Evaluation of the relationship between the expression of AgNOR and Ki67 with the recurrence rate in central granulomatous giant cell lesions: A case-control.

OBJECTIVES: Giant cell granuloma is a local nonneoplastic lesion that is divided into two categories, based on its site of occurrence: Central and peripheral giant cell granuloma. Central giant cell granuloma is an intraosseous lesion that has a tendency to recure even in surgically treated cases. Several studies have proven that there is an association between different lesions clinical behavior and their histological features. The aim of this study was to evaluate the expression of AgNOR and Ki67 in lesions with and without recurrency. MATERIAL AND METHODS: Files and records of 35 patients who had been histologically diagnosed with central giant cell granuloma were investigated. Histological features were studied after performing AgNOR staining and Ki67 marker. The data were analyzed by chi-square, Fisher, and T-test. RESULTS: Acquired data indicated that the count of AgNOR staining and Ki67 marker was significantly higher in lesions with recurrency than the lesions with no recurrency. The same results were attained from Ki67 intensity. CONCLUSION: The current study indicated that AgNOR staining and Ki67 marker have prognostic value in predicting recurrency of central giant cell granuloma lesions.

Benchmarking long-read aligners and SV callers for structural variation detection in Oxford nanopore sequencing data.

Structural variants (SVs) are one of the significant types of DNA mutations and are typically defined as larger-than-50-bp genomic alterations that include insertions, deletions, duplications, inversions, and translocations. These modifications can profoundly impact the phenotypic characteristics and contribute to disorders like cancer, response to treatment, and infections. Four long-read aligners and five SV callers have been evaluated using three Oxford Nanopore NGS human genome datasets in terms of precision, recall, and F1-score statistical metrics, depth of coverage, and speed of analysis. The best SV caller regarding recall, precision, and F1-score when matched with different aligners at different coverage levels tend to vary depending on the dataset and the specific SV types being analyzed. However, based on our findings, Sniffles and CuteSV tend to perform well across different aligners and coverage levels, followed by SVIM, PBSV, and SVDSS in the last place. The CuteSV caller has the highest average F1-score (82.51%) and recall (78.50%), and Sniffles has the highest average precision value (94.33%). Minimap2 as an aligner and Sniffles as an SV caller act as a strong base for the pipeline of SV calling because of their high speed and reasonable accomplishment. PBSV has a lower average F1-score, precision, and recall and may generate more false positives and overlook some actual SVs. Our results are valuable in the comprehensive evaluation of popular SV callers and aligners as they provide insight into the performance of several long-read aligners and SV callers and serve as a reference for researchers in selecting the most suitable tools for SV detection.

Repurposing metformin to manage idiopathic or long COVID Tinnitus: self-report adopting a pathophysiological and pharmacological approach.

Chronic tinnitus is a common neurological disorder that affects millions of patients globally with no available successful pharmacotherapy. It can be extremely bothersome to some patients to the extent that it occasionally qualifies as a disability that can hinder them from leading a normal life. In this short communication, the author discusses how he suffered from idiopathic tinnitus and how he managed to adopt a combined pathophysiological and pharmacological approach to the reason for the first time in the medical literature that low-dose metformin might be safely and effectively repurposed to manage at least a subset of tinnitus patients while discussing the potential role of adenosine receptor agonists as potential future tinnitus therapeutics.

Acute chest syndrome in children with sickle cell disease: Data from a national AIEOP cohort identify priority areas of intervention in a hub-and-spoke system.

Acute chest syndrome (ACS) is a frequent cause of hospitalization in sickle cell disease (SCD). Despite advances in acute care, many settings still lack knowledge about ACS best practices. After the AIEOP Guidelines were published in 2012, suggesting standardized management in Italy, a retrospective study was performed to assess the diagnostic and therapeutic pathways of ACS in children. From 2013 to 2018, 208 ACS episodes were presented by 122/583 kids in 11 centres. 73 were male, mean age 10.9 years, 85% African, 92% HbSS or Sß°. In our hub-and-spoke system, a good adherence to Guidelines was documented, but discrepancies between reference centres and general hospitals were noted. Improvement is needed for timely transfer to reference centres, use of incentive spirometry, oxygen therapy and pain management.

The African Kelleni's roadmap using nitazoxanide and broad-spectrum antimicrobials to abort returning to COVID-19 square one.

For over 3.5 years, SARS CoV-2 is continuing to evolve threatening to return all and any improvement the world has made into square one. In this clinically oriented systematic review and perspective, the author explains how the best current medical evidence is strongly supporting the use of the low cost, widely available and very safe nitazoxanide in early management of COVID-19, debates the relevant theoretical studies that negated or doubted this benefit, and suggests an African roadmap to preempt the worst-case scenario if or when a new SARS CoV-2 (sub) variant or even a new respiratory virus causes a new global surge of morbidity and mortality. Kelleni's protocol, including nitazoxanide as an integral component, is continuing to perfectly save lives of patients infected with many viruses, including SARS CoV-2 and the author stresses that respiratory RNA viruses are best managed with early pharmacological treatment. Broad-spectrum antimicrobials as nitazoxanide and azithromycin together with other therapeutics as non-steroidal anti-inflammatory drugs and the antihistaminic loratadine should be considered first to personalize the clinical management of COVID-19 and selected other alarming viral infections.

Real-world practice of the Egyptian Kelleni's protocol amid changing tropism of SARS-CoV-2 omicron BA.5.2.1.7, XBB 1.5 and CH.1.1 subvariants: a multi-purpose protocol.

The Egyptian immune-modulatory Kelleni's protocol, including nitazoxanide as an integral component, is being safely and effectively practiced to manage SARS-CoV-2, RSV, influenza infections in pediatric, adult and pregnant patients with negligible requirements for the relatively expensive diagnostic molecular tests. Most recently, Kelleni's protocol is being likewise used to manage potential norovirus infection which is currently confused with SARS-CoV-2 Omicron new enterotropic subvariants and the antihistaminic loratadine has been co-administered in selected patients. Notably, Africa has the least mandates, restrictions and SARS-CoV-2 vaccination rates and yet the least COVID-19 mortality.

Wastewater-based monitoring of illicit drugs in Cyprus by UPLC-MS/MS: The impact of the COVID-19 pandemic.

The outbreak and spread of COVID-19 impacted through various ways the lives of millions of humans globally. In this work, wastewater-based epidemiology (WBE) was applied to investigate the effect of the actions taken by the Republic of Cyprus to confine COVID-19 on the use of illicit stimulant drugs. Daily influent samples were collected from the six main wastewater treatment plants (WWTPs) of the country i) before lockdown (3-9 April 2019), ii) during lockdown (21-27 April 2020), iii) during the post-lockdown period (14-20 July 2020), and, iv) during each season of the following year (20-26 April 2021, 19-25 July 2021, 11-17 October 2021, 25 December 2021-2 January 2022), and analyzed for amphetamine, methamphetamine, MDMA and cocaine. In most areas, amphetamine and methamphetamine use was not affected during the confinement period, but as availability of the substances decreased with time, a drop in their use was observed when most restriction measures were eased (up to 9- and 22-fold decrease, respectively). The limitations on social interactions and events during the quarantine period seem to have led to the reduction of MDMA and cocaine and driven a sharp decrease of their use in most areas studied (up to 11 and 6 times lower, respectively). However, the re-opening of activities led to a pronounced consumption increase, reaching maximum daily values of 800 and 2691 mg/1000 inhabitants/day, respectively. In 2021, drug use was re-established to lower levels. The examination of weekly patterns during this year revealed higher weekend use of methamphetamine, MDMA and cocaine. Our results suggest that both the implementation and the easing of COVID-19 related measures affected the availability and the use of drugs. This study also provides the first insight on the consumption of illicit drugs in the Republic of Cyprus during pre-, post- and pandemic times and demonstrates the importance of WBE.

Metagenomic nanopore sequencing versus conventional diagnosis for identification of the dieback pathogens of mango trees.

Dieback is one of the most dangerous fungal diseases affecting mango trees. In this study, nanopore metagenome sequencing of the root-soil samples and infected plant tissues was conducted to identify the fungal pathogens present. Soil analysis of the infected mango trees showed the abundance of the Dikarya subkingdom (59%) including Lasiodiplodia theobromae (15%), Alternaria alternata (6%), Ceratocystis huliohia and Colletotrichum gloeosporioides. Analysis of the infected plant tissues revealed the presence of A. alternata (34%). The data were deposited in the National Center of Biotechnology Information (PRJNA767267). In conclusion, nanopore metagenome sequencing analysis was a valuable tool to rapidly identify dieback-associated fungal pathogens.

Evaluation of the Available Variant Calling Tools for Oxford Nanopore Sequencing in Breast Cancer.

The goal of biomarker testing, in the field of personalized medicine, is to guide treatments to achieve the best possible results for each patient. The accurate and reliable identification of everyone's genome variants is essential for the success of clinical genomics, employing third-generation sequencing. Different variant calling techniques have been used and recommended by both Oxford Nanopore Technologies (ONT) and Nanopore communities. A thorough examination of the variant callers might give critical guidance for third-generation sequencing-based clinical genomics. In this study, two reference genome sample datasets (NA12878) and (NA24385) and the set of high-confidence variant calls provided by the Genome in a Bottle (GIAB) were used to allow the evaluation of the performance of six variant calling tools, including Human-SNP-wf, Clair3, Clair, NanoCaller, Longshot, and Medaka, as an integral step in the in-house variant detection workflow. Out of the six variant callers understudy, Clair3 and Human-SNP-wf that has Clair3 incorporated into it achieved the highest performance rates in comparison to the other variant callers. Evaluation of the results for the tool was expressed in terms of Precision, Recall, and F1-score using Hap.py tools for the comparison. In conclusion, our findings give important insights for identifying accurate variants from third-generation sequencing of personal genomes using different variant detection tools available for long-read sequencing.

NSAIDs/nitazoxanide/azithromycin repurposed for COVID-19: potential mitigation of the cytokine storm interleukin-6 amplifier via immunomodulatory effects.

INTRODUCTION: Mediators of immunity and inflammation are playing a crucial role in COVID-19 pathogenesis and complications as demonstrated by several genetic and clinical studies. Thus, repurposing of drugs that possess anti-inflammatory and/or immune-modulatory effects for COVID-19 is considered a rational approach. AREAS COVERED: We analyze selected studies that correlated COVID-19 with dysregulated interferon and inflammatory responses while reflecting on our academic and real-life experience using non-steroidal anti-inflammatory drugs, nitazoxanide and azithromycin for management of COVID-19. Moreover, we interpret the results that suggested a potential survival benefit of low-dose aspirin and colchicine when used for COVID-19. EXPERT OPINION: Nitazoxanide/azithromycin combination has been first hypothesized by the author and practiced by him and several researchers to benefit COVID-19 patients due to a potential ability to augment the natural interferon response as well as their positive immunomodulatory effects on several cytokines. Furthermore, NSAIDs, that are unfortunately currently at best of second choice after paracetamol, have been early postulated and clinically practiced by the author to prevent or ameliorate COVID-19 complications and mortality due to their anti-inflammatory and immunomodulatory properties. Finally, we repeat our previous call to adopt our observational study that used these drugs in sufficiently powered double blind randomized clinical trials.

NSAIDs and Kelleni's protocol as potential early COVID-19 treatment game changer: could it be the final countdown?

We have previously published several papers illustrating numerous immunomodulatory and anti-inflammatory potential benefits when we repurposed safe, generic non-steroidal anti-inflammatory drugs (NSAIDs)/nitazoxanide/azithromycin (Kelleni's protocol), to early manage our COVID-19 pediatric, adult, and pregnant patients. In this manuscript, we discuss some recently published meta-analysis and clinical studies supporting our practice and discuss a molecular study that might be interpreted as an academic proof that our protocol might also prevent SARS-CoV-2 replication. Moreover, after aspirin has been suggested to be independently associated with reduced risk of mechanical ventilation, ICU admission and in-hospital mortality of COVID-19, we claim that the molecular interpretation of the results that led to this suggestion was not scientifically accurate, and we provide our academic interpretation confirming that low-dose aspirin is least likely to improve COVID-19 mortality through anticoagulation as was suggested. Furthermore, we describe other potential benefits related to aspirin-triggered lipoxins and resolvins while illustrating how NSAIDs interfere with COX-1, COX-2, SARS-CoV-2/ SARS-CoV-2 ORF protein-dependent activation of caspases and their subsequent mitochondrial dysfunction, endoplasmic reticulum stress, apoptosis and necroptosis which were associated with COVID-19 complications. Similarly, NSAIDs are known caspase inhibitors and thus they might independently inhibit other caspase-related COVID-19-associated downstream pathological signaling mechanisms. Finally, we postulated that CARD-14, a caspase recruitment domain-containing protein, polymorphisms might play a role in the development of severe and critical COVID-19 and confirmed our old call to early adopt NSAIDs, as an integral part of Kelleni's protocol, as of choice in its management aiming to end this pandemic.

COVID-19, Ebola virus disease, and Nipah virus infection reclassification as novel acute immune dysrhythmia syndrome (n-AIDS): potential crucial role for immunomodulators.

In this manuscript, COVID-19, Ebola virus disease, Nipah virus infection, SARS, and MERS are suggested to be considered for a novel immunological reclassification as acute onset immune dysrhythmia syndrome (n-AIDS) due to altered monocytic, Th1/Th2, as well as cytokines and chemokines balances. n-AIDs is postulated to be the cause of the acute respiratory distress and multi-inflammatory syndromes which are described with fatal COVID-19, and immunomodulators are suggested to effectively manage the mentioned diseases as well as for other disorders caused by Th1/Th2 imbalance. Meanwhile, para COVID syndrome is suggested to describe various immune-related complications, whether before or after recovery, and to embrace a potential of a latent infection, that might be discovered later, as occurred with Ebola virus disease. Finally, our hypothesis has evolved out of our real-life practice that uses immunomodulatory drugs to manage COVID-19 safely and effectively.

Resveratrol-zinc nanoparticles or pterostilbene-zinc: Potential COVID-19 mono and adjuvant therapy.

In this manuscript we provide the scientific basis to adopt a novel combination of two widely available nutraceuticals; resveratrol and zinc in management of COVID-19 recommending their administration using a nano-carrier based drug-delivery system. Resveratrol, a well-known antioxidant and anti-inflammatory triphenolic stilbene, is abundant in red grapes, red wine, dark chocolate, and peanut butter. Alternatively, pterostilbene-zinc combination might be also considered without using a nano-carrier. We recommend conducting prompt clinical trials to assess the potential of the suggested combinations as a monotherapy for mild COVID-19 with a potential to prevent its progression to moderate-severe disease for which we recommend their trial as an adjuvant therapy. Furthermore, the suggested combinations might also possess a pharmacotherapeutic potential that exceeds COVID-19 to various inflammatory, immunologic, and oncologic diseases.

BCG vaccination potential for COVID-19: an analytical approach.

In order to assess the possible protective potential of BCG vaccination as regards to COVID-19, we have analyzed BCG vaccination status and SARS CoV-2 morbidity and mortality in China and we have also examined other studies performed in other countries to assess the potential of booster doses of BCG vaccination for adults. We have concluded that BCG vaccination early in life is highly unlikely to be a tool that might prevent SARS CoV-2 infection in adults. Furthermore, we have suggested that BCG vaccination potential benefit to decrease COVID-19 morbidity and mortality in children is confounded by many factors, e.g. age limitations of exposure and other vaccines. However, BCG vaccination booster doses in adults might be of protective value until the results of well-designed clinical trials are published to confirm, or refute, this potential.

Tocilizumab, Remdesivir, Favipiravir, and Dexamethasone Repurposed for COVID-19: a Comprehensive Clinical and Pharmacovigilant Reassessment.

In this manuscript, we discuss the expectations versus the real-world results of four repurposed COVID-19 drugs: tocilizumab, remdesivir, favipiravir, and dexamethasone from a clinical and pharmacovigilant point of view. We suggest that though the results of two-phase III double-blind clinical trials have been less than expected, tocilizumab has a real remaining potential to treat selected critical cases of COVID-19 beyond clinical trials until more data are revealed. On the contrary, remdesivir, though its FDA approval, and favipiravir are least likely to benefit COVID-19 patients. Moreover, we recommend that the RECOVERY dexamethasone should only be considered for critical hospitalized COVID-19 patients and we urge physicians in developing countries to avoid using it in mild-moderate COVID-19 cases. Finally, we recommend considering a personalized risk-benefit ratio before a decision is made using any of these drugs.

Geographic and Socioeconomic Factors on Survival in Esthesioneuroblastoma.

OBJECTIVES: Esthesioneuroblastoma (ENB) is a rare sinonasal malignancy with little known regarding how regional and socioeconomic differences in the United States alter disease survival. The aim of this study is to explore the geographic difference in clinical features, socioeconomic factors, and survival outcomes of ENB patients. METHODS: ENB cases were extracted from the Surveillance, Epidemiology, and End Results registry from 1975-2016. Patient data were stratified based on geographical location and comparative analyses of socioeconomic features, disease characteristics, and survival patterns were performed. Kaplan-Meier regression analyses were used to estimate disease-specific survival (DSS). RESULTS: A total of 987 patients were identified: 56.4% West, 14.0% South, 12.7% Midwest, and 16.6% East. The West had the highest proportion of patients with Medicaid coverage (P < .001), stage A malignancy (P < .001), and treated with surgery and adjuvant radiotherapy (P < .001). The South had the highest proportion of patients who were Black (P < .001), uninsured (P < .001), and resided in rural areas (P < .001). Five-year DSS patterns were 81.0% (West), 79.8% (East), 67.4% (Midwest), and 72.7% (South) [P = .018]. Ten-year DSS outcomes were 74.0% (West), 73.7% (East), 60.9% (Midwest), and 63.6% (South) [P = .017]. CONCLUSION: In ENB patients, survival disparity exists in the United States based on geographical region. Patients from the West and East exhibit higher survival than those from the South and Midwest. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2162-E2168, 2021.