In Silico Drug Repositioning for COVID-19: Progress and Challenges

he COVID-19 pandemic caused by SARS-CoV-2 has shown a rapid increase in the number of infected patients with a remarkable mortality rate, making it a global public health concern. Because there is currently no specific anti-viral drug for the treatment of COVID-19, repurposing of already approved drugs for other diseases may be explored. Drug repurposing has become a promising approach due to the opportunity to reduce development timelines and overall costs. In this chapter, we will discuss various computational drug repositioning strategies, the current COVID-19 treatment scenario, and challenges to the correct interpretation of existing preclinical/clinical evidence, as well as the generation of new evidence related to drug repurposing. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

SARS-CoV-2 infection in patients with multiple myeloma: survey in 23 centers across Europe and USA

Introduction: Despite several studies, the impact of coronavirus disease 2019 on patients with multiple myeloma remains uncertain. Material(s) and Method(s): We performed a survey that covered the period of the first and second waves of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in 23 centers inseven countries. Out of 352 patients with myeloma and SARS-CoV-2, 23% died. Results/Conclusions: Logistic regression showed a lower risk of death among patients treated with proteasome inhibitor and a higher risk of death for those who had a severe or a very severe course of disease.Copyright © 2023 Sciendo. All rights reserved.

Deimplementation in the provision of opioid agonist treatment to achieve equity of care for people engaged in treatment: a qualitative study.

BACKGROUND: Deimplementation, the removal or reduction of potentially hazardous approaches to care, is key to progressing social equity in health. While the benefits of opioid agonist treatment (OAT) are well-evidenced, wide variability in the provision of treatment attenuates positive outcomes. During the COVID-19 pandemic, OAT services deimplemented aspects of provision which had long been central to treatment in Australia; supervised dosing, urine drug screening, and frequent in-person attendance for review. This analysis explored how providers considered social inequity in health of patients in the deimplementation of restrictive OAT provision during the COVID-19 pandemic. METHODS: Between August and December 2020, semi-structured interviews were conducted with 29 OAT providers in Australia. Codes relating to the social determinants of client retention in OAT were clustered according to how providers considered deimplementation in relation to social inequities. Normalisation Process Theory was then used to analyse the clusters in relation to how providers understood their work during the COVID-19 pandemic as responding to systemic issues that condition OAT access. RESULTS: We explored four overarching themes based on constructs from Normalisation Process Theory: adaptive execution, cognitive participation, normative restructuring, and sustainment. Accounts of adaptive execution demonstrated tensions between providers' conceptions of equity and patient autonomy. Cognitive participation and normative restructuring were integral to the workability of rapid and drastic changes within the OAT services. Key transformative actors included communities of practice and "thought leaders" who had long supported deimplementation for more humane care. At this early stage of the pandemic, providers had already begun to consider how this period could inform sustainment of deimplementation. When considering a future, post-pandemic period, several providers expressed discomfort at operating with "evidence-enough" and called for narrowly defined types of data on adverse events (e.g. overdose) and expert consensus on takeaway doses. CONCLUSIONS: The possibilities for achieving social equity in health are limited by the divergent treatment goals of providers and people receiving OAT. Sustained and equitable deimplementation of obtrusive aspects of OAT provision require co-created treatment goals, patient-centred monitoring and evaluation, and access to a supportive community of practice for providers.

Autoimmune pulmonary alveolar proteinosis in an adolescent girl with rapidly progressive dyspnea

Autoimmune pulmonary alveolar proteinosis (PAP) is a rare disease, especially in pediatrics, but important to consider, as it may avoid unnecessary and/or invasive investigations and delayed diagnosis. This case report highlights an adolescent girl with rapid onset dyspnea but an unremarkable physical exam and initial testing. However, due to a high index of suspicion, a chest computed tomography (CT) scan was done, revealing a "crazy paving" pattern, which then prompted expedited assessment. This finding, however, is not as specific as often discussed and has a broad differential diagnosis, which will be reviewed in detail as part of this case. Furthermore, this report demonstrates a diagnostic approach for PAP that avoids lung biopsy, previously considered to be required for diagnosis of PAP, but is increasingly becoming unnecessary with more advanced blood tests and understanding of their sensitivity and specificity. Additionally, management strategies for PAP will be briefly discussed.Copyright © 2022 Canadian Thoracic Society.

Factors influencing the SARS-CoV-2 infection and vaccination induced immune response in rheumatoid arthritis.

Background: To investigate the factors that have significant impact on the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection and vaccination induced immune response in rheumatoid arthritis (RA). Methods: Serological response was measured by quantifying anti-SARS-CoV-2 specific antibodies, while the cell-mediated response was measured by a whole-blood test quantifying the interferon (IFN)-γ response to different SARS-CoV-2-specific domains. Results: We prospectively enrolled 109 RA patients and 43 healthy controls. The median time (IQR) between the confirmed infection or the last vaccination dose and the day when samples were taken ("sampling interval") was 3.67 (2.03, 5.50) months in the RA group. Anti-Spike (anti-S) specific antibodies were detected in 94% of RA patients. Among the investigated patient related variables, age (p<0.004), sampling interval (p<0.001), the brand of the vaccine (p<0.001) and targeted RA therapy (TNF-inhibitor, IL-6 inhibitor, anti-CD20 therapy) had significant effect on the anti-S levels. After covariate adjustment TNF-inhibitor therapy decreased the anti-S antibody concentrations by 80% (p<0.001). The same figures for IL-6 inhibitor and anti-CD20 therapy were 74% (p=0.049) and 97% (p=0.002), respectively. Compared to subjects who were infected but were not vaccinated, the RNA COVID-19 vaccines increased the anti-S antibody levels to 71.1 (mRNA-1273) and 36.0 (BNT162b2) fold (p<0.001). The corresponding figure for the ChAdOx1s vaccine is 18.1(p=0.037). Anti-CCP (anti-cyclic citrullinated peptides) positive patients had 6.28 times (p= 0.00165) higher anti-S levels, than the anti-CCP negative patients. Positive T-cell response was observed in 87% of the healthy volunteer group and in 52% of the RA patient group. Following vaccination or infection it declined significantly (p= 0.044) but more slowly than that of anti-S titer (6%/month versus 25%). Specific T-cell responses were decreased by 65% in patients treated with anti-CD20 therapy (p=0.055). Conclusion: Our study showed that the SARS-CoV-2-specific antibody levels were substantially reduced in RA patients treated with TNF-α-inhibitors (N=51) and IL-6-inhibitor (N=15). In addition, anti-CD20 therapy (N=4) inhibited both SARS-CoV-2-induced humoral and cellular immune responses. Furthermore, the magnitude of humoral and cellular immune response was dependent on the age and decreased over time. The RNA vaccines and ChAdOx1s vaccine effectively increased the level of anti-S antibodies.

COVID-19 vaccination status and its impact on psoriatic lesions in patients with psoriasis treated with biologics: a single-center cross-sectional study.

Objective To investigate COVID-19 vaccination status and relevant adverse reactions in patients with psoriasis treated with biological agents, and to explore the effect of COVID-19 vaccination on psoriatic lesions. Methods Clinical data were collected from 572 psoriasis patients aged 18-60 years, who were registered in the management system of psoriasis patients treated with biological agents in the University of Hong Kong-Shenzhen Hospital from May 2019 to June 2021. The COVID-19 vaccination status was investigated by telephone interviews, and the vaccination-related information was obtained by fixed healthcare workers during a fixed time period according to a predesigned questionnaire. Measurement data were compared between two groups by using t test, and enumeration data were compared by using chi- square test or Fisher's exact test. Results The COVID-19 vaccination coverage rate was 43.13%226 casesamong the 524 patients who completed the telephone interview, and was significantly lower in the biological agent treatment group30.79%, 105/341than in the traditional drug treatment group66.12%, 121/183;chi2 = 60.60, P < 0.001. The main reason for not being vaccinated was patients' fear of vaccine safety49.66%, 148/298, followed by doctors' not recommending26.51%, 79/298. In the biological agent treatment group after vaccination, the exacerbation of psoriatic lesions was more common in patients receiving prolonged-interval treatment42.86%, 6/14compared with those receiving regular treatment 4.40%, 4/91;Fisher's exact test, P < 0.001. Skin lesions were severely aggravated in two patients after COVID-19 vaccination, who ever experienced allergic reactions and whose skin lesions did not completely subside after the treatment with biological agents. Conclusions The COVID-19 vaccination coverage rate was relatively low in the psoriasis patients treated with biological agents, and no serious adverse reaction was observed after vaccination. Prolonged-interval treatment due to COVID-19 vaccination ran the risk of exacerbation of skin lesions.Copyright © The Author(s) 2023.

Autoimmune hepatitis after vaccination against COVID-19.

In this case report, we present a 61-year-old patient admitted to the hospital because of tiredness and jaundice less than three weeks after vaccination against SARS-CoV-2 with the first dose of the Comirnaty vaccine (Pfizer/ BioNTech). Based on the patient s medical history, laboratory data, imaging methods and liver biopsy, we diagnosed autoimmune hepatitis. The patient developed acute liver failure, and his liver function did not improve after corticosteroid administration. Therefore, the patient was enrolled in the waiting list and underwent a successful orthotopic liver transplantation.Copyright © 2023 Galen s.r.o.. All rights reserved.

L-Ornithine-L-Aspartate and Intermittent Renal Replacement Therapy in Fulminant Hepatitis A: A Case Report

Hepatitis A is a common viral infection worldwide that is transmitted via the fecal-oral route. Since the introduction of an efficient vaccine, the incidence of infection has decreased but the number of cases has risen due to widespread community outbreaks among unimmunized individuals. Classic symptoms include fever, malaise, dark urine, and jaundice, and are more common in older children and adults. People are often most infectious 14 days prior to and 7 days following the onset of jaundice. We will discuss the case of a young male patient, diagnosed with acute hepatitis A, leading to fulminant hepatitis refractory to conventional therapy and the development of subsequent kidney injury. The medical treatment through the course of hospitalization was challenging and included the use of L-ornithine-L-aspartate and prolonged intermittent hemodialysis, leading to a remarkable outcome. Hepatitis A is usually self-limited and vaccine-preventable;supportive care is often sufficient for treatment, and chronic infection or chronic liver disease rarely develops. However, fulminant hepatitis, although rare, can be very challenging to manage as in the case of our patient.Copyright © 2023 The Author(s).

Cardiovascular complications of COVID-19 severe acute respiratory syndrome

603,711,760 confirmed cases of COVID-19 have been reported throughout the world and 6,484,136 individuals have died from complications of COVID-19 as of September 7, 2022. Significantly, the Omicron variant has produced the largest number of COVID-19 associated hospitalizations since the beginning of the pandemic. Cardiac injury occurs in >= 20% of the hospitalized patients with COVID-19 and is associated with cardiac dysrhythmias in 17 to 44%, cardiac injury with increases in blood troponin in 22 to 40%, myocarditis in 2 to 7%, heart failure in 4 to 21%, and thromboembolic events in 15 to 39%. Risk factors for cardiac complications include age >70 years, male sex, BMI =30 kg/m(2), diabetes, pre-existing cardiovascular disease, and moderate to severe pneumonia at hospital presentation. Patients with prior cardiovascular disease who contract COVID-19 and experience a significant increase in their blood troponin concentration are at risk for mortality rates as high as 69%. This review focuses on the prevalence, the pathophysiologic mechanisms of CoV-2 injury to the cardiovascular system and the current recommended treatments in hospitalized patients with COVID-19 in order that medical personnel can decrease the morbidity and mortality of patients with COVID-19 and effectively treat patients with Covid and post Covid syndrome.

[Early use of tocilizumab in hospitalized patients with severe and critical COVID-19 in the Province of Buenos Aires: a multicentric study]

INTRODUCTION: Tocilizumab (TCZ), an IL-6 receptor antagonist monoclonal antibody is warranted in severe and critically-ill COVID-19 patients. The objective was to evaluate 28-day mortality of patients with severe or critical COVID-19 treated with early vs delayed TCZ. METHODS: Multicenter, retrospective cohort study including patients >18 years hospitalized between 7/1/2021-8/1/2022 with confirmed COVID-19, with 5, 6 and 7 points of WHO Ordinal Initial Severity Scale [SS]. Early or late administration was considered if TCZ was administered before or after 48 hours from admission. Outcomes were 28-day mortality and change of SS. Factors related to 28-day mortality were evaluated with Cox regression. RESULTS: 266 patients were included, 159(60%) male;aged 58(+/- 15);frequent comorbidities were hypertension (42%), obesity (37%) and diabetes (27%). Seventy patients had a SS = 5 (Supplemental O2), 143 had SS = 6 (NIV/ HFNC), and 53 had SS = 7 (IMV). 28-day mortality was 42%(112/266);predictors were age, obesity, higher SS, days between hospitalization and TCZ administration, and fewer days between symptoms onset and TCZ. Mortality of SS 5, 6 and 7 was 26%, 39% and 72% respectively. Compared with baseline SS points, 76% and 62% of patients remained stable or improved on days 3 and 7 since TCZ administration. 28-day mortality was lower when TCZ was administered before 48 hours (39% vs 57%;p = 0.02;HR = 0.63;[0.41-0.99, p = 0.05]). DISCUSSION: This study supports the early use of TCZ in patients with severe or critical COVID-19.

COVID-19 in liver transplant recipients

Coronavirus disease 2019 (COVID-19), an infection caused by severe acute respiratory syndrome coronavirus-type 2 (SARS-CoV-2), has emerged as a serious threat to public health. Liver transplant (LT) recipients may be at increased risk of acquisition of SARS-CoV-2 infection and higher morbidity and mortality due to constant contact with health-care services, the use of immunosuppressants and frequent comorbidities. In the first part of this review we discuss (1) the epidemiology and risk factors for SARS-CoV-2 infection in LT recipients;(2) the clinical and laboratory features of COVID-19 in this specific population, highlighting differences in presenting signs and symptoms with respect to general populations and (3) the natural history and prognostic factors in LT recipients hospitalized with COVID-19, with particular focus on the possible role of immunosuppression. Thereafter, we review the potential therapeutic options for COVID-19 treatment and prevention. Specifically, we give an overview of current practice in immunosuppressant regimen changes, showing the potential benefits of this strategy, and explore safety and efficacy issues of currently approved drugs in LT recipients. The last topic is dedicated to the potential benefits and pitfalls of vaccination.Copyright © 2021 The Authors

The Early Detection of Fraudulent COVID-19 Products From Twitter Chatter: Data Set and Baseline Approach Using Anomaly Detection.

Background: Social media has served as a lucrative platform for spreading misinformation and for promoting fraudulent products for the treatment, testing, and prevention of COVID-19. This has resulted in the issuance of many warning letters by the US Food and Drug Administration (FDA). While social media continues to serve as the primary platform for the promotion of such fraudulent products, it also presents the opportunity to identify these products early by using effective social media mining methods. Objective: Our objectives were to (1) create a data set of fraudulent COVID-19 products that can be used for future research and (2) propose a method using data from Twitter for automatically detecting heavily promoted COVID-19 products early. Methods: We created a data set from FDA-issued warnings during the early months of the COVID-19 pandemic. We used natural language processing and time-series anomaly detection methods for automatically detecting fraudulent COVID-19 products early from Twitter. Our approach is based on the intuition that increases in the popularity of fraudulent products lead to corresponding anomalous increases in the volume of chatter regarding them. We compared the anomaly signal generation date for each product with the corresponding FDA letter issuance date. We also performed a brief manual analysis of chatter associated with 2 products to characterize their contents. Results: FDA warning issue dates ranged from March 6, 2020, to June 22, 2021, and 44 key phrases representing fraudulent products were included. From 577,872,350 posts made between February 19 and December 31, 2020, which are all publicly available, our unsupervised approach detected 34 out of 44 (77.3%) signals about fraudulent products earlier than the FDA letter issuance dates, and an additional 6 (13.6%) within a week following the corresponding FDA letters. Content analysis revealed misinformation, information, political, and conspiracy theories to be prominent topics. Conclusions: Our proposed method is simple, effective, easy to deploy, and does not require high-performance computing machinery unlike deep neural network-based methods. The method can be easily extended to other types of signal detection from social media data. The data set may be used for future research and the development of more advanced methods.

X-Linked Inhibitor of Apoptosis (XIAP) deficiency presenting as hemophagocytic lymphohistiocytosis triggered by drug allergy

X-linked inhibitor of apoptosis (XIAP) deficiency is a primary immunodeficiency associated with recurrent hemophagocytic lymphohistiocytosis (HLH) episodes. The clinical phenotypes of XIAP deficiency vary, ranging from splenomegaly to life-threatening inflammation. We report a case of XIAP deficiency with unusual late-onset HLH presentation likely triggered by a drug allergy. A previously healthy adolescent boy presented to the hospital with fever and rash seven days after starting antibiotics for a neck abscess. Laboratory evaluation demonstrated cytopenias, elevated liver enzymes, and increased inflammatory markers. Initially, antibiotics were discontinued due to concern for drug rash. He continued to deteriorate clinically and became hypotensive. Additional testing revealed decreased NK cell function, as well as elevated ferritin, triglycerides, and soluble IL-2 receptor. SLAM-Associated Protein (SAP) and XIAP evaluation by flow cytometry demonstrated decreased XIAP expression. Subsequently, genetic testing revealed a known pathogenic mutation in BIRC4 (c.421_422del), confirming the diagnosis of XIAP deficiency.Copyright © 2023

Cardiac and vegetative manifestations of long-COVID in children.

Approximately 5-15% of children develop post-COVID-19 syndrome after SARS-CoV-2 infection, which manifests itself with various pathological symptoms for more than 12 weeks. Cardiovascular symptoms range from serious myocardial inflammation, manifestations of essential hypertension to signs of autonomic dysfunction with a tendency to hypersympathicotonia, which negatively affects the quality of life of children. We report a case of subacute myocarditis in a patient with long-COVID after a low-symptomatic acute disease. This case illustrates high clinical significance of timely diagnosis of long-COVID using gadolinium-enhanced magnetic resonance imaging, which was performed in our country for the first time in pediatric practice. We developed criteria for early diagnosis of autonomic dysfunction specific for children and adolescents. We also developed treatment recommendations, including behavioral therapy, drug, and non-drug treatments.Copyright © 2022, Dynasty Publishing House. All rights reserved.

Maternal COVID-19 Infection: A Cause of Neonatal Stroke?

Perinatal arterial ischemic stroke (PAIS) is a rare cause of neonatal seizures, with an incidence of 1 in 2500 to 4000 live births, globally. This is a case of a neonate with PAIS due to transpla-cental passage of COVID-19 IgG antibodies from the mother. A term, male neonate, born to a primigravida with an unevent-ful antenatal history was presented on the second day of life with multiple episodes of focal clonic seizures involving the right upper and lower limbs. Magnetic resonance imaging revealed an acute infarct in the left frontal lobe, extending into the parietal region, anterior limb, and genu of internal capsule suggestive of arterial ischemic stroke. The known causes of PAIS were evaluated and ruled out. The result of reverse transcription polymerase chain reaction analysis for SARS-CoV-2 antigen was negative for both the mother and the neonate. COVID-19 IgG antibodies in the mother and neonate were elevated. Seizures were controlled with antiepileptics. The neonate had no further seizure episodes and was discharged on oral levetiracetam. The infant was developmentally and neurologically normal at 3 months of age. PAIS is a rare cause of neonatal seizures, and maternal COVID-19 infection may be associated with neonatal stroke.Copyright © 2022, Himalaya Wellness Company. All rights reserved.

Targeting Underlying Inflammation in Carcinoma Is Essential for the Resolution of Depressiveness.

In modern clinical practice and research on behavioral changes in patients with oncological problems, there are several one-sided approaches to these problems. Strategies for early detection of behavioral changes are considered, but they must take into account the specifics of the localization and phase in the course and treatment of somatic oncological disease. Behavioral changes, in particular, may correlate with systemic proinflammatory changes. In the up-to-date literature, there are a lot of useful pointers on the relationship between carcinoma and inflammation and between depression and inflammation. This review is intended to provide an overview of these similar underlying inflammatory disturbances in both oncological disease and depression. The specificities of acute and chronic inflammation are considered as a basis for causal current and future therapies. Modern therapeutic oncology protocols may also cause transient behavioral changes, so assessment of the quality, quantity, and duration of behavioral symptoms is necessary to prescribe adequate therapy. Conversely, antidepressant properties could be used to ameliorate inflammation. We will attempt to provide some impetus and present some unconventional potential treatment targets related to inflammation. It is certain that only an integrative oncology approach is justifiable in modern patient treatment.

Identification of Clinical Response Predictors of Tocilizumab Treatment in Patients with Severe COVID-19 Based on Single-Center Experience.

Hyperinflammation in COVID-19 plays a crucial role in pathogenesis and severity; thus, many immunomodulatory agents are applied in its treatment. We aimed to identify good clinical response predictors of tocilizumab (TCZ) treatment in severe COVID-19, among clinical, laboratory, and radiological variables. We conducted a prospective, observational study with 120 patients with severe COVID-19 not improving despite dexamethasone (DEX) treatment. We used parametric and non-parametric statistics, univariate logistic regression, receiver operating characteristic (ROC) curves, and nonlinear factors tertile analysis. In total, 86 (71.7%) patients achieved the primary outcome of a good clinical response to TCZ. We identified forty-nine predictive factors with potential utility in patient selection and treatment monitoring. The strongest included time from symptom onset between 9 and 12 days, less than 70% of estimated radiological lung involvement, and lower activity of lactate dehydrogenase. Additional predictors were associated with respiratory function, vitamin D concentration, comorbidities, and inflammatory/organ damage biomarkers. Adverse events analysis proved the safety of such a regimen. Our study confirmed that using TCZ early in the hyperinflammatory phase, before severe respiratory failure development, is most beneficial. Considering the described predictive factors, employing simple and widely available laboratory, radiological, and clinical tools can optimize patient selection for immunomodulatory treatment with TCZ.