bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectral Probe for Electron Transfer and Addition Reactions of Azide Radicals with Substituted Quinoxalin-2-Ones in Aqueous Solutions
Authors: Skotnicki Konrad , Ostrowski Slawomir , Dobrowolski Jan Cz. , De la Fuente Julio R. , Cañete Alvaro , Bobrowski Krzysztof
Published: January 2021

The azide radical (N3●) is one of the most important one-electron oxidants used extensively in radiation chemistry studies involving molecules of biological significance. Generally, it was assumed that N3● reacts in aqueous solutions only by electron transfer. However, there were several reports indicating the possibility of N3● addition in aqueous solutions to organic compounds containing double bonds. The main purpose of this study was to find an experimental approach that allows a clear assignment of the nature of obtained products either to its one-electron oxidation or its addition products. Radiolysis of water provides a convenient source of one-electron oxidizing radicals characterized by a very broad range of reduction potentials. Two inorganic radicals (SO4●−, CO3●−) and Tl2+ ions with the reduction potentials higher, and one radical (SCN)2●− with the reduction potential slightly lower than the reduction potential of N3● were selected as dominant electron-acceptors. Transient absorption spectra formed in their reactions with a series of quinoxalin-2-one derivatives were confronted with absorption spectra formed from reactions of N3● with the same series of compounds. Cases, in which the absorption spectra formed in reactions involving N3● differ from the absorption spectra formed in the reactions involving other one-electron oxidants, strongly indicate that N3● is involved in the other reaction channel such as addition to double bonds. Moreover, it was shown that high-rate constants of reactions of N3● with quinoxalin-2-ones do not ultimately prove that they are electron transfer reactions. The optimized structures of the radical cations (7-R-3-MeQ)●+, radicals (7-R-3-MeQ)● and N3● adducts at the C2 carbon atom in pyrazine moiety and their absorption spectra are reasonably well reproduced by density functional theory quantum mechanics calculations employing the ωB97XD functional combined with the Dunning’s aug-cc-pVTZ correlation-consistent polarized basis sets augmented with diffuse functions.
Chimeric Antigen Receptor-Engineered T Cell Therapy for the Management of Patients with Metastatic Prostate Cancer: A Comprehensive Review
Authors: Yu Young Dong , Kim Tae Jin
Published: January 2021

Prostate cancer (PCa) has a vast clinical spectrum from the hormone-sensitive setting to castration-resistant metastatic disease. Thus, chemotherapy regimens and the administration of androgen receptor axis-targeted (ARAT) agents for advanced PCa have shown limited therapeutic efficacy. Scientific advances in the field of molecular medicine and technological developments over the last decade have paved the path for immunotherapy to become an essential clinical modality for the treatment of patients with metastatic PCa. However, several immunotherapeutic agents have shown poor outcomes in patients with advanced disease, possibly due to the low PCa mutational burden. Adoptive cellular approaches utilizing chimeric antigen receptor T cells (CAR-T) targeting cancer-specific antigens would be a solution for circumventing the immune tolerance mechanisms. The immunotherapeutic regimen of CAR-T cell therapy has shown potential in the eradication of hematologic malignancies, and current clinical objectives maintain the equivalent efficacy in the treatment of solid tumors, including PCa. This review will explore the current modalities of CAR-T therapy in the disease spectrum of PCa while describing key limitations of this immunotherapeutic approach and discuss future directions in the application of immunotherapy for the treatment of metastatic PCa and patients with advanced disease.
Acute Promyelocytic Leukemia in Children: A Model of Precision Medicine and Chemotherapy-Free Therapy
Authors: Gurnari Carmelo , Voso Maria Teresa , Girardi Katia , Mastronuzzi Angela , Strocchio Luisa
Published: January 2021

Acute promyelocytic leukemia (APL) represents a paradigm of precision medicine. Indeed, in the last decades, the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) completely revolutionized the therapeutic approach to this previously highly fatal disorder. This entirely chemotherapy-free treatment, which provided excellent survival rates, has been initially validated in adults and, recently, translated in the pediatric setting. This review summarizes currently available data on the use of ATRA and ATO combination in pediatric APL, providing a particular focus on peculiar issues and challenges, such as the occurrence of pseudotumor cerebri and death during induction (early death), as well as the advantage offered by the ATO/ATRA combination in sparing long-term sequelae.
The Involvement of Innate and Adaptive Immunity in the Initiation and Perpetuation of Sjögren’s Syndrome
Authors: Chivasso Clara , Sarrand Julie , Perret Jason , Delporte Christine , Soyfoo Muhammad Shahnawaz
Published: January 2021

Sjogren’s syndrome (SS) is a chronic autoimmune disease characterized by the infiltration of exocrine glands including salivary and lachrymal glands responsible for the classical dry eyes and mouth symptoms (sicca syndrome). The spectrum of disease manifestations stretches beyond the classical sicca syndrome with systemic manifestations including arthritis, interstitial lung involvement, and neurological involvement. The pathophysiology underlying SS is not well deciphered, but several converging lines of evidence have supported the conjuncture of different factors interplaying together to foster the initiation and perpetuation of the disease. The innate and adaptive immune system play a cardinal role in this process. In this review, we discuss the inherent parts played by both the innate and adaptive immune system in the pathogenesis of SS.
Time- and Frequency-Domain Steady-State Solutions of Nonlinear Motional Eddy Currents Problems
Authors: Friedrich Léo A.J.
Published: January 2021

This paper presents a comparison of different time- and frequency-domain solvers for the steady-state simulation of the eddy current phenomena, due to the motion of a permanent magnet array, occurring in the soft-magnetic stator core of electrical machines that exhibits nonlinear material characteristics. Three different dynamic solvers are implemented in the framework of the isogeometric analysis, namely the traditional time-stepping backward-Euler technique, the space-time Galerkin approach, and the harmonic balance method, which operates in the frequency domain. Two-dimensional electrical machine benchmarks, consisting of both slotless and slotted stator core, are considered to establish the accuracy, convergence, and computational efficiency of the presented solvers.
Peroral Endoscopic Myotomy in the Management of Zenker’s Diverticulum: A Retrospective Multicenter Study
Authors: Budnicka Aleksandra , Januszewicz Władysław , Białek Andrzej B. , Spychalski Michal , Reguła Jaroslaw , Kaminski Michal F.
Published: January 2021

Background: Peroral endoscopic myotomy (POEM) is an emerging technique in the treatment of Zenker’s diverticulum (ZD). This study aimed to analyze the feasibility of Zenker’s POEM (Z-POEM) in a multicenter setting and assess its performance using a validated Kothari-Haber Scoring System newly developed for symptom measurement in ZD. Materials and methods: This was a multicenter retrospective study involving three Polish tertiary referral endoscopic units. The data of consecutive patients with symptomatic ZD treated with Z-POEM in Poland between May 2019 and August 2020 were retrieved and analyzed. Primary outcome measures were technical success and clinical success rate (<3 points in Kothari-Haber Score at 2–3 months follow-up). Secondary outcome measures included procedures’ duration, length of hospital stay, and adverse events. Results: 22 patients with symptomatic ZD were included. The mean age was 67.6 (±10.7) years, and 14 (63.6%) were male. All but two patients were treatment naïve. The average size of the ZD was 30 mm (IQR, 24–40 mm). Technical success was achieved in all patients (100%), whereas clinical success was 90.9%. The average Kothari-Haber Score was 6.35 before treatment and has dropped to 0.65 after the treatment (p < 0.0001). The mean procedure time was 48.8 (±19.3) minutes, and the median length of hospital stay was 2 days (IQR, 2–3). Three patients (13.6%) had post-procedural emphysema, of which two were mild and self-resolving (9.1%), and one was moderate (4.5%) and complicated with laryngeal edema and prolonged intubation. Conclusions: This feasibility study suggests that Z-POEM is a highly effective and safe treatment for ZD, particularly among treatment-naïve patients. Comparative studies with other treatment modalities over longer follow-up are warranted.
Clinical Features of Iris Cysts in Long-Term Follow-Up
Authors: Konopińska Joanna , Lisowski Łukasz , Mariak Zofia , Obuchowska Iwona
Published: January 2021

This study evaluated the characteristics and clinical course of patients with iris cysts in the long-term follow-up (24–48 months). We retrospectively analyzed the medical records of 39 patients with iris cysts (27 women and 12 men). Age, visual acuity, intraocular pressure (IOP), slit-lamp evaluation, and ultrasound biomicroscopy images were assessed. The mean age at diagnosis was 40.6 ± 17.48 years. Thirty (76.9%) cysts were peripheral, five (12.8%) were located at the pupillary margin, two (5.1%) were midzonal, and two (5.1%) were multichamber cysts extending from the periphery to the pupillary margin. A total of 23 (59%) cysts were in the lower temporal quadrant, 11 (28.2%) were in the lower nasal quadrant, and 5 (12.8%) were in the upper nasal quadrant. Cyst size was positively correlated with patient age (rs = 0.38, p = 0.003) and negatively correlated with visual acuity (rs = −0.42, p = 0.014). Cyst growth was not observed. The only complication was an increase in IOP in three (7.7%) patients with multiple cysts. The anatomical location of the cysts cannot differentiate them from solid tumors. The vast majority of cysts are asymptomatic, do not increase in size, and do not require treatment during long-term follow-up.
Proposal of the Definition for COVID-19-Associated Coagulopathy
Authors: Iba Toshiaki , Warkentin Theodore E. , Thachil Jecko , Levi Marcel , Levy Jerrold H.
Published: January 2021

Thrombotic events are common complications in COVID-19 patients that include both thrombus formation in large vessels and the microvasculature of the lung and other organs. COVID-19-associated coagulopathy (CAC) and disseminated intravascular coagulation (DIC) have similarities and differences, and whether CAC is a form of DIC is the subject of debate. Reported mechanisms of CAC include activated coagulation, endotheliopathy, up-regulated innate and adaptive immunity, and activated complement system. Although the clinical features and laboratory findings of CAC and DIC seem different, there are fundamental similarities that should be considered. Basically, the pathological findings of COVID-19 fall within the scope of the definition of DIC, i.e., systemic activation of coagulation caused by or resulting from the microvascular damage. Therefore, we suggest that although CAC differs from usual infection-associated DIC, its various features indicate that it can be considered a thrombotic phenotype DIC. This review summarizes the current knowledge about CAC including differences and similarities with sepsis-associated DIC.
Donor-Derived Cell-Free DNA in Kidney Transplantation as a Potential Rejection Biomarker: A Systematic Literature Review
Authors: Martuszewski Adrian , Paluszkiewicz Patrycja , Król Magdalena , Banasik Mirosław , Kepinska Marta
Published: January 2021

Kidney transplantation (KTx) is the best treatment method for end-stage kidney disease. KTx improves the patient’s quality of life and prolongs their survival time; however, not all patients benefit fully from the transplantation procedure. For some patients, a problem is the premature loss of graft function due to immunological or non-immunological factors. Circulating cell-free DNA (cfDNA) is degraded deoxyribonucleic acid fragments that are released into the blood and other body fluids. Donor-derived cell-free DNA (dd-cfDNA) is cfDNA that is exogenous to the patient and comes from a transplanted organ. As opposed to an invasive biopsy, dd-cfDNA can be detected by a non-invasive analysis of a sample. The increase in dd-cfDNA concentration occurs even before the creatinine level starts rising, which may enable early diagnosis of transplant injury and adequate treatment to avoid premature graft loss. In this paper, we summarise the latest promising results related to cfDNA in transplant patients.
Nutrition as a Key Modifiable Factor for Periodontitis and Main Chronic Diseases
Authors: Martinon Prescilla , Fraticelli Laurie , Giboreau Agnes , Dussart Claude , Bourgeois Denis , Carrouel Florence
Published: January 2021

Nutrition is recognized as an essential component in the prevention of a number of chronic diseases, including periodontal disease. Based on these considerations, a better understanding is required regarding how the diet, and more particularly the intake of macronutrients and micronutrients, could impact the potential relationship between nutrition and periodontal diseases, periodontal diseases and chronic diseases, nutrition and chronic diseases. To overcome this complexity, an up-to-date literature review on the nutriments related to periodontal and chronic diseases was performed. High-sugar, high-saturated fat, low-polyols, low-fiber and low-polyunsaturated-fat intake causes an increased risk of periodontal diseases. This pattern of nutrients is classically found in the Western diet, which is considered as an ‘unhealthy’ diet that causes cardiovascular diseases, diabetes and cancers. Conversely, low-sugar, high-fiber and high-omega-6-to-omega-3 fatty acid ratio intake reduces the risk of periodontal diseases. The Mediterranean, DASH, vegetarian and Okinawa diets that correspond to these nutritional intakes are considered as ‘healthy’ diets, reducing this risk of cardiovascular diseases, diabetes and cancers. The role of micronutrients, such as vitamin D, E, K and magnesium, remains unclear, while others, such as vitamin A, B, C, calcium, zinc and polyphenols have been shown to prevent PDs. Some evidence suggests that probiotics and prebiotics could promote periodontal health. Periodontal and chronic diseases share, with a time delay, nutrition as a risk factor. Thus, any change in periodontal health should be considered as a warning signal to control the dietary quality of patients and thus reduce the risk of developing chronic diseases later on.
Evidence of Pulmonary Hypertension after SARS-CoV-2 Infection in Subjects without Previous Significant Cardiovascular Pathology
Authors: Tudoran Cristina , Tudoran Mariana , Lazureanu Voichita Elena , Marinescu Adelina Raluca , Pop Gheorghe Nicusor , Pescariu Alexandru Silvius , Enache Alexandra , Cut Talida Georgiana
Published: January 2021

Background: Coronavirus (Covid-19) infection represents a serious medical condition, often associated with cardiovascular complications, pulmonary hypertension (PH), and right ventricle dysfunction (RVD). The aim of this study is to show, by means of transthoracic echocardiography (TTE), the presence of an increased estimated systolic pressure in the pulmonary artery (esPAP) and altered right ventricular global longitudinal strain (RV-GLS) in patients without history of PH. Methods: In a group of 91 patients, aged under 55 years, hospitalized for a moderate Covid-19 infection, a thorough cardiologic and TTE examination were performed two months after discharge. Their initial thorax computer-tomography (TCT) images and laboratory data were accessed from the electronic data base of the hospital. Results: We observed an increased prevalence of PH (7.69%) and RVD (10.28%), significantly correlated with the initial levels of the TCT score and inflammatory factors (p ˂ 0.001), but borderline changes were observed in more patients. Multivariate regression analysis showed that these factors and RV-GLS explain 89.5% of elevated esPAP. Conclusions: In COVID-19 infection, PH and RVD are common complications, being encountered after the recovery even in moderate cases. It appears to be a connection between their severity and the extent of the initial pulmonary injury and of the inflammatory response.
Effectiveness and Safety of Apixaban vs. Warfarin in Venous Thromboembolism Patients with Obesity and Morbid Obesity
Authors: Cohen Alexander , Sah Janvi , Lee Theodore , Rosenblatt Lisa , Hlavacek Patrick , Emir Birol , Keshishian Allison , Yuce Huseyin , Luo Xuemei
Published: January 2021

This study integrated 5 United States healthcare claims databases to evaluate the risk of recurrent venous thromboembolism (VTE) and major bleeding (MB) among VTE patients who initiated apixaban vs. warfarin, stratified by obesity. Obese and morbidly obese patients were identified based on diagnosis codes. Stabilized inverse probability treatment weighting (IPTW) was conducted to balance observed patient characteristics between treatment cohorts. An interaction analysis was conducted to evaluate treatment effects of apixaban vs. warfarin according to obesity status. Cox proportional hazard models were used to evaluate the risk of recurrent VTE and MB among IPTW weighted obese and morbidly obese patients. A total of 112,024 non-obese patients and 43,095 obese patients were identified, of whom 19,751 were morbidly obese. When stratified by obesity status post-IPTW, no significant interactions were observed for effects of apixaban vs. warfarin on recurrent VTE or MB (interaction p > 0.10). Among IPTW obese and morbidly obese patients, apixaban was associated with a significantly lower risk of recurrent VTE (obese: 0.73 [0.64–0.84]; morbidly obese: 0.65 [0.53–0.80]) and MB (obese: 0.73 [0.62–0.85]; morbidly obese: 0.68 [0.54–0.86]) as compared with warfarin. In this large sample of obese and morbidly obese VTE patients, apixaban had a significantly lower risk of recurrent VTE and MB vs. warfarin.
A Prospective Study of Association of Micronutrients Deficiencies during Pregnancy and Neonatal Outcome among Women after Bariatric Surgery
Authors: Ducarme Guillaume , Planche Lucie , Abet Emeric , Desroys du Roure Valérie , Ducet-Boiffard Amélie
Published: January 2021

Little is known about the association of micronutrients deficiencies during pregnancy and neonatal outcome among women after Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). We present a prospective study of 87 consecutive women with a history of RYGB (n = 37) or SG (n = 50) who underwent complete and regular clinical and biological nutritional assessments during pregnancy. Data on maternal characteristics, biological nutritional parameters, antenatal management, and perinatal outcome were collected. The objective was to evaluate serum levels of micronutrients at the second trimester, and to assess the association between micronutrients deficiencies and neonatal outcome. After RYGB, maternal age (34.3 ± 4.9 vs. 31.1 ± 4.6 years; p = 0.003) and pregnancy timing after surgery (64.5 ± 47.0 vs. 38.1 ± 28.1 months; p = 0.002) were significantly higher, and pre-pregnancy BMI was significantly lower (29.8 ± 5.6 vs. 32.9 ± 7.1 kg/m2; p = 0.03). Maternal and neonatal outcomes were similar. Additional supplementations after blood tests were similar in groups. Zinc, selenium, vitamins A1, B1, B6, C, and E levels were not different depending on the type of surgery. Zinc deficiency (7/87) was significantly more frequent after RYGP (18.9% vs. 0%; p = 0.02) and selenium deficiency (15/87) was similar in groups (21.6% after RYGB and 14.0% after SG; p = 0.36). The mean birth weight was significantly lower in selenium deficiency cases (3137 ± 550 vs. 3535 ± 737 g; p = 0.04). Selenium deficiency was negatively correlated with birth weight (r = −0.23; p = 0.03) and with birth weight z-score (r = −0.26; p = 0.01), but not correlated after adjustment for the procedure. The levels of micronutrients surveillance along pregnancy in women with a history of bariatric surgery is necessary to decrease the risk of inadequate fetal growth in the patients.
Urogenital Schistosomiasis—History, Pathogenesis, and Bladder Cancer
Authors: Santos Lúcio Lara , Santos Júlio , Gouveia Maria João , Bernardo Carina , Lopes Carlos , Rinaldi Gabriel , Brindley Paul J. , Costa José M. Correia da
Published: January 2021

Schistosomiasis is the most important helminthiasis worldwide in terms of morbidity and mortality. Most of the infections occurs in Africa, which about two thirds are caused by Schistosoma haematobium. The infection with S. haematobium is considered carcinogenic leading to squamous cell carcinoma (SCC) and urothelial carcinoma of the urinary bladder. Additionally, it is responsible for female genital schistosomiasis leading to infertility and higher risk of human immunodeficiency virus (HIV) transmission. Remarkably, a recent outbreak in Corsica (France) drew attention to its potential re-mergence in Southern Europe. Thus far, little is known related to host-parasite interactions that trigger carcinogenesis. However, recent studies have opened new avenues to understand mechanisms on how the parasite infection can lead cancer and other associated pathologies. Here, we present a historical perspective of schistosomiasis, and review the infection-associated pathologies and studies on host–parasite interactions that unveil tentative mechanisms underlying schistosomiasis-associated carcinogenesis.
Value of Perioperative Chest X-ray for the Prediction of Sternal Wound Complications after Cardiac Surgery in High-Risk Patients: A “Work in Progress” Analysis
Authors: Ardigò Andrea , Francica Alessandra , Veraldi Gian Franco , Tropea Ilaria , Tonelli Filippo , Rossetti Cecilia , Onorati Francesco , Faggian Giuseppe
Published: January 2021

Background. Sternal wound complications are serious events that occur after cardiac surgery. Few studies have investigated the predictive value of chest X-ray radiological measurements for sternal complications. Methods. Several perioperative radiological measurements at chest X-ray and clinical characteristics were computed in 849 patients deemed at high risk for sternal dehiscence (SD) or More than Grade 1 Surgical Site Infection (MG1-SSI). Multivariable analysis identified independent predictors, whilst receiver operating characteristics (ROC) curve analyses highlighted cut-off values of radiological measurements for the prediction of both complications. Results. SD occurred in 8.8% of the patients, MG1-SSI in 6.8%. Chronic obstructive pulmonary disease (COPD) was the only independent predictor for SD (Odds Ratio, O.R. 12.1; p < 0.001); proximal sternal height (PSH) was the only independent protective factor (O.R. 0.58; p < 0.001), with a cut-off value of 11.7 mm (sensitivity 70.5%, specificity 71.0%; ROC area under the curve (AUC) = 0.768, p < 0.001). Diabetes mellitus (O.R. 3.5; p < 0.001) and COPD (O.R. 21.3; p < 0.001) were independent predictors for MG1-SSI; indexed proximal sternal height (iPSH) was as a protective factor (O.R. 0.26; p < 0.001) with a cut-off of 5.97 mm (sensitivity 70.2%, specificity 69.0%; ROC AUC = 0.739, p < 0.001). No other radiological measurements were independently correlated with SD or MG1-SS (p = N.S.). Conclusion. PSH and iPSH at preoperative chest X-ray may act as indicators of high risk for sternal wound complications, allowing for early preventative measures.
The Mutational Concordance of Fixed Formalin Paraffin Embedded and Fresh Frozen Gastro-Oesophageal Tumours Using Whole Exome Sequencing
Authors: Chong Irene Y. , Starling Naureen , Rust Alistair , Alexander John , Aronson Lauren , Llorca-Cardenosa Marta , Chauhan Ritika , Chaudry Asif , Kumar Sacheen , Fenwick Kerry , Assiotis Ioannis , Matthews Nik , Begum Ruwaida , Wotherspoon Andrew , Terlizzo Monica , Watkins David , Chau Ian , Lord Christopher J. , Haider Syed , Rao Sheela , Cunningham David
Published: January 2021

1. Background: The application of massively parallel sequencing has led to the identification of aberrant druggable pathways and somatic mutations within therapeutically relevant genes in gastro-oesophageal cancer. Given the widespread use of formalin-fixed paraffin-embedded (FFPE) samples in the study of this disease, it would be beneficial, especially for the purposes of biomarker evaluation, to assess the concordance between comprehensive exome-wide sequencing data from archival FFPE samples originating from a prospective clinical study and those derived from fresh-frozen material. 2. Methods: We analysed whole-exome sequencing data to define the mutational concordance of 16 matched fresh-frozen and FFPE gastro-oesophageal tumours (N = 32) from a prospective clinical study. We assessed DNA integrity prior to sequencing and then identified coding mutations in genes that have previously been implicated in other cancers. In addition, we calculated the mutant-allele heterogeneity (MATH) for these samples. 3. Results: Although there was increased degradation of DNA in FFPE samples compared with frozen samples, sequencing data from only two FFPE samples failed to reach an adequate mapping quality threshold. Using a filtering threshold of mutant read counts of at least ten and a minimum of 5% variant allele frequency (VAF) we found that there was a high median mutational concordance of 97% (range 80.1–98.68%) between fresh-frozen and FFPE gastro-oesophageal tumour-derived exomes. However, the majority of FFPE tumours had higher mutant-allele heterogeneity (MATH) scores when compared with corresponding frozen tumours (p < 0.001), suggesting that FFPE-based exome sequencing is likely to over-represent tumour heterogeneity in FFPE samples compared to fresh-frozen samples. Furthermore, we identified coding mutations in 120 cancer-related genes, including those associated with chromatin remodelling and Wnt/β-catenin and Receptor Tyrosine Kinase signalling. 4. Conclusions: These data suggest that comprehensive genomic data can be generated from exome sequencing of selected DNA samples extracted from archival FFPE gastro-oesophageal tumour tissues within the context of prospective clinical trials.
Autoimmune Hemolytic Anemia in the Pediatric Setting
Authors: Voulgaridou Aikaterini , Kalfa Theodosia A.
Published: January 2021

Autoimmune hemolytic anemia (AIHA) is a rare disease in children, presenting with variable severity. Most commonly, warm-reactive IgG antibodies bind erythrocytes at 37 °C and induce opsonization and phagocytosis mainly by the splenic macrophages, causing warm AIHA (w-AIHA). Post-infectious cold-reactive antibodies can also lead to hemolysis following the patient’s exposure to cold temperatures, causing cold agglutinin syndrome (CAS) due to IgM autoantibodies, or paroxysmal cold hemoglobinuria (PCH) due to atypical IgG autoantibodies which bind their target RBC antigen and fix complement at 4 °C. Cold-reactive antibodies mainly induce intravascular hemolysis after complement activation. Direct antiglobulin test (DAT) is the gold standard for AIHA diagnosis; however, DAT negative results are seen in up to 11% of warm AIHA, highlighting the need to pursue further evaluation in cases with a phenotype compatible with immune-mediated hemolytic anemia despite negative DAT. Prompt supportive care, initiation of treatment with steroids for w-AIHA, and transfusion if necessary for symptomatic or fast-evolving anemia is crucial for a positive outcome. w-AIHA in children is often secondary to underlying immune dysregulation syndromes and thus, screening for such disorders is recommended at presentation, before initiating treatment with immunosuppressants, to determine prognosis and optimize long-term management potentially with novel targeted medications.
Clinical Outcome of Two-Stage Revision after Periprosthetic Shoulder Infection
Authors: Klingebiel Sebastian , Theil Christoph , Gosheger Georg , Schneider Kristian Nikolaus , Ackmann Thomas , Timme Maximilian , Schorn Dominik , Liem Dennis , Rickert Carolin
Published: January 2021

Background: Periprosthetic shoulder infections are devastating complications after shoulder arthroplasty. A potential treatment concept is a two-stage prosthesis exchange. Data are sparse in terms of clinical outcome, including infection-free survival and patient satisfaction after this procedure. In the present study, we investigated recurrence of infection, revision-free survivorship and clinical outcome following two-stage revision due to periprosthetic shoulder infection. Furthermore, reasons for poor outcome were analyzed. Methods: Sixteen patients undergoing two-stage revision after shoulder joint infection were retrospectively identified. Recurrence of infection was analyzed by Kaplan–Meier survival curve. Clinical outcome was quantified with subjective shoulder value (SSV), “quick” Disabilities of the Arm, Shoulder and Hand (qDASH) and Rowe score. Range of motion (ROM) was measured pre- and postoperatively. Postoperative scores and ROM were compared in a subgroup analysis according to different reimplanted prosthesis types. Results: The reinfection-free implant survival was 81% after one year and at final follow-up (FU; mean of 33.2 months). The overall revision-free survival amounted to 56% after one year and at final FU. Patients who received reverse shoulder arthroplasty (RSA) as part of reimplantation had less disability and long-term complications. This group demonstrated better subjective stability and function compared to patients revised to megaprostheses or large-head hemiarthroplasties. Conclusions: Two-stage revision following periprosthetic joint infection of the shoulder allows appropriate infection control in the majority of patients. However, the overall complications and revision rates due to mechanical failure or reinfection are high. Reimplantation of RSA seem superior to alternative prosthesis models in terms of function and patient satisfaction. Therefore, bone-saving surgery and reconstruction of the glenoid may increase the likelihood of reimplantation of RSA and potentially improve outcome in the case of infection-related two-stage revision of the shoulder.
PI3KCA Mutations in Uterine Cervix Carcinoma
Authors: Voutsadakis Ioannis A.
Published: January 2021

Background: Squamous cervical carcinoma represents an infection-associated malignancy that produces a high mortality when metastatic or recurrent after primary local treatment. There is an urgent need for new therapies for this cancer. Molecular lesions in cervical cancer may provide opportunities for targeted therapies development. Methods: Publicly available data from the Cancer Genome Atlas (TCGA) were analyzed to define the molecular landscape of squamous cervical carcinomas with and without mutations of PIK3CA, the gene encoding the alpha catalytic subunit of phosphatidylinositol 3 kinase (PI3K). Associations with alterations in other critical genes and pathways of cancer and the total mutation burden and copy number alteration burden of cervical cancers were examined. Results: Mutations in PIK3CA are observed in 27.1% of squamous cervical cancers. PIK3CA represents the most frequently mutated gene in these cancers. Mutations in PIK3CA are associated with higher rates of mutations in other genes of important cancer-associated pathways such as the tyrosine kinase receptors/K-Ras/BRAF/MAPK and the Wnt/β catenin pathway. In addition, PIK3CA mutated cervical cancers display a higher tumor mutation burden (TMB) than non-mutated cancers. Conclusion: Frequent mutations of PIK3CA gene in squamous cervical carcinomas may represent an opportunity for targeted therapies development both inhibiting the PI3K kinase and associated pathway defects. Increased TMB may additionally confer immunotherapy sensitivity.
Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection
Authors: Sung Pil Soo , Shin Eui-Cheol
Published: January 2021

Direct-acting antiviral agents (DAAs) that allow for rapid clearance of hepatitis C virus (HCV) may evoke immunological changes. Some cases of rapid de novo hepatocellular carcinoma (HCC) development or early recurrence of HCC after DAA treatment have been reported. During chronic HCV infection, natural killer (NK) cells exhibited a deviant functional phenotype with decreased production of antiviral cytokines and increased cytotoxicity; however, DAA treatment rapidly decreased their cytotoxic function. Effective DAA therapy also suppressed the intrahepatic activation of macrophages/monocytes. This was followed by a decrease in mucosal-associated invariant T (MAIT) cell cytotoxicity without normalization of cytokine production. Rapid changes in the phenotypes of NK and MAIT cells after DAA treatment may attenuate the cytotoxicity of these cells against cancer cells. Moreover, DAA treatment did not normalize the increased frequencies of regulatory T cells even after clearance of HCV infection. Thus, the persistently increased frequency of regulatory T cells may contribute to a local immunosuppressive milieu and hamper the clearance of cancer cells. This review will focus on recent studies describing the changes in innate and adaptive immune responses after DAA treatment in patients with chronic HCV infection in the context of de novo occurrence or recurrence of HCC.
Effects of Transanal Irrigation on Gut Microbiota in Pediatric Patients with Spina Bifida
Authors: Furuta Akira , Suzuki Yasuyuki , Takahashi Ryosuke , Jakobsen Birte Petersen , Kimura Takahiro , Egawa Shin , Yoshimura Naoki
Published: January 2021

Recent studies using 16S rRNA-based microbiota profiling have demonstrated dysbiosis of gut microbiota in constipated patients. The aim of this study was to investigate the changes in gut microbiota after transanal irrigation (TAI) in patients with spina bifida (SB). A questionnaire on neurogenic bowel disfunction (NBD), Bristol scale, and gut microbiota using 16S rRNA sequencing were completed in 16 SB patients and 10 healthy controls aged 6–17 years. Then, 11 of 16 SB patients with moderate to severe NBD scores received TAI for 3 months. Changes in urine cultures were also examined before and after the TAI treatments. In addition, correlation of gut microbiota and Bristol scale was analyzed. Significantly decreased abundance in Faecalibacterium, Blautia and Roseburia, and significantly increased abundance in Bacteroides and Roseburia were observed in the SB patients compared with controls and after TAI, respectively. The abundance of Roseburia was significantly correlated positively with Bristol scale. Urinary tract infection tended to decrease from 82% to 55% after TAI (p = 0.082) despite persistent fecal incontinence. Butyrate-producing bacteria such as Roseburia play a regulatory role in the intestinal motility and host immune system, suggesting the effects of TAI on gut microbiota.
High-Resolution Vessel Wall Magnetic Resonance Imaging of Small Unruptured Intracranial Aneurysms
Authors: Zwarzany Łukasz , Tyburski Ernest , Poncyljusz Wojciech
Published: January 2021

Background: We decided to investigate whether aneurysm wall enhancement (AWE) on high-resolution vessel wall magnetic resonance imaging (HR VW-MRI) coexists with the conventional risk factors for aneurysm rupture. Methods: We performed HR VW-MRI in 46 patients with 64 unruptured small intracranial aneurysms. Patient demographics and clinical characteristics were recorded. The PHASES score was calculated for each aneurysm. Results: Of the 64 aneurysms, 15 (23.4%) showed wall enhancement on post-contrast HR VW-MRI. Aneurysms with wall enhancement had significantly larger size (p = 0.001), higher dome-to-neck ratio (p = 0.024), and a more irregular shape (p = 0.003) than aneurysms without wall enhancement. The proportion of aneurysms with wall enhancement was significantly higher in older patients (p = 0.011), and those with a history of prior aneurysmal SAH. The mean PHASES score was significantly higher in aneurysms with wall enhancement (p < 0.000). The multivariate logistic regression analysis revealed that aneurysm irregularity and the PHASES score are independently associated with the presence of AWE. Conclusions: Aneurysm wall enhancement on HR VW-MRI coexists with the conventional risk factors for aneurysm rupture.
Longitudinal Health-Related Quality of Life Study among Cervical Cancer Patients Treated with Radiotherapy
Authors: Pasek Małgorzata , Suchocka Lilia , Osuch-Pęcak Grażyna , Muzykiewicz Konrad , Iwańska Ewa , Kaducakowa Helena , Goździalska Anna , Goździalska Magdalena
Published: January 2021

Quality of life studies in medicine, particularly in oncology, have become a basic tool used to assess patient’s performance in different types of cancer and different modalities of treatment. The aim of this study was a subjective evaluation of the quality of life in cervical cancer patients treated with radiotherapy. The study has a longitudinal character and comprises four stages: before treatment, at the end of treatment, 5 months and 5 years after treatment. Standardized questionnaires such as EORTC QoL C30, HADS (European Organisation for Research and Treatment of Cancer Quality of life C30 Hospital Anxiety and Depression Scale) and the authors demographic–clinical assessment survey were the study tools. Physical functioning was assessed as the highest before treatment and depreciated to the lowest value 5 years after treatment. Emotional functioning was the lowest before treatment and then decreased again in the fourth stage of the assessment. Global quality of life was the lowest in the fourth stage of the study. Memory and concentration were fairly good at every stage of the study, with the highest score at the end of the treatment. At stages 3 and 4, the respondent’s social functioning was the best, followed by the ability to fulfil their social role. General health and quality of life were assessed by the respondents on a level slightly above average, though five years after treatment the score was slightly below average.
Links between Inflammation and Postoperative Cancer Recurrence
Authors: Kinoshita Tomonari , Goto Taichiro
Published: January 2021

Despite complete resection, cancer recurrence frequently occurs in clinical practice. This indicates that cancer cells had already metastasized from their organ of origin at the time of resection or had circulated throughout the body via the lymphatic and vascular systems. To obtain this potential for metastasis, cancer cells must undergo essential and intrinsic processes that are supported by the tumor microenvironment. Cancer-associated inflammation may be engaged in cancer development, progression, and metastasis. Despite numerous reports detailing the interplays between cancer and its microenvironment via the inflammatory network, the status of cancer-associated inflammation remains difficult to recognize in clinical settings. In the current paper, we reviewed clinical reports on the relevance between inflammation and cancer recurrence after surgical resection, focusing on inflammatory indicators and cancer recurrence predictors according to cancer type and clinical indicators.
The Use of Anterior-Segment Optical-Coherence Tomography for the Assessment of the Iridocorneal Angle and Its Alterations: Update and Current Evidence
Authors: Triolo Giacinto , Barboni Piero , Savini Giacomo , De Gaetano Francesco , Monaco Gaspare , David Alessandro , Scialdone Antonio
Published: January 2021

The introduction of anterior-segment optical-coherence tomography (AS-OCT) has led to improved assessments of the anatomy of the iridocorneal-angle and diagnoses of several mechanisms of angle closure which often result in raised intraocular pressure (IOP). Continuous advancements in AS-OCT technology and software, along with an extensive research in the field, have resulted in a wide range of possible parameters that may be used to diagnose and follow up on patients with this spectrum of diseases. However, the clinical relevance of such variables needs to be explored thoroughly. The aim of the present review is to summarize the current evidence supporting the use of AS-OCT for the diagnosis and follow-up of several iridocorneal-angle and anterior-chamber alterations, focusing on the advantages and downsides of this technology.
Longitudinal Study to Assess the Quantitative Use of Fundus Autofluorescence for Monitoring Disease Progression in Choroideremia
Authors: Dubis Adam M , Lim Wei S , Jolly Jasleen K , Toms Maria , MacLaren Robert E , Webster Andrew R , Moosajee Mariya
Published: January 2021

Background: Characterisation of preserved autofluorescence (PAF) area in choroideremia (CHM) and its validity for monitoring disease progression in clinical trials is of importance. Methods: Eighty patients with molecularly confirmed CHM were recruited. PAF area was measured manually by 2 graders and half-life was calculated based on exponential decay model. Results: Mean age at baseline and follow-up examination was 38.1 (range, 10–69) and 40.7 (range, 11–70) years. Mean follow-up interval was 29 months (range, 6–104). The median LogMAR visual acuity was 0.10 (OD) and 0.18 (OS). Interobserver repeatability for PAF area was −0.99 to 1.03 mm2 (−6.46 to 6.49% of area). There was a statistically significant relationship between age and rate of PAF area loss (r2 = 0.28, p = 0.012). The half-life for PAF area was 13.7 years (range, 1.7–216.0 years). The correlation between half-life and age was stronger than between half-life and log transformed baseline PAF area, although neither was statistically significant. Conclusions: The intra- and inter-observer PAF area measurement variability provides a baseline change, which must be overcome in a clinical trial if this metric were to be used. Treatments must slow progression to alter the exponential decay in a timely manner accounting for naturally slow progression patterns.
Glenoid Component Loosening in Anatomic Total Shoulder Arthroplasty: Association between Radiological Predictors and Clinical Parameters—An Observational Study
Authors: Grob Alexandra , Freislederer Florian , Marzel Alex , Audigé Laurent , Schwyzer Hans-Kaspar , Scheibel Markus
Published: January 2021

The mechanisms of glenoid component loosening in anatomic total shoulder arthroplasty (aTSA) are still unclear, and it remains undetermined which specific radiographic features are associated with clinical outcomes. Patients with primary osteoarthritis who underwent aTSA with a stemless implant and a pegged glenoid between January 2011 and December 2016 were extracted from a local registry. Anteroposterior radiographs were evaluated at six, 12, 24 months, and five years post-TSA for lateral humeral offset (LHO), joint gap (JG), acromiohumeral distance (AHD), and radiolucency (modified Franklin score); 147 patients were included. Mixed-model linear regression was used. Both constant score (CS) and subjective shoulder value (SSV) markedly decreased at five years follow-up compared to one year (p < 0.001 for both). AHD, LHO, and JG all showed a consistent and statistically significant decline over time, with the joint gap decreasing by half. Consistently, smaller JG and AHD were correlated with lower SSV (p = 0.03 and p = 0.07, respectively). Massive loosening was associated with a 14.5 points lower SSV (p < 0.01). Finally, narrowing of the JG was significantly correlated with increased radiolucency (p < 0.001) and tended toward worse SSV (p = 0.06). In summary, radiographic parameters displaying medialization and cranialization after aTSA with a cemented pegged glenoid are useful predictors of impaired shoulder function.
Concurrent Use of Renal Replacement Therapy during Extracorporeal Membrane Oxygenation Support: A Systematic Review and Meta-Analysis
Authors: Mitra Saikat , Ling Ryan Ruiyang , Tan Chuen Seng , Shekar Kiran , MacLaren Graeme , Ramanathan Kollengode
Published: January 2021

Patients supported with extracorporeal membrane oxygenation (ECMO) often receive renal replacement therapy (RRT). We conducted this systematic review and meta-analysis (between January 2000 and September 2020) to assess outcomes in patients who received RRT on ECMO. Random-effects meta-analyses were performed using R 3.6.1 and certainty of evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The primary outcome was pooled mortality. The duration of ECMO support and ICU/hospital lengths of stay were also investigated. Meta-regression analyses identified factors associated with mortality. A total of 5896 adult patients (from 24 observational studies and 1 randomised controlled trial) were included in this review. Overall pooled mortality due to concurrent use of RRT while on ECMO from observational studies was 63.0% (95% CI: 56.0–69.6%). In patients receiving RRT, mortality decreased by 20% in the last five years; the mean duration of ECMO support and ICU and hospital lengths of stay were 9.33 days (95% CI: 7.74–10.92), 15.76 days (95% CI: 12.83–18.69) and 28.47 days (95% CI: 22.13–34.81), respectively, with an 81% increased risk of death (RR: 1.81, 95% CI: 1.56–2.08, p < 0.001). RRT on ECMO was associated with higher mortality rates and a longer ICU/hospital stay compared to those without RRT. Future research should focus on minimizing renal dysfunction in ECMO patients and define the optimal timing of RRT initiation.
The Main Challenges in Systemic Lupus Erythematosus: Where Do We Stand?
Authors: Piga Matteo , Arnaud Laurent
Published: January 2021

Systemic lupus erythematosus (SLE) is an immune-mediated multi-systemic disease characterized by a wide variability of clinical manifestations and a course frequently subject to unpredictable flares. Despite significant advances in the understanding of the pathophysiology and optimization of medical care, patients with SLE still have significant mortality and carry a risk of progressive organ damage accrual and reduced health-related quality of life. New tools allow earlier classification of SLE, whereas tailored early intervention and treatment strategies targeted to clinical remission or low disease activity could offer the opportunity to reduce damage, thus improving long-term outcomes. Nevertheless, the early diagnosis of SLE is still an unmet need for many patients. Further disentangling the SLE susceptibility and complex pathogenesis will allow to identify more accurate biomarkers and implement new ways to measure disease activity. This could represent a major step forward to find new trials modalities for developing new drugs, optimizing the use of currently available therapeutics and minimizing glucocorticoids. Preventing and treating comorbidities in SLE, improving the management of hard-to-treat manifestations including management of SLE during pregnancy are among the remaining major unmet needs. This review provides insights and a research agenda for the main challenges in SLE.