bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimated Population Prevalence of Heart Failure with Reduced Ejection Fraction in Spain, According to DAPA-HF Study Criteria
Authors: Camps-Vilaró Anna , Delgado-Jiménez Juan F. , Farré Núria , Tizón-Marcos Helena , Álvarez-García Jesús , Cinca Juan , Dégano Irene R. , Marrugat Jaume
Published: July 2020

Heart failure (HF) is one of the main causes of morbidity, mortality, and high healthcare costs. Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reduced cardiovascular mortality and hospitalization for HF compared to placebo in patients with chronic HF, and reduced ejection fraction (EF) in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study. Our aim was to estimate the number of patients with DAPA-HF characteristics in Spain. Our literature review identified epidemiological studies whose objective was to quantify the prevalence of HF and its comorbidities in Spain. We estimated the prevalence of HF with reduced EF, of New York Heart Association (NYHA) functional class II–IV, and with a glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m². In this population, we analysed the prevalence of diabetes using data from the REDINSCOR (Spanish Network for Heart Failure) registry. Our estimations indicate there are 594,684 patients ≥45 years old with HF in Spain (2.6% of this population age group), of which 52.4%, 84.0%, and 93.9% have reduced EF, are NYHA II–IV, and have a GFR ≥ 30 mL/min/1.73 m², respectively. By our calculations, approximately 245,789 Spanish patients would meet the DAPA-HF patient profile, and therefore could benefit from the protective cardiovascular effects of dapagliflozin.
PD-(L)1 Inhibitors in Combination with Chemotherapy as First-Line Treatment for Non-Small-Cell Lung Cancer: A Pairwise Meta-Analysis
Authors: García-González Jorge , Ruiz-Bañobre Juan , Afonso-Afonso Francisco J. , Amenedo-Gancedo Margarita , Areses-Manrique María del Carmen , Campos-Balea Begoña , Casal-Rubio Joaquín , Fernández-Núñez Natalia , Fírvida Pérez José Luis , Lázaro-Quintela Martín , Pérez Parente Diego , Crama Leonardo , Ruiz-Gracia Pedro , Santomé-Couto Lucía , León-Mateos Luis
Published: July 2020

The combination of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors with chemotherapy has emerged as a promising therapeutic option for advanced non-small-cell lung cancer (NSCLC). The aim of this meta-analysis was to evaluate the efficacy of the combined strategy in this setting. For this purpose, we performed a literature search of randomized controlled trials comparing PD-(L)1 inhibitors plus platinum-based chemotherapy versus chemotherapy alone in stage IV NSCLC patients. Seven clinical trials with 4562 patients were included. In the intention-to-treat wildtype population, PD-(L)1 inhibitor plus chemotherapy was significantly associated with improved progression-free survival (PFS) (Hazard ratio (HR) = 0.61, 95% confidence interval (CI): 0.57–0.65, p < 0.001) and overall survival (OS) (HR = 0.76, 95% CI: 0.67–0.86; p < 0.001) compared to chemotherapy. A significantly higher overall response rate (ORR) was also observed with the combined strategy (Odds ratio (OR) = 2.12, 95% CI: 1.70–2.63, p < 0.001). Furthermore, in all the analyzed subgroups, addition of PD-(L)1 inhibitors to chemotherapy significantly improved efficacy endpoints. Specifically, stratification according to PD-L1 expression revealed a benefit across all patients, regardless of their PFS status. In conclusion, PD-(L)1 blockade added to standard platinum-based chemotherapy significantly improved PFS, OS, and ORR in the up-front treatment of advanced NSCLC.
Atherosclerosis as Pathogenetic Substrate for Sars-Cov2 Cytokine Storm
Authors: Vinciguerra Mattia , Romiti Silvia , Fattouch Khalil , De Bellis Antonio , Greco Ernesto
Published: July 2020

The severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) outbreak is a public health emergency affecting different regions around the world. The lungs are often damaged due to the presence of Sars-CoV-2 binding receptor ACE2 on epithelial alveolar cells. Severity of infection varies from complete absence of symptomatology to more aggressive symptoms, characterized by sudden acute respiratory distress syndrome (ARDS), multiorgan failure, and sepsis, requiring treatment in intensive care unit (ICU). It is not still clear why the immune system is not able to efficiently suppress viral replication in a small percentage of patients. It has been documented as pathological conditions affecting the cardiovascular system, strongly associated to atherosclerotic progression, such as heart failure (HF), coronary heart disease (CHD), hypertension (HTN) and diabetes mellitus (DM), could serve as predictive factors for severity and susceptibility during Sars-CoV-2 infection. Atherosclerotic progression, as a chronic inflammation process, is characterized by immune system dysregulation leading to pro-inflammatory patterns, including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and IL-1β. Reviewing immune system and inflammation profiles in atherosclerosis and laboratory results reported in severe COVID-19 infections, we hypothesized a pathogenetic correlation. Atherosclerosis may be an ideal pathogenetic substrate for high viral replication ability, leading to adverse outcomes, as reported in patients with cardiovascular factors. The level of atherosclerotic progression may affect a different degree of severe infection; in a vicious circle, feeding itself, Sars-CoV-2 may exacerbate atherosclerotic evolution due to excessive and aberrant plasmatic concentration of cytokines.
ACE2 as a Therapeutic Target for COVID-19; Its Role in Infectious Processes and Regulation by Modulators of the RAAS System
Authors: Michaud Veronique , Deodhar Malavika , Arwood Meghan , Al Rihani Sweilem B , Dow Pamela , Turgeon Jacques
Published: July 2020

Angiotensin converting enzyme 2 (ACE2) is the recognized host cell receptor responsible for mediating infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 bound to tissue facilitates infectivity of SARS-CoV-2; thus, one could argue that decreasing ACE2 tissue expression would be beneficial. However, ACE2 catalytic activity towards angiotensin I (Ang I) and II (Ang II) mitigates deleterious effects associated with activation of the renin-angiotensin-aldosterone system (RAAS) on several organs, including a pro-inflammatory status. At the tissue level, SARS-CoV-2 (a) binds to ACE2, leading to its internalization, and (b) favors ACE2 cleavage to form soluble ACE2: these actions result in decreased ACE2 tissue levels. Preserving tissue ACE2 activity while preventing ACE2 shredding is expected to circumvent unrestrained inflammatory response. Concerns have been raised around RAAS modulators and their effects on ACE2 expression or catalytic activity. Various cellular and animal models report conflicting results in various tissues. However, recent data from observational and meta-analysis studies in SARS-CoV-2-infected patients have concluded that RAAS modulators do not increase plasma ACE2 levels or susceptibility to infection and are not associated with more severe diseases. This review presents our current but evolving knowledge of the complex interplay between SARS-CoV-2 infection, ACE2 levels, modulators of RAAS activity and the effects of RAAS modulators on ACE2 expression.
Child–Adult Transition in Sarcoidosis: A Series of 52 Patients
Authors: Chauveau Simon , Jeny Florence , Montagne Marie-Emeline , Abou Taam Rola , Houdouin Véronique , Meinzer Ulrich , Delacourt Christophe , Epaud Ralph , Cohen Aubart Fleur , Chapelon-Abric Catherine , Israël-Biet Dominique , Juvin Karine , Dossier Antoine , Bodaghi Bahram , Prévot Grégoire , Naccache Jean-Marc , Mattioni Sarah , Deschildre Antoine , Brouard Jacques , Tazi Abdellatif , Meckenstock Roderich , Didier Morgane , Haroche Julien , Clement Annick , Bernaudin Jean-François , Nunes Hilario , Valeyre Dominique , Nathan Nadia ,   for the French Sarcoidosis Group (GSF)
Published: July 2020

(1) Background: Pediatric sarcoidosis is a rare and mostly severe disease. Very few pediatric series with a prolonged follow-up are reported. We aimed to evaluate the evolution of pediatric sarcoidosis in adulthood. (2) Material and methods: Patients over 18-years-old with a pediatric-onset sarcoidosis (≤15-year-old) who completed at least a three-year follow-up in French expert centers were included. Clinical information at presentation and outcome in adulthood were studied. (3) Results: A total of 52 patients were included (34 prospectively in childhood and 18 retrospectively in adulthood), with a mean age of 12 (±2.7) at diagnosis. The median duration time of follow-up was 11.5 years (range 3–44.5). Relapses mostly occurred during treatment decrease (84.5%), others within the three years after treatment interruption (9.1%), and rarely when the disease was stable for more than three years (6.4%). Sarcoidosis was severe in 11 (21.2%) in adulthood. Patients received a high corticosteroid cumulative dose (median 17,900 mg) for a median duration of five years (range 0–32), resulting in mostly mild (18; 35.3%) and rarely severe (2; 3.8%) adverse events. (4) Conclusions: Pediatric-onset sarcoidosis needed a long-term treatment in almost half of the patients. Around one fifth of pediatric-onset sarcoidosis patients had severe sarcoidosis consequences in adulthood.
Both Low and High PAPP-A Concentrations in the First Trimester of Pregnancy Are Associated with Increased Risk of Delivery before 32 Weeks in Twin Gestation
Authors: Saletra-Bielińska Aleksandra , Kosińska-Kaczyńska Katarzyna , Szymusik Iwona , Kaczyński Bartosz , Brawura-Biskupski-Samaha Robert , Kozłowski Szymon , Jarmużek Patrycja , Walasik Izabela , Wielgoś Mirosław
Published: July 2020

In twin gestation, the relationship between pregnancy associated plasma protein (PAPP-A) and perinatal outcome is unclear. The aim of the study was to determine if low and high concentrations of PAPP-A in the first trimester are related to perinatal outcome in twins. A retrospective study was conducted. Medical data of women in twin pregnancies who delivered between 2013 and 2018 were analyzed. PAPP-A concentrations were measured between 10 + 0 and 13 + 6 weeks. The associations between low (<10th percentile) and high (>90th percentile) values of PAPP-A and pregnancy complications were analyzed. A total of 304 patients were included. PAPP-A <10th percentile was associated with a high risk of preterm delivery (OR 6.14; 95% CI 2.1–18), delivery <34 weeks (OR 2.39; 95% CI 1.1–5.1) or <32 weeks (OR3.06; 95% CI 1.4–6.8). Significant relations between PAPP-A >90th percentile and delivery <34 weeks (OR4.09; 95% CI 1.8–9.1) or <32 weeks (OR 2.83; 95% CI 1.2–6.6) were found. PAPP-A >90th percentile was related to high risk of intrauterine fetal demise (OR 10; 95% CI 2.4–42.5). Both low and high PAPP-A concentrations seem to be related to pregnancy outcome. Further research is needed to investigate evaluation of risk of pregnancy complications according to PAPP-A concentrations as a continuous variable.
Levonorgestrel-Releasing Intrauterine System as a Contraceptive Method in Nulliparous Women: A Systematic Review
Authors: Zgliczynska Magdalena , Kocaj Karol , Szymusik Iwona , Dutsch-Wicherek Magdalena Maria , Ciebiera Michal , Kosinska-Kaczynska Katarzyna
Published: July 2020

The aim of this review was to summarize the available evidence about the use of levonorgestrel-releasing intrauterine system (LNG-IUS) as a contraceptive method in nulliparous women. For this purpose, studies evaluating the efficacy, safety, bleeding pattern, satisfaction and discontinuation of the levonorgestrel-releasing intrauterine system in nulliparous women were analyzed. Only original research articles published in English between 1990–27th March 2020 were considered eligible. Reviews, book chapters, case studies, conference papers, opinions, editorials and letters were excluded. The systematic literature search of PubMed/MEDLINE, Scopus, Embase and Cochrane Library databases identified 816 articles, 23 of which were analyzed. The available evidence indicates that LNG-IUS is an effective and safe contraceptive method for nulliparous women that achieves high levels of satisfaction among patients. Moreover, nulliparous women seem to experience fewer expulsions than parous ones. Bleeding pattern is acceptable for the majority of patients, and bleeding disorders mainly occur in the first months after the insertion. More in-depth, long-term prospective studies are needed in this patient group to determine risk factors for the occurrence of side effects and associated discontinuations, which should not, however, delay the wider use of the method in this group, given the number of advantages.
Familial Dysalbuminemic Hyperthyroxinemia: An Underdiagnosed Entity
Authors: Dieu Xavier , Bouzamondo Nathalie , Briet Claire , Illouz Frédéric , Moal Valérie , Boux de Casson Florence , Bouhours-Nouet Natacha , Reynier Pascal , Coutant Régis , Rodien Patrice , Mirebeau-Prunier Delphine
Published: July 2020

Resistance to thyroid hormone (RTH) is a syndrome characterized by impaired sensitivity of tissues to thyroid hormone (TH). The alteration of TH-binding proteins, such as in Familial Dysalbuminemic Hyperthyroxinemia (FDH), can mimic the abnormal serum thyroid tests typical of RTH. We aimed to characterize a population referred to our center with suspected RTH and estimate the proportion of patients with FDH. For 303 different families, we collected clinical and hormonal data and sequenced the thyroid hormone receptor β gene (THRB) and exon 7 of the albumin gene (ALB). We found 56 THRB variants (i.e., 38% of the 303 index cases, called RTHβ group). Among the samples screened for FDH variants, 18% had the variant R218H in ALB (FDH group); in addition, 71% of the cases had neither variant (non-FDH/RTHβ group). Patients with FDH had significantly lower free T3 (fT3) and free T4 (fT4) levels and more often an isolated elevation of fT4 than RTHβ patients. Clinically, patients with FDH had fewer symptoms than patients with RTHβ. Our study suggests that FDH should be systematically considered when examining patients suspected of having RTH. In most cases, they present no clinical symptoms, and their biochemical alterations show an elevation of fT4 levels, while fT3 levels are 1.11 times below the upper limit of the assay.
Frailty and COVID-19: A Systematic Scoping Review
Authors: Maltese Giuseppe , Corsonello Andrea , Di Rosa Mirko , Soraci Luca , Vitale Cristiana , Corica Francesco , Lattanzio Fabrizia
Published: July 2020

Older people have paid a huge toll in terms of mortality during the coronavirus disease-19 (COVID-19) pandemic. Frailty may have contributed to the vulnerability of older people to more severe clinical presentation. We aimed at reviewing available evidence about frailty and COVID-19. We searched PUBMED, Web of Science, and EMBASE from 1 December 2019 to 29 May 2020. Study selection and data extraction were performed by three independent reviewers. Qualitative synthesis was conducted and quantitative data extracted when available. Forty papers were included: 13 editorials, 15 recommendations/guidelines, 3 reviews, 1 clinical trial, 6 observational studies, 2 case reports. Editorials and reviews underlined the potential clinical relevance of assessing frailty among older patients with COVID-19. However, frailty was only investigated in regards to its association with overall mortality, hospital contagion, intensive care unit admission rates, and disease phenotypes in the few observational studies retrieved. Specific interventions in relation to frailty or its impact on COVID-19 treatments have not been evaluated yet. Even with such limited evidence, clinical recommendations on the use of frailty tools have been proposed to support decision making about escalation plan. Ongoing initiatives are expected to improve knowledge of COVID-19 interaction with frailty and to promote patient-centered approaches.
Clinical Performance of Partial and Full-Coverage Fixed Dental Restorations Fabricated from Hybrid Polymer and Ceramic CAD/CAM Materials: A Systematic Review and Meta-Analysis
Authors: Al-Haj Husain Nadin , Özcan Mutlu , Molinero-Mourelle Pedro , Joda Tim
Published: July 2020

The aim of this systematic review and meta-analysis was to evaluate the clinical performance of tooth-borne partial and full-coverage fixed dental prosthesis fabricated using hybrid polymer and ceramic CAD/CAM materials regarding their biologic, technical and esthetical outcomes. PICOS search strategy was applied using MEDLINE and were searched for RCTs and case control studies by two reviewers using MeSH Terms. Bias risk was evaluated using the Cochrane collaboration tool and Newcastle–Ottawa assessment scale. A meta-analysis was conducted to calculate the mean long-term survival difference of both materials at two different periods (≤24, ≥36 months(m)). Mean differences in biologic, technical and esthetical complications of partial vs. full crown reconstructions were analyzed using software package R (p < 0.05). 28 studies included in the systematic review and 25 studies in the meta-analysis. The overall survival rate was 99% (0.95–1.00, ≤24 m) and dropped to 95% (0.87–0.98, ≥36 m), while the overall success ratio was 88% (0.54–0.98; ≤24 m) vs. 77% (0.62–0.88; ≥36 m). No significance, neither for the follow-up time points, nor for biologic, technical and esthetical (88% vs. 77%; 90% vs. 74%; 96% vs. 95%) outcomes was overserved. A significance was found for the technical/clinical performance between full 93% (0.88–0.96) and partial 64% (0.34–0.86) crowns. The biologic success rate of partial crowns with 69% (0.42–0.87) was lower, but not significant compared to 91% (0.79–0.97) of full crowns. The esthetical success rate of partial crowns with 90% (0.65–0.98) was lower, but not significant compared to 99% (0.92–1.00) of full crowns.
The Association between Neighborhood Amenities and Cognitive Function: Role of Lifestyle Activities
Authors: Katayama Osamu , Lee Sangyoon , Makino Keitaro , Chiba Ippei , Bae Seongryu , Shinkai Yohei , Harada Kenji , Shimada Hiroyuki
Published: July 2020

Many of the modifiable risk factors for dementia are lifestyle-related, and multidomain interventions tailored to individual lifestyles are recommended to prevent cognitive decline and dementia. However, studies of the relationship between the environment and cognitive function have shown that cognitive disorders and dementia are more prevalent in rural areas than in urban areas. The purpose of this study was to clarify the role of lifestyle activities on the association between neighborhood amenities and cognitive function. Our data were measured between August 2011 and February 2012. Participants comprised 3786 older adults (mean age: 71.5 years, standard deviation (SD) = ±5.2). We categorized neighborhood amenities as institutional resources that promote cognitively beneficial activities such as physical activity. We calculated the Walk Score® for all participants using their home address and divided them into three groups. We assessed their 12 lifestyle activities performed outdoors. Cognitive function was measured via Mini-Mental Status Exam, word list memory, attention, executive function, and processing speed. We found that participants who were more likely to report many lifestyle activities were more likely to have normal cognition, even in areas where neighborhood amenities were scarce. The clinical significance of this study is that increased lifestyle activity contributes to the prevention of cognitive decline.
Diagnostic Value of 18F-FDG-PET/CT in Patients with FUO
Authors: Georga Stamata , Exadaktylou Paraskevi , Petrou Ioannis , Katsampoukas Dimitrios , Mpalaris Vasilios , Moralidis Efstratios-Iordanis , Arvaniti Kostoula , Papastergiou Christos , Arsos Georgios
Published: July 2020

Conventional diagnostic imaging is often ineffective in revealing the underlying cause in a considerable proportion of patients with fever of unknown origin (FUO). The aim of this study was to assess the diagnostic value of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in patients with FUO. We retrospectively reviewed 18F-FDG-PET/CT scans performed on 50 consecutive adult patients referred to our department for further investigation of classic FUO. Final diagnosis was based on histopathological and microbiological findings, clinical criteria, or clinical follow-up. Final diagnosis was established in 39/50 (78%) of the patients. The cause of FUO was infection in 20/50 (40%), noninfectious inflammatory diseases in 11/50 (22%), and malignancy in 8/50 (16%) patients. Fever remained unexplained in 11/50 (22%) patients. 18F-FDG-PET/CT scan substantially contributed to the diagnosis in 70% of the patients, either by identifying the underlying cause of FUO or by directing to the most appropriate site for biopsy. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of 18F-FDG-PET/CT for active disease detection in patients with FUO were 94.7%, 50.0%, 84.0%, 85.7%, and 75.0%, respectively. In conclusion, whole-body 18F-FDG-PET/CT is a highly sensitive method for detection of the underlining cause of FUO or for correctly targeting suspicious lesions for further evaluation.
Venous Thromboembolism in Patients with Inflammatory Bowel Disease: The Role of Pharmacological Therapy and Surgery
Authors: Papa Alfredo , Tursi Antonio , Danese Silvio , Rapaccini Gianludovico , Gasbarrini Antonio , Papa Valerio
Published: July 2020

Patients with inflammatory bowel disease (IBD) have an increased risk of venous thromboembolism (VTE). Alongside the traditional acquired and genetic risk factors for VTE, patients with IBD have pathogenic and clinical peculiarities that are responsible for the increased number of thromboembolic events occurring during their life. A relevant role in modifying this risk in a pro or antithrombotic manner is played by pharmacological therapies and surgery. The availability of several biological agents and small-molecule drugs with different mechanisms of action allows us to also tailor the treatment based on the individual prothrombotic risk to reduce the occurrence of VTE. Available review articles did not provide sufficient and updated knowledge on this topic. Therefore, we assessed the role of each single treatment, including surgery, in modifying the risk of VTE in patients with IBD to provide physicians with recommendations to minimize VTE occurrence. We found that the use of steroids, particularly if prolonged, increased VTE risk, whereas the use of infliximab seemed to reduce such risk. The data relating to the hypothesized prothrombotic risk of tofacitinib were insufficient to draw definitive conclusions. Moreover, surgery has an increased prothrombotic risk. Therefore, implementing measures to prevent VTE, not only with pharmacological prophylaxis but also by reducing patient- and surgery-specific risk factors, is necessary. Our findings confirm the importance of the knowledge of the effect of each single drug or surgery on the overall VTE risk in patients with IBD, even if further data, particularly regarding newer drugs, are needed.
Factors for Predicting Noninvasive Ventilation Failure in Elderly Patients with Respiratory Failure
Authors: Park Min Jeong , Cho Jae Hwa , Chang Youjin , Moon Jae Young , Park Sunghoon , Park Tai Sun , Lee Young Seok
Published: July 2020

Noninvasive ventilation (NIV) is useful when managing critically ill patients. However, it is not easy to apply to elderly patients, particularly those with pneumonia, due to the possibility of NIV failure and the increased mortality caused by delayed intubation. In this prospective observational study, we explored whether NIV was appropriate for elderly patients with pneumonia, defined factors that independently predicted NIV failure, and built an optimal model for prediction of such failure. We evaluated 78 patients with a median age of 77 years. A low PaCO2 level, a high heart rate, and the presence of pneumonia were statistically significant independent predictors of NIV failure. The predictive power for NIV failure of Model III (pneumonia, PaCO2 level, and heart rate) was better than that of Model I (pneumonia alone). Considering the improvement in parameters, patients with successful NIV exhibited significantly improved heart rates, arterial pH and PaCO2 levels, and patients with NIV failure exhibited a significantly improved PaCO2 level only. In conclusion, NIV is reasonable to apply to elderly patients with pneumonia, but should be done with caution. For the early identification of NIV failure, the heart rate and arterial blood gas parameters should be monitored within 2 h after NIV commencement.
Effect of Non-Surgical Periodontal Treatment on Oxidative Stress Markers in Leukocytes and Their Interaction with the Endothelium in Obese Subjects with Periodontitis: A Pilot Study
Authors: Martínez-Herrera Mayte , Abad-Jiménez Zaida , Silvestre Francisco Javier , López-Domènech Sandra , Silvestre-Rangil Javier , Márquez-Arrico Cecilia Fabiana , Víctor Víctor M. , Rocha Milagros
Published: July 2020

Aim: The primary objective of this pilot study was to evaluate the effect of non-surgical periodontal treatment. The secondary aim was to evaluate the effect of dietary therapy on both parameters of oxidative stress in leukocytes and leukocyte-endothelial cell interactions in an obese population. Methods: This was a pilot study with a before-and-after design. Forty-nine obese subjects with periodontitis were randomized by means of the minimization method and assigned to one of two groups, one of which underwent dietary therapy while the other did not. All the subjects underwent non-surgical periodontal treatment. We determined periodontal, inflammatory and oxidative stress parameters—total reactive oxygen species (ROS), superoxide production, intracellular Ca2+, mitochondrial membrane potential and superoxide dismutase (SOD) activity. We also evaluated interactions between leukocytes and endothelium cells—velocity, rolling flux and adhesion—at baseline and 12 weeks after intervention. Results: Periodontal treatment improved the periodontal health of all the patients, with a reduction in serum retinol-binding protein 4 (RBP4), total superoxide production and cytosolic Ca2+ in leukocytes. In the patients undergoing dietary therapy, there were less leukocyte adhesion to the endothelium, an effect that was accompanied by a decrease in TNFα, P-selectin and total ROS and an increase in SOD activity. Conclusions: Whereas non-surgical periodontal treatment induces an improvement in leukocyte homeostasis, dietary therapy as an adjuvant reduces systemic inflammation and increases antioxidant status which, in turn, modulates leukocyte-endothelium dynamics.
The Community Oncology and Academic Medical Center Alliance in the Age of Precision Medicine: Cancer Genetics and Genomics Considerations
Authors: Melas Marilena , Subbiah Shanmuga , Saadat Siamak , Rajurkar Swapnil , McDonnell Kevin J.
Published: July 2020

Recent public policy, governmental regulatory and economic trends have motivated the establishment and deepening of community health and academic medical center alliances. Accordingly, community oncology practices now deliver a significant portion of their oncology care in association with academic cancer centers. In the age of precision medicine, this alliance has acquired critical importance; novel advances in nucleic acid sequencing, the generation and analysis of immense data sets, the changing clinical landscape of hereditary cancer predisposition and ongoing discovery of novel, targeted therapies challenge community-based oncologists to deliver molecularly-informed health care. The active engagement of community oncology practices with academic partners helps with meeting these challenges; community/academic alliances result in improved cancer patient care and provider efficacy. Here, we review the community oncology and academic medical center alliance. We examine how practitioners may leverage academic center precision medicine-based cancer genetics and genomics programs to advance their patients’ needs. We highlight a number of project initiatives at the City of Hope Comprehensive Cancer Center that seek to optimize community oncology and academic cancer center precision medicine interactions.
Novel Nasal Epithelial Cell Markers of Parkinson’s Disease Identified Using Cells Treated with α-Synuclein Preformed Fibrils
Authors: Kim Hyojung , Kang Seok-Jae , Jo Young Mi , Park Sanggyu , Yun Seung Pil , Lee Yun-Song , Kim Hee-Tae , Lee Nae-Eung , Kim Yong-Sang , Cho Seok Hyun , Lee Yunjong
Published: July 2020

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by olfactory dysfunction in the early stages. α-Synuclein pathologies in the olfactory organs are shown to spread to the brain through the nose-brain axis. We first developed a nasal epithelial PD cellular model by treating RPMI-2650 cells with α-synuclein preformed fibrils (PFF). Upon uptake of PFF, RPMI-2650 cells showed mitochondrial proteome alteration and downregulation of parkin, which has previously been identified as a nasal biomarker of PD. Functional cluster analysis of differentially expressed genes in RPMI-2650 cells revealed various pathways affected by α-synuclein pathology, including the detection of chemical stimulus involved in sensory perception, olfactory receptor activity, and sensory perception of smell. Among genes that were most affected, we validated, by real-time quantitative PCR, the downregulation of MAP3K8, OR10A4, GRM2, OR51B6, and OR9A2, as well as upregulation of IFIT1B, EPN1, OR1D5, LCN, and OTOL1 in PFF-treated RPMI-2650 cells. Subsequent analyses of clinical samples showed a downregulation of OR10A4 and OR9A2 transcripts and an upregulation of IFIT1B in cells isolated from the nasal fluid of PD patients, as compared to those from the controls (cutoff value = 0.5689 for OR9A2, with 72.4% sensitivity and 75% specificity, and 1.4658 for IFIT1B, with 81.8% sensitivity and 77.8% specificity). Expression levels of these nasal PD markers were not altered in nasal fluid cells from SWEDD (scans without evidence of dopaminergic deficits) patients with PD-like motor symptoms. These nasal markers were significantly altered in patients of PD with hyposmia compared to the control hyposmic subjects. Our results validated the α-synuclein-treated nasal epithelial cell model to identify novel biomarkers for PD and suggest the utility of olfactory transcripts, along with olfactory dysfunction, in the diagnosis of PD.
Hormonal Blood Pressure Regulation during General Anesthesia Using a Standardized Propofol Dosage in Children and Adolescents Seems Not to Be Affected by Body Weight
Authors: Hempel Gunther , Maier Anne-Marie , Piegeler Tobias , Stehr Sebastian N. , Kratzsch Jürgen , Höhne Claudia
Published: July 2020

Obesity in pediatric surgical patients is a challenge for the anesthesiologist. Despite potentially beneficial properties, propofol might also induce hypotension. This study examined whether a dose adjustment in overweight children could avoid hypotension and if there would be differences regarding hormonal regulation in children under anesthesia. Fifty-nine children undergoing surgery under general anesthesia were enrolled in this prospective observational trial. Participants were allocated into two groups according to their BMI. The induction of anesthesia was conducted using propofol (“overweight”: 2 mg/kgBW, “regular”: 3.2 mg/kgBW). The maintenance of anesthesia was conducted as total intravenous anesthesia. Hormone levels of renin, angiotensin II, aldosterone, copeptin, norepinephrine and epinephrine were assessed at different timepoints. Blood pressure dropped after the administration of propofol in both groups, with a nadir 2 min after administration—but without a significant difference in the strength of reduction between the two groups. As a reaction, an increase in the plasma levels of renin, angiotensin and aldosterone was observed, while levels of epinephrine, norepinephrine and copeptin dropped. By adjusting the propofol dosage in overweight children, the rate of preincision hypotension could be reduced to the level of normal-weight patients with a non-modified propofol dose. The hormonal counter regulation was comparable in both groups. The release of catecholamines and copeptin as an indicator of arginine vasopressin seemed to be inhibited by propofol.
Advancements in PARP1 Targeted Nuclear Imaging and Theranostic Probes
Authors: Ambur Sankaranarayanan Ramya , Kossatz Susanne , Weber Wolfgang , Beheshti Mohsen , Morgenroth Agnieszka , Mottaghy Felix M.
Published: July 2020

The central paradigm of novel therapeutic approaches in cancer therapy is identifying and targeting molecular biomarkers. One such target is the nuclear DNA repair enzyme Poly-(ADP ribose) polymerase 1 (PARP1). Sensitivity to PARP inhibition in certain cancers such as gBRCAmut breast and ovarian cancers has led to its exploitation as a target. The overexpression of PARP1 in several types of cancer further evoked interest in its use as an imaging target. While PARP1-targeted inhibitors have fast developed and approved in this past decade, determination of PARP1 expression might help to predict the response to PARP inhibitor treatment. This has the potential of improving prognosis and moving towards tailored therapy options and/or dosages. This review summarizes the recent pre-clinical advancements in imaging and theranostic PARP1 targeted tracers. To assess PARP1 levels, several imaging probes with fluorescent or beta/gamma emitting radionuclides have been proposed and three have advanced to ongoing clinical evaluation. Apart from its diagnostic value in detection of primary tumors as well as metastases, this shall also help in delivering therapeutic radionuclides to PARP1 overexpressing tumors. Henceforth nuclear medicine has now advanced towards conjugating theranostic radionuclides to PARP1 inhibitors. This paves the way for a future of PARP1-targeted theranostics and personalized therapy.
Recurrence Patterns for Pancreatic Ductal Adenocarcinoma after Upfront Resection Versus Resection Following Neoadjuvant Therapy: A Comprehensive Meta-Analysis
Authors: Ratnayake Bathiya , Savastyuk Alina Y. , Nayar Manu , Wilson Colin H. , Windsor John A. , Roberts Keith , French Jeremy J. , Pandanaboyana Sanjay
Published: July 2020

Background: Neoadjuvant therapy (NAT) represents a paradigm shift in the management of patients with pancreatic ductal adenocarcinoma (PDAC) with perceived benefits including a higher R0 rate. However, it is unclear whether NAT affects the sites and patterns of recurrence after surgery. This review seeks to compare sites and patterns of recurrence after resection between patients undergoing upfront surgery (US) or after NAT. Methods: The EMBASE, SCOPUS, PubMed, and Cochrane library databases were systematically searched to identify eligible studies that compare recurrence patterns between patients who had NAT (followed by resection) with those that had US. The primary outcome included site-specific recurrence. Results: 26 articles were identified including 4986 patients who underwent resection. Borderline resectable pancreatic cancer (BRPC, 47% 1074/2264) was the most common, followed by resectable pancreatic cancer (RPC 42%, 949/2264). The weighted overall recurrence rates were lower among the NAT group, 63.4% vs. 74% (US) (OR 0.67 (CI 0.52–0.87), p = 0.006). The overall weighted locoregional recurrence rate was lower amongst patients who received NAT when compared to US (12% vs. 27% OR 0.39 (CI 0.22–0.70), p = 0.004). In BRPC, locoregional recurrence rates improved with NAT (NAT 25.8% US 37.7% OR 0.62 (CI 0.44–0.87), p = 0.007). NAT was associated with a lower weighted liver recurrence rate (NAT 19.4% US 30.1% OR 0.55 (CI 0.34–0.89), p = 0.023). Lung and peritoneal recurrence rates did not differ between NAT and US cohorts (p = 0.705 and p = 0.549 respectively). NAT was associated with a significantly longer weighted mean time to first recurrence 18.8 months compared to US (15.7 months) (OR 0.18 (CI 0.05–0.32), p = 0.015). Conclusion: NAT was associated with lower overall recurrence rate and improved locoregional disease control particularly for those with BRPC. Although the burden of liver metastases was less, there was no overall effect upon distant metastatic disease.
Fully Automated 3D Cardiac MRI Localisation and Segmentation Using Deep Neural Networks
Authors: Vesal Sulaiman , Maier Andreas , Ravikumar Nishant
Published: July 2020

Cardiac magnetic resonance (CMR) imaging is used widely for morphological assessment and diagnosis of various cardiovascular diseases. Deep learning approaches based on 3D fully convolutional networks (FCNs), have improved state-of-the-art segmentation performance in CMR images. However, previous methods have employed several pre-processing steps and have focused primarily on segmenting low-resolutions images. A crucial step in any automatic segmentation approach is to first localize the cardiac structure of interest within the MRI volume, to reduce false positives and computational complexity. In this paper, we propose two strategies for localizing and segmenting the heart ventricles and myocardium, termed multi-stage and end-to-end, using a 3D convolutional neural network. Our method consists of an encoder–decoder network that is first trained to predict a coarse localized density map of the target structure at a low resolution. Subsequently, a second similar network employs this coarse density map to crop the image at a higher resolution, and consequently, segment the target structure. For the latter, the same two-stage architecture is trained end-to-end. The 3D U-Net with some architectural changes (referred to as 3D DR-UNet) was used as the base architecture in this framework for both the multi-stage and end-to-end strategies. Moreover, we investigate whether the incorporation of coarse features improves the segmentation. We evaluate the two proposed segmentation strategies on two cardiac MRI datasets, namely, the Automatic Cardiac Segmentation Challenge (ACDC) STACOM 2017, and Left Atrium Segmentation Challenge (LASC) STACOM 2018. Extensive experiments and comparisons with other state-of-the-art methods indicate that the proposed multi-stage framework consistently outperforms the rest in terms of several segmentation metrics. The experimental results highlight the robustness of the proposed approach, and its ability to generate accurate high-resolution segmentations, despite the presence of varying degrees of pathology-induced changes to cardiac morphology and image appearance, low contrast, and noise in the CMR volumes.
Molecular Methods for the Diagnosis of Invasive Candidiasis
Authors: Camp Iris , Spettel Kathrin , Willinger Birgit
Published: July 2020

Invasive infections caused by members of the genus Candida are on the rise. Especially patients in intensive care units, immunocompromised patients, and those recovering from abdominal surgery are at risk for the development of candidemia or deep-seated candidiasis. Rapid initiation of appropriate antifungal therapy can increase survival rates significantly. In the past, most of these infections were caused by C. albicans, a species that typically is very susceptible to antifungals. However, in recent years a shift towards infections caused by non-albicans species displaying various susceptibly patterns has been observed and the prompt diagnosis of the underlying species has become an essential factor determining the therapeutic outcome. The gold standard for diagnosing invasive candidiasis is blood culture, even though its sensitivity is low and the time required for species identification usually exceeds 48 h. To overcome these issues, blood culture can be combined with other methods, and a large number of tests have been developed for this purpose. The aim of this review was to give an overview on strengths and limitations of currently available molecular methods for the diagnosis of invasive candidiasis.
Enhancing the Territorial Heritage of Declining Rural Areas in Spain: Towards Integrating Top-Down and Bottom-Up Approaches
Authors: Ruiz Pulpón Ángel Raúl , Cañizares Ruiz María del Carmen
Published: July 2020

The population of a considerable number of rural areas in the interior of Spain is in decline. Faced with this problem, various institutions are launching initiatives to enhance the territorial heritage (natural and cultural) of these areas and, starting with a minimum of economic diversification, help to reverse these depopulation processes and promote local development overall. Two specific initiatives are analysed here: the Almadén Mining Park and the Molina-Alto Tajo District Geopark, both of which are located in central-southern Spain and have been officially recognised by UNESCO as World Heritage Sites. These two examples allow us to demonstrate, as our main objective, the today importance of territorial revival processes that were initiated by institutions (top-down approach) and then backed up by increasing participation by the local communities (bottom-up approach), encouraged by, among other factors, rural development programmes. In this regard, two aspects are important: the need for an interrelationship between the two approaches in terms of collaborative governance, in order to minimise the current processes of depopulation and territorial dislocation; and the use of the potential synergy between the resources in these two districts to ensure the viability of the initiatives and provide visitors with a high-quality experience.
Coastal Typology: An Analysis of the Spatiotemporal Relationship between Socioeconomic Development and Shoreline Change
Authors: Mack Elizabeth A. , Theuerkauf Ethan , Bunting Erin
Published: July 2020

Globally, coastal communities are impacted by hazards including storm events, rising water levels, and associated coastal erosion. These hazards destroy homes and infrastructure causing human and financial risks for communities. At the same time, the economic and governance capacity of these communities varies widely, impacting their ability to plan and adapt to hazards. In order to identify locations vulnerable to coastal hazards, knowledge of the physical coastal changes must be integrated with the socio-economic profiles of communities. To do this, we couple information about coastal erosion rates and economic data in communities along the Great Lakes to develop a typology that summarizes physical and economic vulnerability to coastal erosion. This typology classifies communities into one of four categories: (1) High physical and economic vulnerability to coastal erosion, (2) High physical but low economic vulnerability to coastal erosion, (3) Low physical and low economic vulnerability to coastal erosion, and (4) High economic but low physical vulnerability to coastal erosion. An analysis of this typology over three time periods (2005–2010), (2010–2014), and (2014–2018) reveals the dynamic nature of vulnerability over this fourteen year time span. Given this complexity, it can be difficult for managers and decision-makers to decide where to direct limited resources for coastal protection. Our typology provides an analytical tool to proactively address this challenge. Further, it advances existing work on coastal change and associated vulnerability in three ways. One, it implements a regional, analytical approach that moves beyond case study-oriented work and facilitates community analyses in a comparative context. Two, the typology provides an integrated assessment of vulnerability that considers economic vulnerability to coastal erosion, which is a contextual variable that compounds or helps mitigate vulnerability. Three, the typology facilitates community comparisons over time, which is important to identifying drivers of change in Great Lakes coastal communities over time and community efforts to mitigate and adapt to these hazards.
On Derivative Free Multiple-Root Finders with Optimal Fourth Order Convergence
Authors: Sharma Janak Raj , Kumar Sunil , Jäntschi Lorentz
Published: July 2020

A number of optimal order multiple root techniques that require derivative evaluations in the formulas have been proposed in literature. However, derivative-free optimal techniques for multiple roots are seldom obtained. By considering this factor as motivational, here we present a class of optimal fourth order methods for computing multiple roots without using derivatives in the iteration. The iterative formula consists of two steps in which the first step is a well-known Traub–Steffensen scheme whereas second step is a Traub–Steffensen-like scheme. The Methodology is based on two steps of which the first is Traub–Steffensen iteration and the second is Traub–Steffensen-like iteration. Effectiveness is validated on different problems that shows the robust convergent behavior of the proposed methods. It has been proven that the new derivative-free methods are good competitors to their existing counterparts that need derivative information.
Fractional Integral Equations Tell Us How to Impose Initial Values in Fractional Differential Equations
Authors: Cao Labora Daniel
Published: July 2020

One major question in Fractional Calculus is to better understand the role of the initial values in fractional differential equations. In this sense, there is no consensus about what is the reasonable fractional abstraction of the idea of “initial value problem”. This work provides an answer to this question. The techniques that are used involve known results concerning Volterra integral equations, and the spaces of summable fractional differentiability introduced by Samko et al. In a few words, we study the natural consequences in fractional differential equations of the already existing results involving existence and uniqueness for their integral analogues, in terms of the Riemann–Liouville fractional integral. In particular, we show that a fractional differential equation of a certain order with Riemann–Liouville derivatives demands, in principle, less initial values than the ceiling of the order to have a uniquely determined solution, in contrast to a widely extended opinion. We compute explicitly the amount of necessary initial values and the orders of differentiability where these conditions need to be imposed.
On Metric-Type Spaces Based on Extended T-Conorms
Authors: Öner Tarkan , Šostak Alexander
Published: July 2020

Kirk and Shahzad introduced the class of strong b-metric spaces lying between the class of b-metric spaces and the class of metric spaces. As compared with b-metric spaces, strong b-metric spaces have the advantage that open balls are open in the induced topology and, hence, they have many properties that are similar to the properties of classic metric spaces. Having noticed the advantages of strong b-metric spaces Kirk and Shahzad complained about the absence of non-trivial examples of such spaces. It is the main aim of this paper to construct a series of strong b-metric spaces that fail to be metric. Realizing this programme, we found it reasonable to consider these metric-type spaces in the context when the ordinary sum operation is replaced by operation ⊕, where ⊕ is an extended t-conorm satisfying certain conditions.
Existence of Nonnegative Solutions of Linear Autonomous Functional Differential Equations
Authors: Pituk Mihály
Published: July 2020

It is shown that if we exclude the existence of nontrivial small solutions, then a linear autonomous functional differential equation has a nontrivial nonnegative solution if and only if it has a nonnegative eigenfunction.