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1.
Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.
Sivapalan, P, Ulrik, CS, Bojesen, RD, Lapperre, TS, Eklöf, JV, Håkansson, KEJ, Browatzki, A, Tidemansen, C, Wilcke, JT, Janner, J, et al
Trials. 2020;(1):513
Abstract
OBJECTIVES The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death. TRIAL DESIGN This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study. PARTICIPANTS 226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals. INCLUSION CRITERIA • Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily. INTERVENTION AND COMPARATOR Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No). BLINDING (MASKING): Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 226 patients randomised 1:1 with 113 in each group. TRIAL STATUS Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020). TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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2.
Early-onset meningitis associated with atezolizumab treatment for non-small cell lung cancer: case report and literature review.
Ogawa, K, Kaneda, H, Kawamoto, T, Tani, Y, Izumi, M, Matsumoto, Y, Sawa, K, Suzumura, T, Watanabe, T, Mitsuoka, S, et al
Investigational new drugs. 2020;(6):1901-1905
Abstract
Immune checkpoint inhibitors (ICIs) have improved the overall survival of many patients with advanced cancers. However, unlike cytotoxic and targeted drugs, ICIs may cause various immune-related adverse events (irAEs). Among these irAEs, autoimmune meningitis is very rare. Here, we report a case of early-onset, atezolizumab-induced meningitis after administration of one dose of atezolizumab. A 56-year-old man with lung adenocarcinoma had received seventh-line treatment with atezolizumab when he experienced dysarthria. Blood examinations, including the measurement of electrolytes, glucose, and organ functions, were unremarkable, but enhanced head magnetic resonance imaging T1-weighted images showed meningeal enhancement. Although cerebral spinal fluid (CSF) examinations revealed elevated lymphocyte and protein levels, no cancer cells were detected in the CSF. CSF cultures and serological tests, including polymerase chain reaction for herpes simplex virus, were negative. The patient was therefore diagnosed with atezolizumab-triggered autoimmune meningitis. With steroid treatment, the patient's clinical and neurological state improved immediately and he recovered to baseline conditions. Prompt diagnosis and therapeutic intervention are essential for the effective treatment of autoimmune meningitis.
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3.
The persistence of amoebosis caused by Entamoeba histolytica in Nigeria and the role of malnutrition.
Chidebelu, PE, Nweze, EI
Annals of parasitology. 2020;(3):271-282
Abstract
Amoebosis, caused by the protozoan parasite Entamoeba histolytica is a gastrointestinal infection and the second leading cause of death from parasitic disease worldwide. The disease is endemic in many developing countries and kills over one hundred thousand persons annually. Adequate nutrition composed of macro- and micronutrients in their balanced proportions is central to effective gut immune response and the homeostasis of commensal organisms in the gastrointestinal tract. Entamoeba histolytica is a gut pathobiont that can exploit a shift in nutritional status to cause amoebosis, with extra-intestinal complications. Although undernutrition is rarely a public health concern in high income settings, bioavailability of functional nutrients remains suboptimal. On the other hand, nutrient deficiencies constitute a chronic challenge in very low-income regions. This study sought to review the pivotal influence of malnutrition on intact microbiota and functional immunity, as determinants of susceptibility to amoebosis in the Nigerian example of tropical regions. The dynamics of the infection such as possible coinfection with opportunistic pathogens were also, evaluated. Based on the available reports, we posit that amoebosis is a common tropical infection perpetuated by malnutrition following poor living standard including unhygienic environmental exposure.
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4.
An Exploratory Gene Expression Study of the Intestinal Mucosa of Patients with Non-Celiac Wheat Sensitivity.
Efthymakis, K, Clemente, E, Marchioni, M, Di Nicola, M, Neri, M, Sallese, M
International journal of molecular sciences. 2020;(6)
Abstract
Non-celiac wheat sensitivity (NCWS) is a recently recognized syndrome triggered by a gluten-containing diet. The pathophysiological mechanisms engaged in NCWS are poorly understood and, in the absence of laboratory markers, the diagnosis relies only on a double-blind protocol of symptoms evaluation during a gluten challenge. We aimed to shed light on the molecular mechanisms governing this disorder and identify biomarkers helpful to the diagnosis. By a genome-wide transcriptomic analysis, we investigated gene expression profiles of the intestinal mucosa of 12 NCWS patients, as well as 7 controls. We identified 300 RNA transcripts whose expression differed between NCWS patients and controls. Only 37% of these transcripts were protein-coding RNA, whereas the remaining were non-coding RNA. Principal component analysis (PCA) and receiver operating characteristic curves showed that these microarray data are potentially useful to set apart NCWS from controls. Literature and network analyses indicated a possible implication/dysregulation of innate immune response, hedgehog pathway, and circadian rhythm in NCWS. This exploratory study indicates that NCWS can be genetically defined and gene expression profiling might be a suitable tool to support the diagnosis. The dysregulated genes suggest that NCWS may result from a deranged immune response. Furthermore, non-coding RNA might play an important role in the pathogenesis of NCWS.
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5.
The Gut Microbiota and Inflammation: An Overview.
Al Bander, Z, Nitert, MD, Mousa, A, Naderpoor, N
International journal of environmental research and public health. 2020;(20)
Abstract
The gut microbiota encompasses a diverse community of bacteria that carry out various functions influencing the overall health of the host. These comprise nutrient metabolism, immune system regulation and natural defence against infection. The presence of certain bacteria is associated with inflammatory molecules that may bring about inflammation in various body tissues. Inflammation underlies many chronic multisystem conditions including obesity, atherosclerosis, type 2 diabetes mellitus and inflammatory bowel disease. Inflammation may be triggered by structural components of the bacteria which can result in a cascade of inflammatory pathways involving interleukins and other cytokines. Similarly, by-products of metabolic processes in bacteria, including some short-chain fatty acids, can play a role in inhibiting inflammatory processes. In this review, we aimed to provide an overview of the relationship between the gut microbiota and inflammatory molecules and to highlight relevant knowledge gaps in this field. Based on the current literature, it appears that as the gut microbiota composition differs between individuals and is contingent on a variety of factors like diet and genetics, some individuals may possess bacteria associated with pro-inflammatory effects whilst others may harbour those with anti-inflammatory effects. Recent technological advancements have allowed for better methods of characterising the gut microbiota. Further research to continually improve our understanding of the inflammatory pathways that interact with bacteria may elucidate reasons behind varying presentations of the same disease and varied responses to the same treatment in different individuals. Furthermore, it can inform clinical practice as anti-inflammatory microbes can be employed in probiotic therapies or used to identify suitable prebiotic therapies.
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6.
Integrating Pharmacology and Microbial Network Analysis with Experimental Validation to Reveal the Mechanism of Composite Sophora Colon-Soluble Capsule against Ulcerative Colitis.
Ding, Y, Chen, M, Wang, Q, Gao, L, Feng, Y, Wang, S, Song, Z, Tong, Z
Evidence-based complementary and alternative medicine : eCAM. 2020;:9521073
Abstract
Ulcerative colitis (UC) has multifactorial pathogenesis that acts synergistically, such as immune system dysregulation and expansion of infectious gut microbiota. Therefore, a multicomponent treatment derived from Chinese herbal medicine that interacts with multiple targets synergistically is needed. Composite sophora colon-soluble capsule (CSCC) is a Chinese herbal formula that has shown therapeutic efficacy against UC in randomized clinical trials. However, its bioactive components and potential target genes against UC remain unclear. Here, we used a network pharmacology approach to detect component-target-pathway interactions of CSCC against UC. A total of 29 gene targets, 91 bioactive components, and 20 enriched pathways of CSCC were identified. The IL-17 signaling pathway activated by infectious gastrointestinal microbes and predicted by the network analysis to be a major pathway modulated by CSCC against UC was studied in a dextran sulfate sodium-induced colitis model. CSCC showed remarkable efficacy against UC with respect to the attenuation of colon length, body weight loss, and disease activity index through gut microbiota recovery and intestinal immune homeostasis. The rectal administration of CSCC reduced the numbers of Th17 cells isolated from both mesenteric lymph nodes and lamina propria mononuclear cells and the levels of IL-17A, IL-6, IL-1β, and TNF-α. Additionally, the percentage of Treg cells and the levels of their hallmark cytokines were upregulated. Rectal administration of CSCC led to microbiota regulation with a significant correlation between suppression of Verrucomicrobiaceae and Ruminococcaceae, as well as the elevation of Lactobacillaceae, and CSCC administration via microbiome correlation heatmaps and cooccurrence network analysis at multiple time points. Thus, our study presents an effective herbal formula, CSCC, for UC treatment and explores its components and mechanisms of efficacy through the examination of gut microbiota and hallmark cytokines in the IL-17 pathway.
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7.
Vitamin D Effects on the Immune System from Periconception through Pregnancy.
Schröder-Heurich, B, Springer, CJP, von Versen-Höynck, F
Nutrients. 2020;(5)
Abstract
Vitamin D is a well-known secosteroid and guardian of bone health and calcium homeostasis. Studies on its role in immunomodulatory functions have expanded its field in recent years. In addition to its impact on human physiology, vitamin D influences the differentiation and proliferation of immune system modulators, interleukin expression and antimicrobial responses. Furthermore, it has been shown that vitamin D is synthesized in female reproductive tissues and, by modulating the immune system, affects the periconception period and reproductive outcomes. B cells, T cells, macrophages and dendritic cells can all synthesize active vitamin D and are involved in processes which occur from fertilization, implantation and maintenance of pregnancy. Components of vitamin D synthesis are expressed in the ovary, decidua, endometrium and placenta. An inadequate vitamin D level has been associated with recurrent implantation failure and pregnancy loss and is associated with pregnancy-related disorders like preeclampsia. This paper reviews the most important data on immunomodulatory vitamin D effects in relation to the immune system from periconception to pregnancy and provides an insight into the possible consequences of vitamin D deficiency before and during pregnancy.
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8.
Impact of level of vitamin D in the body on the severity of COVID-19 - review of the literature.
Ręka, G, Korzeniowska, A, Machowiec, P, Maksymowicz, M, Piecewicz-Szczęsna, H
Przeglad epidemiologiczny. 2020;(4):583-595
Abstract
INTRODUCTION The aim of the study is to present the current state of knowledge on the influence of vitamin D levels on the severity of the course of COVID-19. MATERIAL AND METHODS The latest available literature was reviewed until October 30, 2020 from the PubMed database. RESULTS The literature reports that vitamin D has immunomodulatory and anti-inflammatory effects. It reduces the expression of cytokines such as IL-6, TNF-α and INF-γ, regulates the activity of T helper lymphocytes, and other elements of the immune system at the molecular level. The deficiency of this vitamin promotes the activation of the renin-angiotensin-aldosterone system, contributing to the development of acute respiratory distress syndrome. The severity of the course of SARS-CoV-2 infection depends on comorbidities, the development and course of which may also be affected by vitamin D levels (coagulopathies, pulmonary, cardiological, metabolic diseases). Most of the analyzed research studies from different countries indicated a relationship between insufficient vitamin D levels and a more severe course of COVID-19 and an increase in mortality due to it, especially among the elderly. Researchers agree that further analyzes are necessary concerning both the influence of the vitamin D blood serum levels on the morbidity and mortality due to COVID-19 as well as the use of its supplementation in the struggle against SARS-CoV-2 virus. There are reports of possible beneficial interactions of vitamin D with other substances, such as quercetin, estradiol, some microelements, and other vitamins. CONCLUSIONS Maintaining an adequate level of vitamin D has a positive effect on the functioning of the immune system. At the moment, there is insufficient evidence to establish a clear relationship between vitamin D levels and the severity of COVID-19. It is necessary to conduct further research on a larger study group. The literature does not mention the use of vitamin D as a medication for COVID-19. People at risk of vitamin D deficiency should consider vitamin D supplementation at the current time of the pandemic.
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9.
Vitamin D Deficiency and Autism Spectrum Disorder.
Siracusano, M, Riccioni, A, Abate, R, Benvenuto, A, Curatolo, P, Mazzone, L
Current pharmaceutical design. 2020;(21):2460-2474
Abstract
Vitamin D is a neurosteroid hormone crucially involved in neurodevelopment. Neural cell proliferation, neurotransmission, oxidative stress and immune function represent the main mechanisms mediated by vitamin D in the Central Nervous System. Therefore, its deficiency during pregnancy and early childhood may significantly impact on a developing brain, leading to possible adverse neuropsychological outcomes including Autism Spectrum Disorder (ASD). Significant vitamin D deficiency is described within children affected by ASD and in pregnant mothers whose offspring will later develop ASD, suggesting a possible role of the hormone as a contributing risk factor in the etiopathogenesis of ASD. We reviewed the actual literature on the potential contributing role of prenatal and early postnatal vitamin D deficiency in ASD etiopathogenesis, at both genetic and environmental levels, and the possible effect of vitamin D supplementation in autistic children. Conflicting but promising results emerged on the topic. Further Randomized Controlled Trials studies carried out during pregnancy and early infancy are necessary for better understanding the possible contribution of vitamin D deficiency in the etiopathogenesis of autism and the potential efficacy of the hormone supplementation in the improvement of ASD core symptoms.
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10.
[Selenium and zinc: "antioxidants" for healthy aging?]
Steinbrenner, H, Klotz, LO
Zeitschrift fur Gerontologie und Geriatrie. 2020;(4):295-302
Abstract
Selenium and zinc are essential trace elements and an inadequate dietary intake has been implicated in the decline of immune and cognitive functions in aged persons and in the pathogenesis of age-related disorders. Both micronutrients are often marketed as "antioxidants" in mineral supplements; however, neither selenium nor zinc are antioxidants per se but they may exert beneficial effects as components of enzymes and other proteins that catalyze redox reactions and/or are involved in the maintenance of redox homeostasis. According to epidemiological data older individuals have an increased risk of developing deficiencies in the selenium and zinc status; however, such statistical correlations in epidemiological studies do not imply a causal association. Intervention trials are scarce and have yielded inconsistent and sometimes even adverse results. It should also be noted that the observed deficiencies in micronutrients may not necessarily be attributable to inadequate dietary intake as the absorption and distribution within the body might also be influenced by factors such as medications or interaction with other food ingredients. Thus, any dietary supplementation should be implemented with caution and persons who wish to take mineral supplements should first seek medical advice. This article discusses the role of selenium and zinc in biological antioxidant systems, summarizes findings on the supply and supplementation of aged persons with these trace elements and on the influence they may exert on aging-related health issues, such as cognitive decline and type 2 diabetes mellitus.
