bluuebunny/crossref_metadata_2025 huggingface dataset:
Network Analysis Identifies Gene Regulatory Network Indicating the Role of RUNX1 in Human Intervertebral Disc Degeneration
Authors: Khan Nazir M. , Diaz-Hernandez Martha E , Presciutti Steven M. , Drissi Hicham
Published: July 2020

Intervertebral disc (IVD) degeneration (IDD) is a multifactorial physiological process which is often associated with lower back pain. Previous studies have identified some molecular markers associated with disc degeneration, which despite their significant contributions, have provided limited insight into the etiology of IDD. In this study, we utilized a network medicine approach to uncover potential molecular mediators of IDD. Our systematic analyses of IDD associated with 284 genes included functional annotation clustering, interaction networks, network cluster analysis and Transcription factors (TFs)-target gene network analysis. The functional enrichment and protein–protein interaction network analysis highlighted the role of inflammatory genes and cytokine/chemokine signaling in IDD. Moreover, sub-network analysis identified significant clusters possessing organized networks of 24 cytokine and chemokine genes, which may be considered as key modulators for IDD. The expression of these genes was validated in independent microarray datasets. In addition, the regulatory network analysis identified the role of multiple transcription factors, with RUNX1 being a master regulator in the pathogenesis of IDD. Our analyses highlighted the role of cytokine genes and interacting pathways in IDD and further improved our understanding of the genetic mechanisms underlying IDD.
PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation
Authors: Coco-Martin Rosa M. , Sanchez-Tocino Hortensia T. , Desco Carmen , Usategui-Martín Ricardo , Tellería Juan J.
Published: July 2020

Over 175 pathogenic mutations in the Peripherin-2 (PRPH2) gene are linked to various retinal diseases. We report the phenotype and genotype of eight families (24 patients) with retinal diseases associated with seven distinct PRPH2 gene mutations. We identified a new mutation, c.824_828+3delinsCATTTGGGCTCCTCATTTGG, in a patient with adult-onset vitelliform macular dystrophy (AVMD). One family with the p.Arg46Ter mutation presented with the already described AVMD phenotype, but another family presented with the same mutation and two heterozygous pathogenic mutations (p.Leu2027Phe and p.Gly1977Ser) in the ATP Binding Cassette Subfamily A Member 4 (ABCA4) gene that cause extensive chorioretinal atrophy (ECA), which could be a blended phenotype. The p.Lys154del PRPH2 gene mutation associated with the p.Arg2030Glu mutation in the ABCA4 gene was found in a patient with multifocal pattern dystrophy simulating fundus flavimaculatus (PDsFF), for whom we considered ABCA4 as a possible modifying gene. The mutation p.Gly167Ser was already known to cause pattern dystrophy, but we also found ECA, PDsFF, and autosomal-dominant retinitis pigmentosa (ADRP) as possible phenotypes. Finally, we identified the mutation p.Arg195Leu in a large family with common ancestry, which previously was described to cause central areolar choroidal dystrophy (CACD), but we also found ADRP and observed that it caused ECA more frequently than CACD in this family.
Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED)
Authors: Nessler Jasmin , Hug Petra , Mandigers Paul J. J. , Leegwater Peter A. J. , Jagannathan Vidhya , Das Anibh M. , Rosati Marco , Matiasek Kaspar , Sewell Adrian C. , Kornberg Marion , Hoffmann Marina , Wolf Petra , Fischer Andrea , Tipold Andrea , Leeb Tosso
Published: July 2020

Four female Shetland Sheepdogs with hypertonic paroxysmal dyskinesia, mainly triggered by exercise and stress, were investigated in a retrospective multi-center investigation aiming to characterize the clinical phenotype and its underlying molecular etiology. Three dogs were closely related and their pedigree suggested autosomal dominant inheritance. Laboratory diagnostic findings included mild lactic acidosis and lactaturia, mild intermittent serum creatine kinase (CK) elevation and hypoglycemia. Electrophysiological tests and magnetic resonance imaging of the brain were unremarkable. A muscle/nerve biopsy revealed a mild type II fiber predominant muscle atrophy. While treatment with phenobarbital, diazepam or levetiracetam did not alter the clinical course, treatment with a gluten-free, home-made fresh meat diet in three dogs or a tryptophan-rich, gluten-free, seafood-based diet, stress-reduction, and acetazolamide or zonisamide in the fourth dog correlated with a partial reduction in, or even a complete absence of, dystonic episodes. The genomes of two cases were sequenced and compared to 654 control genomes. The analysis revealed a case-specific missense variant, c.1658G>A or p.Arg553Gln, in the PCK2 gene encoding the mitochondrial phosphoenolpyruvate carboxykinase 2. Sanger sequencing confirmed that all four cases carried the mutant allele in a heterozygous state. The mutant allele was not found in 117 Shetland Sheepdog controls and more than 500 additionally genotyped dogs from various other breeds. The p.Arg553Gln substitution affects a highly conserved residue in close proximity to the GTP-binding site of PCK2. Taken together, we describe a new form of paroxysmal exercise-induced dyskinesia (PED) in dogs. The genetic findings suggest that PCK2:p.Arg553Gln should be further investigated as putative candidate causal variant.
Evolutionary History of the Risk of SNPs for Diffuse-Type Gastric Cancer in the Japanese Population
Authors: Iwasaki Risa L. , Ishiya Koji , Kanzawa-Kiriyama Hideaki , Kawai Yosuke , Gojobori Jun , Satta Yoko
Published: July 2020

A genome wide association study reported that the T allele of rs2294008 in a cancer-related gene, PSCA, is a risk allele for diffuse-type gastric cancer. This allele has the highest frequency (0.63) in Japanese in Tokyo (JPT) among 26 populations in the 1000 Genomes Project database. FST ≈ 0.26 at this single nucleotide polymorphism is one of the highest between JPT and the genetically close Han Chinese in Beijing (CHB). To understand the evolutionary history of the alleles in PSCA, we addressed: (i) whether the C non-risk allele at rs2294008 is under positive selection, and (ii) why the mainland Japanese population has a higher T allele frequency than other populations. We found that haplotypes harboring the C allele are composed of two subhaplotypes. We detected that positive selection on both subhaplotypes has occurred in the East Asian lineage. However, the selection on one of the subhaplotypes in JPT seems to have been relaxed or ceased after divergence from the continental population; this may have caused the elevation of T allele frequency. Based on simulations under the dual structure model (a specific demography for the Japanese) and phylogenetic analysis with ancient DNA, the T allele at rs2294008 might have had high frequency in the Jomon people (one of the ancestral populations of the modern Japanese); this may explain the high T allele frequency in the extant Japanese.
Exploring Health Information Sharing Behavior of Chinese Elderly Adults on WeChat
Authors: Wang Wei , Zhuang Xin , Shao Peng
Published: July 2020

WeChat has increasingly become an important platform for users to acquire and share health information in China. However, little is known about elderly adults’ sharing behavior. This study aims to explore the characteristics and influencing factors of health information sharing behavior among Chinese older adults on WeChat, with the method both of questionnaire survey (N = 336) and in-depth interviews (N = 40). The study finds that sharing health information, mainly represented by four specific methods of forwarding, consulting, replying, and posting, has become an important part of the daily life of elderly adults on WeChat. Social media provide a good opportunity for the flow of health information. However, the purpose to share health information of Chinese older adults is mainly based on relationship maintenance more than real information support; they share health information to friends and relatives first, then to spouses and children, which does not follow the trust model as usual. Experience in online health information, authority orientation, and relationship orientation is positively associated with health information sharing behavior, however, there is no significant correlation between perceived health information credibility and health information sharing behavior. Moreover, social and cultural factors are the important explanation mechanism.
Prediction Model for Dry Eye Syndrome Incidence Rate Using Air Pollutants and Meteorological Factors in South Korea: Analysis of Sub-Region Deviations
Authors: Youn Jong-Sang , Seo Jeong-Won , Park Wonjun , Park SeJoon , Jeon Ki-Joon
Published: July 2020

Here, we develop a dry eye syndrome (DES) incidence rate prediction model using air pollutants (PM10, NO2, SO2, O3, and CO), meteorological factors (temperature, humidity, and wind speed), population rate, and clinical data for South Korea. The prediction model is well fitted to the incidence rate (R2 = 0.9443 and 0.9388, p < 2.2 × 10−16). To analyze regional deviations, we classify outpatient data, air pollutant, and meteorological factors in 16 administrative districts (seven metropolitan areas and nine states). Our results confirm NO2 and relative humidity are the factors impacting regional deviations in the prediction model.
Establishment of a Palliative Care Consultation Service (PCCS) in an Acute Hospital Setting
Authors: Engel Peter Tom , Thavayogarajah Tharshika , Görlich Dennis , Lenz Philipp
Published: July 2020

Background and study aims: Acute health service requires focused palliative care (PC). This study was performed to provide guidance for the establishment of a palliative care consultation service (PCCS). Patients and methods: This study was conceived as a retrospective single-center study for observing, analyzing and evaluating the initial setup of a PCCS from 1 May 2015 to 31 May 2018. Patients from Muenster University Hospital with advanced life-limiting diseases, identified to require PC, were included. Results: PCCS was requested from various departments, for between 20 and 80 patients per month, corresponding to a total of 2359 for the study period. Requests were highest in internal medicine (27.3%), gynecology (18.1%) and radiotherapy (17.6%). Time to referral was significantly shorter in departments with special PCCS ward rounds (6 ± 9 vs. 12 ± 22 days, p < 0.001). The most frequently reported symptoms were fatigue, pain and loss of appetite. Pain was frequently localized in the stomach (20.4%), back (17.1%), or in the head and neck area (14.9%). After the first PCCS consultation, 254 patients (90%) reported sufficient pain relief after 48 h. An introduction/modification of painkiller medication, which was recommended for 142 inpatients, was implemented in 57.0% of cases by the respective departments. Overall, the direct realization of PCCS recommendations reached only 50% on average. Conclusions: Besides an analysis of the ability to address the symptoms of the referred patients by the PCCS, this study highlights the importance of the interaction between PCCS and other departments. It further elucidates the role and possibilities of this service both in regular ward rounds and individual staff contacts.
Burden of Healthcare Utilization among Chronic Obstructive Pulmonary Disease Patients with and without Cancer Receiving Palliative Care: A Population-Based Study in Taiwan
Authors: Kao Li-Ting , Cheng Kuo-Chen , Chen Chin-Ming , Ko Shian-Chin , Chen Ping-Jen , Liao Kuang-Ming , Ho Chung-Han
Published: July 2020

Chronic obstructive pulmonary disease (COPD) is a chronic disease that burdens patients worldwide. This study aims to discover the burdens of health services among COPD patients who received palliative care (PC). Study subjects were identified as COPD patients with ICU and PC records between 2009 and 2013 in Taiwan’s National Health Insurance Research Database. The burdens of healthcare utilization were analyzed using logistic regression to estimate the difference between those with and without cancer. Of all 1215 COPD patients receiving PC, patients without cancer were older and had more comorbidities, higher rates of ICU admissions, and longer ICU stays than those with cancer. COPD patients with cancer received significantly more blood transfusions (Odds Ratio, OR: 1.66; 95% C.I.: 1.11–2.49) and computed tomography scans (OR: 1.88; 95% C.I.: 1.10–3.22) compared with those without cancer. Bronchoscopic interventions (OR: 0.26; 95% C.I.: 0.07–0.97) and inpatient physical restraints (OR: 0.24; 95% C.I.: 0.08–0.72) were significantly more utilized in patients without cancer. COPD patients without cancer appeared to receive more invasive healthcare interventions than those without cancer. The unmet needs and preferences of patients in the life-limiting stage should be taken into consideration for the quality of care in the ICU environment.
Coital Frequency and the Probability of Pregnancy in Couples Trying to Conceive Their First Child: A Prospective Cohort Study in Japan
Authors: Konishi Shoko , Saotome Tomoko T. , Shimizu Keiko , Oba Mari S. , O’Connor Kathleen A.
Published: July 2020

Background: Low fertility persists but remains unexplained in Japan. We examined whether the probability of pregnancy was influenced by coital frequency, age, reproductive age (assessed by antimüllerian hormone, AMH), and BMI. Methods: We established a two-year prospective study with a sample of hormonally monitored Japanese women aged 23–34 years wanting to conceive their first child. For a maximum of 24 weeks participants recorded menstrual bleeding, sexual intercourse, ovulation, and pregnancy. Additional information on pregnancy and infertility treatment was collected one and two years after intake. Results: The natural conception rate and coital frequency were both low in this sample. Among 80 participants, 44% (35) naturally conceived in 24 weeks. After two years, 74% (59) of women had delivered or were currently pregnant, 50% (40) due to natural and 24% (19) due to assisted conception, and 5% (4) were lost to follow-up. By two years, 56% (45) of women had sought fertility treatment. In 18% (58/319) of the observed ovarian cycles across 24 weeks there was no intercourse in a fertile period. Higher coital frequency at intake was associated with increased probability of conception by 24 weeks of follow-up (OR 1.23, 95%CI 1.02, 1.47). Chronological age, reproductive age, and BMI were not associated with the probability of pregnancy at 24 weeks. Conclusions: Our results suggest that first, natural conception rates could potentially increase with more frequent and well timed intercourse, and second that further work is needed to understand why even in a motivated sample of women monitoring their fertile periods, both the conception and coitus rates were low.
A Clean and Tunable Mussel-Inspired Coating Technology by Enzymatic Deposition of Pseudo-Polydopamine (ψ-PDA) Thin Films from Tyramine
Authors: Alfieri Maria Laura , Panzella Lucia , Arntz Youri , Napolitano Alessandra , Ball Vincent , d’Ischia Marco
Published: July 2020

The tyrosinase-catalyzed oxidation of tyramine, leading to the deposition of pseudo-polydopamine (ψ-PDA) thin films, is disclosed herein as a superior technology for surface functionalization and coating at a neutral pH and at a low substrate concentration, compared to the standard autoxidative PDA coating protocols. Smooth ψ-PDA thin films of variable thickness up to 87 nm were obtained from 1 mM tyramine by varying tyrosinase concentrations (5–100 U/mL). Compared to the PDA films obtained by the similar enzymatic oxidation of 1 mM dopamine with tyrosinase (T-PDA), ψ-PDA displayed slower deposition kinetics, lower water contact angles in the range of 11°–28°, denoting higher hydrophilicity but similar UV-vis absorption profiles, as well as electrochemical properties and antioxidant activity. MALDI-MS analysis indicated for ψ-PDA a well defined pattern of peaks compatible with dopamine tetrameric structures degraded to a variable extent. The exposure to a tyramine solution of tyrosinase-loaded alginate spheres, or films deposited on glass or polyethylene, resulted in a rapid gel-confined ψ-PDA formation with no leakage or darkening of the solution, allowing the complete recovery and re-utilization of the unreacted tyramine. In contrast, an abundant PDA precipitation outside the gel was observed with dopamine under the same conditions. The ψ-PDA deposition by tyrosinase-catalyzed tyramine oxidation is thus proposed as a controllable and low-waste technology for selective surface functionalization and coating or for clean eumelanin particle production.
Quality of Life Outcomes in Frontal Sinus Surgery
Authors: Georgalas Christos , Detsis Marios , Geramas Ioannis , Terzakis Dimitris , Liodakis Andreas
Published: July 2020

Introduction: Although significant experience has been gained in the technical nuances of endoscopic sinus surgery procedures, the patient-reported outcomes of frontal endoscopic sinus surgery procedures are still poorly understood. In this study we used the validated patient outcome measure Sino Nasal Outcome Test-22 (SNOT-22) to assess the preoperative and postoperative quality of life in patients undergoing extended endoscopic frontal sinus surgery (Draf type 2 and Draf type 3 procedures). Methods: Out of a total of 680 patients undergoing endoscopic sinus and skull base surgery and 186 patients undergoing frontal sinus surgery, 99 chronic rhinosinusitis patients with (CRSwNP) or without (CRSnNP) nasal polyps undergoing Draf 2 or Draf 3 were assessed. Results: The mean preoperative SNOT-22 was 45.6 points for patients undergoing Draf 2 and 59 for patients undergoing Draf 3, while the mean radiological Lund–Mackay Score was 14.3 and 14.5, respectively. Mean SNOT 22 improvement was 22.9 points for Draf 2 and 37 points for Draf 3 respectively and remained significant in all time intervals, including at 4 years after surgery. With the exception of loss of smell/taste, all symptoms improved by a far bigger extent in Draf 3 group, despite the considerably worse starting point. Effect size (Cohen / Standard Deviations) of Draf 3 was greatest in the following symptoms: “being frustrated/restless/irritable” (1.63), “nasal blockage” (1.43), “reduced concentration” (1.35), “fatigue” (1.29) “runny nose” (1.26) and “need to blow nose” (1.17). Frontal sinus (neo) ostium was patent (fully or partly) at last follow up in 98% of Draf 2 patients and in 88% of patients following Draf 3. Patients with non-patent frontal (neo-) ostium however had a mean postoperative SNOT 22 score of 43 compared to 20 of those with patent frontal sinus (neo-) ostium, although the difference was not statistically significant. Conclusion: Patients undergoing Draf 3 have a greater burden of disease, including both nasal and emotional/general symptoms compared to Draf 2 patients; surgery results in improvement in both groups, although Draf 3 patients have the greatest benefit, especially in emotional / general symptons. In this way both groups achieve similar postoperative quality of life, despite the different starting points.
Should Lung-Sparing Surgery Be the Standard Procedure for Malignant Pleural Mesothelioma?
Authors: Ichiki Yoshinobu , Goto Hidenori , Fukuyama Takashi , Nakanishi Kozo
Published: July 2020

Background: Surgical procedures for malignant pleural mesothelioma (MPM) include extrapleural pneumonectomy (EPP), extended pleurectomy/decortication (P/D) and P/D. EPP has been applied to MPM for a long time, but the postoperative status is extremely poor due to the loss of one whole lung. We compared the mortality, morbidity and median survival time (MST) of lung-sparing surgery (extended P/D or P/D) and lung-sacrificing surgery (EPP) for MPM by performing a systematic review. Methods: We extracted the number of events and patients from the literature identified in electronic databases. Ultimately, 15 reports were selected, and 2674 MPM patients, including 1434 patients undergoing EPP and 1240 patients undergoing extended P/D or P/D, were analyzed. Results: Our systematic review showed that lung-sparing surgery was significantly superior to lung-sacrificing surgery in both the surgical-related mortality (extended P/D vs. EPP: 3.19% vs. 7.65%, p < 0.01; P/D vs. EPP: 1.85% vs. 7.34%, p < 0.01) and morbidity (extended P/D vs. EPP: 35.7% vs. 60.0%, p < 0.01; P/D vs. EPP: 9.52% vs. 20.89%, p < 0.01). Lung-sparing surgery was not inferior to EPP in terms of MST. Conclusion: Although no prospective randomized controlled trial has been conducted, it may be time to change the standard surgical method for MPM from lung-sacrificing surgery to lung-sparing surgery.
Motor and Cognitive Performance in Patients with Liver Cirrhosis with Minimal Hepatic Encephalopathy
Authors: San Martín-Valenzuela Constanza , Borras-Barrachina Aroa , Gallego Juan-José , Urios Amparo , Mestre-Salvador Víctor , Correa-Ghisays Patricia , Ballester María-Pilar , Escudero-García Desamparados , Tosca Joan , Montón Cristina , Ríos María-Pilar , Kosenko Elena , Felipo Vicente , Tabares-Seisdedos Rafael , Selva-Vera Gabriel , Montoliu Carmina
Published: July 2020

Minimal hepatic encephalopathy (MHE) is associated with mild cognitive impairment and frailty. This study aims to identify cognitive and motor differences in cirrhotic patients with and without MHE, and the correlations between motor signs and cognitive performance. Gait, balance, hand strength and motor speed performance were evaluated in 66 cirrhotic patients (38 without and 28 with MHE, according to the Psychometric Hepatic Encephalopathy Score (PHES). Cognitive performance was measured with the Mini-Mental State Examination, Verbal Fluency Test, Aprendizaje Verbal España-Complutense Test (TAVEC), Wechsler Adult Intelligence Scale III, Hamilton Depression and Anxiety Rating Scale and Functioning Assessment Short Test (FAST). MHE patients performed worse than patients without MHE in cognitive and autonomous functioning, learning and long-term memory, and verbal fluency. The same pattern was found in gait, center of pressure movement, variability of hand strength performance and hand motor speed. In MHE patients, high correlations were found between balance and FAST test, gait velocity and verbal skills, hand strength variability and anxiety and depression, and motor speed and FAST and TAVEC. MHE patients showed worse motor and cognitive performance than patients without MHE. MHE patients could have impaired movement control expressed as bradykinesia, and this reduced motor performance could correlate with cognitive performance.
Anti-atherogenic Modification of Serum Lipoprotein Function in Patients with Rheumatoid Arthritis after Tocilizumab Treatment, a Pilot Study
Authors: Greco Daniela , Gualtierotti Roberta , Agosti Pasquale , Adorni Maria Pia , Ingegnoli Francesca , Rota Matteo , Bernini Franco , Meroni Pier Luigi , Ronda Nicoletta
Published: July 2020

Lipid metabolism derangement contributes to increased cardiovascular risk in Rheumatoid Arthritis (RA). It is still debated whether and how tocilizumab, an interleukin-6 receptor inhibitor used in active RA, impacts cardiovascular risk. We studied the effect of tocilizumab on the regulation of macrophage cholesterol homeostasis, measuring patient serum ability to respectively load (cholesterol loading capacity, CLC) and discharge (cholesterol efflux capacity, CEC) cells with cholesterol. Patients with RA (n = 8) were studied before and after 4 and 12 weeks of tocilizumab treatment. CLC was measured by a fluorimetric assay of intracellular cholesterol content in human macrophages and CEC was measured for the three main pathways, mediated by the transporters Scavenger Receptor class B-type I (SR-BI), ATP binding cassette-G1 (ABCG1) and -A1 (ABCA1) in specific cell models. After 12 weeks of tocilizumab treatment, serum LDL cholesterol levels were increased, while CLC was reduced. HDL cholesterol levels were unchanged, but CEC was significantly ameliorated for the SR-BI and ABCG1 pathways with respect to baseline. Tocilizumab reduces LDL pro-atherogenic potential despite increasing their serum levels and increases HDL protective activity in RA. The data of our pilot study suggest that tocilizumab regulates lipoprotein function in selected patient populations and lay the groundwork for future larger studies.
Obesity and COVID-19: Oro-Naso-Sensory Perception
Authors: Khan Amira Sayed , Hichami Aziz , Khan Naim Akhtar
Published: July 2020

Through a recent upsurge of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, the clinical assessment of most of the coronavirus disease 19 (COVID-19) patients clearly presents a health condition with the loss of oro-naso-sensory (ONS) perception, responsible for the detection of flavor and savor. These changes include anosmia and dysgeusia. In some cases, these clinical manifestations appear even before the general flu-like symptoms, e.g., sore throat, thoracic oppression and fever. There is no direct report available on the loss of these chemical senses in obese COVID-19 patients. Interestingly, obesity has been shown to be associated with low ONS cues. These alterations in obese subjects are due to obesity-induced altered expression of olfacto-taste receptors. Besides, obesity may further aggravate the SARS-CoV-2 infection, as this pathology is associated with a high degree of inflammation/immunosuppression and reduced protection against viral infections. Hence, obesity represents a great risk factor for SARS-CoV-2 infection, as it may hide the viral-associated altered ONS symptoms, thus leading to a high mortality rate in these subjects.
Adipose Tissue: A Source of Stem Cells with Potential for Regenerative Therapies for Wound Healing
Authors: Trevor Lucy V , Riches-Suman Kirsten , Mahajan Ajay L , Thornton M Julie
Published: July 2020

Interest in adipose tissue is fast becoming a focus of research after many years of being considered as a simple connective tissue. It is becoming increasingly apparent that adipose tissue contains a number of diverse cell types, including adipose-derived stem cells (ASCs) with the potential to differentiate into a number of cell lineages, and thus has significant potential for developing therapies for regenerative medicine. Currently, there is no gold standard treatment for scars and impaired wound healing continues to be a challenge faced by clinicians worldwide. This review describes the current understanding of the origin, different types, anatomical location, and genetics of adipose tissue before discussing the properties of ASCs and their promising applications for tissue engineering, scarring, and wound healing.
Sjögren’s Syndrome Minor Salivary Gland CD4+ Memory T Cells Associate with Glandular Disease Features and Have a Germinal Center T Follicular Helper Transcriptional Profile
Authors: Joachims Michelle L. , Leehan Kerry M. , Dozmorov Mikhail G. , Georgescu Constantin , Pan Zijian , Lawrence Christina , Marlin M. Caleb , Macwana Susan , Rasmussen Astrid , Radfar Lida , Lewis David M. , Stone Donald U. , Grundahl Kiely , Scofield R. Hal , Lessard Christopher J. , Wren Jonathan D. , Thompson Linda F. , Guthridge Joel M. , Sivils Kathy L. , Moore Jacen S. , Farris A. Darise
Published: July 2020

To assess the types of salivary gland (SG) T cells contributing to Sjögren’s syndrome (SS), we evaluated SG T cell subtypes for association with disease features and compared the SG CD4+ memory T cell transcriptomes of subjects with either primary SS (pSS) or non-SS sicca (nSS). SG biopsies were evaluated for proportions and absolute numbers of CD4+ and CD8+ T cells. SG memory CD4+ T cells were evaluated for gene expression by microarray. Differentially-expressed genes were identified, and gene set enrichment and pathways analyses were performed. CD4+CD45RA− T cells were increased in pSS compared to nSS subjects (33.2% vs. 22.2%, p < 0.0001), while CD8+CD45RA− T cells were decreased (38.5% vs. 46.0%, p = 0.0014). SG fibrosis positively correlated with numbers of memory T cells. Proportions of SG CD4+CD45RA− T cells correlated with focus score (r = 0.43, p < 0.0001), corneal damage (r = 0.43, p < 0.0001), and serum Ro antibodies (r = 0.40, p < 0.0001). Differentially-expressed genes in CD4+CD45RA− cells indicated a T follicular helper (Tfh) profile, increased homing and increased cellular interactions. Predicted upstream drivers of the Tfh signature included TCR, TNF, TGF-β1, IL-4, and IL-21. In conclusion, the proportions and numbers of SG memory CD4+ T cells associate with key SS features, consistent with a central role in disease pathogenesis.
Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma
Authors: Zhou Xiang , Einsele Hermann , Danhof Sophia
Published: July 2020

Despite the introduction of novel agents such as proteasome inhibitors, immunomodulatory drugs, and autologous stem cell transplant, multiple myeloma (MM) largely remains an incurable disease. In recent years, monoclonal antibody-based treatment strategies have been developed to target specific surface antigens on MM cells. Treatment with bispecific antibodies (bsAbs) is an immunotherapeutic strategy that leads to an enhanced interaction between MM cells and immune effector cells, e.g., T-cells and natural killer cells. With the immune synapse built by bsAbs, the elimination of MM cells can be facilitated. To date, bsAbs have demonstrated encouraging results in preclinical studies, and clinical trials evaluating bsAbs in patients with MM are ongoing. Early clinical data show the promising efficacy of bsAbs in relapsed/refractory MM. Together with chimeric antigen receptor-modified (CAR)-T-cells, bsAbs represent a new dimension of precision medicine. In this review, we provide an overview of rationale, current clinical development, resistance mechanisms, and future directions of bsAbs in MM.
New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis
Authors: Kolokotronis Konstantinos , Pluta Natalie , Klopocki Eva , Kunstmann Erdmute , Messroghli Daniel , Maack Christoph , Tejman-Yarden Shai , Arad Michael , Rost Simone , Gerull Brenda
Published: July 2020

Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes.
Strong Correlation of Renal Function with Choroidal Thickness in Patients with Type 2 Diabetes: Retrospective Cross-Sectional Study
Authors: Choi Min Gyu , Kim Jee Taek
Published: July 2020

The purpose of this study was to analyze the correlation between renal function and subfoveal choroidal thickness (SFChT) in treatment-naïve proliferative diabetic retinopathy (PDR) patients. This study included 85 eyes of 52 treatment-naïve PDR patients who underwent kidney function testing and urinalysis and 42 eyes of 33 age-matched controls. Treatment-naïve eyes with PDR were categorized into pachychoroid and leptochoroid groups based on the SFChT of the control group. Kidney function profiles were compared between pachychoroid and leptochoroid groups; the relationship between kidney function profile and SFChT was evaluated using regression analysis. Compared with the pachychoroid group, the leptochoroid group had significantly higher serum creatinine (p = 0.026), cystatin C (p = 0.004), and phosphorus (p < 0.001) levels and a lower estimated glomerular filtration rate (eGFR) (p < 0.001). Multivariate linear regression analyses showed that SFChT was positively correlated with eGFR (Cystatin C) (p = 0.007) and negatively correlated with serum phosphorus (p = 0.001). SFChT of patients with eGFR < 30 mL/min/1.73 m2 and serum phosphorus level ≥4.0 mg/dL was less than that of patients with higher eGFR and lower serum phosphorus level. The choroidal thickness of treatment-naïve PDR patients is closely affected by renal function. Kidney function test should be considered if SFChT of patients with treatment-naïve PDR is reduced.
The Effect of Lactobacillus acidophilus YT1 (MENOLACTO) on Improving Menopausal Symptoms: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial
Authors: Lim Eun Yeong , Lee So-Young , Shin Hee Soon , Lee Jaekwang , Nam Young-Do , Lee Dong Ock , Lee Ji Young , Yeon Sung Hum , Son Rak Ho , Park Chae Lee , Heo Yun Haeng , Kim Yun Tai
Published: July 2020

This study evaluated the efficacy of Lactobacillus acidophilus YT1 (MENOLACTO) for alleviating menopausal symptoms. This study was a multi-center, randomized, double-blinded, placebo-controlled clinical trial involving female subjects (ages: 40–60 years) with menopausal symptoms and a Kupperman index (KMI) score ≥ 20. Subjects were administered 1 × 108 CFU/day MENOLACTO or placebo, with the primary endpoint being total KMI score, and the effect of secondary endpoints on alleviating menopausal symptoms according to individual categories of the modified KMI, as well as a quality of life questionnaire (MENQOL questionnaire). After 12 weeks, total KMI scores decreased significantly, demonstrating improved menopausal symptoms relative to placebo along with improved modified KMI scores. Additionally, quality of life, according to the MENQOL questionnaire, significantly improved in all four symptoms—physical, psychosocial, vasomotor, and sexual symptoms. Moreover, we observed no significant difference between the two groups or significant changes in blood follicle-stimulating hormone and estradiol levels or endometrial thickness. These results demonstrated that MENOLACTO alleviated menopausal symptoms without notable side effects and improved quality of life, suggesting its efficacy as an alternative supplement to alleviate menopausal symptoms in women ineligible for hormonal therapy.
Congruence between Meshes and Library Files of Implant Scanbodies: An In Vitro Study Comparing Five Intraoral Scanners
Authors: Mangano Francesco , Lerner Henriette , Margiani Bidzina , Solop Ivan , Latuta Nadezhda , Admakin Oleg
Published: July 2020

Purpose. To compare the reliability of five different intraoral scanners (IOSs) in the capture of implant scanbodies (SBs) and to verify the dimensional congruence between the meshes (MEs) of the SBs and the corresponding library file (LF). Methods. A gypsum cast of a fully edentulous maxilla with six implant analogues and SBs screwed on was scanned with five different IOSs (PRIMESCAN®, CS 3700®, MEDIT i-500®, ITERO ELEMENTS 5D®, and Emerald S®). Ten scans were taken for each IOS. The resulting MEs were imported to reverse engineering software for 3D analysis, consisting of the superimposition of the SB LF onto each SB ME. Then, a quantitative and qualitative evaluation of the deviations between MEs and LF was performed. A careful statistical analysis was performed. Results. PRIMESCAN® showed the highest congruence between SB MEs and LF, with the lowest mean absolute deviation (25.5 ± 5.0 μm), immediately followed by CS 3700® (27.0 ± 4.3 μm); the difference between them was not significant (p = 0.1235). PRIMESCAN® showed a significantly higher congruence than MEDIT i-500® (29.8 ± 4.8 μm, p < 0.0001), ITERO ELEMENTS 5D® (34.2 ± 9.3 μm, p < 0.0001), and Emerald S® (38.3 ± 7.8 μm, p < 0.0001). CS 3700® had a significantly higher congruence than MEDIT i-500® (p = 0.0004), ITERO ELEMENTS 5D® (p < 0.0001), and Emerald S® (p < 0.0001). Significant differences were also found between MEDIT i-500® and ITERO ELEMENTS 5D® (p < 0.0001), MEDIT i-500® and Emerald S® (p < 0.0001), and ITERO ELEMENTS 5D® and Emerald S® (p < 0.0001). Significant differences were found among different SBs when scanned with the same IOS. The deviations of the IOSs showed different directions and patterns. With PRIMESCAN®, ITERO ELEMENTS 5D®, and Emerald S®, the MEs were included inside the LF; with CS 3700®, the LF was included in the MEs. MEDIT i-500® showed interpolation between the MEs and LF, with no clear direction for the deviation. Conclusions. Statistically different levels of congruence were found between the SB MEs and the corresponding LF when using different IOSs. Significant differences were also found between different SBs when scanned with the same IOS. Finally, the qualitative evaluation revealed different directions and patterns for the five IOSs.
Tacrolimus Prevents TWEAK-Induced PLA2R Expression in Cultured Human Podocytes
Authors: Cuarental Leticia , Valiño-Rivas Lara , Mendonça Luis , Saleem Moin , Mezzano Sergio , Sanz Ana Belen , Ortiz Alberto , Sanchez-Niño Maria Dolores
Published: July 2020

Primary membranous nephropathy is usually caused by antibodies against the podocyte antigen membrane M-type phospholipase A2 receptor (PLA2R). The treatment of membranous nephropathy is not fully satisfactory. The calcineurin inhibitor tacrolimus is used to treat membranous nephropathy, but recurrence upon drug withdrawal is common. TNF superfamily members are key mediators of kidney injury. We have now identified key TNF receptor superfamily members in podocytes and explored the regulation of PLA2R expression and the impact of tacrolimus. Data mining of single cell transcriptomics and glomerular transcriptomics data identified TNFRSF12a/Fn14 as the highest expressed TNF receptor superfamily gene in human membranous nephropathy, and this was confirmed by immunohistochemistry that also identified NFκB activation in membranous nephropathy podocytes. Additionally, glomerular transcriptomics identified PLA2R1 expression as being increased in membranous nephropathy in the parenteral administration of the Fn14 ligand TWEAK increased podocyte PLA2R expression in mice. Furthermore, in cultured human podocytes, TWEAK increased the expression of PLA2R as well as the expression of other genes recently identified by GWAS as linked to membranous nephropathy: NFKB1 and IRF4. Interestingly, IRF4 encodes the FK506-binding protein 52 (FKBP52), a protein associated with tacrolimus. Tacrolimus prevented the increased expression of PLA2R, NFKB1 and IRF4 induced by TWEAK in cultured podocytes. In conclusion, TWEAK upregulates the expression of PLA2R and of other genes linked to membranous nephropathy in podocytes, and this is prevented by tacrolimus. An impact of tacrolimus on the expression of PLA2R and other genes in podocytes may underlie its efficacy in treating the disease as well as the frequent recurrence of nephrotic syndrome upon tacrolimus withdrawal.
Correlation of the Subjective Hip Value with Validated Patient-Reported Outcome Measurements for the Hip
Authors: Krueger David R. , Leopold Vincent J. , Schroeder Joerg H. , Perka Carsten , Hardt Sebastian
Published: July 2020

Background: The subjective hip value (SHV) was developed as a patient-reported outcome measurement (PROM) that is easily and quickly performed and interpreted. The SHV is defined as a patient’s subjective hip measurement tool expressed as a percentage of an entirely normal hip joint, which would score 100%. The hypothesis is that results of the subjective hip value correlate with the results of the modified Harris hip score and the International Hip Outcome Tool in patients with hip-related diseases. Methods: 302 patients completed the modified Harris hip score (mHHS), the International Hip Outcome Tool (iHot-33) as well as the SHV. The SHV consist of only one question: “What is the overall percent value of your hip if a completely normal hip represents 100%?”. The patients were divided into five different groups depending on the diagnosis. Pearson correlation was used to evaluate the correlation between the different PROMs and linear regression analysis was used to calculate R2. Results: 302 complete datasets were available for evaluation. There was a high correlation between the SHV and the iHOT-33 (r = 0.847; r2 = 0.692, p < 0.001) and the mHHS (r = 0.832; r2 = 0.717, p < 0.001). The SHV showed a medium (r = 0.653) to high (r = 0.758) correlation with the mHHS and the iHOT-33 in all diagnosis groups. Conclusion: The SHV offers a useful adjunct to established hip outcome measurements, as it is easily and quickly performed and interpreted. The SHV reflects the view of the patient and is independent of the diagnosis. Further research with prospective studies is needed to test the psychometric properties of the score.
Effects of PrObiotics on the Symptoms and Surgical ouTComes after Anterior REsection of Colon Cancer (POSTCARE): A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Park In Ja , Lee Ju-Hoon , Kye Bong-Hyeon , Oh Heung-Kwon , Cho Yong Beom , Kim You-Tae , Kim Joo Yun , Sung Na Young , Kang Sung-Bum , Seo Jeong-Meen , Sim Jae-Hun , Lee Jung-Lyoul , Lee In Kyu
Published: July 2020

We investigated microbiota changes following surgical colon cancer resection and evaluate effects of probiotics on microbiota and surgical recovery. This randomized double-blind trial was performed at four medical centers in South Korea. Of 68 patients expected to undergo anterior sigmoid colon cancer resection, 60 were eligible, of whom 29 and 31 received probiotics and placebo, respectively, for four weeks, starting at one week preoperatively. Third- and/or fourth-week information on anterior resection syndrome (ARS), inflammatory markers, and quality of life was obtained. Stool sample analysis was conducted after randomization and bowel preparation and at three and four postoperative weeks. Bacteria were categorized into Set I (with probiotic effects) and II (colon cancer-associated). The probiotic group’s ARS score showed an improving trend (p = 0.063), particularly for flatus control (p = 0.030). Serum zonulin levels significantly decreased with probiotics. Probiotic ingestion resulted in compositional changes in gut microbiota; greater increases and decreases in Set I and II bacteria, respectively, occurred with probiotics. Compositional increase in Set I bacteria was associated with reduced white blood cells, neutrophils, neutrophil-lymphocyte ratio, and zonulin. Bifidobacterium composition was negatively correlated with zonulin levels in the probiotic group. Probiotics improved postoperative flatus control and modified postoperative changes in microbiota and inflammatory markers.
Circulating miRNAs as a Predictive Biomarker of the Progression from Prediabetes to Diabetes: Outcomes of a 5-Year Prospective Observational Study
Authors: Sidorkiewicz Iwona , Niemira Magdalena , Maliszewska Katarzyna , Erol Anna , Bielska Agnieszka , Szalkowska Anna , Adamska-Patruno Edyta , Szczerbinski Lukasz , Gorska Maria , Kretowski Adam
Published: July 2020

Due to a global increase in the prevalence of type 2 diabetes mellitus (T2DM), there is an urgent need for early identification of prediabetes, as these people have the highest risk of developing diabetes. Circulating miRNAs have shown potential as progression biomarkers in other diseases. This study aimed to conduct a baseline comparison of serum-circulating miRNAs in prediabetic individuals, with the distinction between those who later progressed to T2DM and those who did not. The expression levels of 798 miRNAs using NanoString technology were examined. Spearman correlation, receiver operating characteristic (ROC) curve analysis, and logistic regression modeling were performed. Gene ontology (GO) and canonical pathway analysis were used to explore the biological functions of the miRNA target genes. The study revealed that three miRNAs were upregulated in the serum samples of patients who later progressed to T2DM. Pathway analysis showed that the miRNA target genes were mainly significantly enriched in neuronal NO synthase (nNOS) signaling in neurons, amyloid processing, and hepatic cholestasis. ROC analysis demonstrated that miR-491-5p, miR-1307-3p, and miR-298 can be introduced as a diagnostic tool for the prediction of T2DM (area under the curve (AUC) = 94.0%, 88.0%, and 84.0%, respectively). Validation by real-time quantitative polymerase chain reaction (qRT-PCR) confirmed our findings. The results suggest that circulating miRNAs can potentially be used as predictive biomarkers of T2DM in prediabetic patients.
Development of Two-Dimensional Non-Hydrostatic Wave Model Based on Central-Upwind Scheme
Authors: Wu Gangfeng , Lin Ying-Tien , Dong Ping , Zhang Kefeng
Published: July 2020

In this study, a two-dimensional depth-integrated non-hydrostatic wave model is developed. The model solves the governing equations with hydrostatic and non-hydrostatic pressure separately. The velocities under hydrostatic pressure conditions are firstly obtained and then modified using the biconjugate gradient stabilized method. The hydrostatic front approximation (HFA) method is used to deal with the wave breaking issue, and after the wave breaks, the non-hydrostatic model is transformed into the hydrostatic shallow water model, where the non-hydrostatic pressure and vertical velocity are set to zero. Several analytical solutions and laboratory experiments are used to verify the accuracy and robustness of the developed model. In general, the numerical simulations are in good agreement with the theoretical or experimental results, which indicates that the model is able to simulate large-scale wave motions in practical engineering applications.
Molecular and Imaging Biomarkers in Alzheimer’s Disease: A Focus on Recent Insights
Authors: Villa Chiara , Lavitrano Marialuisa , Salvatore Elena , Combi Romina
Published: July 2020

Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly, affecting millions of people worldwide and clinically characterized by a progressive and irreversible cognitive decline. The rapid increase in the incidence of AD highlights the need for an easy, efficient and accurate diagnosis of the disease in its initial stages in order to halt or delay the progression. The currently used diagnostic methods rely on measures of amyloid-β (Aβ), phosphorylated (p-tau) and total tau (t-tau) protein levels in the cerebrospinal fluid (CSF) aided by advanced neuroimaging techniques like positron emission tomography (PET) and magnetic resonance imaging (MRI). However, the invasiveness of these procedures and the high cost restrict their utilization. Hence, biomarkers from biological fluids obtained using non-invasive methods and novel neuroimaging approaches provide an attractive alternative for the early diagnosis of AD. Such biomarkers may also be helpful for better understanding of the molecular mechanisms underlying the disease, allowing differential diagnosis or at least prolonging the pre-symptomatic stage in patients suffering from AD. Herein, we discuss the advantages and limits of the conventional biomarkers as well as recent promising candidates from alternative body fluids and new imaging techniques.