Virus-Induced Host Chemokine CCL2 in COVID-19 Pathogenesis: Potential Prognostic Marker and Target of Anti-Inflammatory Strategy.

A wide variety of inflammatory mediators, mainly cytokines and chemokines, are induced during SARS CoV-2 infection. Among these proinflammatory mediators, chemokines tend to play a pivotal role in virus-mediated immunopathology. The C-C chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1) is a potent proinflammatory cytokine and strong chemoattractant of monocytes, macrophages and CD4+ T cells bearing C-C chemokine receptor type-2 (CCR2). Besides controlling immune cell trafficking, CCL2 is also involved in multiple pathophysiological processes including systemic hyperinflammation associated cytokine release syndrome (CRS), organ fibrosis and blood coagulation. These pathological features are commonly manifested in severe and fatal cases of COVID-19. Given the crucial role of CCL2 in COVID-19 pathogenesis, the CCL2:CCR2 axis may constitute a potential therapeutic target to control virus-induced hyperinflammation and multi-organ dysfunction. Herein we describe recent advances on elucidating the role of CCL2 in COVID-19 pathogenesis, prognosis, and a potential target of anti-inflammatory interventions.

Epigenetic regulation of CXCR4 signaling in cancer pathogenesis and progression.

Signaling involving chemokine receptor CXCR4 and its ligand SDF-1/CXL12 has been investigated for many years for its possible role in cancer progression and pathogenesis. Evidence emerging from clinical studies in recent years has further established diagnostic as well as prognostic importance of CXCR4 signaling. CXCR4 and SDF-1 are routinely reported to be elevated in tumors, distant metastases, which correlates with poor survival of patients. These findings have kindled interest in the mechanisms that regulate CXCR4/SDF-1 expression. Of note, there is a particular interest in the epigenetic regulation of CXCR4 signaling that may be responsible for upregulated CXCR4 in primary as well as metastatic cancers. This review first lists the clinical evidence supporting CXCR4 signaling as putative cancer diagnostic and/or prognostic biomarker, followed by a discussion on reported epigenetic mechanisms that affect CXCR4 expression. These mechanisms include regulation by non-coding RNAs, such as, microRNAs, long non-coding RNAs and circular RNAs. Additionally, we also discuss the regulation of CXCR4 expression through methylation and acetylation. Better understanding and appreciation of epigenetic regulation of CXCR4 signaling can invariably lead to identification of novel therapeutic targets as well as therapies to regulate this oncogenic signaling.

Ulinastatin Add-on to Standard of Care in Critically Ill COVID-19 Patients: A Multicenter, Retrospective Study.

AIM: To assess the impact on 30-day mortality with ulinastatin (ULI) used as add-on to standard of care (SOC) compared to SOC alone in coronavirus disease (COVID-19) patients requiring admission to the intensive care unit (ICU). MATERIALS AND METHODS: In this multicentric, retrospective study, we collected data on clinical, laboratory, and outcome parameters in patients with COVID-19. Thirty-day mortality outcome was compared among patients treated with SOC alone and ULI used as add-on to SOC. Odds ratio (OR) and 95% confidence intervals (CI) were determined to identify the predictors of 30-day mortality. RESULTS: Ninety-four patients were identified and enrolled in both groups with comparable baseline parameters. On univariate analysis, 30-day mortality was significantly lower in ULI plus SOC group than SOC alone group (36.2 vs 51.1%, OR 0.54, 95% CI 0.30-0.97, p = 0.040). The effect on mortality was more pronounced in patients who did not require intubation (10.9 vs 34.0%, OR 0.24, 95% CI 0.09-0.66, p = 0.006) and with early administration (within 72 hours of admission) of ULI (30.7 vs 57.9%, OR 0.32, 95% CI 0.11-0.91, p = 0.032). On multivariate analysis, only intubation predicted mortality (adjusted OR 10.13, 95% CI 3.77-27.25, p<0.0001) and the effect of ULI on survival was not significant (adjusted OR 0.58, 95% CI 0.22-1.52, p = 0.270). CONCLUSION: Given the limited options for COVID-19 patients treated in ICU, early administration of ULI may be helpful, especially in patients not requiring intubation to improve the outcomes. Further, a large, randomized study is warranted to confirm these findings.

Real-world Experience with Favipiravir for Treatment of COVID-19 among Indian Healthcare Professionals.

INTRODUCTION: Favipiravir has shown promising results for COVID-19 globally. Though many Indian patients have received favipiravir, there is a lack of realworld data for its clinical use by the practicing physicians. Hence, a qualitative survey was conducted to understand real-world use of favipiravir in management of COVID-19. METHODS: A cross-sectional, web-based, qualitative survey was conducted between September 2020 to October 2020, among Indian physicians from various specialties involved in COVID-19 care and using favipiravir in their practice. Physicians were provided survey link having a structured questionnaire with 32 questions. They were enquired on- 1) demographics,practice information, 2) place of favipiravir in clinical practice, 3) treatment protocol for mild to moderate COVID-19, 4) dosage and duration of favipiravir, 5) effectiveness of favipiravir, 6) tolerability of favipiravir 7) global efficacy and safety assessment of favipiravir. RESULTS: A total of 500 physicians were contacted, of which 50 physicians completed the questionnaire. 25(50.0%) were from south zone followed by 12(24.0%) from west. . Majority physicians (47, 97.9%) stated that favipiravir was used for COVID-19 in outpatient setting. Favipiravir was considered as the current drug of choice for ' mild COVID-19 with fever(86.6%). All physicians agreed that favipiravir was being used as per the recommended dose.. A total of 75% & 62.5% physicians agreed to observed clinical improvement by around 3-5 days & 5-7 days in symptomatic mild & moderate COVID-19 respectively. CONCLUSION: Majority of the physicians considered favipiravir to be safe and effective in treatment of mild to moderate COVID-19.

Therapeutic Options for the Treatment of Carbapenem-resistant Enterobacteriaceae Infections: Hope in the Times of Hype and Despair.

How to cite this article: Ansari AS. Therapeutic Options for the Treatment of Carbapenem-resistant Enterobacteriaceae Infections: Hope in the Times of Hype and Despair. Indian J Crit Care Med 2021;25(7):752-753.

Cytokine Storm in Novel Coronavirus Disease (COVID-19): Expert Management Considerations.

AIM/OBJECTIVE/INTRODUCTION: Cytokine storm or cytokine release syndrome (CRS) is inevitable in severe and critically ill patients with novel coronavirus disease-2019 (COVID-19). This review aimed to discuss current therapeutic options for the management of CRS in COVID-19. BACKGROUND: Cytokine storm is caused by the colossal release of proinflammatory cytokines [e.g., IL (interleukin)-2, IL-6, IL-8 TNF (tumor necrosis factor)-α, etc.] causing dysregulated, hyperimmune response. This immunopathogenesis leads to acute lung injury and acute respiratory distress syndrome (ARDS). Targeting cytokine storm with the therapies that are already available in India with the support of published guidelines and consensus can assist in achieving a better outcome in COVID-19. REVIEW RESULTS: We predominantly included published guidelines or consensus recommendations about the management of cytokine storm in COVID-19. From the existing literature evidence, it is observed that among the currently available agents, low-dose corticosteroids and heparin can be beneficial in managing cytokine storm. The use of serine protease inhibitors such as ulinastatin has been advised by some experts. Though therapies such as high-dose vitamin C and interleukin-6 inhibitors (e.g., tocilizumab) have been advised, the evidence regarding their use for cytokine storm in COVID-19 is limited. Therapies such as Janus kinase inhibitors (JAK) inhibitors and Neurokinin-1 receptor (NK-1) antagonists are still in research. Besides, pharmaceutical treatments, use of blood purification strategies, and convalescent plasma may be life-saving options in some of the critically ill COVID-19 patients. For these therapies, there is a need to generate further evidence to substantiate their use in CRS management. CONCLUSION: Current management of COVID-19 is preventive and supportive. Different therapies can be used to prevent and treat the cytokine storm. More research is needed for further supporting the use of these treatments in COVID-19. HOW TO CITE THIS ARTICLE: Mehta Y, Dixit SB, Zirpe KG, Ansari AS. Cytokine Storm in Novel Coronavirus Disease (COVID-19): Expert Management Considerations. Indian J Crit Care Med 2020;24(6):429-434.

Toxicity and Mutagenicity Evaluation Following RISUG Contraception Reversal in Rats.

Reestablishment of fertility, after a male contraceptive method, is of great concern. In this context, RISUG (Reversible Inhibition of Sperm Under Guidance) has been evaluated for its mutagenicity following reversibility with dimethyl sulfoxide (DMSO)/sodium bicarbonate (NaHCO3) in Wistar albino rats. Animals were divided into 7 groups, namely, sham-operated control, vas occlusion with RISUG for 90 and 360 days, reversal with DMSO and NaHCO3 after 90 and 360 days, respectively. The testis, cauda epididymis, cauda epididymal spermatozoa, and serum were evaluated for apoptosis and hormonal status through various assays. RISUG was subjected to Ames test at dose levels of 10, 50, and 100 µL. Results of terminal deoxynucleotidyl transferase nick end labeling and caspase-3 assays in testes and cauda epididymis revealed that the percentage of positive cells in the experimental groups was comparable to sham-operated control. Annexin V assay in cauda epididymal spermatozoa showed slight elevation in group II ( P < 0.05), whereas in the remaining groups, minimum numbers of positive sperms were found. Hormone profile, namely, testosterone, prolactin, cortisol, prostate-specific antigen, and sperm antibody concentration, remained unchanged. In Ames test, no significant increase was observed in the number of revertant colonies on plates containing RISUG in the presence and absence of S9 mix in all 3 strains. Therefore, the reversal of RISUG-induced contraception by solvent vehicle DMSO/NaHCO3 was successful without any toxicity at the cellular levels.

Fluorescent Organic Nanoparticles of 3-Styrylindoles: Synthesis and Characterization.

Nanoparticles of 3-styrylindoles viz. 3-styryl-1H-indole (1), 3-(4-nitrostyryl)-1H-indole (2), 3-(4-nitrostyryl)-5-methoxy-1H-indole (3) and 3-(4-nitrostyryl)-5-bromo-1H-indole (4) have been synthesized by re-precipitation method. The nanoparticles are formed in the shape of a sphere with mean diameter of about 20­30 nm. The size of nanoparticles is controlled mainly by the fraction of added water and final concentration of the nanoparticles dispersion. The nanoparticles of 1, 2 and 4 showed little change in their fluorescence spectra as compared to the fluorescence spectra of the corresponding isolated molecules in THF. However, nanoparticles of 3 show enhanced fluorescence emission. This is attributed to the presence of methoxy and nitro groups in 3, which may be effective in reducing face-to-face intermolecular interaction in the nanoparticles of 3, inducing formation of J-type morphology responsible for enhanced fluorescence emission. Over a period of time, the nanoparticles progressively tend to clump in to bigger sizes, and become less fluorescent.

Heat shock protein 70-2 (HSP70-2) is a novel therapeutic target for colorectal cancer and is associated with tumor growth.

BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer related deaths worldwide both in men and women. Our recent studies have indicated an association of heat shock protein 70-2 (HSP70-2) with bladder urothelial carcinoma. In the present study, we investigated the association of HSP70-2 with various malignant properties of colorectal cancer cells and clinic-pathological features of CRC in clinical specimens. METHODS: HSP70-2 mRNA and protein was investigated expression by RT-PCR, immunohistochemistry, immunofluorescence, flow cytometry and Western blotting in CRC clinical specimens and COLO205 and HCT116 cell lines. Plasmid-based gene silencing approach was employed to study the association of HSP70-2 with various malignant properties of COLO205 and HCT116 cells in in vitro and with tumor progression in in vivo COLO205 human xenograft mice model. RESULTS: HSP70-2 expression was detected in 78 % of CRC patients irrespective of various stages and grades by RT-PCR and IHC. Our analysis further revealed that HSP70-2 expression was detected in both COLO205 and HCT116 cell lines. Ablation of HSP70-2 expression resulted in reduced cellular growth, colony forming ability, migratory and invasive ability of CRC cells. In addition, ablation of HSP70-2 expression showed significant reduction in tumor growth in COLO205 human xenograft in in vivo mouse model. CONCLUSION: Collectively, our results indicate that HSP70-2 is associated with CRC clinical specimens. In addition, down regulation of HSP70-2 expression reduces cellular proliferation and tumor growth indicating that HSP70-2 may be a potential therapeutic target for CRC treatment.

Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes.

Persistent hepatitis C virus (HCV) infection appears to trigger the onset of immune exhaustion to potentially assist viral persistence in the host, eventually leading to hepatocellular carcinoma. The role of HCV on the spontaneous expression of markers suggestive of immune exhaustion and spontaneous apoptosis in immune cells of chronic HCV (CHC) disease largely remain elusive. We investigated the peripheral blood mononuclear cells of CHC patients to determine the spontaneous recruitment of cellular reactive oxygen species (cROS), immunoregulatory and exhaustion markers relative to healthy controls. Using a commercial QuantiGenePlex(®) 2.0 assay, we determined the spontaneous expression profile of 80 different pro- and anti-apoptotic genes in persistent HCV disease. Onset of spontaneous apoptosis significantly correlated with the up-regulation of cROS, indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2/prostaglandin H synthase (COX-2/PGHS), Foxp3, Dtx1, Blimp1, Lag3 and Cd160. Besides, spontaneous differential surface protein expression suggestive of T cell inhibition viz., TRAIL, TIM-3, PD-1 and BTLA on CD4+ and CD8+ T cells, and CTLA-4 on CD4+ T cells was also evident. Increased up-regulation of Tnf, Tp73, Casp14, Tnfrsf11b, Bik and Birc8 was observed, whereas FasLG, Fas, Ripk2, Casp3, Dapk1, Tnfrsf21, and Cflar were moderately up-regulated in HCV-infected subjects. Our observation suggests the spontaneous onset of apoptosis signaling and T cell exhaustion in chronic HCV disease.

Increased frequency of late-senescent T cells lacking CD127 in chronic hepatitis C disease.

BACKGROUND: Hepatitis C virus (HCV) causes persistent disease in ~85% of infected individuals, where the viral replication appears to be tightly controlled by HCV-specific CD8+ T cells. Accumulation of senescent T cells during infection results in considerable loss of functional HCV-specific immune responses. MATERIALS AND METHODS: We characterized the distinct T-cell phenotypes based on the expression of costimulatory molecules CD28 and CD27, senescence markers PD-1 and CD57, chronic immune activation markers CD38 and HLA-DR, and survival marker CD127 (IL-7R) by flow cytometry following activation of T cells using HCV peptides and phytohemagglutinin. RESULTS: HCV-specific CD4+ and CD8+ T cells from chronic HCV (CHC) patients showed increased expression of PD-1. Furthermore, virus-specific CD4+ T cells of CHC-infected subjects displayed relatively increased expression of HLA-DR and CD38 relative to HCV-specific CD8+ T cells. The CD4+ and CD8+ T cells from HCV-infected individuals showed significant increase of late-differentiated T cells suggestive of immunosenescence. In addition, we found that the plasma viral loads positively correlated with the levels of CD57 and PD-1 expressed on T cells. CONCLUSIONS: Chronic HCV infection results in increased turnover of late-senescent T cells that lack survival potentials, possibly contributing to viral persistence. Our findings challenge the prominence of senescent T-cell phenotypes in clinical hepatitis C infection.

Management of non-healing leg ulcers in Unani system of medicine.

Non-healing leg ulcers are becoming a major public health problem. The high prevalence of leg ulcer directly affects patients' quality of life because it produces psychological (anxiety, depression), social and physical (amputation) handicap. Most leg ulcers become unsightly and they hardly if ever, yield to conventional treatment. Healing of an amputated part may pose a problem, hence amputation cannot be recommended without extensive pre-operative investigations. Prevalence is high among the poor, for whom expenses of surgery are not affordable. Few surgeons try skin graft but unfavourable local condition of the ulcer leads to rejection and all efforts prove futile. Keeping all these factors in mind, we have tested a Unani formulation for its ulcer healing properties; early results were surprising and in some cases unbelievable.

Efficacy of wet cupping in the pain management of cervical spondylosis - A randomized, controlled, open -label, parallel-group clinical trial.

BACKGROUND AND OBJECTIVE: Cervical spondylosis is a chronic degenerative process of the cervical spine characterized by pain in neck, degenerative changes in intervertebral disc and osteophyte formation. Cervical spondylosis is translated as Waja' ur Raqaba, a type of joint pain. The present study was aimed to evaluate the effect of wet cupping in the pain management of cervical spondylosis. METHODS: This Open, randomized, controlled, clinical study was conducted on 44 patients. Subjects in the test group (n = 22) received a series of three-staged wet cupping treatment, performed on 0, 7th and 14th day. Subjects in the control group (n = 22) received 12 sittings of Transcutaneous Electrical Nerve Stimulation (TENS): 6 sittings per week for two weeks. The objective findings of treatment were assessed with the help of VAS, Neck Disability Index (NDI) and Cervical range of motion. RESULTS: Intra group comparison in test group from baseline to 21st day were found highly significant (p < 0.001) in terms of VAS, NDI, Flexion, Extension and Left rotation score. While in Right rotation, Left rotation and Left lateral flexion score were found moderately significant (p < 0.01). Statistically significant difference was observed between two groups at 21st day in VAS scale, NDI, and Cervical range of motion score (p < 0.001). INTERPRETATION AND CONCLUSION: Hijama Bish Shart was found better in the management of pain due to cervical spondylosis than TENS. It can be concluded that Hijama Bish Shart may a better option for the pain management of cervical spondylosis. CLINICAL TRIAL REGISTRATION: The trial was registered on clinical trial registry website (www.ctri.nic.in) bearing a CTRI Number, CTRI/2020/03/024,249.

Mean Activated Clotting Time of Patients Receiving Intravenous Heparin and Undergoing Primary Percutaneous Coronary Intervention for ST Elevation Myocardial Infarction.

Introduction The most prevalent cause of death is acute myocardial infarction (AMI). Primary percutaneous coronary intervention (PPCI) has replaced thrombolysis as the recommended therapeutic option for individuals with ST-segment elevation myocardial infarction (STEMI). However, more effective anticoagulation regimes are required for PCI due to the limitations of unfractionated heparin. Objective This study aimed to ascertain the connection between the mean activated clotting time and the risk of bleeding and infarcts in individuals receiving intravenous heparin during PPCI for STEMI. Methods This was a one-year prospective observational study carried out at the National Institute of Cardiovascular Diseases (NICVD), Karachi, Pakistan. Results The majority (70.15%) were male, with a mean age of 56.08 ± 8.92 years. Following PPCI, the average active clotting time (ACT) was 350.56 ± 39.62 seconds (range 255 to 453), compared to the pre-PPCI mean of 504.15 ± 38.98 seconds. ACT was considerably higher in female patients, smokers, and overweight patients. The mean ACT was not significantly higher in patients with hypertension (HTN) and dyslipidemia (DLD). Conclusion The ACT range in this investigation was 255 to 453 seconds, and there was no discernible relationship between ACT readings and problems related to bleeding and ischemia. To determine who is more at risk, bleeding risk models should be used and improved further before catheterization.

Pediatric penetrating brain injuries with intact neurological function: Two case reports of a pencil and a toy wheel encounter.

Accidental injuries in the pediatric population are common. The response to injury also differs owing to anatomical and physiological differences in children. While such injuries carry a risk of lifelong morbidity, some cases may follow a benign course despite their distressing appearance. We report two cases of accidentally incurred penetrating trauma in the pediatric population with unusual objects, including a pencil and a toy wheel. Despite their intracranial extension, neither of the patients exhibited any discernible neurological deficits. Penetrating brain injuries require early removal and meticulous perioperative care to minimize the risk of long-term adverse neurological events in children.

Interleukin-31: The Inflammatory Cytokine Connecting Pruritus and Cancer.

Interleukin 31 (IL-31) is a proinflammatory cytokine, mainly secreted by Type II helper T cells. It signals through a heterodimeric receptor complex composed of IL-31 receptor α and oncostatin-M receptor ß chain. The hallmark feature of IL-31, in its pathological role, is its ability to induce pruritus in mammals. Pruritus is a common symptom and major reason of morbidity in cancer patients, compromising their quality of life. Although, IL-31 is differentially expressed in different tumor types and could promote or inhibit cancer progression, high expression of IL-31 is a contributing factor to advanced stage tumor and severity of pruritus. The simultaneous existence of pruritus and cancer could either result from the aberrations in common proteins that co-exist in both cancer and pruritus or the therapeutic treatment of cancer could indirectly induce pruritus. Although the biology of IL-31 has predominantly been described in skin diseases such as atopic dermatitis and other inflammatory diseases, the precise role of IL-31 in the tumor biology of different cancer types remains elusive. Herein, we summarize the current understanding on the role of this cytokine in the pathogenesis of different cancers.

Molecular Identification of Hyalomma Ticks and Application of Bacillus thuringiensis Toxins as an Effective Biological Acaricide.

Bacillus thuringiensis (B. thuringiensis) is considered one of the most important entomopathogenic microorganisms. It produces potent toxins against insects. Therefore, the present study investigates the bioacaricidal properties of B. thuringiensis on the Hyalomma tick species. Firstly, we identify Hyalomma ticks based on morphological screening and molecular characterization. The cytochrome C oxidase subunit I (COX1) gene was selected for the polymerase chain reaction (PCR) analysis, which resulted in the amplification of 656 bp. The amplified products were sequenced, and the isolated (COX1) gene of ticks was submitted to the gene bank of NCBI (Accession No. OR077934.1). The nucleotide sequences were retrieved from the NCBI data bank by BLASTn analysis, which confirmed that all obtained sequences belong to genus Hyalomma, and multiple alignments confirmed that the sequence of Hyalomma anatolicum Tandojam-isolate (HA-TJ) 100% aligned with Hyalomma analoticum KP792577.1, Hyalomma detritum KP792595.1, Hyalomma excavatum KX911989.1, and H. excavatum OQ449693.1. The generated phylogenetic tree confirmed that sequences of HA-TJ COX1 clustered with a single clad of H. analoticum, H. excavatum, and H. detritum. The acaricidal effect of B. thuringiensis toxins B. thuringiensis spore crystal mix (BtSCM) and B. thuringiensis crystal proteins (Btcps) was evaluated against larvae and adult life stages of Hyalomma ticks in vitro. We applied Btcps and BtSCM separately with different concentrations and calculated the mortality percentage. Adult mortality was estimated at the 8th, 10th, 12th, and 15th days posttreatment and larval mortality after 24 h. During treatment of the adult life stage, at first, ticks were immersed in different concentrations of Btcps and BtSCM for 5 min after the treatments, and the samples were transferred to sterile containers and placed in an incubator with 80% humidity at 23°C. Furthermore, Btcps produced the highest mortality on Day 15, 89 ± 1.00% at a concentration of 3000 µg/mL, followed by the 12th, 10th, and 8th days produced 83 ± 1.91%, 70 ± 1.15%, and 61 ± 1.00%, respectively. BtSCM produced mortality of 69 ± 1.91% on Day 15 at a concentration of 3000 µg/mL, followed by the 12th, 10th, and 8th days at 57 ± 2.51%, 37 ± 1.91%, and 34 ± 2.00%. The present study revealed that B. thuringiensis toxins produced a significant (p < 0.05) increase in mortality rate in adults of Hyalomma ticks. Additionally, Btcps and BtSCM were used to treat the larval stage. The treatments were applied to calculate the mortality percentage via the Laravel packet test. At a 1500 µg/mL concentration, Btcps resulted in the highest mortality of 98 ± 1.15%; this was followed by 1250 µg/mL, 1000 µg/mL, and 750 µg/mL, which produced mortalities of 76 ± 1.63%, 60 ± 1.63%, and 56 ± 1.63%, respectively. In addition, BtSCM produced a mortality rate of 79 ± 2.51% at a concentration of 1500 µg/mL. Furthermore, 75 ± 2.51%, 65 ± 1.91%, and 58 ± 1.15% mortality were observed at concentrations of 1250 µg/mL, 1000 µg/mL, and 750 µg/mL, respectively. The results showed a significant (p < 0.05) increase in larval mortality compared to the control group. We conclude that B. thuringiensis toxins are applicable as a bioacaricide.

Azithromycin targets the CD27 pathway to modulate CD27hi T-lymphocyte expansion and type-1 effector phenotype.

Macrolide antibiotic azithromycin is widely used in clinical practice to treat respiratory tract infections and inflammatory diseases. However, its mechanism of action is not fully understood. Given the involvement of the CD27 pathway in the pathophysiology of various T-lymphocyte-mediated inflammatory, autoimmune, and lymphoproliferative diseases, we examined the impact of AZM on CD27 regulation and potential consequences on CD4+ and CD8+ T-cell phenotypes. Using cellular immunology approaches on healthy donors' peripheral blood mononuclear cells, we demonstrate AZM-mediated downregulation of surface CD27 expression as well as its extracellular release as soluble CD27. Notably, AZM-exposed CD27high (hi) cells were defective in their ability to expand compared to CD27intermediate (Int) and CD27low (lo) subsets. The defective CD27hi subset expansion was found to be associated with impaired cell proliferation and cell division. At the molecular level, the CD27hi subset exhibited lower mTOR activity than other subsets. Functionally, AZM treatment resulted in marked depletion of helper CD4+ (Th1) and cytotoxic CD8+ T-lymphocyte (Tc1)-associated CXCR3+CD27hi effector cells and inhibition of inflammatory cytokine IFN-γ production. These findings provide mechanistic insights on immunomodulatory features of AZM on T-lymphocyte by altering the CD27 pathway. From a clinical perspective, this study also sheds light on potential clinical benefits observed in patients on prophylactic AZM regimens against various respiratory diseases and opens avenues for future adjunct therapy against Th1- and Tc1-dominated inflammatory and autoimmune diseases.

Emerging Role of the IL-36/IL-36R Axis in Multiple Inflammatory Skin Diseases.

IL-36 is a most recent member of the IL-1 cytokine family, primarily expressed at barrier sites of the body such as the skin, lungs, and intestine. It plays a vital role in inflammation and is implicated in the development of various cutaneous; intestinal; and pulmonary disorders, including psoriasis, inflammatory bowel disease, and chronic obstructive pulmonary disease. IL-36 comprises 4 isoforms: the proinflammatory IL-36α, IL-36ß, and IL-36γ and the anti-inflammatory IL-36R antagonist. An imbalance between proinflammatory and anti-inflammatory IL-36 isoforms can contribute to the inflammatory fate of cells and tissues. IL-36 cytokines signal through an IL-36R heterodimer mediating their function through canonical signaling cacade, including the NF-B pathway. Prominent for its role in psoriasis, IL-36 has recently been associated with disease mechanisms in atopic dermatitis, hidradenitis suppurativa, neutrophilic dermatoses, autoimmune blistering disease, and Netherton syndrome. The major cutaneous source of IL-36 cytokines is keratinocytes, pointing to its role in the communication between the epidermis, innate (neutrophils, dendritic cells) immune system, and adaptive (T helper [Th]1 cells, Th17) immune system. Thus, cutaneous IL-36 signaling is crucial for the immunopathological outcome of various skin diseases. Consequently, the IL-36/IL-36R axis has recently been recognized as a promising drug target for the treatment of inflammatory disorders beyond psoriasis. This review summarizes the current update on IL-36 cytokines in inflammatory skin diseases.

Indian consensus on the managemeNt of carbapenem-resistant enterobacterales infection in critically ill patients II (ICONIC II).

INTRODUCTION: The rising challenge of carbapenem-resistant Enterobacterales (CRE) infections in Indian healthcare settings calls for clear clinical guidance on the management of these infections. The Indian consensus on the management of CRE infection in critically ill patients (ICONIC-II) is a follow-up of the ICONIC-I study, which was undertaken in 2019. AREAS COVERED: A modified Delphi method was used to build expert consensus on CRE management in India, involving online surveys, face-to - face expert meetings, and a literature review. A panel of 12 experts was formed to develop potential clinical consensus statements (CCSs), which were rated through two survey rounds. The CCSs were finalized in a final face-to - face discussion. The finalized CCSs were categorized as consensus, near consensus, and no consensus. EXPERT OPINION: The outcomes included 46 CCSs (consensus: 40; near consensus: 3; and no consensus: 3). The expert panel discussed and achieved consensus on various strategies for managing CRE infections, emphasizing the significance of existing and emerging resistance mechanisms, prompt and tailored empiric therapy, and use of combination therapies. The consensus statements based on the collective expertise of the panel can potentially assist clinicians in the management of CRE infections that lack high-level evidence.