Malignant Pseudothyroiditis after COVID-19 Infection Revealing a Poor-Cellular Variant of a Thyroid Anaplastic Carcinoma (preprint)

ATC is a rare cancer with a slightly growing incidence and a poor prognosis determined by the delay of treatment, usually revealed by an enlarging goiter with compressive symptoms and, more rarely, by inflammatory and thyrotoxic symptoms, a clinic entity called malignant pseudothyroiditis (MPT) mimicking subacute thyroiditis (SAT). With the advent of COVID-19 pandemic, many cases of COVID-19 related SAT were described with the usual clinical presentation enriched by the COVID-19 symptoms, leading to the emergence of atypic clinical pictures. We present the case of a 60-year-old patient who developed, one month after a COVID 19 acute infection, a clinical presentation of SAT with atypical ultrasound features leading to the diagnosis of MPT; histological atypia was misleading, finally making precise diagnosis was difficult. To our best knowledge, this is the first ever reported case of MPT mimicking COVID-19 SAT. We reviewed thirty five cases published to date and discuss the mechanisms underlying MPT physiopathogenesis and the ultrasound and histological features. We point out the similarities between MPT and SAT and the role of ultrasound at clinical presentation workup. Finally there are two key points to remind: First, to perform neck ultrasound in any painful goiter and, in case of atypia, perform a US guided core-needle biopsy, a complementary CT-scan and quickly refer the patient to an expert center. Second, always think that COVID-19 infection is a recent entity and be aware that it can influence the clinical presentation of any disease.

Il funzionamento delle procedure esecutive immobiliari tra riforme e pandemia (Real Estate Foreclosures Between Reforms and the Pandemic) (preprint)

English Abstract: The paper describes how the real estate foreclosure process worked in the period 2014-21. It analyses the effects of the main regulatory changes adopted in recent years to improve their management (Decree Law 83/2015, Decree Law 59/2016, and the 2017 guidelines issued by the High Council of the Judiciary). The paper documents that: i) the number of pending procedures decreased by 39 per cent, due to the combined effect of a reduction in the number of foreclosures initiated and an increase in the number of procedures terminated; ii) the regulatory changes fostered a significant reduction in the time necessary to settle the phases in which it is currently possible to make quantitative assessments (the median duration of the pre-sale and sale phases were shortened by almost 25 per cent and 50 per cent respectively).The improvements appear to be permanent: after lengthening during the most acute phase of the COVID-19-induced health crisis, the duration of all the phases has returned to pre-pandemic levels.]Italian Abstract: Il lavoro fornisce una descrizione del funzionamento delle procedure esecutive immobiliari nel periodo 2014-21 e analizza gli effetti dei principali interventi adottati in quegli anni per migliorarne la gestione (D.L. 83/2015, D.L. 59/2016 e linee guida del Consiglio Superiore della Magistratura del 2017). Nel complesso le analisi condotte indicano un miglioramento nel funzionamento del sistema: i) il numero di procedure pendenti è calato del 39 per cento, per effetto della riduzione del numero di procedure avviate e dell’aumento di quelle chiuse; ii) gli interventi adottati hanno favorito una significativa riduzione dei tempi di definizione delle fasi delle procedure per le quali è possibile al momento fare valutazioni quantitative (la durata mediana della fase di pre-vendita si è ridotta di quasi un quarto, quella di vendita di quasi la metà). I miglioramenti conseguiti sembrano avere carattere permanente: dopo un rallentamento nella fase più acuta della crisi sanitaria determinata dal Covid, i tempi di gestione delle singole fasi sono tornati ai livelli pre-pandemia.

Fatal Case of Possible Thyroid Crisis Induced by SARS-CoV-2 Infection: A Case Report.

Thyroid crisis is an emergency due to impaired thyroid function caused by various conditions, particularly infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that result in the dysfunction of various vital organs. We report a case of a 31-year-old Indonesian female with a 2-year history of hyperthyroidism with elevated thyroid-stimulating hormone (TSH) receptor antibodies. (TRAb) who developed thyroid crisis possibly in association with SARS-CoV-2 pneumonia, sepsis, and disseminated intravascular coagulation (DIC). Prior to admission, she was treated for her hyperthyroidism with propylthiouracil and had been in stable remission for a year. She was admitted to the Emergency Room with complaints of watery stools, icteric sclerae, jaundice, coughing, and shortness of breath. The physical examination showed a World Health Organization (WHO) performance score of 4, delirium, blood pressure within normal limits, tachycardia, tachypnea, axillary temperature of 36.7°C, icteric sclerae, jaundice, and exophthalmos. There was a 3 cm palpable nodule on the right side of the neck. Auscultation of the lungs revealed bilateral pulmonary rales. Abdominal examination noted a palpable liver and enlarged spleen. Laboratory tests showed thrombocytopenia, electrolyte imbalance, hypoalbuminemia and elevated transaminases. The thyroid function tests showed a suppressed TSH level with an elevated free thyroxine (FT4) level. The SARS-CoV-2 polymerase chain reaction (PCR) swab test was positive. Initial patient management was with supportive therapy that included favipiravir and anti-hyperthyroidism medication; however, despite these interventions, her condition continued to deteriorate and she died after a few hours. This case demonstrates no difference in therapy between patients with thyroid crises and COVID-19 or other infections. Proper and timely treatment is important for reducing mortality rates.

SARS-CoV-2 infection induced thyroid storm and heart failure in an adolescent girl.

We report a case of thyroid storm precipitated by SARS-CoV-2 infection in an adolescent girl with a history of Graves disease and dilated cardiomyopathy. This case highlights that SARS-CoV-2 infection can potentially trigger a thyrotoxicosis crisis and acute decompensated heart failure in a patient with underlying thyroid disease and myocardial dysfunction even in the absence of multi-system inflammatory syndrome in children. We systematically reviewed the thyrotoxicosis cases with SARS-CoV-2 infection and described its impact on pre-existing dilated cardiomyopathy.

Safety and Efficacy of the Combination of BCc1 and Hep-S Nanochelating-Based Medicines in Hospitalized COVID-19 Adult Patients: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial (preprint)

Background: The mortality and morbidity of COVID‐19 disease as well as the lack of a proper medication has forced researchers and clinicians to employ urgent efficient technologies to overcome this current pandemic. In the severe forms of COVID-19, the patients develop a cytokine storm syndrome (CSS) where pro-inflammatory cytokines such as IL-6 and TNF-α play a key role in the development of this serious process. The efficiency of nanomedicines - as efficient immunomodulators - that are synthesized based on nanochelating technology have been proved in the previous studies. In the present study, the therapeutic effect of the combination of BCc1 and Hep-S nanomedicines on hospitalized COVID-19 patients was evaluated. Method: Laboratory-confirmed moderate COVID-19 patients at Masih Daneshvari Hospital were enrolled to participate in a randomized, double-blind, placebo-controlled study in two separate groups: combination of BCc1 and Hep-S (N=62) (treatment) or placebo (N=60) (placebo). The primary outcome of the study was evaluating the safety of the nanomedicines combination and its effect on the number of deceased patients, while the secondary outcome was decrease in inflammatory cytokines. Results: : The evaluation of blood biochemical indices as well as clinical symptoms showed that adding the combination of BCc1 and Hep-S nanomedicines to the standard protocol of the treatment caused no adverse effects. The results analysis revealed that 28-day consumption of the nanomedicines led to a significant decrease in the mean level of IL-6 cytokine of the patients in the treatment group (p < 0.05). In addition, the patients in the treatment group had lower TNF-α levels compared to those in the control (p > 0.05) and they also showed less need for oxygen therapy. Finally, the number of the deceased patients in the treatment group was 30% lower than that of the control (p > 0.05). Conclusion: The combination of BCc1 and Hep-S, as safe nanomedicines, inhibits IL-6 as a highly important and well-known cytokine in COVID-19 pathophysiology, and presents a promising view for immunomodulation that can manage CSS and reduce mortality rate in COVID19 patients.Trial registration IRCTID, IRCT20170731035423N2. Registered 12 Jun 2020, http://www.irct.ir/ IRCT20170731035423N2.

Could docosahexaenoic acid (DHA), found in breast milk and artificial baby milks, protect infants and children from COVID-19 and make them less susceptible to COVID-19-related severe illness, as well as treat adult COVID-19 patients in combination with retinoic acid? A plan for observation and intervention (preprint)

SARS-CoV-2, which causes COVID-19, is a new virus that has spread fast over the world. The severity of COVID-19 at different ages has been a notable and constant observation: severity, the requirement for hospitalization, and mortality all grow sharply with age, although severe disease and death are uncommon in children and young adults.. The majority of children infected with SARS-CoV-2 are asymptomatic or have moderate symptoms, which include fever, cough, pharyngitis, gastrointestinal symptoms, and changes in taste and smell. The question of whether children are less likely to be infected with SARS-CoV-2 is still being debated. Children make up only 1 to 2% of all SARS-CoV-2 cases, according to large epidemiological research. these numbers are heavily, depend on testing criteria, and in many reports, testing was limited to those who were symptomatic or required hospitalization, which is less common in children.. According to certain research, children are just as likely as adults to contract SARS-CoV-2.9. Recent research suggests that children are less likely to become infected after coming into touch with a SARS-CoV-2-positive person.According to some reports, children and adolescents have similar virus loads and are hence just as likely to transmit SARS-CoV-2 as adults. Furthermore, the viral load in asymptomatic and symptomatic people may be identical. Reassuringly, transmission of the virus from children to other children or adults in schools has been infrequent.Children are less likely to be infected with SARS-CoV-2 and have less severe symptoms, which is similar to what has been observed with SARS-CoV-1 and Middle East respiratory disease (MERS)-CoV. Infection with most other respiratory viruses (e.g., respiratory syncytial virus (RSV), metapneumovirus, parainfluenza, or influenza viruses), on the other hand, has a far higher prevalence and severity in youngsters. Dr. Mahmoud Elkazzaz and Dr Amr kamel khalil Ahmed, the lead investigators of this observational study, recently published a preprint that demonstrated Docosahexaenoic acid (DHA) had a high binding affinity and greatest interactions with ACE2 active sites, as well as a moderate binding affinity and moderate interactions with the active sites of IL-6. The Docosahexaenoic acid (DHA) interacts with different active sites of IL6 and ACE2 which are involved in direct or indirect contacts with the ACE2 and IL-6 receptors which might act as potential blockers of functional ACE2 and IL-6 receptor complex.. A study proposed, a clinical benefit of targeting IL-17A signaling and the synergic inflammatory cytokine IL-6 to manage COVID-19 patients, particularly those presenting with cytokine storm syndrome.Hypercytokinemia, caused by notably high pro-inflammatory cytokines such as interleukin (IL)-1B, IL-6, IL-8, and IL-17, is mostly linked to the worsened clinical presentation of COVID-19 patients(14). In PBMCs from individuals with relapsing-remitting multiple sclerosis, a combination of docosahexaenoic acid (DHA) and all-trans-retinoic acid (ATRA) inhibits IL-17 gene expression. Conclusions: Docosahexaenoic acid (DHA) was detected in abundance in breast milk and other algal sources milk supplement used for newborns and children's feeding. As a result, we believe that docosahexaenoic acid (DHA) may protect children and newborns thorough competing with COVID-19 for ACE2 receptors and inhibiting IL-6 activity and may possibly help them avoid a cytokine storm and save their lives through inhibiting IL-6 and preventing SARS- CoV-2 RBD attachment to ACE2. In addition to IL-17 was fond to increase COVID-19 inflammatory complication in this case DHA combined with retinoic acid is expected to be effective in inhibiting IL-6 and IL-17.

Natural phytochemicals, Phenformin, and Docosahexaenoic acid (DHA) as a Novel Inhibitors of IL-6 and ACE2 receptors, a Therapeutic Strategy for targeting COVID-19 Cell Entry and Cytokine Storm. An insilico Approach (preprint)

Cytokine storm syndrome (CSS) is a life-threatening consequence of inflammatory immunological illnesses; it can also occur with COVID-19 infection. CSS is characterized by a disruption in cytokine synthesis, including regulatory, pro-inflammatory and anti-inflammatory cytokines, resulting in pathologic stimulation of innate in addition to adaptive (Th17 and Th1 mediated) response. In the pathophysiology of CSS, interleukin-6 could play a key role. The significant role of IL-6 in COVID-19 pathogenesis was established in a wide variety of researches, which reported that the plasma concentration of IL-6 was raised in COVID-19 patients with severe symptoms. COVID-19 spike protein binding to angiotensin-converting enzyme 2 (ACE2), the virus's cellular receptor, causes a cascade of molecular processes that could result in hyperinflammation which may lead to cytokine storm. Therefore, the development of new natural therapies and repurposing some drugs such as Phenformin and Docosahexaenoic acid that could compete with COVID-19 for ACE2 binding or inhibit IL-6 activity may possibly help COVID-19 patients avoid a cytokine storm and save their lives through inhibiting IL-6 and preventing SARS-CoV-2 RBD attachment to ACE2. Herein we made a docking based screening for some natural phytochemicals and drugs that could be repurposed according to our findings to counter COVID-19 cell entry and inhibit the hyper activation of IL-6. Our results revealed that a five phytochemicals including Epigallocatechin gallate (EGCG), bromelain, luteolin, vitexin and isovitexin) showed a high binding affinities with best interactions with the active sites of IL-6. The binding affinities of these phytochemicals including, EGCG, bromelain, luteolin, vitexin and isovitexin with IL-6 were (-7.7, -6.7, -7.4, -7.2 and − 7.3 ), respectively. In addition to, phenformin showed a high binding affinity with best interactions with the active sites of IL-6 and ACE2. The binding affinity of phenformin with IL-6 was (-7.4) and with ACE 2 ( -7.2). Docosahexaenoic acid (DHA) had a moderate binding affinity and moderate interactions with the active sites of IL-6 and had a high binding affinity with best interactions with ACE2 active sites. The binding affinity of Docosahexaenoic acid(DHA) with IL-6 was (-5.3) and with AC2 (-6.3).ConclusionProposing possible IL-6 inhibitors with less adverse effects has been suggested as a way to aid COVID-19 patients who are suffering from severe cytokine storms. This study has been designed to elucidate the potential of potent antiviral phytocompounds as well as phenformin and Docosahexaenoic acid (DHA) as a potent ACE2 and IL-6 inhibitors. The compounds interact with different active sites of IL6 and ACE2 which are involved in direct or indirect contacts with the ACE2 and IL-6 receptors which might act as potential blockers of functional ACE2 and IL-6 receptor complex. It worth mentioning that phenformin which showed high binding affinity with both ACE2 and IL-6 is currently under investigation for treating COVID-19 ClinicalTrials.gov Identifier: NCT05003492

Thyroid storm in the second stage of labour: a case report.

A thyroid storm (or thyroid crisis) is an emergency in endocrinology. It is a form of complication of hyperthyroidism that can be life-threatening. Inadequate control of hyperthyroidism in pregnancy could develop into thyroid storm, especially in the peripartum period. We present a woman came in the second stage of labour, with thyroid storm, superimposed pre-eclampsia, acute lung oedema and impending respiratory failure. Treatment for thyroid storm, pre-eclampsia protocol and corticosteroid was delivered. The baby was born uneventfully, while the mother was discharged after 5 days of hospitalisation. Delivery is an important precipitant in the development of thyroid storm in uncontrolled hyperthyroidism in pregnancy. Although very rare, it can cause severe consequences. Diagnosis and treatment guidelines for thyroid storm were available and should be done aggressively and immediately. Uncontrolled hyperthyroidism should be prevented by adequate control in thyroid hormone levels, especially before the peripartum period.

Case series: Rare Cases of Thyroid Storm in COVID-19 Patients (preprint)

The present study aimed to present two cases with a history of hyperthyroidism who had symptoms of a thyroid storm along with COVID-19 infection. Therefore, the diagnosis and treatment of these special cases along with COVID-19 should be considered important.

Need for Abundant Caution in Prophylactic Application of Chloroquine and Hydroxychloroquine for Viral Infections Including COVID-19: Possibility of Increased Susceptibility (preprint)

Significant interest in application of Chloroquine (CQ) and Hydroxychloroquine (HCQ) for prophylaxis and treatment of COVID-19 has been recently reported throughout the world. In the light of this, it has become important to revisit the mechanisms of action, as well as clinical evidence for efficacy of CQ and HCQ in similar viral infections. We note that while some evidence exists for therapeutic efficacy of CQ and HCQ in mitigating morbidities associated with virus-induced inflammation and immuno-hyperactivity, abundant caution is necessary in expecting prophylactic efficacy in the light of therapeutic evidence. In particular, we intend to draw urgent attention to the fact that the same immuno-suppresive and immuno-modulatory properties of CQ and HCQ which render them useful as therapeutic agents in viral pneumonia and cytokine storm syndrome, are also expected to make them dangerous prophylactic agents against viral infections. We also intend to draw attention to some other potential concerns associated with widespread prophylactic usage of CQ and HCQ.

Peramivir, an anti-influenza virus drug, exhibits potential anti-cytokine storm effects (preprint)

Coronavirus Disease 2019 (COVID-19) infected by Severe Acute Respiratory Syndrome Coronavirus −2 (SARS-CoV-2) has been declared a public health emergency of international concerns. Cytokine storm syndrome (CSS) is a critical clinical symptom of severe COVID-19 patients, and the macrophage is recognized as the direct host cell of SARS-CoV-2 and potential drivers of CSS. In the present study, peramivir was identified to reduce TNF-α by partly intervention of NF-κB activity in LPS-induced macrophage model. In vivo, peramivir reduced the multi-cytokines in serum and bronchoalveolar lavage fluid (BALF), alleviated the acute lung injury and prolonged the survival time in mice. In human peripheral blood mononuclear cells (hPBMCs), peramivir could also inhibit the release of TNF-α. Collectively, we proposed that peramivir might be a candidate for the treatment of COVID-19 and other infections related CSS. Graphic Abstract

The WD and linker domains of ATG16L1 required for non-canonical autophagy limit lethal respiratory infection by influenza A virus at epithelial surfaces (preprint)

Summary Respiratory viruses such as influenza A virus (IAV) and SARS-CoV-2 (Covid-19) cause pandemic infections where cytokine storm syndrome, lung inflammation and pneumonia lead to high mortality. Given the high social and economic cost of these viruses, there is an urgent need for a comprehensive understanding of how the airways defend against virus infection. Viruses entering cells by endocytosis are killed when delivered to lysosomes for degradation. Lysosome delivery is facilitated by non-canonical autophagy pathways that conjugate LC3 to endo-lysosome compartments to enhance lysosome fusion. Here we use mice lacking the WD and linker domains of ATG16L1 to demonstrate that non-canonical autophagy protects mice from lethal IAV infection of the airways. Mice with systemic loss of non-canonical autophagy are exquisitely sensitive to low-pathogenicity murine-adapted IAV where extensive viral replication throughout the lungs, coupled with cytokine amplification mediated by plasmacytoid dendritic cells, leads to fulminant pneumonia, lung inflammation and high mortality. IAV infection was controlled within epithelial barriers where non-canonical autophagy slowed fusion of IAV with endosomes and reduced activation of interferon signalling. This was consistent with conditional mouse models and ex vivo analysis showing that protection against IAV infection of lung was independent of phagocytes and other leukocytes. This establishes non-canonical autophagy pathways in airway epithelial cells as a novel innate defence mechanism that can restrict IAV infection and lethal inflammation at respiratory surfaces.