bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Epigenetics and Non-coding RNAs in Myocardial Infarction: From Mechanisms to Therapeutics
Authors: Chen Jinhong , Liu Zhichao , Ma Li , Gao Shengwei , Fu Huanjie , Wang Can , Lu Anmin , Wang Baohe , Gu Xufang
Published: December 2021

Myocardial infarction (MI) is a complicated pathology triggered by numerous environmental and genetic factors. Understanding the effect of epigenetic regulation mechanisms on the cardiovascular disease would advance the field and promote prophylactic methods targeting epigenetic mechanisms. Genetic screening guides individualised MI therapies and surveillance. The present review reported the latest development on the epigenetic regulation of MI in terms of DNA methylation, histone modifications, and microRNA-dependent MI mechanisms and the novel therapies based on epigenetics.
Macrophage Polarization and Plasticity in Systemic Lupus Erythematosus
Authors: Ahamada Mariame Mohamed , Jia Yang , Wu Xiaochuan
Published: December 2021

Systemic lupus erythematosus (SLE) is an autoimmune disease that attacks almost every organ. The condition mostly happens to adults but is also found in children, and the latter have the most severe manifestations. Among adults, females, especially non-Caucasian, are mostly affected. Even if the etiology of SLE remains unclear, studies show a close relation between this disease and both genetics and environment. Despite the large number of published articles about SLE, we still do not have a clear picture of its pathogenesis, and no specific drug has been found to treat this condition effectively. The implication of macrophages in SLE development is gaining ground, and studying it could answer these gaps. Indeed, both in vivo and in vitro studies increasingly report a strong link between this disease and macrophages. Hence, this review aims to explore the role of macrophages polarization and plasticity in SLE development. Understanding this role is of paramount importance because in-depth knowledge of the connection between macrophages and this systemic disease could clarify its pathogenesis and provide a foundation for macrophage-centered therapeutic approaches.
Increased Plasma Heparanase Activity and Endothelial Glycocalyx Degradation in Dengue Patients Is Associated With Plasma Leakage
Authors: Buijsers Baranca , Garishah Fadel Muhammad , Riswari Silvita Fitri , van Ast Rosalie M. , Pramudo Setyo Gundi , Tunjungputri Rahajeng N. , Overheul Gijs J. , van Rij Ronald P. , van der Ven André , Alisjahbana Bachti , Gasem Muhammad Hussein , de Mast Quirijn , van der Vlag Johan
Published: December 2021

Background

Endothelial hyper-permeability with plasma leakage and thrombocytopenia are predominant features of severe dengue virus infection. It is well established that heparanase, the endothelial glycocalyx degrading enzyme, plays a major role in various diseases with vascular leakage. It is yet to be elucidated whether heparanase activity plays a major role in dengue-associated plasma leakage. Moreover, the major source of heparanase secretion and activation in dengue remains elusive. Since a relatively high amount of heparanase is stored in platelets, we postulate that heparanase released by activated platelets contributes to the increased plasma heparanase activity during dengue virus infection.

Methods

Heparanase activity (plasma and urine), and heparan sulfate and syndecan-1 (plasma levels) were measured in dengue patients with thrombocytopenia in acute phase (n=30), during course of disease (n=10) and in convalescent phase (n=25). Associations with clinical parameters and plasma leakage markers were explored. Platelets from healthy donors were stimulated with dengue non-structural protein-1, DENV2 virus and thrombin to evaluate heparanase release and activity ex vivo.

Results

Heparanase activity was elevated in acute dengue and normalized during convalescence. Similarly, glycocalyx components, such as heparan sulfate and syndecan-1, were increased in acute dengue and restored during convalescence. Increased heparanase activity correlated with the endothelial dysfunction markers heparan sulfate and syndecan-1, as well as clinical markers of plasma leakage such as ascites, hematocrit concentration and gall-bladder wall thickening. Notably, platelet number inversely correlated with heparanase activity. Ex vivo incubation of platelets with thrombin and live DENV2 virus, but not dengue virus-2-derived non-structural protein 1 induced heparanase release from platelets.

Conclusion

Taken together, our findings suggest that the increase of heparanase activity in dengue patients is associated with endothelial glycocalyx degradation and plasma leakage. Furthermore, thrombin or DENV2 activated platelets may be considered as a potential source of heparanase.
Different Effects of Biologics on Systemic Bone Loss Protection in Rheumatoid Arthritis: An Interim Analysis of a Three-Year Longitudinal Cohort Study
Authors: Chen Ming-Han , Yu Shan-Fu , Chen Jia-Feng , Chen Wei-Sheng , Liou The-Ling , Chou Chung-Tei , Hsu Chung-Yuan , Lai Han-Ming , Chen Ying-Chou , Tsai Chang-Youh , Cheng Tien-Tsai
Published: December 2021

Objective

To compare changes in bone mineral density (BMD) in rheumatoid arthritis (RA) patients receiving three-year conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD), tumor necrosis factor-α inhibitors (TNFi), and abatacept.

Methods

Patients with RA were recruited from September 2014 to February 2021. Dual-energy X-ray absorptiometry was used to measure BMD at the femoral neck (FN), total hip (TH), and lumbar spine (L1-4) at enrollment and three years later. Changes in the BMD of each regimen group were analyzed. Multiple ordinary least squares regression was used with the dependent variables to develop a model to predict the change in BMD.

Results

A total of 752 participants were enrolled and 485 completed the three-year follow-up period. Of these, 375 (Group I), 84 (Group II), and 26 (Group III) participants received csDMARDs, TNFi, and abatacept therapy, respectively. Considering both type of therapy and completion of the follow-up period, participants were divided into groups A (csDMARDs, n = 104), B (TNFi, n = 52), and C (abatacept, n = 26). Compared to baseline, BMD decreased significantly at FN (p = 0.003) and L1-4 (p = 0.002) in Group A and at L1-4 (p = 0.005) in Group B, but remained stable at all sites in Group C. In terms of regression-adjusted percent change in BMD, there was a significant difference seen at all measured sites between group C compared to both groups A and B (+0.8%, -2.7%, -1.8% at FN; +0.5%, -1.1%, -1.0% at TH; +0.8%, -2.0%, -3.5% at L1-4, respectively; all p < 0.05). Anti-osteoporosis therapy had a BMD-preserving effect in RA.

Conclusion

Compared with csDMARDs and TNFi, abatacept may have a better BMD-preserving effect in RA. Anti-osteoporosis therapy can prevent systemic bone loss irrespective of RA therapy.
Activation of Sphingomyelinase-Ceramide-Pathway in COVID-19 Purposes Its Inhibition for Therapeutic Strategies
Authors: Abusukhun Murad , Winkler Martin S. , Pöhlmann Stefan , Moerer Onnen , Meissner Konrad , Tampe Björn , Hofmann-Winkler Heike , Bauer Michael , Gräler Markus H. , Claus Ralf A.
Published: December 2021

Effective treatment strategies for severe coronavirus disease (COVID-19) remain scarce. Hydrolysis of membrane-embedded, inert sphingomyelin by stress responsive sphingomyelinases is a hallmark of adaptive responses and cellular repair. As demonstrated in experimental and observational clinical studies, the transient and stress-triggered release of a sphingomyelinase, SMPD1, into circulation and subsequent ceramide generation provides a promising target for FDA-approved drugs. Here, we report the activation of sphingomyelinase-ceramide pathway in 23 intensive care patients with severe COVID-19. We observed an increase of circulating activity of sphingomyelinase with subsequent derangement of sphingolipids in serum lipoproteins and from red blood cells (RBC). Consistent with increased ceramide levels derived from the inert membrane constituent sphingomyelin, increased activity of acid sphingomyelinase (ASM) accurately distinguished the patient cohort undergoing intensive care from healthy controls. Positive correlational analyses with biomarkers of severe clinical phenotype support the concept of an essential pathophysiological role of ASM in the course of SARS-CoV-2 infection as well as of a promising role for functional inhibition with anti-inflammatory agents in SARS-CoV-2 infection as also proposed in independent observational studies. We conclude that large-sized multicenter, interventional trials are now needed to evaluate the potential benefit of functional inhibition of this sphingomyelinase in critically ill patients with COVID-19.
Single-Dose 13-Valent Conjugate Pneumococcal Vaccine in People Living With HIV – Immunological Response and Protection
Authors: Romaru Juliette , Bahuaud Mathilde , Lejeune Gauthier , Hentzien Maxime , Berger Jean-Luc , Robbins Ailsa , Lebrun Delphine , N’Guyen Yohan , Bani-Sadr Firouzé , Batteux Frédéric , Servettaz Amélie
Published: December 2021

Background

Patients living with HIV (PLHIV) are prone to invasive pneumococcal disease. The 13-valent conjugated pneumococcal vaccine (PCV13) is currently recommended for all PLHIV, followed in most guidelines by a 23-valent polysaccharide pneumococcal vaccine. Data are scarce concerning the immunological efficacy of PCV13 among PLHIV.

Objective

To assess the immunological response at one month, and the immunological protection at 1-, 6-, and 12 months in PLHIV with a CD4 cell count above 200 cells/µl after a single dose of PCV13, as measured by both ELISA and opsonophagocytic assay (OPA).

Methods

PLHIV with CD4 cell count >200 cells/µl were included. Specific IgG serum concentrations for eight serotypes by ELISA and seven serotypes by OPA were measured at baseline, 1-, 6-, and 12 months after the PCV13 vaccination. Global response was defined as a two-fold increase from baseline of specific IgG antibody levels (μg/ml) assayed by ELISA or as a four-fold increase in OPA titer from baseline, for at least five serotypes targeted by PCV13. Global protection was defined as an IgG-concentration ≥1 µg/ml by ELISA or as an opsonization titer ≥LLOQ by OPA for at least five tested serotypes targeted by PCV13. Factors associated with global response and global protection were assessed using logistic regression.

Results

Of the 38 PLHIV included, 57.9% and 63.2% were global responders, 92.1% and 78.9% were globally protected at one month, and 64.7% and 55.9% were still protected at 12 months, by ELISA and OPA respectively. A CD4/CD8 ratio of >0.8 was significantly associated with a better global response by OPA (OR=6.11, p=0.02), and a CD4 nadir <200 was significantly associated with a poorer global response by ELISA (OR=0.22, p=0.04). A CD4 cell count nadir <200 and age over 50 years were associated with poorer global protection by OPA at M1 (OR=0.18, p=0.04) and M12 (OR= 0.15, p=0.02), respectively. Plasma HIV RNA viral load <40 copies/ml was significantly associated with a better global protection at M1 by ELISA and OPA (OR=21.33, p=0.025 and OR=8.40, p=0.04)

Conclusion

Vaccination with PCV13 in these patients induced immunological response and protection at one month. At one year, more than half of patients were still immunologically protected.
Cepharanthine Blocks Presentation of Thyroid and Islet Peptides in a Novel Humanized Autoimmune Diabetes and Thyroiditis Mouse Model
Authors: Li Cheuk Wun , Osman Roman , Menconi Francesca , Faustino Larissa C. , Kim Kookjoo , Clarke Oliver B. , Hou Hanxi , Tomer Yaron
Published: December 2021

Autoimmune polyglandular syndrome type 3 variant (APS3v) refers to an autoimmune condition in which both type 1 diabetes (T1D) and autoimmune thyroiditis (AITD) develop in the same individual. HLA-DR3 confers the strongest susceptibility to APS3v. Previously we reported a unique amino acid signature pocket that predisposes to APS3v. We found that this pocket is flexible and can trigger APS3v by presenting both thyroid (Tg.1571, TPO.758) and islet (GAD.492) peptides to induce autoimmune response. We hypothesized that blocking the specific APS3v-HLA-DR3 pocket from presenting thyroid/islet antigens can block the autoimmune response in APS3v. To test this hypothesis we performed a virtual screen of small molecules blocking APS3v-HLA-DR3, and identified 11 small molecules hits that were predicted to block APS3v-HLA-DR3. Using the baculovirus-produced recombinant APS3v-HLA-DR3 protein we tested the 11 small molecules in an in vitro binding assay. We validated 4 small molecule hits, S9, S5, S53 and S15, that could block the APS3v-HLA-DR3 pocket in vitro. We then developed a novel humanized APS3v mouse model induced by co-immunizing a peptide mix of Tg.1571, TPO.758 and GAD.492. The immunized mice developed strong T-cell and antibody responses to the thyroid/islet peptides, as well as mouse thyroglobulin. In addition, the mice showed significantly lower free T4 levels compared to controls. Using the APS3v mouse model, we showed that one of the 4 small molecules, Cepharanthine (S53), blocked T-cell activation by thyroid/islet peptides ex vivo and in vivo. These findings suggested Cepharanthine may have a therapeutic potential in APS3v patients carrying the specific APS3v-HLA-DR3 pocket.
Case Report: Clinical Management of a Patient With Metastatic Non-Small Cell Lung Cancer Newly Receiving Immune Checkpoint Inhibition During Symptomatic COVID-19
Authors: Mellinghoff Sibylle C. , Vanshylla Kanika , Dahlke Christine , Addo Marylyn M. , Cornely Oliver A. , Klein Florian , Persigehl Thorsten , Rybniker Jan , Gruell Henning , Bröckelmann Paul J.
Published: December 2021

Effects of initiation of programmed-death-protein 1 (PD1) blockade during active SARS-CoV-2 infection on antiviral immunity, COVID-19 course, and underlying malignancy are unclear. We report on the management of a male in his early 40s presenting with highly symptomatic metastatic lung cancer and active COVID-19 pneumonia. After treatment initiation with pembrolizumab, carboplatin, and pemetrexed, the respiratory situation initially worsened and high-dose corticosteroids were initiated due to suspected pneumonitis. After improvement and SARS-CoV-2 clearance, anti-cancer treatment was resumed without pembrolizumab. Immunological analyses with comparison to otherwise healthy SARS-CoV-2-infected ambulatory patients revealed a strong humoral immune response with higher levels of SARS-CoV-2-reactive IgG and neutralizing serum activity. Additionally, sustained increase of Tfh as well as activated CD4+ and CD8+ T cells was observed. Sequential CT scans showed regression of tumor lesions and marked improvement of the pulmonary situation, with no signs of pneumonitis after pembrolizumab re-challenge as maintenance. At the latest follow-up, the patient is ambulatory and in ongoing partial remission on pembrolizumab. In conclusion, anti-PD1 initiation during active COVID-19 pneumonia was feasible and cellular and humoral immune responses to SARS-CoV-2 appeared enhanced in our hospitalized patient. However, distinguishing COVID-19-associated changes from anti-PD1-associated immune-related pneumonitis posed a considerable clinical, radiographic, and immunologic challenge.
Temperature and Salinity Inverted for a Mediterranean Eddy Captured With Seismic Data, Using a Spatially Iterative Markov Chain Monte Carlo Approach
Authors: Xiao Wuxin , Sheen Katy Louise , Tang Qunshu , Shutler Jamie , Hobbs Richard , Ehmen Tobias
Published: December 2021

Ocean submesoscale dynamics are thought to play a key role in both the climate system and ocean productivity, however, subsurface observations at these scales remain rare. Seismic oceanography, an established acoustic imaging method, provides a unique tool for capturing oceanic structure throughout the water column with spatial resolutions of tens of meters. A drawback to the seismic method is that temperature and salinity are not measured directly, limiting the quantitative interpretation of imaged features. The Markov Chain Monte Carlo (MCMC) inversion approach has been used to invert for temperature and salinity from seismic data, with spatially quantified uncertainties. However, the requisite prior model used in previous studies relied upon highly continuous acoustic reflection horizons rarely present in real oceanic environments due to instabilities and turbulence. Here we adapt the MCMC inversion approach with an iteratively updated prior model based on hydrographic data, sidestepping the necessity of continuous reflection horizons. Furthermore, uncertainties introduced by the starting model thermohaline fields as well as those from the MCMC inversion itself are accounted for. The impact on uncertainties of varying the resolution of hydrographic data used to produce the inversion starting model is also investigated. The inversion is applied to a mid-depth Mediterranean water eddy (or meddy) captured with seismic imaging in the Gulf of Cadiz in 2007. The meddy boundary exhibits regions of disrupted seismic reflectivity and rapid horizontal changes of temperature and salinity. Inverted temperature and salinity values typically have uncertainties of 0.16°C and 0.055 psu, respectively, and agree well with direct measurements. Uncertainties of inverted results are found to be highly dependent on the resolution of the hydrographic data used to produce the prior model, particularly in regions where background temperature and salinity vary rapidly, such as at the edge of the meddy. This further advancement of inversion techniques to extract temperature and salinity from seismic data will help expand the use of ocean acoustics for understanding the mesoscale to finescale structure of the interior ocean.
Challenges and Opportunities in Coastal Shoreline Prediction
Authors: Splinter Kristen D. , Coco Giovanni
Published: December 2021

Sandy beaches comprise approximately 31% of the world's ice-free coasts. Sandy coastlines around the world are continuously adjusting in response to changing waves and water levels at both short (storm) and long (climate-driven, from El-Nino Southern Oscillation to sea level rise) timescales. Managing this critical zone requires robust, advanced tools that represent our best understanding of how to abstract and integrate coastal processes. However, this has been hindered by (1) a lack of long-term, large-scale coastal monitoring of sandy beaches and (2) a robust understanding of the key physical processes that drive shoreline change over multiple timescales. This perspectives article aims to summarize the current state of shoreline modeling at the sub-century timescale and provides an outlook on future challenges and opportunities ahead.
Effects of Radiation sterilization Dose on the Molecular Weight and Gelling Properties of Commercial Alginate Samples
Authors: Mollah M. Z. I. , Rahaman M S. , Faruque M R I. , Khandaker M U. , Osman Hamid , Alamri Sultan , Al-Assaf Saphwan
Published: December 2021

To estimate the molecular weight (Mw) and gelling properties, a total of 26 alginate samples consisting of control (n = 13) and 15 kGy γ-irradiated (n = 13) samples were characterized through viscometric and gel permeation chromatography (GPC-MALLS) methods. Based on the observations, a remarkable decrease in the intrinsic viscosity of all samples of alginates was evident due to the effects of radiation, with a linear relationship between viscosity and concentration in 0.01 M NaCl solution. The correlation among the Mw, percentage mass recovery, radii of gyration (Rz/Rg), and percentage reduction of Mw assessed by GPC was significant. The Mw decreased dramatically (from 3.1 × 105 to 0.49 × 105 mole/g in sample no. 12) by the effect of radiation with momentous relation to the % reduction of the molecular weight. The highest molecular weight reduction (84%), which is the most sensitive to γ-radiation, and the average reduction rate was ≥50%. The mass recovery was 100% obtained from samples no. 1,3,4,5,7,12, and 13, while the rest of the samples’ recovery rate was significantly higher. The reduction rate of mass molecular weight (Mw) is higher than the average molecular weight (Mv), but they showed a sensitivity towards radiation, consequently their performance are different from each other. The stability test was performed as a critical behaviour in the control, recurrently same as in the irradiated samples. Thus, the sterilization dose of 15 kGy for the Mw distribution, and subsequently for the characterization, was significantly effective.
Effect of Galvanic Corrosion on the Degradability of Biomedical Magnesium
Authors: Peng Hongzhou , Wang Wei , Jiang Haomiao , Zan Rui , Sun Yu , Yu Song , Ni Jiahua , Wang Wenhui , Wang Tao , Wang Jian , Zhang Xiaonong
Published: December 2021

With recent progress in clinical trials and scale-up applications of biodegradable magnesium-based implants, the scenarios of transplanting biodegradable Mg with other non-degradable metals may occur inevitably. Galvanic corrosion appears between two metallic implants with different electrochemical potentials and leads to accelerated degradation. However, a quantitative measurement on the galvanic corrosion of Mg in contact with other metallic implants has not been conducted. Here we study the corrosion behaviors and mechanical attenuation of high purity magnesium (Mg)in contact with stainless steel (316L), pure titanium (TA2), and magnesium alloy (AZ91) respectively to form different galvanic couples in simulated body fluids. The results show that all of these three heterogeneous metal pairs accelerate the degradation of high purity Mg to different degrees, yielding declined tensile strength and mechanical failure after 4 days of immersion. Our observations alert the potential risk of co-implanting different metallic devices in clinical trials.
Vanadium and Tannic Acid-Based Composite Conversion Coating for 6063 Aluminum Alloy
Authors: Zhu Wen , Chen Furui , Luo Youbin , Su Zhijun , Li Wenfang , Yi Aihua , Liao Zhongmiao , Li Kang , Chen Ken , Hu Yiwen , Xu Yashu , Guo Sinan
Published: December 2021

In this study, a vanadium (V) and tannic acid-based composite conversion coating (VTACC) was prepared on 6063 aluminum alloy (AA6063) to increase its corrosion resistance. The surface morphology and compositions of the VTACCs were characterized using scanning electron microscopy (SEM), energy dispersive spectrometry (EDS), and X-ray photoelectron spectroscopy (XPS). The corrosion resistance of the coatings was investigated by linear polarization and electrochemical impedance spectra (EIS). The self-healing ability of the coating was detected by SEM, EDS, and scanning vibrating electrode technique (SVET) measurements. The coating mainly consisted of metal oxides, including Al2O3, VO2, V2O3, and V2O5, and metal organic complexes (Al and V-complexes). The electrochemical measurement results indicated that the best corrosion resistance of VTACC was acquired when the treatment time was 12 min. Furthermore, because a new coating with vanadium rich oxide was developed on the scratch area, artificial scratch VTACC surfaces were repaired after several days of immersion in 3.5-wt% NaCl solution.
Treatment of Inflammatory Bowel Disease: A Comprehensive Review
Authors: Cai Zhaobei , Wang Shu , Li Jiannan
Published: December 2021

Inflammatory bowel disease (IBD), as a global disease, has attracted much research interest. Constant research has led to a better understanding of the disease condition and further promoted its management. We here reviewed the conventional and the novel drugs and therapies, as well as the potential ones, which have shown promise in preclinical studies and are likely to be effective future therapies. The conventional treatments aim at controlling symptoms through pharmacotherapy, including aminosalicylates, corticosteroids, immunomodulators, and biologics, with other general measures and/or surgical resection if necessary. However, a considerable fraction of patients do not respond to available treatments or lose response, which calls for new therapeutic strategies. Diverse therapeutic options are emerging, involving small molecules, apheresis therapy, improved intestinal microecology, cell therapy, and exosome therapy. In addition, patient education partly upgrades the efficacy of IBD treatment. Recent advances in the management of IBD have led to a paradigm shift in the treatment goals, from targeting symptom-free daily life to shooting for mucosal healing. In this review, the latest progress in IBD treatment is summarized to understand the advantages, pitfalls, and research prospects of different drugs and therapies and to provide a basis for the clinical decision and further research of IBD.
CytoSorb Therapy in COVID-19 (CTC) Patients Requiring Extracorporeal Membrane Oxygenation: A Multicenter, Retrospective Registry
Authors: Song Tae , Hayanga Jeremiah , Durham Lucian , Garrison Lawrence , McCarthy Paul , Barksdale Andy , Smith Deane , Bartlett Robert , Jaros Mark , Nelson Peter , Molnar Zsolt , Deliargyris Efthymios , Moazami Nader
Published: December 2021

Introduction: CytoSorb extracorporeal blood purification therapy received FDA Emergency Use Authorization (EUA) to suppress hyperinflammation in critically ill COVID-19 patients. The multicenter CTC Registry was established to systematically collect patient-level data, outcomes, and utilization patterns of CytoSorb under the EUA.

Methods: Patient-level data was entered retrospectively at participating centers. The primary outcome of the registry was ICU mortality. Patient disposition of death, continuing ICU care, or ICU discharge was analyzed up to Day 90 after start of CytoSorb therapy. Demographics, comorbidities, COVID-19 medications, inflammatory biomarkers, and details on CytoSorb use were compared between survivors and non-survivors in the veno-venous extracorporeal membrane oxygenation (ECMO) cohort.

Results: Between April 2020 and April 2021, 52 patients received veno-venous ECMO plus CytoSorb therapy at 5 U.S. centers. ICU mortality was 17.3% (9/52) on day 30, 26.9% (14/52) on day 90, and 30.8% (16/52) at final follow-up of 153 days. Survivors had a trend toward lower baseline D-Dimer levels (2.3 ± 2.5 vs. 19.8 ± 32.2 μg/mL, p = 0.056) compared to non-survivors. A logistic regression analysis suggested a borderline association between baseline D-Dimer levels and mortality with a 32% increase in the risk of death per 1 μg/mL increase (p = 0.055). CytoSorb was well-tolerated without any device-related adverse events reported.

Conclusions: CytoSorb therapy for critically ill COVID-19 patients on ECMO was associated with high survival rates suggesting potential therapeutic benefit. Elevated baseline D-Dimer levels may suggest increased risk of mortality. Prospective controlled studies are warranted to substantiate these results.

Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT0439192, identifier: NCT04391920.
Health Status of Patients With β-Thalassemia in the West Bank: A Retrospective-Cohort Study
Authors: Aldwaik Reem , Abu Mohor Tamara , Idyabi Israa , Warasna Salam , Abdeen Shatha , Karmi Bashar , Abu Seir Rania
Published: December 2021

Management of β-thalassemia in developing countries is demanding in the absence of available therapies rather than recurrent transfusions. This study describes the characteristics and evaluates the hematological, biochemical, and hormonal findings of patients with β-thalassemia in the West Bank. We conducted a retrospective cohort study between January 2017 and December 2018. Data were collected through medical files of the patients with β-thalassemia from eight primary healthcare clinics, nine emergency departments, and 11 governmental hospitals across the West Bank. Results of the hematological, biochemical, and hormonal evaluations, in addition to demographic data and the use of iron chelation were included in the study and analyzed. A total of 309 patients with β-thalassemia were included with a male-to-female ratio of 1:1 and an average age of 23.4 ± 10.4 years. The anemic presentation was reported in 78.6% of the patients as indicated by hemoglobin level (mean ± SD = 8.4 ± 1.4 g/dl), and 73.1% had iron overload with serum ferritin (SF) levels ≥ 1,000 μg/L (mean ± SD = 317.8 ± 3,378.8 μg/L). Evaluation of the liver function tests showed that alanine transaminase (ALT) and aspartate transaminase (AST) levels were high among 38.1 and 61.2% of the patients, respectively. ALT and AST showed significant positive correlations with SF levels, while the kidney tests did not. As for iron chelation medications, patients receiving deferoxamine (26.5%) showed significantly higher SF levels compared with patients receiving deferasirox (73.5%). This study highlights the importance of establishing patient-tailored comprehensive assessment and follow-up protocols for the management of β-thalassemia with an emphasis on blood transfusion and iron chelation practices.
Ab Interno vs. Ab Externo Microcatheter-Assisted Circumferential Trabeculotomy in Treating Patients With Primary Open-Angle Glaucoma
Authors: Zhang Weijia , Wang Yiwei , Xin Chen , Sun Yang , Cao Kai , Wang Huaizhou , Wang Ningli
Published: December 2021

Background: Circumferential trabeculotomy have evolved from ab externo to ab interno approach. Both procedures may lower IOP, but it is unclear which maybe a superior approach.

Purpose: To compare the outcomes of ab interno and ab externo circumferential trabeculotomy in patients with primary open-angle glaucoma.

Design: Retrospective, comparative case series.

Participants: Primary open angle glaucoma patients undergoing ab interno (40 patients in Group 1) or ab externo (54 patients in Group 2) circumferential trabeculotomy, with about one half of them having prior incisional glaucoma surgery.

Methods: Outcomes including intraocular pressure (IOP), glaucoma medications and surgical complications were analyzed.

Main Outcome Measures: IOP, medications and surgical success defined as an IOP of ≤ 21 mmHg and a reduction of IOP ≥20% from baseline (criterion A) or IOP ≤ 18 mmHg and a reduction of IOP 20% from baseline (criterion B) with (qualified success) or without (complete success) medications.

Results: At 1 year, IOP decreased by 37.1% (26.0–14.8 mmHg) in Group 1 and 39.5% (28.5–15.1 mmHg) in Group 2. Medications decreased from 3.5 in Group 1 and 3.6 in Group 2 pre-operatively to 0.6 ± 1.0 and 0.3 ± 0.6 post-operatively, respectively. Success rates did not differ significantly between groups based on criterion A (complete and qualified success: 68.7 and 81.9% in Group 1, and 75.3 and 90.4% in Group 2, respectively) or criterion B (complete and qualified success: 58.2 and 79.3%in Group 1, and 69.5 and 88.4% in Group 2, respectively). For eyes with prior filtration surgeries, the mean percent reduction of IOP (41.7 ± 32.7% in Group 1, 39.7 ± 27.8% in Group 2, P = 0.724) and the mean medication reduction (2.9 ± 1.6 in Group 1, 3.4 ± 1.0 in Group 2, P = 0.454) were not significantly different.

Conclusions: Ab interno circumferential trabeculotomy achieved comparable outcomes to ab externo trabeculotomy and may be an effective surgical option for patients with primary open-angle glaucoma.
Choroidal Thickness Profile in Chorioretinal Diseases: Beyond the Macula
Authors: Kim Young Ho , Oh Jaeryung
Published: December 2021

Enhanced depth imaging optical coherence tomography (EDI-OCT) and swept-source OCT (SS-OCT) have emerged as essential diagnostic tools in the study and management of various chorioretinal diseases. Evidence from early clinical studies using EDI-OCT and SS-OCT indicates that choroidal dysfunction plays a major role in the pathogenesis of chorioretinal diseases. Measurement of choroidal thickness (CT) has already become a major research and clinical method, and CT is considered as an indicator of choroidal status in a variety of ophthalmic diseases. Recently, CT measurement has also been proposed as a non-invasive marker for the early detection and monitoring of various systemic diseases. Among the several possible CT measurement locations, subfoveal CT has rapidly become a reliable parameter for measuring CT in healthy and diseased eyes. Moreover, recent advancements in OCT technology have enabled faster and wider imaging of the posterior part of the eye, allowing the various changes in CT as measured outside the macula to be shown accordingly. In this review, we first provide an overview of the results of clinical studies that have analyzed the healthy macular choroid and that in various chorioretinal diseases, and then summarize the current understanding of the choroid outside the macula. We also examine the CT profile as an index that encompasses both within and outside of the macula. Furthermore, we describe the clinical applications of ultrawide OCT, which enables visualization of the far periphery, and discuss the prospects for the development of more reliable choroidal parameters that can better reflect the choroid's characteristics.
Undetectable Production of the VIM-1 Carbapenemase in an Atlantibacter hermannii Clinical Isolate
Authors: Girlich Delphine , Bonnin Rémy A. , Proust Alexis , Naas Thierry , Dortet Laurent
Published: December 2021

The differential expression of VIM-1 in Atlantibacter hermannii WEB-2 and Enterobacter hormaechei ssp. hoffmannii WEB-1 clinical isolates from a rectal swab of a hospitalized patient in France was investigated. A. hermannii WEB-2 was resistant to all β-lactams except carbapenems. It produced ESBL SHV-12, but the Carba NP test failed to detect any carbapenemase activity despite the production of VIM-1. Conversely, E. hormaechei WEB-1, previously recovered from the same patient, was positive for the detection of carbapenemase activity. The blaVIM–1 gene was located on a plasmid and embedded within class 1 integron. Both plasmids were of the same IncA incompatibility group and conferred the same resistance pattern when electroporated in Escherichia coli TOP10 or Enterobacter cloacae CIP7933. Quantitative RT-PCR experiments indicated a weaker replication of pWEB-2 in A. hermannii as compared to E. hormaechei. An isogenic mutant of A. hermannii WEB-2 selected after sequential passages with increased concentrations of imipenem possessed higher MICs for carbapenems and cephalosporins including cefiderocol, higher levels of the blaVIM–1 gene transcripts, and detectable carbapenemase activity using the Carba NP test. Assessment of read coverage demonstrated that a duplication of the region surrounding blaVIM–1 gene occurred in the A. hermannii mutant with detectable carbapenemase activity. The lack of detection of the VIM-1 carbapenemase activity in A. hermannii WEB-2 isolate was likely due to a weak replication of the IncA plasmid harboring the blaVIM–1 gene. Imipenem as selective pressure led to a duplication of this gene on the plasmid and to the restoration of a significant carbapenem-hydrolyzing phenotype.
The Effects of Sub-inhibitory Antibiotic Concentrations on Pseudomonas aeruginosa: Reduced Susceptibility Due to Mutations
Authors: Ramsay Kay A. , McTavish Sharla M. , Wardell Samuel J. T. , Lamont Iain L.
Published: December 2021

Pseudomonas aeruginosa chronically infects in the lungs of people with cystic fibrosis and other forms of lung disease. Infections are treated with antibiotics, but over time, the bacteria acquire mutations that reduce their antibiotic susceptibility. The effects of inhibitory amounts of antibiotics in selecting for antibiotic-resistant mutants have been well studied. However, the concentrations of antibiotics that reach infecting bacteria can be sub-inhibitory and but may nonetheless promote emergence of antibiotic-resistant bacteria. Therefore, the aim of this research was to investigate the effects of sub-inhibitory concentrations of antibiotics on the antibiotic susceptibility of P. aeruginosa. Two P. aeruginosa reference strains, PAO1 and PA14, and six isolates from individuals with cystic fibrosis were studied. The bacteria were passaged in the presence of antibiotics (ceftazidime, ciprofloxacin, meropenem or tobramycin) at sub-inhibitory amounts. Fifteen populations of bacteria (up to five per strain) were exposed to each of the four antibiotics. Antibiotic susceptibility was determined following 10 passages on agar supplemented with antibiotic and compared with susceptibility prior to antibiotic exposure. Antibiotic exposure resulted in susceptibility being significantly (>2-fold) reduced for 13 of the 60 populations. Seven samples had reduced susceptibility to ciprofloxacin, three to tobramycin, two to ceftazidime and one to meropenem. Whole-genome sequencing revealed the mutations arising following antibiotic exposure. Mutants with reduced antibiotic susceptibility had mutations in genes known to affect antibiotic resistance, including regulators of efflux pumps (mexR, mexS, mexZ and nalC) and the fusA1 gene that is associated with aminoglycoside resistance. Genes not previously associated with resistance, including gacS, sigX and crfX and two genes with no known function, were also mutated in some isolates with reduced antibiotic susceptibility. Our results show that exposure to sub-inhibitory amounts of antibiotics can select for mutations that reduce the susceptibility of P. aeruginosa to antibiotics and that the profile of mutations is different from that arising during selection with inhibitory antibiotic concentrations. It is likely that exposure to sub-inhibitory amounts of antibiotics during infection contributes to P. aeruginosa becoming antibiotic-resistant.
Analysis of the Bioprotective Potential of Different Lactic Acid Bacteria Against Listeria monocytogenes in Cold-Smoked Sea Bass, a New Product Packaged Under Vacuum and Stored at 6 ± 2°C
Authors: Iacumin Lucilla , Cappellari Giorgia , Pellegrini Michela , Basso Marco , Comi Giuseppe
Published: December 2021

The aim of the work was to monitor the presence of Listeria monocytogenes in cold-smoked fish products (trout, salmon, and sea bass) marketed in Italy. Cold-smoked sea bass is a new product that has not yet been commercialized and was collected from the production facility. Monitoring data have shown that cold-smoked products can be contaminated by L. monocytogenes, the presence of which has been highlighted mainly by enrichment culture (presence in 25 g). The isolated Listeria were serotyped and belonged mainly to low-virulence serotypes (1/2c), followed by serotypes 1/2a, 1/2b, and 4b. Furthermore, considering the ability of L. monocytogenes to grow in these products due to their chemical–physical characteristics (pH > 6.0, Aw > 0.97) and long shelf life at 4°C, an additional aim was to verify the activity of different bioprotective starters, including Lactilactobacillus sakei (LAK-23, Sacco srl, Via Alessandro Manzoni 29/A, 22071 Cadorago, CO, Italy), Carnobacterium spp., Lacticaseibacillus casei (SAL 106), and Lacticaseibacillus paracasei (SAL 211), in cold-smoked sea bass. All starters were bacteriocin producers. For this experiment, smoked sea bass samples were intentionally inoculated with a mixture of three different strains of L. monocytogenes and of each starter culture. After inoculation, the smoked sea bass were vacuum-packed and stored at 6 ± 2°C for 60 days, simulating the typical abuse storage temperature of markets and home refrigerators. At 0, 15, 30, 45, and 60 days, the sea bass samples were analyzed to evaluate the effectiveness of the starters against L. monocytogenes. Listeria monocytogenes growth was prevented only by the addition of the LAK-23 starter. Indeed, at the end of the shelf life, the amount of L. monocytogenes observed was similar to that in the inoculum. Consequently, the use of this starter can allow the inclusion of cold-smoked sea bass or smoked fish products in category 1.3 of Regolamento CE 2073/2005, which are products that do not support the growth of this microorganism. Finally, the activity of the LAK-23 starter did not produce an off flavor or off odor in the smoked sea bass.
Enzymatic Switching Between Archaeal DNA Polymerases Facilitates Abasic Site Bypass
Authors: Feng Xu , Zhang Baochang , Xu Ruyi , Gao Zhe , Liu Xiaotong , Yuan Guanhua , Ishino Sonoko , Feng Mingxia , Shen Yulong , Ishino Yoshizumi , She Qunxin
Published: December 2021

Abasic sites are among the most abundant DNA lesions encountered by cells. Their replication requires actions of specialized DNA polymerases. Herein, two archaeal specialized DNA polymerases were examined for their capability to perform translesion DNA synthesis (TLS) on the lesion, including Sulfolobuss islandicus Dpo2 of B-family, and Dpo4 of Y-family. We found neither Dpo2 nor Dpo4 is efficient to complete abasic sites bypass alone, but their sequential actions promote lesion bypass. Enzyme kinetics studies further revealed that the Dpo4’s activity is significantly inhibited at +1 to +3 site past the lesion, at which Dpo2 efficiently extends the primer termini. Furthermore, their activities are inhibited upon synthesis of 5–6 nt TLS patches. Once handed over to Dpo1, these substrates basically inactivate its exonuclease, enabling the transition from proofreading to polymerization of the replicase. Collectively, by functioning as an “extender” to catalyze further DNA synthesis past the lesion, Dpo2 bridges the activity gap between Dpo4 and Dpo1 in the archaeal TLS process, thus achieving more efficient lesion bypass.
Fam20C in Human Diseases: Emerging Biological Functions and Therapeutic Implications
Authors: Xu Rongsheng , Tan Huidan , Zhang Jiahui , Yuan Zhaoxin , Xie Qiang , Zhang Lan
Published: December 2021

Fam20C, a typical member of Fam20 family, has been well-known as a Golgi casein kinase, which is closely associated with Raine Syndrome (RS). It can phosphorylate many secreted proteins and multiple substrates, and thereby plays a crucial role in biological functions. More importantly, Fam20C has also been found to enhance the metastasis of several types of human cancers, such as breast cancer, indicating that Fam20C may be a promising therapeutic target. Accordingly, some small-molecule inhibitors of Fam20C have been reported in cancer. Taken together, these inspiring findings would shed new light on exploiting Fam20C as a potential therapeutic target and inhibiting Fam20C with small-molecule compounds would provide a clue on discovery of more candidate small-molecule drugs for fighting with human diseases.
Scalp Acupuncture Attenuates Brain Damage After Intracerebral Hemorrhage Through Enhanced Mitophagy and Reduced Apoptosis in Rats
Authors: Liu Peng , Yu Xinyang , Dai Xiaohong , Zou Wei , Yu Xueping , Niu Mingming , Chen Qiuxin , Teng Wei , Kong Ying , Guan Ruiqiao , Liu Xiaoying
Published: December 2021

To study the effect of scalp acupuncture (SA) on the mitophagy signaling pathway in the caudate nucleus of Sprague-Dawley rats following intracerebral hemorrhage (ICH). An ICH model was established by injecting autologous arterial blood into the caudate nucleus in 200 male Sprague-Dawley rats, which were divided into five groups: sham, ICH, 3-methyladenine group (3-MA, 30 mg/kg), SA, and SA+3-MA. Animals were analyzed at 6 and 24 h as well as at 3 and 7 days. Composite neurological scale score was significantly higher in the SA group than in the ICH group. Transmission electron microscopy showed less structural damage and more autophagic vacuoles within brain in the SA group than in the ICH group. SA group showed higher levels of Beclin1, Parkin, PINK1, NIX protein, and a lower level of Caspase-9 in brain tissue. These animals consequently showed less neural cell apoptosis. Compared with the SA group, however, the neural function score and levels of mitophagy protein in the SA+3-MA group were decreased, neural cell apoptosis was increased with more severe structural damage, which suggested that 3-MA may antagonize the protective effect of SA on brain in rats with ICH. SA may mitigate the neurologic impairment after ICH by enhancing mitophagy and reducing apoptosis.
The Potential of Ferroptosis-Targeting Therapies for Alzheimer’s Disease: From Mechanism to Transcriptomic Analysis
Authors: Majerníková Nad’a , den Dunnen Wilfred F. A. , Dolga Amalia M.
Published: December 2021

Alzheimer’s disease (AD), the most common form of dementia, currently affects 40–50 million people worldwide. Despite the extensive research into amyloid β (Aβ) deposition and tau protein hyperphosphorylation (p-tau), an effective treatment to stop or slow down the progression of neurodegeneration is missing. Emerging evidence suggests that ferroptosis, an iron-dependent and lipid peroxidation-driven type of programmed cell death, contributes to neurodegeneration in AD. Therefore, how to intervene against ferroptosis in the context of AD has become one of the questions addressed by studies aiming to develop novel therapeutic strategies. However, the underlying molecular mechanism of ferroptosis in AD, when ferroptosis occurs in the disease course, and which ferroptosis-related genes are differentially expressed in AD remains to be established. In this review, we summarize the current knowledge on cell mechanisms involved in ferroptosis, we discuss how these processes relate to AD, and we analyze which ferroptosis-related genes are differentially expressed in AD brain dependant on cell type, disease progression and gender. In addition, we point out the existing targets for therapeutic options to prevent ferroptosis in AD. Future studies should focus on developing new tools able to demonstrate where and when cells undergo ferroptosis in AD brain and build more translatable AD models for identifying anti-ferroptotic agents able to slow down neurodegeneration.
Trajectory Analysis of Orthostatic Hypotension in Parkinson’s Disease: Results From Parkinson’s Progression Markers Initiative Cohort
Authors: Chen Kui , Du Kangshuai , Zhao Yichen , Gu Yongzhe , Zhao Yanxin
Published: December 2021

Background: Orthostatic hypotension (OH) in Parkinson’s disease (PD) can lead to falls, impair quality of life, and increase mortality. A trajectory analysis of OH could be useful to predict and prevent the hypotension incidence early.

Methods: The longitudinal data of 660 patients with PD with disease duration up to 12 years were extracted from an integrated PD database. We used latent class mixed modeling (LCMM) to identify patient subgroups, demonstrating trajectories of changes in orthostatic blood pressure (BP) over time. The optimal number of subgroups was selected by several criteria including the Bayesian Information Criterion. Baseline information comparison between groups and backward stepwise logistic regression were conducted to define the distinguishing characteristics of these subgroups and to investigate the predictors for BP trajectory.

Results: We identified three trajectories for each orthostatic change of systolic blood pressure (ΔSBP), namely, Class 1 (i.e., the increasing class) consisted of 18 participants with low ΔSBP that increased continuously during the follow-up; Class 2 (i.e., the low-stable class) consisted of 610 participants with low ΔSBP that remained low throughout the follow-up; and Class 3 (i.e., the high-stable class) consisted of 32 participants with high ΔSBP at baseline that was relatively stable throughout the follow-up. Several parameters differed among subgroups, but only male sex [odds ratio (OR) = 4.687, 95% confidence interval (CI) = 1.024–21.459], lower supine diastolic blood pressure (DBP) (OR = 0.934, 95% CI = 0.876–0.996), and lower level of total protein at baseline (OR = 0.812, 95% CI = 0.700–0.941) were significant predictors of an increasing ΔSBP trajectory.

Conclusion: This study provides new information on the longitudinal development of ΔSBP in patients with PD with distinct trajectories of rapidly increasing, low-stable, and high-stable class. The parameters such as male sex, lower supine DBP, and lower total proteins help to identify the rapidly increasing class.