bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging
Authors: Leduc-Gaudet Jean-Philippe , Hussain Sabah N. A. , Barreiro Esther , Gouspillou Gilles
Published: July 2021

The maintenance of mitochondrial integrity is critical for muscle health. Mitochondria, indeed, play vital roles in a wide range of cellular processes, including energy supply, Ca2+ homeostasis, retrograde signaling, cell death, and many others. All mitochondria-containing cells, including skeletal muscle cells, dispose of several pathways to maintain mitochondrial health, including mitochondrial biogenesis, mitochondrial-derived vesicles, mitochondrial dynamics (fusion and fission process shaping mitochondrial morphology), and mitophagy—the process in charge of the removal of mitochondria though autophagy. The loss of skeletal muscle mass (atrophy) is a major health problem worldwide, especially in older people. Currently, there is no treatment to counteract the progressive decline in skeletal muscle mass and strength that occurs with aging, a process termed sarcopenia. There is increasing data, including our own, suggesting that accumulation of dysfunctional mitochondria contributes to the development of sarcopenia. Impairments in mitochondrial dynamics and mitophagy were recently proposed to contribute to sarcopenia. This review summarizes the current state of knowledge on the role played by mitochondrial dynamics and mitophagy in skeletal muscle health and in the development of sarcopenia. We also highlight recent studies showing that enhancing mitophagy in skeletal muscle is a promising therapeutic target to prevent or even treat skeletal muscle dysfunction in the elderly.
Design and Synthesis of Fluoro Analogues of Vitamin D
Authors: Kawagoe Fumihiro , Mototani Sayuri , Kittaka Atsushi
Published: July 2021

The discovery of a large variety of functions of vitamin D3 and its metabolites has led to the design and synthesis of a vast amount of vitamin D3 analogues in order to increase the potency and reduce toxicity. The introduction of highly electronegative fluorine atom(s) into vitamin D3 skeletons alters their physical and chemical properties. To date, many fluorinated vitamin D3 analogues have been designed and synthesized. This review summarizes the molecular structures of fluoro-containing vitamin D3 analogues and their synthetic methodologies.
Progressive Mitochondrial SOD1G93A Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis
Authors: Méndez-López Iago , Sancho-Bielsa Francisco J. , Engel Tobias , García Antonio G. , Padín Juan Fernando
Published: July 2021

In recent years, the “non-autonomous motor neuron death” hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). It postulates that cells other than motor neurons participate in the pathology. In fact, the involvement of the autonomic nervous system is fundamental since patients die of sudden death when they become unable to compensate for cardiorespiratory arrest. Mitochondria are thought to play a fundamental role in the physiopathology of ALS, as they are compromised in multiple ALS models in different cell types, and it also occurs in other neurodegenerative diseases. Our study aimed to uncover mitochondrial alterations in the sympathoadrenal system of a mouse model of ALS, from a structural, bioenergetic and functional perspective during disease instauration. We studied the adrenal chromaffin cell from mutant SOD1G93A mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1G93A protein and the down-regulation of optic atrophy protein-1 (OPA1) provoke mitochondrial ultrastructure alterations prior to the onset of clinical symptoms. These changes affect mitochondrial fusion dynamics, triggering mitochondrial maturation impairment and cristae swelling, with increased size of cristae junctions. The functional consequences are a loss of mitochondrial membrane potential and changes in the bioenergetics profile, with reduced maximal respiration and spare respiratory capacity of mitochondria, as well as enhanced production of reactive oxygen species. This study identifies mitochondrial dynamics regulator OPA1 as an interesting therapeutic target in ALS. Additionally, our findings in the adrenal medulla gland from presymptomatic stages highlight the relevance of sympathetic impairment in this disease. Specifically, we show new SOD1G93A toxicity pathways affecting cellular energy metabolism in non-motor neurons, which offer a possible link between cell specific metabolic phenotype and the progression of ALS.
Sex-Based Impact of Creatine Supplementation on Depressive Symptoms, Brain Serotonin and SSRI Efficacy in an Animal Model of Treatment-Resistant Depression
Authors: Kanekar Shami , Ettaro Robert , Hoffman Michael D. , Ombach Hendrik J. , Brown Jadeda , Lynch Cayla , Sheth Chandni S. , Renshaw Perry F.
Published: July 2021

Background: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. Methods: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. Results: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. Conclusions: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.
Analysis and Fine Specificity of the HCMV-Specific Cell-Free and Cell-Associated Antibody-Dependent Cellular Phagocytosis (ADCP) Responses in Lung Transplant Recipients
Authors: Eberhard Simone , Vietzen Hannes , Görzer Irene , Jaksch Peter , Puchhammer-Stöckl Elisabeth
Published: July 2021

Human Cytomegalovirus (HCMV) may cause severe infections in transplant recipients. HCMV-replication can be limited by HCMV-specific antibody responses. The impact of the antibody-dependent cellular phagocytosis (ADCP) on inhibition of HCMV-replication in natural infections has not been clarified. Therefore, we investigated the HCMV-specific ADCP response in a study cohort of lung-transplant recipients (LTRs) with different donor (D) and recipient (R) HCMV-serostatus. Follow-up plasma samples from 39 non/low-viremic and 36 highly viremic (>1000 HCMV copies/mL plasma) LTRs were collected for one (R+ LTRs) or two (D+/R− LTRs) years post-transplantation. The HCMV-specific ADCP responses were assessed by focal expansion assays (FEA) and flow-cytometry. In all LTRs, ADCP responses were detected against HCMV-infected cells and cell-free virions. When measured in fibroblasts as well as with cell-free virus, the HCMV-specific ADPC response was higher in LTRs than in HCMV-seropositive healthy controls. In D+/R− LTRs, a significant ADCP response developed over time after the receipt of an HCMV positive lung, and a level of <19 IE+ cells/focus in the FEA on fibroblasts was associated with further protection from high-level viremia. Taken together, a strong HCMV-specific ADCP response is elicited in transplant recipients, which may contribute to protection from high-level viremia in primary HCMV infection.
The EphB6 Receptor: Kinase-Dead but Very Much Alive
Authors: Strozen Timothy G. , Sharpe Jessica C. , Harris Evelyn D. , Uppalapati Maruti , Toosi Behzad M.
Published: July 2021

The Eph receptor tyrosine kinase member EphB6 is a pseudokinase, and similar to other pseudoenzymes has not attracted an equivalent amount of interest as its enzymatically-active counterparts. However, a greater appreciation for the role pseudoenzymes perform in expanding the repertoire of signals generated by signal transduction systems has fostered more interest in the field. EphB6 acts as a molecular switch that is capable of modulating the signal transduction output of Eph receptor clusters. Although the biological effects of EphB6 activity are well defined, the molecular mechanisms of EphB6 function remain enigmatic. In this review, we use a comparative approach to postulate how EphB6 acts as a scaffold to recruit adaptor proteins to an Eph receptor cluster and how this function is regulated. We suggest that the evolutionary repurposing of EphB6 into a kinase-independent molecular switch in mammals has involved repurposing the kinase activation loop into an SH3 domain-binding site. In addition, we suggest that EphB6 employs the same SAM domain linker and juxtamembrane domain allosteric regulatory mechanisms that are used in kinase-positive Eph receptors to regulate its scaffold function. As a result, although kinase-dead, EphB6 remains a strategically active component of Eph receptor signaling.
Chelerythrine Chloride: A Potential Rumen Microbial Urease Inhibitor Screened by Targeting UreG
Authors: Zhang Xiaoyin , He Yue , Xiong Zhanbo , Li Min , Li Ming , Zheng Nan , Zhao Shengguo , Wang Jiaqi
Published: July 2021

Inhibition of ruminal microbial urease is of particular interest due to its crucial role in regulating urea-N utilization efficiency and nitrogen pollution in the livestock industry. Acetohydroxamic acid (AHA) is currently the only commercially available urease inhibitor, but it has adverse side effects. The urease accessory protein UreG, which facilitates the functional incorporation of the urease nickel metallocentre, has been proposed in developing urease inhibitor through disrupting urease maturation. The objective of this study was to screen natural compounds as potential urease inhibitors by targeting UreG in a predominant ruminal microbial urease. In silico screening and in vitro tests for potential inhibitors were performed using molecular docking and an assay for the GTPase activity of UreG. Chelerythrine chloride was selected as a potential urease inhibitor of UreG with an inhibition concentration IC50 value of 18.13 μM. It exhibited mixed inhibition, with the Ki value being 26.28 μM. We further explored its inhibition mechanism using isothermal titration calorimetry (ITC) and circular dichroism (CD) spectroscopy, and we found that chelerythrine chloride inhibited the binding of nickel to UreG and induced changes in the secondary structure, especially the α-helix and β-sheet of UreG. Chelerythrine chloride formed a pi-anion interaction with the Asp41 residue of UreG, which is an important residue in initiating the conformational changes of UreG. In conclusion, chelerythrine chloride exhibited a potential inhibitory effect on urease, which provided new evidence for strategies to develop novel urease inhibitors targeting UreG to reduce nitrogen excretion from ruminants.
Connecting the Neurobiology of Developmental Brain Injury: Neuronal Arborisation as a Regulator of Dysfunction and Potential Therapeutic Target
Authors: Goikolea-Vives Ane , Stolp Helen B.
Published: July 2021

Neurodevelopmental disorders can derive from a complex combination of genetic variation and environmental pressures on key developmental processes. Despite this complex aetiology, and the equally complex array of syndromes and conditions diagnosed under the heading of neurodevelopmental disorder, there are parallels in the neuropathology of these conditions that suggest overlapping mechanisms of cellular injury and dysfunction. Neuronal arborisation is a process of dendrite and axon extension that is essential for the connectivity between neurons that underlies normal brain function. Disrupted arborisation and synapse formation are commonly reported in neurodevelopmental disorders. Here, we summarise the evidence for disrupted neuronal arborisation in these conditions, focusing primarily on the cortex and hippocampus. In addition, we explore the developmentally specific mechanisms by which neuronal arborisation is regulated. Finally, we discuss key regulators of neuronal arborisation that could link to neurodevelopmental disease and the potential for pharmacological modification of arborisation and the formation of synaptic connections that may provide therapeutic benefit in the future.
Production of Recombinant Human Ceruloplasmin: Improvements and Perspectives
Authors: Bonaccorsi di Patti Maria Carmela , Cutone Antimo , Nemčovič Marek , Pakanová Zuzana , Baráth Peter , Musci Giovanni
Published: July 2021

The ferroxidase ceruloplasmin (CP) plays a crucial role in iron homeostasis in vertebrates together with the iron exporter ferroportin. Mutations in the CP gene give rise to aceruloplasminemia, a rare neurodegenerative disease for which no cure is available. Many aspects of the (patho)physiology of CP are still unclear and would benefit from the availability of recombinant protein for structural and functional studies. Furthermore, recombinant CP could be evaluated for enzyme replacement therapy for the treatment of aceruloplasminemia. We report the production and preliminary characterization of high-quality recombinant human CP in glycoengineered Pichia pastoris SuperMan5. A modified yeast strain lacking the endogenous ferroxidase has been generated and employed as host for heterologous expression of the secreted isoform of human CP. Highly pure biologically active protein has been obtained by an improved two-step purification procedure. Glycan analysis indicates that predominant glycoforms HexNAc2Hex8 and HexNAc2Hex11 are found at Asn119, Asn378, and Asn743, three of the canonical four N-glycosylation sites of human CP. The availability of high-quality recombinant human CP represents a significant advancement in the field of CP biology. However, productivity needs to be increased and further careful glycoengineering of the SM5 strain is mandatory in order to evaluate the possible therapeutic use of the recombinant protein for enzyme replacement therapy of aceruloplasminemia patients.
Enhancement of Anti-Tumoral Immunity by β-Casomorphin-7 Inhibits Cancer Development and Metastasis of Colorectal Cancer
Authors: Mori Shiori , Fujiwara-Tani Rina , Kishi Shingo , Sasaki Takamitsu , Ohmori Hitoshi , Goto Kei , Nakashima Chie , Nishiguchi Yukiko , Kawahara Isao , Luo Yi , Kuniyasu Hiroki
Published: July 2021

β-Casomorphin-7 (BCM) is a degradation product of β-casein, a milk component, and has been suggested to affect the immune system. However, its effect on mucosal immunity, especially anti-tumor immunity, in cancer-bearing individuals is not clear. We investigated the effects of BCM on lymphocytes using an in vitro system comprising mouse splenocytes, a mouse colorectal carcinogenesis model, and a mouse orthotopic colorectal cancer model. Treatment of mouse splenocytes with BCM in vitro reduced numbers of cluster of differentiation (CD) 20+ B cells, CD4+ T cells, and regulatory T cells (Tregs), and increased CD8+ T cells. Administration of BCM and the CD10 inhibitor thiorphan (TOP) to mice resulted in similar alterations in the lymphocyte subsets in the spleen and intestinal mucosa. BCM was degraded in a concentration- and time-dependent manner by the neutral endopeptidase CD10, and the formed BCM degradation product did not affect the lymphocyte counts. Furthermore, degradation was completely suppressed by TOP. In the azoxymethane mouse colorectal carcinogenesis model, the incidence of aberrant crypt foci, adenoma, and adenocarcinoma was reduced by co-treatment with BCM and TOP. Furthermore, when CT26 mouse colon cancer cells were inoculated into the cecum of syngeneic BALB/c mice and concurrently treated with BCM and TOP, infiltration of CD8+ T cells was promoted, and tumor growth and liver metastasis were suppressed. These results suggest that by suppressing the BCM degradation system, the anti-tumor effect of BCM is enhanced and it can suppress the development and progression of colorectal cancer.
Finding Evidence of Fraudster Companies in the CEO’s Letter to Shareholders with Sentiment Analysis
Authors: Bel Núria , Bracons Gabriel , Anderberg Sophia
Published: July 2021

The goal of our research was to assess whether the observation about deceptive texts having a lower positive tone than truthful ones in terms of sentiment could become operative and be used for building a classifier in the particular case of fraudster’s letters written in Spanish. The data were the letters that CEOs address to company shareholders in their annual financial reports, and the task was to identify the letters of companies that committed financial misconduct or fraud. This case was challenging for two reasons: first, most of the research worked with spontaneous written or spoken texts, while these letters did not; second, most of the research in this area worked on English texts, while we validated the linguistic cues found as evidence of deception for Spanish texts. The results of our research confirm that an SVM trained with a bag-of-words model of frequent adjectives can achieve 81% accuracy because these adjectives bring the information about which positive or negative tone and which word combinations in a text turn out to be a characteristic of fraudster’s texts.
Image Watermarking Approach Using a Hybrid Domain Based on Performance Parameter Analysis
Authors: Srivastava Rohit , Tomar Ravi , Gupta Maanak , Yadav Anuj Kumar , Park Jaehong
Published: July 2021

In today’s scenario, image watermarking has been an integral part in various multimedia applications. Watermarking is the approach for adding additional information to the existing image to protect the data from modification and to provide data integrity. Frequency transform domain techniques are complex and costly and degrade the quality of the image due to less embedding of bits. The proposed work utilize the original DCT method with some modifications and applies this method on frequency bands of DWT. Furthermore, the output is used in combination with a pixel modification method for embedding and extraction. The proposed outcome is the improvement of performance achieved in terms of time, imperceptibility, and robustness.
Attention Deficits and ADHD Symptoms in Adults with Fabry Disease—A Pilot Investigation
Authors: Ali Nadia , Caceres Amanda , Hall Eric W. , Laney Dawn
Published: July 2021

The present pilot study examines subjective reported symptoms of attention-deficit/hyperactivity (AD/H) in adults with Fabry disease (FD) in comparison with existing normative control data. Existing data from 69 adults with FD via the Achenbach System of Empirically Based Assessment Adult Self-Report questionnaire were analyzed. The results demonstrated a higher prevalence of AD/H symptoms in adults with FD than in the general United States population, with a roughly equal endorsement of Inattention/Attention Deficit symptoms (AD), Hyperactivity-Impulsivity (H-I) symptoms, and Combined Inattention/hyperactivity-impulsivity (C) symptoms. No gender differences were observed. While all subjects endorsing H-I symptoms fell into the symptomatic range on the AD/H scale, only two-thirds of subjects endorsing AD did so. This suggests that attention difficulties with FD are not solely explained by ADHD. Adults with FD who endorsed the AD, H-I, and C symptoms were also more likely to report mean adaptive functioning difficulties. These findings support the growing literature regarding attention difficulties in adults with FD, as well as suggesting a previously unrecognized risk of AD/H symptoms. Future research involving the objective assessment of ADHD in adults with FD is recommended. When serving adults with FD clinically, healthcare professionals should address multiple areas of care, including physical, psychological, and cognitive arenas.
Patients with Persistent Polyclonal B-Cell Lymphocytosis Share the Symptomatic Criteria of Systemic Exertion Intolerance Disease
Authors: Morizot Romain , de Korwin Jean-Dominique , Feugier Pierre , Broséus Julien , Troussard Xavier , Lesesve Jean-François
Published: July 2021

Introduction: Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare and still poorly understood entity, with 90% of cases occurring in female smokers. Patients often appear tired and in pain, but the clinical symptoms remain imprecise. The main risk is the development of lymphoma in some cases. To better understand the characteristics of the fatigue associated with PPBL and study its relationship with systemic exertion intolerance disease (SEID), we analyzed the symptoms in a cohort of patients with PPBL included in the French national registry. Material and methods: An anonymous questionnaire following the recommendations of the Institute of Medicine/National Academy of Medicine for screening of the new SEID criteria was created in French and mailed to 50 patients. Results: Thirty-nine (78%) contacted patients responded. The studied population was mainly constituted of women (90%) with an average age of 50 (18–59) years. Smoking was a constant factor in all patients. A total of 28/39 (72%) respondents met the SEID symptoms criteria. Severe chronic fatigue for more than 6 months was noted in 36/39 cases (92%). Unrefreshing sleep, post-exertional malaise, cognitive impairment, and orthostatic intolerance were described in 30/39 (77%), 32/39 (82%), 28/39 (72%), and 27/39 (69%) cases, respectively. Pain (arthralgia, myalgia, headache) was present in 26/39 (67%) cases. The most prominent SEID symptoms were fatigue, followed by post-exercise discomfort and cognitive difficulties. The most disabling symptom was non-restorative sleep, followed by pain. An inflammatory and/or autoimmune context was noted in 13 patients (33%), and these comorbidities could have favored the deterioration of the general condition. Three patients also presented with fibromyalgia. However, 3 patients did not mention any complaints. Conclusion: This survey indicated that patients with PPBL most often initially presented with disabling chronic fatigue, chronic pain, and other symptoms suggestive of SEID but requiring more studies to confirm it. Education of medical staff about the symptoms of PPBL should be encouraged to better assess this peculiar condition.
Can VA-ECMO Be Used as an Adequate Treatment in Massive Pulmonary Embolism?
Authors: Giraud Raphaël , Laurencet Matthieu , Assouline Benjamin , De Charrière Amandine , Banfi Carlo , Bendjelid Karim
Published: July 2021

Introduction: Massive acute pulmonary embolism (MAPE) with obstructive cardiogenic shock is associated with a mortality rate of more than 50%. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been increasingly used in refractory cardiogenic shock with very good results. In MAPE, although it is currently recommended as part of initial resuscitation, it is not yet considered a stand-alone therapy. Material and Methods: All patients with MAPE requiring the establishment of VA-ECMO and admitted to our tertiary intensive care unit were analysed over a period of 10 years. The characteristics of these patients, before, during and after ECMO were extracted and analysed. Results: A total of 36 patients were included in the present retrospective study. Overall survival was 64%. In the majority of cases, the haemodynamic and respiratory status of the patient improved significantly within the first 24 h on ECMO. The 30-day survival significantly increased when ECMO was used as stand-alone therapy (odds ratio (OR) 15.58, 95% confidence interval (CI) 2.65–91.57, p = 0.002). Nevertheless, when ECMO was implanted following the failure of thrombolysis, the bleeding complications were major (17 (100%) vs. 1 (5.3%) patients, p < 0.001) and the 30-day mortality increased significantly (OR 0.11, 95% CI 0.022–0.520, p = 0.006). Conclusions: The present retrospective study is certainly one of the most important in terms of the number of patients with MAPE and shock treated with VA-ECMO. This short-term mechanical circulatory support, used as a stand-alone therapy in MAPE, allows for the optimal stabilisation of patients.
Effects of Antidepressant Treatment on Neurotrophic Factors (BDNF and IGF-1) in Patients with Major Depressive Disorder (MDD)
Authors: Mosiołek Anna , Mosiołek Jadwiga , Jakima Sławomir , Pięta Aleksandra , Szulc Agata
Published: July 2021

Major depressive disorder (MDD) remains the subject of ongoing research as a multifactorial disease and a serious public health problem. There is a growing body of literature focusing on the role of neurotrophic factors in pathophysiology of MDD. A neurotrophic hypothesis of depression proposes that abnormalities of neurotrophins serum levels lead to neuronal atrophy and decreased neurogenesis, resulting in mood disorders. Consequently, in accordance with recent findings, antidepressant treatment modifies the serum levels of neurotrophins and thus leads to a clinical improvement of MDD. The purpose of this review is to summarize the available data on the effects of various antidepressants on serum levels of neurotrophins such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1). In addition, the authors discuss their role as prognostic factors for treatment response in MDD. A literature search was performed using the PubMed database. Following the inclusion and exclusion criteria, nine original articles and three meta-analyses were selected. The vast majority of studies have confirmed the effect of antidepressants on BDNF levels. Research on IGF-1 is limited and insufficient to describe the correlation between different antidepressant drugs and factor serum levels; however, four studies indicated a decrease in IGF-1 after treatment. Preliminary data suggest BDNF as a promising predictor of treatment response in MDD patients. The role of IGF-1 needs further investigation.
The Relationship between Gestational Diabetes Metabolic Control and Fetal Autonomic Regulation, Movement and Birth Weight
Authors: Zöllkau Janine , Swiderski Laura , Schmidt Alexander , Weschenfelder Friederike , Groten Tanja , Hoyer Dirk , Schneider Uwe
Published: July 2021

(1) Background: Maternal metabolic control in gestational diabetes is suggested to influence fetal autonomic control and movement activity, which may have fetal outcome implications. We aimed to analyze the relationship between maternal metabolic control, fetal autonomic heart rate regulation, activity and birth weight. (2) Methods: Prospective noninterventional longitudinal cohort monitoring study accompanying 19 patients with specialist clinical care for gestational diabetes. Monthly fetal magnetocardiography with electro-physiologically-based beat-to-beat heart rate recording for analysis of heart rate variability (HRV) and the ‘fetal movement index’ (FMI) was performed. Data were compared to 167 healthy pregnant women retrieved from our pre-existing study database. (3) Results: Fetal vagal tone was increased with gestational diabetes compared to controls, whereas sympathetic tone and FMI did not differ. Within the diabetic population, sympathetic activation was associated with higher maternal blood-glucose levels. Maternal blood-glucose levels correlated positively with birth weight z scores. FMI showed no correlation with birth weight but attenuated the positive correlation between maternal blood-glucose levels and birth weight. (4) Conclusion: Fetal autonomic control is altered by gestational diabetes and maternal blood-glucose level, even if metabolic adjustment and outcome is comparable to healthy controls.
Airway Care Interventions for Invasively Ventilated Critically Ill Adults—A Dutch National Survey
Authors: Stilma Willemke , van der Hoeven Sophia M. , Scholte op Reimer Wilma J. M. , Schultz Marcus J. , Rose Louise , Paulus Frederique
Published: July 2021

Airway care interventions may prevent accumulation of airway secretions and promote their evacuation, but evidence is scarce. Interventions include heated humidification, nebulization of mucolytics and/or bronchodilators, manual hyperinflation and use of mechanical insufflation-exsufflation (MI-E). Our aim is to identify current airway care practices for invasively ventilated patients in intensive care units (ICU) in the Netherlands. A self–administered web-based survey was sent to a single pre–appointed representative of all ICUs in the Netherlands. Response rate was 85% (72 ICUs). We found substantial heterogeneity in the intensity and combinations of airway care interventions used. Most (81%) ICUs reported using heated humidification as a routine prophylactic intervention. All (100%) responding ICUs used nebulized mucolytics and/or bronchodilators; however, only 43% ICUs reported nebulization as a routine prophylactic intervention. Most (81%) ICUs used manual hyperinflation, although only initiated with a clinical indication like difficult oxygenation. Few (22%) ICUs used MI-E for invasively ventilated patients. Use was always based on the indication of insufficient cough strength or as a continuation of home use. In the Netherlands, use of routine prophylactic airway care interventions is common despite evidence of no benefit. There is an urgent need for evidence of the benefit of these interventions to inform evidence-based guidelines.
Increased Pericardial Adipose Tissue in Smokers
Authors: Zimmermann Gregor S. , Ruether Tobias , von Ziegler Franz , Greif Martin , Tittus Janine , Schenzle Jan , Becker Christoph , Becker Alexander
Published: July 2021

Background: Pericardial adipose tissue (PAT), a visceral fat depot directly located to the heart, is associated with atherosclerotic and inflammatory processes. The extent of PAT is related to the prevalence of coronary heart disease and might be used for cardiovascular risk prediction. This study aimed to determine the effect of smoking on the extent of PAT. Methods: We retrospectively examined 1217 asymptomatic patients (490 females, age 58.3 ± 8.3 years, smoker n = 573, non-smoker n = 644) with a multislice CT scanner and determined the PAT volume. Coronary risk factors were determined at inclusion, and a multivariate analysis was performed to evaluate the influence of smoking on PAT independent from accompanying risk factors. Results: The mean PAT volume was 215 ± 107 mL in all patients. The PAT volume in smokers was significantly higher compared to PAT volume in non-smokers (231 ± 104 mL vs. 201 ± 99 mL, p = 0.03). Patients without cardiovascular risk factors showed a significantly lower PAT volume (153 ± 155 mL, p < 0.05) compared to patients with more than 1 risk factor. Odds ratio was 2.92 [2.31, 3.61; p < 0.001] for elevated PAT in smokers. Conclusion: PAT as an individual marker of atherosclerotic activity and inflammatory burden was elevated in smokers. The finding was independent from metabolic risk factors and might therefore illustrate the increased inflammatory activity in smokers in comparison to non-smokers.
Pre-Clinical Investigation of Cardioprotective Beta-Blockers as a Therapeutic Strategy for Preeclampsia
Authors: Binder Natalie K. , MacDonald Teresa M. , Beard Sally A. , de Alwis Natasha , Tong Stephen , Kaitu’u-Lino Tu’uhevaha J. , Hannan Natalie J.
Published: July 2021

Despite significant maternal and fetal morbidity, a treatment for preeclampsia currently remains an unmet need in clinical care. As too does the lifelong cardiovascular risks imparted on preeclampsia sufferers. Endothelial dysfunction and end-organ injury are synonymous with both preeclampsia and cardiovascular disease, including heart failure. We propose that beta-blockers, known to improve endothelial dysfunction in the treatment of cardiovascular disease, and specifically known to reduce mortality in the treatment of heart failure, may be beneficial in the treatment of preeclampsia. Here, we assessed whether the beta-blockers carvedilol, bisoprolol, and metoprolol could quench the release of anti-angiogenic factors, promote production of pro-angiogenic factors, reduce markers of inflammation, and reduce endothelial dysfunction using our in vitro pre-clinical preeclampsia models encompassing primary placental tissue and endothelial cells. Here, we show beta-blockers effected a modest reduction in secretion of anti-angiogenic soluble fms-like tyrosine kinase-1 and soluble endoglin and increased expression of pro-angiogenic placental growth factor, vascular endothelial growth factor and adrenomedullin in endothelial cells. Beta-blocker treatment mitigated inflammatory changes occurring after endothelial dysfunction and promoted cytoprotective antioxidant heme oxygenase-1. The positive effects of the beta-blockers were predominantly seen in endothelial cells, with a less consistent response seen in placental cells/tissue. In conclusion, beta-blockers show potential as a novel therapeutic approach in the treatment of preeclampsia and warrant further investigation.
Switching from Biosimilar to Biosimilar Adalimumab, Including Multiple Switching, in Crohn’s Disease: A Prospective Study
Authors: Ribaldone Davide Giuseppe , Tribocco Elisa , Rosso Chiara , Armandi Angelo , Vernero Marta , Bugianesi Elisabetta , Astegiano Marco , Saracco Giorgio Maria , Caviglia Gian Paolo
Published: July 2021

No data are available regarding the safety and effectiveness of the biosimilar-to-biosimilar switch of adalimumab in any disease, and in particular in Crohn’s disease (CD). The aim of our study was to provide real world data on switching from biosimilar adalimumab to another biosimilar, including multiple switching. We conducted a prospective, single-centre observational study in which we consecutively recruited all CD patients who switched from adalimumab biosimilar ABP 501 to biosimilar SB5 from January to July 2021. Sixty-one patients were included in the final analysis, of whom 43/61 (70.5%) were multiple switches (Humira® → ABP 501 → SB5). After 6 months of follow up, 88.5% (54/61) of patients maintained SB5 on therapy. The success of the switch (defined as no systemic corticosteroids within 6 months, non-discontinuation of SB5, no dose escalation) was achieved by 82.0% (50/61) of patients. At multivariate analysis, C-reactive protein > 5 mg/L predicted switch failure (p = 0.03). Seven patients (11.5%) experienced side effects, compared to one patient (1.6%) in the 6 pre-switch months (p = 0.03). In conclusion, switching from biosimilar to biosimilar of adalimumab did not lead to signs of safety or loss of efficacy other than those already known in the literature for the class of drugs.
Decrease in Incidence Rate of Hospitalizations Due to AIDS-Defining Conditions but Not to Non-AIDS Conditions in PLWHIV on cART in 2008–2018 in Italy
Authors: Nozza Silvia , Timelli Laura , Saracino Annalisa , Gianotti Nicola , Lazzaretti Claudia , Tavelli Alessandro , Puoti Massimo , Lo Caputo Sergio , Antinori Andrea , Monforte Antonella , Mussini Cristina , Girardi Enrico ,   on behalf of ICONA Foundation Study Group
Published: July 2021

Background: We aimed to describe the change in the incidence and causes of hospitalization between 2008 and 2018 among persons living with HIV (PLWHIV) who started antiretroviral therapy (ART) from 2008 onwards in Italy. Methods: We included participants in the ICONA (Italian Cohort Naïve Antiretrovirals) cohort who started ART in 2008. All the hospitalizations occurring during the first 30 days from the start of ART were excluded. Hospitalizations were classified as due to: AIDS-defining conditions (ADC), non-ADC infections and non-infections/non-ADC (i.e., cardiovascular, pulmonary, renal-genitourinary, cancers, gastrointestinal-liver, psychiatric and other diseases). Comparisons of rates across time were assessed using Poisson regression. The Poisson multivariable model evaluated risk factors for hospitalizations, including both demographic and clinical characteristics. Results: A total of 9524 PLWHIV were included; 6.8% were drug users, 48.9% men-who-have sex with men (MSM), 39.6% heterosexual contacts; 80.8% were males, 42.3% smokers, 16.6% coinfected with HCV and 6.8% with HBV (HBsAg-positive). During 36,157 person-years of follow-up (PYFU), there were 1058 hospitalizations in 747 (7.8%) persons; they had HIV-RNA >50 copies mL in 34.9% and CD4 < 200/mmc in 27%. Causes of hospitalization were 23% ADC, 22% non-ADC infections, 55% non-infections/non-ADC (11% cancers; 9% gastrointestinal-liver; 6% cardiovascular; 5% renal-genitourinary; 5% psychiatric; 4% pulmonary; 15% other). Over the study period, the incidence rate (IR) decreased significantly (from 5.8 per 100 PYFU in 2008–2011 to 2.21 per 100 PYFU in 2016–2018). Age > 50 years, intravenous drug use (IDU), family history of cardiovascular disease, HIV-RNA > 50, CD4 < 200, were associated with a higher hospitalization risk. Conclusions: In our population of PLWHIV, the rate of hospitalization decreased over time.
The APAC Score: A Novel and Highly Performant Serological Tool for Early Diagnosis of Hepatocellular Carcinoma in Patients with Liver Cirrhosis
Authors: Lambrecht Joeri , Porsch-Özçürümez Mustafa , Best Jan , Jost-Brinkmann Fabian , Roderburg Christoph , Demir Münevver , Tacke Frank , Mohr Raphael
Published: July 2021

(1) Background: Surveillance of at-risk patients for hepatocellular carcinoma (HCC) is highly necessary, as curative treatment options are only feasible in early disease stages. However, to date, screening of patients with liver cirrhosis for HCC mostly relies on suboptimal ultrasound-mediated evaluation and α-fetoprotein (AFP) measurement. Therefore, we sought to develop a novel and blood-based scoring tool for the identification of early-stage HCC. (2) Methods: Serum samples from 267 patients with liver cirrhosis, including 122 patients with HCC and 145 without, were collected. Expression levels of soluble platelet-derived growth factor receptor beta (sPDGFRβ) and routine clinical parameters were evaluated, and then utilized in logistic regression analysis. (3) Results: We developed a novel serological scoring tool, the APAC score, consisting of the parameters age, sPDGFRβ, AFP, and creatinine, which identified patients with HCC in a cirrhotic population with an AUC of 0.9503, which was significantly better than the GALAD score (AUC: 0.9000, p = 0.0031). Moreover, the diagnostic accuracy of the APAC score was independent of disease etiology, including alcohol (AUC: 0.9317), viral infection (AUC: 0.9561), and NAFLD (AUC: 0.9545). For the detection of patients with (very) early (BCLC 0/A) HCC stage or within Milan criteria, the APAC score achieved an AUC of 0.9317 (sensitivity: 85.2%, specificity: 89.2%) and 0.9488 (sensitivity: 91.1%, specificity 85.3%), respectively. (4) Conclusions: The APAC score is a novel and highly accurate serological tool for the identification of HCC, especially for early stages. It is superior to the currently proposed blood-based algorithms, and has the potential to improve surveillance of the at-risk population.
Neurally-Adjusted Ventilatory Assist (NAVA) versus Pneumatically Synchronized Ventilation Modes in Children Admitted to PICU
Authors: Sugunan Pravin , Hosheh Osama , Garcia Cusco Mireia , Mildner Reinout
Published: July 2021

Traditionally, invasively ventilated children in the paediatric intensive care unit (PICU) are weaned using pneumatically-triggered ventilation modes with a fixed level of assist. The best weaning mode is currently not known. Neurally adjusted ventilatory assist (NAVA), a newer weaning mode, uses the electrical activity of the diaphragm (Edi) to synchronise ventilator support proportionally to the patient’s respiratory drive. We aimed to perform a systematic literature review to assess the effect of NAVA on clinical outcomes in invasively ventilated children with non-neonatal lung disease. Three studies (n = 285) were included for analysis. One randomised controlled trial (RCT) of all comers showed a significant reduction in PICU length of stay and sedative use. A cohort study of acute respiratory distress syndrome (ARDS) patients (n = 30) showed a significantly shorter duration of ventilation and improved sedation with the use of NAVA. A cohort study of children recovering from cardiac surgery (n = 75) showed significantly higher extubation success, shorter duration of ventilation and PICU length of stay, and a reduction in sedative use. Our systematic review presents weak evidence that NAVA may shorten the duration of ventilation and PICU length of stay, and reduce the requirement of sedatives. However, further RCTs are required to more fully assess the effect of NAVA on clinical outcomes and treatment costs in ventilated children.
New Insights into Gastrointestinal Involvement in Late-Onset Pompe Disease: Lessons Learned from Bench and Bedside
Authors: Korlimarla Aditi , Lim Jeong-A , McIntosh Paul , Zimmerman Kanecia , Sun Baodong D. , Kishnani Priya S.
Published: July 2021

Background: There are new emerging phenotypes in Pompe disease, and studies on smooth muscle pathology are limited. Gastrointestinal (GI) manifestations are poorly understood and underreported in Pompe disease. Methods: To understand the extent and the effects of enzyme replacement therapy (ERT; alglucosidase alfa) in Pompe disease, we studied the histopathology (entire GI tract) in Pompe mice (GAAKO 6neo/6neo). To determine the disease burden in patients with late-onset Pompe disease (LOPD), we used Patient-Reported Outcomes Measurements Information System (PROMIS)-GI symptom scales and a GI-focused medical history. Results: Pompe mice showed early, extensive, and progressive glycogen accumulation throughout the GI tract. Long-term ERT (6 months) was more effective to clear the glycogen accumulation than short-term ERT (5 weeks). GI manifestations were highly prevalent and severe, presented early in life, and were not fully amenable to ERT in patients with LOPD (n = 58; age range: 18–79 years, median age: 51.55 years; 35 females; 53 on ERT). Conclusion: GI manifestations cause a significant disease burden on adults with LOPD, and should be evaluated during routine clinical visits, using quantitative tools (PROMIS-GI measures). The study also highlights the need for next generation therapies for Pompe disease that target the smooth muscles.
The Procoagulant Effect of COVID-19 on the Thrombotic Risk of Patients with Hip Fractures Due to Enhanced Clot Strength and Fibrinolysis Shutdown
Authors: Tsantes Andreas G. , Papadopoulos Dimitrios V. , Trikoupis Ioannis G. , Goumenos Stavros , Piovani Daniele , Tsante Konstantina A. , Mavrogenis Andreas F. , Vaiopoulos Aristeidis G. , Koulouvaris Panagiotis , Nikolopoulos Georgios K. , Papagelopoulos Panayiotis J. , Bonovas Stefanos , Tsantes Argirios E.
Published: July 2021

Introduction: Coronavirus disease 2019 (COVID-19) in patients with hip fractures is associated with increased incidence of venous thromboembolism (VTE). The purpose of this study was to evaluate the hemostatic alterations of COVID-19 that are associated with a higher thrombotic risk using rotational thromboelastometry (ROTEM). Methods: A retrospective observational study was performed including 20 COVID-19 patients with hip fractures. To compare the coagulopathy of patients with mild COVID-19 and hip fractures with the coagulopathy associated with each of these two conditions separately, we used two previously recruited groups of patients; 198 hip fracture patients without COVID-19 and 21 COVID-19 patients without hip fractures. The demographics, clinical parameters, conventional coagulation parameters and ROTEM findings of the three groups were analyzed and compared. Results: COVID-19 hip fracture patients had higher amplitude of clot firmness at 10 min (p < 0.001), higher alpha angle (p < 0.001), higher lysis index at 60 min (p < 0.001), and shorter clot formation time (p < 0.001) than non-COVID-19 hip fracture patients, indicating increased clot strength and impaired fibrinolysis due to COVID-19. The value of lysis index at 60 min (99%) in COVID-19 patients with hip fractures was consistent with fibrinolysis shut down. Multivariable linear regression analysis further confirmed that COVID-19 resulted in increased amplitude of clot firmness at 10 min (p < 0.001), increased maximum clot firmness (p < 0.001), increased lysis index at 60 min (p < 0.001) and increased alpha angle (p < 0.001), but significantly shortened clot formation time (p < 0.001). Discussion: The higher thrombotic risk in COVID-19 patients with hip fractures is characterized by increased clot strength and fibrinolysis shutdown, as shown by ROTEM findings. Further prospective studies are warranted to evaluate the need for modification of thromboprophylaxis to balance the hemostatic derangements of COVID-19 patients with hip fractures.
Development and Validation of a Bayesian Network for Supporting the Etiological Diagnosis of Uveitis
Authors: Jamilloux Yvan , Romain-Scelle Nicolas , Rabilloud Muriel , Morel Coralie , Kodjikian Laurent , Maucort-Boulch Delphine , Bielefeld Philip , Sève Pascal
Published: July 2021

The etiological diagnosis of uveitis is complex. We aimed to implement and validate a Bayesian belief network algorithm for the differential diagnosis of the most relevant causes of uveitis. The training dataset (n = 897) and the test dataset (n = 154) were composed of all incident cases of uveitis admitted to two internal medicine departments, in two independent French centers (Lyon, 2003–2016 and Dijon, 2015–2017). The etiologies of uveitis were classified into eight groups. The algorithm was based on simple epidemiological characteristics (age, gender, and ethnicity) and anatomoclinical features of uveitis. The cross-validated estimate obtained in the training dataset concluded that the etiology of uveitis determined by the experts corresponded to one of the two most probable diagnoses in at least 77% of the cases. In the test dataset, this probability reached at least 83%. For the training and test datasets, when the most likely diagnosis was considered, the highest sensitivity was obtained for spondyloarthritis and HLA-B27-related uveitis (76% and 63%, respectively). The respective specificities were 93% and 54%. This algorithm could help junior and general ophthalmologists in the differential diagnosis of uveitis. It could guide the diagnostic work-up and help in the selection of further diagnostic investigations.