bluuebunny/crossref_metadata_2025 huggingface dataset:
Central Sensitization Symptom Severity and Patient-Provider Relationships in a Community Setting
Authors: Wang Xiao Jing , Ebbert Jon O. , Gilman Elizabeth A. , Rosedahl Jordan K. , Ramar Priya , Philpot Lindsey M.
Published: July 2021

Introduction

Central sensitization syndromes (CSS) comprise an overlapping group of clinical conditions with the core feature of “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.” Patients with CSS are known to have challenging interactions with healthcare providers contributing to psychological distress and increased healthcare utilization. CSS symptom severity has been associated with psychologic comorbidities, but little is known about how symptom severity relates to provider interactions.

Methods

We performed a cross-sectional survey among patients with CSS in our primary care practices to examine the relationship between CSS symptom severity and experiences with doctors.

Results

A total of 775 respondents completed the survey (775/5000; 15.5%) with 72% reporting high CSS symptom severity. About 44% of respondents had a prior diagnosis of fibromyalgia, 72% had migraines, and 28% had IBS. Patients with high CSS symptom severity were more likely to report that doctor(s) had often/always told them that they don’t need treatment when they feel like they do (OR = 3.6, 95% CI 1.9-7.5), that doctor(s) often/always don’t understand them (OR = 3.1, 95% CI 1.9-5.4), and that doctor(s) often/always seem annoyed with them when compared with respondents with low-moderate CSS symptom severity (OR = 4.8, 95% CI 2.2-12.5). Patients with high CSS symptom severity were at greater than 5 times odds of reporting being told that their symptoms were “all in their head” when compared to patients with low-moderate symptom severity (OR = 5.4, 95% CI 3.3-9.0).

Conclusion

Patients with CSS spectrum disorders experience frequent pain and decreased quality of life. A high degree of CSS symptom severity is associated with negative experiences with healthcare providers, which deters the establishment of a positive provider-patient relationship. Further research is needed to help understand symptom severity in CSS and harness the power of the therapeutic alliance as a treatment modality.
Low Birth Weight Prevalence in Children Diagnosed with Neurodevelopmental Disorders in Dubai
Authors: Nawaz Faisal A. , Sultan Meshal A.
Published: July 2021

The aim of this study is to evaluate the prevalence of low birth weight and other perinatal risk factors in children diagnosed with neurodevelopmental disorders. This is one of the first studies in the Arabian Gulf region focused on the contribution of these factors toward the development of various disorders such as attention-deficit/hyperactivity disorder, autism spectrum disorder, and other mental disorders. This descriptive study was based on qualitative data analysis. We reviewed retrospective information from the electronic medical records of 692 patients in Dubai, United Arab Emirates. The prevalence of low birth weight in children with mental disorders was significantly higher as compared to the general population (16% vs 6% respectively). Furthermore, other risk factors, including high birth weight and preterm birth were noted to have a significant association with neurodevelopmental disorders. Future research on the impact of perinatal risk factors will contribute to advancement of early intervention guidelines.
Advocacy for a Digital Oral Health That Leaves No One Behind
Authors: Giraudeau N. , Varenne B.
Published: July 2021

During the first wave of the coronavirus disease 2019 (COVID-19) pandemic, the lockdown enforced led to considerable disruption to the activities of dental services, even leading to closures. To mitigate the impact of the lockdowns, systems were quickly put in place in most countries to respond to dental emergencies, giving priority to distance screening, advice to patients by remote means, and treatment of urgent cases while ensuring continuous care. Digital health was widely adopted as a central component of this new approach, leading to new practices and tools, which in turn demonstrated its potential, limitations, and possible excesses.

Political leaders must become aware of the universal availability of digital technology and make use of it as an additional, safe means of providing services to the public. In view of the multiple uses of digital technologies in health—health literacy, teaching, prevention, early detection, therapeutics, and public health policies—deployment of a comprehensive program of digital oral health will require the adoption of a multifaceted approach.

Digital tools should be designed to reduce, not increase, inequalities in access to health care. It offers an opportunity to improve healthy behavior, lower risk factors common to oral diseases and others noncommunicable diseases, and contribute to reducing oral health inequalities. It can accelerate the implementation of universal health coverage and help achieve the 2030 Sustainable Development Agenda, leaving no one behind. Digital oral health should be one of the pillars of oral health care after COVID-19. Universal access to digital oral health should be promoted globally. The World Health Organization’s mOralHealth program aims to do that.

Knowledge Transfer Statement:

This position paper could be used by oral health stakeholders to convince their government to implement digital oral health program.
Correlation between acute ischaemic stroke clot length before mechanical thrombectomy and extracted clot area: Impact of thrombus size on number of passes for clot removal and final recanalization
Authors: Rossi Rosanna , Fitzgerald Seán , Gil Sara M , Mereuta Oana M , Douglas Andrew , Pandit Abhay , Brennan Paul , Power Sarah , Alderson Jack , O’Hare Alan , Gilvarry Michael , McCarthy Ray , Psychogios Klearchos , Magoufis Georgios , Tsivgoulis Georgios , Szikora István , Jood Katarina , Redfors Petra , Nordanstig Annika , Ceder Erik , Tatlisumak Turgut , Rentzos Alexandros , Thornton John , Doyle Karen M
Published: July 2021

Introduction

We assessed the correlation between thrombus size before and after mechanical thrombectomy, measured as length by Computed Tomography Angiography/Non-Contrast Computed Tomography (CTA/NCCT) and Extracted Clot Area, ECA, respectively. We also assessed the influence of thrombus size on the number of passes required for clot removal and final recanalization outcome.

Materials and methods

Acute ischaemic stroke (AIS) thrombi retrieved by mechanical thrombectomy from 500 patients and data of clot length by CTA/NCCT were collected from three hospitals in Europe. ECA was obtained by measuring the area of the extracted clot. Non-parametric tests were used for data analysis.

Results

A strong positive correlation was found between clot length on CTA/NCCT and ECA (rho = 0.619,N = 500,P < 0.0001*). Vessel size influences clot length on CTA/NCCT (H2 = 98.6, P < 0.0001*) and ECA (H2 = 105.6,P < 0.0001*), but the significant correlation between CTA/NCCT length and ECA was evident in all vessels. Poorer revascularisation outcome was associated with more passes (H5 = 73.1, P < 0.0001*). More passes were required to remove longer clots (CTA/NCCT; H4 = 31.4, P < 0.0001*; ECA; H4 = 50.2, P < 0.0001*). There was no significant main association between recanalization outcome and length on CTA/NCCT or ECA, but medium sized clots (ECA 20–40 mm2) were associated with least passes and highest revascularisation outcome (N = 500, X2 = 16.2, P < 0.0001*).

Conclusion

Clot length on CTA/NCCT strongly correlates with ECA. Occlusion location influences clot size. More passes are associated with poorer revascularisation outcome and bigger clots. The relationship between size and revascularisation outcome is more complex. Clots of medium ECA take less passes to remove and are associated with better recanalization outcome than both smaller and larger clots.
Long-term effect of α1-antitrypsin augmentation therapy on the decline of FEV1in deficient patients: an analysis of the AIR database
Authors: Schouten Iris G.M. , Kasteleyn Marise J. , Tsonaka Roula , Bals Robert , Turner Alice C. , Ferrarotti Ilaria , Corsico Angelo G. , Lara Beatriz , Miravitlles Marc , Stockley Robert A. , Stolk Jan
Published: July 2021

Background

Patients with ZZ (Glu342Lys) α-1-antitrypsin deficiency (ZZ-AATD) who received augmentation therapy with α-1-antitrypsin (AAT) in randomised controlled trials over 2–3 years failed to show a significant reduction of the annual decline of forced expiratory volume in 1 s (FEV1).

Methods

To compare the trajectory of FEV1change during 4 or more years in ZZ-AATD patients with emphysema receiving or not receiving intravenous augmentation therapy, a retrospective analysis of FEV1values entered in the Alpha-1 International Registry (AIR) of ZZ-AATD patients from five different European countries (Germany, UK, Spain, Italy and the Netherlands) was performed. The post-bronchodilator FEV1% predicted values for baseline and follow-up over time from patients were analysed using linear mixed effects models.

Results

Data of 374 patients were analysed: 246 untreated and 128 treated with intravenous AAT augmentation therapy. The mean±sdfollow-up duration of the untreated group was 8.60±3.34 years and 8.59±2.62 years for the treated group. The mixed effects model analysis showed a mean FEV1decline of −0.931% predicted per year (95% CI −1.144 to −0.718) in the untreated group and a decline of −1.016% predicted per year (95% CI −1.319 to −0.7145) in the treated group. The likelihood ratio test showed no difference between the two groups (p=0.71).

Conclusion

In our study population, we could not detect a significant difference in the annual decline of FEV1by AAT augmentation treatment over a mean period of 8.6 years. Other approaches are needed to validate any benefit of augmentation therapy.
The influence of feeding ecology and location on total mercury concentrations in Eurasian perch (Perca fluviatilis)
Authors: Suhareva Natalija , Aigars Juris , Poikāne Rita , Tunens Juris
Published: July 2021

Background

Eurasian perch (Perca fluviatilis) is an ecologically significant fish species in the Baltic Sea and has been recognized as a suitable organism to measure concentrations of mercury (Hg) contamination. The adult species occupy a high trophic position; therefore, significant levels of the hazardous substances tend to bioaccumulate in their tissues. However, the ability of the species to inhabit a wide range of feeding ground raises concerns about the adequacy of monitoring data in relation to the representativeness of measured levels of Hg at specific locations. Accounting for the migratory characteristics of this species can shed light on the origin of the analyzed specimens and thus trace Hg uptake chain. Perch samples and potential perch prey were collected at three remote stations in a fully interlinked system river–lake–coastal/transitional waters of the Gulf of Riga. Total mercury (THg) concentration and stable isotope ratios were measured in each sampled item. The perch data were divided into three subgroups associated with specific feeding grounds and one mixed group. A Bayesian mixing model was implemented to quantify the feeding preferences of each group, and based on the results, influence of each food source on Hg uptake by perch was modeled by means of Gaussian GAM model.

Results

Calculated carbon and nitrogen stable isotope values demonstrated clear evidence of perch specimens migrating between the sampling stations. Substantial proportion of specimens sampled in river and lake stations had isotopic signals consistent with feeding in the gulf. The group of perch associated with feeding in the river grounds exhibited the highest THg concentrations with mean value of 209 µg kg−1wet weight. The food itemsC. harengus membrasand Crustacean showed significant mitigating effects on THg concentration. The rest of the food items showed a secondary influence on the variation of THg concentration.

Conclusions

The study clearly showed that the high mobility of perch along associated aquatic systems has a noticeable effect on Hg concentrations measured in the fish. Therefore, trophic position and isotopic signatures, along with identification of the food sources, can serve as important supplementary tools for more accurate data interpretation of Hg accumulation.
A conditional multi-trait sequence GWAS discovers pleiotropic candidate genes and variants for sheep wool, skin wrinkle and breech cover traits
Authors: Bolormaa Sunduimijid , Swan Andrew A. , Stothard Paul , Khansefid Majid , Moghaddar Nasir , Duijvesteijn Naomi , van der Werf Julius H. J. , Daetwyler Hans D. , MacLeod Iona M.
Published: July 2021

Background

Imputation to whole-genome sequence is now possible in large sheep populations. It is therefore of interest to use this data in genome-wide association studies (GWAS) to investigate putative causal variants and genes that underpin economically important traits. Merino wool is globally sought after for luxury fabrics, but some key wool quality attributes are unfavourably correlated with the characteristic skin wrinkle of Merinos. In turn, skin wrinkle is strongly linked to susceptibility to “fly strike” (Cutaneous myiasis), which is a major welfare issue. Here, we use whole-genome sequence data in a multi-trait GWAS to identify pleiotropic putative causal variants and genes associated with changes in key wool traits and skin wrinkle.

Results

A stepwise conditional multi-trait GWAS (CM-GWAS) identified putative causal variants and related genes from 178 independent quantitative trait loci (QTL) of 16 wool and skin wrinkle traits, measured on up to 7218 Merino sheep with 31 million imputed whole-genome sequence (WGS) genotypes. Novel candidate gene findings included the MAT1A gene that encodes an enzyme involved in the sulphur metabolism pathway critical to production of wool proteins, and the ESRP1 gene. We also discovered a significant wrinkle variant upstream of the HAS2 gene, which in dogs is associated with the exaggerated skin folds in the Shar-Pei breed.

Conclusions

The wool and skin wrinkle traits studied here appear to be highly polygenic with many putative candidate variants showing considerable pleiotropy. Our CM-GWAS identified many highly plausible candidate genes for wool traits as well as breech wrinkle and breech area wool cover.
Evolution of transcriptional control of antigenic variation and virulence in human and ape malaria parasites
Authors: Gross Mackensie R. , Hsu Rosie , Deitsch Kirk W.
Published: July 2021

Background

The most severe form of human malaria is caused by the protozoan parasite Plasmodium falciparum. This unicellular organism is a member of a subgenus of Plasmodium called the Laverania that infects apes, with P. falciparum being the only member that infects humans. The exceptional virulence of this species to humans can be largely attributed to a family of variant surface antigens placed by the parasites onto the surface of infected red blood cells that mediate adherence to the vascular endothelium. These proteins are encoded by a large, multicopy gene family called var, with each var gene encoding a different form of the protein. By changing which var gene is expressed, parasites avoid immune recognition, a process called antigenic variation that underlies the chronic nature of malaria infections.

Results

Here we show that the common ancestor of the branch of the Laverania lineage that includes the human parasite underwent a remarkable change in the organization and structure of elements linked to the complex transcriptional regulation displayed by the var gene family. Unlike the other members of the Laverania, the clade that gave rise to P. falciparum evolved distinct subsets of var genes distinguishable by different upstream transcriptional regulatory regions that have been associated with different expression profiles and virulence properties. In addition, two uniquely conserved var genes that have been proposed to play a role in coordinating transcriptional switching similarly arose uniquely within this clade. We hypothesize that these changes originated at a time of dramatic climatic change on the African continent that is predicted to have led to significant changes in transmission dynamics, thus selecting for patterns of antigenic variation that enabled lengthier, more chronic infections.

Conclusions

These observations suggest that changes in transmission dynamics selected for significant alterations in the transcriptional regulatory mechanisms that mediate antigenic variation in the parasite lineage that includes P. falciparum. These changes likely underlie the chronic nature of these infections as well as their exceptional virulence.
Amino acid transporter (AAT) gene family in foxtail millet (Setaria italica L.): widespread family expansion, functional differentiation, roles in quality formation and response to abiotic stresses
Authors: Yang Yang , Chai Yongmao , Liu Jiayi , Zheng Jie , Zhao Zhangchen , Amo Aduragbemi , Cui Chunge , Lu Qiumei , Chen Liang , Hu Yin-Gang
Published: July 2021

Background

Amino acid transporters (AATs) plays an essential roles in growth and development of plants, including amino acids long-range transport, seed germination, quality formation, responsiveness to pathogenic bacteria and abiotic stress by modulating the transmembrane transfer of amino acids. In this study, we performed a genome-wide screening to analyze the AAT genes in foxtail millet (Setaria italica L.), especially those associated with quality formation and abiotic stresses response.

Results

A total number of 94 AAT genes were identified and divided into 12 subfamilies by their sequence characteristics and phylogenetic relationship. A large number (58/94, 62%) of AAT genes in foxtail millet were expanded via gene duplication, involving 13 tandem and 12 segmental duplication events. Tandemly duplicated genes had a significant impact on their functional differentiation via sequence variation, structural variation and expression variation. Further comparison in multiple species showed that in addition to paralogous genes, the expression variations of the orthologous AAT genes also contributed to their functional differentiation. The transcriptomic comparison of two millet cultivars verified the direct contribution of the AAT genes such as SiAAP1, SiAAP8, and SiAUX2 in the formation of grain quality. In addition, the qRT-PCR analysis suggested that several AAT genes continuously responded to diverse abiotic stresses, such as SiATLb1, SiANT1. Finally, combined with the previous studies and analysis on sequence characteristics and expression patterns of AAT genes, the possible functions of the foxtail millet AAT genes were predicted.

Conclusion

This study for the first time reported the evolutionary features, functional differentiation, roles in the quality formation and response to abiotic stresses of foxtail millet AAT gene family, thus providing a framework for further functional analysis of SiAAT genes, and also contributing to the applications of AAT genes in improving the quality and resistance to abiotic stresses of foxtail millet, and other cereal crops.
Exogenous copper exposure causing clinical wilson disease in a patient with copper deficiency
Authors: Lizaola-Mayo Blanca C. , Dickson Rolland C. , Lam-Himlin Dora M. , Chascsa David M.
Published: July 2021

Background

Human Swayback is a disease characterized by acquired copper deficiency which primarily manifests as myeloneuropathy. Common causes include malabsorptive disorders, gastric surgery, total parenteral nutrition and excessive zinc intake. In contrast, copper supplementation should be closely monitored as excessive doses can lead to acute intoxication and in chronic cases, cirrhosis. Copper derangements are rare, however it is important to consider them due to potential severe complications.

Case presentation

We present a middle-aged man who had been previously diagnosed with Human Swayback after presenting with various neurological symptoms. The patient was subsequently placed on copper supplementation. A decade later, he was referred to our hospital for liver transplant evaluation due to new diagnosis of decompensated end-stage liver disease after an abdominal surgery. His initial workup was suggestive of Wilson disease—subsequent ATP7B gene was negative. Ultimately, the patient underwent liver transplantation; liver explant was significant for a copper dry weight concentration of 5436 mcg/g.

Conclusions

Human Swayback is a very rare copper-related disease which deserves awareness due to its potential irreversible health effects in the human body. Additionally, in patients who require copper supplementation, serial levels should be monitored to ensure adequate copper levels.
Hepatitis C virus infection and risk of liver-related and non-liver-related deaths: a population-based cohort study in Naples, southern Italy
Authors: Piselli Pierluca , Serraino Diego , Fusco Mario , Girardi Enrico , Pirozzi Angelo , Toffolutti Federica , Cimaglia Claudia , Taborelli Martina ,   on behalf of the Collaborating Study Group, Capobianchi Mariarosaria , Carletti Fabrizio , Garbuglia Anna R. , Ippolito Giuseppe , Scognamiglio Paola , Di Cicco Pietro , Gigli Letizia , Russospena Silvana , Palombino Raffaele , Panato Chiara , Mattioli Veronica , Dal Maso Luigino
Published: July 2021

Background

Hepatitis C virus (HCV) infection represents a global health issue with severe implications on morbidity and mortality. This study aimed to evaluate the impact of HCV infection on all-cause, liver-related, and non-liver-related mortality in a population living in an area with a high prevalence of HCV infection before the advent of Direct-Acting Antiviral (DAA) therapies, and to identify factors associated with cause-specific mortality among HCV-infected individuals.

Methods

We conducted a cohort study on 4492 individuals enrolled between 2003 and 2006 in a population-based seroprevalence survey on viral hepatitis infections in the province of Naples, southern Italy. Study participants provided serum for antibodies to HCV (anti-HCV) and HCV RNA testing. Information on vital status to December 2017 and cause of death were retrieved through record-linkage with the mortality database. Hazard ratios (HRs) for cause-specific mortality and 95% confidence intervals (CIs) were estimated using Fine-Grey regression models.

Results

Out of 626 deceased people, 20 (3.2%) died from non-natural causes, 56 (8.9%) from liver-related conditions, 550 (87.9%) from non-liver-related causes. Anti-HCV positive people were at higher risk of death from all causes (HR = 1.38, 95% CI: 1.12–1.70) and liver-related causes (HR = 5.90, 95% CI: 3.00–11.59) than anti-HCV negative ones. Individuals with chronic HCV infection reported an elevated risk of death due to liver-related conditions (HR = 6.61, 95% CI: 3.29–13.27) and to any cause (HR = 1.51, 95% CI: 1.18–1.94). The death risk of anti-HCV seropositive people with negative HCV RNA was similar to that of anti-HCV seronegative ones. Among anti-HCV positive people, liver-related mortality was associated with a high FIB-4 index score (HR = 39.96, 95% CI: 4.73–337.54).

Conclusions

These findings show the detrimental impact of HCV infection on all-cause mortality and, particularly, liver-related mortality. This effect emerged among individuals with chronic infection while those with cleared infection had the same risk of uninfected ones. These results underline the need to identify through screening all people with chronic HCV infection notably in areas with a high prevalence of HCV infection, and promptly provide them with DAAs treatment to achieve progressive HCV elimination and reduce HCV-related mortality.
Application of a deep learning image reconstruction (DLIR) algorithm in head CT imaging for children to improve image quality and lesion detection
Authors: Sun Jihang , Li Haoyan , Wang Bei , Li Jianying , Li Michelle , Zhou Zuofu , Peng Yun
Published: July 2021

Background

To evaluate the performance of a Deep Learning Image Reconstruction (DLIR) algorithm in pediatric head CT for improving image quality and lesion detection with 0.625 mm thin-slice images.

Methods

Low-dose axial head CT scans of 50 children with 120 kV, 0.8 s rotation and age-dependent 150–220 mA tube current were selected. Images were reconstructed at 5 mm and 0.625 mm slice thickness using Filtered back projection (FBP), Adaptive statistical iterative reconstruction-v at 50% strength (50%ASIR-V) (as reference standard), 100%ASIR-V and DLIR-high (DL-H). The CT attenuation and standard deviation values of the gray and white matters in the basal ganglia were measured. The clarity of sulci/cisterns, boundary between white and gray matters, and overall image quality was subjectively evaluated. The number of lesions in each reconstruction group was counted.

Results

The 5 mm FBP, 50%ASIR-V, 100%ASIR-V and DL-H images had a subjective score of 2.25 ± 0.44, 3.05 ± 0.23, 2.87 ± 0.39 and 3.64 ± 0.49 in a 5-point scale, respectively with DL-H having the lowest image noise of white matter at 2.00 ± 0.34 HU; For the 0.625 mm images, only DL-H images met the diagnostic requirement. The 0.625 mm DL-H images had similar image noise (3.11 ± 0.58 HU) of the white matter and overall image quality score (3.04 ± 0.33) as the 5 mm 50% ASIR-V images (3.16 ± 0.60 HU and 3.05 ± 0.23). Sixty-five lesions were recognized in 5 mm 50%ASIR-V images and 69 were detected in 0.625 mm DL-H images.

Conclusion

DL-H improves the head CT image quality for children compared with ASIR-V images. The 0.625 mm DL-H images improve lesion detection and produce similar image noise as the 5 mm 50%ASIR-V images, indicating a potential 85% dose reduction if current image quality and slice thickness are desired.
Differences in the clinical presentation, management, and in-hospital outcomes of acute aortic dissection in patients with and without end-stage renal disease
Authors: Xie Jiahe , Zeng Shan , Xie Long , Ding Rongming , Hu Jing , Zeng Hong , Lu Weiling , Hu Yuhua , Li Qingrui , Zhong Gaojun , Zhou Shiju , Liu Ziyou , Liao Yulin , Zhong Yiming , Xie Dongming
Published: July 2021

Background

Few studies have evaluated the clinical presentation, management, and outcomes of patients with end-stage renal disease (ESRD) presenting with acute aortic dissection (AAD) in real-world clinical practice. Thus, this study investigated the clinical characteristics, management, and outcomes of AAD patients with ESRD.

Methods

A total of 217 patients were included. We evaluated the differences in the clinical features, management, and in-hospital outcomes of patients with and without a history of ESRD presenting with AAD.

Results

A history of ESRD was present in 71 of 217 patients. Patients with ESRD had atypical clinical manifestations (p < 0.001) and were more likely to be managed medically compared with patients without ESRD (p = 0.002). Hypertension and type B aortic dissection were significantly more common among patients with ESRD. Moreover, patients with ESRD had lower leucocyte and platelet counts than patients without ESRD in laboratory findings (p < 0.001). However, hospitalization days and in-hospital mortality were similar between the two groups (p > 0.05). Multivariate analysis identified Type A aortic dissection as an independent predictor of in-hospital mortality among patients without ESRD (OR, 13.68; 95% CI, 1.92 to 98.90;P = 0.006).

Conclusions

This study highlights differences in the clinical characteristics, management, and outcomes of AAD patients with ESRD. These patients usually have atypical symptoms and more comorbid conditions and are managed more conservatively. However, these patients have no in-hospital survival disadvantage over those without ESRD. Further studies are needed to better understand and optimize care for patients with ESRD presenting with AAD.
Inference of kinase-signaling networks in human myeloid cell line models by Phosphoproteomics using kinase activity enrichment analysis (KAEA)
Authors: Hallal Mahmoud , Braga-Lagache Sophie , Jankovic Jovana , Simillion Cedric , Bruggmann Rémy , Uldry Anne-Christine , Allam Ramanjaneyulu , Heller Manfred , Bonadies Nicolas
Published: July 2021

Background

Despite the introduction of targeted therapies, most patients with myeloid malignancies will not be cured and progress. Genomics is useful to elucidate the mutational landscape but remains limited in the prediction of therapeutic outcome and identification of targets for resistance. Dysregulation of phosphorylation-based signaling pathways is a hallmark of cancer, and therefore, kinase-inhibitors are playing an increasingly important role as targeted treatments. Untargeted phosphoproteomics analysis pipelines have been published but show limitations in inferring kinase-activities and identifying potential biomarkers of response and resistance.

Methods

We developed a phosphoproteomics workflow based on titanium dioxide phosphopeptide enrichment with subsequent analysis by liquid chromatography tandem mass spectrometry (LC-MS). We applied a novel Kinase-Activity Enrichment Analysis (KAEA) pipeline on differential phosphoproteomics profiles, which is based on the recently published SetRank enrichment algorithm  with reduced false positive rates. Kinase activities were inferred by this algorithm using an extensive reference database comprising five experimentally validated kinase-substrate meta-databases complemented with the NetworKIN in-silico prediction tool. For the proof of concept, we used human myeloid cell lines (K562, NB4, THP1, OCI-AML3, MOLM13 and MV4–11) with known oncogenic drivers and exposed them to clinically established kinase-inhibitors.

Results

Biologically meaningful over- and under-active kinases were identified by KAEA in the unperturbed human myeloid cell lines (K562, NB4, THP1, OCI-AML3 and MOLM13). To increase the inhibition signal of the driving oncogenic kinases, we exposed the K562 (BCR-ABL1) and MOLM13/MV4–11 (FLT3-ITD) cell lines to either Nilotinib or Midostaurin kinase inhibitors, respectively. We observed correct detection of expected direct (ABL, KIT, SRC) and indirect (MAPK) targets of Nilotinib in K562 as well as indirect (PRKC, MAPK, AKT, RPS6K) targets of Midostaurin in MOLM13/MV4–11, respectively. Moreover, our pipeline was able to characterize unexplored kinase-activities within the corresponding signaling networks.

Conclusions

We developed and validated a novel KAEA pipeline for the analysis of differential phosphoproteomics MS profiling data. We provide translational researchers with an improved instrument to characterize the biological behavior of kinases in response or resistance to targeted treatment. Further investigations are warranted to determine the utility of KAEA to characterize mechanisms of disease progression and treatment failure using primary patient samples.

Graphical abstract
Molecular and cellular characterization of two patient-derived ductal carcinoma in situ (DCIS) cell lines, ETCC-006 and ETCC-010
Authors: Samson Julia , Derlipanska Magdalina , Zaheed Oza , Dean Kellie
Published: July 2021

Background

Currently it is unclear how in situ breast cancer progresses to invasive disease; therefore, a better understanding of the events that occur during the transition to invasive carcinoma is warranted. Here we have conducted a detailed molecular and cellular characterization of two, patient-derived, ductal carcinoma in situ (DCIS) cell lines, ETCC-006 and ETCC-010.

Methods

Human DCIS cell lines, ETCC-006 and ETCC-010, were compared against a panel of cell lines including the immortalized, breast epithelial cell line, MCF10A, breast cancer cell lines, MCF7 and MDA-MB-231, and another DCIS line, MCF10DCIS.com. Cell morphology, hormone and HER2/ERBB2 receptor status, cell proliferation, survival, migration, anchorage-independent growth, indicators of EMT, cell signalling pathways and cell cycle proteins were examined using immunostaining, immunoblots, and quantitative, reverse transcriptase PCR (qRT-PCR), along with clonogenic, wound-closure and soft agar assays. RNA sequencing (RNAseq) was used to provide a transcriptomic profile.

Results

ETCC-006 and ETCC-010 cells displayed notable differences to another DCIS cell line, MCF10DCIS.com, in terms of morphology, steroid-receptor/HER status and markers of EMT. The ETCC cell lines lack ER/PR and HER, form colonies in clonogenic assays, have migratory capacity and are capable of anchorage-independent growth. Despite being isogenic, less than 30% of differentially expressed transcripts overlapped between the two lines, with enrichment in pathways involving receptor tyrosine kinases and DNA replication/cell cycle programs and in gene sets responsible for extracellular matrix organisation and ion transport.

Conclusions

For the first time, we provide a molecular and cellular characterization of two, patient-derived DCIS cell lines, ETCC-006 and ETCC-010, facilitating future investigations into the molecular basis of DCIS to invasive ductal carcinoma transition.
The work of managing multiple myeloma and its implications for treatment-related decision making: a qualitative study of patient and caregiver experiences
Authors: Pritlove Cheryl , Jassi Mobin , Burns Bridget , McCurdy Arleigh
Published: July 2021

Background

The evolving nature of multiple myeloma (MM) therapies, including the introduction of novel oral agents, has produced a shift in the delivery of care from hospital to home. Within this context, patients and their caregivers are becoming increasingly engaged in the work of illness management, however the exact nature of this work as well as the ways in which this work informs treatment preferences and decisions within this population has not been explored. This qualitative study sought to develop an in-depth understanding of patient and caregiver experiences with different MM treatments, the work necessitated by MM and treatment management, and the processes of patient/caregiver treatment-related decision making.

Methods

Qualitative interviews were conducted with 16 MM patients and 8 caregivers. Interviews were coded for emergent themes and patterns and a constant comparative approach was used to identify important similarities and differences within and between interviews.

Results

Patient and caregiver participants described four types of work, including the work of accruing and personalizing medical knowledge, illness-related work in the hospital, illness-related work in the home, and psychosocial and relational management. They illuminated the physical, psychological, social and relational toll of this work and traced a pathway through which work informed their treatment-related decisions, sometimes in ways that conflicted with their preferences for treatment.

Conclusions

The work involved in managing MM, its treatment, and side-effects can inform the treatment decisions that patients and caregivers make. We must continue to find meaningful ways for patients and caregivers to discuss goals of care and treatment throughout the cancer trajectory, as well as support health care providers in the delivery of person-centred cancer care. With an increasing emphasis on the importance of shared decision making in MM, an improved understanding of the factors that frame patient’s and caregiver’s treatment decisions will be paramount to ensuring meaningful and high-quality patient-centered care.
Who engages in the arts in the United States? A comparison of several types of engagement using data from The General Social Survey
Authors: Bone Jessica K. , Bu Feifei , Fluharty Meg E. , Paul Elise , Sonke Jill K. , Fancourt Daisy
Published: July 2021

Background

Engaging in the arts is a health-related behavior that may be influenced by social inequalities. While it is generally accepted that there is a social gradient in traditional arts and cultural activities, such as attending classical music performances and museums, previous studies of arts engagement in the US have not adequately investigated whether similar demographic and socioeconomic factors are related to other forms of arts engagement.

Methods

Using cross-sectional data from the General Social Survey (GSS) in the US, we examined which demographic, socioeconomic, residential, and health factors were associated with attendance at arts events, participation in arts activities, membership of creative groups, and being interested in (but not attending) arts events. We combined data from 1993 to 2016 in four analytical samples with a sample size of 8684 for arts events, 4372 for arts activities, 4268 for creative groups, and 2061 for interested non-attendees. Data were analysed using logistic regression.

Results

More education was associated with increased levels of all types of arts engagement. Parental education demonstrated a similar association. Being female, compared to male, was also consistently associated with higher levels of engagement. Attendance at arts events was lower in participants with lower income and social class, poorer health, and those living in less urban areas. However, these factors were not associated with participation in arts activities or creative groups or being an interested non-attendee.

Conclusions

Overall, we found evidence for a social gradient in attendance at arts events, which was not as pronounced in participation in arts activities or creative groups or interest in arts events. Given the many benefits of engagement in the arts for education, health, and wider welfare, our findings demonstrate the importance of identifying factors to reduce barriers to participation in the arts across all groups in society.
Analyzing the paradigmatic cases of two persons with a disorder of consciousness: reflections on the legal and ethical perspectives
Authors: Picozzi Mario , Panzeri Lino , Torri Davide , Sattin Davide
Published: July 2021

Background

Media have increasingly reported on the difficulties associated with end-of-life decision-making in patients with Disorders of Consciousness (DOC), contextualizing such dilemma in detailed accounts of the patient’s life. Two of the first stories debated in the scientific community were those related to the cases of two women, one American, the other Italian, who captured attention of millions of people in the first years of this third millennium.

Methods

Much has been written about the challenges of surrogate decision-making for patients in DOC, but less has been written comparing these challenges across legal systems and cultures. In our paper, we propose a systematic analysis of the final legal documents written by the American and Italian Courts in relation to the two cases, developing our discussion around three areas: the level of certainty/reliability of diagnosis and prognosis, the reconstruction of self-expression, time of illness and time of care. They are examples of the typical issues discussed by legal authors and allow us to understand the link and the difference between the legal and ethical perspectives.

Results

The legal approach to the two cases has some common elements: the need to be certain about the diagnosis and prognosis and the fact that the clinical criteria are necessary in determining the most appropriate treatments, although these criteria are not sufficient unless they are supplemented by the patient’s will. The issue of relations takes on importance both from a legal and an ethical point of view, but from two different perspectives. While ethics safeguards relationships by guaranteeing their differences and makes them reconcilable, law safeguards relationships by guaranteeing the cold forms of respect, equality, impartiality, symmetry, reciprocity, and irreversibility. In this perspective, the link between the time of care and the decision of the family members assumes importance.

Conclusions

The most interesting point that emerges from our analysis is the issue of relationships and how they affect decisions, both from a legal and ethical point of view. For this reason, during the patients’ hospitalization, it is necessary to identify ways in which they might give their opinion about the moral issues underlying their choices.
Validation and minimum important difference of the UCSD Shortness of Breath Questionnaire in fibrotic interstitial lung disease
Authors: Chen Tao , Tsai Amy Po Yu , Hur Seo Am , Wong Alyson W. , Sadatsafavi Mohsen , Fisher Jolene H. , Johannson Kerri A. , Assayag Deborah , Morisset Julie , Shapera Shane , Khalil Nasreen , Fell Charlene D. , Manganas Helene , Cox Gerard , To Teresa , Gershon Andrea S. , Hambly Nathan , Halayko Andrew J. , Wilcox Pearce G. , Kolb Martin , Ryerson Christopher J.
Published: July 2021

Rationale

The University of California, San Diego Shortness of Breath Questionnaire (UCSDSOBQ) is a frequently used domain-specific dyspnea questionnaire; however, there is little information available regarding its use and minimum important difference (MID) in fibrotic interstitial lung disease (ILD). We aimed to describe the key performance characteristics of the UCSDSOBQ in this population.

Methods

UCSDSOBQ scores and selected anchors were measured in 1933 patients from the prospective multi-center Canadian Registry for Pulmonary Fibrosis. Anchors included the St. George’s Respiratory Questionnaire (SGRQ), European Quality of Life 5 Dimensions 5 Levels questionnaire (EQ-5D-5L) and EQ visual analogue scale (EQ-VAS), percent-predicted forced vital capacity (FVC%), diffusing capacity of the lung for carbon monoxide (DLCO%), and 6-min walk distance (6MWD). Concurrent validity, internal consistency, ceiling and floor effects, and responsiveness were assessed, followed by estimation of the MID by anchor-based (linear regression) and distribution-based methods (standard error of measurement).

Results

The UCSDSOBQ had a high level of internal consistency (Cronbach’s alpha = 0.97), no obvious floor or ceiling effect, strong correlations with SGRQ, EQ-5D-5L, and EQ-VAS (|r| > 0.5), and moderate correlations with FVC%, DLCO%, and 6MWD (0.3 < |r| < 0.5). The MID estimate for UCSDSOBQ was 5 points (1–8) for the anchor-based method, and 4.5 points for the distribution-based method.

Conclusion

This study demonstrates the validity of UCSDSOBQ in a large and heterogeneous population of patients with fibrotic ILD, and provides a robust MID estimate of 5–8 points.
Triglyceride-glucose index is associated with in-stent restenosis in patients with acute coronary syndrome after percutaneous coronary intervention with drug-eluting stents
Authors: Zhu Yong , Liu Kesen , Chen Maolin , Liu Yan , Gao Ang , Hu Chengping , Li Hong , Zhu Huagang , Han Hongya , Zhang Jianwei , Zhao Yingxin
Published: July 2021

Background

The triglyceride-glucose (TyG) index is an alternative marker of insulin resistance (IR) and is closely associated with the prevalence and prognosis of atherosclerotic cardiovascular disease (ASCVD). However, the association between the TyG index and in-stent restenosis (ISR) after drug-eluting stent (DES) implantation in patients with acute coronary syndrome (ACS) remains unknown.

Methods

The present study retrospectively recruited patients who were admitted for ACS and underwent coronary angiography at 6 to 24 months after successful DES-based percutaneous coronary intervention (PCI). In addition, we calculated the TyG index with the following formula: Ln(fasting triglyceride [mg/dL] × fasting blood glucose [mg/dL]/2) and divided patients into 3 groups according to the tertile of the TyG index. Most importantly, multivariate logistic regression analysis models were also constructed to assess the association between the TyG index and DES-ISR in patients with ACS.

Results

A total of 1574 patients with ACS (58.4 ± 9.4 years, 77.4% male) were included in this study. At the median follow-up time of 12 (9–14) months, the prevalence of DES-ISR increased stepwise with the increasing tertile of the TyG index (11.6% vs 17.3% vs 19.4%, p = 0.002), and the TyG index was also higher in the ISR group than in the non-ISR group (9.00 ± 0.58 vs 8.84 ± 0.61, p < 0.001). In addition, the positive association between the TyG index and the prevalence of DES-ISR was also determined in the fully adjusted model (TyG, per 1-unit increase: OR 1.424, 95% CI 1.116 to 1.818, p = 0.005; tertile of TyG, the OR (95% CI) values for tertile 2 and tertile 3 were 1.454 (1.013 to 2.087) and 1.634 (1.125 to 2.374), respectively, with tertile 1 as a reference). The association was also reflected in most subgroups. Moreover, adding the TyG index to the predictive model for DES-ISR in patients with ACS could contribute to an increase in C-statistics (0.675 vs 0.659, p = 0.010), categorical net reclassification improvement (0.090, p < 0.001), and integrated discrimination improvement (0.004, p = 0.040).

Conclusion

An elevated TyG index was independently and positively associated with DES-ISR in patients with ACS who underwent PCI. However, the incremental predictive value of the TyG index for DES-ISR was slight. To further confirm our findings, future studies are needed.
LncRNA HAND2-AS1 exerts anti-oncogenic effects on bladder cancer via restoration of RARB as a sponge of microRNA-146
Authors: Shan Liping , Liu Wei , Zhan Yunhong
Published: July 2021

Background

Growing evidence has shown that long noncoding RNA: microRNA: mRNA is implicated in tumor initiation, development, and progression. Long noncoding RNA HAND2-AS1 exhibits anti-cancer effects in diverse cancers. However, the knowledge of HAND-AS1 in bladder cancer development remains unknown.

Methods

LncRNA and miRNA microarray was conducted to explore different expressed RNA in primary bladder cancer specimens. RNA-RNA interaction prediction tools miRcode (http://www.mircode.org/), DIANA-lncBase v2 (https://carolina.imis.athena-innovation.gr/diana_tools/web/index.php?r=lncbasev2%2Findex-experimental), DIANA-TarBase v.8 (https://carolina.imis.athena-innovation.gr/diana_tools/web/index.php?r=tarbasev8%2Findex) and miRDB (http://www.mirdb.org/) were employed to predict the interactions between RNA. Bladder cancer cell lines were used to perform cell proliferation and apoptosis assays. Western blot and quantitative Real-time Polymerase Chain Reaction were used to determine the expression of protein and RNA separately. Dual-luciferase assay was conducted to determine the activity of three prime untranslated region of retinoic acid receptor beta (RARB). Furthermore, 5637 human bladder cancer mouse models were established to investigate the interactions of lncRNA: miRNA: mRNA in vivo.

Results

Based on the RT2 lncRNA PCR Arrays analysis, we validated HAND2-AS1 declined in bladder cancer and negatively correlated with the depth of invasion and grades. The overexpression of HAND2-AS1 in human bladder cancer cells 5637 and RT4 hampered cell proliferation by provoking Caspase 3-triggered cell apoptosis. Besides, one of the HAND2-AS1 sponges, miR-146, elevated in bladder cancer and targeted the tumor suppressor, retinoic acid receptor beta (RARB). We further demonstrated that the HAND2-AS1: miR-146: RARB complex promoted Caspase 3-mediated apoptosis by suppressing COX-2 expression. Finally, the results gained in mouse xenografts suggested that HAND2-AS1 diminished miR-146 expression, thereby reversing the suppression of miR-146 on RARB-mediated apoptosis and contributing to bladder cancer regression.

Conclusion

The present study sheds light on the fact that lncRNA HAND2-AS1 exerted as a tumor suppressor by releasing RARB from miR-146, leading to tumor proliferation and invasion inhibition. The findings expanded HAND2-AS-mediated regulatory networks' knowledge and provided novel insights to improve the RARB-targeted regimens against bladder cancer.