bluuebunny/crossref_metadata_2025 huggingface dataset:
Complex Effects of Sertraline and Citalopram on In Vitro Murine Breast Cancer Proliferation and on In Vivo Progression and Anxiety Level
Authors: Taler Michal , Gil-Ad Irit , Brener Iris , Hornfeld Shay Henry , Weizman Abraham
Published: March 2022

Some selective serotonin reuptake inhibitors (SSRIs), primarily sertraline, demonstrate anti-proliferative activity in malignant cell-lines and in xenografted mouse models of colorectal tumor. There is, however, a paucity of comparative studies on the anti-tumor effects of SSRIs. We compared the in vitro and in vivo effects of sertraline and citalopram on murine 4T1 breast cancer. Grafted mice were used to determine the rate of tumor growth and survival as well as the impact of stress and antidepressant treatment on tumor progression and mortality and on pro-inflammatory cytokines. Sertraline, in the micromolar range, but not citalopram, induced a significant in vitro concentration-dependent inhibition of murine 4T1 cell proliferation and splenocyte viability. In contrast, sertraline (10 mg/kg/d), enhanced in vivo tumor growth. Contrary to the study’s hypothesis, chronic mild stress did not modify tumor growth in grafted mice. The in vitro effects of sertraline on tumor growth seem to be the opposite of its in vivo effects. The impact of sertraline treatment on humans with breast cancer should be further investigated.
Bone Fragility in Gastrointestinal Disorders
Authors: Merlotti Daniela , Mingiano Christian , Valenti Roberto , Cavati Guido , Calabrese Marco , Pirrotta Filippo , Bianciardi Simone , Palazzuoli Alberto , Gennari Luigi
Published: March 2022

Osteoporosis is a common systemic disease of the skeleton, characterized by compromised bone mass and strength, consequently leading to an increased risk of fragility fractures. In women, the disease mainly occurs due to the menopausal fall in estrogen levels, leading to an imbalance between bone resorption and bone formation and, consequently, to bone loss and bone fragility. Moreover, osteoporosis may affect men and may occur as a sequela to different diseases or even to their treatments. Despite their wide prevalence in the general population, the skeletal implications of many gastrointestinal diseases have been poorly investigated and their potential contribution to bone fragility is often underestimated in clinical practice. However, proper functioning of the gastrointestinal system appears essential for the skeleton, allowing correct absorption of calcium, vitamins, or other nutrients relevant to bone, preserving the gastrointestinal barrier function, and maintaining an optimal endocrine-metabolic balance, so that it is very likely that most chronic diseases of the gastrointestinal tract, and even gastrointestinal dysbiosis, may have profound implications for bone health. In this manuscript, we provide an updated and critical revision of the role of major gastrointestinal disorders in the pathogenesis of osteoporosis and fragility fractures.
Neural Crest-Derived Stem Cells (NCSCs) Obtained from Dental-Related Stem Cells (DRSCs): A Literature Review on Current Knowledge and Directions toward Translational Applications
Authors: Solis-Castro Oscar O. , Rivolta Marcelo N. , Boissonade Fiona M.
Published: March 2022

Evidence from dental-related stem cells (DRSCs) suggests an enhanced potential for ectodermal lineage differentiation due to their neural crest origin. Growing evidence that DRSC cultures can produce cells with a neural crest-derived stem cell (NCSC)-like phenotype supports their potential for future therapeutic approaches for neurodegenerative diseases and nerve injuries. However, most of the evidence is limited to the characterization of DRSCs as NCSCs by detecting the expression of neural crest markers. Only a few studies have provided proof of concept of an improved neuro-glial differentiation or direct applicability in relevant models. In addition, a current problem is that several of the existing protocols do not meet manufacturing standards for transferability to a clinical scenario. This review describes the current protocols to obtain NCSCs from DRSCs and their characterization. Also, it provides important considerations from previous work where DRSCs were established and characterized as mesenchymal stromal cells but studied for their neuro-glial differentiation potential. The therapeutic advancement of DRSCs would depend on establishing protocols that can yield a neural crest-like phenotype efficiently, using appropriate manufacturing standards and testing them in relevant models of disease or injury. Achieving these conditions could then facilitate and validate the therapeutic potential of DRSC-NCSCs in regenerative therapies.
Epigenetic Regulation in Uterine Fibroids—The Role of Ten-Eleven Translocation Enzymes and Their Potential Therapeutic Application
Authors: Włodarczyk Marta , Nowicka Grażyna , Ciebiera Michał , Ali Mohamed , Yang Qiwei , Al-Hendy Ayman
Published: March 2022

Uterine fibroids (UFs) are monoclonal, benign tumors that contain abnormal smooth muscle cells and the accumulation of extracellular matrix (ECM). Although benign, UFs are a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor. Many risk factors are involved in the pathogenesis of UFs via genetic and epigenetic mechanisms. The latter involving DNA methylation and demethylation reactions provide specific DNA methylation patterns that regulate gene expression. Active DNA demethylation reactions mediated by ten-eleven translocation proteins (TETs) and elevated levels of 5-hydroxymethylcytosine have been suggested to be involved in UF formation. This review paper summarizes the main findings regarding the function of TET enzymes and their activity dysregulation that may trigger the development of UFs. Understanding the role that epigenetics plays in the pathogenesis of UFs may possibly lead to a new type of pharmacological fertility-sparing treatment method.
Quantification of Species-Preferential Micropylar Chemoattraction in Arabidopsis by Fluorescein Diacetate Staining of Pollen Tubes
Authors: Nagae Takuya T. , Takeuchi Hidenori , Higashiyama Tetsuya
Published: March 2022

Sexual reproduction between males and females of the same species is essential for species maintenance. Ovular micropylar guidance, the last step of pollen tube guidance in angiosperms, contributes to species-preferential reproduction. Previous studies using semi-in vivo attraction assays showed that species-preferential attractant peptides are secreted from the ovule through its micropyle. However, conventional semi-in vivo assays usually depend on transgenic pollen tubes expressing a fluorescent protein to determine whether the tubes are attracted to the ovule to precisely penetrate the micropyle. Here, we found that fluorescein diacetate (FDA) staining was suitable for evaluating the micropylar guidance rate of non-transgenic pollen tubes in semi-in vivo conditions. Micropylar guidance was quantified for ovules and pollen tubes of Arabidopsis thaliana and Arabidopsis lyrata by combining FDA staining with modified semi-in vivo assays. Our results using the simple staining method showed that the ovules of each species secrete species-preferential attractants, and that pollen tubes respond more strongly to attractants of their own species compared with those of closely related species. LURE-type CRP810 attractant peptides were shown to be responsible for micropylar attraction of A. thaliana in the semi-in vivo assay. The POLLEN-SPECIFIC RECEPTOR-LIKE KINASE 6 (PRK6) receptor for LURE1, as well as an unidentified receptor for other LURE-type attractants, are involved in the species-preferential response of these two Arabidopsis species.
Distinct Functional Alterations and Therapeutic Options of Two Pathological De Novo Variants of the T292 Residue of GABRA1 Identified in Children with Epileptic Encephalopathy and Neurodevelopmental Disorders
Authors: Chen Wenlin , Ge Yang , Lu Jie , Melo Joshua , So Yee Wah , Juneja Romi , Liu Lidong , Wang Yu Tian
Published: March 2022

Mutations of GABAAR have reportedly led to epileptic encephalopathy and neurodevelopmental disorders. We have identified a novel de novo T292S missense variant of GABRA1 from a pediatric patient with grievous global developmental delay but without obvious epileptic activity. This mutation coincidentally occurs at the same residue as that of a previously reported GABRA1 variant T292I identified from a pediatric patient with severe epilepsy. The distinct phenotypes of these two patients prompted us to compare the impacts of the two mutants on the receptor function and to search for suitable therapeutics. In this study, we used biochemical techniques and patch-clamp recordings in HEK293 cells overexpressing either wild-type or mutated rat recombinant GABAARs. We found that the α1T292S variant significantly increased GABA-evoked whole-cell currents, shifting the dose–response curve to the left without altering the maximal response. In contrast, the α1T292I variant significantly reduced GABA-evoked currents, shifting the dose–response curve to the right with a severely diminished maximum response. Single-channel recordings further revealed that the α1T292S variant increased, while the α1T292I variant decreased the GABAAR single-channel open time and open probability. Importantly, we found that the T292S mutation-induced increase in GABAAR function could be fully normalized by the negative GABAAR modulator thiocolchicoside, whereas the T292I mutation-induced impairment of GABAAR function was largely rescued with a combination of the GABAAR positive modulators diazepam and verapamil. Our study demonstrated that α1T292 is a critical residue for controlling GABAAR channel gating, and mutations at this residue may produce opposite impacts on the function of the receptors. Thus, the present work highlights the importance of functionally characterizing each individual GABAAR mutation for ensuring precision medicine.
Metabolomic and Transcript Analysis Revealed a Sex-Specific Effect of Glyphosate in Zebrafish Liver
Authors: Giommi Christian , Ladisa Claudia , Carnevali Oliana , Maradonna Francesca , Habibi Hamid
Published: March 2022

Glyphosate is a component of commonly used herbicides for controlling weeds in crops, gardens and municipal parks. There is increasing awareness that glyphosate-based herbicides, in addition to acting on plants, may also exert toxicity in wildlife and humans. In this study, male and female adult zebrafish were exposed to 700 µg/L of glyphosate (GLY), for 28 days. We used the metabolomic approach and UHPLC-ESI-MS to analyze liver samples to investigate the adverse effects of glyphosate on hepatic metabolism. The impact of GLY was found to be sex-specific. In female, GLY exposure affected purine metabolism by decreasing the levels of AMP, GMP and inosinic acid, consequently increasing uric acid levels with respect to the control (CTRL). Exposure to GLY also caused a decrease of UMP levels in the pyrimidine metabolism pathway. In male, GLY exposure decreased the aminoadipic acid within the lysine degradation pathway. Transcript analysis of genes involved in stress response, oxidative stress and the immune system were also performed. Results demonstrated an increased stress response in both sexes, as suggested by higher nr3c1 expression. However, the hsp70.2 transcript level was increased in female but decreased in male. The results demonstrated reduced sod1, sod2, and gpx1a in male following exposure to GLY, indicating an impaired oxidative stress response. At the same time, an increase in the cat transcript level in female was observed. mRNA levels of the pro-inflammatory interleukins litaf and cxcl8b.1 were increased in female. Taken together, the results provide evidence of disrupted nucleotide hepatic metabolism, increased stress inflammatory response in female and disruption of oxidative stress response in male.
pH Responsive Abelmoschus esculentus Mucilage and Administration of Methotrexate: In-Vitro Antitumor and In-Vivo Toxicity Evaluation
Authors: Noreen Sobia , Hasan Sara , Ghumman Shazia Akram , Bukhari Syed Nasir Abbas , Ijaz Bushra , Hameed Huma , Iqbal Huma , Aslam Afeefa , Elsherif Mervat Abdelaziz Mohamed , Noureen Shazia , Ejaz Hasan
Published: March 2022

The rapid progression in biomaterial nanotechnology apprehends the potential of non-toxic and potent polysaccharide delivery modules to overcome oral chemotherapeutic challenges. The present study is aimed to design, fabricate and characterize polysaccharide nanoparticles for methotrexate (MTX) delivery. The nanoparticles (NPs) were prepared by Abelmoschus esculentus mucilage (AEM) and chitosan (CS) by the modified coacervation method, followed by ultra-sonification. The NPs showed much better pharmaceutical properties with a spherical shape and smooth surface of 213.4–254.2 nm with PDI ranging between 0.279–0.485 size with entrapment efficiency varying from 42.08 ± 1.2 to 72.23 ± 2.0. The results revealed NPs to possess positive zeta potential and a low polydispersity index (PDI). The in-vitro drug release showed a sustained release of the drug up to 32 h with pH-dependence. Blank AEM -CS NPs showed no in-vivo toxicity for a time duration of 14 days, accompanied by high cytotoxic effects of optimized MTX loaded NPs against MCF-7 and MD-MBA231 cells by MTT assay. In conclusion, the findings advocated the therapeutic potential of AEM/CS NPs as an efficacious tool, offering a new perspective for pH-responsive routing of anticancer drugs with tumor cells as a target.
C2H2 Zinc Finger Proteins Response to Abiotic Stress in Plants
Authors: Liu Yihua , Khan Ali Raza , Gan Yinbo
Published: March 2022

Abiotic stresses have already exhibited the negative effects on crop growth and development, thereby influencing crop quality and yield. Therefore, plants have developed regulatory mechanisms to adopt against such harsh changing environmental conditions. Recent studies have shown that zinc finger protein transcription factors play a crucial role in plant growth and development as well as in stress response. C2H2 zinc finger proteins are one of the best-studied types and have been shown to play diverse roles in the plant abiotic stress responses. However, the C2H2 zinc finger network in plants is complex and needs to be further studied in abiotic stress responses. Here in this review, we mainly focus on recent findings on the regulatory mechanisms, summarize the structural and functional characterization of C2H2 zinc finger proteins, and discuss the C2H2 zinc finger proteins involved in the different signal pathways in plant responses to abiotic stress.
A C2H2 Zinc Finger Protein PlCZF1 Is Necessary for Oospore Development and Virulence in Peronophythora litchii
Authors: Zhu Honghui , Situ Junjian , Guan Tianfang , Dou Ziyuan , Kong Guanghui , Jiang Zide , Xi Pinggen
Published: March 2022

C2H2 zinc finger is one of the most common motifs found in the transcription factors (TFs) in eukaryotes organisms, which have a broad range of functions, such as regulation of growth and development, stress tolerance and pathogenicity. Here, PlCZF1 was identified to encode a C2H2 zinc finger in the litchi downy blight pathogen Peronophythora litchii. PlCZF1 is conserved in P. litchii and Phytophthora species. In P. litchii, PlCZF1 is highly expressed in sexual developmental and early infection stages. We generated Δplczf1 mutants using the CRISPR/Cas9 method. Compared with the wild type, the Δplczf1 mutants showed no significant difference in vegetative growth and asexual reproduction, but were defective in oospore development and virulence. Further experiments revealed that the transcription of PlM90, PlLLP and three laccase encoding genes were down-regulated in the Δplczf1 mutant. Our results demonstrated that PlCZF1 is a vital regulator for sexual development and pathogenesis in P. litchii.
In Vitro Hepatotoxic and Neurotoxic Effects of Titanium and Cerium Dioxide Nanoparticles, Arsenic and Mercury Co-Exposure
Authors: Rosário Fernanda , Costa Carla , Lopes Cláudia B. , Estrada Ana C. , Tavares Daniela S. , Pereira Eduarda , Teixeira João Paulo , Reis Ana Teresa
Published: March 2022

Considering the increasing emergence of new contaminants, such as nanomaterials, mixing with legacy contaminants, including metal(loid)s, it becomes imperative to understand the toxic profile resulting from these interactions. This work aimed at assessing and comparing the individual and combined hepatotoxic and neurotoxic potential of titanium dioxide nanoparticles (TiO2NPs 0.75–75 mg/L), cerium oxide nanoparticles (CeO2NPs 0.075–10 μg/L), arsenic (As 0.01–2.5 mg/L), and mercury (Hg 0.5–100 mg/L) on human hepatoma (HepG2) and neuroblastoma (SH-SY5Y) cells. Viability was assessed through WST-1 (24 h) and clonogenic (7 days) assays and it was affected in a dose-, time- and cell-dependent manner. Higher concentrations caused greater toxicity, while prolonged exposure caused inhibition of cell proliferation, even at low concentrations, for both cell lines. Cell cycle progression, explored by flow cytometry 24 h post-exposure, revealed that TiO2NPs, As and Hg but not CeO2NPs, changed the profiles of SH-SY5Y and HepG2 cells in a dose-dependent manner, and that the cell cycle was, overall, more affected by exposure to mixtures. Exposure to binary mixtures revealed either potentiation or antagonistic effects depending on the composition, cell type and time of exposure. These findings prove that joint toxicity of contaminants cannot be disregarded and must be further explored.
Short-Term Pharmacological Induction of Arterial Stiffness and Hypertension with Angiotensin II Does Not Affect Learning and Memory and Cerebral Amyloid Load in Two Murine Models of Alzheimer’s Disease
Authors: Hendrickx Jhana O. , Calus Elke , De Deyn Peter Paul , Van Dam Debby , De Meyer Guido R. Y.
Published: March 2022

Given the unprecedented rise in the world’s population, the prevalence of prominent age-related disorders, like cardiovascular disease and dementia, will further increase. Recent experimental and epidemiological evidence suggests a mechanistic overlap between cardiovascular disease and dementia with a specific focus on the linkage between arterial stiffness, a strong independent predictor of cardiovascular disease, and/or hypertension with Alzheimer’s disease. In the present study, we investigated whether pharmacological induction of arterial stiffness and hypertension with angiotensin II (1 µg·kg−1·min−1 for 28 days via an osmotic minipump) impairs the progression of Alzheimer’s disease in two mouse models (hAPP23+/− and hAPPswe/PSEN1dE9 mice). Our results show increased arterial stiffness in vivo and hypertension in addition to cardiac hypertrophy after angiotensin II treatment. However, visuospatial learning and memory and pathological cerebral amyloid load in both Alzheimer’s disease mouse models were not further impaired. It is likely that the 28-day treatment period with angiotensin II was too short to observe additional effects on cognition and cerebral pathology.
A Generic Graph-Based Method for Flexible Aspect-Opinion Analysis of Complex Product Customer Feedback
Authors: Kpiebaareh Michael Y. , Wu Wei-Ping , Agyemang Brighter , Haruna Charles R. , Lawrence Tandoh
Published: March 2022

Product design experts depend on online customer reviews as a source of insight to improve product design. Previous works used aspect-based sentiment analysis to extract insight from product reviews. However, their approaches for requirements elicitation are less flexible than traditional tools such as interviews and surveys. They require costly data labeling or pre-labeled datasets, lack domain knowledge integration, and focus more on sentiment classification than flexible aspect-opinion analysis. Related works lack effective mechanisms for probing the customer feedback of complex configurable products. This study proposes a generic graph-based opinion mining and analysis method for product design improvement. First, a customer feedback data preprocessing and annotation pipeline that can incorporate designer-specified domain knowledge is proposed. Second, an intuitive opinion-aware labeled property graph data model is designed to ingest preprocessed feedback data and perform ad hoc opinion analysis. Applying the generic model to a real-world dataset demonstrates superior functionality and flexibility compared to related works. A wider range of analyses is supported in a single model without repeating data preprocessing and modeling. Specifically, the proposed method supports regular and comparative aspect-opinion analysis, aspect satisfaction/influence ranking, opinion trend extraction, and targeted aspect-opinion summarization.
Effects of Fruit Sizes of Two Camellia Trees on the Larval Sizes of Curculio styracis (Roelofs, 1875): Testing the Endoparasitoid Body Size Hypothesis
Authors: Li Zhiwen , Yang Zhongxia , Li Youzhi
Published: March 2022

The endoparasitoid body size hypothesis suggests that the size of larvae that develop in a single host should be subject to a trade-off: larger size could lead to increase overall fitness but could simultaneously increase the risk of resource depletion and starvation, resulting in a body size just below the host holding capacity. However, this hypothesis has not been rigorously tested using mathematical models thus far. The camellia weevil, C.styracis (Coleoptera: Curculionidae), is a notorious pest attacking fruits of Camellia oleifera Abel. and C. meiocarpa Hu., in which the larvae develop within a single fruit and larval development is limited by the available food resources. We developed a feasible method to test this hypothesis. First, five models were used to describe the relationship between larval mass and host size. Then, the minimum fruit threshold that had to be met for ad libitum larval development and the corresponding larval size (Wa) of this threshold were calculated based on the characteristics of the optimal model. Finally, the difference between the measured larval size and the predicted larval size (Wa) was determined. The results showed that (1) the data were better described by a logistic function than any other equation; (2) larval size in both host plants increased with increasing fruit size until leveling off when the fruits were large enough to allow unconstrained larval development; (3) larval size remained just below the host-fruit holding capacity, as there was no difference between the measured and predicted larval sizes (Wa); and (4) larvae developed in host plant with larger fruits had a larger size. These results confirmed the endoparasitoid body size hypothesis.
Modification of the Leeb Impact Device for Measuring Hardness by the Dynamic Instrumented Indentation Method
Authors: Umanskii Aleksander , Gogolinskii Kirill , Syasko Vladimir , Golev Artem
Published: March 2022

The article is devoted to modification of the impact devices of Leeb hardness testers for the implementation of the dynamic instrumented indentation method. The results obtained made it possible to construct a load–displacement curve using primary EMF signals and made it possible to determine the values of the dissipated and elastic impact body energy, the maximal load of indentation, the maximal and residual penetration depth and the geometric parameters of the indentation region, namely the contact area of the indenter with the surface and the volume of the displaced material. The listed parameters of the indentation process allow us to measure the contact and volume hardness, the elastic modulus and the yield strength of test objects with portable hardness testers.
Conflict Detection and Resolution in IoT Systems: A Survey
Authors: Pradeep Pavana , Kant Krishna
Published: March 2022

Internet of Things (IoT) systems are becoming ubiquitous in various cyber–physical infrastructures, including buildings, vehicular traffic, goods transport and delivery, manufacturing, health care, urban farming, etc. Often multiple such IoT subsystems are deployed in the same physical area and designed, deployed, maintained, and perhaps even operated by different vendors or organizations (or “parties”). The collective operational behavior of multiple IoT subsystems can be characterized via (1) a set of operational rules and required safety properties and (2) a collection of IoT-based services or applications that interact with one another and share concurrent access to the devices. In both cases, this collective behavior often leads to situations where their operation may conflict, and the conflict resolution becomes complex due to lack of visibility into or understanding of the cross-subsystem interactions and inability to do cross-subsystem actuations. This article addresses the fundamental problem of detecting and resolving safety property violations. We detail the inherent complexities of the problem, survey the work already performed, and layout the future challenges. We also highlight the significance of detecting/resolving conflicts proactively, i.e., dynamically but with a look-ahead into the future based on the context.
Minimally Invasive Surgery in Chronic Subdural Hematoma: Prognosis and Recurrence Factors of 516 Cases in a Single Center
Authors: Xu Min , Tan Weiguo , Wang Wenhua , Wang Dongdong , Zeng Wei , Wang Cunzu
Published: March 2022

Objective: To investigate the effects of minimally invasive surgery (MIS) using a novel YL-1 puncture needle and summarize the risk factors of recurrence in chronic subdural hematoma (CSDH). Methods: We performed a retrospective analysis in 516 hospitalized patients with CSDH from January 2013 to December 2018 in Northern Jiangsu People’s Hospital. Patients’ gender, age, history of trauma, use of anticoagulants, history of disturbed liver or renal function, history of heart disease, history of malignant tumor, history of diabetes, hemodialysis, coagulopathy, alcoholism, imaging indicators, and postoperative application of urokinase or atorvastatin were recorded. Recurrence is defined by imaging examination with or without clinical presentation three months after discharge. Results: In total, 483 patients (93.60%) benefited from MIS by YL-1 needle. Gender, age, history of head trauma, history of disturbed liver function, history of heart disease, history of malignant tumor, history of diabetes, history of hemodialysis, coagulopathy, alcoholism, hematoma location, hematoma densities, septum formation, maximum thickness, encephalatrophy, and use of atorvastatin and urokinase were shown to be non-significantly associated with postoperative recurrence (p > 0.05). The use of anticoagulants was significantly associated with postoperative recurrence (p > 0. 05). Logistic analysis showed that the use of anticoagulants is an independent factor predicting postoperative recurrence (p > 0. 05). Conclusions: The novel YL-1 puncture needle turned out to be a safe and effective minimally invasive surgery, and the use of anticoagulants is an independent risk factor predicting postoperative recurrence in CSDH, which can provide MIS and early therapeutic strategies for neurosurgeons.
Impact of Contact Force-Sensing Catheters on Fluoroscopy Time in Interventional Electrophysiology: A European Survey
Authors: Fiedler Lukas , Blessberger Hermann , Balsam Pawel , De Potter Tom , Buchta Piotr , Ernst Sabine , Waldmann Victor , Costa Francisco Moscoso , Bogdan Stefan , Nahler Alexander , Hrncic Denis , Lambert Thomas , Schönbauer Robert , Pfeffer Michael , Roithinger Franz Xaver , Steinwender Clemens , Kosiuk Jedrzej
Published: March 2022

This multicenter European survey systematically evaluated the impact of using contact force-sensing catheters (CFSCs) on fluoroscopy and procedure time in interventional electrophysiology. Data from 25 participating centers were collected and analyzed, also considering important confounders. With the use of CFSCs, fluoroscopy time was reduced for right- and left-sided atrial ablations (median −6.4 to −9.6 min, p < 0.001 for both groups), whereas no such effect could be found for ventricular ablations. Moreover, the use of CFSCs was associated with an increase in procedure time for right-sided atrial and ventricular ablations (median +26.0 and +44.0 min, respectively, p < 0.001 for both groups), but not for left-sided atrial ablations. These findings were confirmed independent of career level and operator volume, except for very highly experienced electrophysiologists, in whom the effect was blunted. In the subset of pulmonary vein isolations (PVIs), CFSCs were shown to reduce both fluoroscopy and procedure time. In conclusion, the use of CFSCs was associated with a reduced fluoroscopy time for atrial ablations and an increased procedure time for right atrial and ventricular ablations. These effects were virtually independent of the operator experience and caseload. When considering only PVIs as an important subset, CFSCs were shown to reduce both fluoroscopy and procedure time.
Stop Using the Eccentric Exercises as the Gold Standard Treatment for the Management of Lateral Elbow Tendinopathy
Authors: Stasinopoulos Dimitrios
Published: March 2022

The most common tendinopathy in the elbow area is the Lateral elbow tendinopathy (LET) [...]
Opiate Prescriptions Vary among Common Urologic Procedures: A Claims Dataset Analysis
Authors: Patel Anish B. , Satarasinghe Praveen N. , Valencia Victoria , Wenzel Jessica L. , Webb Jack C. , Wolf J. Stuart , Osterberg E. Charles
Published: March 2022

Objectives: This study aimed to better understand differences in the total days’ supply and fills of common opiates following urologic procedures. Materials and Methods: The Truven Health MarketScan® database was used to extract CPT codes from adults 18 years or older who underwent a urologic procedure with 90-day follow-up from 2012–2015 within the Austin–Round Rock, Texas metropolitan service area. A multivariate analysis and first hurdle modeling with a logistic outcome for any opiates was used to (1) assess differences in opioid prescribing patterns, (2) investigate opioid prescription outcomes, and (3) explore variability among opiate prescription patterns across seven urologic procedure categories. Results: Among the 2312 patients who met the inclusion criteria, 23.7% received an opiate, with an average total day’s supply of 6.20 (range 2.61–10.59). The proportion of patients receiving opiates varied significantly by procedure type (p = 0.028). Patients that had reconstructive procedures had the highest proportion of any opiates and the highest number of mean opiate prescriptions among the seven procedure categories (42% received opiates, p = 0.028, mean opiate prescriptions were 1.0 among all patients, p = 0.026). After adjustments, the multivariate analysis demonstrated that patients undergoing reconstructive procedures filled more opiate prescriptions (odds ratio (OR) = 1.86, 95% confidence interval (CI) = 1.00–3.50, p = 0.05) compared to other subcategories. Of those that received opiates, reconstructive patients had a shorter time to fills (mean −18.4 days, CI −8.40 to −28.50, p < 0.001). Conclusion: Patients undergoing reconstructive procedures are prescribed and fill more opiates compared to other common urological procedures. The standardization and implementation of postoperative pain regimens may help curtail this variability.
Long-Term Maintenance of Sinus Rhythm Is Associated with Favorable Echocardiographic Remodeling and Improved Clinical Outcomes after Transcatheter Aortic Valve Replacement
Authors: Choi Young , Hwang Byung-Hee , Oh Gyu-Chul , Kim Jin Jin , Choo Eunho , Kim Min-Chul , Kim Juhan , Jung Hae Ok , Youn Ho-Joong , Chung Wook-Sung , Chang Kiyuk
Published: March 2022

Periprocedural atrial fibrillation (AF) is associated with poor prognosis after transcatheter aortic valve replacement (TAVR). We evaluated the impact of long-term sinus rhythm (SR) maintenance on post-TAVR outcomes. We enrolled 278 patients treated with TAVR including 87 patients with periprocedural AF. Patients with periprocedural AF were classified into the AF-sinus rhythm maintained (AF-SRM) group or the sustained AF group according to long-term cardiac rhythm status after discharge. Patients without AF before or after TAVR were classified into the SR group. The primary clinical outcome was a composite of all-cause death, stroke, or heart failure rehospitalization. The AF-SRM and the SR groups showed significant improvements in left ventricular ejection fraction and left atrial volume index at one year after TAVR, while the sustained AF group did not. During 24.5 (±16.1) months of follow-up, the sustained AF group had a higher risk of the adverse clinical event compared with the AF-SRM group (hazard ratio (HR) 4.449, 95% confidence interval (CI) 1.614–12.270), while the AF-SRM group had a similar risk of the adverse clinical event compared with the SR group (HR 0.737, 95% CI 0.285–1.903). In conclusion, SR maintenance after TAVR was associated with enhanced echocardiographic improvement and favorable clinical outcomes.
Graft Failure Due to Nonadherence among 150 Prospectively-Followed Kidney Transplant Recipients at 18 Years Post-transplant: Our Results and Review of the Literature
Authors: Gaynor Jeffrey J. , Guerra Giselle , Roth David , Chen Linda , Kupin Warren , Mattiazzi Adela , Ortigosa-Goggins Mariella , Tabbara Marina M. , Moni Lissett , Burke George W. , Ciancio Gaetano
Published: March 2022

Background: We previously reported that graft failure due to nonadherence (GFNA) was a major cause of graft loss in kidney transplantation. Here, among 150 prospectively-followed kidney transplant recipients at 18 years post-transplant, we provide: updated (longer-term) estimates of cause-specific graft loss probabilities, risk factors for developing GFNA, and detailed characterizations of patients’ overt nonadherent (NA) behavior, including timing, extent, and clinical consequences. Methods: Determination of the patient becoming NA in taking his/her immunosuppressive medications, and the underlying cause of graft loss, were determined prospectively by the attending physicians. For never-functioning-graft, GFNA, GF due to causes other than NA (Other GF), and death with a functioning graft (DWFG), cumulative incidence functions were used to estimate the cumulative probabilities of cause-specific graft loss. Cox stepwise regression was used to determine significant multivariable predictors for the hazard rate of developing GFNA. Results: GFNA was a major cause of graft loss (22/150 patients), particularly among African-American and Hispanic recipients <50 years of age-at-transplant (20/56 experienced GFNA), with estimated percentages of such patients ever developing GFNA ranging between 36.9 and 41.5%. These patients were also at a higher risk of developing Other GF. For the remaining patients (2/94 experienced GFNA), estimated percentages of ever-developing GFNA were much lower (range: 0.0–6.7%). The major cause of graft loss among recipients ≥50 years of age was DWFG; GFNA rarely occurred among older recipients. In 21/22 GFNA patients, NA behavior lasted continuously from the time of developing NA until GFNA. In total, 28/150 patients became NA, and 67.9% (19/28) occurred beyond 36 months post-transplant. A total of 25 of 28 NA patients (89.3%) developed biopsy-proven acute rejection and/or chronic rejection that was directly attributed to the NA behavior. Lastly, 25/28 admitted to NA behavior, with financial and psychological components documented in 71.4% (20/28) and 96.4% (27/28) of NA cases, respectively. Conclusions: These results highlight the importance of performing serial monitoring of patients for overt NA behavior throughout their post-transplant follow-up. Financial and psychological components to NA behavior need to be simultaneously addressed with the goal of achieving complete avoidance/elimination of NA behavior among higher risk patients.
Chronic Renal Failure and Cardiovascular Disease: A Comprehensive Appraisal
Authors: Skalsky Keren , Shiyovich Arthur , Steinmetz Tali , Kornowski Ran
Published: March 2022

Coronary artery disease is highly prevalent in patients with chronic kidney disease. The concomitant renal disease often poses a major challenge in decision making as symptoms, cardiac biomarkers and noninvasive studies for evaluation of myocardial ischemia have different sensitivity and specificity thresholds in this specific population. Moreover, the effectiveness and safety of intervention and medical treatment in those patients is of great doubt as most clinical studies exclude patients with advance CKD. In the present paper, we discuss and review the literature in the diagnosis, treatment and prevention of CAD in the acute and chronic setting, in patients with CKD.
Special Issue “Pulmonary and Critical Care Practice in the Pandemic of COVID-19”
Authors: Mallat Jihad
Published: March 2022

Severe acute respiratory syndrome coronavirus-2 (SAR-CoV-2), which is responsible for the coronavirus disease 2019 (COVID-19), has hit the world as a global pandemic at an unparalleled scale [...]
Monitoring of Unfractionated Heparin Therapy in the Intensive Care Unit Using a Point-of-Care aPTT: A Comparative, Longitudinal Observational Study with Laboratory-Based aPTT and Anti-Xa Activity Measurement
Authors: Lardinois Benjamin , Hardy Michaël , Michaux Isabelle , Horlait Geoffrey , Rotens Thomas , Jacqmin Hugues , Lessire Sarah , Bulpa Pierre , Dive Alain , Mullier François
Published: March 2022

Continuous intravenous unfractionated heparin (UFH) is administered routinely in the intensive care unit (ICU) for the anticoagulation of patients, and monitoring is performed by the activated partial thromboplastin time (APTT) or anti-Xa activity. However, these strategies are associated with potentially large time intervals before dose adjustments, which could be detrimental to the patient. The aim of the study was to compare a point-of-care (POCT) version of the APTT to (i) laboratory-based APTT and (ii) measurements of anti-Xa activity in terms of correlation, agreement and turnaround time (TAT). Thirty-five ICU patients requiring UFH therapy were prospectively included and followed longitudinally for a maximum duration of 15 days. UFH was administered according to a local adaptation of Raschke and Amanzadeh’s aPTT nomograms. Simultaneous measurements of POCT-APTT (CoaguCheck® aPTT Test, Roche Diagnostics) on a drop of fresh whole blood, laboratory-based APTT (C.K. Prest®, Stago) and anti-Xa activity (STA®Liquid anti-Xa, Stago) were systematically performed two to six times a day. Antithrombin, C-reactive protein, fibrinogen, factor VIII and lupus anticoagulant were measured. The time tracking of sampling and analysis was recorded. The overall correlation between POCT-APTT and laboratory APTT (n = 795 pairs) was strongly positive (rs = 0.77, p < 0.0001), and between POCT-APTT and anti-Xa activity (n = 729 pairs) was weakly positive (rs = 0.46, p < 0.0001). Inter-method agreement (Cohen’s kappa (k)) between POCT and laboratory APTT was 0.27, and between POCT and anti-Xa activity was 0.30. The median TATs from sample collection to the lab delivery of results for lab-APTT and anti-Xa were 50.9 min (interquartile range (IQR), 38.4–69.1) and 66.3 min (IQR, 49.0–91.8), respectively, while the POCT delivered results in less than 5 min (p < 0.0001). Although the use of the POCT-APTT device significantly reduced the time to results, the results obtained were poorly consistent with those obtained by lab-APTT or anti-Xa activity, and therefore it should not be used with the nomograms developed for lab-APTT.
Divergent Impact of Enzyme Replacement Therapy on Human Cardiomyocytes and Enterocytes Affected by Fabry Disease: Correlation with Mannose-6-phosphate Receptor Expression
Authors: Frustaci Andrea , Najafian Behzad , Donato Giuseppe , Verardo Romina , Chimenti Cristina , Sansone Luigi , Belli Manuel , Vernucci Enza , Russo Matteo Antonio
Published: March 2022

Background: The impact of enzyme replacement therapy (ERT) on cardiomyocytes and intestinal cells, affected by Fabry disease (FD), is still unclear. Methods: Six patients with FD, including five family members with GLA mutation c.666delC and one with GLA mutation c.658C > T, manifesting cardiomyopathy and intestinal symptoms (abdominal pain, diarrhea and malabsorption) were included in the study. Clinical outcome, cardiac magnetic resonance (CMR), endomyocardial and gastro-intestinal biopsies were evaluated before and after 2 years of treatment with agalsidase-α (0.2 mg/kg every other week). Immunohistochemistry and Western blot assessments of mannose-6-phosphate receptors (IGF-II-R) on intestinal and myocardial frozen tissue were obtained at diagnosis and after 2 years of ERT. Results: After ERT left ventricular maximal wall thickness, ranging from pre (<10.5 mm) to mild (<15 mm) and moderate hypertrophy (16 mm), was not associated with significant changes at CMR. Degree of dyspnea, mean cardiomyocyte diameter and % vacuolated areas of cardiomyocytes, representing intracellular GL3, remained unmodified. In contrast, intestinal symptoms improved with disappearance of diarrhea, recovery of anemia and weight gain, correlating with near complete clearance of the enterocytes from GL3 inclusions. IGF-II-R expression was remarkably higher even at histochemistry in intestinal tissue compared with myocardium (p < 0.001) either at baseline and after ERT, thus justifying intestinal recovery. Conclusions: Human cells affected by FD may respond differently to ERT: while cardiomyocytes retain their GL3 content after 2 years of treatment, gastro-intestinal cells show GL3 removal with recovery of function. This divergent response may be related to differences in cellular turnover, as well as tissue IGF-II-R expression.
Profiling and Association over Time between Disability and Pain Features in Patients with Chronic Nonspecific Neck Pain: A Longitudinal Study
Authors: Ortego Gorka , Lluch Enrique , Herrero Pablo , Boudreau Shellie Ann , Doménech-García Victor
Published: March 2022

Objectives: To longitudinally investigate the relationships between neck/arm disability and pain profile measures in individuals with chronic nonspecific neck pain (NSNP) at baseline, one month, and six months after a standardized physiotherapy intervention. A secondary aim was to compare pain sensitivity of individuals with chronic NSNP at baseline to healthy controls. Methods: A total of sixty-eight individuals with chronic NSNP and healthy controls were recruited. Neck disability index (NDI), the 11-item disabilities of the arm, shoulder, and hand questionnaire (QuickDASH), temporal summation (TS), pressure pain thresholds (PPTs), pain intensity and pain extent were assessed in individuals with chronic NSNP. For the cross-sectional assessment, TS and PPTs were compared to healthy controls. Results: After following a standardized physiotherapy intervention, local and distal PPTs to the neck region decreased at one and six month follow-ups, respectively. Pain extent decreased at one and six months. Furthermore, a positive correlation between neck/arm disability and pain intensity was found at baseline, whereas moderate positive correlations (e.g., between NDI and pain extent) at baseline, one and six month follow-ups and negative correlations at six months (e.g., between arm disability and PPTs) were found. Discussion: Overall, these findings indicate that pain sensitivity can worsen following treatment despite reduced pain extent and unchanged neck disability and pain intensity scores over a six-month period in individuals with chronic NSNP.
Testing for Vitamin D in High-Risk COPD in Outpatient Clinics in Spain: A Cross-Sectional Analysis of the VITADEPOC Study
Authors: Calle Rubio Myriam , Álvarez-Sala José Luis , Vargas Centanaro Gianna , Navarro Ana María Humanes , Hermosa Juan Luis Rodríguez
Published: March 2022

Background: Vitamin D deficiency has been associated with an accelerated deterioration in lung function and increased exacerbations in chronic obstructive pulmonary disease (COPD). 25(OH) vitamin D levels have been indicated as a potentially useful marker for adverse results related to COPD. Methods: VITADEPOC is a cross-sectional clinical study recruiting consecutive patients with high-risk COPD. The objective of our study was to investigate vitamin D determination frequency in patients with high-risk COPD in clinical practice at outpatient clinics in Spain and to describe the factors associated with vitamin D testing. We also aimed to determine the frequency of vitamin D deficiency in these patients. Results: Only 51 (44%) patients underwent vitamin D determination and 33 (28.4%) had received vitamin D supplements in clinical practice. The patients who underwent testing for vitamin D in clinical practice were more often women (58.8% vs. 26.2%, p < 0.001) with comorbidities such as osteoporosis (19.6% vs. 6.2%, p < 0.001) or chronic renal failure (7.8% vs. 0%, p < 0.001) and with exacerbator phenotype (55% vs. 32.3%, p = 0.015). A total of 63 (54.3%) patients had serum vitamin D levels <20 ng/mL at the inclusion visit. Of these, 29 (46%) had serum vitamin D levels <12 ng/mL (severe deficiency). Having a history of inhaled corticosteroids (OR 3.210, p < 0.016), being treated with a cycle of systemic corticosteroids (OR 2.149, p < 0.002), and having a lower physical activity level (OR 3.840, p < 0.004) showed a statistically significant positive association with vitamin D deficiency. Conclusion: The testing of vitamin D levels in patients with high-risk COPD treated at outpatient respiratory clinics in Spain is infrequent. However, when tested, a severe deficiency is detected in one in four patients. Efforts to optimize case detection in COPD are needed.
Early Access to Medicines: Use of Multicriteria Decision Analysis (MCDA) as a Decision Tool in Catalonia (Spain)
Authors: Gasol Montse , Paco Noelia , Guarga Laura , Bosch Josep Àngel , Pontes Caridad , Obach Mercè
Published: March 2022

Early access to medicines allows the prescription of a medicine before it is available in the public formulary to patients with severe or rare diseases with high unmet needs who have no authorised therapeutic alternatives available. In this context, consistent decision making is difficult, and a systematic assessment procedure could be useful to tackle complex situations and guarantee the equity of medicines’ access. A multidisciplinary panel (MP) conducted four workshops to develop an early access framework based on a reflective multiple criteria decision analysis (MCDA). A set of 12 criteria was agreed: eight quantitative (severity of disease, urgency, efficacy, safety, internal and external validity, therapeutic benefit and plausibility) and four qualitative (therapeutic alternative, existence of precedents, management impact and costs). Quantitative criteria were weighted using a five-point scale. The relative importance of quantitative criteria had mean weights from 4.7 to 3.6, showing its relevance in the decisions. The framework was tested using two case studies, and reliability was assessed by re-test. The re-test revealed no statistical differences, indicating the consistency and replicability of the framework developed. MCDA may help to structure discussions for heterogeneous treatment requests, providing predictability and robustness in decision making involving sensitive and complex situations.