bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinician Reasons for Stopping Clozapine
Authors: Grover Sandeep , Chaurasiya Nishtha , Chakrabarti Subho
Published: July 2023

Background

Little information is available on clozapine discontinuation rates in developing country settings.

Aim

The present study aimed to evaluate the incidence and reasons clinicians stopped clozapinine in patients after initiating treatment with the same. In addition, the study also aimed to assess the rechallenge rate, that is, restarting clozapine after a decision to discontinue the same by the clinicians.

Methodology

The treatment records of 859 patients started on clozapine were reviewed to identify the patients for whom the clinician stopped clozapine at least once because of any reason. The reasons for stopping clozapine were reviewed. In addition, the treatment records were also examined for rechallenge with clozapine at a later date.

Results

Clozapine was stopped by the clinicians in 44 of the 859 patients (5.12%). The most common reason for stopping clozapine was blood dyscrasias (n = 12), followed by poor adherence making the hematological monitoring difficult (n = 9), and intolerable sedation (n = 7). In half of the patients (n = 22), clozapine was restarted by the clinicians for further management of schizophrenia. Successful rechallenge was done in 58.33% of patients with blood dyscrasias, 44.44% with poor adherence, and 71.4% with intolerable sedation.

Conclusions

The present study suggests clinicians stop clozapine in only 5.14% of cases. The most common reasons for clozapine discontinuation by clinicians include blood dyscrasias, poor medication adherence making it challenging to monitor the hemogram, and sedation. However, in half of the patient's clozapine was rechallenged, and all the attempts of rechallenging were successful.
Evaluation of Virtual Assessment for a High Stakes' Clinical Examination—Physician Assistant Students' and Their Examiners' Perspectives
Authors: Joyce Pauline , Cassidy Dara , Kenna Laura
Published: July 2023

Purpose

This case study emerged from the necessity to reschedule an in-person long case examination to an online platform for physician assistant students' final clinical examination during COVID-19 restrictions. The aim of this study was to evaluate the experiences of students and examiners for a high stakes' clinical examination online.

Methods

This was an evaluation research study using the Context, Input, Process, Product model, which provided a framework to establish the effectiveness and/or success of an online format for a high stakes' clinical examination. All students and examiners were invited to take part in virtual interviews.

Results

The results suggest that both students (n = 5) and examiners (n = 7) agree that, although the stress of a face-to-face examination was lessened for the student, this was balanced by a new stressor of potential Internet problems. All agreed that a virtual setting for a high stakes' assessment is not transferable, with both groups citing the lack of opportunities to “read the patient” and “showcase their physical examination skills” as challenging.

Conclusion

Our study suggests that, in the context of balancing the risks of the pandemic with graduating health care professionals, the online clinical examination format met the required assessment criteria. Recommendations suggest that the long case could be planned so that students and patients are in the same setting to perform a physical examination, confirming the finding that questions on “how to” examine a patient are no substitute for “doing.”
Characteristics of Hybrid Learning Among Health Professions Programs: A Mixed-Methods Study
Authors: Gordes Karen L. , Kulo Violet , Cawley James F. , Kayingo Gerald
Published: July 2023

Purpose

To characterize current trends in hybrid education within the physician assistant (PA) profession, specifically program design, drivers, and outcomes in comparison with physical therapy hybrid education.

Methods

This was a mixed-methods study involving secondary data analysis and focused interviews with stakeholders to triangulate the data.

Results

Compared with traditional PA programs, hybrid programs have similar admission requirements, higher cost of tuition, larger class size, and higher attrition rate than national mean. Physician Assistant National Certifying Exam outcome data are in line or slightly lower than national scores. Technological advancements and need for faculty/learner flexibility by time and location are frequently cited driving forces.

Conclusions

There is a growing trend toward hybrid education among health professions. Other than cost, attrition rate, and immersion experiences, characteristics of hybrids are similar to traditional programs. It is relevant for PA educators to understand how this educational design may shape the future of PA graduates. Long-term impact should be evaluated with future studies.
Treatment of pediatric spasticity, including children with cerebral palsy, with Botox (onabotulinumtoxinA): Development, insights, and impact
Authors: Gormley Mark , Chambers Henry G. , Kim Heakyung , Leon Judith , Dimitrova Rozalina , Brin Mitchell F.
Published: July 2023

Spasticity is a velocity-dependent increase in muscle tone that has a negative effect on quality of life and hinders the ability of others to provide care. In children, most cases are caused by cerebral palsy. Traditionally, many children are treated with surgery, sometimes performed before their limbs had grown sufficiently to permit long-term success. Nonsurgical treatment comprises oral pharmacological options, but their efficacy is limited and side effects such as drowsiness and decreased short-term memory are common; nerve block procedures can cause painful dysesthesias and muscle scarring. OnabotulinumtoxinA was first approved for the treatment of pediatric lower limb spasticity in Europe in the 1990s and is now licensed for use in pediatric patients in over 80 countries worldwide, based on a large body of clinical evidence demonstrating its efficacy and safety. In 2019 the U.S. Food and Drug Administration approved onabotulinumtoxinA for the treatment of pediatric patients with upper or lower limb spasticity. This approval represents 3 decades of work to refine the dose, measurements, patient selection, and muscle selection. The availability of onabotulinumtoxinA as a treatment for pediatric spasticity can have a substantial impact on a patient’s quality of life. The use of onabotulinumtoxinA in combination with orthoses and occupational/physical therapy can postpone corrective surgery until growth is nearly complete and minimize the number of corrective surgeries.
Early development history of Botox (onabotulinumtoxinA)
Authors: Scott Alan B. , Honeychurch Dennis , Brin Mitchell F.
Published: July 2023

The development of Botox (onabotulinumtoxinA) began in the 1970s as Dr. Scott was attempting to identify an injectable substance that would weaken the extraocular eye muscles in patients with strabismus as an alternative to muscle surgery. This search led to botulinum toxin type A, which was tested and developed over the next 15 years. As botulinum toxin type A moved from an experimental drug to a product in need of licensing by the Food and Drug Administration (FDA), the first manufacturing methods and quality control procedures were developed for Oculinum, the botulinum toxin type A product that would eventually be sold to Allergan and become known as Botox.
Treatment of adult spasticity with Botox (onabotulinumtoxinA): Development, insights, and impact
Authors: Esquenazi Alberto , Jost Wolfgang H. , Turkel Catherine C. , Wein Theodore , Dimitrova Rozalina
Published: July 2023

Upper and lower limb spasticity (ULS, LLS) often occur following a stroke or in patients with other neurological disorders, leading to difficulties in mobility and daily living and decreased quality of life. Prior to the use of onabotulinumtoxinA, antispastic medications had limited efficacy and often caused sedation. Phenol injections were difficult for physicians to perform, painful, and led to tissue destruction. The success of onabotulinumtoxinA in treating cervical dystonia led to its use in spasticity. However, many challenges characterized the development of onabotulinumtoxinA for adult spasticity. The wide variability in the presentation of spasticity among patients rendered it difficult to determine which muscles to inject and how to measure improvement. Another challenge was the initial refusal of the Food and Drug Administration to accept the Ashworth Scale as a primary endpoint. Additional scales were designed to incorporate a goal-oriented, patient-centered approach that also accounted for the variability of spasticity presentations. Several randomized, double-blind, placebo-controlled trials of post-stroke spasticity of the elbow, wrist, and/or fingers showed significantly greater improvements in the modified Ashworth Scale and patient treatment goals and led to the approval of onabotulinumtoxinA for the treatment of ULS in adult patients. Lessons learned from the successful ULS trials were applied to design an LLS trial that led to approval for the latter indication. Additional observational trials mimicking real-world treatment have shown continued effectiveness and patient satisfaction. The use of onabotulinumtoxinA for spasticity has ushered in a more patient-centered treatment approach that has vastly improved patients’ quality of life.
Treatment of cervical dystonia with Botox (onabotulinumtoxinA): Development, insights, and impact
Authors: Jankovic Joseph , Tsui Joseph , Brin Mitchell F.
Published: July 2023

Cervical dystonia (CD), the most common focal dystonia encountered in neurologic practice, is a chronic disorder in which the muscles of the neck involuntarily contract and cause abnormal postures and movements of the head, neck, and shoulders. Treatment of CD prior to botulinum toxin was unsatisfactory, as existing therapies often did not improve symptoms. The use of botulinum toxin for CD grew out of its success in treating blepharospasm, another type of focal dystonia. On the basis of results from a double-blind, placebo-controlled trial, onabotulinumtoxinA was approved in 2000 in the US for the treatment of CD in adults in order to alleviate abnormal head position and neck pain. A subsequent large observational trial further demonstrated the effectiveness of onabotulinumtoxinA for CD, showing improvements in various rating scales, physician-reported measures, and profound positive effects on patient quality of life, including in amelioration of pain and improvements in work productivity. In addition, onabotulinumtoxinA treatment also reduced the complications of CD, as patients no longer develop contractures (permanent muscle and tendon shortening from prolonged untreated dystonia), which markedly limited the range of neck motion. The onset of onabotulinumtoxinA treatment also accompanied advances in understanding the functional anatomy of neck muscles, basal ganglia physiology, and video and other recording technology. Following the success of onabotulinumtoxinA in the treatment of CD, its use has been expanded into numerous other therapeutic indications, and these advances stimulated educational and training programs by various neurologic and other medical societies.
Diagnosis of Acute Pancreatitis Using Postmortem Computed Tomography and Postmortem Magnetic Resonance Imaging
Authors: Chen Xin , Zhang Hui-mao , Zhou Dan-dan , Chen Zhi-ming , Wang Bo , Wang Zhuo , Bai Xiao
Published: July 2023

Acute pancreatitis (AP) is inflammation of the pancreas, which may be due to a wide variety of etiologies that share a final common pathway of premature activation of pancreatic enzymes and resultant autodigestion of pancreatic parenchyma. Acute pancreatitis is easy to diagnose clinically, with the presence of at least 2 of the 3 criteria (upper abdominal pain, serum amylase or lipase level greater than 3 times the upper limit of normal, or characteristic findings on imaging studies) of the revised Atlanta classification. However, postmortem imaging examinations of pancreatitis are extremely rare, and very few successful cases have been reported. Here, we present a case report of a single patient who underwent autopsy and postmortem imaging. Postmortem computed tomography (PMCT) and postmortem magnetic resonance imaging (PMMRI) showed peripancreatic inflammation and acute peripancreatic fluid collection in the left anterior pararenal space, which is consistent with the examination by autopsy. The advantages of PMMRI in AP have also been demonstrated. Our study also confirmed the advantage of PMCT angiography in the diagnosis of AP. To the best of our knowledge, this is the first report of PMCT and PMMRI combined with postmortem pathology in the diagnosis of AP.
Tying Overdose Data to Action: North Carolina's Opioid and Substance Use Action Plan Data Dashboard
Authors: Fliss Mike Dolan , Cox Mary E. , Proescholdbell Scott , Patel Amy , Smith MegAnn
Published: July 2023

From 2000 to 2020, more than 28 000 North Carolina (NC) residents died of drug overdose. In response, NC Department of Health and Human Services worked with community partners to develop an Opioid and Substance Use Action Plan (OSUAP), now in its third iteration. The NC OSUAP data dashboard brings together data on 15 public health indicators and 16 local actions across 8 strategies. We share innovations in design, data structures, user tasks, and visual elements over 5 years of dashboard development and maintenance, with a special focus and supplemental material covering the technical details and techniques that dashboard design and implementation teams may benefit from.
Clinical and Magnetic Resonance Imaging Radiomics–Based Survival Prediction in Glioblastoma Using Multiparametric Magnetic Resonance Imaging
Authors: Bathla Girish , Soni Neetu , Ward Caitlin , Pillenahalli Maheshwarappa Ravishankar , Agarwal Amit , Priya Sarv
Published: July 2023

Introduction

Survival prediction in glioblastoma remains challenging, and identification of robust imaging markers could help with this relevant clinical problem. We evaluated multiparametric magnetic resonance imaging–derived radiomics to assess prediction of overall survival (OS) and progression-free survival (PFS).

Methodology

A retrospective, institutional review board–approved study was performed. There were 93 eligible patients, of which 55 underwent gross tumor resection and chemoradiation (GTR-CR). Overall survival and PFS were assessed in the entire cohort and the GTR-CR cohort using multiple machine learning pipelines. A model based on multiple clinical variables was also developed. Survival prediction was assessed using the radiomics-only, clinical-only, and the radiomics and clinical combined models.

Results

For all patients combined, the clinical feature–derived model outperformed the best radiomics model for both OS (C-index, 0.706 vs 0.597; P < 0.0001) and PFS prediction (C-index, 0.675 vs 0.588; P < 0.001). Within the GTR-CR cohort, the radiomics model showed nonstatistically improved performance over the clinical model for predicting OS (C-index, 0.638 vs 0.588; P = 0.4). However, the radiomics model outperformed the clinical feature model for predicting PFS in GTR-CR cohort (C-index, 0.641 vs 0.550; P = 0.004). Combined clinical and radiomics model did not yield superior prediction when compared with the best model in each case.

Conclusions

When considering all patients, regardless of therapy, the radiomics-derived prediction of OS and PFS is inferior to that from a model derived from clinical features alone. However, in patients with GTR-CR, radiomics-only model outperforms clinical feature–derived model for predicting PFS.
Efficacy and Safety of Tofacitinib in Anti–Melanoma Differentiation–Associated 5 Gene Antibody–Positive Dermatomyositis
Authors: Li Shanshan , Li Sizhao , Wang Jinping , Zhang Ling , Duan Jianghui , Lu Xin , Zhang Lu , Wang Guochun
Published: July 2023

Objectives

This study aimed to evaluate the efficacy and safety of tofacitinib for the treatment of anti–melanoma differentiation–associated 5 gene (anti-MDA5) antibody–positive dermatomyositis (DM).

Methods

This study included 52 patients with anti-MDA5 antibody–positive DM (MDA5+DM) who were treated with tofacitinib and followed up. Clinical and laboratory data of these patients were recorded between January 2019 and June 2022. SPSS was used for all statistical analyses.

Results

The mean age of patients with MDA5+DM was 45 ± 12.4 years, and the median disease duration was 6.5 months (range, 3–13 months). The mean dosage of glucocorticoids was 34.7 ± 20.9 mg/d at the initiation of tofacitinib therapy. Overall, 47 patients were followed up for a mean duration of 7.8 ± 6.2 months. We found that the clinical symptoms of 28 patients (59.6%) were improved, but 1 patient (2.1%) died because of severe infection. Moreover, complications occurred in 25 patients (53.2%), among whom 19 patients had infections. Older age and C-reactive protein levels close to the upper value in reference range at the initial treatment were found to be the potential risk factors of infection. Furthermore, patients with cutaneous ulcers were found to have a lower risk of infection.

Conclusion

Tofacitinib can be used as a potential therapeutic option for MDA5+DM. The occurrence of infection requires special attention during treatment, particularly in patients with older age and C-reactive protein levels close to the upper value in reference range.
An Objective Computer-Assisted Measurement of Sonographic Renal Cortical Echogenicity
Authors: Beutler Bryce D. , El-Sabawi Bassim , Walker Daphne K. , Cen Steven , Tchelepi Hisham
Published: July 2023

Renal cortical echogenicity represents a marker of renal function. However, evaluation of the renal echotexture is subjective and thus disposed to error and interrater variability. Computer-aided image analysis may be used to objectively assess renal cortical echogenicity by comparing the echogenicity of the left kidney to that of the spleen; the resultant ratio is referred to as the splenorenal index (SRI). We performed a retrospective review of all adult patients who received a renal ultrasound over a 45-day period at our institution. Demographic data and kidney function laboratory values were documented for each patient. Regions of interest (ROIs) were selected in the left renal cortex and spleen using ImageJ software. The SRI was calculated as a ratio of the mean pixel brightness of the left kidney cortex ROI to the mean pixel brightness of the spleen ROI. The SRI was then correlated with serum creatinine, blood urea nitrogen, and estimated glomerular filtration rate. We found that among the 94 patients included in the study, the SRI had a significant positive correlation with serum creatinine (r= 0.43,P <0.001) and serum blood urea nitrogen (r= 0.45,P <0.001) and negative correlation with estimated glomerular filtration rate (r= −0.47,P< 0.001). Our data indicate that SRI may serve as a valuable tool for sonographic evaluation of renal parenchymal disease.
Persistent High Long-term Excess Mortality after Elective AAA Repair Especially in Women
Authors: Bulder Ruth M.A. , van der Vorst Joost R. , van Schaik Jan , Bedene Ajda , Lijfering Willem M. , Bastiaannet Esther , Hamming Jaap F. , Lindeman Jan H.N.
Published: July 2023

Objective:

The aim of this time-trend analysis is to estimate long-term excess-mortality and associated cardiovascular risk for abdominal aortic aneurysm (AAA) patients after elective repair, while addressing the changes in AAA management and patient selection over time.

Summary Background Data:

Despite the intensification of endovascular aneurysm repair (EVAR) and cardiovascular risk management (CVRM), Swedish population data suggest that AAA patients retain a persistently high long-term mortality after elective repair. The question is whether this reflects sub-optimal treatment, a changing patient population over time, or a national phenomenon.

Methods:

Nationwide time-trend analysis including 40730 patients (87% men) following elective AAA repair between 1995-2017. Three timeframes were compared, each reflecting changes in the use of EVAR and intensification of CVRM. Relative survival analyses were used to estimate disease-specific excess-mortality. Competing risk of death analysis evaluated the risk of cardiovascular versus non-cardiovascular death. Sensitivity analysis evaluated the impact of changes in patient selection over time.

Results:

Short-term excess-mortality significantly improved over time. Long-term excess-mortality remained high with a doubled mortality risk for women (RER 1.87 (95%CI 1.73–2.02)). Excess-mortality did not differ between age-categories. The risk of cardiovascular versus non-cardiovascular death remained similar over time, with a higher risk of cardiovascular death for women. Changes in patient population (i.e. older and more comorbid patients in the latter period) marginally impacted excess-mortality (2%).

Conclusions:

Despite changes in AAA care, patients retain a high long-term excess-mortality after elective repair with a persistent high cardiovascular mortality risk. In this a clear sex- but no age disparity stands out.
Immunohistochemical expression of TFF1 is a new prognostic marker in retinoblastoma
Authors: Aschero Rosario , Ganiewich Daiana , Lamas Gabriela , Restrepo-Perdomo Camilo A , Ottaviani Daniela , Zugbi Santiago , Camarero Sandra , Néspoli Ezequiel , Vilanova Maria Cuadrado , Perez-Jaume Sara , Pascual-Pasto Guillem , Sampor Claudia , Grigorovski Nathalia , Salas Beatriz , Suñol Mariona , Carcaboso Angel M. , Mora Jaume , de Dávila María T G , Doz François , Radvanyi François , Abramson David H , Llera Andrea S , Schaiquevich Paula S , Lubieniecki Fabiana , Chantada Guillermo L
Published: July 2023

Introduction

The risk of relapse in retinoblastoma is currently determined by the presence of high-risk histopathologic factors in the enucleated eye. However, the probability of developing metastatic disease is heterogeneous among these patients. Evaluating a biological marker to identify high-risk patients could be useful in clinical setting. This study aims to evaluate whether the expression of TFF1, a surrogate for subtype 2 retinoblastoma, is a prognostic marker for relapse and death.

Methods

This multicenter cohort study included 273 patients, 48 of whom had extraocular disease. Immunohistochemical staining were performed for CRX, ARR3, TFF1 and Ki67. Tumors were classified as histological subtype 1 (HS1) if they had low or no expression of TFF1 (quick score (QS) ≤ 50) and as histological subtype 2 (HS2) if they expressed TFF1 diffusely (QS > 50). We studied the association between HS classification and outcome.

Results

Of 273 patients, 35.9% were classified as HS1, 59.3% as HS2 and 4.8% were not evaluable. In multivariate analysis, patients with HS2 tumors had a higher probability of relapse and death than those with HS1 (P< 0.0001 andP= 0.00020, respectively). We identified a higher-risk subgroup among HS2 tumors, presenting non-mutually exclusive expression of ARR3 and TFF1 and had an increased risk of relapse and death compared to tumors that displayed mutually exclusive expression (P= 0.012 andP= 0.027, respectively).

Conclusions

Expression of TFF1, especially when it is not-mutually exclusive with ARR3, is an independent prognostic marker of poor outcome in retinoblastoma.
Validating an Approach for Estimating Appropriate Black Participation in Clinical Trials
Authors: Berg Jeremy M. , Celedón Juan C. , Jonassaint Naudia N.
Published: July 2023

Representation of different groups at appropriate levels in clinical trials is of great importance. Factors affecting what appropriate levels include the demographics at the trial sites and the prevalence of the condition under study in different populations. We examined 359 trials published in New England Journal of Medicine, Journal of the American Medical Association (JAMA), and the Lancet in 2020 for information about Black participation rates. Sufficient information for analysis was available in 58 trials. Simulations including both site demographics and prevalence factors revealed that observed Black participation rates were reasonably well correlated with estimated potential Black participation rates, but that actual participation rates were lower than potential rates in 47 out of 58 trials. This approach could be used to estimate appropriate participation rates prior to trial initiation and for analysis of trials upon completion. Promotion of such transparency standards will aid future analyses and should help drive improvements in representation over time.

Clinical trials represent important opportunities to test potential interventions in groups of individuals who can provide meaningful data and who represent populations who might benefit from the trial results. This has been described and highlighted by the recent report “Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups” from the United States National Academy of Sciences1. One of the overarching conclusions from this report is:
A parametric finite element model of leg campaniform sensilla inDrosophilato study CS location and arrangement
Authors: Saltin Brian D. , Haustein Moritz , Büschges Ansgar , Blanke Alexander
Published: July 2023

Campaniform sensilla (CS) are mechanosensors embedded within the cuticle of many insects at key locations such as nearby leg segment joints or halters. CS located at leg segments were found to respond to cuticle bending which can be induced by walking or jumping movements or by the underlying tensile forces of the muscles. ForDrosophilait is unclear how CS location and material property variation influence stress levels within and around CS but this information is crucial to understand how flies might use CS input to adjust walking behaviour. Here, we designed a parametric model of the femoral CS field forDrosophilato allow for a systematic testing of the influence of CS location, orientation and material property variation on stress levels. The model consists of 7 changeable parameters per CS and 12 which can be changed for the CS field. Simulations of leg bending are in line with general beam bending theory: At the specific proximal CS field location nearby the trochantero-femoral leg joint, displacements are smaller than distal, while stresses are higher. When changing CS location towards more distal leg parts the situation changes towards more displacement and less stress. Changes in material property values for CS substructures or whole CS fields have a very low influence on stress or displacement magnitudes (regarding curve shape and amplitude) at the CS caps to which the nerve cells attach. Taken together, our simulation results indicate that for CS fields located at proximal leg parts, the displacements induced by other sources such as muscle tensile forces might be more relevant stimuli than the overall leg bending induced by typical locomotion scenarios. Future parametric finite element models should contain experimentally validated information on the anisotropic and viscoelastic properties of materials contained in this sensory system to further our understanding of CS activation patterns.
Identification of consensus head and neck cancer-associated microbiota signatures: a meta-analysis of 16S rRNA and The Cancer Microbiome Atlas datasets
Authors: Yeo Kenny , Li Runhao , Wu Fangmeinuo , Bouras George , Mai Linh T.H. , Smith Eric , Wormald Peter-John , Valentine Rowan , Psaltis Alkis James , Vreugde Sarah , Fenix Kevin
Published: July 2023

Objective

Multiple reports have attempted to describe the tumour microbiota in head and neck cancer. However, these have failed to produce a consistent microbiota signature which may undermine understanding the importance of bacterial-mediated effects in head and neck cancer. The aim of this study is to consolidate these datasets and identify a consensus microbiota signature in head and neck cancer.

Methods

We analysed 11 published head and neck cancer 16S ribosomal RNA microbial datasets collected from cancer, cancer-adjacent and non-cancer tissue to generate a consensus microbiota signature. These signatures were then validated using The Cancer Microbiome Atlas database.

Results

We identified unique bacteria enrichment within tissue types and correlated it with possible functional and clinical outcomes.

Conclusions

Our meta-analysis demonstrates a consensus microbiota signature for head and neck cancer, highlighting its potential importance in this disease.

Highlights

The first meta-analysis of tissue microbiome in head and neck cancer containing eleven 16S ribosomal RNA and The Cancer Microbiome Atlas dataset.

Microbiome from head and neck tissues were able to distinguish tissue types (cancer, cancer-adjacent, non-cancer) using 16S rRNA sequencing and whole genome sequencing datasets.

Specific bacterial genera correlate with different tumour microenvironment phenotypes.

High abundanceFusobacteriumin tumour tissue correlates with better overall survival.
DKK1, a negative regulator of Wnt signaling, is a novel inducer of neuroblastoma differentiation
Authors: Krishna Shubham , Prajapati Bharat , Seth Pankaj , Sinha Subrata
Published: July 2023

Background

This study aimed to analyze the role of Dickopff1 [DKK1] as a potential differentiating agent for the neuroblastoma cell line SHSY5Y and neurospheres derived from it.

Materials and Methods

SHSY5Y neurospheres were formed from undifferentiated adherent cultures. The cellular properties and gene expression were used to study the effect of DKK1 on SHSY5Y-formed neurospheres. Its effect on SHSY5Y neuronal differentiation was also studied.

Results

SHSY5Y adherent undifferentiated cells were grown as neurospheres. Treatment of neurospheres resulted in their fragmentation. It also resulted in reduced mRNA expression of markers of cancer stem cells, pluripotency, and proliferation [p≤0.05]. DKK1 treatment also resulted in reduced mRNA expression of β-catenin and TCF genes. There was significantly higher expression of neuronal differentiation genes in SHSY5Y adherent cells grown in complete DMEM media containing DKK1 as compared to cells grown without DKK1. We also found DKK1 synergized with retinoic acid-induced differentiation of neuroblastoma cells.

Conclusion

DKK1 was able to convincingly abrogate neurosphere formation and promote neuronal differentiation of SHSY5Y cells, including synergy with retinoic acid. This was accompanied by corresponding changes in mRNA markers of cancer stem cells, pluripotency and proliferation. These results may have implications for neuroblastoma stemness and differentiation.
E-cadherin biointerfaces reprogram collective cell migration and cell cycling by forcing homeostatic conditions
Authors: Suh Kevin , Cho Youn Kyoung , Breinyn Isaac B. , Cohen Daniel J.
Published: July 2023

Cells attach to the world around them in two ways—cell:extracellular-matrix adhesion and cell:cell adhesion—and conventional biomaterials are made to resemble the matrix to encourage integrin-based cell adhesion. However, interest is growing for cell-mimetic interfaces that mimic cell-cell interactions using cadherin proteins, as this offers a new way to program cell behavior and design synthetic implants and objects that can integrate directly into living tissues. Here, we explore how these cadherin-based materials affect collective cell behaviors, focusing specifically on collective migration and cell cycle regulation in cm-scale epithelia. We built culture substrates where half of the culture area was functionalized with matrix proteins and the contiguous half was functionalized with E-cadherin proteins, and we grew large epithelia across this ‘Janus’ interface. Parts of the tissues in contact with the matrix side of the Janus interface exhibited normal collective dynamics, but an abrupt shift in behaviors happened immediately across the Janus boundary onto the E-cadherin side, where cells formed hybrid E-cadherin junctions with the substrate, migration effectively froze in place, and cell-cycling significantly decreased. E-cadherin materials suppressed long-range mechanical correlations in the tissue and mechanical information reflected off the substrate interface. These effects could not be explained by conventional density, shape index, or contact inhibition explanations. E-cadherin surfaces nearly doubled the length of the G0/G1 phase of the cell cycle, which we ultimately connected to the exclusion of matrix focal adhesions induced by the E-cadherin culture surface.
Immune experience at time of circulation and time since virus circulation are predictors of HAI titre
Authors: Gibson Joseph C. , de Jong Simon P. J. , Russell Colin A.
Published: July 2023

Nearly everyone is infected with seasonal influenza viruses multiple times over the course of their lives due to the antigenic evolution of the virus to escape immunity induced by prior infections and vaccinations. Because antibody escape is usually partial, the antibody response to new infections depends on prior responses which wane and are boosted throughout life. We used serum antibody binding measurements of 864 individuals against a range of historical A/H3N2 viruses collected in previous studies in combination with statistical models to investigate how metrics of age and strain heterogeneities affect haemagglutination inhibition titres. We refine prior modelling of antigenic seniority by characterising immune experience as years of life since a (sub)type’s emergence at time of strain circulation, rather than age at time of circulation. Using Bayesian statistical modeling, we show that this variable, combined with time since circulation of the variant and an individual’s age at circulation, yields the best model fit. Based on the best-fit model, we devised a novel parametric model, and use it to demonstrate and estimate how effects of antigenic seniority, individual age, strain age and strain effects act in concert to shape an individual’s HAI titre.
International perspective on physician knowledge, attitude and practices related to medical cannabis
Authors: Syed Shariful A. , Singh Jatinder , Elkholy Hussien , Rojnic Palavra Irena , Tomicevic Marko , Petek Eric Anamarija , Pinto da Costa Mariana , Guloksuz Sinan , Radhakrishnan Rajiv
Published: July 2023

Background

The trends of recreational use of cannabis and use of cannabis for medical indications (i.e. “medical cannabis”) have grown in recent years. Despite that, there is still limited scientific evidence to guide clinical decision-making and the strength of evidence for the medical use of cannabis is currently considered to be low. In contrast, there’s growing evidence for negative health outcomes related to use of cannabis. In this rapidly shifting landscape, the role of physician’s attitudes regarding the therapeutic value of cannabis has become essential. This study aimed to characterize knowledge/experience, attitudes, and potential predictors of clinical practice regarding medical cannabis.

Methods

We conducted a cross-sectional survey of physicians from 17 countries between 2016-2018. The survey comprised of 28 questions designed to explore physician knowledge, attitude, and practices regarding the use of medical cannabis. Descriptive statistics were used to examine willingness to recommend medical cannabis for medical and psychiatric indications, followed by regression analysis to identify predictors of physician willingness to recommend medical cannabis.

Results

A total of 323 physicians responded to the survey. Mean age was 35.4± 9.5 years, with 10.04 ±8.6 years of clinical experience. 53 percent of physicians were women. Clinical experience with medical cannabis was overall limited (51.4% noted never having recommended medical cannabis; 33% noted inadequate knowledge regarding medical cannabis). Overall willingness to recommend medical cannabis was highest for chemotherapy-induced nausea, refractory chronic neuropathic pain, and spasticity in amyotropic lateral sclerosis (ALS).

Conclusion

This international study examining knowledge, attitudes and practices related to medical cannabis among physicians revealed that there are significant gaps in domain-specific knowledge related to medical cannabis. There is wide variability in willingness to recommend medical cannabis that is not consistent with the current strength of evidence. This study thus highlights the need for greater education related to domain-specific knowledge about medical cannabis.
Chronic Shedding of a SARS-CoV-2 Alpha Variant Lineage Q.3/Q.4 in Wastewater
Authors: Conway Michael J. , Yang Hannah , Revord Lauren A. , Ward Avery S. , Abel Jackson D. , Williams Maggie R. , Uzarski Rebecca L. , Alm Elizabeth W.
Published: July 2023

Central Michigan University (CMU) participated in a state-wide SARS-CoV-2 wastewater monitoring program since 2021. Wastewater samples were collected from on-campus sites and nine off-campus wastewater treatment plants servicing small metropolitan and rural communities. SARS-CoV-2 genome copies were quantified using droplet digital PCR and results were reported to the health department. One rural, off-campus site consistently produced higher concentrations of SARS-CoV-2 genome copies. Samples from this site were sequenced and initially contained predominately Alpha variant lineage Q.3, which transitioned to lineage Q.4. Alpha variant lineage Q.3/Q.4 was detected at this site beginning in fall 2021 and continued until summer 2023. Mutational analysis of reconstructed genes revealed divergence from the Alpha variant lineage Q.3 clinical sequence over time, including numerous mutations in the surface glycoprotein RBD and NTD. We discuss the possibility that a chronic SARS-CoV-2 infection accumulated adaptive mutations that promoted long-term infection. This study reveals that small wastewater treatment plants can enhance resolution of rare events and facilitate reconstruction of viral genomes due to the relative lack of contaminating sequences.
Detection ofMycobacterium tuberculosistransrenal DNA in urine samples among adult patients in Peru
Authors: Mesman Annelies W , Calderon Roger I , Hauns Laura , Pollock Nira R , Mendoza Milagros , Holmberg Rebecca C , Franke Molly F
Published: July 2023

Diagnosis of tuberculosis (TB) relies on a sputum sample, which cannot be obtained from all symptomatic patients.Mycobacterium tuberculosis (Mtb)transrenal DNA (trDNA) has been detected in urine, an easily obtainable, noninvasive, alternative sample type. However, reported sensitivities have been variable and likely depend on collection/assay procedures and aspects of trDNA biology. We analyzed three serial urine samples from each of 75 adults with culture-confirmed pulmonary TB disease in Lima, Peru for detection of trDNA using short-fragment real-time PCR. Additionally, we examined host, urine, and sampling factors associated with detection. Overall sample sensitivity was 38% (95% Confidence Interval [CI] 30–45%). On a patient level (i.e., any of three samples positive), sensitivity was 73% (95% CI: 62-83%). Sensitivity was highest among samples from patients with smear-positive TB, 92% (95% CI: 62-100%). Specificity from a single sample from each of 10 healthy controls was 100% (95% CI: 69-100%). Adjusting our assay positivity threshold increased patient-level sensitivity to 88% (95% CI: 78-94%) overall without affecting the specificity. We did not find associations betweenMtbtrDNA detection and either patient characteristics or urine sample characteristics. Overall, our results support the potential of trDNA detection for TB diagnosis.
Self-reported reactions to the front-of-package warning labelling in Mexico among parents of school-aged children
Authors: Batis Carolina , Aburto Tania C. , Pedraza Lilia S. , Angulo Erick , Hernández Zugey , Jáuregui Alejandra , Taillie Lindsey Smith , Rivera Juan A. , Barquera Simón
Published: July 2023

Background

To improve the food environment and guide consumers to select healthier foods, the implementation of a front of package warning labelling (FOPWL) started in Mexico in October 2020. We aimed to identify the self-reported support, understanding, use and perceived impact of the FOPWL 1-5 months after its implementation among parents of school-aged children across socioeconomic categories and nutrition knowledge and attitudes.

Methods

EPHA-niñ@s is a national web-based cohort of Mexican children 5-10 y and one of their parents aiming to monitor their food and food policy perception and opinions and children’s dietary intake. Recruitment was conducted primarily through paid advertisements on social media. Data was collected online with a self-administered questionnaire answered by the parent and an interviewer-administered questionnaire answered by the child during a video call. This analysis was conducted with data from the parent’s questionnaire from the first wave of data collection (November 2020-March 2021) which included 2,071 participants from all over the country. We evaluated differences by socioeconomic status (SES), education and nutrition knowledge and consciousness, while adjusting by other sociodemographic characteristics using multinomial logistic regression.

Results

The sample was predominantly from middle and high socioeconomic status (SES). Most parents (85%) agree/strongly agree with the FOPWL (support), 86% correctly identified that a product with one warning is healthier than a product with three (understanding), 65% compared the number of warnings sometimes to very often (use), and 63% reported buying less and 25% stopped buying products with warnings for their children (perceived impact). The perceived impact was higher when products were for their children than for themselves. Perceived impact also differed by food group, being higher for sodas, juices, and cereal bars and lower for chips and chocolate powder. Responses were more favorable for five-six questions (out of seven) among those with higher nutrition knowledge, and higher nutrition consciousness, and for three questions among those with higher education level.

Conclusion

Within six months of implementation, the immediate self-reported responses related to support, understanding, use, and perceived impact to the Mexican FOPWL were favorable. Further studies in other populations including low SES participants and impact evaluations, are needed.
Patient-derived organoids assist personalized treatment for a patient with multiple metastatic neuroendocrine carcinoma of the cervix
Authors: Liu Ruimei , Gao Xinyu , Yue Xiaoni , Yu Ying , Xu Zhaoting , Zhu Feng , Shi Leming , Cheng Xinghua , Lin Xinhua , Zheng Yuanting
Published: July 2023

Neuroendocrine carcinoma of the cervix (NECC) is a rare subtype of cervical cancer with rapid metastasis. Lack of treatment regimens for metastatic NECC highlights the need for preclinical models and personalized treatment. Here, we established two patient-derived NECC organoid lines from lung metastases from the same patient, one of which was drug-free and the other exhibited tolerance to carboplatin plus etoposide (EP). The two organoids recapitulated the histopathology and genomic spectrum of the original tumors. Whole-genome sequencing revealed genomic structural variations (SVs), including HPV16 infection, NEUROD2, and ERBB2 amplification. The sensitivity phenotype of organoids to ERBB2 inhibitors coincides with the genomic features of ERBB2 amplification. In addition, the patient after relapse responded well to the paclitaxel plus carboplatin (TC) regimen as recommended by organoid drug screening, underscoring the utility of organoids as preclinical models. We first provide two NECC organoids of lung metastases with comprehensive molecular characteristics as valuable resources for this rare cancer and give a typical application for personalized treatment based on organoids.
Macrophage inhibitor clodronate enhances liver transduction of lentiviral but not AAV vectors or mRNA lipid nanoparticlesin vivo
Authors: Touramanidou Loukia , Gurung Sonam , Cozmescu Claudiu A. , Perocheau Dany P. , Moulding Dale , Ridout Deborah , Cavedon Alex , Siddiqui Summar , Rice Lisa , Finn Patrick F. , Martini Paolo G.V. , Frassetto Andrea , Waddington Simon N. , Counsell John R. , Gissen Paul , Baruteau Julien
Published: July 2023

Recently approved adeno-associated viral (AAV) vectors for liver monogenic diseases hemophilia A and B are exemplifying the success of liver-directed viral gene therapy. In parallel, additional strategies are rapidly emerging to overcome some inherent AAV limitations, such as non-persistence of episomal transgene in rapidly growing liver and immune response. Integrating lentiviral vectors and non-viral lipid nanoparticles encapsulating mRNA (LNP-mRNA) are rapidly being developed, currently at preclinical and clinical stages respectively. Macrophages are first effector cells of the innate immune response triggered by gene therapy vectors. Macrophage uptake and activation following administration of viral gene therapy and LNPs has been reported. In this study, we assessed the biodistribution of AAV, lentiviral and LNP-mRNA gene therapy following inhibition of tissue macrophages by clodronate liposomes in neonatal and juvenile mice. Juvenile clodronate-treated mice showed significant increase of lentiviral-transduced hepatocytes, and increasing trend of transduction was shown in neonatally-injected mice. In contrast, AAV- and LNP-mRNA-treated neonatal and juvenile animals did not show significant increase of liver biodistribution following clodronate administration. These findings will have translational application for liver-targeting gene therapy programmes.
Development and experimental verification of innovative corrosion protection epoxy coatings for steel
Authors: Balachandra Anagi , Nassar Roz-Ud-Din , Soroushian Parviz
Published: July 2023

Purpose

This study aims to report the development and experimental evaluation of three innovative corrosion-resistant modified epoxy coatings, namely, nanocomposite/toughened, self-healing and hybrid epoxy coatings, for application on steel substrates.

Design/methodology/approach

The corrosion resistance of these coatings was evaluated in a highly corrosive environment of salt fog spray for 2,500 h of exposure. Electrochemical impedance spectroscopy (EIS) measurements in sustained exposure to NaCl in a saturated Ca(OH)2 solution, rust creepage measurements at the location of scribe formed in the coatings and adhesion strength test were used to assess the performance of the innovative coatings. Commercially available marine-grade protective epoxy coatings were used as the reference coatings.

Findings

The test results showed that the modified epoxy coatings exhibited excellent corrosion resistance when exposed to an aggressive environment for extended periods. The EIS measurements, rust creepage measurements, pull-off strength and visual appearance of the aged modified–epoxy–coated specimens confirmed the enhanced corrosion resistance of the modified epoxy coatings.

Originality/value

Among the three types of modified coatings, the hybrid epoxy coating stands out to be the best performer.