Genome-wide association study reveals the genetic basis of amino acids contents variations in Peanut (Arachis hypogaea L.).

Peanut is a significant source of protein for human consumption. One of the primary objectives in peanut breeding is the development of new cultivars with enhanced nutritional values. To further this goal, a genome-wide association study (GWAS) was conducted to analyze seed amino acids contents in 390 diverse peanut accessions collected worldwide, mainly from China, India, and the United States, in 2017 and 2018. These accessions were assessed for their content of 10 different amino acids. Variations in amino acids contents were observed, and arginine (Arg) was found to have the highest average value among all the amino acids quantified. The geographical distribution of the accessions also revealed variations in amino acids contents. High and positive correlation coefficients were observed among the amino acids, suggesting linked metabolic pathways or genetic regulation. A total of 88 single nucleotide polymorphisms (SNPs) spanning various chromosomes were identified, each associated with different amino acids. By using a combination of GWAS, expression anlaysis, and genomic polymorphisim comparisions, the Ahy_A09g041582 (LAC15) gene located on chromrosome A09 was identified as the key candidate which might be involved in plant growth and regulation and may alter amino acids levels. Expression analysis indicated that Ahy_A09g041582 has higher expressions in the shells and seeds than other genes located in the candidate region. This study may help with marker-based breeding of peanuts with higher nutritional value and offers fresh insights into the genetic basis of the amino acids contents of peanuts.

Iodine/DMSO-catalyzed oxidative deprotection of N-tosylhydrazone for benzoic acid synthesis.

An oxidative deprotection of tosylhyrdazones has been demonstrated to afford benzoic acids using iodine and DMSO system. This efficient oxidative deprotection protocol offers exceptional functional group toleration under mild reaction conditions without any initiators or bases. Notably, the tosylhydrazone with the heteroaryl ring or with the aryl ring having base-sensitive hydroxyl and ester functional groups smoothly afforded the corresponding benzoic acid analogues under developed conditions. Moreover, this method features short reaction times, high product yields and easy purification by avoiding column-chromatographic purification.

Glioblastoma induces the recruitment and differentiation of dendritic-like "hybrid" neutrophils from skull bone marrow.

Tumor-associated neutrophil (TAN) effects on glioblastoma (GBM) biology remain under-characterized. We show here that neutrophils with dendritic features-including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate major histocompatibility complex (MHC)II-dependent T cell activation-accumulate intratumorally and suppress tumor growth in vivo. Trajectory analysis of patient TAN scRNA-seq identifies this "hybrid" dendritic-neutrophil phenotype as a polarization state that is distinct from canonical cytotoxic TANs, and which differentiates from local precursors. These hybrid-inducible immature neutrophils-which we identified in patient and murine glioblastomas-arise not from circulation, but from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a contributor of antitumoral myeloid antigen-presenting cells (APCs), including TANs, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow-such as intracalvarial AMD3100, whose survival-prolonging effect in GBM we report-present therapeutic potential.

Genetic dissection of value-added quality traits and agronomic parameters through genome-wide association mapping in bread wheat (T. aestivum L.).

Bread wheat (T. aestivum) is one of the world's most widely consumed cereals. Since micronutrient deficiencies are becoming more common among people who primarily depend upon cereal-based diets, a need for better-quality wheat varieties has been felt. An association panel of 154 T. aestivum lines was evaluated for the following quality traits: grain appearance (GA) score, grain hardness (GH), phenol reaction (PR) score, protein percent, sodium dodecyl sulfate (SDS) sedimentation value, and test weight (TWt). In addition, the panel was also phenotyped for grain yield and related traits such as days to heading, days to maturity, plant height, and thousand kernel weight for the year 2017-18 at the Borlaug Institute for South Asia (BISA) Ludhiana and Jabalpur sites. We performed a genome-wide association analysis on this panel using 18,351 genotyping-by-sequencing (GBS) markers to find marker-trait associations for quality and grain yield-related traits. We detected 55 single nucleotide polymorphism (SNP) marker trait associations (MTAs) for quality-related traits on chromosomes 7B (10), 1A (9), 2A (8), 3B (6), 2B (5), 7A (4), and 1B (3), with 3A, 4A, and 6D, having two and the rest, 4B, 5A, 5B, and 1D, having one each. Additionally, 20 SNP MTAs were detected for yield-related traits based on a field experiment conducted in Ludhiana on 7D (4) and 4D (3) chromosomes, while 44 SNP MTAs were reported for Jabalpur on chromosomes 2D (6), 7A (5), 2A (4), and 4A (4). Utilizing these loci in marker-assisted selection will benefit from further validation studies for these loci to improve hexaploid wheat for better yield and grain quality.

Collagen VI deposition primes the glioblastoma microenvironment for invasion through mechanostimulation of ß-catenin signaling.

While glioblastoma (GBM) progression is associated with extensive extracellular matrix (ECM) secretion, the causal contributions of ECM secretion to invasion remain unclear. Here we investigate these contributions by combining engineered materials, proteomics, analysis of patient data, and a model of bevacizumab-resistant GBM. We find that GBM cells cultured in engineered 3D hyaluronic acid hydrogels secrete ECM prior to invasion, particularly in the absence of exogenous ECM ligands. Proteomic measurements reveal extensive secretion of collagen VI, and collagen VI-associated transcripts are correspondingly enriched in microvascular proliferation regions of human GBMs. We further show that bevacizumab-resistant GBM cells deposit more collagen VI than their responsive counterparts, which is associated with marked cell-ECM stiffening. COL6A3 deletion in GBM cells reduces invasion, ß-catenin signaling, and expression of mesenchymal markers, and these effects are amplified in hypoxia. Our studies strongly implicate GBM cell-derived collagen VI in microenvironmental remodeling to facilitate invasion.

Substance use patterns and mental health comorbidities in youth with a history of depression or suicidality: Findings from TX-YDSRN.

BACKGROUND: There is a robust relationship between depression and substance use in youth, with higher levels of substance use associated with greater depressive symptomatology. However, previous research has examined individual substances, without consideration of psychiatric comorbidities. Here, we investigate patterns of substance use among depressed and/or suicidal youth within the context of psychiatric comorbidities. METHODS: 945 youth with depression and/or suicidality from the Texas Youth Depression and Suicide Research Network (TX-YDSRN) were assessed for current use of alcohol, nicotine, cannabis, and other drugs and comorbid psychiatric diagnoses. We used latent class analysis to identify patterns of past-year substance use, then examined if demographics or psychiatric disorders predicted class membership. RESULTS: We identified three patterns of substance use: non-use (63.4 %), moderate likelihood of using alcohol, nicotine and cannabis (23.8 %), and high likelihood of using all substances (12.7 %). Compared to non-users, individuals in the moderate and high likelihood classes were more likely to be older. Individuals in the high likelihood class were more likely to have a substance use disorder, ADHD, and higher suicidality scores. LIMITATIONS: We cannot ascertain the causal or temporal ordering of substance use and psychiatric diagnoses due to the cross-sectional nature of the study. CONCLUSIONS: Using a brief, self-report measure of substance use, we identified three classes of substance users differing in probability of past-year use, which were predicted by older age and some psychiatric comorbidities. While research on universal screening of substance use in youth remains limited, we discuss who may benefit from such screening among depressed youth.

Kappa Opioid Receptor Activation Induces Epigenetic Silencing of Brain-Derived Neurotropic Factor via HDAC5 in Depression.

Treatment-resistant depression (TRD) occurs in almost 50% of the depressed patients. Central kappa opioid receptor (KOR) agonism has been demonstrated to induce depression and anxiety, while KOR antagonism alleviates depression-like symptoms in rodent models and TRD in clinical studies. Previously, we have shown that sustained KOR activation leads to a TRD-like phenotype in mice, and modulation of brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex (PFC) appears to be one of the molecular determinants of the antidepressant response. In the present study, we observed that sustained KOR activation by a selective agonist, U50488, selectively reduced the levels of Bdnf transcripts II, IV, and Bdnf CDS (protein-coding Exon IX) in the PFC and cultured primary cortical neurons, which was blocked by selective KOR antagonist, norbinaltorphimine. Considering the crucial role of epigenetic pathways in BDNF expression, we further investigated the role of various epigenetic markers in KOR-induced BDNF downregulation in mice. We observed that treatment with U50488 resulted in selective and specific downregulation of acetylation at the ninth lysine residue of the histone H3 protein (H3K9ac) and upregulation of histone deacetylase 5 (HDAC5) expression in the PFC. Further, using anti-H3K9ac and anti-HDAC5 antibodies in the chromatin immune precipitation assay, we detected decreased enrichment of H3K9ac and increased HDAC5 binding at Bdnf II and IV transcripts after U50488 treatment, which were blocked by a selective KOR antagonist, norbinaltorphimine. Further mechanistic studies using HDAC5 selective inhibitor, LMK235, in primary cortical neurons and adeno-associated viral shRNA-mediated HDAC5-knockdown in the PFC of mice demonstrated an essential role of HDAC5 in KOR-mediated reduction of Bdnf expression in the PFC and in depression-like symptoms in mice. These results suggest that KOR engages multiple pathways to induce depression-like symptoms in mice and provide novel insights into the mechanisms by which activation of KOR regulates major depressive disorders.

Ba15Zr14Te42: a new complex ternary telluride structure with low thermal conductivity.

Heavier metal-based tellurides with complex structures are of great interest for thermoelectric (TE) applications. Herein, we report the synthesis of a new telluride Ba15Zr14Te42 using high-temperature reactions of elements. Our single-crystal X-ray diffraction study reveals that it crystallizes in the space group R3̄c of the trigonal crystal system and is isostructural to its Se analogue Ba15Zr14Se42 complex. The unit cell of the structure accommodates 426 atoms with cell dimensions of a = b = 13.2666(10) Å, c = 96.195(9) Å, and V = 14 662(3) Å3. This structure consists of 18 unique crystallographic atoms (3 × Ba, 8 × Zr, and 7 × Te). The bonding of Zr and Te atoms creates chains of ∞1[Zr14Te42]30-, which are separated by the Ba2+ cations. Although all the Zr atoms have a coordination number of 6, they form two types of coordination polyhedra by bonding with six Te atoms: slightly distorted octahedral and trigonal prisms of ZrTe6. We have synthesized polycrystalline Ba15Zr14Q42 (Q = Se/Te) samples, which were characterized by optical absorption studies to reveal direct bandgaps of <0.5 eV for the Te analogue and 1.3(1) eV for the Se analogue. The lattice thermal conductivity (klat) values of the samples are ultralow: ∼0.46 W mK-1 and ∼0.30 W mK-1 at 773 K for the Te and Se analogues, respectively. Temperature-dependent resistivity and thermopower studies were carried out for the Ba15Zr14Te42, which showed the p-type degenerate semiconducting nature of the sample at high temperatures. The theoretical DFT studies predict a bandgap of 0.14 eV for the Ba15Zr14Te42 phase.

Comparison of Intrathecal Morphine Versus Erector Spinae Plane Block for Perioperative Analgesia in Patients Undergoing Lumbar Spine Surgery: A Randomized Control Trial.

BACKGROUND: Lumbar spine surgery is associated with a significant degree of moderate-to-severe perioperative pain which can be alleviated by using different pain-relieving modalities; of these, erector spinae plane block and intrathecal morphine have promise. PURPOSE: To compare the analgesic efficacy between intrathecal morphine (ITM) versus erector spinae plane block (ESPB) for perioperative analgesia in patients undergoing lumbar spine surgery. METHOD: A total of 74 patients aged between 20 and 65 years of either sex were posted for elective lumbar spine surgery. Patients were divided into two groups: Group A patients received 0.3 mg intrathecal morphine and Group B received bilateral erector spinae plane block at L3 level by using 30 mL of 0.5% ropivacaine before starting the surgery for perioperative analgesia. In the perioperative period, pain was assessed by hemodynamic parameters (heart rate and mean arterial pressure), numeric rating scale (NRS), and patient satisfaction score.  Result: The difference in heart rate and mean arterial pressure was found to be statistically significant between groups at three, six, 12, and 24 hours (p<0.05). The patients who required rescue analgesia in Group A and Group B were 23 (62.2%) and 37 (100%) patients in the first 24 hours. The rate of complication was higher in Group A than in Group B (45% vs 5.4%). The patient satisfaction score was found to be better in Group A than in Group B. CONCLUSION: Intrathecal morphine provides more substantial and extended analgesia up to 48 hours postoperatively as compared to erector spinae plane block.

Transperitoneal Laparoscopic Pyelolithotomy in Pelvic Ectopic Kidneys: Experience From a Northern Indian Tertiary Care Institution.

Introduction The ectopic pelvic kidneys have a higher likelihood of developing renal stones due to urinary stasis caused by the abnormal position of the renal pelvis, altered course of the ureter, and kidney malrotation. This retrospective study highlights the safety, efficacy, and feasibility of performing transperitoneal laparoscopic pyelolithotomy in cases of pelvic ectopic kidney. Methodology The 15 patients with ectopic pelvic kidneys and nephrolithiasis underwent laparoscopic pyelolithotomy. The kidney was exposed either by moving the bowel or using a trans-mesocolic approach. A surgical procedure was performed to remove stones from the renal pelvis using laparoscopic forceps. Following the placement of a double J stent, the incision in the renal pelvis was closed. The procedure was completed after the intraperitoneal drain was inserted. Results A total of 15 patients underwent the transperitoneal laparoscopic pyelolithotomy procedure, with a male-to-female ratio of 3:2. The average age of the patients was 41 (25-58) years, while the average size of the stones was 3.8 cm. Additionally, seven (46.6%) patients had the presence of caliceal stones in conjunction with the pelvic stone. Out of the 15 patients, some had stones on the left side (n = 9, 60%), while others had stones on the right side (n = 6, 40%). The operation with an average duration was 125 minutes with a range of (90-190). Fourteen (93.3%) patients were found to be free of stones. A patient required extracorporeal shock wave lithotripsy (ESWL) to address a small caliceal residual stone measuring 8 mm. After just one session of ESWL, this stone was completely cleared. All stones were successfully removed, resulting in a 100% stone-free rate. Conclusions Laparoscopic pyelolithotomy is a highly effective and efficient procedure for treating large and numerous stones in the ectopic pelvic kidney. This method has a significant level of efficiency in removing stones with limited consequences.

Transcriptional Dynamics of NRF2 Overexpression and KEAP1-NRF2 Inhibitors in Human Cell Line and Primary Lung Cells.

Oxidative stress in the human lung is caused by both internal (e.g., inflammation) and external stressors (smoking, pollution, and infection) to drive pathology in a number of lung diseases. Cellular damage caused by oxidative damage is reversed by several pathways, one of which is the antioxidant response. This response is regulated by the transcriptional factor NRF2, which has the ability to regulate the transcription of more than 250 genes. In disease, this balance is overwhelmed, and the cells are unable to return to homeostasis. Several pharmacological approaches aim to improve the antioxidant capacity by inhibiting the interaction of NRF2 with its key cytosolic inhibitor, KEAP1. Here, we evaluate an alternative approach by overexpressing NRF2 from chemically modified RNAs (cmRNAs). Our results demonstrate successful expression of functional NRF2 protein in human cell lines and primary cells. We establish a kinetic transcriptomic profile to compare antioxidant response gene expression after treatment of primary human bronchial epithelial cells with either KEAP1 inhibitors or cmRNAs. The key gene signature is then applied to primary human lung fibroblasts and alveolar macrophages to uncover transcriptional preferences in each cell system. This study provides a foundation for the understanding of NRF2 dynamics in the human lung and provides initial evidence of alternative ways for pharmacological interference.

Clinical and sociodemographic features of the Texas resilience against depression (T-RAD) study: Findings from the initial cohort.

OBJECTIVE: The burden of major depressive disorder is compounded by a limited understanding of its risk factors, the limited efficacy of treatments, and the lack of precision approaches to guide treatment selection. The Texas Resilience Against Depression (T-RAD) study was designed to explore the etiology of depression by collecting comprehensive socio-demographic, clinical, behavioral, neurophysiological/neuroimaging, and biological data from depressed individuals (D2K) and youth at risk for depression (RAD). METHODS: This report details the baseline sociodemographic, clinical, and functional features from the initial cohort (D2K N = 1040, RAD N = 365). RESULTS: Of the total T-RAD sample, n = 1078 (76.73 %) attended ≥2 in-person visits, and n = 845 (60.14 %) attended ≥4 in-person visits. Most D2K (84.82 %) had a primary diagnosis of any depressive disorder, with a bipolar disorder diagnosis being prevalent (13.49 %). RAD participants (75.89 %) did not have a psychiatric diagnosis, but other non-depressive diagnoses were present. D2K participants had 9-item Patient Health Questionnaire scores at or near the moderate range (10.58 ± 6.42 > 24 yrs.; 9.73 ± 6.12 10-24 yrs). RAD participants were in the non-depressed range (2.19 ± 2.65). While the age ranges in D2K and RAD differ, the potential to conduct analyses that compare at-risk and depressed youth is a strength of the study. The opportunity to examine the trajectory of depressive symptoms in the D2K cohort over the lifespan is unique. LIMITATIONS: As a longitudinal study, missing data were common. CONCLUSION: T-RAD will allow data to be collected from multiple modalities on a clinically well-characterized sample. These data will drive important discoveries on diagnosis, treatment, and prevention of depression.

Acute Kidney Injury in Inflammatory Bowel Disease Patients: A Nationwide Comparative Analysis.

Rationale & Objective: About 25%-40% of patients with inflammatory bowel disease (IBD) may have extraintestinal manifestations, mainly involving the liver, skin, and joints. Kidney involvement in patients with IBD has been reported, but there are no estimates of its prevalence in population-based studies in the United States. We compared the frequency of acute kidney injury (AKI) among hospitalizations with IBD with that among hospitalizations with collagen vascular diseases and hospitalizations with neither condition. Study Design: Retrospective, population-based cohort study. Setting & Participants: Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database. Outcomes: AKI and AKI requiring dialysis. Analytical Approach: Regression models were used to compare the occurrence of AKI among groups. Inverse probability of treatment weighting was applied to balance groups on covariates. Results: The final sample comprised 5,735,804 hospitalizations, including 57,121 with IBD, 159,930 with collagen vascular diseases, and 5,518,753 with neither IBD nor collagen vascular diseases. AKI was observed in 13%, 15%, and 12.2% of hospitalizations with IBD, collagen vascular diseases, and the general population, respectively. When adjusting for demographic, hospital, and clinical characteristics using inverse probability of treatment weighting, hospitalizations with IBD had higher odds of being diagnosed with AKI than both those with collagen vascular diseases (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.27-1.38) and the general population (OR, 1.27; 95% CI, 1.23-1.31) and also had higher odds of being diagnosed with AKI requiring dialysis than those with collagen vascular diseases (OR, 1.59; 95% CI, 1.31-1.94) or than the general population (OR, 1.45; 95% CI, 1.25-1.68). Limitations: Cross-sectional analysis, underreporting of International Classification of Diseases codes, and analyses relevant to in-hospital stays only. Conclusions: The prevalence and risk of AKI among hospitalizations with IBD is greater than that of hospitalizations with collagen vascular diseases and the general population. Coexisting kidney disease should be considered among patients with a known diagnosis of IBD.

As a nephrologist, we have evaluated many patients with inflammatory bowel disease with various forms of kidney disease, both inflammatory and noninflammatory. Based on a multitude of factors, we have always wondered if there are shared immune mechanisms between the gut and kidney that could explain the underlying inflammation in both organs. In addition, based on recent studies of other autoimmune/inflammatory diseases, there is growing interest in the role of the gut microbiome (microorganisms that reside in our gut) and its influence on the immune system as well as how both the altered microbiome and immune system affect the kidneys. As a first step, we wanted to understand if some forms of kidney disease are more prevalent in patients with inflammatory bowel disease than in the general population, which possibly suggests a shared pathogenesis.

Effect of Virtual Reality Glasses and Melody on Cortisol and Adrenocorticotropic Hormone Levels in Patients With Knee Replacement Surgery Under Combined Spinal Epidural Anaesthesia.

BACKGROUND: With advanced virtual reality (VR) technology, its usage in health care is creating an impact on patient outcomes. Patients undergoing knee replacement surgery are already anxious due to the surgery, anaesthesia, and unfamiliar environment of the operation theatre. In addition to that, the unpleasant noise of tools makes it worse. Peri-operative anxiety correlates with increased anaesthesia requirements and prolonged recovery. It causes the release of stress hormones such as cortisol, adrenaline, and norepinephrine, which can lead to difficult intravascular access due to vasoconstriction and heightened cardiovascular responses. Studies on music therapy have shown a reduction in cortisol levels, contributing to anxiety alleviation. VR glasses create immersive environments to distract patients from various stress factors. Investigating the use of VR/music on serum cortisol and adrenocorticotropic hormone (ACTH) levels in knee replacement surgery can improve peri-operative care, improving patient outcomes. AIM: The study was done to investigate the impact of virtual reality glasses and music therapy on serum cortisol and ACTH levels in patients undergoing knee replacement surgery under combined spinal epidural anaesthesia. METHODS: In this prospective randomised control, single-centric study, patients of either sex, aged between 18 and 65 years, undergoing knee replacement surgery under combined spinal and epidural (CSE) anaesthesia, were included. The primary objective was to compare serum cortisol and ACTH levels, while the secondary objective was to compare the State-Trait Anxiety Inventory for State Anxiety (STAI-SA) score and Patient Satisfaction Score (PSS) in the peri-operative period. A total of 100 patients were assessed for eligibility, and 66 patients met the inclusion and exclusion criteria and were finally randomised and equally assigned to group M-VR (music-virtual reality) and group C (control). Three blood samples were collected for serum cortisol and serum ACTH levels one hour before surgery (T1), one hour after skin incision (T2), and two hours after the completion of surgery (T3). STAI-SA was measured one hour before surgery (T1) and two hours after the completion of surgery (T2), while PSS was recorded two hours after the completion of surgery. Hemodynamic parameters were noted during the entire peri-operative period. RESULTS: The demographic and anthropometric parameters were comparable in both groups. Hemodynamic parameters (heart rate [HR], mean arterial pressure [MAP]) were found to be comparable in the pre-operative period, while significant differences (p > 0.05) were noted after 30 minutes of surgery and continued till the end of surgery. Serum cortisol and serum ACTH levels were comparable in the pre-operative period but showed significantly lower variations in group M-VR in comparison to group C in the intra-operative period. PSS was significantly higher in group M-VR in comparison to group C. CONCLUSION: This study substantiates the role of virtual reality and music therapy (VR/music) on anxiety reduction, improved satisfaction scores, and lesser ACTH/cortisol level variations in knee replacement surgery. It further emphasises larger randomised controlled studies in various other surgical populations, along with long-term follow-up and outcome assessment.

Determinants of Readmission in the Intensive Care Unit: A Prospective Observational Study.

Background The antecedents of readmission among survivors of intensive care units (ICUs) are complex and comprise an array of elements that impact the rehabilitation process after leaving the ICU. The aforementioned determinants may comprise socioeconomic factors, access to follow-up healthcare, the nature and severity of the initial illness or injury, the presence of comorbidities, the sufficiency of transitional care and rehabilitation services, and patient and family support systems. Added to this, the risk of readmission may be increased by complications that develop during the ICU stay, including but not limited to infections, organ dysfunction, and psychological distress. Comprehending these determinants is of the utmost importance for healthcare providers in order to execute focused interventions that seek to diminish readmission rates, enhance patient outcomes, and elevate the standard of care for survivors of ICUs. Objective The objective of the study is to determine the factors associated with readmission among ICU survivors and the cause of readmission. Methodology This prospective observational study was conducted in a tertiary-level ICU. The duration of the study was one year and we enrolled 108 ICU survivors in our study. We have recorded patient demographic data, comorbidity, primary diagnosis, previous treatment history (vasopressor, sedation), causes of readmission, duration of previous ICU stay, and outcome of readmitted patient (discharge, death, and transfer to lower facility). Result The incidence of readmission in our ICU is 10.4%; 50-70 age groups are more prone to readmission of which the male sex is predominant (64.81%). In our study, hypertension (cardiac, 18.52%) and diabetes mellitus (11.11%) were the most common comorbidities reported in readmitted patients. The majority of patients who get readmission suffered from blunt trauma abdomen. In the majority of readmitted patients, sedation was used in the previous admission for ventilation and patient comfort (66.67%). Most of the readmitted patients (68.51%) have a previous ICU stay of more than five days. Patients were readmitted mainly because of respiratory (30.56%) and neurological (25%) complications. In this study, readmitted patients have high mortality (59.26%). Conclusion In a tertiary care ICU, the incidence rate of readmitted patients was 10.4%. Respiratory and neurological problems were the main cause of readmission. In readmitted patients, mortality was high up to 59.26%. Old age, male sex, prolonged ICU stay, comorbidities like hypertension, blunt trauma abdomen, use of sedation, and prolonged mechanical ventilation in previous ICU admission are major risk factors for ICU readmission.

Infectious Complications Following CD30 Chimeric Antigen Receptor T-Cell Therapy in Adults.

Infections are increasingly recognized as a common complication of chimeric antigen receptor (CAR) T-cell therapy. The incidence of clinically-defined infection after CD19.CAR T-cell therapy for relapsed/refractory lymphoma ranges from 60-90% in the first year after CAR T-cell therapy and is the most common cause for non-relapse mortality. However, infectious risk after CAR T-cell therapy targeting other malignancies is not well understood. Herein, we report for the first time, infectious complications after CD30.CAR T-cell treatment for patients with Hodgkin's lymphoma and peripheral T-cell lymphoma. Since CD30 is only expressed on a subset of activated T and B-cells, we hypothesized that CD30.CAR T-cell patients would have reduced incidence and severity of infections after infusion compared to CD19.CAR T-cell patients. We retrospectively evaluated all 64 patients who received CD30.CAR T-cells at a single institution between 2016-2021, and assessed infections within one year after cell infusion, comparing these data to a contemporary cohort of 50 patients who received CD19.CAR T-cells at the same institution between 2018-2021. 23 CD30.CAR T-cell patients (36%) and 18 CD19.CAR T-cell patients (36%) developed a microbiologically confirmed infection. Infection severity and bacterial infections were higher in the CD19.CAR T-cell group compared to CD30.CAR T-cell recipients who more commonly had grade 1 respiratory viral infections. Our data reflect expected outcomes for severity and infection type in CD19.CAR T-cell patients and provide a benchmark for comparison with the novel CD30.CAR T-cell product. Although our findings require replication in a larger cohort, they have implications for antimicrobial prophylaxis guidelines after CD30.CAR T-cell therapy. KEY POINTS: 1) The incidence of infections within the first year after CD30.CAR T-cell therapy was equivalent to that following CD19.CAR T-cell therapy2) Viral infections were more common after CD30.CAR T-cell therapy but bacterial infections predominated after CD19.CAR T-cell therapy.

Polarized Raman, infrared and dielectric spectra of lead-free K0.5Na0.5NbO3piezoelectric system: insights fromab-initiotheoretical and experimental studies.

The K0.5Na0.5NbO3(KNN) system has emerged as one of the most promising lead-free piezoelectric over the years. In this work, we perform a comprehensive investigation of electronic structure, lattice dynamics and dielectric properties of room temperature phase of KNN by combiningab-initioDFT based theoretical analysis and experimental characterization. We assign the symmetry labels to KNN vibrational modes and obtainab-initiopolarized Raman spectra, Infrared reflectivity, Born-effective charge tensors, oscillator strengths etc. The KNN ceramic samples are prepared using conventional solid-state method and Raman and UV-Vis diffuse reflectance spectra are obtained. The computed Raman spectrum is found to agree well with the experimental spectrum. In particular, the results suggest that the mode in range ∼840-870 cm-1reported in the experimental studies is longitudinal optical withA1symmetry. The Raman mode intensities are calculated for different light polarization set-ups that suggests the observation of different symmetry modes in different polarization set-ups. The electronic structure of KNN is investigated and optical absorption spectrum is obtained. Further, the performances of DFT semi-local, meta-GGA and hybrid exchange-correlations functionals, in the estimation of KNN band gaps are investigated. The KNN bandgap computed using GGA-1/2 and HSE06 hybrid functional schemes are found to be in excellent agreement with the experimental value. The COHP, electron localization function and Bader charge analysis is also performed to deduce the nature of chemical bonding in the KNN. Overall, our study provides several bench-mark important results on KNN that have not been reported so far.

Limitations and potential of κOR biased agonists for pain and itch management.

The concept of ligand bias is based on the premise that different agonists can elicit distinct responses by selectively activating the same receptor. These responses often determine whether an agonist has therapeutic or undesirable effects. Therefore, it would be highly advantageous to have agonists that specifically trigger the therapeutic response. The last two decades have seen a growing trend towards the consideration of ligand bias in the development of ligands to target the κ-opioid receptor (κOR). Most of these ligands selectively favor G-protein signaling over ß-arrestin signaling to potentially provide effective pain and itch relief without adverse side effects associated with κOR activation. Importantly, the specific role of ß-arrestin 2 in mediating κOR agonist-induced side effects remains unknown, and similarly the therapeutic and side-effect profiles of G-protein-biased κOR agonists have not been established. Furthermore, some drugs previously labeled as G-protein-biased may not exhibit true bias but may instead be either low-intrinsic-efficacy or partial agonists. In this review, we discuss the established methods to test ligand bias, their limitations in measuring bias factors for κOR agonists, as well as recommend the consideration of other systematic factors to correlate the degree of bias signaling and pharmacological effects. This article is part of the Special Issue on "Ligand Bias".

Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic tumors.

The application of extracellular vesicles, particularly exosomes (EXs), is rapidly expanding in the field of medicine, owing to their remarkable properties as natural carriers of biological cargo. This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues (NAF-EXs) for personalized medicine, which can be derived at the time of diagnosis by endoscopic ultrasound. Herein, we show that exosomes (EXs) derived from NAFs demonstrate differential bio-physical characteristics, efficient cellular internalization, drug loading efficiency, pancreatic tumor targeting and delivery of payloads. NAF-derived EXs (NAF-EXs) were used for loading ormeloxifene (ORM), a potent anti-cancer and desmoplasia inhibitor as a model drug. We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype, which may be due to regulation of Ca2+ influx in fibroblast cells. NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition (EMT) and repressed tumor growth in xenograft mouse model. In conclusion, our data suggests preferential tropism of NAF-EXs for PDAC tumors, thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs. Additionally, it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.