bluuebunny/crossref_metadata_2025 huggingface dataset:
Opioid Addiction and Opioid Receptor Dimerization: Structural Modeling of the OPRD1 and OPRM1 Heterodimer and Its Signaling Pathways
Authors: Wu Bohua , Hand William , Alexov Emil
Published: September 2021

Opioid addiction is a complex phenomenon with genetic, social, and other components. Due to such complexity, it is difficult to interpret the outcome of clinical studies, and thus, mutations found in individuals with these addictions are still not indisputably classified as opioid addiction-causing variants. Here, we computationally investigated two such mutations, A6V and N40D, found in the mu opioid receptor gene OPRM1. The mutations are located in the extracellular domain of the corresponding protein, which is important to the hetero-dimerization of OPRM1 with the delta opioid receptor protein (OPRD1). The hetero-dimerization of OPRD1–OPRM1 affects the signaling pathways activated by opioids and natural peptides and, thus, could be considered a factor contributing to addiction. In this study, we built four 3D structures of molecular pathways, including the G-protein signaling pathway and the β-arrestin signaling pathway of the heterodimer of OPRD1–OPRM1. We also analyzed the effect of mutations of A6V and N40D on the stability of individual OPRM1/OPRD1 molecules and the OPRD1–OPRM1 heterodimer with the goal of inferring their plausible linkage with opioid addiction. It was found that both mutations slightly destabilize OPRM1/OPRD1 monomers and weaken their association. Since hetero-dimerization is a key step for signaling processes, it is anticipated that both mutations may be causing increased addiction risk.
Smoothelin-Like Protein 1 Regulates the Thyroid Hormone-Induced Homeostasis and Remodeling of C2C12 Cells via the Modulation of Myosin Phosphatase
Authors: Major Evelin , Keller Ilka , Horváth Dániel , Tamás István , Erdődi Ferenc , Lontay Beáta
Published: September 2021

The pathological elevation of the active thyroid hormone (T3) level results in the manifestation of hyperthyroidism, which is associated with alterations in the differentiation and contractile function of skeletal muscle (SKM). Myosin phosphatase (MP) is a major cellular regulator that hydrolyzes the phosphoserine of phosphorylated myosin II light chain. MP consists of an MYPT1/2 regulatory and a protein phosphatase 1 catalytic subunit. Smoothelin-like protein 1 (SMTNL1) is known to inhibit MP by directly binding to MP as well as by suppressing the expression of MYPT1 at the transcriptional level. Supraphysiological vs. physiological concentration of T3 were applied on C2C12 myoblasts and differentiated myotubes in combination with the overexpression of SMTNL1 to assess the role and regulation of MP under these conditions. In non-differentiated myoblasts, MP included MYPT1 in the holoenzyme complex and its expression and activity was regulated by SMTNL1, affecting the phosphorylation level of MLC20 assessed using semi-quantitative Western blot analysis. SMTNL1 negatively influenced the migration and cytoskeletal remodeling of myoblasts measured by high content screening. In contrast, in myotubes, the expression of MYPT2 but not MYPT1 increased in a T3-dependent and SMTNL1-independent manner. T3 treatment combined with SMTNL1 overexpression impeded the activity of MP. In addition, MP interacted with Na+/K+-ATPase and dephosphorylated its inhibitory phosphorylation sites, identifying this protein as a novel MP substrate. These findings may help us gain a better understanding of myopathy, muscle weakness and the disorder of muscle regeneration in hyperthyroid patients.
Revealing Electrical and Mechanical Performances of Highly Oriented Electrospun Conductive Nanofibers of Biopolymers with Tunable Diameter
Authors: Munawar Muhammad A. , Schubert Dirk W.
Published: September 2021

The present study outlines a reliable approach to determining the electrical conductivity and elasticity of highly oriented electrospun conductive nanofibers of biopolymers. The highly oriented conductive fibers are fabricated by blending a high molar mass polyethylene oxide (PEO), polycaprolactone (PCL), and polylactic acid (PLA) with polyaniline (PANi) filler. The filler-matrix interaction and molar mass (M) of host polymer are among governing factors for variable fiber diameter. The conductivity as a function of filler fraction (φ) is shown and described using a McLachlan equation to reveal the electrical percolation thresholds (φc) of the nanofibers. The molar mass of biopolymer, storage time, and annealing temperature are significant factors for φc. The Young’s modulus (E) of conductive fibers is dependent on filler fraction, molar mass, and post-annealing process. The combination of high orientation, tunable diameter, tunable conductivity, tunable elasticity, and biodegradability makes the presented nanofibers superior to the fibers described in previous literature and highly desirable for various biomedical and technical applications.
Molecular Pathways Involved in Frontotemporal Lobar Degeneration with TDP-43 Proteinopathy: What Can We Learn from Proteomics?
Authors: Mol Merel O. , Miedema Suzanne S. M. , van Swieten John C. , van Rooij Jeroen G. J. , Dopper Elise G. P.
Published: September 2021

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder clinically characterized by behavioral, language, and motor symptoms, with major impact on the lives of patients and their families. TDP-43 proteinopathy is the underlying neuropathological substrate in the majority of cases, referred to as FTLD-TDP. Several genetic causes have been identified, which have revealed some components of its pathophysiology. However, the exact mechanisms driving FTLD-TDP remain largely unknown, forestalling the development of therapies. Proteomic approaches, in particular high-throughput mass spectrometry, hold promise to help elucidate the pathogenic molecular and cellular alterations. In this review, we describe the main findings of the proteomic profiling studies performed on human FTLD-TDP brain tissue. Subsequently, we address the major biological pathways implicated in FTLD-TDP, by reviewing these data together with knowledge derived from genomic and transcriptomic literature. We illustrate that an integrated perspective, encompassing both proteomic, genetic, and transcriptomic discoveries, is vital to unravel core disease processes, and to enable the identification of disease biomarkers and therapeutic targets for this devastating disorder.
The Impact of m1A Methylation Modification Patterns on Tumor Immune Microenvironment and Prognosis in Oral Squamous Cell Carcinoma
Authors: Gao Li , Chen Ru , Sugimoto Masahiro , Mizuta Masanobu , Kishimoto Yo , Omori Koichi
Published: September 2021

N1-methyladenosine (m1A) modification widely participates in the occurrence and progression of numerous diseases. Nevertheless, the potential roles of m1A in the tumor immune microenvironment (TIME) are still not fully understood. Based on 10 m1A methylation regulators, we comprehensively explored the m1A modification patterns in 502 patients with oral squamous cell carcinoma (OSCC). The m1A modification patterns were correlated with TIME characteristics and the m1A score was established to evaluate the effect of the m1A modification patterns on individual OSCC patients. The TIME characteristics and survival outcomes under the three m1A modification patterns were significantly distinct. OSCC patients in the high m1A score group were characterized by poorer prognosis, lower immune infiltration, lower ssGSEA score, lower expression levels of immune checkpoint molecules, and higher tumor mutation loads. The present study revealed that m1A modification might be associated with the TIME in OSCC, and has potential predictive ability for the prognosis of OSCC.
On the Applicability of Transfer Function Models for SSI Embedment Effects
Authors: Cavalieri Francesco , Correia António A. , Pinho Rui
Published: September 2021

Soil-structure interaction (SSI) effects are typically neglected for relatively lightweight buildings that are less than two-three storeys high with a limited footprint area and resting on shallow foundations (i.e., not featuring a basement). However, when the above conditions are not satisfied, and in particular when large basements are present, important kinematic SSI may develop, causing the foundation-level motion to deviate from the free-field one due to embedment effects. In the literature, transfer function models that estimate the filtering effect induced by rigid massless embedded foundations are available to “transform” foundation-level recordings into free-field ones, and vice-versa. This work describes therefore a numerical study aimed at assessing potential limits of the applicability of such transfer functions through the employment of a 3D nonlinear soil-block model representing a layered soil, recently developed and validated by the authors, and featuring on top a large heavy building with basement. A number of finite element site response analyses were carried out for different seismic input signals, soil profiles and embedment depths of the building’s basement. The numerically obtained transfer functions were compared with the curves derived using two analytical models. It was observed that the latter are able to reliably predict the embedment effects in “idealised” soil/input conditions under which they have been developed. However, in real conditions, namely when a non-homogeneous profile with nonlinear behaviour under a given seismic excitation is considered, especially in presence of a basement that is more than one storey high, they may fail in capturing some features, such as the frequency-dependent amplification of the motion at the basement level of a building with respect to the free-field one.
Different Host Plants Distinctly Influence the Feeding Ability of the Brown Citrus Aphid Toxoptera citricida
Authors: Zhao Runa , Wu Chengxu , He Yingqin , Yu Chun , Liu Jianfeng , Li Taisheng , Zhou Changyong , Chen Wenlong
Published: September 2021

Piercing–sucking insects are important crop pests, and an understanding of their feeding behavior and population development plays a crucial role in studying insect population dynamics and crop resistance. In our study, we examined the probing behavior of the brown citrus aphid, Toxoptera citricida, using electropenetrography and assessed its population development after 8 days on seven host plants: Yuzu, Citrus junos Sieb. ex Tanaka; Rough Lemon, C. jambhiri Lush.; ‘Luofu’ kumquat, Fortunella margarita Swingle; ‘Olinda’ valencia orange, C. sinensis (L.) Osbeck; ‘Yanxiwanlu’ Ponkan, C. reticulata Blanco; ‘Rohde Red’ valencia orange, C. sinensis; and ‘Eureka’ lemon, C. limon (L.) Osbeck. The results demonstrated that probing by the brown citrus aphid differed significantly according to the target hosts. Toxoptera citricida produced significantly more pathway activities on Eureka than on Rough Lemon and Yuzu. Toxoptera citricida spent more time from the first probe to first salivation into phloem sieve elements on Eureka compared to Yuzu. In addition, the total duration of ingestion from sieve cells of each aphid in the phloem-feeding phase was shortest on Eureka, and this was significantly shorter than that on Yuzu, Rough Lemon, Luofu, and Olinda. The population number of T. citricida on Eureka after 8 days was significantly lower than that on the other hosts. Overall, Eureka was found to have obvious resistance to T. citricida, whereas Yuzu and Rough Lemon were susceptible host plants. These results provide a theoretical basis for exploring aphid-resistant fruit tree resources using resistant varieties.
Biocontrol of Invasive Conical Snails by the Parasitoid Fly Sarcophaga villeneuveana in South Australia 20 Years after Release
Authors: Muirhead Kate A. , Perry Kym D.
Published: September 2021

Two conical snail species introduced to Australia from the Mediterranean region during the 20th century are major pests of pastures and grain crops. In 2000, a parasitoid fly, Sarcophaga villeneuveana, was introduced into South Australia for biocontrol of the conical snail, Cochlicella acuta. The fly successfully established in the region but assessments of its impact in different snail aestivation microhabitats were limited. Twenty years on, field surveys were conducted to assess the geographic distribution and parasitism rates of S. villeneuveana on conical snails in the Yorke Peninsula region. Nineteen sites were sampled on four occasions in January and April of both 2019 and 2020. In total, >85,600 C. acuta and >2400 C. barbara were collected from cryptic (ground or plant refuge) and exposed (open ground or elevated substrate) aestivation habitats and assessed for parasitism. The fly was detected at 13 of 19 sampled sites up to 34 km from nursery release sites. Total parasitism rates of suitably sized snails (≥5 mm shell height) were 2.9% for C. acuta and 3.4% for C. barbara. Maximum parasitism rates of 48% for C. acuta and 29% for C. barbara were found at sites adjacent to spring- and summer-flowering native vegetation. Across 13 sites, parasitism rates were higher for C. acuta (5.4%) and C. barbara (15.2%) in exposed habitats above ground level. However, only 34% of C. acuta and 14% of C. barbara were found in elevated habitats as most snails were found in cryptic refuges. There was a seasonal decline in abundance of C. acuta (66%) and C. barbara (45%) between January and April, suggesting natural mortality. Although the overall impact of the fly is limited, high parasitism rates in local environments with flowering resources indicates the potential to enhance biocontrol of both invasive conical snail species.
Application of Next Generation Semiconductor-Based Sequencing for the Identification of Apis mellifera Complementary Sex Determiner (csd) Alleles from Honey DNA
Authors: Bovo Samuele , Ribani Anisa , Utzeri Valerio Joe , Taurisano Valeria , Schiavo Giuseppina , Bolner Matteo , Fontanesi Luca
Published: September 2021

The complementary sex determiner (csd) gene plays an essential role in the sex determination of Apis mellifera L. Females develop only if fertilized eggs have functional heterozygous genotypes at this gene whereas males, being haploids, are hemizygous. Two identical csd alleles produce non vital males. In light of the recent decline in honey bee populations, it is therefore important to monitor the allele variability at this gene. In this study, we tested the application of next generation semiconductor-based sequencing technology (Ion Torrent) coupled with environmental honey DNA as a source of honey bee genome information to retrieve massive sequencing data for the analysis of variability at the hypervariable region (HVR) of the csd gene. DNA was extracted from 12 honey samples collected from honeycombs directly retrieved from 12 different colonies. A specifically designed bioinformatic pipeline, applied to analyze a total of about 1.5 million reads, identified a total of 160 different csd alleles, 55% of which were novel. The average number of alleles per sample was compatible with the number of expected patrilines per colony, according to the mating behavior of the queens. Allele diversity at the csd could also provide information useful to reconstruct the history of the honey.
Left Cardiac Remodelling Assessed by Echocardiography Is Associated with Rho-Kinase Activation in Long-Distance Runners
Authors: Contreras-Briceño Felipe , Vega Julián , Mandiola Jorge , Ocaranza María Paz , Herrera Sebastián , Salinas Manuel , Fernández Rodrigo , Jalil Jorge E. , Lavandero Sergio , Chiong Mario , Godoy Paz , Castro Pablo F. , Sitges Marta , Gabrielli Luigi
Published: September 2021

This single-blind and cross-sectional study evaluated the role of Rho-kinase (ROCK) as a biomarker of the cardiovascular remodelling process assessed by echocardiography in competitive long-distance runners (LDRs) during the training period before a marathon race. Thirty-six healthy male LDRs (37.0 ± 5.3 years; 174.0 ± 7.0 height; BMI: 23.8 ± 2.8; V˙ O2-peak: 56.5 ± 7.3 mL·kg−1·min−1) were separated into two groups according to previous training level: high-training (HT, n = 16) ≥ 100 km·week−1 and low-training (LT, n = 20) ≥ 70 and < 100 km·week−1. Also, twenty-one healthy nonactive subjects were included as a control group (CTR). A transthoracic echocardiography was performed and ROCK activity levels in circulating leukocytes were measured at rest (48 h without exercising) the week before the race. The HT group showed a higher left ventricular mass index (LVMi) and left atrial volume index (LAVi) than other groups (p < 0.05, for both); also, higher levels of ROCK activity were found in LDRs (HT = 6.17 ± 1.41 vs. CTR = 1.64 ± 0.66 (p < 0.01); vs. LT = 2.74 ± 0.84; (p < 0.05)). In LDRs a direct correlation between ROCK activity levels and LVMi (r = 0.83; p < 0.001), and LAVi (r = 0.70; p < 0.001) were found. In conclusion, in male competitive long-distance runners, the load of exercise implicated in marathon training is associated with ROCK activity levels and the left cardiac remodelling process assessed by echocardiography.
Sinus Augmentation—Expect the Unexpected: Diagnostic Anatomical Study
Authors: Haj Yahya Bahaa , Bar-Hai Dror , Samehov David , Chaushu Gavriel , Hamzani Yafit
Published: September 2021

“Big-nose variant” is an anatomical phenomenon defined as the pneumatization of inferior third of the nasal cavity within the alveolar ridge while simultaneously displacing the maxillary sinus laterally. The purpose of the present study was to assess the prevalence of the big-nose variant phenomenon and suggest a morphology classification system. Diagnostic anatomical evaluation was performed in a tertiary medical center on 321 randomly selected maxillary cone beam computerized tomography scans of patients who presented at an oral and maxillofacial department. Two anatomical categories were defined for anatomical identification: classes for horizontal mesiodistal distribution, and divisions for vertical distribution. Class 2, defined as location of the nasal/sinus border between the distal edge of the canine up to the distal edge of second premolar, was found to be the most prevalent (64.6%). Class 3, defined as location of the nasal/sinus border distal to mesial edge of the first molar, was found in 17.9% of cases. Regarding the divisions category, in 96% and 58.2% of teeth examined, nasal cavity alone was found to be superior to the canine and first premolar, respectively, defined as Division A. In 46.9% and 85.6% of teeth examined, maxillary sinus alone was located above the second premolar and first molar, respectively, defined as Division C. Identifying Class 3 on the paraxial reconstruction is the first step in identifying big-nose variant, with further assurance gained from each determining division. The use of the classes and divisions may enable better maxillary treatment planning, alert surgeons for the unexpected, and avoid complications.
Performing Microdissection Testicular Sperm Extraction: Surgical Pearls from a High-Volume Infertility Center
Authors: Colpi Giovanni M. , Caroppo Ettore
Published: September 2021

Microdissection testicular sperm extraction (mTESE) has been demonstrated to be the gold-standard surgical technique for retrieving testicular sperm in patients with non-obstructive azoospermia (NOA) as it enables the exploration of the whole testicular parenchyma at a high magnification, allowing the identification of the rare dilated seminipherous tubules that may contain sperm, usually surrounded by thinner or atrophic tubules. MTESE requires a skilled and experienced surgeon whose learning curve may greatly affect the sperm retrieval rate, as demonstrated in previous reports. The present review is intended to offer a precise and detailed description of the mTESE surgical procedure, accompanied by an extensive iconography, to provide urologists with valuable information to be translated into clinical practice. Advice about the pre-surgical and post-surgical management of patients is also offered.
Age at Natural Menopause and Blood Pressure Traits: Mendelian Randomization Study
Authors: Roa-Díaz Zayne M. , Asllanaj Eralda , Amin Hasnat A. , Rojas Lyda Z. , Nano Jana , Ikram Mohammad Arfan , Drenos Fotios , Franco Oscar H. , Pazoki Raha , Marques-Vidal Pedro , Voortman Trudy , Muka Taulant
Published: September 2021

Observational studies suggest that early onset of menopause is associated with increased risk of hypertension. Whether this association is causal or due to residual confounding and/or reverse causation remains undetermined. We aimed to evaluate the observational and causal association between age at natural menopause (ANM) and blood pressure traits in Caucasian women. A cross-sectional and one-sample Mendelian randomization (MR) study was conducted in 4451 postmenopausal women from the CoLaus and Rotterdam studies. Regression models were built with observational data to study the associations of ANM with systolic and diastolic blood pressure (SBP/DBP) and hypertension. One-sample MR analysis was performed by calculating a genetic risk score of 54 ANM-related variants, previously identified in a genome-wide association study (GWAS) on ANM. In the two-sample MR analysis we used the estimates from the ANM-GWAS and association estimates from 168,575 women of the UK Biobank to evaluate ANM-related variants and their causal association with SBP and DBP. Pooled analysis from both cohorts showed that a one-year delay in menopause onset was associated with 2% (95% CI 0; 4) increased odds of having hypertension, and that early menopause was associated with lower DBP (β = −1.31, 95% CI −2.43; −0.18). While one-sample MR did not show a causal association between ANM and blood pressure traits, the two-sample MR showed a positive causal association of ANM with SBP; the last was driven by genes related to DNA damage repair. The present study does not support the hypothesis that early onset of menopause is associated with higher blood pressure. Our results suggest different ANM-related genetic pathways could differently impact blood pressure.
Clinical Features of Familial Hypercholesterolemia in Children and Adults in EAS-FHSC Regional Center for Rare Diseases in Poland
Authors: Lewek Joanna , Konopka Agnieszka , Starostecka Ewa , Penson Peter E. , Maciejewski Marek , Banach Maciej
Published: September 2021

Background: Familial hypercholesterolemia (FH) is a genetic autosomal co-dominant metabolic disorder leading to elevated circulating concentrations of low-density lipoprotein cholesterol (LDL-C). Early development of atherosclerotic cardiovascular disease (ASCVD) is common in affected patients. We aimed to evaluate the characteristics and differences in the diagnosis and therapy of FH children and adults. Methods: All consecutive patients who were diagnosed with FH, both phenotypically and with genetic tests, were included in this analysis. All patients are a part of the European Atherosclerosis Society FH-Study Collaboration (FHSC) regional center for rare diseases at the Polish Mother’s Memorial Hospital Research Institute (PMMHRI) in Lodz, Poland. Results: Of 103 patients with FH, there were 16 children (15.5%) at mean age of 9 ± 3 years and 87 adults aged 41 ± 16; 59% were female. Children presented higher mean levels of total cholesterol, LDL-C, and high-density lipoprotein cholesterol (HDL-C) measured at the baseline visit (TC 313 vs. 259 mg/dL (8.0 vs. 6.6 mmol/L), p = 0.04; LDL 247 vs. 192 mg/dL (6.3 vs. 4.9 mmol/L), p = 0.02, HDL 53 vs. 48 mg/dL (1.3 vs. 1.2 mmol/L), p = 0.009). Overall, 70% of adult patients and 56% of children were prescribed statins (rosuvastatin or atorvastatin) on admission. Combination therapy (dual or triple) was administered for 24% of adult patients. Furthermore, 13.6% of adult patients and 19% of children reported side effects of statin therapy; most of them complained of muscle pain. Only 50% of adult patients on combination therapy achieved their treatment goals. None of children achieved the treatment goal. Conclusions: Despite a younger age of FH diagnosis, children presented with higher mean levels of LDL-C than adults. There are still urgent unmet needs concerning effective lipid-lowering therapy in FH patients, especially the need for greater use of combination therapy, which may allow LDL-C targets to be met in most of the patients.
Potential Nociceptive Role of the Thoracolumbar Fascia: A Scope Review Involving In Vivo and Ex Vivo Studies
Authors: Sinhorim Larissa , Amorim Mayane dos Santos , Ortiz Maria Eugênia , Bittencourt Edsel Balduino , Bianco Gianluca , da Silva Fabiana Cristina , Horewicz Verônica Vargas , Schleip Robert , Reed William R. , Mazzardo-Martins Leidiane , Martins Daniel F.
Published: September 2021

Nociceptive innervation of the thoracolumbar fascia (TLF) has been investigated over the past few decades; however, these studies have not been compiled or collectively appraised. The purpose of this scoping review was to assess current knowledge regarding nociceptive innervation of the TLF to better inform future mechanistic and clinical TLF research targeting lower back pain (LBP) treatment. PubMed, ScienceDirect, Cochrane, and Embase databases were searched in January 2021 using relevant descriptors encompassing fascia and pain. Eligible studies satisfied the following: (a) published in English; (b) preclinical and clinical (in vivo and ex vivo) studies; (c) original data; (d) included quantification of at least one TLF nociceptive component. Two-phase screening procedures were conducted by a pair of independent reviewers, after which data were extracted and summarized from eligible studies. The search resulted in 257 articles of which 10 met the inclusion criteria. Studies showed histological evidence of nociceptive nerve fibers terminating in lower back fascia, suggesting a TLF contribution to LBP. Noxious chemical injection or electrical stimulation into fascia resulted in longer pain duration and higher pain intensities than injections into subcutaneous tissue or muscle. Pre-clinical and clinical research provides histological and functional evidence of nociceptive innervation of TLF. Additional knowledge of fascial neurological components could impact LBP treatment.
Neutrophil-to-Lymphocyte Ratio Could Predict Outcome in Patients Presenting with Acute Limb Ischemia
Authors: Taurino Maurizio , Aloisi Francesco , Del Porto Flavia , Nespola Martina , Dezi Tommaso , Pranteda Chiara , Rizzo Luigi , Sirignano Pasqualino
Published: September 2021

Introduction: Acute limb ischemia (ALI), classified according to Rutherford’s classification (RC), is a vascular emergency burdened by high rates of mortality and morbidity. The need of new and different prognostic values for ALI has emerged, and, among all, the neutrophil-to-lymphocyte ratio (NLR) has been proven as a strong outcome predictor in vascular disease. The aim of this study is to investigate the role of preoperative NLR in predicting clinical outcomes in patients presenting acute limb ischemia. Material and Methods: A single-center retrospective study was conducted between January 2015 and December 2019. Demographic and clinical characteristics, procedural technical aspects, postoperative and early (up to 30-day) outcomes were recorded. All enrolled patients were categorized into low- and high-NLR at baseline, using a cut-off value of 5. Study outcomes were 30-day all-cause mortality and amputation rates. Results: A total of 177 ALI patients were included in the final analysis (6 RC I, 44 RC IIA, 108 RC IIB, and 19 RC III), 115 males (65%), mean age 78.9 ± 10.4 years. Mean NLR at hospital presentation was 6.65 ± 6.75 (range 0.5–35.4), 108 (61.1%) patients presented a low-NLR, 69 (38.9%) a high-NLR. Immediate technical success was achieved in 90.1% of cases. At 30 days, freedom from amputation and freedom from death rates were 87.1% and 83.6%, respectively. At the univariate analysis, amputation (p < 0.0001, OR: 9.65, 95%CI: 3.7–25.19), mortality (p = 0.0001, OR: 9.88, 95%CI: 3.19–30.57), and cumulative event rates (p < 0.001, OR: 14.45, 95%CI: 6.1–34.21), were significantly different between the two groups according to NLR value. Multivariate analysis showed that a high baseline NLR value was an independent predictor of unfavorable outcomes in all enrolled patients. Consistently, at ROC analysis, a preoperative NLR > 5 was strongly associated with all outcome occurrences. Conclusion: Preoperative NLR value seems to be strongly related to ALI outcomes in this unselected population. The largest series should be evaluated to confirm present results.
NT-proBNP as a Potential Marker of Cardiovascular Damage in Children with Chronic Kidney Disease
Authors: Skrzypczyk Piotr , Okarska-Napierała Magdalena , Pietrzak Radosław , Pawlik Katarzyna , Waścińska Katarzyna , Werner Bożena , Pańczyk-Tomaszewska Małgorzata
Published: September 2021

Assessing cardiovascular disease (CVD) in children with chronic kidney disease (CKD) is difficult. Great expectations have been associated with biomarkers, including the N-terminal pro-brain natriuretic peptide (NT-proBNP). This study aimed to determine the correlation between NT-proBNP and cardiovascular complications in children with CKD. Serum NT-proBNP, arterial stiffness, common carotid artery intima-media thickness (cIMT), echocardiographic (ECHO) parameters (including tissue Doppler imaging), and biochemical and clinical data were analyzed in 38 pediatric patients with CKD (21 boys, 12.2 ± 4.2 years). Mean NT-proBNP in CKD patients was 1068.1 ± 4630 pg/mL. NT-proBNP above the norm (125 pg/mL) was found in 16 (42.1%) subjects. NT-proBNP correlated with glomerular filtration rate (GFR) (r = −0.423, p = 0.008), and was significantly higher in CKD G5 (glomerular filtration rate grade) patients compared to CKD G2, G3, and G4 children (p = 0.010, p = 0.004, and p = 0.018, respectively). Moreover, NT-proBNP correlated positively with augmentation index (AP/PP: r = 0.451, p = 0.018, P2/P: r = 0.460, p = 0.016), cIMT (r = 0.504, p = 0.020), and E/E’ in ECHO (r = 0.400, p = 0.032). In multivariate analysis, logNT-proBNP was the only significant predictor of cIMT Z-score (beta = 0.402, 95CI (0.082–0.721), p = 0.014) and P2/P1 (beta = 0.130, 95CI (0.082–0.721), p = 0.014). Conclusions: NT-proBNP may serve as a possible marker of thickening of the carotid artery wall in pediatric patients with CKD. The final role of NT-proBNP as a biomarker of arterial damage, left ventricular hypertrophy, or cardiac diastolic dysfunction in CKD children needs confirmation in prospective studies.
Autologous Bone Grafting in Trauma and Orthopaedic Surgery: An Evidence-Based Narrative Review
Authors: Migliorini Filippo , Cuozzo Francesco , Torsiello Ernesto , Spiezia Filippo , Oliva Francesco , Maffulli Nicola
Published: September 2021

Autologous bone grafting is common in trauma and orthopaedic surgery. Both the Reamer Irrigator Aspirator (RIA) and Iliac Crest Bone Graft (ICBG) aim to obtain autologous bone graft. Although the process of harvesting a bone graft is considered simple, complications may occur. This study examined morbidity and pain at the donor site, blood loss, and iatrogenic fractures, comparing RIA and ICBG. The source of the autologous bone graft, the alternative graft sites, and the storage modalities of the harvested bone marrow were also evaluated. In May 2021, PubMed, Embase, Scopus, and Google Scholar were accessed, with no time constraints. RIA may produce greater blood loss, but with less morbidity and complications, making it a potential alternative source of bone grafting.
Epidemiologic, Postmortem Computed Tomography-Morphologic and Biomechanical Analysis of the Effects of Non-Invasive External Pelvic Stabilizers in Genuine Unstable Pelvic Injuries
Authors: Kleber Christian , Haussmann Mirja , Hetz Michael , Tsokos Michael , Buschmann Claas T.
Published: September 2021

Unstable pelvic injuries are rare (3–8% of all fractures) but are associated with a mortality of up to 30%. An effective way to treat venous and cancellous sources of bleeding prehospital is to reduce intrapelvic volume with external noninvasive pelvic stabilizers. Scientifically reliable data regarding pelvic volume reduction and applicable pressure are lacking. Epidemiologic data were collected, and multiple post-mortem CT scans and biomechanical measurements were performed on real, unstable pelvic injuries. Unstable pelvic injury was shown to be the leading source of bleeding in only 19%. All external non-invasive pelvic stabilizers achieved intrapelvic volume reduction; the T-POD® succeeded best on average (333 ± 234 cm3), but with higher average peak traction (110 N). The reduction results of the VBM® pneumatic pelvic sling consistently showed significantly better results at a pressure of 200 mmHg than at 100 mmHg at similar peak traction forces. All pelvic stabilizers exhibited the highest peak tensile force shortly after application. Unstable pelvic injuries must be considered as an indicator of serious concomitant injuries. Stabilization should be performed prehospital with specific pelvic stabilizers, such as the T-POD® or the VBM® pneumatic pelvic sling. We recommend adjusting the pressure recommendation of the VBM® pneumatic pelvic sling to 200 mmHg.
Impact of Epithelial–Mesenchymal Immunophenotype on Local Aggressiveness in Papillary Thyroid Carcinoma Invading the Airway
Authors: Mandarano Martina , Andolfi Marco , Colella Renato , Monacelli Massimo , Polistena Andrea , Moretti Sonia , Bellezza Guido , Puxeddu Efisio , Sanguinetti Alessandro , Sidoni Angelo , Avenia Nicola , Puma Francesco , Vannucci Jacopo
Published: September 2021

Primary thyroid tumours show different levels of aggressiveness, from indolent to rapidly growing infiltrating malignancies. The most effective therapeutic option is surgery when radical resection is feasible. Biomarkers of aggressiveness may help in scheduling extended resections such as airway infiltration, avoiding a non-radical approach. The aim of the study is to evaluate the prognostic role of E-cadherin, N-cadherin, Aryl hydrocarbon receptor (AhR), and CD147 in different biological behaviours. Fifty-five samples from three groups of thyroid carcinomas were stained: papillary thyroid carcinomas (PTCs) infiltrating the airway (PTC-A), papillary intra-thyroid carcinomas (PTC-B) and poorly differentiated or anaplastic thyroid carcinomas (PDTC/ATC). High expressions of N-cadherin and AhR were associated with higher locoregional tumour aggressiveness (p = 0.005 and p < 0.001 respectively); PDTC/ATC more frequently showed a high expression of CD147 (p = 0.011), and a trend of lower expression of E-cadherin was registered in more aggressive neoplasms. Moreover, high levels of AhR were found with recurrent/persistent diseases (p = 0.031), particularly when tumours showed a concomitant high N-cadherin expression (p = 0.043). The study suggests that knowing in advance onco-biological factors with a potential role to discriminate between different subsets of patients could help the decision-making process, providing a more solid therapeutic indication and an increased expectation for radical surgery.
Should We Use Unilateral or Bilateral Tasks to Assess Maximal and Explosive Knee Extensor Strength in Patients with Knee Osteoarthritis? A Cross-Sectional Study
Authors: Pfeifle Jonas , Hasler David , Maffiuletti Nicola A.
Published: September 2021

Deficits in maximal and explosive knee extensor strength, which are usually assessed with unilateral tasks, are substantial in patients with knee osteoarthritis (KOA). The aim of this study was to investigate the clinical relevance of unilateral vs. bilateral tasks for assessing knee extensor strength in patients with KOA. This was achieved primarily by comparing unilateral and bilateral inter-limb strength asymmetries and secondarily by examining the relationship between unilaterally and bilaterally measured strength, and performance-based and self-reported function. Twenty-four patients with unilateral KOA (mean age: 65 ± 7 years) performed isometric gradual and explosive maximal voluntary contractions to assess, respectively their maximal and explosive strength. Performance-based and self-reported function were also evaluated with standard functional tests and questionnaires, respectively. Inter-limb asymmetries of maximal and explosive strength did not differ significantly between unilateral (mean asymmetry: 26 ± 15%) and bilateral tasks (22 ± 21%). In the same way, the relationships between knee extensor strength—measured either unilaterally or bilaterally—and performance-based or self-reported function were not influenced by the type of task. In conclusion, it does not seem to make a difference in terms of clinical relevance whether maximal and explosive knee extensor strength are evaluated with unilateral or bilateral tasks in KOA patients.
FibroScan-AST Score Predicts 30-Day Mortality or Need for Mechanical Ventilation among Patients Hospitalized with COVID-19
Authors: Zelenika Marko , Lucijanic Marko , Bokun Tomislav , Bozin Tonci , Barisic Jaman Mislav , Tjesic Drinkovic Ida , Pastrovic Frane , Madir Anita , Luksic Ivica , Piskac Zivkovic Nevenka , Luetic Kresimir , Krznaric Zeljko , Ostojic Rajko , Filipec Kanizaj Tajana , Bogadi Ivan , Virovic Jukic Lucija , Kukla Michal , Grgurevic Ivica
Published: September 2021

Background: Liver involvement in Coronavirus disease 2019 (COVID-19) has been recognised. We aimed to investigate the correlation of non-invasive surrogates of liver steatosis, fibrosis and inflammation using transient elastography (TE) and FibroScan-AST (FAST) score with (a) clinical severity and (b) 30-day composite outcome of mechanical ventilation (MV) or death among patients hospitalized due to COVID-19. Method: Patients with non-critical COVID-19 at admission were included. Liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were assessed by TE. Clinical severity of COVID-19 was assessed by 4C Mortality Score (4CMS) and need for high-flow nasal cannula (HFNC) oxygen supplementation. Results: 217 patients were included (66.5% males, median age 65 years, 4.6% with history of chronic liver disease). Twenty-four (11.1%) patients met the 30-day composite outcome. Median LSM, CAP and FAST score were 5.2 kPa, 274 dB/m and 0.31, respectively, and neither was associated with clinical severity of COVID-19 at admission. In multivariate analysis FAST > 0.36 (OR 3.19, p = 0.036), 4CMS (OR 1.68, p = 0.002) and HFNC (OR 7.03, p = 0.001) were independent predictors of adverse composite outcome. Conclusion: Whereas LSM and CAP failed to show correlation with COVID-19 severity and outcomes, FAST score was an independent risk factor for 30-day mortality or need for MV.
Frequency and Factors of Indeterminate QuantiFERON-TB Gold In-Tube and QuantiFERON-TB Gold PLUS Test Results in Rheumatic Diseases
Authors: Ahn Sung Soo , Kim Hyung Woo , Park Younhee
Published: September 2021

We compared the results and differences of indeterminate rates between the QuantiFERON-TB Gold In-Tube (QFT-GIT) and QuantiFERON-TB Gold PLUS (QFT-PLUS) tests in patients with rheumatic diseases and analyzed the associated factors. Data of patients with rheumatic diseases who had undergone the QFT-GIT or QFT-PLUS test were used, and information regarding patient demographics, primary diagnosis, laboratory results, and medications was collected. Furthermore, indeterminate result rates of the patient cohort and healthy controls were also compared. A total of 177 (43.4%) and 231 (56.6%) patients had undergone QFT-GIT and QFT-PLUS tests, respectively. Among them, four (2.3%) and seven (3.0%) patients had indeterminate results, which did not differ between the QFT-GIT and QFT-PLUS groups. Indeterminate results were significantly higher among patients with rheumatic diseases than in healthy controls (2.7% vs. 0.2%, p < 0.001). Multivariate logistic regression revealed that the lymphocyte count (hazard ratio (HR) 0.998, 95% confidence interval (CI) 0.997, 1.000; p = 0.012) and albumin level (HR 0.366, 95% CI 0.150, 0.890; p = 0.027) were predictive of indeterminate results. A lymphocyte count of ≤810/mm3 and an albumin level of ≤3.7 mg/dL were capable of discriminating between indeterminate and determinate results. The QFT-GIT and QFT-PLUS tests have comparable diagnostic performances in patients with rheumatic diseases. Decreased lymphocyte and albumin levels contribute to indeterminate results.
Fear of COVID-19 among Healthcare Workers: The Role of Neuroticism and Fearful Attachment
Authors: Troisi Alfonso , Nanni Roberta Croce , Riconi Alessandra , Carola Valeria , Di Cave David
Published: September 2021

Fear of becoming infected is an important factor of the complex suite of emotional reactions triggered by the COVID-19 pandemic. Among healthcare workers (HWs), fear of infection can put at risk their psychological well-being and occupational efficiency. The aim of this study was to analyze the role of personality (i.e., the big five traits) and adult attachment in predicting levels of fear (as measured by the FCV-19S) in 101 HWs employed in a COVID-19 university hospital. The three significant predictors retained by the stepwise regression model were age (beta = 0.26, t = 2.89, p < 0.01), emotional stability (i.e., the inverse of neuroticism) (beta = −0.26, t = −2.89, p < 0.01), and fearful attachment (beta = 0.25, t = 2.75, p < 0.01). Older HWs with higher levels of neuroticism and fearful attachment reported more intense fear of COVID-19. Our results can be useful to identify vulnerable subgroups of HWs and to implement selective programs of prevention based on counseling and psychological support.
Tocilizumab and Desensitization in Kidney Transplant Candidates: Personal Experience and Literature Review
Authors: Weinhard Jules , Noble Johan , Jouve Thomas , Malvezzi Paolo , Rostaing Lionel
Published: September 2021

Desensitization (DES) allows kidney transplantation for highly HLA-sensitized subjects. Due to the central role of IL-6 in the immunological response, tocilizumab may improve DES efficacy. Thus, we conducted a PubMed systematic review using the MeSH terms tocilizumab, interleukin-6, kidney transplantation, and desensitization. Tocilizumab (TCZ) was first studied for DES as the second-line treatment after failure of a standard DES protocol (SP) (apheresis, rituximab +/− IVIg). Although TCZ (as a monotherapy) attenuated anti-HLA antibody rates, it did not permit transplantation. However, lymphocyte immuno-phenotyping has shown that TCZ hinders B-cell maturation and thus could improve the long-term efficacy of DES by limiting anti-HLA rebound and so avoid antibody-mediated rejection. This hypothesis is supported by a recent study where clazakizumab, a monoclonal antibody directed against IL-6, was continued after kidney transplantation in association with an SP. Nine out of ten patients were then eligible for transplantation, and there were no donor-specific antibodies at 6 months post-transplantation. In association with an SP, tocilizumab does not seem to significantly improve kidney-allograft access (short-term efficacy) vs. a SP only. However, it could improve the long-term prognosis of HLA-incompatible transplantation by hindering B-cell maturation and, thereby, avoiding donor-specific antibody rebounds post-transplantation.
Towards a Consensus on Alzheimer’s Disease Comorbidity?
Authors: Avitan Iska , Halperin Yudit , Saha Trishna , Bloch Naamah , Atrahimovich Dana , Polis Baruh , Samson Abraham O. , Braitbard Ori
Published: September 2021

Alzheimer’s disease (AD) is often comorbid with other pathologies. First, we review shortly the diseases most associated with AD in the clinic. Then we query PubMed citations for the co-occurrence of AD with other diseases, using a list of 400 common pathologies. Significantly, AD is found to be associated with schizophrenia and psychosis, sleep insomnia and apnea, type 2 diabetes, atherosclerosis, hypertension, cardiovascular diseases, obesity, fibrillation, osteoporosis, arthritis, glaucoma, metabolic syndrome, pain, herpes, HIV, alcoholism, heart failure, migraine, pneumonia, dyslipidemia, COPD and asthma, hearing loss, and tobacco smoking. Trivially, AD is also found to be associated with several neurodegenerative diseases, which are disregarded. Notably, our predicted results are consistent with the previously published clinical data and correlate nicely with individual publications. Our results emphasize risk factors and promulgate diseases often associated with AD. Interestingly, the comorbid diseases are often degenerative diseases exacerbated by reactive oxygen species, thus underlining the potential role of antioxidants in the treatment of AD and comorbid diseases.
The Common Combination of Aortic Stenosis with Mitral Regurgitation: Diagnostic Insight and Therapeutic Implications in the Modern Era of Advanced Echocardiography and Percutaneous Intervention
Authors: Mantovani Francesca , Barbieri Andrea , Albini Alessandro , Bonini Niccolò , Fanti Diego , Fezzi Simone , Setti Martina , Rossi Andrea , Ribichini Flavio , Benfari Giovanni
Published: September 2021

The combination of aortic stenosis (AS) and mitral regurgitation (MR) is common in patients with degenerative valvular disease. It is characterized by having complex pathophysiology, leading to potential diagnostic pitfalls. Evidence is scarce in the literature to direct the diagnostic framework and treatment of patients with this particular combination of multiple valvular diseases. In this complex scenario, the appropriate use of advanced echocardiography and multimodality imaging methods plays a central role. Transcatheter mitral valve replacement or repair and transcatheter aortic valve replacement widen the surgical options for valve diseases. Therefore, there is an increasing need to reconsider the function, timing, and mode intervention for patients with a combination of AS with MR towards more personalized treatment.
Neutrophil-to-Lymphocyte Ratios and Infections after Traumatic Brain Injury: Associations with Hospital Resource Utilization and Long-Term Outcome
Authors: Levochkina Marina , McQuillan Leah , Awan Nabil , Barton David , Maczuzak John , Bianchine Claudia , Trombley Shannon , Kotes Emma , Wiener Joshua , Wagner Audrey , Calcagno Jason , Maza Andrew , Nierstedt Ryan , Ferimer Stephanie , Wagner Amy
Published: September 2021

Traumatic brain injury (TBI) induces immune dysfunction that can be captured clinically by an increase in the neutrophil-to-lymphocyte ratio (NLR). However, few studies have characterized the temporal dynamics of NLR post-TBI and its relationship with hospital-acquired infections (HAI), resource utilization, or outcome. We assessed NLR and HAI over the first 21 days post-injury in adults with moderate-to-severe TBI (n = 196) using group-based trajectory (TRAJ), changepoint, and mixed-effects multivariable regression analysis to characterize temporal dynamics. We identified two groups with unique NLR profiles: a high (n = 67) versus a low (n = 129) TRAJ group. High NLR TRAJ had higher rates (76.12% vs. 55.04%, p = 0.004) and earlier time to infection (p = 0.003). In changepoint-derived day 0–5 and 6–20 epochs, low lymphocyte TRAJ, early in recovery, resulted in more frequent HAIs (p = 0.042), subsequently increasing later NLR levels (p ≤ 0.0001). Both high NLR TRAJ and HAIs increased hospital length of stay (LOS) and days on ventilation (p ≤ 0.05 all), while only high NLR TRAJ significantly increased odds of unfavorable six-month outcome as measured by the Glasgow Outcome Scale (GOS) (p = 0.046) in multivariable regression. These findings provide insight into the temporal dynamics and interrelatedness of immune factors which collectively impact susceptibility to infection and greater hospital resource utilization, as well as influence recovery.