bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-effectiveness of the top 100 drugs by public spending in Canada, 2015–2021: a repeated cross-sectional study
Authors: Gaudette Étienne , Rizzardo Shirin , Zhang Yvonne , Pothier Kevin R , Tadrous Mina
Published: March 2024

Objectives

To assess the distribution and spending by cost-effectiveness category among those drugs with the highest public spending levels in Canada.

Design

Repeated cross-sectional study.

Setting

The Canadian provinces of Manitoba, Ontario, New Brunswick, Nova Scotia, Prince Edward Island and Newfoundland.

Main outcomes and measures

Cost-effectiveness assessments by the Canadian Agency for Drugs and Technologies in Health (CADTH) for top-100 brand-name outpatient drugs by gross public plan spending in any year between 2015 and 2021 in Canada Institute for Health Information’s National Prescription Drug Utilization Information System data. Gross public plan spending by cost-effectiveness category.

Results

From 2015 to 2021, 152 brand-name drugs occupied a top-100 rank and were included in the analysis. Of those, 117 had been assessed by CADTH. During the 7-year period, there was an increase in both top-100 drugs with cost-effective (from 18 to 24) and cost-ineffective (from 29 to 41) assessments, while drugs not assessed or with an unclear assessment declined (from 31 to 19 and from 22 to 16, respectively). As a share of spending on top-100 drugs with an assessment, spending on cost-effective drugs was mostly stable at 40%–46% from 2015 to 2021, while spending on cost-ineffective drugs increased from 30% to 45%.

Conclusion

A large and growing share of public drug spending has been allocated to cost-ineffective drugs in Canada. Dedicating large budgets to such treatments prevents spending with greater health impact elsewhere in the healthcare system and could restrain the capacity to pay for groundbreaking pharmaceutical innovation in the future.
Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial
Authors: Schadendorf Dirk , Luke Jason John , Ascierto Paolo A , Long Georgina V , Rutkowski Piotr , Khattak Adnan , Del Vecchio Michele , de la Cruz-Merino Luis , Mackiewicz Jacek , Sileni Vanna Chiarion , Kirkwood John M , Robert Caroline , Grob Jean-Jacques , Dummer Reinhard , Carlino Matteo S , Zhao Yujie , Kalabis Mizuho , Krepler Clemens , Eggermont Alexander , Scolyer Richard A
Published: March 2024

Background

Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics.

Methods

Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (<5 per mm2(median) vs ≥5 per mm2), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present).

Results

Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0–39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for >4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate <5 per mm2and 0.57 (0.40 to 0.80) for ≥5 per mm2; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS.

Conclusions

In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma.

Trial registration number

ClinicalTrials.gov,NCT03553836.
End-of-life care
Authors: Nitkunan Arani
Published: March 2024

My 96-year-old aunt taught me so much about end-of-life care. As doctors dealing with long-term neurological conditions, our relationships with patients over many years should enable us to be much more involved in helping them make decisions about the ceilings of treatment.
Models based analysis of radiative induced MHD hybrid nanofluid flow over an exponentially stretching sheet
Authors: Khan Nasrullah , Abbas Nadeem , Shaheen Aqila , Shatanawi Wasfi
Published: March 2024

The study focuses on the flow of hybrid nanofluid, induced by magnetic and radiation effects, across an exponentially stretched sheet. The research examines the impact of temperature-dependent properties of the hybrid nanofluid on the sheet. Water is used as the base fluid, and SWCNT and MWCNT are employed as nanoparticles. The study includes a discussion of the Yamada–Ota, Xue and Tiwari–Das models of hybrid nanofluids. The governing system of flow is presented mathematically, and boundary layer approximations are used to reduce differential equations. The differential equations are transformed into dimensionless ordinary differential equations (ODEs) by using transformations. The dimensionless system of equations is then solved numerically. The results of the flow model are offered in tabular and graphical forms. We observed that Tiwari–Das model of hybrid nanofluid achieved more heat transfer and friction factor values when compared to other models of Xue and Yamada–Ota models of hybrid nanofluid. Temperature curves are noted to be enhanced by enlargement in the nano-concentration factor. If the nano-concentration increased in the fluid which boosted the thermal conductivity of the liquid, then as a result, the temperature of fluid enhanced at surface.
Automatic Speckle Noise Reduction in SAR Imagery Using Optimized Kernel Support Vector Machine
Authors: Parhad Saurabh Vijay , Warhade Krishna K. , Shitole Sanjay S.
Published: March 2024

Speckle noise (SN) is one of the major types of noise that frequently occurs in different coherent imaging systems such as medical imaging, Synthetic Aperture Radar (SAR) and active Radar images. SAR is a powerful imaging technology that generates fine-resolution images and monitors the earth’s surface in order to identify its physical properties. The satellite images captured by SAR are mainly affected by SN, which reduces the quality of images and complicates the image representation. Therefore, removing SN from SAR images is one of the major challenges and needs significant attention. The proposed study introduces an optimal Machine Learning (ML) classifier named Kernel Support Vector Machine-Improved Aquila Optimization (KSVM-IAO) for reducing SN in SAR images. This study uses a two-step process called filtering and enhanced despeckling to minimize the consequence of speckle suppression. In the first step, different imaging filters, namely Improved Lee Filter (ILF), Improved Frost Filter (IFF), Improved Kuan Filter (IKF) and Improved Boxcar Filter (IBF), are utilized to remove the SN in SAR images. Next, the denoised image is fed to the second stage, which makes use of an optimized KSVM-IAO classifier to obtain an enhanced despeckle image. The hyperparameters of KSVM are tuned using the IAO algorithm, which reduces overfitting issues and increases accuracy. MATLAB is the simulation tool used for the analysis of SAR images. The simulation outcomes reveal that the proposed KSVM-IAO method obtained excellent SN removal while preserving the edges and fine details with low computational complexity.
Integrately design hybrid lithium-air battery based on the nasicon solid electrolyte and zinc single atoms electrochemical catalysts
Authors: Wang Hui , Li Nairan
Published: March 2024

The instability of lithium metal and insoluble discharging products, [Formula: see text], has been a formidable challenge that hinders the widespread implementation of lithium-air batteries (LABs). Hybrid electrolyte-based LABs have been proposed as one of the most promising strategies to solve these issues. However, the complex device designs together with a suitable solid electrolyte membrane is one of the key parameters that determine the battery run. Herein, we present a novel approach featuring a three-phase “organic-solid-aqueous” hybrid electrolyte for LABs, incorporating a NASICON-based solid electrolyte and zinc single atoms catalysts. It is clarified that [Formula: see text] (LATP) shows much-enhanced stability compared with the pulverization of [Formula: see text] (LAGP) by the reduction of Ge upon the [Formula: see text] transport across. Combined with the bifunction of Zn SAs/CNF catalysts in ORR/OER, the 4[Formula: see text] pathway has been proven to be established as a primary contributor to the battery’s high efficiency, which can well run over 100 h in the ambient air at room temperature. These innovative methodologies and insights hold promise for advancing the practical application of safe LABs and may extend to various air battery technologies.
Overlapping Batch Confidence Intervals on Statistical Functionals Constructed from Time Series: Application to Quantiles, Optimization, and Estimation
Authors: Su Ziwei , Pasupathy Raghu , Yeh Yingchieh , Glynn Peter
Published: March 2024

We propose a general purpose confidence interval procedure (CIP) for statistical functionals constructed using data from a stationary time series. The procedures we propose are based on derived distribution-free analogues of the χ
2
and Student’s
t
random variables for the statistical functional context and hence apply in a wide variety of settings including quantile estimation, gradient estimation, M-estimation, Conditional Value at Risk (CVaR) estimation, and arrival process rate estimation, apart from more traditional statistical settings. Like the method of subsampling, we use overlapping batches (OB) of time-series data to estimate the underlying variance parameter; unlike subsampling and the bootstrap, however, we assume that the implied point estimator of the statistical functional obeys a central limit theorem (CLT) to help identify the weak asymptotics (called OB-x limits, x = I, II, III) of batched Studentized statistics. The OB-x limits, certain functionals of the Wiener process parameterized by the size of the batches and the extent of their overlap, form the essential machinery for characterizing dependence and, consequently, the correctness of the proposed CIPs. The message from extensive numerical experimentation is that in settings where a functional CLT on the point estimator is in effect, using
large overlapping batches
alongside OB-x critical values yields confidence intervals that are often of significantly higher quality than those obtained from more generic methods like subsampling or the bootstrap. We illustrate using examples from CVaR estimation, ARMA parameter estimation, and non-homogeneous Poisson process rate estimation; R and MATLAB code for OB-x critical values is available at 
web.ics.purdue.edu/∼pasupath
.
Extended Reality (XR) Toward Building Immersive Solutions: The Key to Unlocking Industry 4.0
Authors: Alhakamy A’aeshah
Published: March 2024

When developing XR applications for Industry 4.0, it is important to consider the integration of visual displays, hardware components, and multimodal interaction techniques that are compatible with the entire system. The potential use of multimodal interactions in industrial applications has been recognized as a significant factor in enhancing humans’ ability to perform tasks and make informed decisions. To offer a comprehensive analysis of the current advancements in industrial XR, this review presents a structured tutorial that provides answers to the following research questions: (R.Q.1) What are the similarities and differences between XR technologies, including augmented reality (AR), mixed reality (MR), Augmented Virtuality (AV), and virtual reality (VR) under Industry 4.0 consideration? (R.Q.2) What types of visual displays and hardware devices are needed to present XR for Industry 4.0? (R.Q.3) How did the multimodal interaction in XR perceive and relate to Industry 4.0? (R.Q.4) How have modern adaptations of XR technologies dealt with the theme of Industry 4.0? (R.Q.5) How can XR technologies in Industry 4.0 develop their services and usages to be more solution-inclusive? This review showcases various instances that demonstrate XR’s potential to transform how humans interact with the physical world in Industry 4.0. These advancements can increase productivity, reduce costs, and enhance safety.
Predicting sex differences in the effects of diuretics in renal epithelial transport during angiotensin II-induced hypertension
Authors: Zheng Kaixin , Layton Anita T.
Published: March 2024

Sex differences in the prevalence of hypertension are found in human and animal models. The kidney, which regulates blood pressure, exhibits sex differences in morphology, hemodynamics, and membrane transporter distributions. This computational modeling study provides insights into how the sexually dimorphic responses to a 14-day angiotensin II infusion differentially impact segmental electrolyte transport in rats. Simulations of diuretic administration explain how the natriuretic and diuretic effects differ between normotension and hypertension and between the sexes.
Chemoradiation to the submental muscles alters hyoid movement during swallowing in a rat model
Authors: King Suzanne N. , Kuntz Abigail , Scott Nathan , Smiley Brittany , Portocarrero Bonifaz Andres , Blackburn Megan
Published: March 2024

Chemoradiation treatment for head and neck cancer can cause functional impairments in swallowing, which can adversely affect quality of life. This study provides new evidence that chemoradiation targeted to the submental muscles provokes early adaptations in hyoid movement during swallowing, which correlate with changes in bolus size. We also demonstrate a method for tracking the hyoid during swallowing in a rat model of chemoradiation injury.
Differential changes in blood flow and oxygen utilization in active muscles between voluntary exercise and electrical muscle stimulation in young adults
Authors: Katagiri Makoto , Nakabayashi Mikie , Matsuda Yasuhiro , Ono Yumie , Ichinose Masashi
Published: March 2024

This is the first study to visualize continuous changes in blood flow and oxygen utilization within contracted muscles during and after electrical muscle stimulation (EMS) using combined diffuse correlation and near-infrared spectroscopy. We found that initiating EMS increases blood flow at a rate comparable to that during voluntary (VOL) exercise but enhances oxygen extraction, resulting in higher oxygen consumption. Furthermore, EMS increased postexercise muscle perfusion and oxygen consumption compared with that after VOL exercise.
Neurobiology and systems biology of stress resilience
Authors: Kalisch Raffael , Russo Scott J. , Müller Marianne B.
Published: March 2024

Stress resilience is the phenomenon that some people maintain their mental health despite exposure to adversity or show only temporary impairments followed by quick recovery. Resilience research attempts to unravel the factors and mechanisms that make resilience possible and to harness its insights for the development of preventative interventions in individuals at risk for acquiring stress-related dysfunctions. Biological resilience research has been lagging behind the psychological and social sciences but has seen a massive surge in recent years. At the same time, progress in this field has been hampered by methodological challenges related to finding suitable operationalizations and study designs, replicating findings, and modeling resilience in animals. We embed a review of behavioral, neuroimaging, neurobiological, and systems biological findings in adults in a critical methods discussion. We find preliminary evidence that hippocampus-based pattern separation and prefrontal-based cognitive control functions protect against the development of pathological fears in the aftermath of singular, event-type stressors [as found in fear-related disorders, including simpler forms of posttraumatic stress disorder (PTSD)] by facilitating the perception of safety. Reward system-based pursuit and savoring of positive reinforcers appear to protect against the development of more generalized dysfunctions of the anxious-depressive spectrum resulting from more severe or longer-lasting stressors (as in depression, generalized or comorbid anxiety, or severe PTSD). Links between preserved functioning of these neural systems under stress and neuroplasticity, immunoregulation, gut microbiome composition, and integrity of the gut barrier and the blood-brain barrier are beginning to emerge. On this basis, avenues for biological interventions are pointed out.
Citrus sunki Peel Extract, Containing Nobiletin and Tangeretin, Enhances Proliferation and Differentiation in 3T3-L1 Adipocytes
Authors: Oh Sehyuk , Park Sanghun , Park Gyutae , Choi Nayoung , Kim Chaeri , Lee Solhee , Choi Jungseok
Published: March 2024

In this experiment, effects of Citrus sunki peel extract (CPE) on proliferation and differentiation of 3T3-L1 cells were analyzed. Citrus sunki peel was extracted with ethanol to obtain CPE. Results of measuring DPPH and hydrogen peroxide radical scavenging activity revealed that CPE had an antioxidant ability. The 3T3-L1 cells were cultured in the basal medium (C) or with 0.05% dimethyl-sulfoxide (CDMSO) or with 50, 100, 200, 300, and 400 μg/mL CPE (CPE50, CPE100, CPE200, CPE300, and CPE400, respectively). As a result of cell counting and MTS assay, CPE significantly enhanced proliferation capacity of 3T3-L1 cells. To analyze the effect of CPE on the differentiation capacity of 3T3-L1 cells, relative gene and protein expression levels of Cebpb, Cebpa, and FASN related to adipogenesis were measured by RT-qPCR and Western blot. CPE increased adipogenesis-related gene and protein expression in 3T3-L1 cells, with CPE300 being especially effective. In Oil Red O staining, adipogenesis was significantly greater in CPE200, CPE300, and CPE400 than in C. This was confirmed image wise through Nile Red staining. Through HPLC analysis, it was confirmed that nobiletin and tangeretin were most abundant in CPE. To analyze effects of nobiletin and tangeretin on 3T3-L1 cells, the cells were cultured with various concentrations of nobiletin, tangeretin, and both. As a result of cell counting and MTS assay, nobiletin and tangeretin significantly decreased the proliferation capacity of 3T3-L1 cells. In RT-qPCR, western blot, Oil Red O staining, and Nile Red staining to analyze differentiation capacity, nobiletin and tangeretin significantly enhanced the expression of genes and proteins related to adipogenic differentiation compared to the control group. In conclusion, CPE, which had high antioxidant capacity, enhanced proliferation and differentiation in 3T3-L1 adipocytes. This improvement in differentiation is due to the influence of nobiletin and tangeretin contained in CPE.
Unusual Presentation of Leiomyoma in the Hindfoot
Authors: Zaher Abdullah , Yasser Jaouad , Badaro Daniel , Sekkach Noureddine
Published: March 2024

A leiomyoma is a benign smooth muscle tumor that is most commonly found in the uterus. Limited studies have reported leiomyoma of the foot, rendering it an usual finding. We present a case of a 57‐year‐old female patient who presented to the clinic for a painless mass on the posteromedial side of the right heel. It was diagnosed by the radiologist on MRI as a probable schwannoma. The patient underwent surgical excision of this mass which turned out to be a leiomyoma on pathology report. Although foot leiomyoma is a rare finding, leiomyoma should be listed in the differential diagnosis when evaluating foot soft tissue masses. It is difficult to confirm the diagnosis clinically and radiographically, yet a histologic evaluation can affirm the diagnosis. Surgical excision is the treatment of choice offering immediate symptomatic relief.
Chemical Profiling and Biological Activities on Nepalese Medicinal Plant Extracts and Isolation of Active Fraction of Nyctanthes arbor-tristis
Authors: Khadka Anita , Budha Magar Akash , Sharma Khaga Raj
Published: March 2024

The importance of medicinal plants for the treatment of different diseases is high from the aspects of the pharmaceutical industry and traditional healers. The present study involves nine different medicinal plants, namely, Neolamarckia cadamba, Nyctanthes arbor-tristis, Pogostemon benghalensis, Equisetum debile, Litsea monopetala, Spilanthes uliginosa, Desmostachya bipinnata, Mallotus philippensis, and Phoenix humilis, collected from Chitwan district of Nepal for biochemical analysis followed by the isolation of active plant fractions from the bioactive plant extract. The methanolic extracts of roots, barks, seeds, seed cover, and the other aerial parts of plants were used for the phytochemical analysis and biological activities. The DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging assay was adopted to evaluate the antioxidant activity. Antibacterial activity was evaluated using the agar well diffusion method. The antidiabetic activity was studied by the α-amylase enzyme inhibition assay. The highest antioxidant activity was observed in extracts of Nyctanthes arbor-tristis followed by Mallotus philippensis (seed cover), Pogostemon benghalensis, Litsea monopetala, Phoenix humilis, and Neolamarckia cadamba with IC50 values of 27.38 ± 1.35, 32.08 ± 2.81, 32.75 ± 2.13, 33.82 ± 1.07, 40.14 ± 0.93, and 50.44 ± 3.75 µg/mL, respectively. The highest antidiabetic activity was observed in extracts of Phoenix humilis followed by Desmostachya bipinnata and Pogostemon benghalensis with IC50 values of 95.69 ± 6.97, 99.24 ± 12.6, and 106.3 ± 12.89 µg/mL, respectively. The mild α-amylase enzyme inhibition was found in extracts of Nyctanthes arbor-tristis, Spilanthes uliginosa Swartz, Litsea monopetala, and Equisetum debile showing IC50 values of 110.4 ± 7.78, 115.98 ± 10.24, 149.83 ± 8.3, and 196.45 ± 6.04 µg/mL, whereas Mallotus Philippensis (seed cover), Mallotus philippensis (seed), and Desmostachya bipinnata showed weak α-amylase inhibition with IC50 values of 208.87 ± 1.76, 215.41 ± 2.09, and 238.89 ± 9.27 µg/mL, respectively. The extract of Nyctanthes arbor-tristis showed high zones of inhibition against S. aureus (ATCC 25923) and E. coli (ATCC 25922) of ZOI 26 and 22 mm, respectively. The chemical constituents isolated from the active plant Nyctanthes arbor-tristis were subjected to GCMS analysis where the major chemical compounds were 11,14,17-eicosatrienoic acid and methyl ester. These results support the partial scientific validation for the traditional uses of these medicinal plants in the treatment of diabetes and infectious diseases by the people living in different communities of Chitwan, Nepal.
CFD Simulation of an Industrial Dust Cyclone Separator: A Comparison with Empirical Models: The Influence of the Inlet Velocity and the Particle Size on Performance Factors in Situation of High Concentration of Particles
Authors: Vermande Paganel Tchinda , Fabrice Alban Epee , Cyrille Mezoue Adiang , Ngayihi Abbe Claude Valery
Published: March 2024

The present work is dedicated to the study of multiphase turbulent and three‐dimensional rotational flow in dust cyclones, a contribution to air pollution control. Cyclones are widely used devices for the separation of constituents from solid‐gas mixtures in industry. In order to improve the filtration efficiency of cyclones, and to reduce the pressure drop, parametric numerical simulation studies using the Fluent code have been conducted to characterise the effects of the parameters affecting the operation of these devices through their performance indicators. In this work, the effect of inlet velocity and the particle size on the turbulent flow air in the cyclone is presented. Numerical simulation of the flow by Fluent code using three numerical models: the first based on the dissipation of kinetic energy by viscosity (RNG) K‐epsilon and standard K‐epsilon as well as the last based on the solution of Reynolds stress equations (RSM), combined with the multiphase mixing model, gave interesting results in terms of the pressure and flow field in the separator, the variation of inlet velocity, and the variation of particle size. Validation with experimental and empirical results showed the advantage of the Reynolds stress turbulence model (RSM) over the standard K‐epsilon and RNG K‐epsilon. The RSM model better captures physical phenomena in an intense vortex flow in the presence of walls. But it is characterised by a very long calculation time and requires large machine resources. An alternative to this model is RNG K‐epsilon model, which offers a reasonable calculation time with acceptable results (maximum deviation of 5 %) for speed values below 10 m/s. In the absence of numerical resources, certain empirical models such as those of First (for the evaluation of pressure drop) and Iozia and Leith (for evaluation of efficiency) may well be useful for the dimensioning of the cyclone.
Polymyalgia Rheumatica Post-SARS-CoV-2 Infection
Authors: Duarte-Salazar Carolina , Vazquez-Meraz José Eugenio , Ventura-Ríos Lucio , Hernández-Díaz Cristina , Arellano-Galindo José
Published: March 2024

There is growing evidence that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to dysregulation of the immune system and, consequently, the development of autoimmune phenomena. Here, we describe the case of a 75-year-old woman with rheumatic manifestations characterized by intense musculoskeletal pain and stiffness in the neck and shoulders, with sudden onset and with the inability to raise her arms. The patient was admitted with severe pain located in the neck and shoulders. Previously, she had oropharyngeal pain, severe fatigue, and fever; a real-time polymerase chain reaction test for COVID-19 was positive. Two weeks later, the patient presented localized musculoskeletal pain in the neck and shoulders. Relevant laboratory results included an erythrocyte sedimentation rate of 46 mm/hr and a negative rheumatoid factor test; ultrasound findings with bilateral subacromial–subdeltoid bursitis were observed. A diagnosis of polymyalgia rheumatica (PMR) was initially made according to the EULAR/ACR provisional classification criteria for PMR; however, due to C-reactive protein negativity, the diagnosis was established based on symptoms. Management was with prednisone at the dose of 25 mg/day for 4 weeks and progressive reduction until prednisone suspension. The patient showed complete recovery at 6 months of follow-up. In this case, COVID-19 was implicated in the development of autoimmune and inflammatory rheumatic manifestations. PMR is a rare rheumatic condition that should be included in the wide range of rheumatologic manifestations expressed post-SARS-CoV-2 infection.
FUME-TCRseq Enables Sensitive and Accurate Sequencing of the T-cell Receptor from Limited Input of Degraded RNA
Authors: Baker Ann-Marie , Nageswaran Gayathri , Nenclares Pablo , Ronel Tahel , Smith Kane , Kimberley Christopher , Laclé Miangela M. , Bhide Shreerang , Harrington Kevin J. , Melcher Alan , Rodriguez-Justo Manuel , Chain Benny , Graham Trevor A.
Published: March 2024

Genomic analysis of the T-cell receptor (TCR) reveals the strength, breadth, and clonal dynamics of the adaptive immune response to pathogens or cancer. The diversity of the TCR repertoire, however, means that sequencing is technically challenging, particularly for samples with low-quality, degraded nucleic acids. Here, we developed and validated FUME-TCRseq, a robust and sensitive RNA-based TCR sequencing methodology that is suitable for formalin-fixed paraffin-embedded samples and low amounts of input material. FUME-TCRseq incorporates unique molecular identifiers into each molecule of cDNA, allowing correction for sequencing errors and PCR bias. Using RNA extracted from colorectal and head and neck cancers to benchmark the accuracy and sensitivity of FUME-TCRseq against existing methods demonstrated excellent concordance between the datasets. Furthermore, FUME-TCRseq detected more clonotypes than a commercial RNA-based alternative, with shorter library preparation time and significantly lower cost. The high sensitivity and the ability to sequence RNA of poor quality and limited amount enabled quantitative analysis of small numbers of cells from archival tissue sections, which is not possible with other methods. Spatially resolved FUME-TCRseq analysis of colorectal cancers using macrodissected archival samples revealed the shifting T-cell landscapes at the transition to an invasive phenotype and between tumor subclones containing distinct driver alterations. In summary, FUME-TCRseq represents an accurate, sensitive, and low-cost tool for the characterization of T-cell repertoires, particularly in samples with low-quality RNA that have not been accessible using existing methodology.

Significance:

FUME-TCRseq is a TCR sequencing methodology that supports sensitive and spatially resolved detection of TCR clones in archival clinical specimens, which can facilitate longitudinal tracking of immune responses through disease course and treatment.
Supplemental Table 1 from Impact of Tumor-intrinsic Molecular Features on Survival and Acquired Tyrosine Kinase Inhibitor Resistance in ALK-positive NSCLC
Authors: Nakazawa Mari , Harada Guilherme , Ghanem Paola , Bubie Adrian , Kiedrowski Lesli A. , Murray Joseph C. , Marrone Kristen A. , Scott Susan C. , Houseknecht Stefanie , Falcon Christina J. , Evans Patrick , Feliciano Josephine , Hann Christine L. , Ettinger David S. , Smith Kellie N. , Anagnostou Valsamo , Forde Patrick M. , Brahmer Julie R. , Levy Benjamin , Drilon Alexander , Lam Vincent K.
Published: March 2024

Baseline characteristics of patients with ALK-positive NSCLC in liquid biopsy cohort
Elevated Urine Hyaluronan Concentrations Are Associated with an Unfavorable Respiratory Outcome in Preterm Neonates at 40 Weeks Postmenstrual Age
Authors: MacFarlane Peter Mathew , Chen Zhengyi , Minich Nori , Mayer Catherine Ann , Martin Richard John , Di Fiore Juliann Marie , Raffay Thomas Michael , Hibbs Anna Maria
Published: March 2024

Introduction: Hyaluronan (HA) is a major component of the extracellular matrix. Increased pulmonary HA concentrations are associated with several respiratory disorders and is a pathophysiological feature of lung disease. We investigated whether elevated urine HA is a biomarker of an unfavorable 40-week respiratory outcome in preterm infants. Methods: Infants comprised a cohort of preterm neonates <31 weeks gestational age (GA) from the Prematurity-Related Ventilatory Control (Pre-Vent) multicenter study. HA was quantified in urine obtained at 1 week and 1 month of age. Respiratory status at 40 weeks post-menstrual age (PMA) was classified as unfavorable [either (1) deceased at or before 40 weeks PMA, (2) an inpatient on respiratory medication, O2 or other respiratory support at 40 weeks, or (3) discharged prior to 40 weeks on medications/O2/other respiratory support], or favorable (alive and previously discharged, or inpatient and off respiratory medications, off O2, and off other respiratory support at 40 weeks PMA). The association between urine HA and the unfavorable 40 week PMA outcome was examined using a multivariate logistic generalized estimation equation model. Results: Infants with higher HA at 1 week (but not 1 month) showed increased odds of unfavorable respiratory outcome at 40 weeks PMA (OR [95% CI] = 1.87 per 0.01 mg [1.27, 2.73]). Discussion and Conclusion: Neonatal urine screening for HA could identify infants at risk for death or need for respiratory support at term-corrected age (40 weeks PMA). The relationship between elevated HA at 1 week and an unfavorable 40 week outcome was stronger in infants with lower GA.
LncRNA ZFAS1 Alleviated NLRP3 Inflammasome-Mediated Pyroptosis through Regulating miR-96-5p/Smad7 Signaling in Allergic Rhinitis
Authors: Zhan Jiabin , Qi Yanyan , Fu Yunlong , Zheng Jing , Wu Jinli , Wei Xin , Zeng Min
Published: March 2024

Introduction: The NLR family pyrin domain containing 3 (NLRP3)-mediated pyroptosis was positively correlated with the allergic rhinitis progression and was reported to be regulated by SMAD family member 7 (Smad7). Bioinformatics analysis revealed that Smad7 might be targeted by miR-96-5p, and miR-96-5p might be targeted by long noncoding RNA zinc finger antisense 1 (ZFAS1). However, the effects and regulatory mechanisms of the ZFAS1/miR-96-5p/Smad7 functional axis in allergic rhinitis have not been investigated. Methods: Human nasal mucosa epithelial cell line RPMI 2650 and C57BL/6 mice were obtained for in vitro and in vivo studies. Dual-luciferase reporter assay and RNA immunoprecipitation were implemented for detecting molecular interactions. Cell counting kit-8 and flow cytometry were used for measuring cell viability and pyroptosis. ELISA was obtained for monitoring cytokine secretion. RT-qPCR and Western blot were examined for determining RNA and protein expression. Results: In vitro studies revealed that ZFAS1 was downregulated in interleukin (IL)-13-treated RPMI 2650 cells, while overexpression of ZFAS1 enhanced cell viability and inhibited NLRP3-mediated pyroptosis and inflammatory response. ZFAS1 directly inhibited miR-96-5p to suppress NLRP3-mediated pyroptosis in IL-13-treated RPMI 2650 cells. MiR-96-5p bound to the 3′-untranslated region of Smad7 and knockdown of Smad7 significantly reversed the effects of miR-96-5p depletion. Moreover, in vivo experiments further confirmed the findings of in vitro studies and showed ZFAS1 overexpression or miR-96-5p inhibition alleviated allergic rhinitis in vivo. Conclusion: ZFAS1 downregulated the expression of miR-96-5p to upregulate Smad7 level, which subsequently inhibited NLRP3-mediated pyroptosis and inflammatory response to ameliorate allergic rhinitis.
Sex and Socioeconomic Disparities in Dementia Risk: A Population-Attributable Fraction Analysis in Argentina
Authors: Calandri Ismael Luis , Livingston Gill , Paradela Regina , Ossenkoppele Rik , Crivelli Lucia , Allegri Ricardo F. , Suemoto Claudia K.
Published: March 2024

Introduction: Twelve modifiable risk factors (RFs) account for 40% of dementia cases worldwide. However, limited data exist on such factors in middle- and low-income countries. We aimed to estimate the population-attributable fractions (PAFs) for the 12 RFs in Argentina, assessing changes over a decade and exploring socioeconomic and sex influences. Methods: We conducted cross-sectional analyses of the 12 RFs from Argentinian surveys conducted in 2009, 2015, and 2018, including 96,321 people. We calculated PAFs and stratified estimates based on sex and income. Results: We estimated an overall PAF of 59.6% (95% CI = 58.9–60.3%). The largest PAFs were hypertension = 9.3% (8.7–9.9%), physical inactivity = 7.4% (6.8–8.2%), and obesity = 7.4% (6.8–7.9%). Men were more impacted by excessive alcohol, while women by isolation and smoking. Lower income linked to higher PAFs in education, hypertension, and obesity. Discussion: Argentina has a higher PAF for dementia than the world population, with distinct RF distribution. PAF varied by sex and economic status, advocating tailored prevention strategies.
Influence of the Intracranial Contents on the Head Motion under Bone Conduction
Authors: von Mitzlaff Christian , Dobrev Ivo , Farahmandi Tahmine , Pfiffner Flurin , Röösli Christof
Published: March 2024

Introduction: The mechanism of non-osseous bone conduction pathways, involving the intracranial contents (ICC) of the skull, is still not well understood. This study aimed to investigate the influence of the ICC on the skull bone wave propagation, including dependence on stimulation location and coupling. Methods: Three Thiel-embalmed whole-head cadaver specimens were studied before and after the removal of the ICC. Stimulation was via the electromagnetic actuators from commercial bone conduction hearing aids. Osseous pathways were sequentially activated by mastoid, forehead, and bone-anchored hearing aid location stimulation via a 5-Newton steel headband or percutaneously implanted screw. Non-osseous pathways were activated by stimulation on the eye and dura via a 5-Newton steel headband and a custom-made pneumatic holder, respectively. Under each test condition, the 3D motion of the superior skull bone was monitored at ∼200 points. Results: The averaged response of the skull surface showed limited differences due to the removal of the ICC. In some isolated cases, the modal pattern on the skull surface showed a trend for an upshift (∼1/2 octave) in the observed natural frequencies for drained heads. This was also consistent with an observed trend for an upshift in the transition frequency in the estimated deformation across the lateral surfaces of the temporal bones. Such changes were consistent with the expected reduction in mass and damping due to the absence of the ICC. Conclusion: Overall, the ICC affect to a limited extent the motion of the skull bone, with a limited trend for a reduction of its natural frequencies.
Empowering Preventive Strategies: The Role of Dietitians in Modifying Lifestyle Factors Associated with Inflammatory Bowel Disease Development
Authors: Guney-Coskun Merve , Carnevale Sara
Published: March 2024

Background: Various environmental risk factors have been associated with the pathogenesis of inflammatory bowel disease. In this study we aimed to identify lifestyle factors that affect the onset of Crohn’s disease and ulcerative colitis. Methods: 2294 patients from the Swiss IBD Cohort Study received a questionnaire regarding physical activity, nutritional habits and status of weight. In addition, a control group was formed comprising patients’ childhood friends, who grew up in a similar environment. Results: Overall, 1111 questionnaires were returned (response rate: 48.4%). Significantly more patients with inflammatory bowel disease reported no regular practice of sport during childhood and beginning of adulthood compared to the control group (p = 0.0001). No association between intake of refined sugar and onset of inflammatory bowel disease was observed. More patients with Crohn’s disease compared to ulcerative colitis and controls suffered from overweight during childhood (12.8% vs. 7.7% and 9.7%, respectively; p = 0.027). Conclusions: Our study underlines the relevance of environmental factors in the development of inflammatory bowel disease. Our results imply a protective effect of physical activity regarding the onset of inflammatory bowel disease.
Identification of Potential Blood-Based Biomarkers for Frailty by Using an Integrative Approach
Authors: Suganuma Mutsumi , Furutani Motoki , Hosoyama Tohru , Mitsumori Risa , Otsuka Rei , Takemura Marie , Matsui Yasumoto , Nakano Yukiko , Niida Shumpei , Ozaki Kouichi , Satake Shosuke , Shigemizu Daichi
Published: March 2024

Introduction: Although frailty is a geriatric syndrome that is associated with disability, hospitalization, and mortality, it can be reversible and preventable with the appropriate interventions. Additionally, as the current diagnostic criteria for frailty include only physical, psychological, cognitive, and social measurements, there is a need for promising blood-based molecular biomarkers to aid in the diagnosis of frailty. Methods: To identify candidate blood-based biomarkers that can enhance current diagnosis of frailty, we conducted a comprehensive analysis of clinical data, messenger RNA-sequencing (RNA-seq), and aging-related factors using a total of 104 older adults aged 65–90 years (61 frail subjects and 43 robust subjects) in a cross-sectional case-control study. Results: We identified two candidate biomarkers of frailty from the clinical data analysis, nine from the RNA-seq analysis, and six from the aging-related factors analysis. By using combinations of the candidate biomarkers and clinical information, we constructed risk prediction models. The best models used combinations that included skeletal muscle mass index measured by dual-energy X-ray absorptiometry (adjusted p = 0.026), GDF15 (adjusted p = 1.46E-03), adiponectin (adjusted p = 0.012), CXCL9 (adjusted p = 0.011), or apelin (adjusted p = 0.020) as the biomarker. These models achieved a high area under the curve of 0.95 in an independent validation cohort (95% confidence interval: 0.79–0.97). Our risk prediction models showed significantly higher areas under the curve than did models constructed using only basic clinical information (Welch’s t test p < 0.001). Conclusion: All five biomarkers showed statistically significant correlations with components of the frailty diagnostic criteria. We discovered several potential biomarkers for the diagnosis of frailty. Further refinement may lead to their future clinical use.
Pengantar Rekayasa Genetika
Authors: Sutrisno Aji , Wardani Agustin Krisna
Published: March 2024

Rekayasa genetika atau teknologi DNA rekombinan adalah teknologi manipulasi, modifikasi, dan rekombinasi DNA atau molekul asam nukleat lainnya untuk memodifikasi suatu organisme atau populasi organisme. Rekayasa genetika telah membantu para peneliti dalam pengembangan penelitian dasar di bidang biokimia, biologi molekuler dan genetika. Rekayasa genetika telah menunjukkan manfaat dalam membawa kemajuan dalam kehidupan manusia. Teknologi ini memiliki penerapan multidisiplin dan telah menghasilkan produk-produk yang penting kehidupan manusia di bidang kesehatan, pertanian dan lingkungan. Buku "Pengantar Rekayasa Genetika" ini disusun sebagai upaya untuk memberikan gambaran secara umum kepada pelajar / mahasiswa Indonesia tentang rekayasa genetika dan perannya dalam kehidupan sehari-hari. Buku ini terdiri dari tiga bagian yaitu dasar-dasar rekayasa genetika, metodologi modifikasi gen yang berisikan tentang teknik-teknik rekayasa genetika dan aplikasi rekayasa genetika pada berbagai bidang terpilih. Penyusun berharap dengan adanya buku ini akan dapat memberikan informasi dan wawasan yang utuh tentang rekayasa genetika, potensi serta manfaatnya dalam kehidupan sehari-hari. Semoga buku ini memberikan manfaat bagi semua pihak serta memberikan manfaat untuk kemajuan bioteknologi dan bidang terkait di Indonesia.
Publicidade e os agonizantes modelos de comunicação de marketing
Authors:   Universidade de São Paulo. Escola de Comunicações e Artes, Giacomini Filho Gino
Published: March 2024

O modelo atual da comunicação de marketing mostra-se imerso em um novo sistema social e de mercado, configurado pelo empoderamento do cidadão, tecnologias interativas da comunicação, consumerismo e mediadores público-privados, o que pode significar um redesenho para a forma como conteúdos publicitários têm sido empregados até então. A publicidade oferece valioso suporte ao conteúdo livre, ao jornalismo de qualidade e às conexões sociais; os consumidores, no entanto, estão muito frustrados com anúncios que prejudicam sua experiência nas relações de consumo. Esse aparente descompasso da agenda do consumidor com a agenda da propaganda comercial tem o potencial de provocar tensões, reações e desdobramentos diversos, mas pouco desejáveis tanto para o cidadão como para a indústria da propaganda. Nos últimos anos, o empoderamento do consumidor da publicidade atingiu tal patamar que, independentemente de leis, normas ou esforços dos atores ligados à publicidade, ele pode decidir se aceita ou como recepciona um anúncio, notadamente em ambientes virtuais. Um sinalizador prático e real desse modelo é o adblock. Consumidores, cansados de tantos anúncios invasivos, injustos e irrelevantes, resolvem utilizar bloqueadores de anúncios que, em outras palavras, significa uma interrupção da comunicação desejada pelo anunciante, organização ou agente publicitário. O bloqueio de anúncios é um basta à comunicação publicitária deceptiva. É uma medida radical do consumidor que abre mão de anúncios úteis e significativos para não ter que lidar com peças irritantes, desrespeitosas e impertinentes. É o resultado extremo para uma prática publicitária que rompe o contrato social e escancara um modelo agonizante de comunicação.
Frauen in Furcht
Authors: Neumann Nils
Published: March 2024

Trembling with fear is a typically feminine phenomenon in the Gospel of Mark. The hermorrhaging woman as well as the women at the empty tomb tremble as they are afraid. Male characters, on the contrary, never tremble in Mark, although the male disciples frequently do exhibit fear. The present article explains these observations in the context of ancient medicine and philosophy of the body. Against this backdrop it is plausible that the women’s fearful trembling illustrates some form of embodied understanding of the divine presence that breaks into the earthly realm within the works of Jesus. This calls into question William Wrede’s contrasting juxtaposition of faith and fear in Mark.
The Western Mongol World in the Early Eighteenth Century: Kalmyks and Oirats in Vasilis Vatatzēs’s Periēgētikon and His 1732 Map of Central Asia
Authors: Kordosis Stefanos
Published: March 2024

The article revolves around the information on the Kalmyks and Oirats contained in Vasilis Vatatzēs’s Periēgētikon (Voyages). Vatatzēs, a Greek-Ottoman merchant who travelled in Central Asia in the first half of the eighteenth century, supplemented his text with a map (engraved and published in 1732 in London) and produced a biography of Shah Nader of Persia, the founder of the short-lived Afsharid dynasty. Vatatzēs travelled along the caravan routes connecting the cities of southern Siberia with the Khanates of Central Asia, as demonstrated by a reconstruction of his itineraries, reaching as far as Bukhara. Focusing on the nations of Central Asia, Vatatzēs’s accounts and map provide much information regarding western Mongolic nations, starting with the Kalmyks in the Volga region and reaching as far as the Oirats, to the NW of China.