version of DamID, to mark genomic DNA bound in vivo by interacting or juxtapositioned transcription factors. Inactive halves of DAM (DNA adenine methyltransferase) were fused to protein pairs to be queried. Either direct interaction between proteins or proximity enabled DAM reconstitution and methylation of adenine in GATC. Inducible SpDamID was used to analyze Notch-mediated transcriptional activation. We demonstrate that Notch complexes label RBP sites broadly across the genome and show that a subset of these complexes that recruit MAML and p300 undergo changes in chromatin accessibility in response to Notch signaling. SpDamID differentiates between monomeric and dimeric binding, thereby allowing for identification of half-site motifs used by Notch dimers. Motif enrichment of Notch enhancers coupled with SpDamID reveals co-targeting of regulatory sequences by Notch and Runx1. SpDamID represents a sensitive and powerful tool that enables dynamic analysis of combinatorial protein-DNA transactions at a genome-wide level.