Relationship of Endotracheal Tube Cuff Pressures with Changes in Body Positions of Critically Ill Patients on Mechanical Ventilation: An Observational Study.

Aims and background: Endotracheal tube cuff pressure (ETCP) is an important factor to determine the development of complications associated with invasive mechanical ventilation. To avoid preventable complications arising out of immobilization, frequent changes in body positioning are necessary. Such variations in body position can affect ETCP in critically ill patients who are on mechanical ventilation. So, our study aimed to assess the effect of changes in body position on ETCP in patients who are on mechanical ventilation. Materials and methods: This prospective observational study included 31 critically ill intubated patients. Each study subject was first placed in a neutral starting position with a 30º head elevation. Then, they were subjected to a sequential change in body position based on the 16 most used positions as part of the critical care unit's (CCUs) daily routine. Endotracheal tube cuff pressure was measured after each position change. Data were analyzed using standard statistical tests. Results: Statistically significant difference in ETCP was observed during anteflexion of neck, hyperextension of neck, left lateral flexion of neck, right lateral flexion of neck, left lateral rotation of neck, right lateral rotation of neck, 10o recumbent position, supine position, Trendelenburg position, and right lateral 30° and 45° positions. Maximum increase in ETCP was seen during anteflexion of neck (31 ± 4.5; 22-42 cm H2O). Conclusion: Our study demonstrates significant deviations in ETCP from the recommended range following changes in the body position of mechanically ventilated patients, highlighting the need for the measurement of ETCP after each position change and maintenance of the same within the target range. How to cite this article: Roy O, Dasgupta S, Chandra A, Biswas P, Choudhury A, Ghosh S, et al. Relationship of Endotracheal Tube Cuff Pressures with Changes in Body Positions of Critically Ill Patients on Mechanical Ventilation: An Observational Study. Indian J Crit Care Med 2024;28(1):36-40.

SGLT2 Inhibitors in the Management of Chronic Kidney Disease: An Expert Consensus.

Despite the availability of multiple therapies for chronic kidney disease (CKD), there still exists an unmet need for better options to slow down disease progression and prevent complications. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial, which demonstrated the renoprotective effects of the sodium-glucose cotransporter-2 inhibitor (SGLT2i) dapagliflozin, independent of diabetes, with improved survival, even in patients with CKD with estimated glomerular filtration rate (eGFR) as low as 25 mL/min/1.73 m2 , has highlighted the potential beneficial role of SGLT2i in patients with CKD. These benefits were also achieved in patients who were already receiving optimal therapies for slowing the progression of CKD. The potential candidature of SGLT2i for CKD therapy is now being widely discussed in the nephrology community. Therefore, a consensus meeting was held in September 2020 with a group of expert nephrologists from India, to discuss the need to improve CKD management and assess the position of SGLT2i, based on compelling evidence from recent studies. This document summarizes the expert opinions and views on the position of SGLT2i in CKD management and aims to enhance the current understanding of the applicability of SGLT2i in patients with CKD. This will aid nephrologists and physicians across the country in decision-making on the management of patients with CKD using SGLT2i. Keywords: Chronic kidney disease, Dapagliflozin, Estimated glomerular filtration rate, SGLT2i inhibitors, Type 2 diabetes mellitus.

CCL20 neutralization by a monoclonal antibody in healthy subjects selectively inhibits recruitment of CCR6+ cells in an experimental suction blister.

AIMS: GSK3050002, a humanized IgG1κ antibody with high binding affinity to human CCL20, was administered in a first-in-human study to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). An experimental skin suction blister model was employed to assess target engagement and the ability of the compound to inhibit recruitment of inflammatory CCR6 expressing cells. METHODS: This study was a randomized, double-blind (sponsor open), placebo-controlled, single-centre, single ascending intravenous dose escalation trial in 48 healthy male volunteers. RESULTS: GSK3050002 (0.1-20 mg kg-1 ) was well tolerated and no safety concerns were identified. The PK was linear over the dose range, with a half-life of approximately 2 weeks. Complex of GSK3050002/CCL20 increased in serum and blister fluid with increasing doses of GSK3050002. There were dose-dependent decreases in CCR6+ cell recruitment to skin blisters with maximal effects at doses of 5 mg kg-1 and higher, doses at which GSK3050002/CCL20 complex in serum and blister fluid also appeared to reach maximum levels. CONCLUSIONS: These results indicate a relationship between PK, target engagement and PD, suggesting a selective inhibition of recruitment of CCR6+ cells by GSK3050002 and support further development of GSK3050002 in autoimmune and inflammatory diseases.

Qualification of a 21-valent pneumococcal urine antigen detection assay and development of clinical positivity cutoffs.

Aim: Serotype-specific assays detecting pneumococcal polysaccharides in bodily fluids are needed to understand the pneumococcal serotype distribution in non-bacteremic pneumonia. Methods: We developed a urine antigen detection assay and using urine samples from adult outpatients without pneumonia developed positivity cutoffs for both a previously published 15-valent and the new 21-valent assay. Clinical sensitivity was confirmed with samples from patients with invasive pneumococcal disease. Results: Total assay precision ranged from 7.6 to 17.8% coefficient of variation while accuracy ranged between 80 and 150% recovery, except for three serotypes where recoveries ranged from 32 to 60%. Clinical sensitivity was 86.4% and specificity was 96.5% across all 30 serotypes. Conclusion: The assay could potentially assess serotype-distribution in non-infected and infected participants with pneumococcal disease.

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B cells require "nurturing" by CD4 T cells during development in order to respond in chronic graft-versus-host model of systemic lupus erythematosus.

The murine chronic GVH (cGVH) model of SLE is induced by allo-recognition of foreign major histocompatibility complex (MHC) class II determinants. Previous studies have shown that syngeneic CD4(+) T cells are needed during B cell development in order to induce cGVH response in CD4KO mice. Our present studies show that B cells require "nurturing" by CD4 T cells through much of their ontogeny in order to respond to allo-signaling and become autoreactive. The nurturing process does not require antigen-specific cognate interactions between CD4 T cells and B cells. It is mediated by IL-4, but not IL-10, IL-6 and IFN-gamma. The CD4 T cell nurturing may be supplanted by large doses of IL-4 and/or by agonistic anti-CD40 mAb. Understanding the mechanism of this "nurturing" process may yield clues to the role of CD4 T cells in lupus and in host defense in general.

Disrupted Mer receptor tyrosine kinase expression leads to enhanced MZ B-cell responses.

Control of lymphocyte homeostasis is essential to ensure efficient immune responses and to prevent autoimmunity. Splenic marginal zone B cells are important producers of autoantibodies, and are subject to stringent tolerance mechanisms to prevent autoimmunity. In this paper, we explore the role of the Mer tyrosine kinase (Mertk) in regulating autoreactive B cells. This receptor tyrosine kinase serves to bind apoptotic cells, to mediate their phagocytosis, and to regulate subsequent cytokine production. Mice lacking Mertk suffer from impaired apoptotic cell clearance and develop a lupus-like autoimmune syndrome. Here we show that such Mertk-KO mice have expanded numbers of splenic marginal zone B cells. Mertk-KO mice bearing a DNA-specific immunoglobulin heavy-chain transgene (3H9) produced anti-DNA antibodies that appeared to be secreted largely by marginal zone B cells. Finally, Mertk-KO mice developed greater antibody responses after NP-Ficoll immunization than their B6 counterparts. Taken together, our data show that Mertk has a major effect on the development of the marginal zone B-cell compartment. Mertk is also important in establishing DNA-specific B-cell tolerance in 3H9 anti-DNA transgenic mice.

Analysis of Neonatal Outcome with Supplemental Oxygen to Mother during Elective Cesarean Section under Spinal Anesthesia: A Prospective Randomized Controlled Trial.

BACKGROUND: Many questions have arisen on benefits of routine use of supplemental oxygen during elective cesarean section (CS) under spinal anesthesia. AIMS: The aim of this randomized controlled study was to evaluate neonatal outcome in immediate postpartum period with or without supplemental oxygen to mother, undergoing elective CS under spinal anesthesia. MATERIALS AND METHODS: One hundred and thirty-four nonlaboring term pregnant women were allocated randomly into two groups to breathe room air (air group) or oxygen (oxygen group). Times from starting oxygen supplementation to delivery interval, skin incision to delivery (I-D) interval, and uterine incision to delivery (U-D) interval were recorded. APGAR scores were assessed at 1 min and 5 min after delivery. Umbilical cord blood gas analysis was done immediately to measure pH, oxygen partial pressure, carbon dioxide partial pressure (PCO2), and bicarbonate. STATISTICAL ANALYSIS: Statistical comparisons were performed using either Student's t-test or Mann-Whitney U-test. RESULTS: For oxygen group versus air group, In Oxygen group, proportion of fetal acidosis was significantly less; umbilical arterial (UA) blood pH (7.22 ± 0.05 vs. 7.19 ± 0.05, P = 0.001) as well as umbilical venous (UV) blood pH (7.26 ± 0.05 vs. 7.22 ± 0.06, P < 0.001) were significantly higher and UA PCO2 (55.4 ± 9.9 vs. 62.9 ± 6.9, P = 0.001) and UV PCO2 (51.4 ± 8.2 vs. 54.3 ± 7.2, P = 0.036) were significantly lower compared to air group. APGAR scores were similar between the groups. CONCLUSIONS: Supplemental oxygen has potential benefits as demonstrated by less proportion of FA in mothers receiving supplemental oxygen.

Accelerated atherosclerosis in ApoE deficient lupus mouse models.

The accelerated development of atherosclerosis with increased risk of cardiovascular disease in systemic lupus erythematosus (SLE) patients is not well understood. An appropriate mouse model would greatly help to understand the mechanisms of this association. We have therefore combined the ApoE(-/-) model of atherosclerosis with three different murine models of SLE. We found that induction of cGVH in B6.ApoE(-/-) mice, breeding a Fas null gene onto the B6.ApoE(-/-) mice, and breeding the ApoE(-/-) defect onto MRL/lpr mice all caused a modest increase of atherosclerosis at 24 weeks of age compared to B6.ApoE(-/-) controls. B cells in B6.ApoE(-/-) mice had certain phenotypic differences compared to congenic C57BL/6 mice, as indicated by high expression of MHC II, Fas, CD86, and by increased number of cells bearing marginal zone phenotype. Furthermore, B6ApoE(-/-) mice had significant titers of anti-oxLDL and anti-cardiolipin autoantibodies compared to their B6 counterparts. Our studies also indicate that, following induction of cGVH, marginal zone B cells in B6.ApoE(-/-) are depleted, and there is considerable increase in anti-oxLDL and anti-cardiolipin abs along with secretion of lupus-specific autoantibodies, such as anti-dsDNA and anti-chromatin abs. Histological sections showed that cGVH and/or Fas deficiency could exacerbate atherosclerosis. The production of anti-oxLDL and anti-cardiolipin in ApoE(-/-) mice was also increased. These observations define a connection between induction of lupus-like symptoms and development of severe atherosclerosis in ApoE deficient lupus mouse models.

Spectrum of renal allograft biopsy: A five-year experience at a tertiary care center of Eastern India.

Renal allograft dysfunction (RAD) can have myriad causes and presentations. Allograft biopsy remains the gold standard for optimum management. This is a retrospective study carried out at a tertiary care institute from August 2011 to March 2016. Details of the renal allograft biopsy requisitions were recorded and analyzed. Two hundred and two patients had undergone kidney transplantation (KT) during the study period. One hundred and twenty-six had undergone renal biopsy for RAD. The acute asymptomatic rise of serum creatinine was the most common clinical presentation (47.61%) followed by chronic RAD (CRAD) (19.84%), proteinuria (15.87%), immediate graft dysfunction (10.31%), and persistent active urinary sediments (6.34%) in that order. The incidence of delayed graft function was 1.98%. The overall incidence of biopsy-proven rejection was 8.41% within oneyear and 8.91% beyond oneyear of transplant. Acute cellular rejection (ACR) [with or without antibody-mediated rejection (AMR)] was found in 65%; AMR was found in 40% and 15% had both ACR and AMR. Borderline acute cell-mediated rejection was found in 22.5% of biopsies. CRAD was due to chronic rejection and chronic calcineurin inhibitor toxicity in only about one-fourth of the cases. Incidence of glomerulo-nephritis was 10.89% and most of these occurred two years after KT. Renal allograft biopsy was associated with minor complications in 3.17% of cases. Clinical presentations do not reliably distinguish the various causes of RAD. Allograft biopsy is a mainstay in the diagnosis of RAD and is safe. Results of live donor first transplantation using complement-dependent cytotoxi-city crossmatch are comparable to those programs using newer methods like solid-phase assays. However, the direct comparison of these results with other studies may not be completely applicable.

Post renal transplant pure red cell aplasia-is tacrolimus a culprit?

Anemia is not uncommon in the post-renal transplant period and has been reported in up to 40% of renal transplant recipients. It is commonly due to drugs and infections. While post-transplantation anemia is usually due to graft dysfunction and drugs such as mycophenolate and cotrimoxazole, tacrolimus is an uncommon cause. Tacrolimus is usually not believed to be significantly myelosuppressive, but it can cause anemia due to thrombotic microangiopathy. A literature review shows a very small number of reported cases of pure red cell aplasia (PRCA) where tacrolimus seemed to be a causative agent. We report a case series of three renal transplant recipients who were on tacrolimus and presented with chronic transfusion requiring anemia due to PRCA.

Osmotic stress of salmon stimulates upregulation of a cold inducible RNA binding protein (CIRP) similar to that of mammals and amphibians.

Salmon are subjected to hyperosmotic stress during transition from freshwater to the marine environment. A variety of mechanisms have evolved to allow movement of the animal from a hydrating to a dehydrating environment. Using differential assay of mRNA expression, a 1.3 kb transcript was found to be upregulated in branchial lamellae of salmon exposed to hyperosmotic conditions. The transcript contains an open reading frame of 618 nt coding for a 205 amino acid protein with a molecular mass of 21.5 kDa. The putative protein, dubbed salmon glycine-rich RNA binding protein (SGRP), possesses a high degree of identity (>70%) with the cold inducible RNA binding proteins (CIRP) of mammals and amphibians and contains the canonical features of these proteins including a single RNA recognition motif (RRM), high glycine content and conserved flanking motifs. SGRP mRNA was observed to increase in response to hyperosmotic stress of branchial tissue with maximum levels of expression after 48 h of exposure. Transcript also was observed in liver, kidney and heart but was not upregulated significantly by osmotic stress in these tissues. Exposure of isolated lamellae to heat stress and sodium arsenite, known inducers of hsps, did not stimulate accumulation of SGRP transcript. Similarly, inhibition of protein synthesis with cycloheximide and the MAPK and MEK signal transduction pathways with SB202190 and PD98059 failed to alter expression of the gene. Of significance was the absence of an increase in expression of SGRP in response to cold stress (DeltaT = 5 and 12 degrees C for 12 and 24 h). The findings of this research suggest that ectothermic salmon inhabiting boreal waters possess a protein analogous to the CIRPs currently identified in mammals and amphibians. In contrast to the function of CIRPs, SGRP appears to have a more prominent role in adaptation to hyperosmotic conditions rather than cold stress.

The anti-DNA knock-in model of systemic autoimmunity induced by the chronic graft-vs-host reaction.

The injection of spleen cells from bm12 mice into C57BL/6 recipients induces a chronic graft-vs-host reaction characterized by systemic autoimmunity, including anti-double-stranded DNA (anti-dsDNA) autoantibodies and immune complex-type proliferative glomerulonephritis. If the B6 recipient mice express an anti-DNA Vh site-directed transgene, the repertoire is skewed even more toward the anti-DNA response. Over a period of several weeks, high titers of serum anti-DNA antibodies appear and the mice develop renal damage. This permits the examination of the role of somatic immunoglobulin genetics and B-cell tolerance in a model of systemic lupus erythematosus.

An in silico appraisal of azoic and disulphide derivatives for anticancer activity against HPV E6 oncoprotein to medicate cervical cancer.

Cervical cancer is the second largest form of cancer to infest the leading cause of death in women worldwide. There are many causes of cancer but viruses are the most common among them. Human papillomaviruses (HPVs) are found to be the causative organism in almost 99.7% of the cases. HPV16 is the most frequent HPV type in malignant neoplastic growth in about 60% of cervical carcinoma cases. There is limited success achieved in surgical removal or by immune modulation and more effective therapies are under investigation. Observing the mortality rate we theorize a need for alternative treatment approaches and propose a blueprint of compounds with desirable properties that may lead to the development of drugs to treat HPV-associated neoplasias. E6 oncoprotein of HPV16 has a potential zinc finger domain critical for binding to E6AP, causing p53 degradation and malignancy. Some azoics and disulfides were selected depending on their affinity towards E6 zinc finger and thereby preventing E6-E6AP complex formation. Combinatorial nontoxic derivatives of these azoics and disulfides were docked and validated against the oncoprotein to inhibit E6-E6AP interaction. Among these, two compounds (E)-N-(2-amino-2-oxoethyl)-N-(4-chlorophenyl) diazene-1,2-dicarboxamide and (E)-N-(2- amino-2-methylpropyl)-N-(thiophen-2-yl)diazene-1,2-dicarboxamide showed binding affinity of -23.70, -19.53 and -5.49, -4.65 Kcal/mol respectively in FlexX and Autodock4.2. These compounds are found more effective than those of the approved E6-E6AP binding inhibitors. Pharmacophores of these compounds were generated to confirm it with pharm mapping mechanism. The study may confer the way of design of new mechanism and new compounds to treat cervical cancer.

Mature B cells preferentially lose tolerance in the chronic graft-versus-host disease model of systemic lupus erythematosus.

Chronic graft-vs-host (cGVH) disease is a well-characterized systemic lupus erythematosus (SLE) model. Induction of cGVH in anti-DNA H chain knockin (3H9KI) transgenic mice results in specific activation of anti-dsDNA B cells. In this study, we show that B cells from 3H9KI mice were activated by cGVH even when adoptively transferred into irradiated JHT-/- recipients that lack endogenous B cells. This process of activation was reflected by high autoantibody titers and changes in phenotypic markers. We have used this system to characterize the particular B cell subsets that were responsible for secreting autoantibodies during cGVH response. We isolated splenic B cell subsets based on their expression of specific cell surface markers and used them in our adoptive transfer studies. We found that mature B cells were the most vulnerable to the allostimulus and were the major source of autoantibodies compared with immature B cells. The greater susceptibility of mature B cells to become activated and thereby lose tolerance was unanticipated and has implications for maintenance of peripheral tolerance and for the development of autoimmunity. Furthermore, of the mature B cells, marginal zone B cells were particularly responsible for mounting the initial response to the cGVH stimulus. This observation underscores the critical role of marginal zone B cells in activation and production of autoantibodies.

TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus.

TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, is a prominent inducer of proinflammatory cytokines in vitro and in vivo. We previously found that kidney cells display the TWEAK receptor Fn14, and that TWEAK stimulation of mesangial cells and podocytes induces a potent proinflammatory response. Several of the cytokines up-regulated in the kidney in response to TWEAK are instrumental in Lupus nephritis; we therefore hypothesized that TWEAK/Fn14 interactions may be important in the cascade(s) leading to renal damage in systemic Lupus erythematosus. In this study, we analyzed the effects of Fn14 deficiency in the chronic graft-vs-host model of SLE, and the benefits of treatment with an anti-TWEAK mAb in this mouse model. We found that anti-nuclear Ab titers were no different between C57BL/6 Fn14 wild-type and deficient mice injected with alloreactive bm12 splenocytes. However, kidney disease was significantly less severe in Fn14 knockout mice. Furthermore, kidney IgG deposition, IL-6, MCP-1, RANTES, and IP-10, as well as macrophage infiltration, were significantly decreased in Fn14-deficient mice with induced lupus. Similarly, mice with induced Lupus treated with an anti-TWEAK neutralizing mAb had significantly diminished kidney expression of IL-6, MCP-1, IL-10, as well as proteinuria, but similar autoantibody titers, as compared with control-treated mice. We conclude that TWEAK is an important mediator of kidney damage that acts by promoting local inflammatory events, but without impacting adaptive immunity in this experimental LN model. Thus, TWEAK blockade may be a novel therapeutic approach to reduce renal damage in SLE.

The role of host CD4 T cells in the pathogenesis of the chronic graft-versus-host model of systemic lupus erythematosus.

Systemic lupus erythematosus is characterized by production of autoantibodies and glomerulonephritis. The murine chronic graft-vs-host (cGVH) model of systemic lupus erythematosus is induced by allorecognition of foreign MHC class II determinants. Previous studies have shown that cGVH could not be induced in CD4 knockout (CD4KO) mice. We have further explored the role of host CD4 T cells in this model. Our studies now show that B cells in CD4KO mice have intrinsic defects that prevent them from responding to allohelp. In addition, B cells in CD4KO mice showed phenotypic differences compared with congeneic C57BL/6 B cells, indicating some degree of in vivo activation and increased numbers of cells bearing a marginal zone B cell phenotype. The transfer of syngeneic CD4 T cells at the time of initiation of cGVH did not correct these B cell abnormalities; however, if CD4 T cells were transferred during the development and maturation of B cells, then the B cells from CD4KO mice acquire the ability to respond in cGVH. These studies clearly indicate that B cells need to coexist with CD4 T cells early in their development to develop full susceptibility to alloactivation signals.