bluuebunny/crossref_metadata_2025 huggingface dataset:
Statins Aggravate the Risk of Insulin Resistance in Human Muscle
Authors: Grunwald Stefanie A. , Haafke Stefanie , Grieben Ulrike , Kassner Ursula , Steinhagen-Thiessen Elisabeth , Spuler Simone
Published: February 2022

Beside their beneficial effects on cardiovascular events, statins are thought to contribute to insulin resistance and type-2 diabetes. It is not known whether these effects are long-term events from statin-treatment or already triggered with the first statin-intake. Skeletal muscle is considered the main site for insulin-stimulated glucose uptake and therefore, a primary target for insulin resistance in the human body. We analyzed localization and expression of proteins related to GLUT4 mediated glucose uptake via AMPKα or AKT in human skeletal muscle tissue from patients with statin-intake >6 months and in primary human myotubes after 96 h statin treatment. The ratio for AMPKα activity significantly increased in human skeletal muscle cells treated with statins for long- and short-term. Furthermore, the insulin-stimulated counterpart, AKT, significantly decreased in activity and protein level, while GSK3ß and mTOR protein expression reduced in statin-treated primary human myotubes, only. However, GLUT4 was normally distributed whereas CAV3 was internalized from plasma membrane around the nucleus in statin-treated primary human myotubes. Statin-treatment activates AMPKα-dependent glucose uptake and remains active after long-term statin treatment. Permanent blocking of its insulin-dependent counterpart AKT activation may lead to metabolic inflexibility and insulin resistance in the long run and may be a direct consequence of statin-treatment.
A Route to Translate a Silk-Based Medical Device from Lab to Clinic: The Silk Biomaterials Srl Experience
Authors: Bassani Giulia Alessandra , Vincoli Valentina , Biagiotti Marco , Valsecchi Elisa , Zucca Marta Virginia , Clavelli Claudia , Alessandrino Antonio , Freddi Giuliano
Published: February 2022

The medical device is a nerve conduit entirely made of Bombyx mori silk fibroin. It is a tubular scaffold used for repairing peripheral nerve gaps, whose function is to protect the severed nerves and to favor their natural healing process. As any implantable medical device, the conduit must perform its function without causing adverse effects to the patient, meaning that it must be compliant with a range of regulations aimed at evaluating the risks related to the constituent materials and the manufacturing process, the toxicological impact of the processing aids, the biological safety, the functional performance, and the ability to sustain tissue regeneration processes. An exhaustive on-bench testing plan has been performed for the determination of the morphological, geometrical, physical, structural, and mechanical properties. For the toxicological analysis, the device was extracted with solvent and the number of leachable substances was determined by suitable chromatographic techniques. The biological safety was assessed by means of a set of tests, including cytotoxicity, delayed hypersensitivity, intracutaneous reactivity, pyrogen test, LAL (Limulus Amebocyte Lysate) test, acute systemic toxicity, and genotoxicity. Overall, the accumulated results demonstrated the suitability of the device for the intended use and supported the starting of a first-in-human clinical trial.
Genetic Differences among Established Populations of Aromia bungii (Faldermann, 1835) (Coleoptera: Cerambycidae) in Japan: Suggestion of Multiple Introductions
Authors: Tamura Shigeaki , Shoda-Kagaya Etsuko
Published: February 2022

Aromia bungii (Faldermann) (Coleoptera: Cerambycidae) is an invasive pest, damaging Rosaceae trees (particularly Prunus) in Japan and Europe. The establishment of this beetle in Japan was first detected in 2012, and subsequently, it has rapidly expanded its distribution. Currently, Japanese populations of A. bungii are widely distributed in six non-contiguous regions. In this study, we compared the nucleotide sequences of mitochondrial cytochrome oxidase subunit 1 of the populations in these six regions in Japan to examine whether multiple introductions or human-mediated long-distance dispersal have contributed to the non-contiguous distribution of A. bungii. Seven haplotypes were detected from Japanese populations, and one of these was identical to a sequence deposited from China. One to two haplotypes were detected in each region, suggesting a genetic bottleneck. Detected haplotypes differed between introduced regions, although two regions shared a single haplotype. These results suggest that multiple independent introductions of A. bungii have contributed to its non-contiguous distribution in Japan. Quarantine measures for wood-packing materials in trade need to be strengthened to prevent the establishment of further populations of A. bungii.
The First Fossil Representatives of the Sawfly Genera Emphytus and Empria from the upper Miocene of France (Hymenoptera, Tenthredinidae)
Authors: Nel André , Sammut Rose , Wei Meicai , Niu Gengyun , Jouault Corentin
Published: February 2022

Emphytusmiocenicus sp. nov., first fossil representative of this genus, is described from the upper Miocene of the diatom paleolake of Montagne d’Andance (Ardèche, France). Its placement is ensured by an in-depth comparison with all the extant and fossil genera of the subfamily Allantinae. The representatives of Emphytus are distributed in the Palearctic, Nearctic, and Oriental regions. Empria sammuti sp. nov., second representative of the latter genus, is described from the latest Miocene of the diatom paleolake of Sainte-Reine (Cantal, France). The placement of this new species is based on a detailed comparison with the extant genera of the tribe Empriini. The larvae of the extant Emphytus and Empria spp. are known to be phytophagous on angiosperm leaves of several families, all present as fossils in the taphocenoses of la Montagne d’Andance and Sainte-Reine. Emphytus miocenicus sp. nov. represents the oldest record of this genus and of its crown group, corroborating the estimate of a middle Eocene–middle Oligocene age for its stem group. Throughout our study, it appears that the first described fossil of the genus Empria, E. oligocaenica, from the Oligocene of Germany, needs to be revised and redescribed. It should preferably be treated until the revision as incertae sedis in Allantinae sensu lato.
The Increased Abundance of Commensal Microbes Decreases Drosophila melanogaster Lifespan through an Age-Related Intestinal Barrier Dysfunction
Authors: Lee Hye-Yeon , Lee Shin-Hae , Min Kyung-Jin
Published: February 2022

Background: Commensal microbiota live in their host with a symbiotic relationship that affects the host’s health and physiology. Many studies showed that microbial load and composition were changed by aging and observed that increasing the abundance and changing the composition of commensal microbes had detrimental effects on host lifespan. We hypothesized that dysbiosis of the intestinal microbiota leads to systemic effects in aging flies as a result of the increased intestinal permeability. Methods: We used the fruit fly, Drosophila melanogaster, laboratory strains w1118, as a model system with many advantages for microbe–host studies. Results: The incidence of intestinal dysfunction was increased with age, and intestinal dysfunction increased the permeability of the fly intestine to resident microbes. The lifespan of flies with an intestinal barrier dysfunction was increased by removal of the microbes. Interestingly, some bacteria were also found in the hemolymph of flies with intestinal barrier dysfunction. Conclusion: Our findings suggest the possibility that, as the host ages, there is an increase in intestinal permeability, which leads to an increased intestinal microbial load and a reduction in the host lifespan. Our data therefore indicate a connection between commensal microbes and host lifespan.
Diurnal Variability of Platelet Aggregation in Patients with Myocardial Infarction Treated with Prasugrel and Ticagrelor
Authors: Adamski Piotr , Barańska Malwina , Ostrowska Małgorzata , Kuliczkowski Wiktor , Buszko Katarzyna , Kościelska-Kasprzak Katarzyna , Karolko Bożena , Mysiak Andrzej , Kubica Jacek
Published: February 2022

Background: Contemporary antiplatelet treatment in acute myocardial infarction (AMI) is based on one of two P2Y12 receptor inhibitors, prasugrel or ticagrelor. The aim of this study was to compare diurnal variability of platelet reactivity between patients receiving prasugrel and ticagrelor during the initial phase of maintenance treatment after AMI. Methods: It was a prospective, two-center, pharmacodynamic, observational study. Blood for platelet testing was sampled at four time points on day four after AMI (8:00, 12:00, 16:00, 20:00). Diurnal variability of platelet reactivity was expressed as a coefficient of variation (CV) of the above-mentioned measurements. Results: 73 invasively-treated patients were enrolled (ticagrelor: n = 47, prasugrel: n = 26). CV was greater in patients treated with ticagrelor compared with prasugrel according to a VASP assay (47.8 [31.6–64.6]% vs. 21.3 [12.9–25.5]%, p < 0.001), while no statistical differences were detected when the CVs of platelet aggregation according to Multiplate were compared between ticagrelor- and prasugrel-treated patients. Ticagrelor-treated patients showed more pronounced platelet inhibition than prasugrel at 16:00 and 20:00 (VASP16:00: 20.6 ± 15.0 vs. 24.9 ± 12.8 PRI, p = 0.049; VASP20:00: 18.6 ± 17.7 vs. 26.0 ± 11.7 PRI, p = 0.002). Conclusions: Ticagrelor shows greater diurnal variability in platelet aggregation than prasugrel during the initial maintenance phase of AMI treatment, and this is due to the continuous increase of platelet inhibition after the morning maintenance dose. Both drugs provide an adequate antiplatelet effect early after AMI. Evaluation of the clinical significance of these findings warrants further investigation.
Hepatocellular Carcinoma in Hepatitis B Virus-Infected Patients and the Role of Hepatitis B Surface Antigen (HBsAg)
Authors: Kaur Satinder P. , Talat Arslan , Karimi-Sari Hamidreza , Grees Andrew , Chen Hao Wei , Lau Daryl T. Y. , Catana Andreea M.
Published: February 2022

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related death worldwide. Hepatitis B virus (HBV) infection is among the main risk factors for HCC. The risk of HCC is not eliminated completely after viral suppression, due to HBV DNA integrated into human chromosomes. Cirrhosis, HBV viral DNA levels, age, male gender, the immune response of the host against HBV, and a combination of obesity and diabetes are among the main risk factors for HCC. Active viral replication and long-standing active disease with inflammation are associated with a higher risk of HCC. Treatment of HBV with nucleos(t)ide analogues (NAs) decreased HCC risk by effectively decreasing viral load and inflammation. Similar risk factors have been reported in hepatitis B patients after seroclearance. Studies have reported decreased risk of HCC after seroclearance, but there were also conflicting results from a few studies indicating no difference in risk of developing HCC. The difference in HCC rates could be because of other factors such as coinfection, occult HBV infection, family history, HBV genotype, and other comorbidities. Due to the persistent risk of HCC after seroclearance, HCC surveillance is critical for early detection, especially in high-risk patients. However, long-term studies might be needed to further validate the results.
Acetylcholine Use in Modern Cardiac Catheterization Laboratories: A Systematic Review
Authors: Marrone Andrea , Pavasini Rita , Scollo Ennio , Gibiino Federico , Pompei Graziella , Caglioni Serena , Biscaglia Simone , Campo Gianluca , Tebaldi Matteo
Published: February 2022

Background: The use of acetylcholine for the diagnosis of vasospastic angina is recommended by international guidelines. However, its intracoronary use is still off-label due to the absence of safety studies. We aimed to perform a systematic review of the literature to identify adverse events related to the intracoronary administration of acetylcholine for vasoreactivity testing to fill this gap. Methods and results: We conducted a systematic review of observational studies and randomized controlled trials dealing with the intracoronary administration of acetylcholine. Articles were searched in MEDLINE (PubMed) using the MeSH strategy. Three independent reviewers determined whether the studies met the inclusion and exclusion criteria. A total of 434 articles were selected. Data concerning clinical characteristics, study population, acetylcholine dosage, and adverse effects were retrieved from the articles. Overall, 71,566 patients were included, of which only 382 (0.5%) developed one adverse event, and there were no fatal events reported (0%). Conclusions: Intracoronary administration of acetylcholine in the setting of coronary spasm provocation testing is safe and plays a central role in the evaluation of coronary vasomotion disorders, making it worthy of becoming a part of clinical practice in all cardiac catheterization laboratories.
Why Should Constant Stimulation of Saccular Afferents Modify the Posture and Gait of Patients with Bilateral Vestibular Dysfunction? The Saccular Substitution Hypothesis
Authors: Curthoys Ian S. , Smith Paul F. , de Miguel Angel Ramos
Published: February 2022

An ongoing EU Horizon 2020 Project called BionicVEST is investigating the effect of constant electrical stimulation (ES) of the inferior vestibular nerve in patients with bilateral vestibular dysfunction (BVD). The evidence is that constant ES results in improved postural stability and gait performance, and so the question of central importance concerns how constant ES of mainly saccular afferents in these BVD patients could cause this improved performance. We suggest that the constant ES substitutes for the absent saccular neural input to the vestibular nuclei and the cerebellum in these BVD patients and indirectly via these structures to other structures, which have been of great recent interest in motor control. One target area, the anterior midline cerebellum (the uvula), has recently been targeted as a location for deep-brain stimulation in human patients to improve postural stability and gait. There are projections from midline cerebellum to basal ganglia, including the striatum, which are structures involved in the initiation of gait. It may be that the effect of this activation of peripheral saccular afferent neurons is analogous to the effect of deep-brain stimulation (DBS) by electrodes in basal ganglia acting to help alleviate the symptoms of patients with Parkinson’s disease.
Burden of Endometriosis: Infertility, Comorbidities, and Healthcare Resource Utilization
Authors: Eisenberg Vered H. , Decter Dean H. , Chodick Gabriel , Shalev Varda , Weil Clara
Published: February 2022

The goal of our study was to evaluate the burden of endometriosis in the community by comparing healthcare resource utilization, total direct medical costs, infertility, and comorbidity rates of women with and without a diagnosis of endometriosis. A retrospective case–control study was performed using the databases of a 2.1 million-member nationwide healthcare plan. The study population included women aged 15–55 years enrolled in the healthcare plan. Women with a diagnosis (ICD-9) of endometriosis were compared to controls without diagnosed endometriosis. Women were individually matched (1:4) on age and residence area. Patient characteristics were described, including infertility, comorbidities, and annual healthcare resource utilization. Total direct medical costs were analyzed in a generalized linear model adjusting for age. Women with endometriosis (n = 6146, mean age ± SD: 40.4 ± 8.0 y) were significantly more likely than controls (n = 24,572) to have a lower BMI and a higher socioeconomic status. After adjusting for BMI and socioeconomic status, endometriosis was significantly associated with infertility (OR = 3.3; 95% CI 3.1–3.5), chronic comorbidities, higher utilization of healthcare services (hospitalization: OR = 2.3; 95% CI 2.1–2.5), pain medications, and antidepressants. Women aged 15–19 y with endometriosis had substantially higher utilization of primary care visits (57.7% vs. 14.4%) and oral contraceptive use (76.9% vs. 9.6%). Direct medical costs associated with endometriosis were higher than those for controls (OR = 1.75; 95% CI 1.69–1.85). Endometriosis is associated with a high burden of comorbidities, increased healthcare resource utilization, and excess costs, particularly for younger patients whose healthcare needs may differ widely from the older population.
Sex Differences in Baseline Characteristics Do Not Predict Early Outcomes after Percutaneous Coronary Intervention: Results from the Australian GenesisCare Cardiovascular Outcomes Registry (GCOR)
Authors: Conradie Andre , Delacroix Sinny , Duong MyNgan , Schwarz Nisha , Chowdhury Enayet , Worthley Stephen , Atherton John , Eccleston David
Published: February 2022

Objective: The effect of baseline differences between men and women on early outcomes after percutaneous coronary intervention (PCI). Design, setting, participants: This is an observational study of all participants in the GenesisCare Cardiovascular Outcomes Registry, undergoing PCI. The registry holds data for both emergency and elective procedures. Data was collected on 10,989 consecutive patients from 12 Australian Private Hospitals, including baseline demographics, co-morbidities, risk factors, PCI procedures, and lesion characteristics. Main outcome measures: Outcome was measured for complications (in-hospital death, peri-procedural myocardial infarctions, and bleeding events), at discharge and at 30-days for death, myocardial infarction, target lesion revascularisation (TLR), major adverse cardiac events (MACE), and unplanned readmissions. Results: Women represented 23% of the study population, were significantly older, with a higher rate of hypertension and hyperlipidaemia. Heart failure was more common in women and was associated with a significantly higher average ejection fraction than in men. Women had a lower rate of pre-existing coronary artery disease (CAD), had less complex CAD, and needed fewer stents. Periprocedural complications were similar, but major bleeding was more common in women. The 30-day outcome was similar between men and women for death, myocardial infarction, target lesion revascularisation (TLR), major adverse cardiovascular events (MACE), and unplanned readmissions. Conclusions: Although significant differences were observed between women and men in both clinical presentation and complexity of disease, the 30-day outcome was similar for death and MACE. Women had a higher rate of major bleeding events, and lower adherence to statins and dual antiplatelet therapy (DAPT).
Carisoprodol Single and Multiple Dose PK-PD. Part II: Pharmacodynamics Evaluation Method for Central Muscle Relaxants. Double-Blind Placebo-Controlled Clinical Trial in Healthy Volunteers
Authors: Calvo Aitana , González-Hidalgo Mercedes , Terleira Ana , Fernández Nieves , Portolés Antonio
Published: February 2022

Centrally acting skeletal muscle relaxants (CMR) such as carisoprodol are used to treat acute, painful musculoskeletal conditions, though its precise mode of action has not been characterized. A double-blinded, placebo-controlled, randomized clinical trial was designed to evaluate the pharmacokinetics–pharmacodynamics (PKPD) of CMR after single (350 mg), double (700 mg), and multiple doses (up to 350 mg/8 h, 14 days) of carisoprodol. Muscular (Electromyogram–EMG, muscular strength dynamometry), central (sedation), and tolerability (psychomotor activity test, adverse events) parameters, as well as withdrawal symptoms, were evaluated. Thirteen healthy volunteers were enrolled. No evidence of direct muscle relaxation was evidenced, but some differences on sedation were evidenced throughout the study, suggesting that CMRs act, at least partly, through sedation. Most significant differences were detected at 1.5 h after dosing. The effect on psychomotor impairment was variable, most prominently after 1.5 h, too, suggesting that it is produced by carisoprodol rather than by meprobamate. No withdrawal symptoms were detected, so the risk of dependence following maximum doses and duration of treatment recommended, and under medical supervision, should be low.
Healthcare Utilization and Costs in Sepsis Survivors in Germany–Secondary Analysis of a Prospective Cohort Study
Authors: Schmidt Konrad , Huelle Katharina , Reinhold Thomas , Prescott Hallie , Gehringer Rebekka , Hartmann Michael , Lehmann Thomas , Mueller Friederike , Reinhart Konrad , Schneider Nico , Schroevers Maya , Kosilek Robert , Vollmar Horst , Heintze Christoph , Gensichen Jochen ,   the SMOOTH Study Group
Published: February 2022

Background: Survivors of sepsis often face long-term sequelae after intensive care treatment. Compared to the period of hospitalization, little is known about the ambulatory healthcare utilization in sepsis patients. The study evaluated healthcare utilization and associated costs of sepsis care including allied health professions after initial hospitalization. Methods: Secondary analysis was performed on data in 210 sepsis patients prospectively enrolled from nine intensive care study centers across Germany. Data was collected via structured surveys among their Primary care (Family-) physicians (PCPs) within the first month after discharge from ICU (baseline) and again at 6, 12 and 24 months after discharge, each relating to the period following the last survey. Costs were assessed by standardized cost unit rates from a health care system’s perspective. Changes in healthcare utilization and costs over time were calculated using the Wilcoxon rank-sum test. Results: Of the 210 patients enrolled, 146 (69.5%) patients completed the 24 months follow-up. In total, 109 patients were hospitalized within the first 6 months post-intensive care. Mean total direct costs per patient at 0–6 months were €17,531 (median: €6047), at 7–12 months €9029 (median: €3312), and at 13–24 months €18,703 (median: €12,828). The largest contributor to the total direct costs within the first 6 months was re-hospitalizations (€13,787 (median: €2965). After this first half year, we observed a significant decline in inpatient care costs for re-hospitalizations (p ≤ 0.001). PCPs were visited by more than 95% of patients over 24 months. Conclusions: Sepsis survivors have high health care utilization. Hospital readmissions are frequent and costly. Highest costs and hospitalizations were observed in more than half of patients within the first six months post-intensive care. Among all outpatient care providers, PCPs were consulted most frequently. Clinical impact: Sepsis survivors have a high healthcare utilization and related costs which persist after discharge from hospital. Within outpatient care, possible needs of sepsis survivors as physiotherapy or psychotherapy seem not to be met appropriately. Development of sepsis aftercare programs for early detection and treatment of complications should be prioritized.
Clinical Utility of Plasma Cell-Free DNA EGFR Mutation Analysis in Treatment-Naïve Stage IV Non-Small Cell Lung Cancer Patients
Authors: Kim Bo-Guen , Jang Ja-Hyun , Kim Jong-Won , Shin Sun Hye , Jeong Byeong-Ho , Lee Kyungjong , Kim Hojoong , Kwon O Jung , Ahn Myung-Ju , Um Sang-Won
Published: February 2022

Background: Plasma cell-free Deoxyribo nucleic acid epidermal growth factor receptor (EGFR) mutation tests are widely used at initial diagnosis and at progression in stage IV non-small cell lung cancer (NSCLC). We analyzed the factors associated with plasma EGFR mutation detection and the effect of plasma EGFR genotyping on the clinical outcomes of the patients with treatment-naïve stage IV NSCLC. Methods: In this retrospective cohort study, we included subjects with treatment-naïve stage IV NSCLC who underwent plasma EGFR genotyping between 2018 and 2020. The presence of plasma EGFR mutation was determined by real-time polymeric chain reaction. Results: The prevalence of EGFR mutation in this cohort was 52.7% (164/311). Among 164 EGFR mutant subjects, 34 (20.7%) were positive for the plasma EGFR mutation assay only. In multivariable analysis, the detection of plasma EGFR mutation was significantly related to higher serum carcinoembryonic antigen levels, never-smoker status, N3 stage, and brain or intrathoracic metastasis. The time to treatment initiation (TTI) of the plasma EGFR mutation-positive group (14 days) was shorter than that of the plasma EGFR mutation-negative group (21 days, p < 0.001). More patients received the 1st line EGFR-TKI in the plasma positive group compared with the tissue positive group. Conclusion: Smoking status and the factors reflecting tumor burden were associated with the detection of plasma EGFR mutation. The plasma EGFR mutation assay can shorten the TTI, and facilitate the 1st line EGFR-TKI therapy for patients with treatment-naïve stage IV NSCLC, especially in the region of high-prevalence of EGFR mutation.
Dynamic Features of Herd Immunity: Similarities in Age-Specific Anti-Measles Seroprevalence Data between Two Countries of Different Epidemiological History
Authors: Böröcz Katalin , Samardžić Senka , Drenjančević Ines , Markovics Ákos , Berki Tímea , Németh Péter
Published: February 2022

(1) Background: Measles immunization gap(s) raise the concern of potential outbreaks. Both Croatia and Hungary are situated in the vicinity of measles-endemic countries. Potentially compromised immunization activities due to the COVID-19 surge is a ground for concern. Our aim was to compare age-stratified seroprevalence results in the cross-border region. (2) Methods: Anti-MMR specific antibody levels (IgG) of 950 anonymous Croatian samples were compared with previous Hungarian results (n > 3500 samples), and former Croatian seroprevalence data (n = 1205). Seropositivity ratios were determined using our self-developed anti-MMR indirect ELISA (Euroimmun IgG ELISA kits were used as control). (3) Results: Measured seropositivity ratios of the Croatian samples were largely overlapping with our earlier published Hungarian data (the lowest seropositivity ratios were measured among individuals of 34–43 years of age with 78% of seropositivity) and are in accordance with earlier published data of Croatian researchers. (4) Conclusion: Although the epidemiological histories of the two countries are different, analogies in age-specific measles susceptibility have been discovered. We suggest that besides the potential coincidence in vaccination ineffectiveness, the inherent biological dynamics of vaccination-based humoral protection might have also contributed to the experienced similarities. Our findings may also serve as a lesson regarding the current anti-COVID-19 vaccination strategy.
Controversies in Choledochal Malformation in Children: An International Survey among Pediatric Hepatobiliary Surgeons and Gastroenterologists
Authors: Hulscher Jan B. F. , Kuebler Joachim F. , Bruggink Janneke M. , Davenport Mark , Scholz Stefan , Petersen Claus , Madadi-Sanjani Omid , Schukfeh Nagoud
Published: February 2022

Background: While congenital choledochal malformation (CCM) is relatively well known within the pediatric surgical and pediatric gastroenterological communities, many controversies and questions remain. Methods: In this paper, we will discuss the results of an international Delphi survey among members of the European Reference Network RARE-LIVER and of the faculty of the Biliary Atresia and Related Diseases (BARD) network to identify the most common practices as well as controversies regarding diagnosis, treatment and follow-up of this still enigmatic disease. Results: Twenty-two individual respondents completed the survey. While there seems to be agreement on the definitions of CCM, preoperative workup, surgical approach and follow-up still vary considerably. The mainstay of treatment remains the removal of the entire extrahepatic biliary tract, clearance of debris both proximally and distally, followed by reconstruction with (according to 86% of respondents) a Roux-en-Y hepaticojejunostomy. Nonetheless, both laparoscopic and robotic-assisted resections are gaining ground with the suggestion that this might be facilitated by concentration of care and resources in specialized centers. However, long-term outcomes are still lacking. Conclusions: As even post-surgical CCM has to be considered as having premalignant potential, follow-up should be well-organized and continued into adulthood. This seems to be lacking in many centers. International cooperation for both benchmarking and research is paramount to improving care for this rare disease.
Management and Sustainable Exploitation of Marine Environments through Smart Monitoring and Automation
Authors: Glaviano Francesca , Esposito Roberta , Cosmo Anna Di , Esposito Francesco , Gerevini Luca , Ria Andrea , Molinara Mario , Bruschi Paolo , Costantini Maria , Zupo Valerio
Published: February 2022

Monitoring of aquatic ecosystems has been historically accomplished by intensive campaigns of direct measurements (by probes and other boat instruments) and indirect extensive methods such as aero-photogrammetry and satellite detection. These measurements characterized the research in the last century, with significant but limited improvements within those technological boundaries. The newest advances in the field of smart devices and increased networking capabilities provided by emerging tools, such as the Internet of Things (IoT), offer increasing opportunities to provide accurate and precise measurements over larger areas. These perspectives also correspond to an increasing need to promptly respond to frequent catastrophic impacts produced by drilling stations and intense transportation activities of dangerous materials over ocean routes. The shape of coastal ecosystems continuously varies due to increasing anthropic activities and climatic changes, aside from touristic activities, industrial impacts, and conservation practices. Smart buoy networks (SBNs), autonomous underwater vehicles (AUVs), and multi-sensor microsystems (MSMs) such as smart cable water (SCW) are able to learn specific patterns of ecological conditions, along with electronic “noses”, permitting them to set innovative low-cost monitoring stations reacting in real time to the signals of marine environments by autonomously adapting their monitoring programs and eventually sending alarm messages to prompt human intervention. These opportunities, according to multimodal scenarios, are dramatically changing both the coastal monitoring operations and the investigations over large oceanic areas by yielding huge amounts of information and partially computing them in order to provide intelligent responses. However, the major effects of these tools on the management of marine environments are still to be realized, and they are likely to become evident in the next decade. In this review, we examined from an ecological perspective the most striking innovations applied by various research groups around the world and analyzed their advantages and limits to depict scenarios of monitoring activities made possible for the next decade.
Predicting the Instability Trajectory of an Obliquely Loaded Pipeline on a Clayey Seabed
Authors: Wang Ning , Qi Wengang , Gao Fuping
Published: February 2022

Predicting the instability trajectory of an obliquely loaded pipeline on the seabed is vital for the global buckling assessment. To numerically investigate the obliquely loaded pipe–soil interactions, a plane strain elastoplastic finite element model incorporating the adaptive meshing technique and the contact-pair algorithm is employed and verified with the existing experimental data and the analytical predictions. The evolution of slip mechanisms within the underlying soil is simulated, indicating the instability direction of the pipe, and the corresponding ultimate soil resistance is closely correlated. It is also indicated that the ultimate load angle is in the positive correlation with the movement angle, the dimensionless embedment of the pipe and the roughness coefficient of the pipe–soil interface. On the basis of numerous simulations, a force-resultant plasticity model including the bearing capacity envelope and the flow rule is proposed for predicting the behavior of a partially embedded pipeline on the clayey seabed. Finally, an explicit expression with respect to the critical submerged weight of the pipe is derived for distinguishing the lateral instability of a pipe between the ‘light’ and the ‘heavy’ mode.
A Fish and Dolphin Biophony in the Boat Noise-Dominated Soundscape of the Cres-Lošinj Archipelago (Croatia)
Authors: Picciulin Marta , Bolgan Marta , Rako-Gospić Nikolina , Petrizzo Antonio , Radulović Marko , Falkner Raffaela
Published: February 2022

Spatio-temporal variability of marine soundscapes reflects environmental dynamics and local habitat health. This study characterizes the coastal soundscape of the Cres-Lošinj Natura 2000 Site of Community Importance, encompassing the non-tourist (11–15 March 2020) and the tourist (26–30 July 2020) season. A total of 240 h of continuous recordings was manually analyzed and the abundance of animal vocalizations and boat noise was obtained; sound pressure levels were calculated for the low (63–2000 Hz) and high (2000–20,000 Hz) frequency range. Two fish sound types were drivers of both seasonal and diel variability of the low-frequency soundscape. The first is emitted by the cryptic Roche’s snake blenny (Ophidion rochei), while the second, whose emitter remains unknown, was previously only described in canyons and coralligenous habitats of the Western Mediterranean Sea. The high-frequency bands were characterized by bottlenose dolphin (Tursiops truncatus) vocalizations, indicating dolphins’ use of area for various purposes. Boat noise, however, dominated the local soundscape along the whole considered periods and higher sound pressure levels were found during the Tourist season. Human-generated noise pollution, which has been previously found 10 years ago, is still present in the area and this urges management actions.
Investigation on a Large-Scale Braceless-TLP Floating Offshore Wind Turbine at Intermediate Water Depth
Authors: Zhou Yiming , Ren Yajun , Shi Wei , Li Xin
Published: February 2022

Tension leg platform (TLP) is a cost-effective and high-performance support structure for floating offshore wind turbine (FOWT) because of its small responses in heave, pitch, and roll with the constraint of the tendons. China, as the largest market of offshore wind energy, has shown a demand for developing reliable, viable floating platform support structures, especially aiming at the intermediate water depth. The present paper described a newly proposed 10-MW Braceless-TLP FOWT designed for a moderate water depth of 60 m. The numerical simulations of the FOWT are carried out using the coupled aero-hydro-servo-elastic-mooring calculation tool FAST. The measured wind and wave data of the target site close to the Fujian Province of China were used to evaluate the performance of the FOWT under the 100-, 50-, 5-, and 2-year-return stochastic weather conditions. The natural periods of the platform in surge, sway, heave, pitch, roll, and yaw were found to be within the range recommended by the design standard DNV-RP-0286 Coupled Analysis of Floating Wind Turbines. The largest surge of the water depth ratio among all the load cases was 15%, which was smaller than the admissible ratio of 23%. The tower top displacements remained between −1 m and 1 m, which were at a similar order to those of a 10-MW monopile-supported offshore wind turbine. The six tendons remained tensioned during the simulation, even under the operational and extreme (parked) environmental conditions. The Braceless-TLP FOWT showed an overall satisfying performance in terms of the structural stability and illustrates the feasibility of this type of FOWT at such a moderate water depth.
Reward Deficiency Syndrome (RDS) Surprisingly Is Evolutionary and Found Everywhere: Is It “Blowin’ in the Wind”?
Authors: Blum Kenneth , McLaughlin Thomas , Bowirrat Abdalla , Modestino Edward J. , Baron David , Gomez Luis Llanos , Ceccanti Mauro , Braverman Eric R. , Thanos Panayotis K. , Cadet Jean Lud , Elman Igor , Badgaiyan Rajendra D. , Jalali Rehan , Green Richard , Simpatico Thomas A. , Gupta Ashim , Gold Mark S.
Published: February 2022

Reward Deficiency Syndrome (RDS) encompasses many mental health disorders, including a wide range of addictions and compulsive and impulsive behaviors. Described as an octopus of behavioral dysfunction, RDS refers to abnormal behavior caused by a breakdown of the cascade of reward in neurotransmission due to genetic and epigenetic influences. The resultant reward neurotransmission deficiencies interfere with the pleasure derived from satisfying powerful human physiological drives. Epigenetic repair may be possible with precision gene-guided therapy using formulations of KB220, a nutraceutical that has demonstrated pro-dopamine regulatory function in animal and human neuroimaging and clinical trials. Recently, large GWAS studies have revealed a significant dopaminergic gene risk polymorphic allele overlap between depressed and schizophrenic cohorts. A large volume of literature has also identified ADHD, PTSD, and spectrum disorders as having the known neurogenetic and psychological underpinnings of RDS. The hypothesis is that the true phenotype is RDS, and behavioral disorders are endophenotypes. Is it logical to wonder if RDS exists everywhere? Although complex, “the answer is blowin’ in the wind,” and rather than intangible, RDS may be foundational in species evolution and survival, with an array of many neurotransmitters and polymorphic loci influencing behavioral functionality.
Homologous Recombination Deficiency (HRD) and BRCA 1/2 Gene Mutation for Predicting the Effect of Platinum-Based Neoadjuvant Chemotherapy of Early-Stage Triple-Negative Breast Cancer (TNBC): A Systematic Review and Meta-Analysis
Authors: Chai Yue , Chen Yujie , Zhang Di , Wei Yuce , Li Zhijun , Li Qiao , Xu Binghe
Published: February 2022

Background: Platinum-based agents may benefit patients with triple-negative breast cancer (TNBC) whose tumors are dysfunctional in DNA repair mechanisms associated with the homologous recombination repair (HRR) genes. The purpose of this meta-analysis was to assess the values of BRCA1/2 and homologous recombination deficiency (HRD) in the prediction of the pathological complete response (pCR) rates of patients with TNBC treated with platinum-based neoadjuvant chemotherapy (NAC). Patients and Methods: Patients with TNBC with BRCA or HRD status from platinum-based NAC trials were analyzed. The odds ratios (ORs) with 95% confidence intervals (CI) for the identified studies were calculated. Results: 13 eligible studies between January 2000 and September 2021 were included through systematic literature searches of Embase, PubMed, Cochrane, and Web of Science databases. In 12 trials with BRCA status, 629 of 1266 (49.7%) patients with TNBC achieved pCR with platinum-based NAC, including 134 out of 222 (60.4%) BRCA1/2-mutated patients and 495 out of 1044 (47.4%) BRCA wildtype patients (OR, 1.62; 95% CI, 1.20–2.20). The prevalence of HRD was higher than BRCA1/2 mutations in patients with TNBC (69.2% vs. 17.5%). In six trials with HRD information, pCR rates of HRD-positive patients with TNBC were significantly higher than those of HRD-negative patients with TNBC (241/412, 58.5% vs. 60/183, 32.8%, OR, 3.01; 95% CI, 2.07–4.39, p < 0.001). Conclusions: BRCA1/2-mutated and HRD-positive patients with TNBC could benefit from platinum-based NAC. In the future, a prospective study using unified HRD testing criteria is warranted for further investigation.
miR-155: A Potential Biomarker for Predicting Mortality in COVID-19 Patients
Authors: Kassif-Lerner Reut , Zloto Keren , Rubin Nadav , Asraf Keren , Doolman Ram , Paret Gidi , Nevo-Caspi Yael
Published: February 2022

COVID-19, a pandemic of severe acute respiratory syndrome caused by Coronavirus 2 (SARS-CoV-2), continues to pose diagnostic and therapeutic challenges due to its unpredictable clinical course. Prognostic biomarkers may improve care by enabling quick identification of patients who can be safely discharged home versus those who may need careful respiratory monitoring and support. MicroRNAs (miRNAs) have risen to prominence as biomarkers for many disease states and as tools to assist in medical decisions. In the present study, we aimed to examine circulating miRNAs in hospitalized COVID-19 patients and to explore their potential as biomarkers for disease severity. We studied, by quantitative PCR, the expressions of miR-21, miR-146a, miR-146b, miR-155, and miR-499 in peripheral blood. We found that mild COVID-19 patients had 2.5-fold less circulating miR-155 than healthy people, and patients with a severe COVID-19 disease had 5-fold less circulating miR-155 than healthy people. In addition, we found that miR-155 is a good predictor of COVID-19 mortality. We suggest that examining miR-155 levels in patients’ blood, upon admission to hospital, will ameliorate the care given to COVID-19 patients.
Price and Volatility Transmissions among Natural Gas, Fertilizer, and Corn Markets: A Revisit
Authors: Yang Zhengliang , Du Xiaoxue , Lu Liang , Tejeda Hernan
Published: February 2022

In this paper, we revisit price and volatility transmission among natural gas, fertilizer, and corn markets; an important issue was explored in previous work. An update of the results is urgently needed due to the recent enormous price volatility in the commodities, fertilizer, and energy markets. We followed the same methodology as previous work and used the vector error correction model and the multivariate generalized autoregressive heteroskedasticity model, but we adopted a new methodology to gather higher frequency data for fertilizer to estimate the interactions and examine the mechanisms between these market prices. Our results are consistent with previous research showing that natural gas price returns in the short-term are significantly affected by its lagged returns from itself and corn markets, and it will be affected by its lagged return sand fertilizer markets. However, we did not find a significant relationship among fertilizer, corn, and natural gas markets from May to November 2021. Moreover, the lagged conditional volatility of corn prices will affect the conditional volatility in the natural gas market but not vice versa.
Effects of Recasts, Metalinguistic Feedback, and Students’ Proficiency on the Acquisition of Greek Perfective Past Tense
Authors: Ioannou Sophia , Tsagari Dina
Published: February 2022

The role of interactional corrective feedback in second language assessment has attracted both teachers’ and second language researchers’ interest, as they are concerned with when corrective feedback can be implemented to assist second language acquisition. This quasi-experimental intervention study aims to investigate the impact of two corrective feedback types, namely recasts and metalinguistic feedback, and students’ proficiency in the acquisition of the Greek perfective past tense. The sample consists of ten adult beginners’ classes (n = 86 students) of the Modern Greek Language Teaching Center of the University of Athens. The classes were randomly assigned to three treatment conditions: (a) recast; (b) metalinguistic feedback; (c) no feedback and participated in form-focused production activities. A grammaticality judgment pretest and posttest were administrated to measure participants’ development on the explicit knowledge of perfective past tense morphology. After the treatment, participants were divided in the database into high and low beginner students based on their performance on a placement test administrated prior to the treatment. Results revealed that the groups that received corrective feedback outperformed the control group, while no statistical significance was found between the two treatment groups. Moreover, high-beginner learners benefited equally from both feedback types, whereas low-beginner learners benefited significantly from metalinguistic feedback.
SIRT1: A Key Player in Male Reproduction
Authors: Khawar Muhammad , Sohail Abdullah , Li Wei
Published: February 2022

Reproduction is the way to immortality for an individual, and it is essential to the continuation of the species. Sirtuins are involved in cellular homeostasis, energy metabolism, apoptosis, age-related problems, and sexual reproduction. Sirtuin 1 (SIRT1) belongs to the sirtuin family of deacetylases, and it is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase. It removes the acetyl group from a variety of substrates. SIRT1 regulates endocrine/metabolic, reproductive, and placental development by deacetylating histone, different transcription factors, and signal transduction molecules in a variety of cellular processes. It also plays a very important role in the synthesis and secretion of sex hormones via regulating the hypothalamus-pituitary-gonadal (HPG) axis. Moreover, SIRT1 participates in several key stages of spermatogenesis and sperm maturation. The current review will give a thorough overview of SIRT1’s functions in male reproductive processes, thus paving the way for more research on restorative techniques and their uses in reproductive medicine.
SmileGNN: Drug–Drug Interaction Prediction Based on the SMILES and Graph Neural Network
Authors: Han Xueting , Xie Ruixia , Li Xutao , Li Junyi
Published: February 2022

Concurrent use of multiple drugs can lead to unexpected adverse drug reactions. The interaction between drugs can be confirmed by routine in vitro and clinical trials. However, it is difficult to test the drug–drug interactions widely and effectively before the drugs enter the market. Therefore, the prediction of drug–drug interactions has become one of the research priorities in the biomedical field. In recent years, researchers have been using deep learning to predict drug–drug interactions by exploiting drug structural features and graph theory, and have achieved a series of achievements. A drug–drug interaction prediction model SmileGNN is proposed in this paper, which can be characterized by aggregating the structural features of drugs constructed by SMILES data and the topological features of drugs in knowledge graphs obtained by graph neural networks. The experimental results show that the model proposed in this paper combines a variety of data sources and has a better prediction performance compared with existing prediction models of drug–drug interactions. Five out of the top ten predicted new drug–drug interactions are verified from the latest database, which proves the credibility of SmileGNN.