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In this article, we report the temperature-dependent transistor characteristic of Epi-Gd2O3/AlGaN/GaN metal oxide semiconductor high electron mobility transistor (MOSHEMT) and compare its properties with that of AlGaN/GaN metal-Schottky high electron mobility transistor (HEMT) grown on 150 mm Si (111) substrate. Introducing an epitaxial single crystalline Gd2O3 between the metal gate and AlGaN barrier not only improves the gate leakage current significantly but also enhances its thermal stability. We observe that there is no significant change in the gate leakage current even at 473 K compared to that measured at room temperature (RT) (298 K), and this is also evident in the transistor’s subthreshold behavior at 473 K. We have determined the electric field within the Gd2O3 as well as AlGaN and investigated the leakage conduction mechanism through Gd2O3. The ION/IOFF of the transistor was measured as high as ~108 even at 473 K with the lowest VTH shift (91.4 mV) with temperature. Our measurements also confirm the presence of polar optical phonon scattering, which directly affects the 2-D electron gas (2DEG) mobility at high temperatures and thus the electrical characteristics of HEMT and MOSHEMT. [ABSTRACT FROM AUTHOR]

Background: Distal femur fractures are one of the most frequent fractures seen in high-velocity trauma, and they are associated with substantial morbidity if not treated properly. Stiffness, secondary arthritis, shortening, and disturbance in the activity of daily living can occur as a result of this fracture. Open reduction and internal fixation with locking compression plates (LCPs) is the preferred treatment. The anatomic contoured LCP for the distal femur has been found to provide one of the best outcomes in terms of anatomical reduction with joint congruity, soft-tissue healing, fracture union, and functional ability. This study was done to evaluate the functional outcome of distal femur fractures managed with LCP. Materials and Methods: Thirty patients with distal femur fractures were treated at our institute using LCP were analyzed for the outcome in terms of clinical, radiological union, and functional results. Results: Twenty-one patients were male and nine were female. The average age was 41.55 years with a range of 21–60 years. In 22 patients, cause of fracture was road traffic accidents and in eight were fall at various occasions. Twenty-one patients had right-side fractures. The average time for radiological union was 14.2 weeks. The average flexion of the knee was 107.16°. Functional outcome was assessed using Sanders' Functional Evolution Scale. The outcome was excellent in 30%, good in 40%, fair in 17%, and poor in 13%. Conclusion: Locking compression plating is an excellent internal fixation option for both extra- articular and intra-articular distal femur fractures, and it is particularly helpful in osteoporotic metaphyseal fractures.

Background: This study was done to know whether patients with hip injury have pre-existing osteoporosis due to which, the patient sustained the fracture, subsequent fracture of the contralateral hip, any osteoarthritic changes of the contralateral hip at the time of index fracture, and ten-year probability of a major osteoporotic fracture by calculating fracture risk assessment percentage (FRAX%). Methods: 34 patients were evaluated for age, gender, body mass index (BMI), fracture type, Singh index, bone mineral density (BMD), T-scores using dual-energy X-ray absorptiometry (DEXA) scan, and ten-year probability of fracture using FRAX%. Results: Average age of the patients with hip fractures was 72.1 years. About 85% of patients were women. 67.6% of the patients were with BMI of 18.5-25 kg/m2. The Singh index for osteoporosis fell in grades 2 and 3 in most patients. The mean interval between index fracture and contralateral hip injury was 4.25 years. Osteoarthritis of the contralateral hip was seen in 9%. The probability in ten years of hip fracture in 30 indexed patients using the FRAX% tool was 15%, and for 4 patients who were having bilateral hip fractures was 22.75%. There was a significant relationship between FRAX% with the Singh index and osteoarthritis of the contralateral hip. FRAX% was high in female patients. Conclusion: Contralateral hip fracture in patients with osteoporosis was high in women and patients with low and high BMI. Fractures were also high in patients with low Singh index and T-scores. FRAX% increased with an increase in age and increased with a decrease in T-score.

Purpose: To investigate the pharmacokinetics and disposition of [(14)C]pomalidomide following a single oral dose to healthy male subjects.Methods: Eight subjects were administered a single 2 mg oral suspension of [(14)C]pomalidomide. Blood (plasma), urine and feces were collected. Mass balance of radioactivity and the pharmacokinetics of radioactivity, pomalidomide and metabolites were determined. Metabolite profiling and characterization was performed. The enzymes involved in pomalidomide metabolism and the potential pharmacological activity of metabolites were evaluated in vitro.Results: Mean recovery was 88 %, with 73 and 15 % of the radioactive dose excreted in urine and feces, respectively, indicating good oral absorption. Mean C(max), AUC(0-∞) and t(max) values for pomalidomide in plasma were 13 ng/mL, 189 ng*h/mL and 3.0 h. Radioactivity and pomalidomide were rapidly cleared from circulation, with terminal half-lives of 8.9 and 11.2 h. Pomalidomide accounted for 70 % of the circulating radioactivity, and no circulating metabolite was present at >10 % of parent compound. Pomalidomide was extensively metabolized prior to excretion, with excreted metabolites being similar to those observed in circulation. Clearance pathways included cytochrome P450-mediated hydroxylation with subsequent glucuronidation (43 % of the dose), glutarimide ring hydrolysis (25 %) and excretion of unchanged drug (10 %). 5-Hydroxy pomalidomide, the notable oxidative metabolite, was formed primarily via CYP1A2 and CYP3A4. The hydroxy metabolites and hydrolysis products were at least 26-fold less pharmacologically active than pomalidomide in vitro.Conclusions: Following oral administration, pomalidomide was well absorbed, with parent compound being the predominant circulating component. Pomalidomide was extensively metabolized prior to excretion, and metabolites were eliminated primarily in urine. [ABSTRACT FROM AUTHOR]

Purpose: Assessment of the absorption, metabolism and excretion of [(14)C]-lenalidomide in healthy male subjects following a single oral dose.Methods: Six healthy male subjects were administered a single 25 mg oral suspension dose of [(14)C]-lenalidomide. Blood (plasma), semen and excreta were collected. Mass balance assessments were done by radioactivity measurements. Metabolite profiling and quantitation were accomplished using liquid chromatography with mass spectrometric and radiochemical detection.Results: [(14)C]-Lenalidomide was rapidly absorbed (T (max) 0.77-1.0 h), and the levels declined with a terminal half-life of approximately 3 h, with similar profiles for total blood and plasma radioactivity as well as plasma lenalidomide. The whole blood to plasma radioactivity exposure levels were comparable, suggesting equal distribution between plasma and blood cells. On average, 94% of the administered radioactivity was recovered within 10 days, with >88% recovered within 24 h. Urinary excretion was the primary route of elimination (90% of radioactive dose), with minor amounts excreted in feces (4%). Semen contained a small amount of the radioactive dose (0.0062%). Lenalidomide was the primary radioactive component in plasma (92% of the [(14)C]-area under the concentration-time curve) and urine (>90% of the radioactivity in urine). The remaining radioactivity was composed of primarily two metabolites: 5-hydroxy-lenalidomide and N-acetyl-lenalidomide, each accounting for less than 5% of the total radioactivity as well as lenalidomide levels in plasma and excreta.Conclusions: In summary, following oral administration, lenalidomide is highly absorbed and bioavailable, metabolized minimally, and eliminated predominantly via urinary excretion in the unchanged form in humans. [ABSTRACT FROM AUTHOR]

Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by deficiency of homogentisate 1,2-dioxygenase, an enzyme that converts homogentisic acid (HGA) to maleylacetoacetic acid in the tyrosine degradation pathway. The three major features of AKU are the presence of HGA in the urine, ochronosis (bluish-black pigmentation in connective tissue), and arthritis of the spine and larger joints. We present a case of 48-year-old woman with a history of low back pain and left sided sciatica. Preoperative radiograph and computed tomography scan showed multiple calcified discs. Magnetic resonance imaging demonstrated an extruded disc at L4-L5, which was the culprit for her symptoms. She underwent complete discectomy. During discectomy, the disc found to be brittle and dark pigmented. Histopathology reported the disc had ochronoid pigment, and her urine turns dark after alkalization, and she admitted that she passed dark urine since childhood. Prolapsed lumbar disc is a rare entity in calcified discs of ochronotic spine. It requires discectomy in symptomatic patients. It requires long-term follow-up.

Drought is a major constraint for rainfed lowland and upland rice productivity throughout world. A backcross inbred population derived from ‘Swarna’ and ‘WAB450-I-B-P-157-2-1’ (Oryza sativa L. x O. glaberrima) was evaluated under both irrigated and lowland drought stresses for yield and yield related traits across three different seasons. Significant differences were found among all the analyzed traits. Coefficients of variation were recorded relatively high for filled grains per panicle, spikelet fertility, test weight, harvest index and grain yield and low for panicle length under both conditions during the study interval. Broad sense heritability varied from 0.28 (panicle number) to 0.83 (plant height) under stress and 0.31 (test weight) to 0.86 (plant height) under control. However, heritability estimates for grain yield and harvest index were found to be similar under both conditions. Traits such as filled grains per panicle, spikelet fertility, harvest index and grain yield recorded higher values of both heritability, as well as genetic advance under both conditions, indicating the suitability of these traits as selection criteria to derive high yielding genotypes for drought prone regions. Harvest index exhibited maximum positive direct effect on grain yield under both the conditions; in addition, filled grains per panicle, spikelet fertility and biomass had positive direct effect on grain yield under both irrigated and lowland drought stresses state. Hence, for improving the rice yield under lowland drought ecology, a genotype should posses a large number of panicles per plant, filled grains per panicle, high spikelet fertility and maintains higher biomass and harvest index.

Flurbiprofen, a primary component of a nonsteroidal anti-inflammatory drug (NSAID) used to relieve symptoms of arthritis, and is a considerable interest in medicinal chemistry due to its demonstrated potential as an effective agent in various therapeutic applications. In consideration of the 1,3,4-oxadiazole therapeutic potential and anticancer activity, a new series of flurbiprofen scaffolds have been prepared through a straightforward reaction between 5-(1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-1,3,4-oxadiazole-2-thiol (4) and various organic active 2-chloro-N-phenyl acetamides (5). The synthesized series (6a-6k) was characterized using a combination of spectroscopic techniques, including FT-IR, mass, 1 H-NMR, and 13 C NMR, followed by physical data. The cytotoxicity of the newly synthesized congeners was investigated against MCF-7 (human breast cancer cell line) and A-549 (human lung carcinoma epithelial) cell lines and anti-inflammatory activity as DPPH and H 2 O 2 radical scavenging ability. In the series, analogues 6c, 6e, 6h, and 6k showed excellent inhibitory activity against MCF-7 cells in the range of IC 50 values of 9.10-13.67 μg mL -1 compared to DXN (IC 50 =9.24 μg mL -1 ). In this series, analogues 6c, 6f, 6h, and 6j show remarkable H 2 O 2 radical scavenging inhibition IC 50 of 48.25±0.21, 47.33±0.15, 51.10±0.25, and 44.40±0.07 μM by using ascorbic acid as a standard, whose IC 50 is 49.90±0.27 μM. According to the docking results, the most potent cytotoxic compounds have a stronger binding affinity with the Flurbiprofen complex (PDB: 1R9O) because of their interactions with residues such as Arg 416 (A), Trp 103 (A), Phe 97 (A), Gly 279 (A), Ile 188 (A), Glu 283 (A), Thr 287 (A), Val 462 (A), Phe 459 (A), Leu 345 (A), Ile 417 (A), and Cys 418 (A). Furthermore, in silico drug-likeness prediction analysis suggested that the majority of the synthesized compounds exhibit good oral bioavailability based on their Lipinski's Rule of Five and toxicity using ADME/Tox predictions., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Frequency mixer is an essential block in radio-frequency signal processing for frequency translation and phase comparison. The most common mixers are fabricated using passive elements which suffer from significant conversion loss and low isolation. Mixers using active devices are used less frequently and rather less matured on GaN technology. Here, we demonstrate a mixer based on GaN split-gate nanowire transistor, allowing low conversion loss and high isolation. A constriction is formed by electrostatic modulation of the effective gate width. The threshold voltage of the transistor is modified by one of the gate voltages through the width variation, while the other gate voltage biases the transistor in the saturation region. The nonlinear dependency of the transistor characteristics on the two gate voltages facilitates frequency translation. The mixing characteristics of this architecture are verified both experimentally and theoretically. The output power spectral density peaks at the difference frequency with a minimal conversion loss. Extremely high isolation is measured using three-port S-parameter measurements. The proposed architecture shows multiple benefits, additionally facilitating monolithic mixers on the GaN platform., (© 2024 IOP Publishing Ltd.)

Purpose: Tympanostomy tube (TT) placement is the most frequently performed ambulatory surgery in children under 15. After the procedure it is recommended that patients follow up regularly for "tube checks" until TT extrusion. Such visits incur direct and indirect costs to families in the form of days off from work, copays, and travel expenses. This pilot study aims to compare the efficacy of tympanic membrane (TM) evaluation by an artificial intelligence algorithm with that of clinical staff for determining presence or absence of a tympanostomy tube within the TM., Methods: Using a digital otoscope, we performed a prospective study in children (ages 10 months-10 years) with a history of TTs who were being seen for follow up in a pediatric otolaryngology clinic. A smartphone otoscope was used by study personnel who were not physicians to take ear exam images, then through conventional otoscopic exam, ears were assessed by a clinician for tubes being in place or tubes having extruded from the TM. We trained and tested a deep learning (artificial intelligence) algorithm to assess the images and compared that with the clinician's assessment., Results: A total of 123 images were obtained from 28 subjects. The algorithm classified images as TM with or without tube in place. Overall classification accuracy was 97.7 %. Recall and precision were 100 % and 96 %, respectively, for TM without a tube present, and 95 % and 100 %, respectively, for TM with a tube in place., Discussion: This is a promising deep learning algorithm for classifying ear tube presence in the TM utilizing images obtained in awake children using an over-the-counter otoscope available to the lay population. We are continuing enrollment, with the goal of building an algorithm to assess tube patency and extrusion., Competing Interests: Declaration of competing interest The COHI Group provided the digital otoscope and iPod touch for research purposes. There are no other conflicts of interest to report. There was no source of funding for this study. No artificial intelligence platforms were utilized to aid in the writing of this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: This study aimed to determine agreement between reported percentage pain reduction (RPPR) and calculated percentage pain reduction (CPPR) in patients with percutaneous spinal cord stimulation (SCS) implants, and to correlate RPPR and CPPR with patient satisfaction. We also sought to determine which patient-reported outcome measures are most improved in patients with SCS., Materials and Methods: Fifty patients with percutaneous spinal cord stimulator implants with a mean follow-up of 51.1 months were interviewed and surveyed to assess their pain level, impression of degree of pain relief, satisfaction with the therapy, and desire to have the device again. Baseline pain level was obtained from their preimplant records., Results: Overall, RPPR was found to be 53.3%, whereas CPPR was 44.4%. Of all patients, 21 reported <50% pain reduction; however, most of these (12/21, 57%) were satisfied with the outcome of therapy. In terms of individual improvement in outcomes, activities of daily life was the most improved measure at 82%, followed by mood, sleep, medication use, and health care utilization at 74%, 62%, 50%, and 48%, respectively., Conclusions: RPPR appears to be a complex outcome measure that may not agree with CPPR. Overall RPPR is greater than the CPPR. On the basis of our data, these independently valid measures should not be used interchangeably. A 50% pain reduction threshold is not a requisite for patient satisfaction and desire to have the device again. Activities of daily living was the most improved measure in this cohort, followed by mood, sleep, medication usage, and decrease in health care utilization., Competing Interests: Conflict of Interest Thomas Simopoulos reports presentation fees from Nevro and Boston Scientific. The remaining authors reported no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

The risk of further periodontal breakdown increases with a deep intrabony defect. Non-surgical periodontal therapy could pose a challenge and surgical intervention is mainly required to manage the defect. Autologous platelet concentrates such as Injectable platelet rich fibrin (i-PRF) and concentrated growth factor (CGF) may improve surgical outcome due to its enrichment with growth factors. Total of 04 patients involved in this study. After conventional flap debridement of intrabony defects, CGF is placed in 2 patients and the other 2 patients received i-PRF in their respective intrabony defects. Volumetric analysis was done pre-operative and 6 months post operatively in both the groups. Bone volume is significantly increased in both CGF and i-PRF group but higher in CGF group when compared to i-PRF group has high regenerative and reconstructive growth factors which helps aids in early and high bone fill when compared to i-PRF., Competing Interests: There are none, (© 2024 Biomedical Informatics.)

Objectives: To describe incidence and risk factors of loss of previous independent living through nonhome discharge or discharge home with health assistance in survivors of intensive care unit (ICU) admission for coronavirus disease 2019 (COVID-19)., Design: Multicenter observational study including patients admitted to the ICU from January 2020 till June 30, 2021., Hypothesis: We hypothesized that there is a high risk of nonhome discharge in patients surviving ICU admission due to COVID-19., Setting: Data were included from 306 hospitals in 28 countries participating in the SCCM Discovery Viral Infection and Respiratory Illness Universal Study COVID-19 registry., Patients: Previously independently living adult ICU survivors of COVID-19., Interventions: None., Measurements and Main Results: The primary outcome was nonhome discharge. Secondary outcome was the requirement of health assistance among patients who were discharged home. Out of 10 820 patients, 7101 (66%) were discharged alive; 3791 (53%) of these survivors lost their previous independent living status, out of those 2071 (29%) through nonhome discharge, and 1720 (24%) through discharge home requiring health assistance. In adjusted analyses, loss of independence on discharge among survivors was predicted by patient age ≥ 65 years (adjusted odds ratio [aOR] 2.78, 95% confidence interval [CI] 2.47-3.14, P  < .0001), former and current smoking status (aOR 1.25, 95% CI 1.08-1.46, P   =  .003 and 1.60 (95% CI 1.18-2.16), P   =  .003, respectively), substance use disorder (aOR 1.52, 95% CI 1.12-2.06, P   =  .007), requirement for mechanical ventilation (aOR 4.17, 95% CI 3.69-4.71, P  < .0001), prone positioning (aOR 1.19, 95% CI 1.03-1.38, P   =  .02), and requirement for extracorporeal membrane oxygenation (aOR 2.28, 95% CI 1.55-3.34, P  < .0001)., Conclusions: More than half of ICU survivors hospitalized for COVID-19 are unable to return to independent living status, thereby imposing a significant secondary strain on health care systems worldwide.

Recently, multiple chimeric antigen receptor T-cell (CAR-T)-based therapies have been approved for treating hematological malignancies, targeting CD19 and B-cell maturation antigen. Unlike protein or antibody therapies, CAR-T therapies are "living cell" therapies whose pharmacokinetics are characterized by expansion, distribution, contraction, and persistence. Therefore, this unique modality requires a different approach for quantitation compared with conventional ligand binding assays implemented for most biologics. Cellular (flow cytometry) or molecular assays (polymerase chain reaction (PCR)) can be deployed with each having unique advantages and disadvantages. In this article, we describe the molecular assays utilized: quantitative PCR (qPCR), which was the initial platform used to estimate transgene copy numbers and more recently droplet digital PCR (ddPCR) which quantitates the absolute copy numbers of CAR transgene. The comparability of the two methods in patient samples and of each method across different matrices (isolated CD3 + T-cells or whole blood) was also performed. The results show a good correlation between qPCR and ddPCR for the amplification of same gene in clinical samples from a CAR-T therapy trial. In addition, our studies show that the qPCR-based amplification of transgene levels was well-correlated, independent of DNA sources (either CD3 + T-cells or whole blood). Our results also highlight that ddPCR can be a better platform for monitoring samples at the early phase of CAR-T dosing prior to expansion and during long-term monitoring as they can detect samples with very low copy numbers with high sensitivity, in addition to easier implementation and sample logistics., (© 2023 Bristol Myers Squibb. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

The 16 th Workshop on Recent Issues in Bioanalysis (16 th WRIB) took place in Atlanta, GA, USA on September 26-30, 2022. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 16th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on the ICH M10 BMV final guideline (focused on this guideline training, interpretation, adoption and transition); mass spectrometry innovation (focused on novel technologies, novel modalities, and novel challenges); and flow cytometry bioanalysis (rising of the 3rd most common/important technology in bioanalytical labs) were the special features of the 16 th edition. As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues. This 2022 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2022 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1A) covers the recommendations on Mass Spectrometry and ICH M10. Part 1B covers the Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine. Part 2 (LBA, Biomarkers/CDx and Cytometry) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 15 of Bioanalysis, issues 15 and 14 (2023), respectively.

Pre-existing adeno-associated viruses (AAV) neutralizing antibodies (NAb) can prevent AAV vectors from transducing target tissues. The immune responses can include binding/total antibodies (TAb) and neutralizing antibodies (NAb). This study is aimed at comparing total antibody assay (TAb) and cell-based NAb assay against AAV8 to help inform the best assay format for patient exclusion criteria. We developed a chemiluminescence-based enzyme-linked immunosorbent assay to analyze AAV8 TAb in human serum. The specificity of AAV8 TAb was determined using a confirmatory assay. A COS-7-based assay was used to analyze anti-AAV8 NAbs. The TAb screening cut point factor was determined to be 2.65, and the confirmatory cut point (CCP) was 57.1%. The prevalence of AAV8 TAb in 84 normal subjects was 40%, of which 24% were NAb positive and 16% were NAb negative. All NAb-positive subjects were confirmed to be TAb-positive and also passed the CCP-positive criteria. All 16 NAb-negative subjects did not pass the CCP criterion for the positive specificity test. There was a high concordance between AAV8 TAb confirmatory assay and NAb assay. The confirmatory assay improved the specificity of the TAb screening test and confirmed neutralizing activity. We proposed a tiered assay approach, in which an anti-AAV8 screening assay should be followed by a confirmatory assay during pre-enrollment for patient exclusions for AAV8 gene therapy. This approach can be used in lieu of developing a NAb assay and can be also implemented as a companion diagnostic assay for post-marketing seroreactivity assessments due to ease of development and use., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

In cancer patients, chronic paclitaxel (PTX) treatment causes excruciating pain, limiting its use in cancer chemotherapy. The neuroprotective potential of synthetic cannabidiol (CBD) and CBD formulated in extracellular vesicles (CBD-EVs) isolated from human umbilical cord derived mesenchymal stem cells was investigated in C57BL/6J mice with PTX-induced neuropathic pain (PIPN). The particle size of EVs and CBD-EVs, surface roughness, nanomechanical properties, stability, and release studies were all investigated. To develop neuropathy in mice, PTX (8 mg/kg, i.p.) was administered every other day (four doses). In terms of decreasing mechanical and thermal hypersensitivity, CBD-EVs treatment was superior to EVs treatment or CBD treatment alone ( p < 0.001). CBD and CBD-EVs significantly reduced mitochondrial dysfunction in dorsal root ganglions and spinal homogenates of PTX-treated animals by modulating the AMPK pathway ( p < 0.001). Studies inhibiting the AMPK and 5HT1A receptors found that CBD did not influence the neurobehavioral or mitochondrial function of PIPN. Based on these results, we hypothesize that CBD and CBD-EVs mitigated PIPN by modulating AMPK and mitochondrial function.

Drosophila trachea is a premier model to study tube morphogenesis. After the formation of continuous tubes, tube maturation follows. Tracheal tube maturation starts with an apical secretion pulse that deposits extracellular matrix components to form a chitin-based apical luminal matrix (aECM). This aECM is then cleared and followed by the maturation of taenidial folds. Finally, air fills the tubes. Meanwhile, the cellular junctions are maintained to ensure tube integrity. Previous research has identified several key components (ER, Golgi, several endosomes) of protein trafficking pathways that regulate the secretion and clearance of aECM, and the maintenance of cellular junctions. The Osiris (Osi) gene family is located at the Triplo-lethal (Tpl) locus on chromosome 3R 83D4-E3 and exhibits dosage sensitivity. Here, we show that three Osi genes (Osi9, Osi15, Osi19), function redundantly to regulate adherens junction (AJ) maintenance, luminal clearance, taenidial fold formation, tube morphology, and air filling during tube maturation. The localization of Osi proteins in endosomes (Rab7-containing late endosomes, Rab11-containing recycling endosomes, Lamp-containing lysosomes) and the reduction of these endosomes in Osi mutants suggest the possible role of Osi genes in tube maturation through endosome-mediated trafficking. We analyzed tube maturation in zygotic rab11 and rab7 mutants, respectively, to determine whether endosome-mediated trafficking is required. Interestingly, similar tube maturation defects were observed in rab11 but not in rab7 mutants, suggesting the involvement of Rab11-mediated trafficking, but not Rab7-mediated trafficking, in this process. To investigate whether Osi genes regulate tube maturation primarily through the maintenance of Rab11-containing endosomes, we overexpressed rab11 in Osi mutant trachea. Surprisingly, no obvious rescue was observed. Thus, increasing endosome numbers is not sufficient to rescue tube maturation defects in Osi mutants. These results suggest that Osi genes regulate other aspects of endosome-mediated trafficking, or regulate an unknown mechanism that converges or acts in parallel with Rab11-mediated trafficking during tube maturation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Scholl et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose of Review: The purpose of this review is to present an overview of common sleep disturbance pathologies and their impact on chronic pain, while examining various factors that are implicit in the relationship between sleep disturbance and chronic pain, including neurobiochemistry, anatomy, and systemic mediators, and reviewing recent and landmark literature., Recent Findings: Earlier literature reviews and studies have introduced the bidirectional relationship between sleep disturbance and chronic pain; that is, impaired sleep may worsen chronic pain, and chronic pain causes sleep disturbance. However, more recent reviews and studies seem to show a more associative, rather than causative relationship. There have been recent studies that attempt to determine mechanisms that link sleep disturbance and chronic pain; the results of these studies were more varied, ultimately concluding that there may be a separate, yet-to-be discovered mechanism that shows the causative relationship between sleep disturbance and pain. There are several neurotransmitters that are involved in the mediation of chronic pain and sleep disturbance as separate entities, and some studies have shown that there may be mechanisms that govern both chronic pain and sleep disturbance as a single unit. Other neuroendocrine substances also serve to mediate chronic pain and sleep disturbance. All these substances are found to be associated with various sleep disorders and are also associated with chronic pain symptoms as well. Inflammation plays a role in chronic pain and sleep disturbance, with an increase in inflammatory substances and mediators associated with an increase or worsening in chronic pain symptoms and sleep disorders. The HPA axis plays a role in chronic pain and sleep disorders, influencing pain and sleep pathways through stress response, inflammation, and maintenance of homeostasis. There are several variables that influence both chronic pain and sleep disturbance, and more research into these variables may further our understanding into the complex pathways governing the influence of sleep disturbance on pain, and ultimately to improve treatment for this issue., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Fedratinib is an orally administered Janus kinase (JAK) 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. In vitro, fedratinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Coadministration of fedratinib with CYP3A4 inhibitors is predicted to increase systemic exposure to fedratinib. This study evaluated the effect of multiple doses of the dual CYP3A4 and CYP2C19 inhibitor, fluconazole, on the pharmacokinetics of a single dose of fedratinib., Methods: In this non-randomized, fixed-sequence, open-label study, healthy adult participants first received a single oral dose of fedratinib 100 mg on day 1. Participants then received fluconazole 400 mg on day 10 and fluconazole 200 mg once daily on days 11-23, with a single oral dose of fedratinib 100 mg on day 18. Pharmacokinetic parameters were calculated for fedratinib administered with and without fluconazole., Results: A total of 16 participants completed the study and were included in the pharmacokinetic population. Coadministration of fedratinib with fluconazole increased maximum observed plasma concentration (C max ) and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC 0-t ) of fedratinib by 21% and 56%, respectively, compared with fedratinib alone. Single oral doses of fedratinib 100 mg administered with or without fluconazole were well tolerated., Conclusions: Systemic exposure after a single oral dose of fedratinib was increased by up to 56% when fedratinib was coadministered with fluconazole compared with fedratinib alone., Trial Registry: CLINICALTRIALS.GOV: NCT04702464., (© 2022. The Author(s).)

Purpose of Review: The purpose of this review is to examine the impact of smoking and its role on the development of chronic pain and provide a critical review of recent literature., Recent Findings: Recent studies demonstrate the bidirectional and dependent relationship between smoking and chronic pain. Those who are in pain have a more difficult time in the cessation of smoking as well as an increased sensitivity to pain during abstinence, lower confidence, and higher relapse rates. The fear of pain and the anxiety and depression that abstinence causes results in a grim outcome for long-term cessation. The dependent nature between chronic pain and smoking is affected by numerous variables. Providers should consider a multiprong approach to treating chronic pain and targeting smoking cessation treatment by providing motivational therapy, nicotine replacement, and medication therapies to prevent relapse, and providing those who are more likely to relapse with a higher level of care., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The purpose of this study was to evaluate if phytocannabinoids, synthetic cannabidiol (CBD), and tetrahydrocannabivarin (THCV), and their combination, could protect mice from Paclitaxel-induced peripheral neuropathy (PIPN). Six groups of C57BL/6J mice (n = 6) were used in this study. The mice were given paclitaxel (PTX) (8 mg/kg/day, i.p.) on days 1, 3, 5, and 7 to induce neuropathy. Mice were evaluated for behavioral parameters, and dorsal root ganglions (DRG) were collected from the animals and subjected to RNA sequencing and westernblot analysis at the end of the study. On cultured DRGs derived from adult male rats, immunocytochemistry and mitochondrial functional assays were also performed. When compared to individual treatments, the combination of CBD and THCV improved thermal and mechanical neurobehavioral symptoms in mice by twofold. Targets for CBD and THCV therapy were identified by KEGG (RNA sequencing). PTX reduced the expression of p-AMPK, SIRT1, NRF2, HO1, SOD2, and catalase while increasing the expression of PI3K, p-AKT, p-P38 MAP kinase, BAX, TGF-β, NLRP3 inflammasome, and caspase 3 in DRG homogenates of mice. Combination therapy outperformed monotherapy in reversing these protein expressions. The addition of CBD and THCV to DRG primary cultures reduced mitochondrial superoxides while increasing mitochondrial membrane potentials. WAY100135 and rimonabant altered the neuroprotective effects of CBD and THCV respectively by blocking 5-HT1A and CB1 receptors in mice and DRG primary cultures. The entourage effect of CBD and THCV against PIPN appears to protect neurons in mice via 5HT1A and CB1 receptors respectively., (Copyright © 2022. Published by Elsevier B.V.)

Introduction Undergraduate Medical Education (UME) prepares future residents for many aspects of medical practice, but it is rarely all-inclusive. Death pronouncement (DP), a highly important aspect of clinical training for residents, seems to be inadequately addressed and taught in undergraduate institutions. Studies have indicated that most first-year residents received minimal DP training and felt unprepared for this duty. Despite being a challenging situation, a formal teaching course is not universally taught, with most institutions merely delivering point-of-care DP instruction to medical trainees provided by supervising faculty, senior residents, and nurses. Our primary objective was to provide formal education in Duties When Life Ends (DWLE), with the goal of enhancing familiarity, knowledge, and confidence in addressing the circumstances surrounding death for graduating medical students transitioning to residency. Methods As a part of a Transition to Residency (TTR) course for students entering nonsurgical specialties, we developed a curriculum to provide formal education to fourth-year medical students in DWLE that included a two-hour didactic session delivered virtually, followed by an in-person simulation session. The didactic session covered the history, processes of DP, death physical examination, identification of medical examiner (ME) case, education on how to deliver death news to family, information about autopsies and organ donation, distinction between the cause and mechanism of death, and documentation of death notes and certificates, as well as provider self-reflection and appropriate coping mechanisms for patient death. In the 45-minute simulation, students were divided into small groups and given a case summary. During the first half, they performed a physical examination and a verbal pronouncement on cadavers, followed by an interactive small group session where students reviewed the case and worked to identify the cause of death, determine if the death was a medical examiner's case, deliver death news to the family, and complete a death progress note and certificate. Pre- and post-session questionnaires were administered, assessing three components: process familiarity, knowledge, and confidence. Finally, participants assessed course usefulness and had a free response opportunity for comments and feedback.  Results Overall, 198 students participated in all sessions, with 182 completing both pre- and post-session questionnaires. Pre-survey revealed that 70% of participants reported witnessing DP previously, with only 20% being familiar with the process of DP and 6% with documentation. Following the intervention, a comparison of the pre- and post-course questionnaires assessing process familiarity, knowledge, and confidence using a five-point Likert scale demonstrated statistically significant improvement in the mean scores in all three domains, with reported course usefulness of 96%. Conclusion A DWLE curriculum, as a part of the TTR course, was effective in improving self-reported familiarity, knowledge, and confidence regarding physician duties associated with patient death. The curriculum was well received by students. The incorporation of DWLE curriculum into TTR courses allows for vital preparation and education in the duties related to patient death. This may make a stressful process somewhat less stressful and may aid future physicians in developing competence in conducting these final physician duties., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Kaloti et al.)

The 15th edition of the Workshop on Recent Issues in Bioanalysis (15th WRIB) was held on 27 September to 1 October 2021. Even with a last-minute move from in-person to virtual, an overwhelmingly high number of nearly 900 professionals representing pharma and biotech companies, contract research organizations (CROs), and multiple regulatory agencies still eagerly convened to actively discuss the most current topics of interest in bioanalysis. The 15th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on biomarker assay development and validation (BAV) (focused on clarifying the confusion created by the increased use of the term "Context of Use - COU"); mass spectrometry of proteins (therapeutic, biomarker and transgene); state-of-the-art cytometry innovation and validation; and, critical reagent and positive control generation were the special features of the 15th edition. This 2021 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2021 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1A) covers the recommendations on Endogenous Compounds, Small Molecules, Complex Methods, Regulated Mass Spec of Large Molecules, Small Molecule, PoC. Part 1B covers the Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine. Part 2 (ISR for Biomarkers, Liquid Biopsies, Spectral Cytometry, Inhalation/Oral & Multispecific Biotherapeutics, Accuracy/LLOQ for Flow Cytometry) and Part 3 (TAb/NAb, Viral Vector CDx, Shedding Assays; CRISPR/Cas9 & CAR-T Immunogenicity; PCR & Vaccine Assay Performance; ADA Assay Comparabil ity & Cut Point Appropriateness) are published in volume 14 of Bioanalysis, issues 10 and 11 (2022), respectively.

The wild-type SARS-CoV-2 has continuously evolved into several variants with increased transmissibility and virulence. The Delta variant which was initially identified in India created a devastating impact throughout the country during the second wave. While the efficacy of the existing vaccines against the latest SARS-CoV-2 variants remains unclear, extensive research is being carried out to develop potential antiviral drugs through approaches like in silico screening and drug-repurposing. This study aimed to conduct the docking-based virtual screening of 50 potential phytochemical compounds against a Spike glycoprotein of the wild-type and the Delta SARS-CoV-2 variant. Subsequently, molecular docking was performed for the five best compounds, such as Lupeol, Betulin, Hypericin, Corilagin, and Geraniin, along with synthetic controls. From the results obtained, it was evident that Lupeol exhibited a remarkable binding affinity towards the wild-type Spike protein (-8.54 kcal/mol), while Betulin showed significant binding interactions with the mutated Spike protein (-8.83 kcal/mol), respectively. The binding energy values of the selected plant compounds were slightly higher than that of the controls. Key hydrogen bonding and hydrophobic interactions of the resulting complexes were visualized, which explained their greater binding affinity against the target proteins-the Delta S protein of SARS-CoV-2, in particular. The lower RMSD, the RMSF values of the complexes and the ligands, Rg, H-bonds, and the binding free energies of the complexes together revealed the stability of the complexes and significant binding affinities of the ligands towards the target proteins. Our study suggests that Lupeol and Betulin could be considered as potential ligands for SARS-CoV-2 spike antagonists. Further experimental validations might provide new insights for the possible antiviral therapeutic interventions of the identified lead compounds and their analogs against COVID-19 infection.

Background: Literature regarding trends for incidence and mortality of scleroderma renal crisis (SRC) in systemic sclerosis (SSc) within the United States (US) emergency departments (EDs) is limited., Objective: To study the mortality of SRC among SSc patient encounters within the US EDs., Methods: Data from the National Emergency Department Sample (NEDS) constitutes 20% sample of hospital-owned EDs and inpatient sample in the US were analyzed for SSc with and without SRC using ICD-9 codes. A linear p-trend was used to assess the trends., Results: Of the total 180,435 encounters with the diagnosis of SSc in NEDS for the years 2009 2014, 771 or 4.27/1000 patients (mean age 59.6 ± 15.5 years, 75.4% females) were recorded with SRC. The numerical differences in mortality among SRC (32 or 4.1%) and non-SRC subgroups (5487 or 3.1%) did not reach statistical significance (p = 0.3). Major complications among SRC in comparison to non-SRC subgroup include ischemic stroke (5.6% vs 0.98%, p = 0.001), new-onset AF (8% vs 6.9%, p = 0.001), new-onset congestive heart failure (24.1% vs 8.8%, p = 0.001), pulmonary arterial hypertension (15.8% vs 10.9%, p = 0.001), respiratory failure (27.5% vs 10.5%, p = 0.001), and deep vein thrombosis (4.7% vs 4.6%, p = 0.001). Congestive heart failure (CHF) was strongly associated with SRC among SSc (OR 4.3 95%CI 2.7-6.7; p < 0.001). The absolute yearly rate of SRC had increased over the study years from 2.11/1000 to 5.79/1000 (linear p-trend 0.002) while the mortality trend remained steady., Conclusion: SRC is a relatively rare medical emergency. Although there has been a significant rise in the rate of SRC among SSc patients over the study years, mortality rates had remained steady. SSc patients with CHF should be considered to have low threshold for admission to inpatient services from EDs., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Breast cancer (BC) is a foremost type of cancer in women globally with an increased mortality rate in developing countries. Information regarding hereditary factors, lifestyle, work environment, food habits, and personal history could be useful in diagnosing breast cancer. Among such food habits, the reuse of edible oil for preparing food is a common practice in any developing country. The repeated heating of oils enhances the oxidative degradation of oil to produce polyaromatic hydrocarbons (PAH) which could disrupt the redox balance and generate reactive oxygen species. These reactive toxic intermediates can lead to BRCA1 mutations that are responsible for breast cancer. Mutations in DNA are the main cause for the conversion of proto-oncogenes into oncogenes which leads to change in expression and an increase in cell proliferation wherein a normal cell gets transformed into a malignant neoplastic cell. This review summarizes the possible mechanism involved in the induction of breast cancer due to repeated heating of edible.

In the present study, a machine learning (ML) model was developed to predict the epistatic phenomena of combination mutants to improve the anticancer antibody-drug trastuzumab's binding affinity towards its antigen human epidermal growth factor receptor 2 (HER2). An ML algorithm, Support Vector Regression (SVR) was used to develop ML models with a data set consists of 193 affinity values of single mutants of trastuzumab and its associated various amino acid sequence derived descriptors. The subset selection of descriptors and SVR hyperparameters were done using the Genetic Algorithm (GA) within the SVR and the wrapper approach called GA-SVR. A 100 evolutionary cycles of GA produced the best 100 probable GA-SVR models based on their fitness score   ( Q 2 ) estimated using a stratified 5 fold cross-validation procedure. The final ML model found to be highly predictive of test data set of six combination mutants and one single mutant with R pre 2 = 0.71. The analysis of descriptors in the ML model highlighted the importance of mutant induced secondary structural variation causes the binding affinity variation of the trastuzumab. The same was verified using a short 20 ns and a long 100 ns in duplicate molecular dynamics simulation of a wild and mutant variant of trastuzumab. The secondary structure induced affinity change due to mutations in the CDR-H3 is a novel insight that came out of this study. That should help rational mutant selection to develop a biobetter trastuzumab with a multifold improved binding affinity into the market quickly.Communicated by Ramaswamy H. Sarma.

Introduction: Fedratinib, an oral, selective Janus kinase 2 inhibitor, has been shown to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The objective of this study was to evaluate the influence of fedratinib on the pharmacokinetics (PK) of digoxin (P-gp substrate), rosuvastatin (OATP1B1/1B3 and BCRP substrate), and metformin (OCT2 and MATE1/2-K substrate)., Methods: In this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.25 mg, rosuvastatin 10 mg, and metformin 1000 mg administered as a drug cocktail (day 1, period 1). After a 6-day washout, participants received oral fedratinib 600 mg 1 h before the cocktail on day 7 (period 2). An oral glucose tolerance test (OGTT) was performed to determine possible influences of fedratinib on the antihyperglycemic effect of metformin., Results: Plasma exposure to the three probe drugs was generally comparable in the presence or absence of fedratinib. Reduced metformin renal clearance by 36% and slightly higher plasma glucose levels after OGTT were observed in the presence of fedratinib. Single oral doses of the cocktail ± fedratinib were generally well tolerated., Conclusions: These results suggest that fedratinib has minimal impact on the exposure of P-gp, BCRP, OATP1B1/1B3, OCT2, and MATE1/2-K substrates. Since renal clearance of metformin was decreased in the presence of fedratinib, caution should be exercised in using coadministered drugs that are renally excreted via OCT2 and MATEs., Trial Registration: Clinicaltrials.gov NCT04231435 on January 18, 2020., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

CC-90001 is predominantly metabolised via glucuronidation, while oxidative metabolism is a minor pathway in human hepatocytes and liver microsomes. In vitro , CC-90001 glucuronidation was catalysed by UGT1A9, UGT1A4, and UGT1A1, while oxidative metabolism was primarily mediated by CYP3A4/5 with minor contributions from CYP1A2, CYP2C9, CYP2B6, and CYP2D6.CC-90001 in vitro inhibits CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 ≤ 55% at 100 μM, and the inhibition was negligible at ≤30 μM. CC-90001 is not a time-dependent CYP inhibitor.In human hepatocytes CC-90001 is an inducer of CYP2B6 and CYP3A, with mRNA levels increased 34.4% to 52.8% relative to positive controls. In vitro CC-90001 is a substrate of P-gp, and an inhibitor of P-gp, BCRP, OAT3, OATP1B1, OATP1B3, OCT2, MATE1, and MATE2k with IC 50 values of 30.3, 25.8, 17.7, 0.417, 19.9, 0.605, 4.17, and 20 μM, respectively.A clinical study demonstrated that CC-90001 has no or little impact on the exposure of warfarin (CYP2C9), omeprazole (CYP2C19), midazolam (CYP3A) or metformin (OCT2, MATE1/2k). CC-90001 co-administration increases the AUC t and C max 176% and 339% for rosuvastatin (BCRP/OATP1B1/3), 116% and 171% for digoxin (P-gp), and 266% and 321% for nintedanib (CYP3A & P-gp), respectively.In conclusion, CC-90001 in unlikely to be a victim or perpetrator of clinically relevant interactions involving CYPs or UGTs. Weak to moderate interactions are expected in clinic with substrates of P-gp and OATP1B1 due to CC-90001 inhibition of these transporters.