bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved Transformation and Regeneration of Indica Rice: Disruption of SUB1A as a Test Case via CRISPR-Cas9
Authors: Liang Yuya , Biswas Sudip , Kim Backki , Bailey-Serres Julia , Septiningsih Endang M.
Published: June 2021

Gene editing by use of clustered regularly interspaced short palindromic repeats (CRISPR) has become a powerful tool for crop improvement. However, a common bottleneck in the application of this approach to grain crops, including rice (Oryza sativa), is efficient vector delivery and calli regeneration, which can be hampered by genotype-dependent requirements for plant regeneration. Here, methods for Agrobacterium-mediated and biolistic transformation and regeneration of indica rice were optimized using CRISPR-Cas9 gene-editing of the submergence tolerance regulator SUBMERGENCE 1A-1 gene of the cultivar Ciherang-Sub1. Callus induction and plantlet regeneration methods were optimized for embryogenic calli derived from immature embryos and mature seed-derived calli. Optimized regeneration (95%) and maximal editing efficiency (100%) were obtained from the immature embryo-derived calli. Phenotyping of T1 seeds derived from the edited T0 plants under submergence stress demonstrated inferior phenotype compared to their controls, which phenotypically validates the disruption of SUB1A-1 function. The methods pave the way for rapid CRISPR-Cas9 gene editing of recalcitrant indica rice cultivars.
PRP4 Promotes Skin Cancer by Inhibiting Production of Melanin, Blocking Influx of Extracellular Calcium, and Remodeling Cell Actin Cytoskeleton
Authors: Ahmed Muhammad Bilal , Islam Salman Ul , Lee Young Sup
Published: June 2021

Pre-mRNA processing factor 4B (PRP4) has previously been shown to induce epithelial-mesenchymal transition (EMT) and drug resistance in cancer cell lines. As melanin plays an important photoprotective role in the risk of sun-induced skin cancers, we have investigated whether PRP4 can induce drug resistance and regulate melanin biosynthesis in a murine melanoma (B16F10) cell line. Cells were incubated with a crucial melanogenesis stimulator, alpha-melanocyte-stimulating hormone, followed by transfection with PRP4. This resulted in the inhibition of the production of melanin via the downregulation of adenylyl cyclase-cyclic adenosine 3′,5′-monophosphate (AC)–(cAMP)–tyrosinase synthesis signaling pathway. Inhibition of melanin production by PRP4 leads to the promotion of carcinogenesis and induced drug resistance in B16F10 cells. Additionally, PRP4 overexpression upregulated the expression of β-arrestin 1 and desensitized the extracellular calcium-sensing receptor (CaSR), which in turn, inhibited the influx of extracellular Ca2+ ions. The decreased influx of Ca2+ was confirmed by a decreased expression level of calmodulin. We have demonstrated that transient receptor potential cation channel subfamily C member 1 was involved in the influx of CaSR-induced Ca2+ via a decreasing level of its expression. Furthermore, PRP4 overexpression downregulated the expression of AC, decreased the synthesis of cAMP, and modulated the actin cytoskeleton by inhibiting the expression of Ras homolog family member A (RhoA). Our investigation suggests that PRP4 inhibits the production of melanin in B16F10 cells, blocks the influx of Ca2+ through desensitization of CaSR, and modulates the actin cytoskeleton through downregulating the AC–cAMP pathway; taken together, these observations collectively lead to the promotion of skin carcinogenesis.
Neural Contributions of the Hypothalamus to Parental Behaviour
Authors: Orikasa Chitose
Published: June 2021

Parental behaviour is a comprehensive set of neural responses to social cues. The neural circuits that govern parental behaviour reside in several putative nuclei in the brain. Melanin concentrating hormone (MCH), a neuromodulator that integrates physiological functions, has been confirmed to be involved in parental behaviour, particularly in crouching behaviour during nursing. Abolishing MCH neurons in innate MCH knockout males promotes infanticide in virgin male mice. To understand the mechanism and function of neural networks underlying parental care and aggression against pups, it is essential to understand the basic organisation and function of the involved nuclei. This review presents newly discovered aspects of neural circuits within the hypothalamus that regulate parental behaviours.
Impact of Porcine Pancreas Decellularization Conditions on the Quality of Obtained dECM
Authors: Klak Marta , Łojszczyk Ilona , Berman Andrzej , Tymicki Grzegorz , Adamiok-Ostrowska Anna , Sierakowski Maciej , Olkowski Radosław , Szczepankiewicz Andrzej Antoni , Kamiński Artur , Dobrzyń Agnieszka , Wszoła Michał
Published: June 2021

Due to the limited number of organ donors, 3D printing of organs is a promising technique. Tissue engineering is increasingly using xenogeneic material for this purpose. This study was aimed at assessing the safety of decellularized porcine pancreas, together with the analysis of the risk of an undesirable immune response. We tested eight variants of the decellularization process. We determined the following impacts: rinsing agents (PBS/NH3·H2O), temperature conditions (4 °C/24 °C), and the grinding method of native material (ground/cut). To assess the quality of the extracellular matrix after the completed decellularization process, analyses of the following were performed: DNA concentration, fat content, microscopic evaluation, proteolysis, material cytotoxicity, and most importantly, the Triton X-100 content. Our analyses showed that we obtained a product with an extremely low detergent content with negligible residual DNA content. The obtained results confirmed the performed histological and immuno-fluorescence staining. Moreover, the TEM microscopic analysis proved that the correct collagen structure was preserved after the decellularization process. Based on the obtained results, we chose the most favorable variant in terms of quality and biology. The method we chose is an effective and safe method that gives a chance for the development of transplant and regenerative medicine.
The Use of Natural Compounds as a Strategy to Counteract Oxidative Stress in Animal Models of Diabetes Mellitus
Authors: Salazar-García Marcela , Corona Juan Carlos
Published: June 2021

Diabetes mellitus (DM) is a chronic metabolic disease characterised by insulin deficiency, resulting in hyperglycaemia, a characteristic symptom of type 2 diabetes mellitus (DM2). DM substantially affects numerous metabolic pathways, resulting in β-cell dysfunction, insulin resistance, abnormal blood glucose levels, impaired lipid metabolism, inflammatory processes, and excessive oxidative stress. Oxidative stress can affect the body’s normal physiological function and cause numerous cellular and molecular changes, such as mitochondrial dysfunction. Animal models are useful for exploring the cellular and molecular mechanisms of DM and improving novel therapeutics for their safe use in human beings. Due to their health benefits, there is significant interest in a wide range of natural compounds that can act as naturally occurring anti-diabetic compounds. Due to rodent models’ relatively similar physiology to humans and ease of handling and housing, they are widely used as pre-clinical models for studying several metabolic disorders. In this review, we analyse the currently available rodent animal models of DM and their advantages and disadvantages and highlight the potential anti-oxidative effects of natural compounds and their mechanisms of action.
Cellular Senescence in Lung Fibrosis
Authors: Hernandez-Gonzalez Fernanda , Faner Rosa , Rojas Mauricio , Agustí Alvar , Serrano Manuel , Sellarés Jacobo
Published: June 2021

Fibrosing interstitial lung diseases (ILDs) are chronic and ultimately fatal age-related lung diseases characterized by the progressive and irreversible accumulation of scar tissue in the lung parenchyma. Over the past years, significant progress has been made in our incomplete understanding of the pathobiology underlying fibrosing ILDs, in particular in relation to diverse age-related processes and cell perturbations that seem to lead to maladaptation to stress and susceptibility to lung fibrosis. Growing evidence suggests that a specific biological phenomenon known as cellular senescence plays an important role in the initiation and progression of pulmonary fibrosis. Cellular senescence is defined as a cell fate decision caused by the accumulation of unrepairable cellular damage and is characterized by an abundant pro-inflammatory and pro-fibrotic secretome. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. However, recent evidence strengthens the idea that it also drives degenerative processes such as lung fibrosis, most likely by promoting molecular and cellular changes in chronic fibrosing processes. Here, we review how cellular senescence may contribute to lung fibrosis pathobiology, and we highlight current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence.
Pancracine, a Montanine-Type Amaryllidaceae Alkaloid, Inhibits Proliferation of A549 Lung Adenocarcinoma Cells and Induces Apoptotic Cell Death in MOLT-4 Leukemic Cells
Authors: Koutová Darja , Havelek Radim , Peterová Eva , Muthná Darina , Královec Karel , Breiterová Kateřina , Cahlíková Lucie , Řezáčová Martina
Published: June 2021

Pancracine, a montanine-type Amaryllidaceae alkaloid (AA), is one of the most potent compounds among natural isoquinolines. In previous studies, pancracine exhibited cytotoxic activity against diverse human cancer cell lines in vitro. However, further insight into the molecular mechanisms that underlie the cytotoxic effect of pancracine have not been reported and remain unknown. To fill this void, the cell proliferation and viability of cancer cells was explored using the Trypan Blue assay or by using the xCELLigence system. The impact on the cell cycle was determined by flow cytometry. Apoptosis was evaluated by Annexin V/PI and by quantifying the activity of caspases (-3/7, -8, and -9). Proteins triggering growth arrest or apoptosis were detected by Western blotting. Pancracine has strong antiproliferative activity on A549 cells, lasting up to 96 h, and antiproliferative and cytotoxic effects on MOLT-4 cells. The apoptosis-inducing activity of pancracine in MOLT-4 cells was evidenced by the significantly higher activity of caspases. This was transmitted through the upregulation of p53 phosphorylated on Ser392, p38 MAPK phosphorylated on Thr180/Tyr182, and upregulation of p27. The pancracine treatment negatively altered the proliferation of A549 cells as a consequence of an increase in G1-phase accumulation, associated with the downregulation of Rb phosphorylated on Ser807/811 and with the concomitant upregulation of p27 and downregulation of Akt phosphorylated on Thr308. This was the first study to glean a deeper mechanistic understanding of pancracine activity in vitro. Perturbation of the cell cycle and induction of apoptotic cell death were considered key mechanisms of pancracine action.
Innate Immune Response to SARS-CoV-2 Infection: From Cells to Soluble Mediators
Authors: Ricci Daniela , Etna Marilena Paola , Rizzo Fabiana , Sandini Silvia , Severa Martina , Coccia Eliana Marina
Published: June 2021

The vulnerability of humankind to SARS-CoV-2 in the absence of a pre-existing immunity, the unpredictability of the infection outcome, and the high transmissibility, broad tissue tropism, and ability to exploit and subvert the immune response pose a major challenge and are likely perpetuating the COVID-19 pandemic. Nevertheless, this peculiar infectious scenario provides researchers with a unique opportunity for studying, with the latest immunological techniques and understandings, the immune response in SARS-CoV-2 naïve versus recovered subjects as well as in SARS-CoV-2 vaccinees. Interestingly, the current understanding of COVID-19 indicates that the combined action of innate immune cells, cytokines, and chemokines fine-tunes the outcome of SARS-CoV-2 infection and the related immunopathogenesis. Indeed, the emerging picture clearly shows that the excessive inflammatory response against this virus is among the main causes of disease severity in COVID-19 patients. In this review, the innate immune response to SARS-CoV-2 infection is described not only in light of its capacity to influence the adaptive immune response towards a protective phenotype but also with the intent to point out the multiple strategies exploited by SARS-CoV-2 to antagonize host antiviral response and, finally, to outline inborn errors predisposing individuals to COVID-19 disease severity.
The Composites of PCL and Tetranuclear Titanium(IV)-oxo Complexes as Materials Exhibiting the Photocatalytic and the Antimicrobial Activity
Authors: Kubiak Barbara , Radtke Aleksandra , Topolski Adrian , Wrzeszcz Grzegorz , Golińska Patrycja , Kaszkowiak Ewelina , Sobota Michał , Włodarczyk Jakub , Stojko Mateusz , Piszczek Piotr
Published: June 2021

Excessive misuse of antibiotics and antimicrobials has led to a spread of microorganisms resistant to most currently used agents. The resulting global threats has driven the search for new materials with optimal antimicrobial activity and their application in various areas of our lives. In our research, we focused on the formation of composite materials produced by the dispersion of titanium(IV)-oxo complexes (TOCs) in poly(ε-caprolactone) (PCL) matrix, which exhibit optimal antimicrobial activity. TOCs, of the general formula [Ti4O2(OiBu)10(O2CR’)2] (R’ = PhNH2 (1), C13H9 (2)) were synthesized as a result of the direct reaction of titanium(IV) isobutoxide and 4-aminobenzoic acid or 9-fluorenecarboxylic acid. The microcrystalline powders of (1) and (2), whose structures were confirmed by infrared (IR) and Raman spectroscopy, were dispersed in PCL matrixes. In this way, the composites PCL + nTOCs (n = 5 and 20 wt.%) were produced. The structure and physicochemical properties were determined on the basis of Raman microscopy, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), electron paramagnetic resonance spectroscopy (EPR), and UV–Vis diffuse reflectance spectroscopy (DRS). The degree of TOCs distribution in the polymer matrix was monitored by scanning electron microscopy (SEM). The addition of TOCs micro grains into the PCL matrix only slightly changed the thermal and mechanical properties of the composite compared to the pure PCL. Among the investigated PCL + TOCs systems, promising antibacterial properties were confirmed for samples of PCL + n(2) (n = 5, 20 wt.%) composites, which simultaneously revealed the best photocatalytic activity in the visible range.
Bleeding Disorders in Primary Fibrinolysis
Authors: Franchini Massimo , Zaffanello Marco , Mannucci Pier Mannuccio
Published: June 2021

Fibrinolysis is a complex enzymatic process aimed at dissolving blood clots to prevent vascular occlusions. The fibrinolytic system is composed of a number of cofactors that, by regulating fibrin degradation, maintain the hemostatic balance. A dysregulation of fibrinolysis is associated with various pathological processes that result, depending on the type of abnormality, in prothrombotic or hemorrhagic states. This narrative review is focused on the congenital and acquired disorders of primary fibrinolysis in both adults and children characterized by a hyperfibrinolytic state with a bleeding phenotype.
Perturbations of the Proteome and of Secreted Metabolites in Primary Astrocytes from the hSOD1(G93A) ALS Mouse Model
Authors: Stella Roberto , Bonadio Raphael Severino , Cagnin Stefano , Massimino Maria Lina , Bertoli Alessandro , Peggion Caterina
Published: June 2021

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose pathophysiology is largely unknown. Despite the fact that motor neuron (MN) death is recognized as the key event in ALS, astrocytes dysfunctionalities and neuroinflammation were demonstrated to accompany and probably even drive MN loss. Nevertheless, the mechanisms priming astrocyte failure and hyperactivation are still obscure. In this work, altered pathways and molecules in ALS astrocytes were unveiled by investigating the proteomic profile and the secreted metabolome of primary spinal cord astrocytes derived from transgenic ALS mouse model overexpressing the human (h)SOD1(G93A) protein in comparison with the transgenic counterpart expressing hSOD1(WT) protein. Here we show that ALS primary astrocytes are depleted of proteins—and of secreted metabolites—involved in glutathione metabolism and signaling. The observed increased activation of Nf-kB, Ebf1, and Plag1 transcription factors may account for the augmented expression of proteins involved in the proteolytic routes mediated by proteasome or endosome–lysosome systems. Moreover, hSOD1(G93A) primary astrocytes also display altered lipid metabolism. Our results provide novel insights into the altered molecular pathways that may underlie astrocyte dysfunctionalities and altered astrocyte–MN crosstalk in ALS, representing potential therapeutic targets to abrogate or slow down MN demise in disease pathogenesis.
Evidence for the Role of Mitochondrial DNA Release in the Inflammatory Response in Neurological Disorders
Authors: Moya Gonzalo E. , Rivera Phillip D. , Dittenhafer-Reed Kristin E.
Published: June 2021

Mitochondria are regarded as the metabolic centers of cells and are integral in many other cell processes, including the immune response. Each mitochondrion contains numerous copies of mitochondrial DNA (mtDNA), a small, circular, and bacterial-like DNA. In response to cellular damage or stress, mtDNA can be released from the mitochondrion and trigger immune and inflammatory responses. mtDNA release into the cytosol or bloodstream can occur as a response to hypoxia, sepsis, traumatic injury, excitatory cytotoxicity, or drastic mitochondrial membrane potential changes, some of which are hallmarks of neurodegenerative and mood disorders. Released mtDNA can mediate inflammatory responses observed in many neurological and mood disorders by driving the expression of inflammatory cytokines and the interferon response system. The current understanding of the role of mtDNA release in affective mood disorders and neurodegenerative diseases will be discussed.
Thrombopoietin Contributes to Enhanced Platelet Activation in Patients with Type 1 Diabetes Mellitus
Authors: Bosco Ornella , Vizio Barbara , Gruden Gabriella , Schiavello Martina , Lorenzati Bartolomeo , Cavallo-Perin Paolo , Russo Isabella , Montrucchio Giuseppe , Lupia Enrico
Published: June 2021

Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM). Enhanced platelet reactivity is considered a main determinant of the increased atherothrombotic risk of diabetic patients. Thrombopoietin (THPO), a humoral growth factor able to stimulate megakaryocyte proliferation and differentiation, also modulates the response of mature platelets by enhancing both activation and binding to leukocytes in response to different agonists. Increased THPO levels have been reported in different clinical conditions characterized by a generalized pro-thrombotic state, from acute coronary syndromes to sepsis/septic shock, and associated with elevated indices of platelet activation. To investigate the potential contribution of elevated THPO levels in platelet activation in T1DM patients, we studied 28 T1DM patients and 28 healthy subjects. We measured plasma levels of THPO, as well as platelet-leukocyte binding, P-selectin, and THPO receptor (THPOR) platelet expression. The priming activity of plasma from diabetic patients or healthy subjects on platelet–leukocyte binding and the role of THPO on this effect was also studied in vitro. T1DM patients had higher circulating THPO levels and increased platelet–monocyte and platelet–granulocyte binding, as well as platelet P-selectin expression, compared to healthy subjects, whereas platelet expression of THPOR did not differ between the two groups. THPO concentrations correlated with platelet–leukocyte binding, as well as with fasting glucose and Hb1Ac. In vitro, plasma from diabetic patients, but not from healthy subjects, primed platelet–leukocyte binding and platelet P-selectin expression. Blocking THPO biological activity using a specific inhibitor prevented the priming effect induced by plasma from diabetic patients. In conclusion, augmented THPO may enhance platelet activation in patients with T1DM, potentially participating in increasing atherosclerotic risk.
Determination of Two Differently Manufactured Silicon Dioxide Nanoparticles by Cloud Point Extraction Approach in Intestinal Cells, Intestinal Barriers and Tissues
Authors: Yoo Na-Kyung , Jeon Ye-Rin , Choi Soo-Jin
Published: June 2021

Food additive amorphous silicon dioxide (SiO2) particles are manufactured by two different methods—precipitated and fumed procedures—which can induce different physicochemical properties and biological fates. In this study, precipitated and fumed SiO2 particles were characterized in terms of constituent particle size, hydrodynamic diameter, zeta potential, surface area, and solubility. Their fates in intestinal cells, intestinal barriers, and tissues after oral administration in rats were determined by optimizing Triton X-114-based cloud point extraction (CPE). The results demonstrate that the constituent particle sizes of precipitated and fumed SiO2 particles were similar, but their aggregate states differed from biofluid types, which also affect dissolution properties. Significantly higher cellular uptake, intestinal transport amount, and tissue accumulation of precipitated SiO2 than of fumed SiO2 was found. The intracellular fates of both types of particles in intestinal cells were primarily particle forms, but slowly decomposed into ions during intestinal transport and after distribution in the liver, and completely dissolved in the bloodstream and kidneys. These findings will provide crucial information for understanding and predicting the potential toxicity of food additive SiO2 after oral intake.
The Human Digitalisation Journey: Technology First at the Expense of Humans?
Authors: Hassani Hossein , Huang Xu , Silva Emmanuel
Published: June 2021

The ongoing COVID-19 pandemic has enhanced the impact of digitalisation as a driver of transformation and advancements across almost every aspect of human life. With the majority actively embracing smart technologies and their benefits, the journey of human digitalisation has begun. Will human beings continue to remain solitary unaffected beings in the middle of the whirlpool—a gateway to the completely digitalised future? This journey of human digitalisation probably started much earlier, before we even realised. This paper, in the format of an objective review and discussion, aims to investigate the journey of human digitalisation, explore the reality of domination between technology and humans, provide a better understanding of the human value and human vulnerability in this fast transforming digital era, so as to achieve valuable and insightful suggestion on the future direction of the human digitalisation journey.
Biology of an Adventive Population of the Armored Scale Rhizaspidiotus donacis, a Biological Control Agent of Arundo donax in California
Authors: Braman Charles A. , Lambert Adam M. , Özsoy A. Zeynep , Hollstien Ellen N. , Sheehy Kirsten A. , McKinnon Tara , Moran Patrick , Gaskin John F. , Goolsby John A. , Dudley Thomas L.
Published: June 2021

Arundo donax (giant reed) is invasive in Mediterranean, sub-, and tropical riparian systems worldwide. The armored scale Rhizaspidiotus donacis is approved for biocontrol in North America, but an adventive population was recently discovered in southern California. We documented this population’s distribution, phylogeny, phenology, potential host spillover to Phragmites spp., and potential for parasitism by a common biocontrol parasitoid of citrus scale. The adventive scale was found within a single watershed and is genetically closest to Iberian scale genotypes. Rhizaspidiotus donacis developed on Phragmites haplotypes but at much lower densities than Arundo. The adventive population is univoltine, producing crawlers from March-June. Aphytis melinus parasitoids exhibited sustained interest in R. donacis during choice and no-choice trials and oviposition resulted in a small second generation. Rhizaspidiotus donacis appears limited in distribution by its univoltinism and sessile adult females. This presents challenges for broad biocontrol implementation but allows for targeted application. The genetic differentiation between imported biocontrol samples and adventive populations presents an opportunity for exploring benefits of hybrids and/or alternative genotypes where establishment has been difficult. While unlikely to occur in situ, spillover to vulnerable endemic Phragmites or deleterious parasitoid effects on scale biocontrol agents warrants consideration when planning use of R. donacis.
Management of High-Risk Atherosclerotic Patients by Statins May Be Supported by Logistic Model of Intima-Media Thickening
Authors: Formanowicz Dorota , Krawczyk Jacek B. , Perek Bartłomiej , Lipski Dawid , Tykarski Andrzej
Published: June 2021

While the use of statins in treating patients with atherosclerosis is an undisputed success, the questions regarding an optimal starting time for treatment and its strength remain open. We proposed in our earlier paper published in Int. J. Mol. Sci. (2019, 20) that the growth of intima-media thickness of the carotid artery follows an S-shape (i.e., logistic) curve. In our subsequent paper in PLoS ONE (2020, 15), we incorporated this feature into a logistic control-theoretic model of atherosclerosis progression and showed that some combinations of patient age and intima-media thickness are better suited than others to start treatment. In this study, we perform a new and comprehensive calibration of our logistic model using a recent clinical database. This allows us to propose a procedure for inferring an optimal age to start statin treatment for a particular group of patients. We argue that a decrease in the slope of the IMT logistic growth curve, induced by statin treatment, is most efficient where the curve is at its steepest, whereby the efficiency means lowering the future IMT levels. Using the procedure on an aggregate group of severely sick men, 38 years of age is observed to correlate with the steepest point of the logistic curve, and, thus, it is the preferred time to start statin treatment. We believe that detecting the logistic curve’s steepest fragment and commencing statin administration on that fragment are courses of action that agree with clinician intuition and may support decision-making processes.
Kidney Transplantation in COVID Pandemic—A Review of Guidelines
Authors: Gut Gabriela , Góral Agata , Dal Canton Zofia , Poznański Paweł , Krajewska Magdalena , Kusztal Mariusz
Published: June 2021

The paper describes problems with the transplantation process during the COVID-19 pandemic. Transplantation procedures and programs have been impacted by COVID-19. The number of transplants has fallen noticeably. The first part of the paper points out changes in service organization, in particular donor and recipient pre-transplant and peri-transplant management. If the patients during pre-transplant evaluation need to attend face-to-face appointments, such as blood testing or other investigations, the risk of contracting or spreading COVID-19 should be minimized. “Clear green areas”, which are COVID-19-free pathways, are highly recommended in hospitals during transplant procedures. Diagnostic procedures concerning donors, including CT scans and coronavirus testing (nasopharyngeal swab), are necessary before transplant surgery. COVID-19 symptoms and risks of the transplant population are described. Detailed guidelines from transplant societies concerning changes in immunosuppression in infected recipients are discussed. Management of infected or suspected medical staff is mentioned. The paper ends with guidelines concerning vaccination against COVID-19 in transplant recipients.
Arguments against the Requirement of a Biological License Application for Human Pancreatic Islets: The Position Statement of the Islets for US Collaborative Presented during the FDA Advisory Committee Meeting
Authors: Witkowski Piotr , Odorico Jon , Pyda Jordan , Anteby Roi , Stratta Robert , Schrope Beth , Hardy Mark , Buse John , Leventhal Joseph , Cui Wanxing , Hussein Shakir , Niederhaus Silke , Gaglia Jason , Desai Chirag , Wijkstrom Martin , Kandeel Fouad , Bachul Piotr , Becker Yolanda , Wang Ling-Jia , Robertson R. , Olaitan Oyedolamu , Kozlowski Tomasz , Abrams Peter , Josephson Michelle , Andreoni Kenneth , Harland Robert , Kandaswamy Raja , Posselt Andrew , Szot Gregory , Ricordi Camillo ,   on behalf of the Islets for US Collaborative
Published: June 2021

The Food and Drug Administration (FDA) has been regulating human islets for allotransplantation as a biologic drug in the US. Consequently, the requirement of a biological license application (BLA) approval before clinical use of islet transplantation as a standard of care procedure has stalled the development of the field for the last 20 years. Herein, we provide our commentary to the multiple FDA’s position papers and guidance for industry arguing that BLA requirement has been inappropriately applied to allogeneic islets, which was delivered to the FDA Cellular, Tissue and Gene Therapies Advisory Committee on 15 April 2021. We provided evidence that BLA requirement and drug related regulations are inadequate in reassuring islet product quality and potency as well as patient safety and clinical outcomes. As leaders in the field of transplantation and endocrinology under the “Islets for US Collaborative” designation, we examined the current regulatory status of islet transplantation in the US and identified several anticipated negative consequences of the BLA approval. In our commentary we also offer an alternative pathway for islet transplantation under the regulatory framework for organ transplantation, which would address deficiencies of in current system.
Contemporary Outcomes after Transurethral Procedures for Bladder Neck Contracture Following Endoscopic Treatment of Benign Prostatic Hyperplasia
Authors: Rosenbaum Clemens , Vetterlein Malte , Fisch Margit , Reiss Philipp , Worst Thomas , Kranz Jennifer , Steffens Joachim , Kluth Luis , Pfalzgraf Daniel ,   on behalf of the Trauma and Reconstructive Urology Working Party of the European Association of Urology (EAU) Young Academic Urologists (YAU)
Published: June 2021

Objectives: Bladder neck contracture (BNC) is a bothersome complication following endoscopic treatment for benign prostatic hyperplasia (BPH). The objective of our study was to give a more realistic insight into contemporary endoscopic BNC treatment and to evaluate and identify risk factors associated with inferior outcome. Material and Methods: We identified patients who underwent transurethral treatment for BNC secondary to previous endoscopic therapy for BPH between March 2009 and October 2016. Patients with vesico-urethral anastomotic stenosis after radical prostatectomy were excluded. Digital charts were reviewed for re-admissions and re-visits at our institutions and patients were contacted personally for follow-up. Our non-validated questionnaire assessed previous urologic therapies (including radiotherapy, endoscopic, and open surgery), time to eventual further therapy in case of BNC recurrence, and the modality of recurrence management. Results: Of 60 patients, 49 (82%) and 11 (18%) underwent transurethral bladder neck resection and incision, respectively. Initial BPH therapy was transurethral resection of the prostate (TURP) in 54 (90%) and holmium laser enucleation of the prostate (HoLEP) in six (10%) patients. Median time from prior therapy was 8.5 (IQR 5.3–14) months and differed significantly in those with (6.5 months; IQR 4–10) and those without BNC recurrence (10 months; IQR 6–20; p = 0.046). Thirty-three patients (55%) underwent initial endoscopic treatment, and 27 (45%) repeated endoscopic treatment for BNC. In initially-treated patients, time since BPH surgery differed significantly between those with a recurrence (median 7.5 months; IQR 6–9) compared to those treated successfully (median 12 months; IQR 9–25; p = 0.01). In patients with repeated treatment, median time from prior BNC therapy did not differ between those with (4.5 months; IQR 2–12) and those without a recurrence (6 months; IQR 6–10; p = 0.6). Overall, BNC treatment was successful in 32 patients (53%). The observed success rate of BNC treatment was significantly higher after HoLEP compared to TURP (100% vs. 48%; p = 0.026). Type of BNC treatment, number of BNC treatment, and age at surgery did not influence the outcome. Conclusions: A longer time interval between previous BPH therapy and subsequent BNC incidence seems to favorably affect treatment success of endoscopic BNC treatment, and transurethral resection and incision appear equally effective. Granted the relatively small sample size, BNC treatment success seems to be higher after HoLEP compared to TURP, which warrants validation in larger cohorts.
Optical Coherence Tomography Angiography as a New Tool for Evaluation of the Subclinical Retinal Involvement in Patients with Systemic Lupus Erythematosus—A Review
Authors: Mimier-Janczak Małgorzata , Kaczmarek Dorota , Janczak Dawid , Kaczmarek Radosław
Published: June 2021

Knowing the proven relationship between lupus retinopathy and systemic changes and disease activity, it is crucial to find the possibility of early diagnosis of retinal changes at a subclinical level in order to provide faster medical intervention and protect the patient from irreversible changes in the eye and other organs. The aim of this review is an analysis of studies investigating early pathological changes in retinal vascularization obtained by optical coherence tomography angiography (OCTA) and their relationship to the systemic lupus erythematosus (SLE). A literature search was performed to identify all relevant articles, regarding detection of subclinical retinal changes using OCTA in systemic lupus erythematosus listed in PubMed database. Seven out of seven papers found showed a decrease in superficial capillary plexus in ocular asymptomatic patients diagnosed with SLE. A decrease in retinal vessel density measured by OCTA may be a good marker of SLE activity and poor prognosis. OCTA in a safe manner can give clinicians a new perspective on processes of vessel remodeling and answer the question of how SLE might impact the eye from a structural point of view. Adding OCTA to the standard diagnostic process of SLE patients, may detect systemic changes early and prevent further visual deterioration by stopping progression of lupus retinopathy.
Endoscopic Papillary Abnormalities and Stone Recognition (EPSR) during Flexible Ureteroscopy: A Comprehensive Review
Authors: Almeras Christophe , Pradere Benjamin , Estrade Vincent , Meria Paul ,   on behalf of the Lithiasis Committee of the French Urological Association
Published: June 2021

Introduction: The increasing efficiency of the different lasers and the improved performance of endoscopic devices have led to smaller stone fragments that impact the accuracy of microscopic evaluation (morphological and infrared). Before the stone destruction, the urologist has the opportunity to analyze the stone and the papillary abnormalities endoscopically (endoscopic papillary recognition (EPR) and endoscopic stone recognition (ESR)). Our objective was to evaluate the value for those endoscopic descriptions. Methods: The MEDLINE and EMBASE databases were searched in February 2021 for studies on endoscopic papillary recognition and endoscopic stone recognition. Results: If the ESR provided information concerning the main crystallization process, EPR provided information concerning the origin of the lithogenesis and its severity. Despite many actual limitations, those complementary descriptions could support the preventive care of the stone formers in improving the diagnosis of the lithogenesis mechanism and in identifying high-risk stone formers. Conclusion: Until the development of an Artificial Intelligence recognition, the endourologist has to learn EPSR to minimize the distortion effect of the new lasers on the stone analysis and to improve care efficiency of the stone formers patients.
Is Shear-Wave Elastography a Clinical Severity Indicator of Myofascial Pain Syndrome? An Observational Study
Authors: Valera-Calero Juan Antonio , Sánchez-Jorge Sandra , Buffet-García Jorge , Varol Umut , Gallego-Sendarrubias Gracia María , Álvarez-González Javier
Published: June 2021

Since manual palpation is a subjective procedure for identifying and differentiate Myofascial Trigger Points -MTrPs-, the use of Shear Wave Elastography -SWE- as an objective alternative is increasing. This study aimed to analyze pain pressure thresholds -PPTs- and SWE differences between active MTrPs, latent MTrPs and control points located in the upper trapezius to analyze the association of SWE features with clinical severity indicators (e.g., pain extension area, PPTs, neck pain and neck disability). An observational study was conducted to calculate the correlation and to analyze the differences of sociodemographic, clinical and SWE features on 34 asymptomatic subjects with latent MTrPs and 19 patients with neck pain and active MTrPs. Significant PPT differences between active with latent MTrPs (p < 0.001) and control points (p < 0.001) were found, but no differences between latent MTrPs and control points (p > 0.05). No stiffness differences were found between active MTrPs with latent MTrPs or control points (p > 0.05). However, significant control point stiffness differences between-samples were found (p < 0.05). SWE showed no significant correlation with clinical severity indicators (p > 0.05). No stiffness differences between active and latent MTrPs were found. Neck pain patients showed increased control point stiffness compared with asymptomatic subjects. SWE showed no association with clinical severity indicators.
Ocular Comorbidities in Rosacea: A Case-Control Study Based on Seven Institutions
Authors: Woo Yu Ri , Cho Minah , Ju Hyun Jeong , Bae Jung Min , Cho Sang Hyun , Lee Jeong Deuk , Kim Hei Sung
Published: June 2021

Rosacea is a facial inflammatory dermatosis that is linked with various systemic illnesses. With regards to the eye, rosacea patients have been described to manifest ocular surface changes, such as blepharitis and conjunctivitis. However, studies that examine the association of rosacea with a wider array of ocular diseases are limited. Thus, our aim was to identify the range of ocular comorbidities in the Korean patient population and create a reference data set. A multi-institutional, case-control study was conducted, where 12,936 rosacea patients and an equal number of sex- and age-matched control subjects were extracted over a 12-year period. We were able to discover a notable association between rosacea and blepharitis (adjusted odds ratio (aOR) 3.44; 95% confidence interval, 2.71–4.36, p < 0.001), conjunctivitis (aOR 1.65; 95% CI, 1.50–1.82, p < 0.001), glaucoma (aOR 1.93; 95% CI, 1.70–2.20, p < 0.001), dry eye syndrome (aOR 1.89; 95% CI, 1.70–2.09, p < 0.001), and chalazion (aOR 3.26; 95% CI, 1.41–7.57, p = 0.006) from logistic regression analysis. Female subjects and individuals younger than 50 exclusively showed higher odds for chalazion. Our study suggests that ocular comorbidities (i.e., glaucoma, dry eye syndrome, and chalazion as well as blepharitis and conjunctivitis) are more prevalent among Koreans with rosacea. Clinicians should proactively check ocular symptoms in rosacea and employ joint care with an ophthalmologist in cases of need.
OnabotulinumtoxinA in Migraine: A Review of the Literature and Factors Associated with Efficacy
Authors: Ray Jason C. , Hutton Elspeth J. , Matharu Manjit
Published: June 2021

The efficacy of onabotulinumtoxinA (OnaB-A) as a preventative treatment for chronic migraine, emerging fortuitously from clinical observation is now supported by class one evidence and over two decades of real-world clinical data. There is still limited ability to predict a clinically meaningful response to OnaB-A for individual patients, however. This review summarises briefly the proposed mechanism of OnaB-A in chronic migraine, the literature of predictors of clinical response, and recent developments in the field.
Repeatability and Reproducibility of Macular Hole Size Measurements Using Optical Coherence Tomography
Authors: Baumann Carmen , Almarzooqi Ahmed , Blobner Katharina , Zapp Daniel , Kirchmair Katharina , Schwer Lydia S. , Lohmann Chris P. , Kaye Stephen B.
Published: June 2021

The purpose of this study was to assess the repeatability and reproducibility of measuring the minimum linear diameter (MLD) of macular holes (MHs) using horizontal linear and radial scan modes in optical coherence tomography (OCT). Patients with concurrent sets of radial and horizontal linear OCT volume scans were included. The MLD was measured twice in both scan modes by six raters of three different experience levels (groups). Outcome measures were the reliability and repeatability of MLD measurements. Fifty patients were included. Mean MLD was 317.21(±170.63) µm in horizontal linear and 364.52 (±161.71) µm in radial mode, a difference of 47.31 (±26.48) µm (p < 0.001). In the radial scan mode, MLD was identified within 15° of the horizontal meridian in 27% and within 15° of the vertical meridian in 26.7%, with the remainder (46.3%) in oblique meridians. The intra-group coefficients of repeatability (CR) for horizontal linear mode were 23 µm, 33 µm and 45 µm, and for radial mode 25 µm, 44 µm and 57 µm for groups 1, 2 and 3, respectively. The inter-group CR, taking group 1 as reference standard for groups 2 and 3, were 74 µm and 71 µm for the linear mode, and 62 µm and 78 µm for radial mode. The radial mode provides good repeatability and reliability for measurement of MLD. In a majority of cases the MLD does not lie in the horizontal meridian and would be underestimated using a horizontal OCT mode.
An Artificial Intelligence Approach to Bloodstream Infections Prediction
Authors: Pai Kai-Chih , Wang Min-Shian , Chen Yun-Feng , Tseng Chien-Hao , Liu Po-Yu , Chen Lun-Chi , Sheu Ruey-Kai , Wu Chieh-Liang
Published: June 2021

This study aimed to develop an early prediction model for identifying patients with bloodstream infections. The data resource was taken from 2015 to 2019 at Taichung Veterans General Hospital, and a total of 1647 bloodstream infection episodes and 3552 non-bloodstream infection episodes in the intensive care unit (ICU) were included in the model development and evaluation. During the data analysis, 30 clinical variables were selected, including patients’ basic characteristics, vital signs, laboratory data, and clinical information. Five machine learning algorithms were applied to examine the prediction model performance. The findings indicated that the area under the receiver operating characteristic curve (AUROC) of the prediction performance of the XGBoost model was 0.825 for the validation dataset and 0.821 for the testing dataset. The random forest model also presented higher values for the AUROC on the validation dataset and testing dataset, which were 0.855 and 0.851, respectively. The tree-based ensemble learning model enabled high detection ability for patients with bloodstream infections in the ICU. Additionally, the analysis of importance of features revealed that alkaline phosphatase (ALKP) and the period of the central venous catheter are the most important predictors for bloodstream infections. We further explored the relationship between features and the risk of bloodstream infection by using the Shapley Additive exPlanations (SHAP) visualized method. The results showed that a higher prothrombin time is more prominent in a bloodstream infection. Additionally, the impact of a lower platelet count and albumin was more prominent in a bloodstream infection. Our results provide additional clinical information for cut-off laboratory values to assist clinical decision-making in bloodstream infection diagnostics.
Path Analysis of the Impact of Obesity on Postoperative Outcomes in Colorectal Cancer Patients: A Population-Based Study
Authors: Chung Kuan-Chih , Lee Ko-Chao , Chen Hong-Hwa , Cheng Kung-Chuan , Wu Kuen-Lin , Song Ling-Chiao
Published: June 2021

Background: Obesity is adversely affecting perioperative outcomes; however, long-term outcomes do not appear to be affected by excess body weight (the obesity paradox). The purpose of this study is to examine the association between obesity and surgical outcomes in patients with colorectal cancer (CRC) using data from the United States National Inpatient Sample (NIS). Methods: Patients ≥20 years old diagnosed with CRC who received surgery were identified in the 2004–2014 NIS database. Patients who were obese (ICD-9-CM code: 278.0) were matched with controls (non-obese) in a 1:4 ratio for age, sex, and severity of CRC (metastasis vs. no metastasis). Linear regression and path analysis were used to compare outcomes between obese and non-obese patients. A total of 107,067 patients (53,376 males, 53,691 females) were included in the analysis, and 7.86% were obese. Results: The rates of postoperative infection, shock, bleeding, wound disruption, and digestive system complications were significantly different between the obese and non-obese groups. The obesity group had increased incidence of postoperative infection by 1.9% (∂P/∂X = 0.019), shock by 0.25% (∂P/∂X = 0.0025), postoperative bleeding by 0.5% (∂P/∂X = 0.005), wound disruption by 0.6% (∂P/∂X = 0.006), and digestive system complications by 1.35% (∂P/∂X = 0.0135). Path analysis showed that obesity group had higher in-hospital mortality through mentioned above five complications by 66.65 × 10−5%, length of hospital stay by 0.32 days, and total hospital charges by 2384 US dollars. Conclusions: Obesity increases the risk of postoperative complications in patients with CRC undergoing surgery. It also increased in-hospital mortality, length of hospital stay, and total hospital charges. Therefore, patients with obesity might require a higher level of preoperative interventions and complications monitoring to improve outcomes.
Bone Metabolism and RANKL/OPG Ratio in Rheumatoid Arthritis Women Treated with TNF-α Inhibitors
Authors: Jura-Półtorak Agnieszka , Szeremeta Anna , Olczyk Krystyna , Zoń-Giebel Aleksandra , Komosińska-Vassev Katarzyna
Published: June 2021

The aim of this study was to evaluate the effect of anti-tumor necrosis factor α (anti-TNF-α) therapy in combination with methotrexate on bone remodeling and osteoclastogenesis in female patients with RA. Serum levels of bone turnover markers (i.e., C- and N-terminal propeptides of type I procollagen (PICP and PINP), C- and N-terminal cross-linking telopeptides of type I collagen (CTX-I and NTX-I), and soluble receptor activator of nuclear factor κB ligand (sRANKL) and osteoprotegerin (OPG)) were determined by immunoassay at baseline and 15 months after initiation of treatment. Bone mineral density was measured by dual-energy x-ray absorptiometry. We found a significant decrease in serum PINP levels, a biomarker of bone formation, and higher levels of CTX-I and sRANKL indicative of increased bone resorption in RA patients prior to TNFαI treatment compared to the controls. Anti-TNF-α therapy was effective in improving bone metabolism in RA patients as reflected in a decrease in CTX-I (at least partially due to the RANKL/OPG reduction) and a concomitant increase in PINP levels. The bone metabolism changes were independent of the type of TNFαI used. PINP and CTX-I were found to be useful markers of bone metabolism, which may prove the effectiveness of TNF-α therapy earlier than the bone density assessment.