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Abstract: Adenomyosis lacks approved pharmacological treatment even after decades of its identification. We performed this study to review the status of clinical research on adenomyosis for finding an effective drug therapy and to identify the most common endpoints used in adenomyosis trials. A systematic search was performed in the PubMed and Clinicaltrials.gov registries to identify interventional trials for analysis without any time and language restrictions. Our search revealed that barely 15 drugs have been assessed for the management of adenomyosis from 2001 to 2021. Among these, LNG-IUS was found to be the most evaluated drug, followed by dienogest. In these trials, the most commonly assessed endpoints included VAS, NPRS for pain, haemoglobin and PBAC for menstrual bleeding, uterine volume, and serum estradiol. There appears to be a need for developing a comprehensive score that takes into consideration all disease symptoms as well as incorporates some objective elements to evaluate the disease.

The auditory tube (AT), an osteocartilaginous channel, connects the nasopharynx to the middle ear cavity. At the nasopharyngeal opening of the AT, there are dense collections of submucosal glands. In a recent article, Valstar et al. proposed these nasopharyngeal tubal glands conglomerate as salivary glands, which starkly contrasts with their previously known anatomy for being a component of the respiratory tract. This study examines the contesting views regarding the taxonomical categorization of the nasopharyngeal tubal glands.The AT glands in context were examined in human cadavers grossly, and microscopically using routine and special (Hematoxylin and Eosin [HE] and Periodic acid-Schiff [PAS] respectively), as well as immunohistochemical (for alpha-SMA and salivary amylase) staining methods and compared with the major and minor salivary glands and the submucosal glands in the trachea. Further, a biochemical analysis was performed to detect the presence of salivary amylase in the oral and nasopharyngeal secretions of the four living human subjects, representing major salivary glands and tubal glands, respectively.The submucosal seromucous glands with a surface lining of respiratory epithelium were observed at the nasopharyngeal end of AT. The cells in the tubal glands showed cytoplasmic positivity for alpha-SMA, which indicated the presence of the myoepithelial cells; however, this expression was significantly lower than in the seromucous submucosal glands within the trachea. Salivary alpha-amylase was undetectable in the cadaveric tissue samples. Moreover, the amylase level in the nasopharyngeal swabs was negligible compared to the oral swabs.The anatomical location along the respiratory tract, the presence of respiratory epithelium in the overlying mucosa, their morpho-functional resemblance to the seromucous glands in the trachea, and the absence of salivary amylase strongly indicate that the tubal glands are taxonomically different from the salivary glands. Given the available evidence, their existing recognition as a part of the respiratory tract and an integral component of the AT seems more appropriate.

Stringent emissions and fuel economy regulations have necessitated the need to boost the research interest in oxygenated alternate fuels such as n-pentanol and biodiesel under low-temperature combustion strategies due to their renewability and cleaner combustion characteristics. Being higher alcohol, n-pentanol has desirable fuel properties that are comparable to mineral diesel, which enable easy blending of these fuels. In the present study, the Reactivity Controlled Compression Ignition (RCCI) operation in a modified single-cylinder diesel engine operating at the rated speed of 1500 rpm and 50% load was investigated with non-edible karanja oil-based biodiesel–diesel blend with B20 as high reactivity fuel (HRF) and n-pentanol as low reactivity fuel (LRF). The intake temperature was maintained constant at 40 °C, intake pressure was ambient and the LRF was varied from 20% to 50%. The engine's performance with split injection was investigated by sweeping starts of injection (SOI) crank angles and these were optimized at 47°, 27°, and 17° bTDC for SOI 1, SOI 2, and SOI 3 respectively at 400 bar injection pressure. The engine performance characteristics were investigated by introducing 10% to 30% cooled exhaust gas recirculation (EGR) and was optimized at 25%, based on the stable operation of the engine with acceptable ringing intensity and emission. The combined effect of EGR, multiple injections (three), and varying PFI mass fractions was investigated and compared with a single injection of HRF. A simultaneous reduction of 76% smoke and 91.5% NOX emission was obtained with a marginal increase in CO and HC emissions.

Among all the cancer-related deaths globally, pancreatic ductal adenocarcinoma (PDAC) accounts for the seventh leading cause of mortality. A dysregulated immune system disrupts anti-tumor immunity by abnormal accumulation of myeloid-derived suppressor cells (MDSCs), but the underlying mechanisms are still inconclusive. To gain new insights into the role of MDSCs in tumor settings, we aimed to determine the mechanism of expansion of various subsets of MDSCs in PDAC patients and their role in promoting invasiveness. We assessed the load of MDSCs, chemokines responsible for the recruitment of MDSCs in PDAC patients by flow cytometry. We investigated the chemokine profile of tumor tissue using qRT-PCR and the status of epithelial-mesenchymal transition (EMT) related markers E-Cadherin, N-Cadherin, Snail, and ZEB1 by qRT-PCR and immunohistochemistry. We found a higher frequency of tumor infiltrated MDSCs in PDAC patients. Chemokine ligands CCL2 and the receptor CCR4 were markedly elevated in the PDAC tumor, while CCR4

Background Multimodal optical imaging, incorporating reflectance and fluorescence modalities, is a promising tool to detect oral premalignant lesions in real‐time. Methods Images were acquired from 171 sites in 66 patient visits for clinical evaluation of oral lesions. An automated algorithm was used to classify lesions as high‐ or low‐risk for neoplasia. Biopsies were acquired at clinically indicated sites and those classified as high‐risk by imaging, at the surgeon's discretion. Results Twenty sites were biopsied based on clinical examination or imaging. Of these, 12 were indicated clinically and by imaging; 58% were moderate dysplasia or worse. Four biopsies were indicated by imaging evaluation only; 75% were moderate dysplasia or worse. Finally, four biopsies were indicated by clinical evaluation only; 75% were moderate dysplasia or worse. Conclusion Multimodal imaging identified more cases of high‐grade dysplasia than clinical evaluation, and can improve detection of high grade precancer in patients with oral lesions.

In the present work, an attempt has been made to operate a low-temperature reactivity controlled compression ignition (RCCI) engine using fuel produced from agro/food industry waste. Biodiesel produced from residual cooking oil (RCOB) and n-hexanol has been used as high reactivity fuel (HRF) and low reactivity fuel (LRF) respectively, in a modified diesel engine. The engine was operated at mid-load and 1500 rpm with RCOB injected in-cylinder at higher injection pressures (Pinj) of 400–600 bar whereas hexanol was injected into the inlet manifold at a lower Pinj of 3 bar. The proportion of Hexanol to RCOB was varied from 20% to 50%. Two injection pulses per cycle were used for injection of RCOB and the injection timing, duration, and fuel quantity were varied whereas hexanol injection was maintained at 355° bTDC. The injection parameters, along with exhaust gas recirculation (EGR) were optimized for the lowest smoke and NO emissions. It was observed that smoke and NO emissions reduced with late main injection, whereas smoke increased and NO reduced with advanced pilot injection. The test engine was operated at these optimized conditions and the combustion and emission data were collected and compared to that of a single injection of HRF. A maximum reduction in NO emissions by 96% and smoke emission by 80% were observed with 25% EGR. The increase of 1% in indicated thermal efficiency is an added benefit.

Background Saroglitazar—a unique dual peroxisome proliferator-activated receptor agonist was approved marketing authorization in India in 2013 for diabetic dyslipidemia. Postmarketing studies have additionally shown improvement in liver parameters in diabetic dyslipidemia patients with nonalcoholic fatty liver disease (NAFLD) who received saroglitazar. Aim The aim of this study was to evaluate the effect of saroglitazar on liver function test, liver fibrosis score by FibroScan, lipid profiles, HbA1c in NAFLD patients with diabetic dyslipidemia in southern India. Methodology A prospective, interventional, pilot study was performed to study the safety and efficacy of saroglitazar in NAFLD patients having type 2 diabetes mellitus. About 97 patients were screened, of which 85 patients were involved in the study based on the inclusion criteria. The clinical parameters and liver stiffness were measured at the baseline and also after 12 weeks of treatment with administration of saroglitazar 4 mg once daily. The change in the parameters at the baseline and after the end of the treatment was measured and was subjected to statistical analysis using SPSS software. Results The recruited patients received saroglitazar and were followed up for a period of 12 weeks. The clinical parameters such as fasting blood sugar, postprandial blood sugar, HbA1c, total cholesterol, triglycerides, SGPT, and liver stiffness showed significant difference after 12 weeks of treatment when compared with the baseline values. No adverse drug reaction was reported in patients receiving saroglitazar during the study. Conclusion Saroglitazar was found to show significant improvement in liver parameters in NAFLD patients with a significant reduction in liver fibrosis and triglycerides level.

Pancreatic cancer has been identified as one of the deadliest malignancies because it remains asymptomatic and usually presents in the advanced stage. Tumor immune evasion is a well-known mechanism of tumorigenesis in various forms of human malignancies. Chronic inflammation via complex networking of various inflammatory cytokines in the local tissue microenvironment dysregulate the immune system and support tumor development. Pro-inflammatory mediators present in the tumor microenvironment increase the tumor burden by causing immune suppression through the generation of myeloid-derived suppressor cells and T regulatory cells. These cells, along-with myofibroblasts, create a highly immunosuppressive and resistant tumor microenvironment and are thus considered as one of the culprits for the failure of anti-cancer chemotherapies in pancreatic adenocarcinoma patients. Targeting these myeloid-derived suppressor cells using various combinatorial approaches might have the potential for abrogating the resistance and suppressive nature of the pancreatic tumor microenvironment. Therefore, there is more curiosity in studying the crosstalk of myeloid-derived suppressor cells with other immune cells during pathological conditions and the underlying mechanisms of immunosuppression in the current scenario. In this article, the possible role of myeloid-derived suppressor cells in inflammation-mediated tumor progression of pancreatic adenocarcinoma has been discussed.

Despite the presence of chondrogenic progenitor cells (CPCs) in knee osteoarthritis patients they are unable to repair the damaged cartilage. This study aimed to evaluate the oxidative stress, cellular senescence, and senescence-associated secretory phenotype (SASP) in the CPCs derived from osteoarthritic cartilage and compare with the CPCs of healthy articular cartilage.Isolated CPCs were characterized based on phenotypic expression of stem cell markers, clonogenicity, and tri-lineage differentiation assay. Production of ROS was measured using DCFDA assay. Cellular senescence in CPCs was assessed by senescence-associated beta-galactosidase assay and expression of senescence markers at the gene level using real-time PCR. Morphological features associated with senescent OA-CPCs were studied using scanning electron microscopy. To study SASP, the production of inflammatory cytokines was assessed in the culture supernatant using a flow-cytometer based cytometric bead array.OA-CPCs exhibited elevated ROS levels along with a relatively high percentage of senescent cells compared to non-OA CPCs, and a positive correlation exists between ROS production and senescence. The morphological assessment of senescent CPCs revealed increased cell size and multiple nuclei in senescent OA-CPCs. These results were further validated by elevated expression of senescence genes p16, p21, and p53. Additionally, culture supernatant of senescent OA-CPCs expressed IL-6 and IL-8 cytokines indicative of SASP.Despite exhibiting similar expression of stem cell markers and clonogenicity, CPCs undergo oxidative stress in diseased knee joint leading to increased production of intracellular ROS in chondrogenic progenitor cells that support cellular senescence. Further, senescence in OA-CPCs is mediated via the release of pro-inflammatory cytokines, IL-6 and IL-8.

Stringent emissions and fuel economy regulations have necessitated the need to boost the research interest in oxygenated alternate fuels such as

With increasing pollution concerns and stringent emission regulations, it has become difficult to meet the emission standards with the use of a single fuel. Binary and ternary fuel mixtures are bei...

Stabilization of linear time-invariant multi-inputmulti-output (LTI-MIMO) systems is presented distinctively and efficiently in this paper. The idea is to decouple the system state matrix depending on different inputs and outputs using the special canonical transformation proposed. Due to the decoupled form of the observer based controller system, it’s possible to use separate transformation for observer and controller design. Since the decoupled state matrix resembles the single-input-single-output (SISO) case, the generalized equation for the system is first obtained, and then it’s extended to the MIMO system. The computational complexity in getting the controller and observer gain matrix coefficients are further reduced due to the special form of gain matrices taken.

Highlights • Dupilumab can reduce the risk of severe asthma exacerbations. • FEV1 values were improved with dupilumab treated groups when compared to placebo-treated groups. • Safety outcomes of dupilumab and placebo treated groups were compared and showed greater prevalence of injection site reaction in dupulimab treated group. • Future studies need to be focused on the concerns like the use of dupilumab in vulnerable population, evaluation of long term use and comparison of efficacy with other biologics which may facilitate wider acceptance globally., Background Asthma affects millions of patients across the globe and also accounts for numerous mortalities every year. The current pharmacologic approach to the treatment of asthma includes the use of glucocorticoids and beta-agonists mainly. However, these conventional therapies have poor controllability of moderate-to-severe asthma and also produce several side effects on their long-term use. These limitations had led to the development of biologics targeting the mediators involved in T helper 2-inflammation associated with the pathogenesis of asthma such as interleukin (IL) 4, IL-5, and IL-13. dupilumab, a fully human monoclonal antibody, an IL-4 receptor alpha-antagonist targeting IL-13 and IL-4 has a potential role in treatment of moderate-to-severe asthma and was approved by the Food and Drug Administration on October 19, 2018. The dual-antagonistic action of dupilumab on IL-4 and IL-13 receptors renders it more efficient in asthma treatment. Objectives To review the efficacy and safety profile of dupilumab in the treatment of moderate-to-severe asthma. Methods Systematic search was performed via PubMed, Cochrane library, Embase, and ClinicalTrials.gov using the key words dupilumab, moderate-to-severe asthma, interleukin, IL-13, IL-4, and monoclonal antibody. Randomized controlled trials that compared between placebo and dupilumab in patients with uncontrolled asthma were included and observational studies were excluded in this review. Results The review of selected literature reveals that addition of dupilumab to conventional therapy improves forced expiratory volume in 1 second and reduces the risk of severe asthma exacerbations in patients. No significant differences in incidence of adverse drug reactions/adverse drug events were observed between dupilumab and placebo groups except higher rates of injection site reactions in the dupilumab group. Conclusions Concomitant use of dupilumab with long-acting beta agonists used in combination with inhaled corticosteroids, improves clinical outcomes and quality of life in patients with moderate to severe asthma. Although dupilumab has a promising role in treatment of patients with asthma, it is still in the emerging stage for its acceptance globally. Ongoing studies will help to determine dupilumab's long-term efficacy and safety for its future extensive use.

Increasing evidence suggests a role of inflammation during the pathogenesis of osteoarthritis (OA). The local and systemic inflammation was studied in 33 patients of different KL grades, grade2 (n = 11), grade3 (n = 6) and grade4 (n = 16). The levels of cytokines, adipokines and matrix metalloproteinases (MMPs) were measured in serum and synovial fluid (SF) by flow cytometry and ELISA, respectively. The frequency of T cells and CD161 expression was measured by flow cytometry. The levels of IL-1β, IL-6 and IL-10 were significantly higher in sera and SF of patients with OA as compared to healthy control's serum. Higher levels of MMP9 and leptin and lower levels of adiponectin were observed in SF as compared to serum. The MMP9 in SF and MMP13 levels in serum and SF decreased in KL grade 4 cases. In these patients, higher levels of leptin and lower levels of adiponectin were observed in SF versus patients of lower grades. There was increased infiltration of CD8+ T cells in SF of OA cases with decreased frequency in grade 4 cases. The expression of CD161 on T cells was significantly higher in SF than peripheral blood with significant upregulation in grade 4 patients. The CD161 expression had significant positive correlation with IL-17 in the serum of patients. The ROC curves of CD161 expression significantly distinguished grade 2 and grade 4 patients. Collectively, an elevated CD161 expression on T cells in circulation and synovial compartment clearly distinguished lower and higher grade patients warranting studies to assess its role as a contributing factor towards OA progression.

The sudden outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in Wuhan city, China, has resulted in a global pandemic, posing a major health concern worldwide. Despite multiple therapeutic interventions, no treatment has yet proven effective in treating COVID-19. Furthermore, the complicated virology of SARS-CoV-2 makes the process of identifying effective treatments, an arduous task. COVID-19, being affecting the upper and lower respiratory tract, is associated with consequent release of pro-inflammatory cytokines in which interleukin (IL)-6 receptor plays a key role. The elevated inflammatory cytokines resulting in a cytokine storm play a major role in the pathology of COVID-19. Siltuximab has become a keen interest for researchers because it is a chimeric, human-murine, immunoglobulin G monoclonal antibody that binds and neutralises human IL-6 with high affinity and specificity. In this article, we tried to evaluate why siltuximab is not a suitable option for treating novel coronavirus from the clinical study evidence.

In the present work, biofuels produced from agricultural waste have been proposed as a substitute for petroleum-based fuel. Biodiesel produced from waste vegetable oil has been used alongside hexanol in a reactivity controlled compression ignition engine. The waste vegetable oil biodiesel was prepared by trans-esterification and was directly injected inside the cylinder. Hexanol was injected into the port during early suction stroke. A modified 1-cylinder water-cooled diesel engine was used for the tests. The modified engine was tested at medium load and rated load for injection pressures of 400, 500 and 600 bar. The proportion of hexanol to waste vegetable oil biodiesel was also varied to find the optimal combination. The results were mapped and analyzed with diesel operation at similar conditions. A maximum increase of 1.5% in thermal efficiency was observed compared to Diesel. Oxides of nitrogen and smoke emissions reduced simultaneously for biodiesel-hexanol combinations compared to diesel. Injection pressure of 500 bar and hexanol proportion of 30% at medium load and 60% at rated load were found to be optimum concerning lowest emissions. This study proposes that waste vegetable oil biodiesel and hexanol combination in reactivity controlled compression ignition mode can be an effective replacement for conventional fossil fuel.

In this study, a compact kinetic model consisting of 588 reactions and 139 species is proposed for 1-Hexanol and used vegetable oil (UVO) biodiesel blend for simulating internal combustion (IC) engines. Suitable modifications were made to the pre-exponential factor to ascertain predictive performance comparable to the investigational results. This reduced reaction model was validated with experimental data from the published work for laminar flames speed, ignition delay and species mole fractions. The reduced mechanism and the experimental results are comparable within a factor of 1.3–2.5. A zero-dimensional single zone model was employed for simulating internal combustion engine conditions with the reduced mechanism using Cantera software and the results are analogous and as expected from the simulation study. The reduced reaction mechanism could be utilized by the researchers working on alternative fuels to simulate and study the combustion of used vegetable oil/1-Hexanol blend in an engine using computational fluid dynamics (CFD) modeling software.

Oral premalignant lesions (OPLs), such as leukoplakia, are at risk of malignant transformation to oral cancer. Clinicians can elect to biopsy OPLs and assess them for dysplasia, a marker of increased risk. However, it is challenging to decide which OPLs need a biopsy and to select a biopsy site. We developed a multimodal optical imaging system (MMIS) that fully integrates the acquisition, display, and analysis of macroscopic white-light (WL), autofluorescence (AF), and high-resolution microendoscopy (HRME) images to noninvasively evaluate OPLs. WL and AF images identify suspicious regions with high sensitivity, which are explored at higher resolution with the HRME to improve specificity. Key features include a heat map that delineates suspicious regions according to AF images, and real-time image analysis algorithms that predict pathologic diagnosis at imaged sites. Representative examples from ongoing studies of the MMIS demonstrate its ability to identify high-grade dysplasia in OPLs that are not clinically suspicious, and to avoid unnecessary biopsies of benign OPLs that are clinically suspicious. The MMIS successfully integrates optical imaging approaches (WL, AF, and HRME) at multiple scales for the noninvasive evaluation of OPLs.