bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurement problems of miniature electrical machines
Authors: Bodnicki M
Published: November 2021

The article presents the issue related to experimental research on the determination of static and dynamic properties of miniature electrical machines. The tested objects are, for example, micromotors with body diameters in the order of single millimetres, or linear drives with millimetre dimensions. The main measurement problems were presented and the specificity of these measurements was characterized. First of all, electromechanical time constants have small values due to small values of masses or mass moments of inertia. The force quantities (forces and torques) generated by such actuators also require the use of unconventional measuring transducers. The research may concern the identification of static and dynamic characteristics, but also methods of dynamic measurement of the quantities used in the control of such micromachines are presented. Practical examples of original measurement methods and systems are presented.
Model of the pressing and drying system of organic material
Authors: Domek G , Talaśka K
Published: November 2021

The following paper presents a model of a system operating and drying food waste. This paper was written in response to the challenge of reducing food waste, minimizing environmental pollution, decay processes, and exploring the possibility of using said waste. The design of such a system has proven to be innovative, despite still being under construction. Whilst the pressing and drying process itself is not new, the list of process parameters has not previously been used, thus proving innovative in the developed model. High pressure pressing does not only change the geometric form or the physical properties of the material. Such a process also changes the physicochemical properties.

The authors' previous experience in pressing organic materials is referenced in this work. Basic parameters such as temperature, pressure and process duration have been developed in earlier studies. In the proposed model, the friction against the walls in the compression chamber have been eliminated. This changes the parameters inside the compression chamber and will certainly improve the lifetime of the system. Previous solutions, such as screw presses, or for higher power - piston ones, were not durable and very energy-consuming. The new solution is much more durable and allows for use of higher pressures. Depending on the materials selected for the process, it will be possible to obtain new products that have not been produced before, due to the limitations of the pressing process.

The developed model of pressing and drying organic materials will also allow the further production of ecological fuels from waste materials, like from the waste of the wood industry. It will also allow the use of straw in the production of new building materials. After making the model, there will be a wide scope for further research.
Thermal analysis and experimental testing of clamping jaws for thermomechanical simulator
Authors: Kalina T , Marek V , Jenicek S , Letak R
Published: November 2021

This paper presents a thermal analysis of clamping jaws for a thermomechanical simulator, which is compared with the results from a thermal camera and thermocouples placed directly on the specimens during experimental testing. The clamping jaws have several cooling circuits inside of them and are actively cooled throughout the process. The test specimens are in turn heated by high-frequency electrical resistance heating. During the testing, it was observed whether the cooling system is sufficient, partly because polymeric materials are also used on the jaws to electrically insulate the system. Based on the measurements, it was found that even though the test specimen is heated almost to 1000 °C for a long time, the temperature of the jaws does not exceed 40 °C. The suitability of the proposed cooling system was proved and also the satisfactory agreement of experimental measurements with numerical simulations was achieved.
Chitin conduits modified with DNA-peptide coating promote the peripheral nerve regeneration
Authors: Liu Songyang , Zhou Liping , Li Ci , Min Tiantian , Lu Changfeng , Han Shuai , Zhang Meng , Wen Yongqiang , Zhang Peixun , Jiang Baoguo
Published: November 2021

Peripheral nerve injury (PNI) is one of the common clinical injuries which needs to be addressed. Previous studies demonstrated the effectiveness of using biodegradable chitin (CT) conduits small gap tubulization technology as a substitute for traditional epineurial neurorrhaphy. Aiming to improve the effectiveness of CT conduits in repairing PNI, we modified their surface with a DNA-peptide coating. The coating consisted of single strand DNA (ssDNA) and its complementary DNAʹ-peptide mimics. First, we immobilize ssDNA (DNA1 + 2) on CT conduits by carbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) method to construct CT/DNA conduits. EDC/NHS was used to activate carboxyl groups of modified ssDNA for direct reaction with primary amines on the CT via amide bond formation. Then, DNA1ʹ-BDNF + DNA2ʹ-VEGF mimic peptide (RGI + KLT) were bonded to CT/DNA conduits by complementary base pairing principle at room temperature to form CT/RGI + KLT conduits. When the surrounding environment rose to a certain point (37 °C), the CT/RGI + KLT conduits achieved sustainable release of DNA′-peptide. In vitro, the CT conduits modified with the DNA-peptide coating promoted the proliferation and secretion of Schwann cells by maintaining their repair state. It also promoted the proliferation of human umbilical vein vessel endothelial cells and axon outgrowth of dorsal root ganglion explants. In vivo, CT/RGI + KLT conduits promoted regeneration of injured nerves and functional recovery of target muscles, which was facilitated by the synergistic contribution of angiogenesis and neurogenesis. Our research brings DNA and DNA-peptide hybrids into the realm of tissue engineering to repair PNI.
Thin homotopy and the holonomy approach to gauge theories
Authors: Meneses Claudio
Published: November 2021

We survey several mathematical developments in the holonomy approach to gauge theory. A cornerstone of this approach is the introduction of group structures on spaces of based loops on a smooth manifold, relying on certain homotopy equivalence relations — such as the so-called thin homotopy — and the resulting interpretation of gauge fields as group homomorphisms to a Lie group

G
G

satisfying a suitable smoothness condition, encoding the holonomy of a gauge orbit of smooth connections on a principal

G
G

-bundle. We also prove several structural results on thin homotopy, and in particular we clarify the difference between thin equivalence and retrace equivalence for piecewise-smooth based loops on a smooth manifold, which are often used interchangeably in the physics literature. We conclude by listing a set of questions on topological and functional analytic aspects of groups of based loops, which we consider to be fundamental to establish a rigorous differential geometric foundation of the holonomy formulation of gauge theory.
Associations between Low to Moderate Consumption of Alcoholic Beverage Types and Health Outcomes: A Systematic Review
Authors: Estruch Ramon , Hendriks Henk F J
Published: November 2021

Aims

There is limited research comparing light to moderate wine, beer and spirits consumption and their impact on long-term health. This systematic review aims to investigate the studies published in the past 10 years and qualitatively assess the similarities and differences between the three main beverages, when consumed at a low to moderate level, for their associations with various health outcomes.

Methods

A systematic search was conducted for comparative studies published in English language (2010 to mid-2021) of beverage-specific low to moderate alcohol consumption associated with all-cause mortality, cancer, cardiovascular disease and diabetes mellitus type II.

Results

The search yielded a total of 24 studies (8 meta-analyses; 15 prospective studies and 1 pooled analysis). Overall, most studies showed similar associations of different alcoholic beverages with chronic conditions, including all-cause mortality, many types of cancer, cardiovascular disease and diabetes mellitus type II. Not all data are consistent. Some studies show more beneficial or detrimental effects of wine than other beverage types, whereas other studies show such effects for other beverages.

Conclusion

Moderate consumption of one specific alcoholic beverage (wine, beer or spirits) may not be consistently associated with higher or lower risks for common health outcomes as compared with moderate consumption of any of the other alcoholic beverages.
Development and Validation of Reversed-Phase HPLC Method for the Determination of Epirubicin and Its Application to the Pharmacokinetic Study of Epirubicin Loaded Polymeric Nanoparticle Formulations in Rats
Authors: Khalil Saifullah Khan , Iqbal Zafar , Niaz Nabeela , Iftikhar Tayyaba
Published: November 2021

Epirubicin, commonly used as anticancer drug for various types of tumors like breast, liver, lung, stomach, ovaries, and bladder for its improved antitumor efficacy and safety. A rapid, sensitive, and reliable bioanalytical method was developed and validated for epirubicin using conventional reverse phase HPLC with UV detection. The developed method was successfully applied to investigate the pharmacokinetics of epirubicin after intravenous administration of a reference epirubicin and its designed nano-formulations to rats. C18 column was used in an isocratic mode for analyte elution at a flow rate of 1.0 mL/min with UV detection of 234 nm. The mobile phase was composed of acetonitrile 22% (channel A) and 0.025% tri fluoro-acetic acid in water (channel B). Ondansetron was added as an internal standard, and the plasma samples were analyzed after protein precipitation. A concentration range of 0.016–1.024 μg/mL was selected for the construction of calibration curves, with LLOQ of 0.016 μg/mL. Results showed that the value of AUC, half-life, and mean residence time of designed nano-formulation were bounce to 10, 9, and 11 times higher, when compared to the reference epirubicin after intravenous dose of 10 mg/kg of epirubicin to rats, respectively. The designed epirubicin nano-formulations achieved clinically significant pharmacokinetic values in rats. Current method will help epirubicin future research using clinical samples and drug bioequivalence studies on various novel formulations for drug safety purposes.
Primary hyperoxaluria: the pediatric nephrologist's point of view
Authors: Ben-Shalom Efrat , Garrelfs Sander F , Groothoff Jaap W
Published: November 2021

The clinical presentation of primary hyperoxaluria in children ranges from mildly symptomatic nephrocalcinosis to very early onset end-stage kidney failure with systemic oxalosis, a devastating complication. We review the various manifestations of pediatric hyperoxaluria, treatment options for children with preserved kidney function and appropriate dialysis regimens. Liver or combined liver/kidney transplantation is currently the only definitive treatment for primary hyperoxaluria type 1, but novel RNA interference treatments offer hope for the future. Finally, we address the medical and ethical dilemmas facing pediatricians treating children with hyperoxaluria.
Differential Serum-intestinal Dynamics of Infliximab and Adalimumab in Inflammatory Bowel Disease Patients
Authors: Bar-Yoseph Haggai , Blatt Alexandra , Gerassy Shiran , Pressman Sigal , Mousa Amjad , Sabo Edmond , Waterman Matti , Ungar Bella , Ben-Horin Shomron , Chowers Yehuda
Published: November 2021

Background and Aims

Therapeutic drug monitoring is used to guide anti-tumour necrosis factor [TNF] therapy. However, the associations between serum drug levels [SDL], TNF-bound, and free anti-TNF in the target tissue are incompletely defined. We aimed to assess the interactions between these parameters in inflammatory bowel disease [IBD] patients.

Methods: Enzyme-linked immunosorbent

assays [ELISA assays] were used to detect free drug and TNF-drug complexes in intestinal tissues. Concurrent SDL, anti-drug antibodies [ADA], pharmacotherapy, clinical response, endoscopic appearance, and histological severity were determined. Comparisons between anti-TNFs and paired inflamed/non-inflamed tissue were performed. Variables were correlated and potential interactions detected using multivariate analysis.

Results

A total of 95 biopsies taken from 49 anti-TNF treated IBD patients [26 receiving infliximab and 23 adalimumab] were studied. Free drug levels were higher in inflamed compared with non-inflamed paired specimens. Tissue free-drug and TNF-drug complexes levels were higher in adalimumab-treated patients. In adalimumab-treated patients, SDL were correlated with free drug, but not TNF-drug complex levels, in both inflamed and non-inflamed segments. In infliximab-treated patients, higher SDL were associated with the presence of tissue free drug in both inflamed and non-inflamed segments, whereas TNF-drug complexes were mostly detected in non-inflamed but not in inflamed tissue. In the presence of ADA, neither free drug nor TNF-infliximab complexes were measured in the tissue. Tissue levels did not correlate well with clinical, endoscopic, or histological scores.

Conclusions

SDL correlated with tissue free drug levels; however, different dynamics were observed for TNF-drug complex levels. Infliximab and adalimumab tissue drug dynamics differ. Better understanding of these interactions may allow future therapeutic optimisation.
Genome-Scale Data Reveal Deep Lineage Divergence and a Complex Demographic History in the Texas Horned Lizard (Phrynosoma cornutum) throughout the Southwestern and Central United States
Authors: Finger Nicholas , Farleigh Keaka , Bracken Jason T , Leaché Adam D , François Olivier , Yang Ziheng , Flouri Tomas , Charran Tristan , Jezkova Tereza , Williams Dean A , Blair Christopher
Published: November 2021

The southwestern and central United States serve as an ideal region to test alternative hypotheses regarding biotic diversification. Genomic data can now be combined with sophisticated computational models to quantify the impacts of paleoclimate change, geographic features, and habitat heterogeneity on spatial patterns of genetic diversity. In this study, we combine thousands of genotyping-by-sequencing (GBS) loci with mtDNA sequences (ND1) from the Texas horned lizard (Phrynosoma cornutum) to quantify relative support for different catalysts of diversification. Phylogenetic and clustering analyses of the GBS data indicate support for at least three primary populations. The spatial distribution of populations appears concordant with habitat type, with desert populations in AZ and NM showing the largest genetic divergence from the remaining populations. The mtDNA data also support a divergent desert population, but other relationships differ and suggest mtDNA introgression. Genotype–environment association with bioclimatic variables supports divergence along precipitation gradients more than along temperature gradients. Demographic analyses support a complex history, with introgression and gene flow playing an important role during diversification. Bayesian multispecies coalescent analyses with introgression (MSci) analyses also suggest that gene flow occurred between populations. Paleo-species distribution models support two southern refugia that geographically correspond to contemporary lineages. We find that divergence times are underestimated and population sizes are overestimated when introgression occurred and is ignored in coalescent analyses, and furthermore, inference of ancient introgression events and demographic history is sensitive to inclusion of a single recently admixed sample. Our analyses cannot refute the riverine barrier or glacial refugia hypotheses. Results also suggest that populations are continuing to diverge along habitat gradients. Finally, the strong evidence of admixture, gene flow, and mtDNA introgression among populations suggests that P. cornutum should be considered a single widespread species under the General Lineage Species Concept.
Balancing Animal Welfare, Human Safety, and Research in Agriculture High Containment
Authors: Pickering Brad , Lewis Charles E
Published: November 2021

Livestock research is paramount to understanding the risks associated with unintentional and intentional introductions of emerging, reemerging, and transboundary animal diseases, including their relationship to both the security of the economy and the nation’s food supply. Research involving large animal species conducted in maximum containment Biosafety Level (BSL)-3Ag and BSL-4 facilities include Health and Human Services and United States Department of Agriculture Select Agents that can have severe consequences on both animal agricultural industry and public health. This themed issue of ILAR spans the spectrum of concerns related to this special niche within the animal research community with an emphasis on a review of available research, current trends, and novel approaches relevant to those conducting large animal research with high-risk agents and those charged with regulating those facilities and programs. Articles are authored by those embedded in the high- and maximum-containment community, directly involved with the work, detailing the unique challenges associated with BSL-3 and BSL-4 livestock research.
Impact of rapid susceptibility testing on antimicrobial therapy and clinical outcomes in Gram-negative bloodstream infections
Authors: Anton-Vazquez Vanesa , Suarez Cristina , Planche Timothy
Published: November 2021

Background

Rapid antimicrobial susceptibility testing (rAST) has the potential to improve care of bloodstream infections.

Objectives

The aim of this service evaluation was to assess the impact of rAST on antimicrobial therapy and clinical outcomes in patients with Gram-negative bloodstream infection.

Methods

A prospective service evaluation was conducted from March 2018 to December 2018. A rAST system (Alfred 60AST) was run Monday–Friday before midday and results were communicated to clinicians on the same day as positive blood culture, with subsequent conventional AST performed. Times to antibiotic therapy and clinical outcomes were compared between rAST and conventional AST.

Results

One hundred and ninety-one patients with Gram-negative bacteraemia were included (93 in the rapid group and 98 in the conventional group). Aminoglycoside combination therapy was stopped earlier in the rapid group [32 h (0–795) versus 54 h (4–216), P = 0.002]. The median time to optimal antibiotic based on AST results was significantly shorter than that in the conventional group [50 h (10–339) versus 69.5 h (20–872), P = 0.034]. In the subgroup of patients on ineffective empirical antibiotic, time to effective antibiotic was shorter in the rapid group [39.5 h (32–97) versus 57 h (49–83), P = 0.036]. No differences were found in 28 day mortality or length of stay.

Conclusions

Rapid susceptibility testing resulted in faster discontinuation of aminoglycosides and a shorter time to starting effective and optimal antibiotic when compared with conventional AST results. rAST has potential clinical benefits and points to the need for larger future studies in areas of high antibiotic resistance.
Scirtothrips dorsalis (Thysanoptera: Thripidae) Is a Pest of Celery, Apium graveolens (Apiales: Apiaceae): First Report and Diagnostic Characters
Authors: Sreerama Kumar Prakya , Remani Rachana Rajan
Published: November 2021

Scirtothrips dorsalis (Hood), the chilli thrips, is reported for the first time as a pest of celery, Apium graveolens L. Infested celery plants in a polyhouse at Kalahalli village (13°05′46.0′′N, 77°47′12.2′′E) in Hoskote taluk of Bengaluru Rural district, Karnataka, India, had light to dark brownish scars on various parts besides discolored and distorted leaves. Association of fungal or bacterial disease was dismissed based on microscopic analysis of tissue sections. Eggs, juveniles, and adults of thrips were abundant, especially on the leaves. Diagnostic characters of the adult S. dorsalis collected on celery are presented here along with photomicrographs. Juvenile and adult stages of S. dorsalis were also recorded on 27 other plant species in 18 families during the surveys conducted in 18 districts of Karnataka from 2015 to 2021. The possible role of S. dorsalis as a vector of tospoviruses in celery needs to be investigated.
Recent progress and future perspective of electron cryomicroscopy for structural life sciences
Authors: Namba Keiichi , Makino Fumiaki
Published: November 2021

The three-dimensional structure of biological macromolecules, such as proteins and nucleic acids, and their complexes is the fundamental information not only for life sciences but also for medical sciences and drug design. Electron cryomicroscopy has become an extremely powerful tool for high-resolution structural analysis of biological macromolecules, not just in addition to X-ray crystallography and nuclear magnetic resonance sepectroscopy (NMR) that have been used as the basic techniques in structural biology. By the development of hardware and software, such as transmission electron cryomicroscopes with highly stable and controllable electron optics, cold field emission gun and energy filter, complementary metal oxide semiconductor (CMOS)-based direct electron detectors with high frame rate and high sensitivity, high-speed computers and software programs for image analysis, electron cryomicroscopy now allows structure determination of biological macromolecules at atomic levels within a few days even from a drop of solution sample with an amount as small as a few micrograms. How can the structures of macromolecules be imaged and analyzed at atomic level resolution in their native states despite their high sensitivity to radiation damage at a relatively low level of electron irradiation? We describe recent progress and future perspective of electron cryomicroscopy for structural life sciences.
S1417CD: A Prospective Multicenter Cooperative Group-Led Study of Financial Hardship in Metastatic Colorectal Cancer Patients
Authors: Shankaran Veena , Unger Joseph M , Darke Amy K , Suga Jennifer Marie , Wade James L , Kourlas Peter J , Chandana Sreenivasa R , O’Rourke Mark A , Satti Suma , Liggett Diane , Hershman Dawn L , Ramsey Scott D
Published: November 2021

Background

Financial toxicity is a growing problem in oncology, but no prior studies have prospectively measured the financial impact of cancer treatment in a diverse national cohort of newly diagnosed cancer patients. S1417CD was the first cooperative group-led multicenter prospective cohort study to evaluate financial hardship in metastatic colorectal cancer (mCRC) patients.

Methods

Patients aged 18 years or older within 120 days of mCRC diagnosis completed quarterly questionnaires for 12 months. We estimated the cumulative incidence of major financial hardship (MFH), defined as 1 or more of increased debt, new loans from family and/or friends, selling or refinancing home, or 20% or more income decline. We evaluated the association between patient characteristics and MFH using multivariate cox regression and the association between MFH and quality of life using linear regression.

Results

A total of 380 patients (median age = 59.9 years) were enrolled; 77.7% were White, 98.0% insured, and 56.5% had annual income of $50 000 or less. Cumulative incidence of MFH at 12 months was 71.3% (95% confidence interval = 65.7% to 76.1%). Age, race, marital status, and income (split at $50 000 per year) were not statistically significantly associated with MFH. However, income less than $100 000 and total assets less than $100 000 were both associated with greater MFH. MFH at 3 months was associated with decreased social functioning and quality of life at 6 months.

Conclusions

Nearly 3 out of 4 mCRC patients experienced MFH despite access to health insurance. These findings underscore the need for clinic and policy solutions that protect cancer patients from financial harm.
An Imaging Biomarker of Tumor-Infiltrating Lymphocytes to Risk-Stratify Patients With HPV-Associated Oropharyngeal Cancer
Authors: Corredor Germán , Toro Paula , Koyuncu Can , Lu Cheng , Buzzy Christina , Bera Kaustav , Fu Pingfu , Mehrad Mitra , Ely Kim A , Mokhtari Mojgan , Yang Kailin , Chute Deborah , Adelstein David J , Thompson Lester D R , Bishop Justin A , Faraji Farhoud , Thorstad Wade , Castro Patricia , Sandulache Vlad , Koyfman Shlomo A , Lewis James S , Madabhushi Anant
Published: November 2021

Background

Human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (OPSCC) has excellent control rates compared to nonvirally associated OPSCC. Multiple trials are actively testing whether de-escalation of treatment intensity for these patients can maintain oncologic equipoise while reducing treatment-related toxicity. We have developed OP-TIL, a biomarker that characterizes the spatial interplay between tumor-infiltrating lymphocytes (TILs) and surrounding cells in histology images. Herein, we sought to test whether OP-TIL can segregate stage I HPV-associated OPSCC patients into low-risk and high-risk groups and aid in patient selection for de-escalation clinical trials.

Methods

Association between OP-TIL and patient outcome was explored on whole slide hematoxylin and eosin images from 439 stage I HPV-associated OPSCC patients across 6 institutional cohorts. One institutional cohort (n = 94) was used to identify the most prognostic features and train a Cox regression model to predict risk of recurrence and death. Survival analysis was used to validate the algorithm as a biomarker of recurrence or death in the remaining 5 cohorts (n = 345). All statistical tests were 2-sided.

Results

OP-TIL separated stage I HPV-associated OPSCC patients with 30 or less pack-year smoking history into low-risk (2-year disease-free survival [DFS] = 94.2%; 5-year DFS = 88.4%) and high-risk (2-year DFS = 82.5%; 5-year DFS = 74.2%) groups (hazard ratio = 2.56, 95% confidence interval = 1.52 to 4.32; P < .001), even after adjusting for age, smoking status, T and N classification, and treatment modality on multivariate analysis for DFS (hazard ratio = 2.27, 95% confidence interval = 1.32 to 3.94; P = .003).

Conclusions

OP-TIL can identify stage I HPV-associated OPSCC patients likely to be poor candidates for treatment de-escalation. Following validation on previously completed multi-institutional clinical trials, OP-TIL has the potential to be a biomarker, beyond clinical stage and HPV status, that can be used clinically to optimize patient selection for de-escalation.
Updated Guidance on Use and Prioritization of Monoclonal Antibody Therapy for Treatment of COVID-19 in Adolescents
Authors: Wolf Joshua , Abzug Mark J , Anosike Brenda I , Vora Surabhi B , Waghmare Alpana , Sue Paul K , Olivero Rosemary M , Oliveira Carlos R , James Scott H , Morton Theodore H , Maron Gabriela M , Young Jennifer L , Orscheln Rachel C , Schwenk Hayden T , Bio Laura L , Willis Zachary I , Lloyd Elizabeth C , Hersh Adam L , Huskins Charles W , Soma Vijaya L , Ratner Adam J , Hayes Molly , Downes Kevin , Chiotos Kathleen , Grapentine Steven P , Wattier Rachel L , Lamb Gabriella S , Zachariah Philip , Nakamura Mari M
Published: November 2021

Background

Starting in November 2020, the US Food and Drug Administration (FDA) has issued Emergency Use Authorizations (EUAs) for multiple novel virus-neutralizing monoclonal antibody therapies, including bamlanivimab monotherapy (now revoked), bamlanivimab and etesivimab, casirivimab and imdevimab (REGEN-COV), and sotrovimab, for treatment or postexposure prophylaxis of Coronavirus disease 2019 (COVID-19) in adolescents (≥12 years of age) and adults with certain high-risk conditions. Previous guidance is now updated based on new evidence and clinical experience.

Methods

A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacotherapy, and pediatric critical care medicine from 18 geographically diverse US institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on a review of the best available evidence and expert opinion.

Results

The course of COVID-19 in children and adolescents is typically mild, though more severe disease is occasionally observed. Evidence supporting risk stratification is incomplete. Randomized controlled trials have demonstrated the benefit of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific monoclonal antibody therapies in adults, but data on safety and efficacy in children or adolescents are limited. Potential harms associated with infusion reactions or anaphylaxis are reportedly low in adults.

Conclusions

Based on evidence available as of August 31, 2021, the panel suggests a risk-based approach to administration of SARS-CoV-2 monoclonal antibody therapy. Therapy is suggested for the treatment of mild to moderate COVID-19 in adolescents (≥12 years of age) at the highest risk of progression to hospitalization or severe disease. Therapeutic decision-making about those at moderate risk of severe disease should be individualized. Use as postexposure prophylaxis could be considered for those at the highest risk who have a high-risk exposure but are not yet diagnosed with COVID-19. Clinicians and health systems should ensure safe and timely implementation of these therapeutics that does not exacerbate existing healthcare disparities.
Perinuclear positioning of endosomes can affect PS-ASO activities
Authors: Liang Xue-hai , Nichols Joshua G , Tejera Dario , Crooke Stanley T
Published: November 2021

Phosphorothioate (PS) modified antisense oligonucleotide (ASO) drugs that act on cellular RNAs must enter cells and be released from endocytic organelles to elicit antisense activity. It has been shown that PS-ASOs are mainly released by late endosomes. However, it is unclear how endosome movement in cells contributes to PS-ASO activity. Here, we show that PS-ASOs in early endosomes display Brownian type motion and migrate only short distances, whereas PS-ASOs in late endosomes (LEs) move linearly along microtubules with substantial distances. In cells with normal microtubules and LE movement, PS-ASO-loaded LEs tend to congregate perinuclearly. Disruption of perinuclear positioning of LEs by reduction of dynein 1 decreased PS-ASO activity, without affecting PS-ASO cellular uptake. Similarly, disruption of perinuclear positioning of PS-ASO-LE foci by reduction of ER tethering proteins RNF26, SQSTM1 and UBE2J1, or by overexpression of P50 all decreased PS-ASO activity. However, enhancing perinuclear positioning through reduction of USP15 or over-expression of RNF26 modestly increased PS-ASO activity, indicating that LE perinuclear positioning is required for ensuring efficient PS-ASO release. Together, these observations suggest that LE movement along microtubules and perinuclear positioning affect PS-ASO productive release.
Crohn disease
Authors: Snyder Elizabeth F. , Davis Stephanie , Aldrich Kristina , Veerabagu Manjakkollai , Larussa Tiziana , Abenavoli Ludovico , Boccuto Luigi
Published: November 2021

Crohn disease is an inflammatory bowel disorder affecting children and adults. With its increasing prevalence, healthcare providers need adequate resources to assist with diagnosis and management. This article discusses early diagnosis, disease severity and classification, familial predisposition and genomics, and clinical management in the primary care setting.
CHIPS
Authors: El Hussein Mohamed Toufic , Ha Calla
Published: November 2021

Contrast-induced nephropathy is the leading cause of acute kidney injury in hospital settings. Practitioners must have a comprehensive understanding of preventive interventions. This article provides a mnemonic NPs can use to prevent contrast-induced nephropathy. The mnemonic, CHIPS, addresses Contrast minimizations, Hemofiltration, Iso-osmolar/low osmolar contrast, Pharmacologic interventions, and Saline I.V. hydration.
TCR-independent Activation in Presence of a Src-family Kinase Inhibitor Improves CAR-T Cell Product Attributes
Authors: Lamture Gauri , Baer Alan , Fischer Joseph W. , Colon-Moran Winston , Bhattarai Nirjal
Published: November 2021

Chimeric antigen receptor expressing T cells (CAR-T cells) have shown remarkable efficacy against some blood cancers and have potential to treat many other human diseases. During CAR-T cell manufacturing, T cells are activated via engagement of the T-cell receptor (TCR); however, persistent TCR engagement can induce unchecked activation, differentiation, and exhaustion, which can negatively affect CAR-T cell product quality and in vivo potency. In addition, T cells may not uniformly respond to TCR-dependent activation (TCRD) contributing to lot-to-lot variability, poor expansion, and manufacturing failures. TCRD also presents challenges during manufacturing of allogeneic CAR-T cells when endogenous TCR is deleted to prevent graft-versus-host disease. Thus, novel strategies to activate T cells may help improve CAR-T cell product attributes and reduce manufacturing failures. In this study, we compared the effect of TCRD and TCR-independent activation (TCRI) on CAR-T cell product attributes. We found that TCRI in presence of a Src-kinase inhibitor significantly improved CAR-T cell expansion and yield without affecting viability and CD4/CD8 ratio. Markers of T-cell activation, exhaustion and differentiation were also reduced in these CAR-T cells compared with CAR-T cells manufactured by TCRD. TCRI did not affect CAR-T cell in vitro potency; however, following co-culture with target cells, CAR-T cells manufactured by TCRI released significantly less inflammatory cytokines compared with CAR-T cells manufactured by TCRD. Together, these data suggest that manufacturing CAR-T cells by TCRI activation in the presence of a Src-kinase inhibitor improves product quality attributes and may help reduce manufacturing failures and improve CAR-T cell safety and efficacy in vivo.
Mycobacterium tuberculosis latency-associated antigen Rv1733c SLP improves the accuracy of differential diagnosis of active tuberculosis and latent tuberculosis infection
Authors: Zhang Lifan , Ma Huimin , Wan Shijun , Zhang Yueqiu , Gao Mengqiu , Liu Xiaoqing
Published: November 2021

Background:

Differential diagnosis of active tuberculosis (ATB) and latent tuberculosis infection (LTBI) has been a challenge for clinicians in high TB burden countries. The purpose of this study was to improve the accuracy of differential diagnosis of ATB and LTBI by using fluorescent immunospot (FluoroSpot) assay to detect specific Th1 cell immune responses. The novel mycobacterium tuberculosis (MTB) latency-associated antigens Rv1733c and synthetic long peptides derived from Rv1733c (Rv1733c SLP) were used based on virulence factors early secreting antigen target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10).

Methods:

Fifty-seven ATB cases, including 20 pathogen-confirmed ATB and 37 clinically diagnosed ATB, and 36 LTBI cases, were enrolled between January and December 2017. FluoroSpot assay was used to detect the interferon γ (IFN-γ) and interleukin 2 (IL-2) secreted by the specific T cells after being stimulated with MTB virulence factors ESAT-6 and CFP-10, MTB latency-associated antigens Rv1733c and Rv1733c SLP. The receiver operating characteristic (ROC) curve was used to define the best cutoff value of latency-associated antigens in the use of differentiating ATB and LTBI. The sensitivity, specificity, predictive value, and likelihood ratio of ESAT-6 and CFP-10-FluoroSpot combined with latency-associated antigen in the differential diagnosis of ATB and LTBI were also calculated.

Results:

Following the stimulation with Rv1733c and Rv1733c SLP, the frequency of single IL-2-secreting T cells stimulated by Rv1733c SLP had the largest area under the ROC curve, which was 0.766. With a cutoff value of 1 (spot-forming cells [SFCs]/2.5 × 105 peripheral blood mononuclear cells) for frequency, the sensitivity and specificity of distinguishing ATB from LTBI were 72.2% and 73.7%, respectively. ESAT-6 and CFP-10-FluoroSpot detected the frequency and proportion of single IFN-γ-secreting T cells; the sensitivity and specificity of distinguishing ATB from LTBI were 82.5% and 66.7%, respectively. Combined with the frequency of single IL-2-secreting T cells stimulated by Rv1733c SLP on the basis of ESAT-6 and CFP-10-FluoroSpot, the sensitivity and specificity increased to 84.2% and 83.3%, respectively.

Conclusion:

Rv1733c SLP, combined with ESAT-6 and CFP-10, might be used as a candidate antigen for T cell-based tuberculosis diagnostic tests to differentiate ATB from LTBI.
Characteristics and outcomes following transcatheter aortic valve replacement in China: a report from China aortic valve transcatheter replacement registry (CARRY)
Authors: Li Yi-Ming , Xiong Tian-Yuan , Xu Kai , Fang Zhen-Fei , Jiang Lei , Jin Jun , He Sheng-Hu , Yang Yi-Ning , He Jing-Jing , Jia Yu-Heng , Zhang Yi , Peng Yong , Feng Yuan , Chen Mao
Published: November 2021

Background:

The past decade has witnessed an ever-increasing momentum of transcatheter aortic valve replacement (TAVR) and a subsequent paradigm shift in the contemporary management of severe aortic stenosis (AS). We conducted a multi-centric TAVR registry based on Chinese patients (the China Aortic valve tRanscatheter Replacement registrY [CARRY]) to delineate the clinical characteristics and outcomes of Chinese patients who underwent TAVR and compare the results between different valve types in different Chinese regions.

Methods:

CARRY is an all-comer registry of aortic valve disease patients undergoing TAVR across China and was designed as an observational study that retrospectively included all TAVR patients at each participating site. Seven hospitals in China participated in the CARRY, and 1204 patients from April 2012 to November 2020 were included. Categorical variables were compared using the chi-squared test, and continuous variables were analyzed using a t test or analysis of variance (ANOVA) test. The Kaplan–Meier curve was used to estimate the risk of adverse events during follow-up.

Results:

The mean age of the patients was 73.8 ± 6.5 years and 57.2% were male. The median Society of Thoracic Surgeon-Predicted Risk of Mortality score was 6.0 (3.7–8.9). Regarding the aortic valve, the proportion of bicuspid aortic valve (BAV) was 48.5%. During the hospital stay, the stroke rate was 0.7%, and the incidence of high-degree atrioventricular block indicating permanent pacemaker implantation was 11.0%. The in-hospital all-cause mortality rate was 2.2%. After 1 year, the overall mortality rate was 4.5%. Compared to patients with tricuspid aortic valve (TAV), those with BAV had similar in-hospital complication rates, but a lower incidence of in-hospital mortality (1.4% vs. 3.3%) and 1 year mortality (2.3% vs. 5.8%).

Conclusions:

TAVR candidates in China were younger, higher proportion of BAV, and had lower rates of post-procedural complications and mortality than other international all-comer registries. Given the use of early generation valves in the majority of the population, patients with BAV had similar rates of complications, but lower mortality than those with TAV. These findings further propel the extension of TAVR in low-risk patients.

Trial Registration:

https://www.chictr.org.cn/ (No. ChiCTR2000038526).
Methotrexate as a Steroid-Sparing Agent in Myasthenia Gravis: A Preliminary Retrospective Study
Authors: Rodolico Carmelo , Bonanno Carmen , Brizzi Teresa , Nicocia Giulia , Trimarchi Giuseppe , Lupica Antonino , Pugliese Alessia , Musumeci Olimpia , Toscano Antonio
Published: November 2021

Objectives:

Treatment approach of myasthenia gravis (MG) is still debated; corticosteroids alone or in combination with immunosuppressive agents are the most used drugs. Azathioprine (AZA) has been shown to be effective for MG with a significant steroid-sparing activity, although burdened by side effects. Few studies on methotrexate (MTX) administration showed controversial results. In this cohort, we evaluated the role of MTX as a effective steroid-sparing agent.

Methods:

Fifteen MG patients treated with MTX, previously treated with AZA for at least 12 months, with poor benefits and uncomfortable side effects AZA related, have been selected. Each patient was evaluated through MG-Activity of Daily Living and Quantitative MG scores 5 times/yr.

Results:

Patients treated with MTX had a significant improvement of MG-Activity of Daily Living and Quantitative MG scores. Furthermore, all patients reduced prednisone dosage, and none complained of side effects.

Conclusions:

We suggest MTX is effective and well tolerated and could be considered as a steroid-sparing agent in MG treatment.
Evaluating the Efficacy of an Evidence-Based Charge Nurse Professional Development Activity at a Highly Complex Veterans Affairs Medical Center
Authors: Breedlove David W. , Amiri Azita , Arris Latonia
Published: November 2021

Incompetent charge nurses negatively impact quality patient care. An analysis of a charge nurse professional development activity intervention included pre- and posttests, an activity curriculum evaluation, and staff satisfaction surveys. Posttest scores improved significantly (t = 60, p = .001). All participants rated the professional development activity as highly appropriate and beneficial to their nursing practice.
The Great Auricular Nerve Trigger Site: Anatomy, Compression Point Topography, and Treatment Options for Headache Pain
Authors: Schoenbrunner Anna , Konschake Marko , Zwierzina Marit , Egro Francesco M. , Moriggl Bernhard , Janis Jeffrey E.
Published: November 2021

Background:

Peripheral nerve decompression surgery can effectively address headache pain caused by compression of peripheral nerves of the head and neck. Despite decompression of known trigger sites, there are a subset of patients with trigger sites centered over the postauricular area coursing. The authors hypothesize that these patients experience primary or residual pain caused by compression of the great auricular nerve.

Methods:

Anatomical dissections were carried out on 16 formalin-fixed cadaveric heads. Possible points of compression along fascia, muscle, and parotid gland were identified. Ultrasound technology was used to confirm these anatomical findings in a living volunteer.

Results:

The authors’ findings demonstrate that the possible points of compression for the great auricular nerve are at Erb’s point (point 1), at the anterior border of the sternocleidomastoid muscle in the dense connective tissue before entry into the parotid gland (point 2), and within its intraparotid course (point 3). The mean topographic measurements were as follows: Erb’s point to the mastoid process at 7.32 cm/7.35 (right/left), Erb’s point to the angle of the mandible at 6.04 cm/5.89 cm (right/left), and the posterior aspect of the sternocleidomastoid muscle to the mastoid process at 3.88 cm/4.43 cm (right/left). All three possible points of compression could be identified using ultrasound.

Conclusions:

This study identified three possible points of compression of the great auricular nerve that could be decompressed with peripheral nerve decompression surgery: Erb’s point (point 1), at the anterior border of the sternocleidomastoid muscle (point 2), and within its intraparotid course (point 3).
Patient and Caregiver Health-related Quality of Life and Caregiver Burden While Awaiting Heart Transplantation: Findings From the Sustaining Quality of Life of the Aged: Heart Transplant or Mechanical Support (SUSTAIN-IT) Study
Authors: Grady Kathleen L. , Okwuosa Ike , Andrei Adin-Cristian , Wu Tingqing , Elenbaas Christian , Warzecha Anna , Baldridge Abigail , Petty Michael
Published: November 2021

Background.

We sought to compare change over time (baseline to 2 y) in health-related quality of life (HRQOL) between older (60–80 y) patients awaiting heart transplantation (HT) with mechanical circulatory support (MCS) versus without MCS and their caregivers and caregiver burden.

Methods.

This study was conducted at 13 United States sites. Patient HRQOL was examined using the EuroQol 5-dimensional questionnaire (EQ-5D-3L) and Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12). Caregiver measures included the EQ-5D-3L and Oberst Caregiving Burden Scale, measuring time on task and difficulty. Analyses included analysis of variance, χ2, and linear regression.

Results.

We enrolled 239 HT candidates (n = 118 with MCS and n = 121 without MCS) and 193 caregivers (n = 92 for candidates with MCS and n = 101 for candidates without MCS). Baseline differences in HRQOL were observed between HT candidates with and without MCS: EQ-5D-3L visual analog scale (VAS) score (67.7 ± 17.6 versus 54.1 ± 23.3, P < 0.001) and KCCQ-12 overall summary score (59.9 ± 21.0 versus 48.9 ± 21.6, P < 0.001), respectively. HT candidates with MCS had significantly higher EQ-5D-3L VAS scores and KCCQ-12 overall summary score across time versus without MCS. Baseline EQ-5D-3L VAS scores did not differ significantly between caregivers of HT candidates with and without MCS (84.6 ± 12.9 versus 84.3 ± 14.4, P = 0.9), respectively, nor were there significant between-group differences over time. Caregivers for HT candidates with MCS reported more task difficulty (range: 1 = not difficult to 5 = extremely difficult) versus caregivers for those without MCS at baseline (1.4 ± 0.5 versus 1.2 ± 0.3, P = 0.004) and over time.

Conclusions.

Understanding differences in HRQOL and caregiver burden among older HT candidates with and without MCS and their caregivers may inform strategies to enhance HRQOL and reduce burden.
Clonal hematopoiesis in individuals with ANKRD26 or ETV6 germline mutations
Authors: Drazer Michael W. , Homan Claire C. , Yu Kai , de Andrade Silva Marcela Cavalcante , McNeely Kelsey E. , Pozsgai Matthew J. , Acevedo Maria G. , Segal Jeremy P. , Wang Peng , Feng Jinghua , King-Smith Sarah L. , Kim Erika , Korotev Sophia C. , Lawrence David M. , Schreiber Andreas W. , Hahn Christopher N. , Scott Hamish S. , Sood Raman ,   NISC Comparative Sequencing Program, Velloso Elvira D R P , Brown Anna L. , Liu Paul P. , Godley Lucy A.
Published: November 2021

Currently, there are at least a dozen recognized hereditary hematopoietic malignancies (HHMs), some of which phenocopy others. Among these, three HHMs driven by germline mutations in ANKRD26, ETV6, or RUNX1 share a phenotype of thrombocytopenia, qualitative platelet defects, and an increased lifetime risk of hematopoietic malignancies (HMs). Prior work has demonstrated that RUNX1 germline mutation carriers experience an elevated lifetime risk (66%) for developing clonal hematopoiesis (CH) prior to age 50. Germline mutations in ANKRD26 or ETV6 phenocopy RUNX1 germline mutations, but no studies have focused on the risk of CH in individuals with germline mutations in ANKRD26 or ETV6.

To determine the prevalence of CH in individuals with germline mutations in ANKRD26 or ETV6, we performed next generation sequencing on hematopoietic tissue from twelve individuals with either germline ANKRD26 or germline ETV6 mutations. Each patient had thrombocytopenia but had not developed HMs. Among the seven individuals with germline ANKRD26 mutations, one patient had a CH clone driven by a somatic SF3B1 mutation (p.Lys700Glu). This mutation increased from a variant allele frequency (VAF) of 9.4% at age 56 to 17.4% at age 60. None of the germline ETV6 mutation carriers had evidence of CH at the limits of detection of the NGS assay (5% VAF). Unlike individuals with germline mutations in RUNX1, no individuals under the age of 50 with germline mutations in ANKRD26 or ETV6 had detectable CH. This work demonstrates that ANKRD26 germline mutation carriers, but not ETV6 mutation carriers, experience elevated risk for CH.