bluuebunny/crossref_metadata_2025 huggingface dataset:
Artificial neural network-based rapid predictor of biological nerve fiber activation for DBS applications
Authors: Golabek Justin , Schiefer Matthew , Wong Joshua K , Saxena Shreya , Patrick Erin
Published: January 2023

Objective. Computational models are powerful tools that can enable the optimization of deep brain stimulation (DBS). To enhance the clinical practicality of these models, their computational expense and required technical expertise must be minimized. An important aspect of DBS models is the prediction of neural activation in response to electrical stimulation. Existing rapid predictors of activation simplify implementation and reduce prediction runtime, but at the expense of accuracy. We sought to address this issue by leveraging the speed and generalization abilities of artificial neural networks (ANNs) to create a novel predictor of neural fiber activation in response to DBS. Approach. We developed six variations of an ANN-based predictor to predict the response of individual, myelinated axons to extracellular electrical stimulation. ANNs were trained using datasets generated from a finite-element model of an implanted DBS system together with multi-compartment cable models of axons. We evaluated the ANN-based predictors using three white matter pathways derived from group-averaged connectome data within a patient-specific tissue conductivity field, comparing both predicted stimulus activation thresholds and pathway recruitment across a clinically relevant range of stimulus amplitudes and pulse widths. Main results. The top-performing ANN could predict the thresholds of axons with a mean absolute error (MAE) of 0.037 V, and pathway recruitment with an MAE of 0.079%, across all parameters. The ANNs reduced the time required to predict the thresholds of 288 axons by four to five orders of magnitude when compared to multi-compartment cable models. Significance. We demonstrated that ANNs can be fast, accurate, and robust predictors of neural activation in response to DBS.
Explicit and efficient error estimation for convex minimization problems
Authors: Bartels Sören , Kaltenbach Alex
Published: January 2023

We combine a systematic approach for deriving general a posteriori error estimates for convex minimization problems based on convex duality relations with a recently derived generalized Marini formula. The a posteriori error estimates are quasi constant-free and apply to a large class of variational problems including the

p
p

-Dirichlet problem, as well as degenerate minimization, obstacle and image de-noising problems. In addition, these a posteriori error estimates are based on a comparison to a given non-conforming finite element solution. For the

p
p

-Dirichlet problem, these a posteriori error bounds are equivalent to residual type a posteriori error bounds and, hence, reliable and efficient.
Composition operators and generalized primes
Authors: Kouroupis Athanasios
Published: January 2023

We study composition operators on the Hardy space

H

2

\mathcal {H}^2

of Dirichlet series with square summable coefficients. Our main result is a necessary condition, in terms of a Nevanlinna-type counting function, for a certain class of composition operators to be compact on

H

2

\mathcal {H}^2

. To do that we extend our notions to a Hardy space

H

Λ

2

\mathcal {H}_{\Lambda }^2

of generalized Dirichlet series, induced in a natural way by a sequence of Beurling’s primes.
Remarks on orbital stability of steady vortex rings
Authors: Cao Daomin , Qin Guolin , Zhan Weicheng , Zou Changjun
Published: January 2023

In this paper, we study nonlinear orbital stability of steady vortex rings without swirl, which are special global solutions of the three-dimensional incompressible Euler equations. We prove the existence of orbitally stable steady vortex rings. The proof is based on the classical variational method.
Katnip is needed to maintain microtubule function and lysosomal delivery to autophagosomes and phagosomes
Authors: Starling Georgina P. , Phillips Ben A. , Ganesh Sahana , King Jason S.
Published: January 2023

Katnip is a highly conserved gene found mutated in some ciliopathies. In Dictyostelium, Katnip plays a general role in microtubule regulation and is required for lysosomal trafficking and digestion of autophagosomes and phagosomes.
CLASP2 facilitates dynamic actin filament organization along the microtubule lattice
Authors: Rodgers N. C. , Lawrence E. J. , Sawant A. V. , Efimova N. , Gonzalez-Vasquez G. , Hickman T. T. , Kaverina I. , Zanic M.
Published: January 2023

CLASP2α directly cross-links multiple actin filaments to the microtubule lattice. CLASP2α-mediated cross-linking facilitates dynamic organization of actin filaments templated by microtubules. Furthermore, CLASP depletion results in disorganized actin fibers and reduced coalignment of actin fibers with microtubules, suggesting that microtubule–CLASP–actin interaction may influence overall cytoskeletal organization in cells.
Nonparametric identification of random coefficients in aggregate demand models for differentiated products
Authors: Dunker Fabian , Hoderlein Stefan , Kaido Hiroaki
Published: January 2023

This paper studies nonparametric identification in market-level demand models for differentiated products with heterogeneous consumers. We consider a general class of models that allows for the individual-specific coefficients to vary continuously across the population and give conditions under which the density of these coefficients, and hence also functionals such as the fractions of individuals who benefit from a counterfactual intervention, is identified.
Dissection of theCaenorhabditis elegans Microprocessor
Authors: Nguyen Thuy Linh , Nguyen Trung Duc , Ngo Minh Khoa , Nguyen Tuan Anh
Published: January 2023

Microprocessor (MP) is a complex involved in initiating the biogenesis of microRNAs (miRNAs) by cleaving primary microRNAs (pri-miRNAs). miRNAs are small single-stranded RNAs that play a key role in the post-transcriptional regulation of gene expression. Thus, understanding the molecular mechanism of MP is critical for interpreting the roles of miRNAs in normal cellular processes and during the onset of various diseases. MP comprises a ribonuclease enzyme, DROSHA, and a dimeric RNA-binding protein, which is called DGCR8 in humans and Pasha in Caenorhabditis elegans. DROSHA cleaves stem-loop structures located within pri-miRNAs to generate pre-miRNAs. Although the molecular mechanism of human MP (hMP; hDROSHA-DGCR8) is well understood, that of Caenorhabditis elegans MP (cMP; cDrosha-Pasha) is still largely unknown. Here, we reveal the molecular mechanism of cMP and show that it is distinct from that of hMP. We demonstrate that cDrosha and Pasha measure ∼16 and ∼25 bp along a pri-miRNA stem, respectively, and they work together to determine the site of cMP cleavage in pri-miRNAs. We also demonstrate the molecular basis for their substrate measurement. Thus, our findings reveal a previously unknown molecular mechanism of cMP; demonstrate the differences between the mechanisms of hMP and cMP; and provide a foundation for revealing the mechanisms regulating miRNA expression in different animal species.
Neutrophil function following treatment of psoriatic arthritis patients with secukinumab: altered cytokine signalling but no impairment of host defence
Authors: Cross Andrew L , Hawkes Jenny , Frankland Helen , Mediana Ayren , Wright Helen L , Goodson Nicola J , Edwards Steven W , Moots Robert J
Published: January 2023

Objectives

Identifying that dysfunction of the IL-23/17 axis underlies PsA has led to the development of effective targeted therapies such as the IL-17A inhibitor secukinumab. As IL-17A stimulates the secretion of neutrophil chemoattractants, such as CXCL8 (IL-8), we examined the effect of secukinumab on neutrophil function in PsA.

Methods

Nineteen patients with active PsA were treated with secukinumab. Clinical response [PsA Response Criteria (PsARC) and Psoriasis Area and Severity Index (PASI)] and peripheral blood neutrophil function (apoptosis, receptor expression, phagocytosis/killing, chemotaxis and RNA expression) were measured at 12 week intervals for 48 weeks and compared with age- and sex-matched healthy controls.

Results

At 12 weeks, 12/16 (75%) patients had a PsARC response (100% at 36 weeks) and 10/14 (71%) achieved a 90% PASI response. At baseline, there were no differences in PsA neutrophil reactive oxygen species generation, constitutive or cytokine-delayed apoptosis, chemotaxis or phagocytosis of opsonized Staphylococcus aureus compared with healthy controls. Similarly, there were no differences in these functions from baseline to 12 weeks of therapy. However, surface levels of CD11b/CD18 and CD63 increased and expression of CD16 decreased during therapy. In addition, in a subgroup of early (12 week) responders to secukinumab, RNA sequencing revealed transcriptome changes predicting down-regulation of cytokine signalling and chemotaxis pathways and up-regulation of de novo gene expression pathways, including translation initiation, mRNA catabolism and translation.

Conclusion

Complex changes in the properties of circulating neutrophils occur with secukinumab treatment in PsA that may indicate altered responsiveness to changes in both local and systemic levels of pro-inflammatory cytokines. However, host defence processes of neutrophils were unaltered.
Education Value Units in Medical Education: A Scoping Review
Authors: Gottlieb Michael , Regan Linda , Jordan Jaime , Westrick Jennifer , Bailitz John
Published: January 2023

Purpose

On the basis of the tripartite mission of patient care, research, and education, a need has arisen to better support faculty in non-revenue-generating activities, such as education. As a result, some programs have developed education value unit (EVU) systems to incentivize these activities. The purpose of this scoping review is to analyze the existing literature on EVUs to identify current structures and future directions for research.

Method

The authors conducted a literature search of 5 databases without restrictions, searching for any articles on EVU systems published from database inception to January 12, 2022. Two authors independently screened articles for inclusion. Two authors independently extracted data and all authors performed quantitative and qualitative synthesis, consistent with best practice recommendations for scoping reviews.

Results

Fifty-eight articles were included. The most common rationale was to incentivize activities prioritized by the department or institution. Of those reporting funding, departmental revenue was most common. The majority of EVU systems were created using a dedicated committee, although composition of the committees varied. Stakeholder engagement was a key component for EVU system development. Most EVU systems also included noneducational activities, such as clinical activities, scholarship activities, administrative or leadership activities, and citizenship. Incentive models varied widely but typically involved numeric- or time-based quantification. EVUs were generally seen as positive, having increased equity and transparency as well as a positive impact on departmental metrics.

Conclusions

This scoping review summarizes the existing literature on EVU systems, providing valuable insights for application to practice and areas for future research.
Framework for Patient and Informal Caregiver Participation in Research (PAICPAIR) Part 2
Authors: Staats Katrine , Grov Ellen Karine , Tranvåg Oscar
Published: January 2023

Previously, we described the development of the first part of the framework of Patient and Informal Caregiver Participation in Research (PAICPAIR part 1) and how it was implemented in the empirical study Dying With Dignity. Currently, we present our choices and experiences gained in PAICPAIR part 2, highlighting how PAICPAIR guided us as a modifiable and adaptable framework, with a particular emphasis on identifying and meeting the individual needs of our vulnerable coresearchers. This framework can be used as a methodological approach and study design in future research and inspire researchers to include patients receiving palliative care and informal caregivers—as coresearchers.
Self-doubt in Nursing Students
Authors: Aller Loretta , Almrwani Abdulaziz Mofdy
Published: January 2023

Self-doubt may negatively affect the development of prelicensure nursing students as they prepare to become practice-ready members of the workforce. Walker and Avant's method of analysis was used to explore generalized self-doubt as well as within the context of a contemporary nursing education framework: Aller's Development of Decision-Making and Self-Efficacy Model (ADD-SEM). Results indicate that several attributes of generalized self-doubt, as a form of low psychological capital, were consistent with this construct of the ADD-SEM and should be considered as nurse educators strive to ensure new nurses are prepared for the complexity of today's health care systems.
The current status of immunotherapy in the treatment of primary advanced and recurrent endometrial cancer
Authors: Fontenot Virginia E. , Tewari Krishnansu
Published: January 2023

Purpose of review

Despite the recent upward trends in incidence and mortality of endometrial cancer, there are still limited FDA-approved therapies for patients with primary advanced and recurrent endometrial cancer. This disparity presents the opportunity for further investigation of targeted therapies in this patient population.

Recent findings

One such area of adjuvant therapy is immunotherapy, which has shown improved progression-free survival in patients with several solid tumors, including endometrial, leading to the FDA approval of two immune checkpoint inhibitors. Additionally, with further study of precision medicine, the current adjuvant treatment paradigms that exist based on histopathologic subtype alone may be shifting towards a new genomic-based approach.

This article is a snapshot of the origins of immunotherapy use in this patient population as well as a guide to its future use. The author's hope with this article is to describe the patient population as well as the history of the integration of immunotherapy use into the adjuvant treatment of endometrial cancer leading up to FDA approval of Pembrolizumab and Dostarlimab. This article also consolidates the current literature as well as ongoing clinical trials that will hopefully lead to FDA approval of more immunotherapeutic agents in the near future.
Polygenic risk scores in coronary artery disease
Authors: Christiansen Morten Krogh , Nyegaard Mette , Jensen Henrik Kjærulf
Published: January 2023

Purpose of review

Recent advances in genetics have facilitated the calculation of polygenic risk scores (PRSs) based on common genetic risk variants of coronary artery disease (CAD). Here, we provide an explanation of the genetic basis for PRSs and review recent literature investigating PRSs and the clinical utility for different aspects of CAD.

Recent findings

CAD-based PRSs are strongly associated with atherosclerosis burden in the coronary arteries and other vascular beds. In multiple studies, PRSs have proven to be a measure of CAD risk, more powerful than most established risk factors alone, that can be used from early life to stratify individuals into varying trajectories of lifetime risk. When implemented in risk stratification models for primary prevention of cardiovascular disease, PRSs provide modest improvements in discrimination (C-index generally increasing 0–4% points) and reclassification, but yield significant clinical benefit as a risk enhancer. Additionally, data suggest possible value of PRSs for aiding decisions in other aspects of diagnostics and treatment in CAD.

Once genotyped, the genetic information may be used to calculate an infinite number of PRSs and contribute to personalize medicine providing clinical value for risk stratification, diagnostics and treatment in CAD as well as in other diseases.
Expanding heart transplantation in 2022 and beyond
Authors: Rivera Nina Thakkar , Baran David A.
Published: January 2023

Purpose of review

Despite advances in the technology of mechanical circulatory support, the need for heart transplantation continues to grow. The longevity of heart transplants continues to be superior to mechanical solutions, though the short-term differences are shrinking. In this review, we cover three timely developments and summarize the recent literature.

Recent findings

After stagnant rates of heart transplant activity for some years, recently, transplant volume has increased. The developments that have ignited interest have been the use of hepatitis C infected donors, which can now be safely transplanted with the advent of curative oral regimens, and the worldwide use of donors following withdrawal of life support as opposed to traditional brain death donors. In addition, the recent experience of human cardiac xenotransplantation has been very exciting, and though it is not of clinical utility yet, it holds the promise for a virtually unlimited supply of organs at some time in the future.

Much work remains to be done, but together, all three of these developments are exciting and important to be aware of in the future. Each will contribute to additional donors for human heart transplantation and hopefully will alleviate suffering and death on the waiting list.
Prospective Observational Study of Pain Severity and Pain Interference Outcomes Following Percutaneous MRI-guided Laser Ablation or Cryoablation for Focal Painful Peripheral, Soft Tissue Vascular Malformations: 12-month Outcomes
Authors: Thompson Scott M. , Knavel Koepsel Erica M. , Powell Garret M. , Bendel Emily C. , Bjarnason Haraldur , Polites Stephanie F. , Adamo Daniel A. , Howe-Clayton Desirae L. , Favazza Christopher P. , Lu Aiming , Anderson Katelyn R. , Tollefson Megha M. , Woodrum David A.
Published: January 2023

Background:

Percutaneous image-guided thermal ablation has emerged as a treatment option for vascular malformations (VM). However, prospective data on intermediate to long-term effectiveness with uniform follow-up are lacking.

Purpose:

To prospectively evaluate the 12-month pain severity and pain interference outcomes following percutaneous MRI-guided laser ablation and cryoablation of focal painful, peripheral soft tissue VM.

Materials and Methods:

Participants undergoing clinically indicated MRI-guided laser ablation and cryoablation for focal painful (worst pain ≥4 out of 10 on Visual Analog Scale), peripheral soft tissue vascular malformations (VM) were enrolled in an IRB-approved prospective, observational study after giving informed consent. Participants completed the Brief Pain Inventory questionnaire prior to ablation and 1, 3, 6, and 12-month postablation. Differences in pain severity and interference outcomes from baseline on a 0 to 10 scale were compared using a paired t-test.

Results:

Seventeen participants (15 female; mean age 28.3 ± 9.3 years) underwent 24 MRI-guided and monitored ablation sessions including laser (n = 21), cryoablation (n = 2), or both (n = 1) for treatment of painful slow-flow (n = 16) or high-flow (n = 1) VM. Median maximal VM diameter was 5.7 cm (range 1.1 to 31.0 cm). Mean (±SD) preablation worst pain score was 7.9 ± 1.4. There was a significant decrease in worst pain at 1-month postablation (–3.5 ± 2.9; P = .0007) that was sustained at 3 (–3.4 ± 3.2; P = .0007), 6 (–4.2 ± 3.6; P = .0003), and 12 months (–3.6 ± 3.9; P = .002), with similar results for average, current, and least pain scores. There was a significant improvement in pain interference outcomes at 12-month postablation: general activity (P = .018), walking ability (P = .008), work (P = .003), sleep (P = .007), and enjoyment of life (P = .033).

Conclusions:

These data suggest that MRI-guided and monitored thermal ablation is safe and provides early and sustained significant improvements in pain severity and pain interference outcomes during the first year of follow-up in participants with focal painful peripheral soft tissue VM.
Thrombin generation assay: the present and the future
Authors: Wu Yi , Lu Yi , Zhang Jingyu
Published: January 2023

The need for a more precise test that replicates the in vivo hemostatic conditions is increasingly being recognized. Up to now, the thrombin generation assay (TGA) has become the most reliable approach to evaluate the status of coagulation activation. The clinical potential for the TGA is most promising in the prediction of venous thromboembolism recurrence. However, there is currently an urgent need for a standardized global test that can reliably detect, predict and monitor coagulation disorders in both clinical and experimental studies. We have recently modified the TGA to analyze not only tissue factor-driven coagulation, but the intrinsic coagulation pathway as well. In the present review, we discuss different TG tests, emphasizing the requirement for a better understanding of the evaluation of distinct coagulation pathways using this technique, as well as the standardization and clinical validation.
Xenosterolemia in clinical practice: what is in a name?
Authors: Loh Wann Jia , Watts Gerald F.
Published: January 2023

Purpose of review

The aim of this study was to assess the potential value of the measurement of plasma xenosterols (or phytosterols) concentrations in clinical practice.

Recent findings

Recent genetic studies suggest that individuals with elevated plasma phytosterol concentrations due to monogenic and polygenic variants are at an increased risk of coronary artery disease. This supports early observations that elevated plasma phytosterol concentrations are per se atherogenic.

Measurement of plasma phytosterols can identify individuals with xenosterolemia (or phytosterolemia). This may be clinically useful in four ways: Establishing a diagnosis and informing management of patients with homozygous phytosterolemia; Providing a comprehensive differential diagnosis for familial hypercholesterolemia; Providing an index of cholesterol absorption that may inform personalized pharmacotherapy; and Informing more precise assessment of risk of cardiovascular disease.
Mechanisms of leptin-induced endothelial dysfunction
Authors: Mellott Elisabeth , Faulkner Jessica L.
Published: January 2023

Purpose of review

Endothelial dysfunction is a major risk factor for many cardiovascular diseases, notably hypertension. Obesity increases the risk of endothelial dysfunction in association with increasing production of the adipokine leptin. Preclinical studies have begun to unravel the mechanisms whereby leptin leads to the development of endothelial dysfunction, which are sex-specific. This review will summarize recent findings of mechanisms of leptin-induced endothelial impairment in both male and females and in pregnancy.

Recent findings

Leptin receptors are found in high concentrations in the central nervous system (CNS), via which leptin promotes appetite suppression and upregulates sympathetic nervous system activation. However, leptin receptors are expressed in many other tissues, including the vascular endothelial cells and smooth muscle cells. Recent studies in mice with vascular endothelial or smooth muscle-specific knockdown demonstrate that endothelial leptin receptor activation plays a protective role against endothelial dysfunction in male animals, but not necessarily in females. Clinical studies indicate that women may be more sensitive to obesity-associated vascular endothelial dysfunction. Emerging preclinical data indicates that leptin and progesterone increase aldosterone production and endothelial mineralocorticoid receptor activation, respectively. Furthermore, decades of clinical studies indicate that leptin levels increase in the hypertensive pregnancy disorder preeclampsia, which is characterized by systemic endothelial dysfunction. Leptin infusion in mice induces the clinical characteristics of preeclampsia, including endothelial dysfunction.

Novel preclinical data indicate that the mechanisms whereby leptin promotes endothelial dysfunction are sex-specific. Leptin-induced endothelial dysfunction may also play a role in hypertensive pregnancy as well.
Radiosynthesis, optimization and pharmacokinetic study of the 99mTc-labeled human epidermal growth factor receptor 2 affibody molecule probe 99mTc-(HE)3ZHER2:V2
Authors: Hu Xianwen , Liang Zhigang , Qi Lili , Li Fangming , Cai Xiaojia , Cai Jiong
Published: January 2023

Objective

To prepare a single-photon molecular probe easily labeled with 99mTc for evaluating the expression status of the human epidermal growth factor receptor 2 (HER2) receptor in ovarian cancer.

Materials and methods

The HEHEHE tag was added to the amino terminus of the affibody ZHER2:V2 by the method of gene recombinant expression, and a new affibody was synthesized which was easy to be labeled with 99mTc. The newly prepared affibody was labeled with 99mTc, and pharmacokinetic studies were carried out.

Results

A new affibody (HE)3ZHER2:V2 was prepared by the method of gene recombination and expression, which is easy to be labeled with 99mTc. The 99mTc labeling of the affibody can reach about 95% at 90°C. The pharmacokinetic study has shown that the 99mTc-labeled molecular probe has a fast clearance time in the blood and little side effect, which may be a promising single-photon emission computed tomography (SPECT) imaging agent.

Conclusion

The affibody (HE)3ZHER2:V2 is easy to be labeled with 99mTc, has a high yield and has a suitable half-life in vivo, which is suitable for the next step in ovarian cancer model imaging research.
Hepatitis E Virus Infection in Pediatric Oncology
Authors: Lenglart Anna , Chappé Céline , Grulois Isabelle , Hervé Françoise , Gandemer Virginie , Robert Guillaume
Published: January 2023

Background:

In the 2016 ESPGHAN recommendations on how to deal with hepatitis E virus infection in immunocompromised children, patients treated with chemotherapy were not specifically mentioned.

Observations:

Two teenagers treated with chemotherapy for acute leukemia and medulloblastoma, respectively, were diagnosed with hepatic cytolysis. After numerous investigations hepatitis E was found, limiting the good progress of the chemotherapy treatment.

Conclusion:

In the case of liver cytolysis in immunocompromised children treated with chemotherapy, hepatitis E virus infection has to be promptly diagnosed.
The Vitamin D Status in Children With Newly Diagnosed Acute Lymphoblastic Leukemia and Its Potential Impact on the Primary Symptoms of Leukemia and Course of Induction Treatment
Authors: Malecka Anna , Hennig Marcin , Jaworski Radoslaw , Irga-Jaworska Ninela
Published: January 2023

Background:

Vitamin D deficiency is ubiquitous within the population of children. A similar problem is recognized among pediatric patients with acute lymphoblastic leukemia. The purpose of this study was to analyze the prevalence of vitamin D deficiency and to investigate the connection between vitamin D status and the course of induction treatment of ALL.

Materials and Methods:

A cross-sectional study including 59 patients with newly diagnosed ALL from May 2017 until November 2020.

Results:

Vitamin D deficiency was found in 39% of the patients. There were no seasonal differences in vitamin D status. Patients with optimal 25(OH)D concentration presented more profound thrombocytopenia (P=0.015) and required more frequent platelet transfusions (P=0.018). Good prognosis factors such as B phenotype and hyperdiploidy were also more frequent among children with higher 25(OH)D concentration (P=0.01 and 0.014, respectively).

Conclusions:

The study showed that patients with a higher serum concentration of 25(OH)D presented deeper thrombocytopenia and needed more frequent transfusions. Moreover, those patients showed higher rates of B-cell leukemia and hyperdiploid karyotype. We did not find any influence of the possible exposure to sunlight (defined as the season of the year on admission) on serum 25(OH)D concentration, which supports the argument for supplementing vitamin D all year round. Moreover, the supplementing of vitamin D seems to be safe and does not cause any renal complications connected to calcium and phosphorus imbalance as no correlation between their levels and 25(OH)D concentration was found.
Hypogammaglobulinemia in Children After Hematopoietic Stem Cell Transplantation and Rituximab Treatment: Relevance of B Cell Subsets
Authors: Marzollo Antonio , Serena Tiziana , Mainardi Chiara , Calore Elisabetta , Pillon Marta , Carraro Elisa , Tosato Francesca , Biffi Alessandra , Tumino Manuela
Published: January 2023

Rituximab (RTX) is widely employed to treat Epstein-Barr virus reactivation in children undergoing Hematopoietic Cell Transplantation (HCT). The resulting loss of B cells may cause persistent hypogammaglobulinemia. This retrospective cross-sectional study aims to identify flow cytometry biomarkers associated with persistent hypogammaglobulinemia in patients receiving RTX after HCT. We analyzed 5 patients (cases group) requiring immunoglobulin substitution due to low level of IgG (IgG <5 g/L) detected after RTX treatment and 5 patients (controls group) not requiring long-term immunoglobulin (Ig) substitution. We investigated the B cell reconstitution, and in patients group we observed a significantly lower count in B total, IgD+CD27+ marginal B cells and IgD-CD27+ switched-memory B cells, after a median of 5 years from HCT, compared with the control group. Despite the importance limits of our study and the heterogeneity of our data (age of included patients, time of evaluation, interval between RTX dose and assessment) we conclude that RTX given early after HCT might cause a deranged B cell maturation, contributing to the delation in B cell recovery following HCT, and switched memory and marginal zone B cell counts could be a promising biomarker to identify patients requiring long-term Ig substitution.
A Comprehensive Review of Neuropsychologic Studies Supports the Concept That Adequate Folinic Acid Rescue Prevents Post Methotrexate Neurotoxicity
Authors: Sadeh Michelle , Toledano Helen , Cohen Ian J.
Published: January 2023

Purpose:

To review all studies providing evidence of the correlation between folinic acid (FA) rescue inadequacy and long-term cognitive damage in neuropsychological studies of children with acute lymphoblastic leukemia or osteogenic sarcoma treated under protocols using high-dose methotrexate and FA rescue.

Methods:

A comprehensive literature search was performed of all databases of the Web of Science Citation Index, during 1990–2020, for the terms: neuropsychological, neurocognitive, and cognitive, together with acute lymphoblastic (and lymphocytic) leukemia and osteogenic sarcoma. English-language peer-reviewed articles on neuropsychological assessments of children who had been treated with high-dose methotrexate without irradiation, and which included details of methotrexate and FA schedules, were selected. In addition, a personal database of over 500 reprints of articles from over 130 journals was reviewed on the subjects of methotrexate and FA and their side effects.

Results:

Three groups of studies were found and analyzed, with (1) no evidence of cognitive deterioration, (2) evidence of cognitive deterioration, and (3) more than 1 protocol grouped together, preventing separate analysis of any protocols, Protocols without cognitive deterioration reported adequate FA rescue, and those with cognitive deterioration reported inadequate FA rescue.

Conclusion:

Neuropsychological evaluation supported inadequate FA being the cause of neurocognitive damage after high-dose methotrexate and that adequate FA rescue prevents this complication.
Mentoring New Graduates to Voice Safety Concerns
Authors: Zuck Erin M. , Lampley Tammy M.
Published: January 2023

New graduate nurses often lack professional confidence to voice safety concerns. An evidence review was conducted to determine how participating in a mentorship program impacts the development of assertive communication during the first year of practice. Evidence indicates that providing a supportive environment, with physical and emotional access to mentors, should be used to increase new graduate nurses’ self-perceived ability and willingness to voice safety concerns.
Development of Distance Simulation Educator Guidelines in Healthcare
Authors: Bajwa Maria , Ahmed Rami , Lababidi Hani , Morris Melissa , Morton Alex , Mosher Cynthia , Wawersik Dawn , Herx-Weaver Anne , Gross Isabel T. , Palaganas Janice C.
Published: January 2023

Introduction

The abrupt disruption of in-person instruction in health care during the COVID-19 pandemic resulted in the rapid adoption of distance simulation as an immediate alternative to providing in-person simulation-based education. This massive instructional shift, combined with the lack of educator training in this domain, led to challenges for both learners and educators. This study aimed to disseminate the first set of competencies required of and unique to effective distance simulation educators.

Methods

This was a multiphasic and iterative modified Delphi study validating the content of carefully and rigorously synthesized literature. Experts were invited from around the globe to participate in this study with mandatory attendance at an annual health care simulation conference to openly discuss the guidelines presented as competencies in this document. We divided each competency into “Basic” and “Advanced” levels, and agreement was sought for these levels individually. The experts provided their opinion by choosing the options of “Keep, Modify, or Delete.” A free-marginal kappa of 0.60 was chosen a priori.

Results

At the conclusion of the Delphi process, the number of competencies changed from 66 to 59, basic subcompetencies from 216 to 196, and advanced subcompetencies from 179 to 182.

Conclusions

This article provides the first set of consensus guidelines to distance simulation educators in health care, and paved the way for further research in distance simulation as a modality.
Adaptation to a limiting element involves mitigation of multiple elemental imbalances
Authors: Jeyasingh Punidan D. , Sherman Ryan E. , Prater Clay , Pulkkinen Katja , Ketola Tarmo
Published: January 2023

About 20 elements underlie biology and thus constrain biomass production. Recent systems-level observations indicate that altered supply of one element impacts the processing of most elements encompassing an organism (i.e. ionome). Little is known about the evolutionary tendencies of ionomes as populations adapt to distinct biogeochemical environments. We evolved the bacterium
Serratia marcescens
under five conditions (i.e. low carbon, nitrogen, phosphorus, iron or manganese) that limited the yield of the ancestor compared with replete medium, and measured the concentrations and use efficiency of these five, and five other elements. Both physiological responses of the ancestor, as well as evolutionary responses of descendants to experimental environments involved changes in the content and use efficiencies of the limiting element, and several others. Differences in coefficients of variation in elemental contents based on biological functions were evident, with those involved in biochemical building (C, N, P, S) varying least, followed by biochemical balance (Ca, K, Mg, Na), and biochemical catalysis (Fe, Mn). Finally, descendants evolved to mitigate elemental imbalances evident in the ancestor in response to limiting conditions. Understanding the tendencies of such ionomic responses will be useful to better forecast biological responses to geochemical changes.
Effects of peristaltic amplitude and frequency on gastric emptying and mixing: a simulation study
Authors: Ebara Rika , Ishida Shunichi , Miyagawa Taimei , Imai Yohsuke
Published: January 2023

The amplitude and frequency of peristaltic contractions are two major parameters for assessing gastric motility. However, it is not fully understood how these parameters affect the important functions of the stomach, such as gastric mixing and emptying. This study aimed to quantify the effects of peristaltic amplitude and frequency on gastric mixing and emptying using computational fluid dynamics simulation of gastric flow with an anatomically realistic model of the stomach. Our results suggest that both the increase and decrease in peristaltic amplitude have a significant impact on mixing strength and emptying rate. For example, when the peristaltic amplitude was 1.2 times higher than normal, the emptying rate was 2.7 times faster, whereas when the amplitude was half, the emptying rate was 4.2 times slower. Moreover, the emptying rate increased more than proportionally with the peristaltic frequency. The nearest contraction wave to the pylorus and the subsequent waves promoted gastric emptying. These results suggest the importance of maintaining parameters within normal ranges to achieve healthy gastric function.
Sequential antibiotic therapy in the laboratory and in the patient
Authors: Nyhoegen Christin , Uecker Hildegard
Published: January 2023

Laboratory experiments suggest that rapid cycling of antibiotics during the course of treatment could successfully counter resistance evolution. Drugs involving collateral sensitivity could be particularly suitable for such therapies. However, the environmental conditions
in vivo
differ from those
in vitro
. One key difference is that drugs can be switched abruptly in the laboratory, while in the patient, pharmacokinetic processes lead to changing antibiotic concentrations including periods of dose overlaps from consecutive administrations. During such overlap phases, drug–drug interactions may affect the evolutionary dynamics. To address the gap between the laboratory and potential clinical applications, we set up two models for comparison—a ‘laboratory model’ and a pharmacokinetic-pharmacodynamic ‘patient model’. The analysis shows that in the laboratory, the most rapid cycling suppresses the bacterial population always at least as well as other regimens. For patient treatment, however, a little slower cycling can sometimes be preferable if the pharmacodynamic curve is steep or if drugs interact antagonistically. When resistance is absent prior to treatment, collateral sensitivity brings no substantial benefit unless the cell division rate is low and drug cycling slow. By contrast, drug–drug interactions strongly influence the treatment efficiency of rapid regimens, demonstrating their importance for the optimal choice of drug pairs.
Explaining workers’ inactivity in social colonies from first principles
Authors: Khajehnejad Moein , García Julian , Meyer Bernd
Published: January 2023

Social insects are among the ecologically most successful collectively living organisms, with efficient division of labour a key feature of this success. Surprisingly, these efficient colonies often have a large proportion of inactive workers in their workforce, sometimes referred to aslazy workers. The dominant hypotheses explaining this are based on specific life-history traits, specific behavioural features or uncertain environments where inactive workers can provide a ‘reserve’ workforce that can spring into action quickly. While there is a number of experimental studies that show and investigate the presence of inactive workers, mathematical and computational models exploring specific hypotheses are not common. Here, using a simple mathematical model, we show that a parsimonious hypothesis can explain this puzzling social phenomenon. Our model incorporates social interactions and environmental influences into a game-theoretical framework and captures how individuals react to environment by allocating their activity according to environmental conditions. This model shows that inactivity can emerge under specific environmental conditions as a by-product of the task allocation process. Our model confirms the empirical observation that in the case of worker loss, prior homeostatic balance is re-established by replacing some of the lost force with previously inactive workers. Most importantly, our model shows that inactivity in social colonies can be explained without the need to assume an adaptive function for this phenomenon.
Sarcina Organism in Association with Gastric Ulcer: A Case Report
Authors: Simkhada Ankita , Acharya Pritha , Shrivastav Shreya
Published: January 2023

Sarcina ventriculi is a gram postitive bacteria which has been reported in patients with delayed gastric emptying as well as in association with cases of gastric ulcer and gastric carcinoma. Although it has been reported frequently in veterinary cases as a cause of fatal diseases, exact pathogenesis in humans is yet to be identified. We report here, a case of an elderly male who presented with hematemesis following which an upper gastrointestinal endoscopy was done and a gastric ulcer was revealed. Histopathological examination revealed Sarcina organism in association with ulcer.
Nirmatrelvir Resistance in SARS-CoV-2 Omicron_BA.1 and WA1 Replicons and Escape Strategies
Authors: Lan Shuiyun , Neilsen Grace , Slack Ryan L. , Cantara William A. , Castaner Andres Emanuelli , Lorson Zachary C. , Lulkin Nicole , Zhang Huanchun , Lee Jasper , Cilento Maria E. , Tedbury Philip R. , Sarafianos Stefan G.
Published: January 2023

The antiviral component of Paxlovid, nirmatrelvir (NIR), forms a covalent bond with Cys145 of SARS-CoV-2 nsp5. To explore NIR resistance we designed mutations to impair binding of NIR over substrate. Using 12 Omicron (BA.1) and WA.1 SARS-CoV-2 replicons, cell-based complementation and enzymatic assays, we showed that in both strains, E166V imparted high NIR resistance (∼55-fold), with major decrease in WA1 replicon fitness (∼20-fold), but not BA.1 (∼2-fold). WA1 replicon fitness was restored by L50F. These differences may contribute to a potentially lower barrier to resistance in Omicron than WA1. E166V is rare in untreated patients, albeit more prevalent in paxlovid-treated EPIC-HR clinical trial patients. Importantly, NIR-resistant replicons with E166V or E166V/L50F remained susceptible to a) the flexible GC376, and b) PF-00835231, which forms additional interactions. Molecular dynamics simulations show steric clashes between the rigid and bulky NIR t-butyl and β-branched V166 distancing the NIR warhead from its Cys145 target. In contrast, GC376, through “wiggling and jiggling” accommodates V166 and still covalently binds Cys145. PF-00835231 uses its strategically positioned methoxy-indole to form a β-sheet and overcome E166V. Drug design based on strategic flexibility and main chain-targeting may help develop second-generation nsp5-targeting antivirals efficient against NIR-resistant viruses.
Subjective survival probabilities by employment category and job satisfaction among the fifty-plus population in Japan
Authors: Wels Jacques
Published: January 2023

Background

Subjective Survival Probabilities (SSP) are known to be associated with mortality but little is known about the relationship they might have with employment categories and job satisfaction. We assess such a relationship looking at the fifty-plus population in Japan that is characterized by a stratified labour market for the older workers and high working time intensity.

Method

We use the four waves (2007-2013) of the Japanese Study of Aging and Retirement (JSTAR), a panel dataset tracking 7,082 50-plus respondents in 10 Japanese prefectures. We use a mixed-effects quantile regression model to investigate the relationship between SSP and employment status (model 1) and job satisfaction (model 2). Both models additively control for demographic and socio-economic cofounders as well as other health measurements. Multiple imputations are used to correct sample attrition.

Results

In model 1, retirement (−0.27, 95%CI =-0.51;-0.03) and contract work (−0.51, 95%CI=-0.79;-0.23) are negatively associated with SSP in comparison with full-time employment. In model 2, low job satisfaction appears to be strongly associated with SSP (−1.37, 95%CI=-1.84;-0.91) in comparison with high job satisfaction. The same trend is observed regardless of the way job satisfaction is calculated. Both working time and employment category are not significantly associated with SSP after controlling for job satisfaction which indicates that job satisfaction is a main driver of SSP discrepancies.

Discussion

SSP variations can be explained by employment category with contract work more at risk. Job dissatisfaction is a main explanation of low SSP. Both work and employment explain SSP variations.
Nanoparticle-Conjugated TLR9 Agonists Improve the Potency, Durability, and Breadth of COVID-19 Vaccines
Authors: Ou Ben S. , Baillet Julie , Picece Vittoria C.T.M. , Gale Emily C. , Powell Abigail E. , Saouaf Olivia M. , Yan Jerry , Nejatfard Anahita , Hernandez Hector Lopez , Appel Eric A.
Published: January 2023

Development of effective vaccines for infectious diseases has been one of the most successful global health interventions in history. Though, while ideal subunit vaccines strongly rely on antigen and adjuvant(s) selection, the mode and timescale of exposure to the immune system has often been overlooked. Unfortunately, poor control over the delivery of many adjuvants, which play a key role in enhancing the quality and potency of immune responses, can limit their efficacy and cause off-target toxicities. There is critical need for new adjuvant delivery technologies to enhance their efficacy and boost vaccine performance. Nanoparticles have been shown to be ideal carriers for improving antigen delivery due to their shape and size, which mimic viral structures, but have been generally less explored for adjuvant delivery. Here, we describe the design of self-assembled poly(ethylene glycol)-b-poly(lactic acid) nanoparticles decorated with CpG, a potent TLR9 agonist, to increase adjuvanticity in COVID-19 vaccines. By controlling the surface density of CpG, we show that intermediate valency is a key factor for TLR9 activation of immune cells. When delivered with the SARS-CoV-2 spike protein, CpG nanoparticle (CpG-NP) adjuvant greatly improve the magnitude and duration of antibody responses when compared to soluble CpG, and result in overall greater breadth of immunity against variants of concern. Moreover, encapsulation of CpG-NP into injectable polymeric-nanoparticle (PNP) hydrogels enhance the spatiotemporal control over co-delivery of CpG-NP adjuvant and spike protein antigen such that a single immunization of hydrogel-based vaccines generates comparable humoral responses as a typical prime-boost regimen of soluble vaccines. These delivery technologies can potentially reduce the costs and burden of clinical vaccination, both of which are key elements in fighting a pandemic.