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Abstract The alarming rise of pathogen antibiotic resistance presents a major global health challenge and demands a novel way to control the microbial infections. Simultaneously, nanotechnology has found numerous uses in electrical as well as electronic systems, including timing, filtering, power factor adaptation, and capacitors for energy storage. This work investigates the synthesis and characterization of a silver nanoparticle (AgNPs) utilizing Calotropis procera (CPL) leaf extract. The optimization of synthesis process and the reduction of nanoparticles (NPs) were validated by UV–visible spectroscopy. AgNPs' was exhaustively characterized for morphology, crystallinity, zeta-potential, and structural properties. The produced NPs demonstrated a wide range of characteristics, such as antioxidant, antidiabetic, antibacterial, and antifungal effects. Furthermore, remarkable electrochemical performance was indicated by the CPL-AgNPs electrode, which has mesoporous, clustered sphere-shaped particles onto a flexible stainless-steel substrate. This highlights the electrode's potential in energy storage applications. Copper monosulfide served as the anode and CPL-AgNPs as the cathode electrode in tested hybrid supercapacitor devices, which proved remarkable specific capacitances, high specific energy, and exceptionally high specific power. In order to address the twin challenges of antimicrobial resistance alongside advanced energy storage, this study provides a novel and thorough analysis of the basic electrochemistry as well biological properties of AgNPs, clarifying their potential storage of charges mechanisms and biomedical applications. Graphical abstract

Abstract Background The human skin, as the body’s largest organ, is particularly sensitive to many chemical mutagens and carcinogens encountered in daily life. Skin cancer has become a notable global health concern, partly due to increased exposure to environmental pollutants and UV rays. Various treatments are available to treat skin cancer. Imiquimod is approved for the treatment of actinic keratosis and basal cell carcinoma. The present investigation aimed to develop nanoemulsion-based gel with imiquimod (2.5% w/w) and carbopol ultrez 10 NF using a modified method to enhance the solubility, permeation, and therapeutic effectiveness of imiquimod to treat skin cancer. Combinations of rose oil and oleic acid, with Tween 20/Propylene glycol as Smix, were used in the formulation. The formulation underwent evaluation for parameters such as % drug content, in vitro drug diffusion studies, viscosity, skin irritation, in vitro cytotoxicity assay (MTT assay) and the DMBA/ croton oil skin cancer in vivo model. Results The formulation showed a minimum globule size of 118 nm, a zeta potential– 56.26 mV, a PDI of 0.378 and a drug content of 99.77%. In vitro drug release exhibited 45.00% of imiquimod release within 8 h, while approximately 34.32% release was found from the commercial cream. The imiquimod-loaded nanoemulsion-based gel showed significant cytotoxicity (p

Abstract Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer’s disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n = 388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology.

Introduction: The importance of feedback from medical students to improve the quality of teaching methods and their effectiveness has been extensively studied. However, there remains a need for further exploration of the feedback of medical students during their ENT clinical rotation. Therefore, this study aims to examine the feedback of Phase II medical students during their ENT clinical rotation in a tertiary care teaching hospital. In this study, we investigated the medical students' perceptions regarding the quality of the ENT clinical rotation program, including the methods of teaching, clinical exposure, and support provided by clinical supervisors. Methodology: This Descriptive Qualitative cross-sectional study was conducted among 142 phase II medical students using a Semi-structured Questionnaire. Results: Our findings suggest that although most of the students (~90%) were satisfied with the level of skill and clinical training provided during the rotation, 92% identified a gap between the clinical rotation and theory. This discrepancy can be addressed by adding a few hours of ENT theory sessions to the Phase II curriculum, which can run simultaneously with the clinical rotation. The students also felt that attending clinical sessions regularly increases their confidence. When asked for ideas to improve their participation, most of the responses were to increase the exposure of students to cases and increase OR visits and clinical discussions. Conclusion: This cross-sectional survey helped us understand the mindset of the students attending the clinical rotation and thereby wishes to change our approach, making sure every student who attends the ENT clinical rotation postings is heard and attended to.

Abstract Objective The study aimed to investigate otolaryngologists' knowledge, trust, acceptance, and concerns with clinical applications of artificial intelligence (AI). Methods This study used mixed methods with survey and semistructured interviews. Survey was e‐mailed to American Rhinologic Society members, of which a volunteer sample of 86 members responded. Nineteen otolaryngologists were purposefully recruited and interviewed until thematic saturation was achieved. Results Seventy‐six respondents (10% response rate) completed the majority of the survey: 49% worked in academic settings and 43% completed residency 10 or fewer years ago. Of 19 interviewees, 58% worked in academic settings, and 47% completed residency 10 or fewer years ago. Familiarity: Only 8% of survey respondents reported having AI training in residency, although 72% had familiarity with general AI concepts; 0 interviewees had personal experience with AI in clinical settings. Expected uses: Of the surveyed otolaryngologists, 82% would use an AI‐based clinical decision aid and 74% were comfortable with AI proposing treatment recommendations. However, only 44% of participants would trust AI to identify malignancy and 53% to interpret radiographic images. Interviewees trusted AI for simple tasks, such as labeling septal deviation, more than complex ones, such as identifying tumors. Factors influencing AI adoption: 89% of survey participants would use AI if it improved patient satisfaction, 78% would be willing to use AI if experts and studies validated the technologies, and 73% would only use AI if it increased efficiency. Sixty‐one percent of survey respondents expected AI incorporation into clinical practice within 5 years. Interviewees emphasized that AI adoption depends on its similarity to their clinical judgment and to expert opinion. Concerns included nuanced or complex cases, poor design or accuracy, and the personal nature of physician‐patient relationships. Conclusion Few physicians have experience with AI technologies but expect rapid adoption in the clinic, highlighting the urgent need for clinical education and research. Otolaryngologists are most receptive to AI “augmenting” physician expertise and administrative capacity, with respect for physician autonomy and maintaining relationships with patients. Level of Evidence Level VI, descriptive or qualitative study.

This study investigates Ficus Macrocarpa tree bark fibers (FMB) as a sustainable alternative reinforcement for polymer composites. The Industrial Revolution marked the evolution of polymer composites with synthetic material reinforcement, leading to environmental concerns. Natural fibers have recently gained prominence as efficient alternatives for polymer composites. Despite numerous natural fibers being considered, ensuring a sustainable raw material source remains crucial. In this study, fibers were extracted from FMB and subjected to alkali treatment to evaluate their impact on physical, chemical, and thermal properties. Initially, the extracted fibers measured 253.80 ± 15 μm in diameter, reduced to 223.27 ± 12 μm post-alkali treatment. Chemical analysis showed an increase in cellulose content to 59.7 wt%, a 23.34 % improvement over untreated fibers (48.4 wt%). The crystalline index for untreated and treated fibers measured 80.20 % and 84.75 %, respectively, with no noticeable changes in the cellulose phase. Additionally, the crystalline size increased to 3.21 nm. Thermogravimetric analysis demonstrated enhanced stability of treated fibers up to 378.87 °C, while the kinetic activation energy remained constant at 64.76 kJ/mol for both the treated and the untreated fibers. The alkali treatment further improved surface roughness to 39.26, confirmed by scanning electron microscopic images. These findings highlight the potential of cellulose fibers from Ficus Macrocarpa bark as a sustainable and environmentally friendly replacement for synthetic fibers in polymer composites. The enhanced physical properties and excellent thermal stability make them a promising choice for eco-conscious materials.

Antifungal drugs target specific components or processes within fungal cells to prevent or eliminate their growth. Various antifungal targets exist, including the cell membrane disrupted by drugs such as azoles and polyenes. The cell wall is also a common target, with drugs such as echinocandins inhibiting enzymes that synthesize or disrupt the structure. Ergosterol synthesis is another target that can be inhibited by drugs such as azoles. Drugs such as Fluconazole and flucytosine that target the synthesis of nucleic acids are essential for fungal cell growth and replication. Fungal mitochondria, vital for energy production, also target some antifungal drugs, such as griseofulvin. It's important to note that specific antifungal targets and their mechanisms of action vary based on the fungus being treated and the specific drug being used. In this review, the critical analysis of various research carried out from 2010, and the targets identified were studied and elaborated comprehensively. The review also highlights ongoing clinical trials and patent information on antifungal drugs. It provides narrative data for all the researchers working on developing antifungal drugs.

Physical and psychological stress has an inverse relation with male libido and sperm quality. The present study investigates the potential fertility-enhancing properties of Desmodium gangeticum (DG) root extracts in male Wister rats subjected to immobilization-induced stress (SIMB). DG roots were extracted using n-hexane (HEDG), chloroform (CEDG), and water (AEDG). In the pilot study, aphrodisiac protentional was investigated at two doses (125 and 250 mg kg−1) of each extract. In the main study, the HEDG and AEDG at 125 and 250 mg kg−1 were challenged for the stress by immobilization (SIMB), for 6 h daily over 28 days. Parameters assessed included aphrodisiac effects, gonadosomatic index (GSI), semen quality, sperm quantity, fructose content, serum hormonal levels, testicular oxidative stress, and testicular histopathology. Additional in silico studies, including the lipid solubility index, molecular docking, molecular dynamics, and SymMap studies were conducted for validation. HEDG demonstrated significant aphrodisiac activity, improved – GSI, sperm quality and quantity, and fructose content, serum testosterone levels, histological changes induced by SIMB in the testes. Swiss ADME studies indicated Gangetin (a pterocarpan) had a high brain permeation index (4.81), a superior docking score (-8.22), and higher glide energy (-42.60), compared with tadalafil (-7.17). The 'Lig fit Prot' plot in molecular dynamics simulations revealed a strong alignment between Gangetin and phosphodiesterase type 5 (PDE5). HEDG exerts aphrodisiac effects by increasing blood testosterone levels and affecting PDE5 activity. The protective effects on spermatozoa-related parameters and testicular histological changes are attributed to the antioxidant and anti-inflammatory properties, of pterocarpan (gangetin).

The internet, like automated tools, has grown to better our daily lives. Interacting IoT products and cyber-physical systems. Generative Adversarial Network's (GANs') generator and discriminator may have different inputs, allowing feedback in supervised models. AI systems use neural networks, and adversarial networks analyse neural network feedback. Cyber-physical production systems (CPPS) herald intelligent manufacturing . CPPS may launch cross-domain attacks since the virtual and real worlds are interwoven. This project addresses enhanced Cyber-Physical System(CPS) feedback structure for Denial-of-Service (DoS) defence . Comparing sensor-controller and controller-to-actuator DoS attack channels shows a swapping system modelling solution for the CPS's complex response feedback. Because of the differential in bandwidth between the two channels and the suspects' limited energy, one person can only launch so many DoS assaults. DoS attacks are old and widespread. Create a layered switching paradigm that employs packet-based transfer techniques to prevent assaults. The discriminator's probability may be used to assess whether feedback samples came from real or fictional data. Cognitive feedback can assess GA feedback data.

Biogenic nanoparticle production is in demand as it is secure, has great promise, and is environmental friendly. This study aimed at green synthesis, characterization, and evaluation of Terminalia arjuna selenium nanoparticles (TA-SeNPs) for their antioxidant, antibacterial, anticancer activities, and their incorporation in gel for biomedical applications. The bio-reduction attributes of the T. arjuna (TA) bark extract were utilized to fabricate selenium nanoparticles. The TA bark extract is abundant in phenolics (193.63 ± 1.61 mg gallic acid equivalents/g), flavonoids (88.23 ± 0.39 mg quercetin equivalents/g), and tannins (109.46 ± 1.16 mg catechin equivalents/g), which perform as effective capping and stabilizing agents, thus enabling the fabrication of stable SeNPs. The fabrication of TA-SeNPs was corroborated by UV–visible spectra, which exhibited surface plasmon resonance at 291 nm. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) demonstrated nano-sized spherical TA-SeNPs with an average diameter ranging from 100 to 150 nm. Zeta potential analysis revealed that TA-SeNPs were negatively charged (−26.1 mV). X-ray diffraction presented amorphous TA-SeNPs with a quantification of 82.36 ± 10.2 μg/mL resulting from ICP-AES. The IC50 45.18 ± 0.11 μg/mL for the DPPH assay and 66.51% reducing power capacity values indicated that the TA-SeNPs possessed excellent radical scavenging efficacy. Moreover, the TA-SeNPs exhibited a broad spectrum of antimicrobial activity against potential pathogens. Additionally, the TA-SeNPs exhibited a dose-dependent cytotoxic effect on the MCF-7 breast cancer cell line, with an IC50 of 23.41 μg/mL. Furthermore, the TA-SeNP-incorporated gel showed excellent spreadability, extrudability, and consistency with retention of antimicrobial properties and hydrophilic contact angle. As an outcome, TA-SeNPs offer the possibility of the formulation and growth of sustainably designed green SeNPs that can be produced, conserved, and marketed securely across the globe.

BACKGROUND: India suffers a quarter of the global burden of cervical cancer (CC) but is controllable by taking some precautions. The major issue is the low amount of participation among women in screening and vaccination for disease. The objective of the research is to evaluate knowledge, attitude, and practice (KAP) regarding CC among college going students residing in the Rayalaseema region of Andhra Pradesh—India. MATERIAL AND METHODS: A cross-sectional study was conducted on a total of 380 subjects whose ages ranged from 15 to 25 and older. The questionnaires were circulated through google forms. The socio-demographic variables and KAP levels are represented by descriptive statistics. The Chi-square test is used to determine the relationship between sociodemographic factors and KAP levels. RESULTS: Among 380 subjects, 172 (54.7%) are aware of CC, 71% have poor knowledge, and 20% have good knowledge about CC. More than three-fourths of women 374 (98.4%) are not having regular practice towards CC. CONCLUSION: The awareness about CC is very low in the population, so prevention of CC relies on routine screening, proper vaccination, and treatment. Awareness programs and promoting knowledge about cervical health in social media are required.

Abstract Wearable data is a rich source of information that can provide a deeper understanding of links between human behaviors and human health. Existing modelling approaches use wearable data summarized at subject level via scalar summaries in regression, temporal (time-of-day) curves in functional data analysis (FDA), and distributions in distributional data analysis (DDA). We propose to capture temporally local distributional information in wearable data using subject-specific time-by-distribution (TD) data objects. Specifically, we develop scalar on time-by-distribution regression (SOTDR) to model associations between scalar response of interest such as health outcomes or disease status and TD predictors. Additionally, we show that TD data objects can be parsimoniously represented via a collection of time-varying L-moments that capture distributional changes over the time-of-day. The proposed method is applied to the accelerometry study of mild Alzheimer’s disease (AD). We found that mild AD is significantly associated with reduced upper quantile levels of physical activity, particularly during morning hours. In-sample cross validation demonstrated that TD predictors attain much stronger associations with clinical cognitive scales of attention, verbal memory, and executive function when compared to predictors summarized via scalar total activity counts, temporal functional curves, and quantile functions. Taken together, the present results suggest that SOTDR analysis provides novel insights into cognitive function and AD.

Background Antagonists to the P2X purinergic receptors on airway sensory nerves relieve refractory or unexplained chronic cough (RCC/UCC) but can evoke unwanted dysgeusias because the gustatory nerves innervating taste buds express this same family of receptors. However, the subunit composition of the P2X receptors in these systems may differ, with implications for pharmacological intervention of RCC/UCC. In most species, the extrapulmonary airway nerves involved in cough predominantly express P2X3 subunits that form homotrimeric P2X3 receptors. In contrast, most sensory nerves innervating taste buds in mice express both P2X2 and P2X3 subunits, so the majority of receptors in that system are likely P2X2/P2X3 heteromers. Methods Since neural P2X subunit composition can differ across species, we used immunohistochemistry to test whether taste nerves in humans and rhesus macaque monkeys express both P2X2 and P2X3 as in mice. Results In taste bud samples of fungiform papillae and larynx from humans and monkeys, all taste bud samples exhibited P2X3+ nerve fibres, but the majority lacked substantial P2X2+. Of the 35 human subjects, only four (one laryngeal and three fungiform) showed strong P2X2 immunoreactivity in taste nerves; none of the rhesus monkey samples showed immunoreactivity for P2X2. Conclusions These findings suggest that for most humans, unlike mice, taste buds are innervated by nerve fibres predominantly expressing only P2X3 homomeric receptors and not P2X2/P2X3 heteromers. Thus, antagonists specific for P2X3 homomeric receptors might not be spared from affecting taste function in RCC/UCC patients.

In this paper, we explore Blockchain technology can be used to build a reliable decentralised authentication system. High security for the bioacoustics signal authentication mechanism is guaranteed by using an optimised number of secured features from the bioacoustics signal rather than conventional biometric features for authentication, and by utilising a blockchain model to improve the robustness of multiple checks on the data. It allows for trustworthy authentication and the tracking of terminal activity. Then, light weighted cryptography (LWC) is developed to offer protection at each edge node and terminal. Finally, the belief propagation (BP) algorithm for retraining the features of the bioacoustics signal serves as the foundation for the catching method. It improves hit ratio while decreasing delay time. The experimental setup uses the bioacoustics signals for authentication instead of conventional biometric features, and the use of a blockchain model for data transparency improves the efficiency of multiple checks. When this happens, privacy and safety are both boosted.

(1) Objective: Systemic lupus erythematosus (SLE) is a complex disease involving immune dysregulation, episodic flares, and poor quality of life (QOL). For a decentralized digital study of SLE patients, machine learning was used to assess patient-reported outcomes (PROs), QOL, and biometric data for predicting possible disease flares. (2) Methods: Participants were recruited from the LupusCorner online community. Adults self-reporting an SLE diagnosis were consented and given a mobile application to record patient profile (PP), PRO, and QOL metrics, and enlisted participants received smartwatches for digital biometric monitoring. The resulting data were profiled using feature selection and classification algorithms. (3) Results: 550 participants completed digital surveys, 144 (26%) agreed to wear smartwatches, and medical records (MRs) were obtained for 68. Mining of PP, PRO, QOL, and biometric data yielded a 26-feature model for classifying participants according to MR-identified disease flare risk. ROC curves significantly distinguished true from false positives (ten-fold cross-validation: p < 0.00023; five-fold: p < 0.00022). A 25-feature Bayesian model enabled time-variant prediction of participant-reported possible flares (P(true) > 0.85, p < 0.001; P(nonflare) > 0.83, p < 0.0001). (4) Conclusions: Regular profiling of patient well-being and biometric activity may support proactive screening for circumstances warranting clinical assessment.

Introduction: Salivary gland tumors (SGTs) are relatively uncommon and show a wide variety of morphological heterogeneities. The incidence of SGTs is said to be affected by geographical and racial factors. Histopathological diagnosis plays a major role in the diagnosis of these neoplasms. Objectives: This study investigated the incidence of SGTs and histopathological features of various SGTs, aimed at knowing the epidemiological pattern of these tumors and comparing the results of our study with other studies of SGTs in the literature. Materials and Methods: A retrospective study was conducted on SGTs at the Pathology Department of the Government Medical College and Hospital for a period of 5 years. Clinical and demographic data were documented and analyzed concerning histopathologic type. Results: A total of 86 SGTs were identified, 65.12% of which were classified as benign and 34.88% as malignant. Most tumors occurred in the parotid gland (59.14%). Pleomorphic adenoma (PA) was the most common tumor (56.98%), followed by mucoepidermoid carcinoma (MEC) (17.44%). The tumors occurred more often in men (51.16%) than in women (48.84%). Conclusion: SGTs exhibit broad morphological heterogeneity and these tumors are rare. The parotid gland is the most common location, and PA is the most frequent benign tumor. MEC followed by adenoid cystic carcinoma is the most common malignancy of the salivary gland.

The main objective of this review is to provide a comprehensive overview of the current evidence regarding the use of chitosan-based hydrogels to manage skin infections. Chitosan, a naturally occurring polysaccharide derived from chitin, possesses inherent antimicrobial properties, making it a promising candidate for treating various dermal infections. This review follows a systematic approach to analyze relevant studies that have investigated the effectiveness of chitosan-based hydrogels in the context of dermal infections. By examining the available evidence, this review aims to evaluate these hydrogels’ overall efficacy, safety, and potential applications for managing dermal infections. This review’s primary focus is to gather and analyze data from different recent studies about chitosan-based hydrogels combating dermal infections; this includes assessing their ability to inhibit the growth of microorganisms and reduce infection-related symptoms. Furthermore, this review also considers the safety profile of chitosan-based hydrogels, examining any potential adverse effects associated with their use. This evaluation is crucial to ensure that these hydrogels can be safely utilized in the management of dermal infections without causing harm to patients. The review aims to provide healthcare professionals and researchers with a comprehensive understanding of the current evidence regarding the use of chitosan-based hydrogels for dermal infection management. The findings from this review can contribute to informed decision-making and the development of potential treatment strategies in this field.

Abstract The role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

Abstract Social determinants of health (SDoH) can impact the vulnerable pulmonary arterial hypertension (PAH) population, especially during the COVID‐19 pandemic. Providers' understanding of SDoH at the point of care and their impact is unknown. We conducted semi‐structured virtual interviews with US clinicians at 17 pulmonary hypertension (PH) centers and one patient advocate from the Pulmonary Hypertension Association. We sought participants' perspective on SDoH in PAH and their impact. Transcripts were developed and analyzed for key themes to assess potential policy implications. Participants served a large PAH population and demonstrated high awareness of SDoH and its impact on treatment and outcomes. They reported that patients' SDoH, including socioeconomic status, health insurance, access to health care, education levels, health literacy, employment status, and insecurities associated with housing, food, transportation, and family support, impacted health and well‐being. COVID‐19‐related social isolation, mental health, and substance abuse contributed to significant inequities in care provision and outcomes. While telemedicine helped clinicians manage patients remotely during the pandemic, there was a concern for patients with limited access to this medium. Participants reported no formal screening for SDoH at the point of care. With the recognition and the desire to act upon health inequities associated with SDoH, participants felt that it was vital for their centers to have a dedicated PH social worker and support staff to optimize care and outcomes. An approach that integrates SDoH in PAH care management, streamlined through institutional policy, could address health disparities leading to improved healthcare access, outcomes, and quality of care.

Abstract Background Understanding viral infection of the olfactory epithelium is essential because the olfactory nerve is an important route of entry for viruses to the central nervous system. Specialized chemosensory epithelial cells that express the transient receptor potential cation channel subfamily M member 5 (TRPM5) are found throughout the airways and intestinal epithelium and are involved in responses to viral infection. Results Herein we performed deep transcriptional profiling of olfactory epithelial cells sorted by flow cytometry based on the expression of mCherry as a marker for olfactory sensory neurons and for eGFP in OMP-H2B::mCherry/TRPM5-eGFP transgenic mice (Mus musculus). We find profuse expression of transcripts involved in inflammation, immunity and viral infection in TRPM5-expressing microvillous cells compared to olfactory sensory neurons. Conclusion Our study provides new insights into a potential role for TRPM5-expressing microvillous cells in viral infection of the olfactory epithelium. We find that, as found for solitary chemosensory cells (SCCs) and brush cells in the airway epithelium, and for tuft cells in the intestine, the transcriptome of TRPM5-expressing microvillous cells indicates that they are likely involved in the inflammatory response elicited by viral infection of the olfactory epithelium.

In the 21st century, melanoma and non-melanoma skin cancers have become an epidemic outbreak worldwide. Therefore, the exploration of all potential preventative and therapeutic measures based on either physical or bio-chemical mechanisms is essential via understanding precise pathophysiological pathways (Mitogen-activated protein kinase, Phosphatidylinositol 3-kinase Pathway, and Notch signaling pathway) and other aspects of such skin malignancies. Nano-gel, a three-dimensional polymeric cross-linked porous hydrogel having a diameter of 20–200 nm, possesses dual properties of both hydrogel and nanoparticle. The capacity of high drug entrapment efficiency with greater thermodynamic stability, remarkable solubilization potential, and swelling behavior of nano-gel becomes a promising candidate as a targeted drug delivery system in the treatment of skin cancer. Nano-gel can be either synthetically or architectonically modified for responding to either internal or external stimuli, including radiation, ultrasound, enzyme, magnetic, pH, temperature, and oxidation-reduction to achieve controlled release of pharmaceuticals and several bio-active molecules such as proteins, peptides, genes via amplifying drug aggregation in the active targeted tissue and reducing adverse pharmacological effects. Several drugs, such as anti-neoplastic biomolecules having short biological half-lives and prompt enzyme degradability capacity, must be appropriate for administration employing either chemically bridged or physically constructed nano-gel frameworks. The comprehensive review summarizes the advancement in the preparation and characterization methods of targeted nano-gel with enhanced pharmacological potential and preserved intracellular safety limits for the mitigation of skin malignancies with a special emphasize on skin cancer inducing pathophysiological pathways and prospective research opportunities for skin malignancy targeted nano-gels.

Background: Limited information is available on the aetiology and semen profiles of male infertility in Indian population. Aim: The aim of this study is to study the clinical and semen characteristics of men attending the infertility clinic and also to understand the impact of World Health Organization (WHO) 2010 reference values on the diagnosis of male infertility. Setting and Design: A retrospective study evaluating the medical case records (January 2005 to December 2015, [n = 1906]) of men attending infertility clinic in Mumbai, India. Materials and Methods: The aetiology was classified based on the andrology evaluation and other investigations. Semen profiles were compared during the years 2005–2010 and 2011–2015 using WHO 1999 and WHO 2010 criteria, respectively. Statistical Analysis: The Chi-square and Mann–Whitney U tests were performed using Open Source Epidemiological software and Social science calculators. Results: The aetiology of male infertility was determined in 62% of the men; while the cause remained undetermined in 38%. Varicocele (25%), urogenital infections (10%), sexual dysfunctions (8%) and vas aplasia (8%) were identified as major aetiologies in our cohort. Men with sexual dysfunctions and vas aplasia were significantly higher during the years 2011–2015 as compared to 2005–2010. Men having normozoospermia (10%) and azoospermia (3%) were increased, whereas those having oligoasthenozoospermia (17%) were reduced in 2011–2015 as compared to 2005–2010. According to WHO 1999 criteria , 12-15% of men showed abnormal semen profiles. The semen parameters of these men became normal on using WHO 2010 reference values. Conclusions: Varicocele is the most common aetiology in infertile men. Idiopathic infertility was seen in a higher proportion among the infertile men.

Abstract Treatment for pulmonary arterial hypertension (PAH) has evolved over the past decade, including approval of new medications and growing evidence to support earlier use of combination therapy. Despite these changes, few studies have assessed real‐world treatment patterns, healthcare resource utilization (HCRU), and costs among people with PAH using recent data. We conducted a retrospective cohort study using administrative claims from the HealthCore Integrated Research Database®. Adult members with claims for a PAH diagnosis, right heart catheterization, and who initiated PAH treatment (index date) between October 1, 2015 and November 30, 2020 were identified. Members had to be continuously enrolled in the health plan for 6 months before the index date (baseline) and ≥30 days after. Treatment patterns, HCRU, and costs were described. A total of 843 members with PAH (mean age 62.3 years, 64.2% female) were included. Only 21.0% of members received combination therapy as their first‐line treatment, while most members (54.6%) received combination therapy as second‐line treatment. All‐cause HCRU remained high after treatment initiation with 58.0% of members having ≥1 hospitalization and 41.3% with ≥1 emergency room visit. Total all‐cause costs declined from $15,117 per patient per month at baseline to $14,201 after treatment initiation, with decreased medical costs ($14,208 vs. $6,349) more than offsetting increased pharmacy costs ($909 vs. $7,852). In summary, despite growing evidence supporting combination therapy, most members with PAH initiated treatment with monotherapy. Total costs decreased following treatment, driven by a reduction in medical costs even with increases in pharmacy costs.

Background: In prior phase 3, randomized, placebo-controlled trials, fluticasone propionate exhalation delivery system (EDSFLU) over 24 weeks showed significant reduction in total polyp score compared with EDS-placebo. The goal of this study was to observe nasal endoscopy improvement(s) along with patient-reported symptoms associated with EDS-FLU administration over 24 weeks. Methods: This open-label, multicenter study enrolled adults with bilateral nasal polyp grade of ≥3 (out of 6), 22-Item Sino-Nasal Outcome Test (SNOT-22) scores ≥20, and previous sinus surgery. All patients received EDS-FLU 186 μg BID for 24 weeks. Nasal endoscopy was performed, and disease-specific quality of life and sense of smell were assessed with SNOT-22 and “Sniffin’ Sticks” at baseline, 3 months, and 6 months. An independent reviewer evaluated videos and performed blinded polyp grading and Lund-Kennedy (LK) assessments. Results: Eleven patients were enrolled. At baseline, mean polyp grade was 3.1/6. SNOT-22 scores were 48.8, and Sniffin’ Sticks measurements were 11.8/48. A clinically meaningful reduction in SNOT-22 was noted at 24 weeks. Olfaction improved by 4.7 points. The mean polyp grade was reduced from 3.1 to 2.4 at week 24. LK edema scores were reduced by 2.2. Conclusion: EDS-FLU 186 μg BID given over 24 weeks resulted in clinically meaningful reduction in SNOT-22 scores and polyp grade improvement in most subjects. Endoscopic documentation showed reduced inflammation and edema not adequately captured with polyp-scoring methodology.

Background: Identification of HER2 protein overexpression and/or amplification of the HER2 gene are required to qualify breast cancer patients for HER2 targeted therapies. In situ hybridization (ISH) assays that identify HER2 gene amplification function as a stand-alone test for determination of HER2 status and rely on the manual quantification of the number of HER2 genes and copies of chromosome 17 to determine HER2 amplification. Methods: To assist pathologists, we have developed the uPath HER2 Dual ISH Image Analysis for Breast (uPath HER2 DISH IA) algorithm, as an adjunctive aid in the determination of HER2 gene status in breast cancer specimens. The objective of this study was to compare uPath HER2 DISH image analysis vs manual read scoring of VENTANA HER2 DISH-stained breast carcinoma specimens with ground truth (GT) gene status as the reference. Three reader pathologists reviewed 220, formalin-fixed, paraffin-embedded (FFPE) breast cancer cases by both manual and uPath HER2 DISH IA methods. Scoring results from manual read (MR) and computer-assisted scores (image analysis, IA) were compared against the GT gene status generated by consensus of a panel of pathologists. The differences in agreement rates of HER2 gene status between manual, computer-assisted, and GT gene status were determined. Results: The positive percent agreement (PPA) and negative percent agreement (NPA) rates for image analysis (IA) vs GT were 97.2% (95% confidence interval [CI]: 95.0, 99.3) and 94.3% (95% CI: 90.8, 97.3) respectively. Comparison of agreement rates showed that the lower bounds of the 95% CIs for the difference of PPA and NPA for IA vs MR were –0.9% and –6.2%, respectively. Further, inter- and intra-reader agreement rates in the IA method were observed with point estimates of at least 96.7%. Conclusions: Overall, our data show that the uPath HER2 DISH IA is non-inferior to manual scoring and supports its use as an aid for pathologists in routine diagnosis of breast cancer.

Chronic rhinosinusitis (CRS) is a clinical syndrome defined by symptoms including nasal congestion, facial pain and pressure, anosmia, and rhinorrhea lasting more than 12 weeks. Several mechanistically distinct processes lead to the development of clinical symptoms in CRS including innate immune dysfunction, dysregulated eicosanoid metabolism and perturbations in host-microbiome interactions [1]. We developed a database comprised of patient demographic information, lipid mediator metabolomic profiles, and 16S bacterial rRNA gene sequence data from 66 patients undergoing endoscopic sinus surgery. Briefly, ethmoid sinus tissue and middle meatal swabs were collected from patients, including non-CRS controls, CRS with polyps (CRSwNP), and CRS without polyps (CRSsNP). Lipid mediator pathways from arachidonic acid (AA) and docosahexanoic acid (DHA) were analyzed by liquid chromatography/tandem mass spectrometry. Bacterial taxa were profiled in parallel by 16S rRNA gene sequencing. This database provides a useful compendium of AA/DHA metabolomic profiles and associated bacterial microbiota in patients with varying disease subtypes, demographics, and risk factors/comorbidities.

BackgroundWhile Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis.Methods and findingsWe used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = 4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings.ConclusionsWe combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.

Abstract Introduction Few studies have explored whether gait measured continuously within a community setting can identify individuals with Alzheimer's disease (AD). This study tests the feasibility of this method to identify individuals at the earliest stage of AD. Methods Mild AD (n = 38) and cognitively normal control (CNC; n = 48) participants from the University of Kansas Alzheimer's Disease Center Registry wore a GT3x+ accelerometer continuously for 7 days to assess gait. Penalized logistic regression with repeated five‐fold cross‐validation followed by adjusted logistic regression was used to identify gait metrics with the highest predictive performance in discriminating mild AD from CNC. Results Variability in step velocity and cadence had the highest predictive utility in identifying individuals with mild AD. Metrics were also associated with cognitive domains impacted in early AD. Discussion Continuous gait monitoring may be a scalable method to identify individuals at‐risk for developing dementia within large, population‐based studies.

[This corrects the article DOI: 10.1371/journal.pmed.1003012.].

BackgroundThere is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways.Methods and findingsWe first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators.ConclusionsIn this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.

Abstract Drug discovery for disease‐modifying therapies for Alzheimer's disease and related dementias (ADRD) based on the traditional paradigm of experimental animal models has been disappointing. We describe the rationale and design of the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study, an innovative multidisciplinary alternative to traditional drug discovery. First, we use a systems biology perspective in the "hypothesis generation" phase to identify metabolic abnormalities that may either precede or interact with the accumulation of ADRD neuropathology, accelerating the expression of clinical symptoms of the disease. Second, in the "hypothesis refinement" phase we propose use of large patient cohorts to test whether drugs approved for other indications that also target metabolic drivers of ADRD pathogenesis might alter the trajectory of the disease. We emphasize key challenges in population‐based pharmacoepidemiologic studies aimed at quantifying the association between medication use and ADRD onset and outline robust causal inference principles to safeguard against common pitfalls. Candidate ADRD treatments emerging from this approach will hold promise as plausible disease‐modifying therapies for evaluation in randomized controlled trials.

Previous genetic studies on susceptibility to otitis media and airway infections have focused on immune pathways acting within the local mucosal epithelium, and outside of allergic rhinitis and asthma, limited studies exist on the overlaps at the gene, pathway or network level between the upper and lower airways. In this report, we compared [1] pathways identified from network analysis using genes derived from published genome-wide family-based and association studies for otitis media, sinusitis, and lung phenotypes, to [2] pathways identified using differentially expressed genes from RNA-sequence data from lower airway, sinus, and middle ear tissues, in particular cholesteatoma tissue compared to middle ear mucosa. For otitis media, a large number of genes (n = 1,806) were identified as differentially expressed between cholesteatoma and middle ear mucosa, which in turn led to the identification of 68 pathways that are enriched in cholesteatoma. Two differentially expressed genes CR1 and SAA1 overlap in middle ear, sinus, and lower airway samples and are potentially novel genes for otitis media susceptibility. In addition, 56 genes were differentially expressed in both tissues from the middle ear and either sinus or lower airways. Pathways that are common in upper and lower airway diseases, whether from published DNA studies or from our RNA-sequencing analyses, include chromatin organization/remodeling, endocytosis, immune system process, protein folding, and viral process. Taken together, our findings from genetic susceptibility and differential tissue expression studies support the hypothesis that the unified airway theory wherein the upper and lower respiratory tracts act as an integrated unit also applies to infectious and nonallergic airway epithelial disease. Our results may be used as reference for identification of genes or pathways that are relevant to upper and lower airways, whether common across sites, or unique to each disease.

The g-factor and the static quadrupole moment of a magnetic rotational band head 212− at 2121 keV in 131La have been determined by means of the time-differential perturbed angular distribution technique. The measured value of the g-factor, +1.060(4), is in agreement with the theoretical value for a three quasi-proton, π3{112−[505]⊗52+[422]⊗52+[413]} Nilsson configuration assignment. The observed spectroscopic quadrupole moment ratio, Qs(212−,131La)Qs(192−,137La)=0.457(4), supports the collective oblate shape (γ∼−60°) with quadrupole deformation β2

(1) Background: As of 13 December 2020, Afghanistan reported around 48,952 confirmed COVID-19 cases and 1960 deaths. Lack of knowledge and perceptions among healthcare workers (HCWs) can pose challenges to disease control. Therefore, targeted, timely assessment of knowledge and perceptions are needed to address practices that might hinder efforts to stop the spreading of COVID-19 in Afghanistan. This study aimed to assess COVID-19-related knowledge, perceptions, and risk prevention practices (KPP) among frontline HCWs in Afghanistan; (2) Methods: A cross-sectional study was conducted with the support of field teams who were deployed in Afghanistan, surveyed from 14 to 22 April 2020 in eight provinces in Afghanistan with varying cumulative incidence of COVID-19 cases. A 28-item KPP survey instrument was adapted from other internationally validated questionnaires related to COVID-19. (3) Results: The survey was conducted among 213 frontline HCWs engaged in screening and treating COVID-19 patients. Survey results indicated that basic awareness of COVID-19 was 100% across all the participants. Knowledge and understanding of COVID-19 transmission, symptoms, incubation period and complications associated with COVID-19 are comprehensive and high (>90%), except available treatment for COVID-19 (84%). HCWs’ perceptions towards the prevention and control of COVID-19 were positive. However, only 63% believed that the use of N-95 face masks and disposable and fluid-resistant gowns (76%) could prevent COVID-19 transmission. This survey showed high knowledge and positive perception (72%), and only 48% of frontline HCWs had shown risk prevention practices. Addressing their perceptions and placing additional focus on practices across all health facilities is recommended as a preparedness measure.

Accelerator Mass Spectrometry is a technique commonly used to approach low concentrations of certain long half-life radioisotopes. The most important contribution of the technique is the accurate measure of organic sample ages, by separating masses 12,13 and 14 in the case of carbon allocated in such samples. However, the reach of AMS could cover many other scientific scopes, since it can give us a precise measure of a very small concentration of a radioisotope. On this direction, AMS can be used to approach reactions of interest for astrophysics, if we spot an specific radioisotope which concentration can be measure with AMS. Starting with this, we have selected specific reactions involving 14C, 10Be and 26Al, produced with slow neutrons from a reactor and positive ions at an accelerator. The main idea is to produce a particular reaction and later to measure the radioisotopic concentration using AMS. In this study our first results for 14C and 10Be nuclei produced with neutrons, and the preliminary results for 26Al nuclei produced with deuterium are shown.

Rapid lifestyle and dietary changes have contributed to a rise in the global prevalence of metabolic syndrome (MetS), which presents a potential healthcare crisis, owing to its association with an increased burden of multiple cardiovascular and neurological diseases. Prior work has identified the role that genetic, lifestyle, and environmental factors can play in the prevalence of MetS. Metabolomics is an important tool to study alterations in biochemical pathways intrinsic to the pathophysiology of MetS. We undertook a metabolomic study of MetS in serum samples from two ethnically distinct, well-characterized cohorts—the Baltimore Longitudinal Study of Aging (BLSA) from the U.S. and the Tsuruoka Metabolomics Cohort Study (TMCS) from Japan. We used multivariate logistic regression to identify metabolites that were associated with MetS in both cohorts. Among the top 25 most significant (lowest p-value) metabolite associations with MetS in each cohort, we identified 18 metabolites that were shared between TMCS and BLSA, the majority of which were classified as amino acids. These associations implicate multiple biochemical pathways in MetS, including branched-chain amino acid metabolism, glutathione production, aromatic amino acid metabolism, gluconeogenesis, and the tricarboxylic acid cycle. Our results suggest that fundamental alterations in amino acid metabolism may be central features of MetS.

Metabolic syndrome (MetS) affects an increasing number of older adults worldwide. Cross-cultural comparisons can provide insight into how factors, including genetic, environmental, and lifestyle, may influence MetS prevalence. Metabolomics, which measures the biochemical products of cell processes, can be used to enhance a mechanistic understanding of how biological factors influence metabolic outcomes. In this study we examined associations between serum metabolite concentrations, representing a range of biochemical pathways and metabolic syndrome in two older adult cohorts: The Tsuruoka Metabolomics Cohort Study (TMCS) from Japan (n = 104) and the Baltimore Longitudinal Study of Aging (BLSA) from the United States (n = 146). We used logistic regression to model associations between MetS and metabolite concentrations. We found that metabolites from the phosphatidylcholines-acyl-alkyl, sphingomyelin, and hexose classes were significantly associated with MetS and risk factor outcomes in both cohorts. In BLSA, metabolites across all classes were uniquely associated with all outcomes. In TMCS, metabolites from the amino acid, biogenic amines, and free fatty acid classes were uniquely associated with MetS, and metabolites from the sphingomyelin class were uniquely associated with elevated triglycerides. The metabolites and metabolite classes we identified may be relevant for future studies exploring disease mechanisms and identifying novel precision therapy targets for individualized medicine.

Introduction A role for bacteria and other microbes has long been suspected in the chronic inflammatory sinonasal diseases. Recent studies utilizing culture-independent, sequence-based identification have demonstrated aberrant shifts in the sinus microbiota of chronic rhinosinusitis subjects, compared with ostensibly healthy controls. Examining how such microbiota shifts occur and the potential for physician-prescribed interventions to influence microbiota dynamics are the topics of the current article. Methods The nasal cavity microbiota of 5 subjects was serially examined over an 8-week period using pan-bacterial 16S rRNA gene sequencing. Four of the subjects were administered topical mometasone furoate spray, while 1 subject underwent a mupirocin decolonization procedure in anticipation of orthopedic surgery. Results Measures of microbial diversity were unaffected by intranasal treatment in 2 patients and were markedly increased in the remaining 3. The increase in microbial diversity was related to clearance of Moraxella spp. and a simultaneous increase in members of the phylum Actinobacteria. Both effects persisted at least 2 weeks beyond cessation of treatment. Transient changes in the relative abundance of several bacterial genera, including Staphylococcus and Priopionibacteria , were also observed during treatment. Conclusions The effects of intranasal steroids on the sinonasal microbiome are poorly understood, despite their widespread use in treating chronic sinonasal inflammatory disorders. In this longitudinal study, administration of intranasal mometasone furoate or mupirocin resulted in shifts in microbial diversity that persisted to some degree following treatment cessation. Further characterization of these effects as well as elucidation of the mechanism(s) underlying these changes is needed.

BACKGROUND:The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression. METHODS AND FINDINGS:Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ [identification and quantification] p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and "asymptomatic Alzheimer's disease" (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes-sphingolipids and glycerophospholipids-that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer's Disease Neuroimaging Initiative [ADNI], N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer's Disease [EASE-AD]). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio [HR] = 4.430, 95% confidence interval [CI] = 1.703-11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516-7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373-9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047-4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-β (Aβ) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples. CONCLUSIONS:We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD.

Background: Allopurinol and febuxostat are xanthine oxidase inhibitors which are used in the treatment of hyperuricemia and gout. Pain is one of the important symptoms in gout patients. The present study was to evaluate the analgesic activity of allopurinol and febuxostat in two analgesic models in mice. Materials and Methods: The analgesic activity of allopurinol (39 mg/kg) and febuxostat (15.6 mg/kg) was evaluated using central analgesic model of Eddy′s hot plate and peripheral analgesic model of acetic acid induced writhing. Both drugs were compared with the positive control, pentazocine for a hot plate method and aspirin for the writhing method. Furthermore, both allopurinol and febuxostat were compared with each other. Results: Both allopurinol and febuxostat showed significant increase in reaction time at various time periods in hot plate method and also showed significant delay in onset of writhing as well as decrease in number of writhes in writhing method. As compared to positive control result, allopurinol and febuxostat result were lower. Febuxostat shows better analgesic activity as compared to that of allopurinol. Conclusion: Allopurinol and febuxostat exhibited analgesic activity in both central and peripheral models of pain.

Background: Assessment of severity by echocardiography includes two-dimensional planimetry of the valve orifice and doppler-derived measurements of the gradient, pressure half-time (PHT), and deceleration time. For that Transesophageal echocardiography (TEE) or transthoracic echocardiography (TTE) can be used. Data regarding the comparison of TEE and TTE in assessment of severity of MS during mitral valve replacement surgery is inadequately available. Objective: To assess severity of MS using TTE and TEE compared with actual MVA measured directly with the help of Hegar's dilator. To determine the superiority of TEE over TTE. Methods: The present prospective observational study was carried out in the department of Anesthesiology (CVTS OT), Government Medical College and Superspeciality Hospital, Nagpur from November 2012 to October 2013. Thirty five patients of MS undergoing mitral valve replacement surgery were included in present study. For every patient, after the induction of general anesthesia TTE and TEE was performed and primary outcome measures were noted. During the mitral valve replacement surgery, after opening left Atrium, direct measurements of MVA were done with the aid of Hegar's dilator in every patient. Results:The mean age was 35.26±10.35 years, mean weight was 54.26±9.62 kg; mean height was 155.97±5.61 cm. There were 15 male and 20 female patients in the study. When TEE and TTE were compared with direct measurement, it was found that both the methods were comparable i.e. as per our hypothesis, TEE was not found superior over TTE. Conclusion: Based on these study findings, we conclude that both TEE and TTE are comparable and no method is superior over the other.