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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.

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.

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.

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.

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 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 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.

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.

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.

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.

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.

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.

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 Transnasal endoscopic sphenopalatine artery ligation is becoming the procedure of choice for surgical management of intractable posterior epistaxis. Landmarks for localization of the sphenopalatine foramen can assist in rapid surgical exposure of the sphenopalatine artery. Objective This study examined distances from easily identified endoscopic surgical landmarks to the sphenopalatine foramen. Methods By using computed tomography of the sinus to study radiologic anatomy in 50 adults, distances were measured between five simple endoscopic landmarks and the sphenopalatine foramen. The two-tailed t-test was used for statistical analysis. Results Right- and left-sided measurements were similar. The mean (standard deviation [SD]) anteroposterior distances to the sphenopalatine foramen were the following: from the maxillary line (36.7 ± 5.5 mm), anterior head of the middle turbinate (33.8 ± 6.7 mm), basal lamella (11.8 ± 1.9 mm), and choanal arch (–9.2 ± 1.4 mm). The mean (SD) distance in the vertical dimension from the nasal floor was 26.6 ± 2.6 mm. Female patients had statistically shorter distances to the sphenopalatine foramen from the maxillary line, anterior head of the middle turbinate, choanal arch, and nasal floor. Conclusion Reliable endoscopic landmarks exist in relation to consistent anatomic structures and can be used to help quickly estimate the location of the sphenopalatine foramen at the onset of the procedure.