bluuebunny/crossref_metadata_2025 huggingface dataset:
Leptin as a Key Player in Insulin Resistance of Liver Cirrhosis? A Cross-Sectional Study in Liver Transplant Candidates
Authors: Košuta Iva , Mrzljak Anna , Kolarić Branko , Vučić Lovrenčić Marijana
Published: February 2020

Insulin resistance is associated with increased risk of death and liver transplantation in the cirrhotic population, independent of disease aetiology. However, factors accounting for insulin resistance in the context of cirrhosis are incompletely understood. This study aimed to investigate the association between adiponectin and leptin with insulin resistance in cirrhotic patients and to assess the influence of disease severity on insulin resistance and metabolic status. This cross-sectional study included 126 non-diabetic cirrhotic transplant candidates. The homeostasis model assessment 2 model was used to determine the insulin resistance index, and fasting adiponectin, leptin, insulin, c-peptide, glucose, HbA1c, and lipid profiles were analysed. Insulin resistance was detected in 83% of subjects and associated with increased leptin, fasting plasma glucose and body mass index, and lower triglyceride levels. Logistic regression analysis identified leptin and triglycerides as independent predictors of insulin resistance (OR 1.247, 95% CI 1.076–1.447, p = 0.003; OR 0.357, 95% CI 0.137–0.917, p = 0.032.). Leptin levels remained unchanged, whereas adiponectin levels increased (p < 0.001) with disease progression, and inversely correlated with HbA1c (ρ = −0.349, p < 0.001). Our results indicate that leptin resistance, as indicated by elevated leptin levels, can be regarded as a contributing factor to insulin resistance in cirrhotic patients, whereas triglycerides elicited a weak protective effect. Progressively increasing adiponectin levels elicited a positive effect on glucose homeostasis, but not insulin sensitivity across disease stages.
New First Line Treatment Options of Clear Cell Renal Cell Cancer Patients with PD-1 or PD-L1 Immune-Checkpoint Inhibitor-Based Combination Therapies
Authors: Grimm Marc-Oliver , Leucht Katharina , Grünwald Viktor , Foller Susan
Published: February 2020

In metastatic renal cell carcinoma (mRCC) the PD-1 immune-checkpoint inhibitor (ICI) Nivolumab became a standard second line treatment option in 2015 based on a significant improvement of overall survival compared to Everolimus. Current pivotal phase 3 studies showed that PD-1 ICI-based combinations were more efficacious than the VEGFR-TKI Sunitinib, a previous standard of care, leading to approval of three new regimens as guideline-recommended first-line treatment. Nivolumab plus Ipilimumab is characterized by a survival advantage, a high rate of complete response and durable remissions in intermediate and poor prognosis patients. Despite frequent immune-mediated side effects, fewer symptoms and a better quality of life were observed compared to Sunitinib. Pembrolizumab or Avelumab plus Axitinib were characterized by an improved progression-free-survival and a high response rate with a low rate of intrinsic resistance. In addition, Pembrolizumab plus Axitinib reached a significant survival benefit. The side effect profile is driven by the chronic toxicity of Axitinib, but there is additional risk of immune-mediated side effects of the PD-1/PD-L1 ICIs. The quality of life data published so far do not suggest any improvement regarding patient-reported outcomes compared to the previous standard Sunitinib. The PD-1/PD-L1 ICIs thus form the backbone of the first-line therapy of mRCC.
Correction: Association between Gait Deviation Index and Physical Function in Children with Bilateral Spastic Cerebral Palsy: A Cross-Sectional Study. J. Clin. Med. 2020, 9, 28
Authors: Ito Tadashi , Noritake Koji , Sugiura Hiroshi , Kamiya Yasunari , Tomita Hidehito , Ito Yuji , Sugiura Hideshi , Ochi Nobuhiko , Yoshihashi Yuji
Published: February 2020

The authors wish to make the following corrections to this paper [...]
Identification of Clonality through Genomic Profile Analysis in Multiple Lung Cancers
Authors: Higuchi Rumi , Nakagomi Takahiro , Goto Taichiro , Hirotsu Yosuke , Shikata Daichi , Yokoyama Yujiro , Otake Sotaro , Amemiya Kenji , Oyama Toshio , Mochizuki Hitoshi , Omata Masao
Published: February 2020

In cases of multiple lung cancers, individual tumors may represent either a primary lung cancer or both primary and metastatic lung cancers. In this study, we investigated the differences between clinical/histopathological and genomic diagnoses to determine whether they are primary or metastatic. 37 patients with multiple lung cancers were enrolled in this study. Tumor cells were selected from tissue samples using laser capture microdissection. DNA was extracted from those cells and subjected to targeted deep sequencing. In multicentric primary lung cancers, the driver mutation profile was mutually exclusive among the individual tumors, while it was consistent between metastasized tumors and the primary lesion. In 11 patients (29.7%), discrepancies were observed between genomic and clinical/histopathological diagnoses. For the lymph node metastatic lesions, the mutation profile was consistent with only one of the two primary lesions. In three of five cases with lymph node metastases, the lymph node metastatic route detected by genomic diagnosis differed from the clinical and/or pathological diagnoses. In conclusion, in patients with multiple primary lung cancers, cancer-specific mutations can serve as clonal markers, affording a more accurate understanding of the pathology of multiple lung cancers and their lymphatic metastases and thus improving both the treatment selection and outcome.
Preeclampsia: The Interplay between Oxygen-Sensitive miRNAs and Erythropoietin
Authors: Gusar Vladislava , Timofeeva Angelika , Chagovets Vitaliy , Kan Nataliya , Vasilchenko Oksana , Prozorovskaya Kseniya , Ivanets Tatyana , Sukhikh Gennadiy
Published: February 2020

Changes in the oxygen partial pressure caused by a violation of uteroplacental perfusion are considered a powerful inducer of a cascade of reactions leading to the clinical manifestation of preeclampsia (PE). At the same time, the induction of oxygen-dependent molecule expression, in particular, miRNA and erythropoietin, is modulated. Therefore, the focus of our study was aimed at estimating the miRNA expression profile of placental tissue and blood plasma in pregnant women with preeclampsia using deep sequencing and quantitative RT-PCR, as well as determining the concentration of erythropoietin. The expression of miR-27b-3p, miR-92b-3p, miR-125b-5p, miR-181a-5p, and miR-186-5p, as regulated by hypoxia/reoxygenation, was significantly increased in blood plasma during early-onset preeclampsia. The possibility of detecting early PE according to the logistic regression model (miR-92b-3p, miR-125b-5p, and miR-181a-5p (AUC = 0.91)) was evaluated. Furthermore, the erythropoietin level, which is regulated by miR-125b-5p, was significantly increased. According to PANTHER14.1, the participation of these miRNAs in the regulation of pathways, such as the hypoxia’s response via HIF activation, oxidative stress response, angiogenesis, and the VEGF signaling pathway, were determined.
Characteristics of and Public Health Responses to the Coronavirus Disease 2019 Outbreak in China
Authors: Deng Sheng-Qun , Peng Hong-Juan
Published: February 2020

In December 2019, cases of unidentified pneumonia with a history of exposure in the Huanan Seafood Market were reported in Wuhan, Hubei Province. A novel coronavirus, SARS-CoV-2, was identified to be accountable for this disease. Human-to-human transmission is confirmed, and this disease (named COVID-19 by World Health Organization (WHO)) spread rapidly around the country and the world. As of 18 February 2020, the number of confirmed cases had reached 75,199 with 2009 fatalities. The COVID-19 resulted in a much lower case-fatality rate (about 2.67%) among the confirmed cases, compared with Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). Among the symptom composition of the 45 fatality cases collected from the released official reports, the top four are fever, cough, short of breath, and chest tightness/pain. The major comorbidities of the fatality cases include hypertension, diabetes, coronary heart disease, cerebral infarction, and chronic bronchitis. The source of the virus and the pathogenesis of this disease are still unconfirmed. No specific therapeutic drug has been found. The Chinese Government has initiated a level-1 public health response to prevent the spread of the disease. Meanwhile, it is also crucial to speed up the development of vaccines and drugs for treatment, which will enable us to defeat COVID-19 as soon as possible.
Classic and Novel Biomarkers as Potential Predictors of Ventricular Arrhythmias and Sudden Cardiac Death
Authors: Shomanova Zornitsa , Ohnewein Bernhard , Schernthaner Christiane , Höfer Killian , Pogoda Christian A. , Frommeyer Gerrit , Wernly Bernhard , Brandt Mathias C. , Dieplinger Anna-Maria , Reinecke Holger , Hoppe Uta C. , Strohmer Bernhard , Pistulli Rudin , Motloch Lukas J.
Published: February 2020

Sudden cardiac death (SCD), most often induced by ventricular arrhythmias, is one of the main reasons for cardiovascular-related mortality. While coronary artery disease remains the leading cause of SCD, other pathologies like cardiomyopathies and, especially in the younger population, genetic disorders, are linked to arrhythmia-related mortality. Despite many efforts to enhance the efficiency of risk-stratification strategies, effective tools for risk assessment are still missing. Biomarkers have a major impact on clinical practice in various cardiac pathologies. While classic biomarkers like brain natriuretic peptide (BNP) and troponins are integrated into daily clinical practice, inflammatory biomarkers may also be helpful for risk assessment. Indeed, several trials investigated their application for the prediction of arrhythmic events indicating promising results. Furthermore, in recent years, active research efforts have brought forward an increasingly large number of “novel and alternative” candidate markers of various pathophysiological origins. Investigations of these promising biological compounds have revealed encouraging results when evaluating the prediction of arrhythmic events. To elucidate this issue, we review current literature dealing with this topic. We highlight the potential of “classic” but also “novel” biomarkers as promising tools for arrhythmia prediction, which in the future might be integrated into clinical practice.
Relationships Among and Predictive Values of Obesity, Inflammation Markers, and Disease Severity in Pediatric Patients with Obstructive Sleep Apnea Before and After Adenotonsillectomy
Authors: Chuang Hai-Hua , Huang Chung-Guei , Chuang Li-Pang , Huang Yu-Shu , Chen Ning-Hung , Li Hsueh-Yu , Fang Tuan-Jen , Hsu Jen-Fu , Lai Hsin-Chih , Chen Jau-Yuan , Lee Li-Ang
Published: February 2020

Both obstructive sleep apnea (OSA) and obesity are major health issues that contribute to increased systemic inflammation in children. To date, adenotonsillectomy (AT) is still the first-line treatment for childhood OSA. However, the relationships among and predictive values of obesity, inflammation, and OSA severity have not been comprehensively investigated. This prospective study investigated body mass index (BMI), serum inflammatory markers, and OSA severity before and after AT in 60 pediatric patients with OSA. At baseline, differences in levels of interleukin-6, interleukin-9, basic fibroblast growth factor, platelet-derived growth factor-BB, as well as regulated on activation, normal T cell expressed and secreted (RANTES) were significant among the various weight status and OSA severity subgroups. After 3 months postoperatively, the differences in these inflammatory markers diminished along with a decrease in OSA severity while obesity persisted. The rate of surgical cure (defined as postoperative obstructive apnea-hypopnea index < 2.0 and obstructive apnea index < 1.0) was 62%. Multivariate analysis revealed that age, BMI z-score, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein-1, and RANTES independently predicted surgical cure. Despite the significant reductions in inflammatory markers and OSA severity after AT, an inter-dependent relationship between obesity and OSA persisted. In addition to age and BMI, several inflammatory markers helped to precisely predict surgical cure.
Communicating the Risk of Death from Novel Coronavirus Disease (COVID-19)
Authors: Kobayashi Tetsuro , Jung Sung-mok , Linton Natalie M. , Kinoshita Ryo , Hayashi Katsuma , Miyama Takeshi , Anzai Asami , Yang Yichi , Yuan Baoyin , Akhmetzhanov Andrei R. , Suzuki Ayako , Nishiura Hiroshi
Published: February 2020

To understand the severity of infection for a given disease, it is common epidemiological practice to estimate the case fatality risk, defined as the risk of death among cases. However, there are three technical obstacles that should be addressed to appropriately measure this risk. First, division of the cumulative number of deaths by that of cases tends to underestimate the actual risk because deaths that will occur have not yet observed, and so the delay in time from illness onset to death must be addressed. Second, the observed dataset of reported cases represents only a proportion of all infected individuals and there can be a substantial number of asymptomatic and mildly infected individuals who are never diagnosed. Third, ascertainment bias and risk of death among all those infected would be smaller when estimated using shorter virus detection windows and less sensitive diagnostic laboratory tests. In the ongoing COVID-19 epidemic, health authorities must cope with the uncertainty in the risk of death from COVID-19, and high-risk individuals should be identified using approaches that can address the abovementioned three problems. Although COVID-19 involves mostly mild infections among the majority of the general population, the risk of death among young adults is higher than that of seasonal influenza, and elderly with underlying comorbidities require additional care.
A Population-Based Study of Diabetes during Pregnancy in Spain (2009–2015): Trends in Incidence, Obstetric Interventions, and Pregnancy Outcomes
Authors: López-de-Andrés Ana , Perez-Farinos Napoleón , Hernández-Barrera Valentín , Palomar-Gallego María A. , Carabantes-Alarcón David , Zamorano-León José J. , De Miguel-Diez Javier , Jimenez-Garcia Rodrigo
Published: February 2020

(1) Background: We examined trends in incidence and outcomes in women with existing type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) compared with a control group without diabetes. (2) Methods: This was an observational, retrospective epidemiological study using the National Hospital Discharge Database. (3) Results: There were 2,481,479 deliveries in Spain between 2009 and 2015 (5561 mothers with T1DM, 4391 with T2DM, and 130,980 with GDM). Incidence and maternal age of existing diabetes and GDM increased over time. Women with T2DM were more likely to have obstetric comorbidity (70.12%) than those with GDM (60.28%), T1DM (59.45%), and no diabetes (41.82%). Previous cesarean delivery, preeclampsia, smoking, hypertension, and obesity were the most prevalent risk factors in all types of diabetes. Women with T1DM had the highest rate of cesarean delivery (Risk Ratio (RR) 2.34; 95% Confidence Interval (CI) 2.26–2.43) and prolonged maternal length of stay. Labor induction was higher in T2DM (RR 1.99; 95% CI 1.89–2.10). Women with T1DM had more severe maternal morbidity (RR 1.97; 95% CI 1.70–2.29) and neonatal morbidity (preterm birth, RR 3.32; 95% CI 3.14–3.51, and fetal overgrowth, RR 8.05; 95% CI 7.41–8.75). (4) Conclusions: existing and GDM incidence has increased over time. We found differences in the prevalence of comorbidities, obstetric risk factors, and the rate of adverse obstetric outcomes among women with different types of diabetes. Pregnant women with diabetes have the highest risk of adverse pregnancy outcomes.
High Platelet Reactivity after Transition from Cangrelor to Ticagrelor in Hypothermic Cardiac Arrest Survivors with ST-Segment Elevation Myocardial Infarction
Authors: Buchtele Nina , Herkner Harald , Schörgenhofer Christian , Merrelaar Anne , Laggner Roberta , Gelbenegger Georg , Spiel Alexander O. , Domanovits Hans , Lang Irene , Jilma Bernd , Schwameis Michael
Published: February 2020

Transition from cangrelor to oral P2Y12 inhibitors after PCI carries the risk of platelet function recovery and acute stent thrombosis. Whether the recommended transition regimen is appropriate for hypothermic cardiac arrest survivors is unknown. We assessed the rate of high platelet reactivity (HPR) after transition from cangrelor to ticagrelor in hypothermic cardiac arrest survivors. Adult survivors of out-of-hospital cardiac arrest with ST-segment elevation myocardial infarction (STEMI), who were treated for hypothermia (33 °C ± 1) and received intravenous cangrelor during PCI and subsequent oral loading with 180mg ticagrelor were enrolled in this prospective observational cohort study. Platelet function was assessed using whole blood aggregometry. HPR was defined as AUC > 46U. The primary endpoint was the rate of HPR (%) at predefined time points during the first 24 h after cangrelor cessation. Poisson regression was used to estimate the relationship between the overlap time of cangrelor and ticagrelor co-administration and the number of subsequent HPR episodes, expressed as incidence rate ratio (IRR) with 95% confidence interval (95%CI). Between December 2017 and October 2019 16 patients (81% male, 58 years) were enrolled. On average, ticagrelor was administered 39 min (IQR 5–50) before the end of cangrelor infusion. The rate of HPR was highest 90 min after cangrelor cessation and was present in 44% (7/16) of patients. The number of HPR episodes increased significantly with decreasing overlap time of cangrelor and ticagrelor co-administration (IRR 1.03, 95%CI 1.01–1.05; p = 0.005). In this selected cohort of hypothermic cardiac arrest survivors who received cangrelor during PCI, ticagrelor loading within the recommended time frame before cangrelor cessation resulted in a substantial amount of patients with HPR.
rAAV-Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application
Authors: Blanc Fabian , Mondain Michel , Bemelmans Alexis-Pierre , Affortit Corentin , Puel Jean-Luc , Wang Jing
Published: February 2020

Over the last decade, pioneering molecular gene therapy for inner-ear disorders have achieved experimental hearing improvements after a single local or systemic injection of adeno-associated, virus-derived vectors (rAAV for recombinant AAV) encoding an extra copy of a normal gene, or ribozymes used to modify a genome. These results hold promise for treating congenital or later-onset hearing loss resulting from monogenic disorders with gene therapy approaches in patients. In this review, we summarize the current state of rAAV-mediated inner-ear gene therapies including the choice of vectors and delivery routes, and discuss the prospects and obstacles for the future development of efficient clinical rAAV-mediated cochlear gene medicine therapy.
Effectiveness of Vestibular Training for Balance and Dizziness Rehabilitation in People with Multiple Sclerosis: A Systematic Review and Meta-Analysis
Authors: García-Muñoz Cristina , Cortés-Vega María-Dolores , Heredia-Rizo Alberto Marcos , Martín-Valero Rocío , García-Bernal María-Isabel , Casuso-Holgado María Jesús
Published: February 2020

Postural instability and dizziness are commonly observed in people with multiple sclerosis (PwMS). The aim of this systematic review was to evaluate the evidence for the use of vestibular rehabilitation, in comparison with other exercise interventions or no intervention, to treat balance impairments and dizziness in PwMS. An electronic search was conducted by two independent reviewers in the following databases: MEDLINE (Pubmed), Scopus, the Physiotherapy Evidence Database (PEDro), Web of Science (WOS), Lilacs, CINHAL and the Cochrane Database of Systematic Reviews (CDSR). A quality assessment was performed using the PEDro scale and the Cochrane Risk of Bias Tool. When possible, the data were pooled in a meta-analysis (95%CI). This systematic review followed the PRISMA guideline statement and was registered in the PROSPERO database (CRD42019134230). Seven studies were included, with a total of 321 participants analysed. Compared with no intervention, vestibular rehabilitation was more effective for balance development (SMD = 2.12; 95% CI = 0.49, 3.75; p = 0.01; I2 = 89%) and dizziness symptoms improvement (SMD = −17.43; 95% CI = −29.99, −4.87; p= 0.007; I2= 66%). Compared with other exercise interventions, improvements in favour of the experimental group were observed, but statistical significance for the differences between groups was not reached.
Sleep Apnea, Hypertension and the Sympathetic Nervous System in the Adult Population
Authors: Venkataraman Shreyas , Vungarala Soumya , Covassin Naima , Somers Virend K.
Published: February 2020

Sleep apnea is very common in patients with cardiovascular disease, especially in patients with hypertension. Over the last few decades a number of discoveries have helped support a causal relationship between the two and even resistant hypertension. The role neurogenic mechanisms play has gathered more attention in the recent past due to their immediate bedside utility. Several innovative discoveries in pathogenesis including those exploring the role of baroreflex gain, cardiovascular variability, chemoreceptor reflex activation and the sympathetic nervous system have emerged. In this review, we discuss the epidemiology of sleep apnea and hypertension and the pathogenic mechanisms contributing to neurogenic hypertension. Furthermore, recent management strategies in addition to continuous positive airway pressure (CPAP), such as upper airway stimulation and renal denervation that target these pathogenic mechanisms, are also discussed.
Collaborating with Complementary and Alternative Medicine (CAM) Providers When Writing HPV Vaccine Review Articles
Authors: Deml Michael J. , Dietrich Léna G. , Wingeier Bernhard , Etter Gisela , Gallmann Caesar , Berger Christoph , Suggs L. Suzanne , Huber Benedikt M. , Tarr Philip E.
Published: February 2020

Novel strategies are needed to address vaccine hesitancy (VH), which correlates with complementary and alternative medicine (CAM). In Switzerland, CAM providers play important roles in vaccine counseling of vaccine hesitant (VH) parents, and traditional vaccination messaging tends to overlook CAM provider perspectives. In the setting of a Swiss national research program on VH, our key strategy has been to work together closely with CAM providers. To assess the feasibility of generating educational human papillomavirus (HPV) vaccine materials that would interest VH healthcare providers (HCPs), we invited four CAM providers to co-author two HPV vaccine review articles for general practitioners. We conducted thematic analysis of CAM provider comments to identify patterns that could complement and improve vaccination messaging from CAM perspectives. We identified several themes and generated an inventory of CAM provider messaging recommendations related to language use, presentation of background information, nuanced statements regarding HPV vaccine efficacy and safety, and communication tools that would be important to VH HCPs. Contrary to our initial expectations, and in an inclusive, respectful atmosphere of open dialogue, we were able to productively finalize our manuscripts. In the opinion of the CAM co-authors, the manuscripts effectively considered the communication needs and perspectives of VH HCPs. Engaging with CAM providers appears to be a feasible and innovative avenue for providing vaccine information and designing communication tools aimed at VH healthcare providers.
Choroidal Vascularity Index: An In-Depth Analysis of This Novel Optical Coherence Tomography Parameter
Authors: Iovino Claudio , Pellegrini Marco , Bernabei Federico , Borrelli Enrico , Sacconi Riccardo , Govetto Andrea , Vagge Aldo , Di Zazzo Antonio , Forlini Matteo , Finocchio Lucia , Carnevali Adriano , Triolo Giacinto , Giannaccare Giuseppe
Published: February 2020

Remarkable improvements in optical coherence tomography (OCT) technology have resulted in highly sophisticated, noninvasive machines allowing detailed and advanced morphological evaluation of all retinal and choroidal layers. Postproduction semiautomated imaging analysis with dedicated public-domain software allows precise quantitative analysis of binarized OCT images. In this regard, the choroidal vascularity index (CVI) is emerging as a new imaging tool for the measurement and analysis of the choroidal vascular system by quantifying both luminal and stromal choroidal components. Numerous reports have been published so far regarding CVI and its potential applications in healthy eyes as well as in the evaluation and management of several chorioretinal diseases. Current literature suggests that CVI has a lesser variability and is influenced by fewer physiologic factors as compared to choroidal thickness. It can be considered a relatively stable parameter for evaluating the changes in the choroidal vasculature. In this review, the principles and the applications of this advanced imaging modality for studying and understanding the contributing role of choroid in retinal and optic nerve diseases are discussed. Potential advances that may allow the widespread adoption of this tool in the routine clinical practice are also presented.
Radiosynoviorthesis after Surgery in the Treatment of Patients with Ankle Pigmented Villonodular Synovitis: A Case Series
Authors: Iakovou Ioannis , Symeonidis Panagiotis , Kotrotsios Dimitrios , Giannoula Evanthia , Sachpekidis Christos
Published: February 2020

Pigmented villonodular synovitis (PVNS) of the ankle is a very rare, locally aggressive, proliferative disorder. Although surgical excision represents the standard curative treatment, the PVNS relapse rate is high. We present our study of five young athletes (range 20–36 years) with a histopathological diagnosis of PVNS of the ankle, who were treated by surgery and adjuvant radiosynoviorthesis (RSO). The operation involved either arthroscopic (four patients) or open (one patient) debridement, followed by intraarticular RSO with the radiopharmaceutical erbium-169 (169Er). They were evaluated with the Foot Function Index (FFI) and a visual analog scale (VAS) for pain. At a median follow up period of 47 months (range 36–54 months), all five patients reported marked pain relief with improvements in their daily activities. In particular, the median FFI decreased from 77% (range 71.0%–84.5%) pre-treatment, to 0.5% (range 0%–6%) after treatment. The median VAS score decreased from 4 (range 3–7) to 0 (range 0–1), respectively. Throughout the follow-up period, there were no major complications regarding either therapeutic intervention (arthroscopic or open debridement, RSO). Based on these results, it can be concluded that adjuvant RSO with 169Er following surgical excision is effective and safe in the treatment of PVNS of the ankle.
p53 CRISPR Deletion Affects DNA Structure and Nuclear Architecture
Authors: Rangel-Pozzo Aline , Booth Samuel , Yu Pak Lok Ivan , Singh Madhurendra , Selivanova Galina , Mai Sabine
Published: February 2020

The TP53 gene is a key tumor suppressor. Although the tumor suppressor p53 was one of the first to be characterized as a transcription factor, with its main function potentiated by its interaction with DNA, there are still many unresolved questions about its mechanism of action. Here, we demonstrate a novel role for p53 in the maintenance of nuclear architecture of cells. Using three-dimensional (3D) imaging and spectral karyotyping, as well as super resolution microscopy of DNA structure, we observe significant differences in 3D telomere signatures, DNA structure and DNA-poor spaces as well gains or losses of chromosomes, between normal and tumor cells with CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-deleted or wild-type TP53. Additionally, treatment with Nutlin-3 results in differences in nuclear architecture of telomeres in wild-type but not in p53 knockout MCF-7 (Michigan Cancer Foundation-7) cells. Nutlin-3 binds to the p53-binding pocket of mouse double minute 2 (MDM2) and blocks the p53-MDM2 interaction. Moreover, we demonstrate that another p53 stabilizing small molecule, RITA (reactivation of p53 and induction of tumor cell apoptosis), also induces changes in 3D DNA structure, apparently in a p53 independent manner. These results implicate p53 activity in regulating nuclear organization and, additionally, highlight the divergent effects of the p53 targeting compounds Nutlin-3 and RITA.
Gestational Diabetes Mellitus and the Long-Term Risk for Glucose Intolerance and Overweight in the Offspring: A Narrative Review
Authors: Nijs Hannah , Benhalima Katrien
Published: February 2020

Gestational diabetes mellitus (GDM) is a common condition with increasing prevalence worldwide. GDM is associated with an increased risk for maternal and neonatal complications. In this review we provide an overview of the most recent evidence on the long-term metabolic risk associated with GDM in the offspring. We conducted an extensive literature search on PubMed and Embase between February 2019 and December 2019. We performed a narrative review including 20 cohort studies, one cross-sectional study, and two randomized controlled trials. Our review shows that the prevalence of overweight/obesity and glucose intolerance is higher in children exposed to GDM compared to unexposed children. Maternal overweight is an important confounding factor, but recent studies show that in general the association remains significant after correction for maternal overweight. There is limited evidence suggesting that the association between GDM and adverse metabolic profile in the offspring becomes more significant with increasing offspring age and is also more pronounced in female offspring than in male offspring. More research is needed to evaluate whether treatment of GDM can prevent the long-term metabolic complications in the offspring.
Instruments of Choice for Assessment and Monitoring Diabetic Foot: A Systematic Review
Authors: Fernández-Torres Raúl , Ruiz-Muñoz María , Pérez-Panero Alberto J. , García-Romero Jerónimo , Gónzalez-Sánchez Manuel
Published: February 2020

Diabetic foot is the most frequent disorder among the chronic complications of diabetes, happening in 25% of patients. Objective clinical outcome measures are tests or clinical instruments that provide objective values for result measurement. The aim of this study was to carry out a systematic review of specific objective clinical outcome measures focused on the assessment and monitoring of diabetic foot disorders. The databases used were PubMed, CINAHL, Scopus, PEDro, Cochrane, SciELO and EMBASE. Search terms used were foot, ankle, diabet*, diabetic foot, assessment, tools, instruments, objective outcome measures, valid*, reliab*. Because of the current published evidence, diabetic neuropathy assessment via sudomotor analysis, cardiovascular autonomic neuropathy and peripheral vascular disease detection by non-invasive electronic devices, wound 3D dimensional measurement, hyperspectral imaging for ulcer prediction and the probe-to-bone test for osteomyelitis diagnosis were highlighted in this study.
First Multi-Center All-Comers Study for the Aquablation Procedure
Authors: Bach Thorsten , Gilling Peter , El Hajj Albert , Anderson Paul , Barber Neil
Published: February 2020

Waterjet-based prostate resection (Aquablation procedure) is an increasingly recognized treatment for symptomatic benign prostatic hyperplasia (BPH). We confirmed the safety and effectiveness of the Aquablation procedure in the commercial setting in 178 men at five sites. The mean prostate volume was 59 cc. The procedure time averaged 24 min and total anesthesia duration was 50 min. The International Prostate Symptom Score (IPSS) decreased from 21.6 at the baseline to 6.5 at the 12-month follow-up, a 15.3-point improvement (p < 0.0001). The maximum urinary flow rate increased from 10 cc/s at the baseline to 20.8 cc/s at month 12 (increase of 11.8 cc, p < 0.0001). Ejaculatory function was relatively preserved. Prostate volume assessed with transrectal ultrasound decreased 36% by month three. Five patients (2.7%) underwent a transfusion in the first week after the procedure. Real-world evidence shows that Aquablation is safe and effective for the treatment of BPH.
Characterization of Burn Eschar Pericytes
Authors: Evdokiou Alexander , Kanisicak Onur , Gierek Stephanie , Barry Amanda , Ivey Malina , Zhang Xiang , Bodnar Richard , Satish Latha
Published: February 2020

Pericytes are cells that reside adjacent to microvasculature and regulate vascular function. Pericytes gained great interest in the field of wound healing and regenerative medicine due to their multipotential fate and ability to enhance angiogenesis. In burn wounds, scarring and scar contractures are the major pathologic feature and cause loss of mobility. The present study investigated the influence of burn wound environment on pericytes during wound healing. Pericytes isolated from normal skin and tangentially excised burn eschar tissues were analyzed for differences in gene and protein expression using RNA-seq., immunocytochemistry, and ELISA analyses. RNA-seq identified 443 differentially expressed genes between normal- and burn eschar-derived pericytes. Whereas, comparing normal skin pericytes to normal skin fibroblasts identified 1021 distinct genes and comparing burn eschar pericytes to normal skin fibroblasts identified 2449 differential genes. Altogether, forkhead box E1 (FOXE1), a transcription factor, was identified as a unique marker for skin pericytes. Interestingly, FOXE1 levels were significantly elevated in burn eschar pericytes compared to normal. Additionally, burn wound pericytes showed increased expression of profibrotic genes periostin, fibronectin, and endosialin and a gain in contractile function, suggesting a contribution to scarring and fibrosis. Our findings suggest that the burn wound environment promotes pericytes to differentiate into a myofibroblast-like phenotype promoting scar formation and fibrosis.
Impact of Having a Planned Additional Operation at Time of Liver Transplant on Graft and Patient Outcomes
Authors: Salimi Shirin , Pandya Keval , Sastry Vinay , West Claire , Virtue Susan , Wells Mark , Crawford Michael , Pulitano Carlo , McCaughan Geoffrey W. , Majumdar Avik , Strasser Simone I. , Liu Ken
Published: February 2020

Advances in liver transplantation (LT) have allowed for expanded indications and increased surgical complexity. In select cases, additional surgery may be performed at time of LT rather than prior to LT due to the significant risks associated with advanced liver disease. We retrospectively studied the characteristics and outcomes of patients who underwent an additional planned abdominal or cardiac operation at time of LT between 2011–2019. An additional operation (LT+) was defined as a planned operation performed under the same anesthetic as the LT but not directly related to the LT. In total, 547 patients were included in the study, of which 20 underwent LT+ (4%). Additional operations included 10 gastrointestinal, 5 splenic, 3 cardiac, and 2 other abdominal operations. Baseline characteristics between LT and LT+ groups were similar. The median total operating time was significantly longer in LT+ compared to LT only (451 vs. 355 min, p = 0.002). Graft and patient survival, intraoperative blood loss, transfusion of blood products, length of hospital stay, and post-operative complications were not significantly different between groups. In carefully selected patients undergoing LT, certain additional operations performed at the same time appear to be safe with equivalent short-term outcomes and liver graft survival as those undergoing LT alone
Risk Factors for Postural and Functional Balance Impairment in Patients with Chronic Obstructive Pulmonary Disease
Authors: Park Jaekwan K. , Deutz Nicolaas E. P. , Cruthirds Clayton L. , Kirschner Sarah K. , Park Hangue , Madigan Michael L. , Engelen Mariëlle P. K. J.
Published: February 2020

Reduced balance function has been observed during balance challenging conditions in the chronic obstructive pulmonary disease (COPD) population and is associated with an increased risk of falls. This study aimed to examine postural balance during quiet standing with eyes open and functional balance in a heterogeneous group of COPD and non-COPD (control) subjects, and to identify risk factors underlying balance impairment using a large panel of methods. In COPD and control subjects, who were mostly overweight and sedentary, postural and functional balance were assessed using center-of-pressure displacement in anterior-posterior (AP) and medio-lateral (ML) directions, and the Berg Balance Scale (BBS), respectively. COPD showed 23% greater AP sway velocity (p = 0.049). The presence of oxygen therapy, fat mass, reduced neurocognitive function, and the presence of (pre)diabetes explained 71% of the variation in postural balance in COPD. Transcutaneous oxygen saturation, a history of exacerbation, and gait speed explained 83% of the variation in functional balance in COPD. Neurocognitive dysfunction was the main risk factor for postural balance impairment in the control group. This suggests that specific phenotypes of COPD patients can be identified based on their type of balance impairment.
A Mortality Prediction Rule for Hematology Patients with Invasive Aspergillosis Based on Serum Galactomannan Kinetics
Authors: Mercier Toine , Wera Joachim , Chai Louis Y. A. , Lagrou Katrien , Maertens Johan
Published: February 2020

In invasive aspergillosis (IA), an early and adequate assessment of the response to the initial antifungal therapy remains problematic. We retrospectively analyzed 206 hematology patients with proven or probable IA, and collected serial serum galactomannan (sGM) values and survival status through week 6 and week 12. We created a model for survival at week 6 based on the sGM taken at baseline and on early sGM kinetics. This resulted in a rule predicting that patients with a baseline sGM index >1.4, who failed to lower that index to <0.5 after one week, had a mortality rate of 48.1% at week 6. Conversely, patients presenting with a baseline sGM index ≤1.4 that obtained a negative sGM (<0.5) after one week, had a mortality that was almost five times lower at only 10.1% by week 6. These findings were confirmed in an external cohort from an independent prospective study. In conclusion, sGM kinetics correlate well with treatment outcomes in hematology patients with IA. We present a rule which is easy to use at the bedside and has good accuracy in predicting week 6 survival.
Correlations between Sleep Bruxism and Temporomandibular Disorders
Authors: Ohlmann Brigitte , Waldecker Moritz , Leckel Michael , Bömicke Wolfgang , Behnisch Rouven , Rammelsberg Peter , Schmitter Marc
Published: February 2020

The aim of this study was to identify correlations between sleep bruxism (SB) and temporomandibular disorders (TMD) as diagnosed by means of the research diagnostic criteria for temporomandibular disorders (RDC/TMD). Sleep bruxism was diagnosed on the basis of I) validated questionnaires, II) clinical symptoms, and III) electromyographic/electrocardiographic data. A total of 110 subjects were included in the study. Fifty-eight patients were identified as bruxers and 52 as nonbruxers. A psychosocial assessment was also performed. An RDC/TMD group-I diagnosis (myofascial pain) was made for 10 out of 58 bruxers, whereas none of the nonbruxers received a diagnosis of this type. No significant differences were found between bruxers and nonbruxers with regard to RDC/TMD group-II (disc displacement) and group-III (arthralgia, arthritis, arthrosis) diagnoses. Somatization was significantly more common among bruxers than nonbruxers. Multivariate logistic regression analysis revealed that somatization was the only factor significantly correlated with the diagnosis of myofascial pain. The results of this study indicate a correlation between myofascial pain, as diagnosed using the RDC/TMD, and somatization. It seems that somatization is a stronger predictor of an RDC/TMD diagnosis of myofascial pain than sleep bruxism is.
Chromothripsis and DNA Repair Disorders
Authors: Nazaryan-Petersen Lusine , Bjerregaard Victoria Alexandra , Nielsen Finn Cilius , Tommerup Niels , Tümer Zeynep
Published: February 2020

Chromothripsis is a mutational mechanism leading to complex and relatively clustered chromosomal rearrangements, resulting in diverse phenotypic outcomes depending on the involved genomic landscapes. It may occur both in the germ and the somatic cells, resulting in congenital and developmental disorders and cancer, respectively. Asymptomatic individuals may be carriers of chromotriptic rearrangements and experience recurrent reproductive failures when two or more chromosomes are involved. Several mechanisms are postulated to underlie chromothripsis. The most attractive hypothesis involves chromosome pulverization in micronuclei, followed by the incorrect reassembly of fragments through DNA repair to explain the clustered nature of the observed complex rearrangements. Moreover, exogenous or endogenous DNA damage induction and dicentric bridge formation may be involved. Chromosome instability is commonly observed in the cells of patients with DNA repair disorders, such as ataxia telangiectasia, Nijmegen breakage syndrome, and Bloom syndrome. In addition, germline variations of TP53 have been associated with chromothripsis in sonic hedgehog medulloblastoma and acute myeloid leukemia. In the present review, we focus on the underlying mechanisms of chromothripsis and the involvement of defective DNA repair genes, resulting in chromosome instability and chromothripsis-like rearrangements.
Heart Failure Is a Risk Factor for Suffering and Dying of Clostridium difficile Infection. Results of a 15-Year Nationwide Study in Spain
Authors: Méndez-Bailón Manuel , Jiménez-García Rodrigo , Hernández-Barrera Valentín , de Miguel-Díez Javier , de Miguel-Yanes José M. , Muñoz-Rivas Nuria , Lorenzo-Villalba Noel , Carabantes-Alarcon David , Zamorano-León José J. , Astasio-Arbiza Paloma , Ortega-Molina Paloma , López-de-Andrés Ana
Published: February 2020

Background: We aimed to (1) analyze time trends in the incidence and in-hospital outcomes of heart failure (HF) patients suffering Clostridioides difficile infection (CDI); (2) compare clinical characteristics of CDI patients between those with HF and matched non-HF patients; and (3) identify predictors of in-hospital mortality (IHM) among HF patients suffering CDI. Methods: Retrospective study using the Spanish National Hospital Discharge Database from 2001 to 2015. Patients of age ≥40 years with CDI were included. For each HF patient, we selected a year, age, sex, and readmission status-matched non-HF patient. Results: We found 44,695 patients hospitalized with CDI (15.46% with HF). HF patients had a higher incidence of CDI (202.05 vs. 145.09 per 100,000 hospitalizations) than patients without HF (adjusted IRR 1.35; 95% CI 1.31–1.40). IHM was significantly higher in patients with HF when CDI was coded as primary (18.39% vs. 7.63%; p < 0.001) and secondary diagnosis (21.12% vs. 14.76%; p < 0.001). Among HF patient’s predictor of IHM were older age (OR 8.80; 95% CI 2.55–20.33 for ≥85 years old), those with more comorbidities (OR 1.68; 95% CI 1.12–2.53 for those with Charlson Comorbidity index ≥2), and in those with severe CDI (OR 6.19; 95% CI 3.80–10.02). Conclusions: This research showed that incidence of CDI was higher in HF than non-HF patients. HF is a risk factor for IHM after suffering CDI.
Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression
Authors: Pará Camila , Bose Poulomee , Pshezhetsky Alexey V.
Published: February 2020

About two thirds of the patients affected with lysosomal storage diseases (LSD) experience neurological manifestations, such as developmental delay, seizures, or psychiatric problems. In order to develop efficient therapies, it is crucial to understand the neuropathophysiology underlying these symptoms. How exactly lysosomal storage affects biogenesis and function of neurons is still under investigation however recent research highlights a substantial role played by synaptic defects, such as alterations in synaptic spines, synaptic proteins, postsynaptic densities, and synaptic vesicles that might lead to functional impairments in synaptic transmission and neurodegeneration, finally culminating in massive neuronal death and manifestation of cognitive symptoms. Unveiling how the synaptic components are affected in neurological LSD will thus enable a better understanding of the complexity of disease progression as well as identify crucial targets of therapeutic relevance and optimal time windows for targeted intervention.
OVOL2-Mediated ZEB1 Downregulation May Prevent Promotion of Actinic Keratosis to Cutaneous Squamous Cell Carcinoma
Authors: Murata Maho , Ito Takamichi , Tanaka Yuka , Yamamura Kazuhiko , Furue Kazuhisa , Furue Masutaka
Published: February 2020

Progression of actinic keratosis (AK) to cutaneous squamous cell carcinoma (cSCC) is rare. Most cases of AK remain as intraepidermal lesions, owing to the suppression of the epithelial-to-mesenchymal transition (EMT). Ovo-like transcriptional repressor 1 (OVOL1) and ovo-like zinc finger 2 (OVOL2) are important modulators of EMT in some tumors, but their roles in skin tumors remain elusive. This study elucidated the roles of OVOL1/2 in AK and cSCC using 30 AK/30 cSCC clinical samples, and an A431 human SCC cell line using immunohistochemistry and molecular biological approaches. Immunohistochemically, OVOL1/2 were upregulated in AK and downregulated in cSCC. Meanwhile, EMT-related factors, vimentin and zinc finger E-box binding homeobox 1 (ZEB1) were downregulated in AK and upregulated in cSCC. Moreover, ZEB1 expression was higher in tumors in which OVOL2 expression was low. Thus, we observed an inverse association between OVOL2 and ZEB1 expression in AK and cSCC. Although knockdown of OVOL1 or OVOL2 increased the mRNA and protein levels of ZEB1, only OVOL2 knockdown increased the invasive ability of A431. In conclusion, OVOL2 inhibits ZEB1 expression and may inhibit the promotion of AK into cSCC. OVOL2/ZEB1 axis may be a potential target for preventing the development of cSCC.