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Background: Exposure-response (E-R) models were developed for the primary endpoint of hospitalization or death in COVID-19 patients from the Phase 3 portion of the MOVe-OUT study (Clinicaltrials.gov NCT04577797). Beyond dose, these models can identify other determinants of response, highlight the relationship of virologic response with clinical outcomes, and provide a basis for differential efficacy across trials. Method(s): Logistic regression models were constructed using a multi-step process with influential covariates identified first using placebo arm data only. Subsequently the assessment of drug effect based on drug exposure was determined using placebo and molnupiravir (MOV) arm data. To validate the models, the rate of hospitalization/death was predicted for published studies of COVID-19 treatment. All work was performed using R Version 3.0 or later. Result(s): A total of 1313 participants were included in the E-R analysis, including subjects having received MOV (N=630) and placebo (N=683). Participants with missing baseline RNA or PK were excluded (79 from MOV and 16 from placebo arms). The covariates shown to be significant determinants of response were baseline viral load, baseline disease severity, age, weight, viral clade, and co-morbidities of active cancer and diabetes. Day 5 and Day 10 viral load were identified as strong on-treatment predictors of hospitalization/death, pointing to sustained high viral load as driving negative outcomes. Estimated AUC50 was 19900 nM*hr with bootstrapped 95% C.I. of (9270, 32700). In an external validation exercise based on baseline characteristics, the E-R model predicted the mean (95% CI) placebo hospitalization rates across trials of 9.3% (7.6%, 11.7%) for MOVe-OUT, 7.2% (5.3%, 9.8%) for the nirmatrelvir/ritonavir EPIC-HR trial, and 3.2% (1.9%, 5.5%) for generic MOV trials by Aurobindo and Hetero, consistent with the differing observed placebo rates in these trials. The relative reduction in hospitalization/death rate predicted with MOV treatment (relative to placebo) also varied with the above patient populations. Conclusion(s): Overall, the exposure-response results support the MOV dose of 800 mg Q12H for treatment of COVID-19. The results further support that many clinical characteristics impacted hospitalization rate beyond drug exposures which can vary widely across studies. These characteristics also influenced the magnitude of relative risk reduction achieved by MOV in the MOVe-OUT study.
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Aim: To elucidate the factors that influence beta-lactam pharmacokinetic (PK) and pharmacodynamic (PD) variability in infective endocarditis (IE) and to examine optimal PK/PD target parameters for therapy. Background(s): Beta-lactam antibiotics are the mainstay of therapy for most bacterial causes of IE. Traditionally considered as agents with a broad therapeutic index there has been increasing recognition that standard doses may be subtherapeutic or toxic in critically ill patients. Optimising therapy for efficacy requires an established PK/PD target associated with clinical and microbiological cure. Method(s): Clinical and laboratory in vivo animal or human studies examining PK and/or PD of beta-lactam antibiotics in IE were eligible. Ovid MEDLINE, Embase and Cochrane Central Registry were searched using defined terms. Two authors reviewed s and full texts using Covidence software. Result(s): 62 articles were selected for review and synthesis. We identified 45 animal studies investigating the broad categories of beta-lactam diffusion into vegetations, PK/PD determinants of outcome, mode of antibiotic delivery and synergistic impact of agents. 17 human case studies/series totalling 347 participants reported antibiotic serum concentrations and clinical outcomes. Findings generally supported the importance of time-dependent killing for beta-lactams but heterogeneous data limited the determination of an optimal PK/PD target for IE treatment. Conclusion(s): Beta-lactam PK and PD in endocarditis is variable and specific to the particular antibiotic-organism combination. Timedependent killing is important, consistent with non-endocarditis studies, but there is little agreement on optimal drug exposure. Clinical studies examining various PK/PD targets in endocarditis patients are required to further inform drug selection and dosing.Copyright © 2023 Southern Society for Clinical Investigation.
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BACKGROUND: The goal of this analysis was to investigate the relationship of molnupiravir pharmacokinetics (PK) and clinical outcomes (primary endpoint of hospitalization or death) in patients with COVID-19 in the phase 3 cohort of MOVe-OUT (clinicaltrials.gov NCT04577797).1 METHODS: Logistic regression models were constructed using a multi-step process with influential covariates identified first using placebo arm data only and subsequently assessment of drug effect as a function of exposures evaluated using placebo and MOV arm data. Individual estimates of exposure were derived from population PK modeling of sparse samples collected in all patients. All work was performed using R v3.0 or later. RESULT(S): A total of 1,313 participants were included in the exposure-response (E-R) analysis, including subjects on MOV (N = 630) and placebo (N = 683). Participants with missing PK or baseline RNA were excluded (79 from MOV and 16 from placebo arms). The covariates shown to be significant determinants of response were baseline viral load, baseline disease severity, age, weight, viral clade, active cancer, and diabetic risk factors. An additive AUC-based Emax model with a fixed hill coefficient of 1 best represented exposure-dependency in drug effect. Estimated AUC50 was 19,900 nM*hr with bootstrapped 95% confidence interval of (9,270, 32,700). Patients at 800 mg achieved near maximal response, which was larger than the response projected for 200 or 400 mg. CONCLUSION(S): Overall, the E-R results support the MOV dose of 800 mg Q12H for treatment of COVID-19. Many patient characteristics, beyond drug exposures, impacted the risk of hospitalization or death.
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Young children who experience trauma and adverse experiences are at an increased risk of developing an insecure attachment style as well as negative physical and mental health problems. These can include internalizing and externalizing behavioral problems, developmental delay, emotional dysregulation, and aggression. Several evidence-based interventions exist to treat young children with symptoms related to trauma, each with different foundational theories. This article presents the case of a 4-year-old boy with posttraumatic stress disorder who was in the middle of a legal fight between caregivers and transitioning between caregivers' homes. Initially, therapy began with Child-Parent Psychotherapy to address caregivers' first concerns. Later, the therapeutical approach was switched to Parent-Child Interaction Therapy due to difficulty with treatment fidelity related to caregivers' symptoms and conflict. This case demonstrates great improvement in treatment fidelity and subsequently problem behaviors after switching to an intervention that allowed to address behavior management shortcomings in a family with ongoing conflict.Copyright © The Author(s) 2022.
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Background & Aims: Liver injury with autoimmune features after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is increasingly reported. We investigated a large international cohort of individuals with acute hepatitis arising after SARS-CoV-2 vaccination, focusing on histological and serological features. Methods: Individuals without known pre-existing liver diseases and transaminase levels ≥5x the upper limit of normal within 3 months after any anti-SARS-CoV-2 vaccine, and available liver biopsy were included. Fifty-nine patients were recruited;35 females;median age 54 years. They were exposed to various combinations of mRNA, vectorial, inactivated and protein-based vaccines. Results: Liver histology showed predominantly lobular hepatitis in 45 (76%), predominantly portal hepatitis in 10 (17%), and other patterns in four (7%) cases;seven had fibrosis Ishak stage ≥3, associated with more severe interface hepatitis. Autoimmune serology, centrally tested in 31 cases, showed anti-antinuclear antibody in 23 (74%), anti-smooth muscle antibody in 19 (61%), anti-gastric parietal cells in eight (26%), anti-liver kidney microsomal antibody in four (13%), and anti-mitochondrial antibody in four (13%) cases. Ninety-one percent were treated with steroids ± azathioprine. Serum transaminase levels improved in all cases and were normal in 24/58 (41%) after 3 months, and in 30/46 (65%) after 6 months. One patient required liver transplantation. Of 15 patients re-exposed to SARS-CoV-2 vaccines, three relapsed. Conclusion: Acute liver injury arising after SARS-CoV-2 vaccination is frequently associated with lobular hepatitis and positive autoantibodies. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. A close follow-up is warranted to assess the long-term outcomes of this condition. Impact and implications: Cases of liver injury after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have been published. We investigated a large international cohort of individuals with acute hepatitis after SARS-CoV-2 vaccination, focusing on liver biopsy findings and autoantibodies: liver biopsy frequently shows inflammation of the lobule, which is typical of recent injury, and autoantibodies are frequently positive. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. Close follow-up is warranted to assess the long-term outcome of this condition. © 2022 The Author(s)
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Background: Current research on COVID-19-related outcomes in patients with psoriasis, particularly regarding influence of treatments, are subject to lack of comparator group, selection bias, and insufficient statistical power.1 Accordingly, it remains uncertain whether immunomodulatory treatments for psoriasis enhance or decrease the risk of severe COVID-19-related outcomes, including hospitalization. Objective(s): To compare the risk of COVID-19-related hospitalization according to immunomodulator treatment type in patients with psoriasis Methods: Retrospective cohort study of the Explorys database in the United States between March 1st, 2020 and December 31st, 2020. Psoriasis diagnosis was defined by at least 2 ICD-9 or ICD-10 diagnosis codes prior to March 1st, 2020. Drug exposure was classified as biologic or traditional immunosuppressive (methotrexate, cyclosporine, apremilast) treatment based on prescription order in the 3 months preceding March 1st, 2020. Biologic treatments included TNFalpha, IL-12/IL-23, IL-17A, IL-23 and JAK inhibitors. The primary outcome was defined as hospital admission with diagnosis of COVID-19 or positive lab test occurring between admission and discharge date. Propensity score weighting was used to compare COVID-19-related hospitalization between treatment groups, adjusting for comorbidities and demographic characteristics. Result(s): A total of 51,606 psoriasis patients aged 18-88 were included. Crude cumulative incidence of COVID-19 hospitalization per 1,000 psoriasis patients was 3.4 in the biologic group (9/2,669), 9.5 in the traditional immunosuppressive group (15/1,585), and 3.9 in those receiving neither drug class (184/47,352). Incidence was 4.7 (6/1,282) and 14 (13/898) per 1,000 patients among those receiving TNF-alpha inhibitors and methotrexate, respectively. After propensity-score weighting, risk of COVID-19-related hospitalization for patients receiving any biologic was lower than that of patients receiving traditional immunosuppressives (RR 0.39, 95% CI 0.16, 0.92), and those receiving neither drug class (RR 0.66, 95% CI 0.32, 1.34). TNF-alpha inhibitor use was associated with lower risk of hospitalization relative to methotrexate use (adjusted RR 0.39, 95% CI 0.14, 1.06). Adjusted relative risk of hospitalization for methotrexate users relative to those receiving neither drug class was 2.78 (95% CI 1.47, 5.26). Conclusion(s): During the first wave of the pandemic in 2020, psoriasis patients using biologics were at lower risk of COVID-19-related hospitalization compared to those using traditional immunosuppressives, particularly methotrexate. Methotrexate use was associated with a substantial increase in risk of hospitalization relative to those who did not receive systemic treatments.
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Introduction: Resembling Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Virus Reactivation with Eosinophilia and Systemic Symptoms (VRESS) occurs triggered by members of Herpesviridae family viruses. Case Description: A 12-year-old male was hospitalized with a 5-day history of fever, pruritic erythematous rash on the trunk and extremities, and facial edema. The patient was exposed to a cousin diagnosed with Multisystem Inflammatory Syndrome in Children (MIS-C) 10 days prior. No history of traveling, unusual food intake, URI, drug ingestion during the prior 3 months. Patient was treated with clindamycin x 10 days for possible Staphylococcal Scalded Skin Syndrome. Patient was noted to have eosinophilia of >2000 that persisted through the hospital course and thereafter, transaminitis with direct bilirubinemia, transient microscopic hematuria, elevated CRP and C3, normal EKG and chest radiograph, normal T/B/NKC counts, normal levels of immunoglobulins and elevated IgE (2163>1579IU/mL). IgG and IgM were negative for: CMV, adenovirus, strongyloidces, HAV, HBV, and HIV. IgG positive to: EBV, HHV-6, mycoplasma, HHV-6, HSV1, and parvovirus. Negative cultures for MRSA and group A Streptococcus. Negative PCRs for COVID -19. At 8 week follow up, skin erythema evolved into desquamation in the fingers and eosinophilia persisted. Discussion(s): VRESS should be on the differential for patients presenting with a DRESS-like symptoms in the absence of drug exposures. VRESS is often triggered by members of the Herpesviridae family of viruses including EBV and HHV-6, to both of which this patient was exposed to in the past. While diagnosis is one of exclusion, early identification can guide appropriate management. Copyright © 2022
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Diabetes Mellitus predisposes patients to invasive fungal infections. There has been a recent surge of Mucormycosis with COVID 19 infection particularly in patients with diabetes. This study aims to study the clinical spectrum of CAM (COVID-associated Mucormycosis) with diabetes and subsequent outcomes. Material(s) and Method(s): Descriptive study was conducted among the patients attending Ophthalmology OPD in a Tertiary Care Centre in Telangana with COVID Associated Mucormycosis(CAM) from March 2021 to June 2021. Result(s): Among 200 patients who attended OPD with CAM, Diabetes Mellitus was the most common co-morbidity. The majority of the patients had poor glycaemic control with a mean HbA1c of 9.06%. Pre-existing diabetes mellitus (DM) was present in 84% of cases. Out of the total study population, 89% had prior exposure to high dose corticosteroids. Conclusion(s): The disease has surged in COVID 19 pandemic due to uncontrolled diabetes and improper corticosteroid use. Copyright © 2023, Institute of Medico-legal Publication. All rights reserved.
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In the last years, several studies on new and/or repurposing antiviral drugs were initiated to fight Coronavirus disease 2019 (COVID-19) pandemic. Three antivirals have so far been authorised in Italy for the treatment of COVID-19 in adults who do not need supplemental oxygen and who are at high risk of progressing to severe COVID-19. Specifically, the drugs currently authorized are Remdesivir (intravenous route) and the orally administered Molnupiravir and Nirmatrelvir-Ritonavir (Paxlovid). Remdesivir is a prodrug of the nucleotide analogue (GS-441524) which inhibits the SARS-CoV-2 RNA-dependent RNA polymerase. Remdesivir has been shown to improve the COVID-19 outcome in different settings. Molnupiravir is a prodrug that after entering in the cells changes into an active form of triphosphate, ready to be incorporated into viral genome causing many errors in SARS-CoV-2 RNA. In a clinical trial, Molnupiravir compared to placebo showed a 30% reduction of COVID-19-related hospitalizations. Paxlovid is a combination of Nirmatrelvir and Ritonavir. Nirmatrelvir acts by inhibiting protease enzyme, essential step to transform some viral proteins into their final functional form. The relative risk reduction of hospitalization or all-cause death at day 28 for Paxlovid compared to placebo was 88%. To guarantee safe and effectiveness of the pharmacological therapies, the evaluation of patient's pharmacokinetics (PK) profile is mandatory. Therefore, the monitoring of drug concentration of antivirals against SARS-CoV2 could be pivotal to optimise drug regimens, increase efficacy and avoid drug-related toxicity and to evaluate intra-individual variability and drug-drug interactions. Actually, few data on antiviral drugs concentrations in COVID-19 subjects are published. Among them, the most interesting are the following: i) Remdesivir and its main metabolite showed high PK interpatient variability due to both age and renal function in COVID-19 inpatients. The PK variability may have a potential effect in determining the efficacy of Remdesivir administration in patients affected by COVID-19. ii) Molnupiravir metabolite penetration into upper airways and mucosal secretions was demostred. These data could support the use of molnupiravir in a prophylaxis for SARS-CoV-2 infection iii) Nirmatrelvir displays a short half-life, which could result in suboptimal drug exposure and difficulties in achieving efficacy. Therefore, there is the need to use ritonavir (CYP3A4 Inhibitor) to slow down the metabolism and to increase the plasma concentrations of Nirmetrelvir. Drug-drug interactions are expected when drugs metabolized by CYP3A4 are co-administered with Paxlovid. Further research on antiviral drugs concentrations in COVID-19 patients could help to define therapeutic strategies more efficient and appropriate to treat SARSCoV-2 infection.
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Introduction: AKI in patients with COVID-19 is common. Among glomerular pathologies in COVID 19, COVID 19 Associated Collapsing Glomerulopathy (COVAN) remains the most common pattern of injury. AIN is a less common finding in patients with COVID-19. Reports of a subtype of AIN, granulomatous interstitial nephritis (GIN), among COVID-19 patients, are rare and have not been reported in association with COVAN. Here, we report a case of COVAN associated with severe GIN Case Description: A 52YOM who presented with fever and fatigue. The physical exam was remarkable. The patient tested positive for COVID-19 and was found to have oliguric AKI with a creatinine of 9.6 mg/dl and nephrotic range proteinuria. Therefore iHD was initiated. Serologies and infection studies were negative. Fungal serologies were negative. A kidney biopsy revealed up to 32 glomeruli, four of which were globally sclerotic. Up to four glomeruli had features of glomerular collapse. The interstitium showed severe, diffuse edematous change with inflammatory infiltrates and focal interstitial granulomas. EM showed extensive foot process effacement and multiple TRI. Additional stains were negative. After the biopsy results returned, the patient was started on high-dose steroid. He experienced side effects with the high dose and therefore was transitioned to an every other day regimen. Losartan was added and prednisone taper was started. He was doing very well clinically at the last visit with resolving AKI and proteinuria Discussion: We have presented a rare case of GIN in a patient with COVAN. With negative infectious and autoimmune evaluation, it is possible the GIN was secondary to drug exposure and/or potentiated by the inflammatory mileu of COVID-19 infection. Even several years into the pandemic, we continue to find new kidney pathology among COVID-19. Kidney biopsy was absolutely necessary in this case and informed a dedicated treatment plan that allowed a remarkable recovery of kidney function.
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There is no doubt that scientific progress has accelerated the discovery and development of innovative medicines, a phenomenon acutely visible through the rapid advancement of vaccines against SARS-CoV-2. Outside of dealing with a global pandemic, the process of drug discovery and development remains painfully slow, extremely costly and can, despite appropriate measures, result in patient-safety concerns. Because only around 12% of drugs that enter clinical trials make it to approval, governments in the United States and Europe are taking steps towards modernizing the process of drug discovery and development. Whilst several solutions will ultimately be required, there are growing calls for the utilization of 21st century tools within drug discovery pipelines. One such tool is organ-on-a-chip technology that employs microfluidic systems engineering to recapitulate in vivo cell and tissue microenvironments in an organ-specific context. This is achieved by recreating tissue-tissue interfaces and providing fine control over fluid flow and mechanical forces, optionally including supporting interactions with immune cells and microbiome, and reproducing clinical drug exposure profiles. This seminar will showcase the Emulate Organ-Chip platform and will present the findings of the first of its kind Organ-Chip study which utilized the pharma consortium Innovation and Quality (IQ) roadmap for developing in vitro liver models for the prediction of drug-induced liver injury1. Using 780 Liver-Chips across a test set of 27 small molecule drugs, data will be presented indicating that the Liver-Chip has a 87% sensitivity and 100% specificity, thus making it a highly predictive tool compared to animal models and prior preclinical in vitro models. The seminar will complete with an overview on how such a tool can be implemented into drug discovery workflows whilst providing adopting organizations a significant productivity gain.
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Background: Recent published data have emerged some concerns about safety of Janus kinase (JAK) inhibitors and FDA have established prescribing restrictions. Objectives: The aim of this study was to analyze the safety profile of current approved JAK inhibitors in Europe with data from a Real World cohort. Methods: A single center observational study was performed including patients who had initiated treatment with Tofacitinib, Baricitinib or Upadacitinib from September, 2017 to January, 2022. Demographic, clinical, laboratory and safety variables were collected from baseline and at months 1, 3, 6 and every six months. Safety data was collected including any adverse event (AE) due to any cause. An AE was considered serious if it was life-threatening or result in hospitaliza-tion, disability or in death. All AE and SAE were expressed adjusted by exposure (E/100 PY). Results: A total of 194 patients were included whom baseline demographic and disease characteristics are exposed in Table 1. Drug exposure was 265.5 patient-years. Overall, 214 AE were detected being mild upper tract respiratory infection the most frequently registered (15.82 E/100PY) followed by Urinary tract Infection accounting 7.16 E/100PY. 10 Serious Infections were detected in 10 patients of which 5 were pneumonia (1.88 E/100PY), 1 cellulitis (0.38 E/100PY) and 2 COVID-19 (0.76 E/100PY). 12 herpetic infection were detected in 9 patients (4.52 E/100PY) of which 7 were caused by herpes zoster (2.64 E/100PY) and 5 by herpes simplex (1.88 E/100PY) 3 cases were mono-metameric and 4 multi-metameric. Moreover, 2 patient developed postherpetic neuralgia. A patient with RA developed Miliary Tuberculosis (0.38 E/100PY) with a negative IGRA test prior to the JAKi. A patient with RA suffered a Myocardial Infarction (0.38 E/100PY). 7 RA patients developed malignancy (2.64 E/100PY), one with oral squamous cell carcinoma, two Bowen carcinoma, one breast cancer, 2 basal cell carcinoma and a colorectal metastatic cancer. Not a single case of thromboembolic event nor Hepatitis B Virus reactivation were registered. 2 patients died, one with cancer and the other suffered a severe COVID-19 (unvaccinated). Conclusion: In this updated analysis of 194 patients treated with JAKi, the three approved JAKi showed a safety profile consistent with data from RCT. The patients under JAK therapy should be carefully evaluated on their follow-up.
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Introduction: Covid-19 infection has been spreading worldwide since December 2019. Skin manifestations are common as 60% of patients had skin involvement such as rashes, chilblains, urticaria, purpura and vasculitis (1). Toxic Epidermal Necrolysis (TEN) is a life-threatening dermatological disease with > 30% of body surface area involved. TEN pathophysiology is linked to immune system activation triggered by drugs or infections or unknown causes (2). We are reporting a case of biopsy confirmed TEN in pediatrics patient with history of recent Covid19 infection. Case Description: A 6-year-old boy with history of mild Covid 19 infection two weeks ago presented with fever, oral ulcers and maculopapular rash on the trunk and extremities for 2 days. He was admitted for supportive care. His skin rash was progressing to violaceous targetoid lesions on the trunk and extremities with genital erosion, Nickolsky sign was positive. He had purulent conjunctivitis and crusted lips lesions with deepithelization of the oral mucosa. SCROTEN score was 2 for detachment more than 30%, low bicarbonate of 19. All virology tests came out negative including respiratory and blood PCR testing. A 4-mm punch skin biopsy histopathology was consistent with TEN. He was treated with supportive care, IVIG 1 g/Kg daily for 5 days, IV dexamethasone shifted later to oral Prednisolone, Cyclosporin 3 mg/kg/day. His rash and oral mucositis improved within 1 week and he was discharged in stable condition. He was seen in the clinic after 1 month of discharge and recovery of the skin, oral and eye mucosa was observed. Discussion: This report presented a case of a child with TEN and history of recent Covid-19 infection. Most cases of TEN are triggered by drugs and some by infections (3)(4). There were case reports of TEN associated with Covid 19 infection in adults with probable association with drugs such as hydroxychloroquine (3), Allopurinol (5), Lamotrigine (6), one case with no history of drug exposure (7). In a report of more than 5000 pediatrics patients with Covid-19 infection only one patient had SJS (8). Another case of 8-year-old boy with Covid-19 infection who developed SJS rash was reported (9). Both pediatrics cases had history of Amoxicillin- Clavulanate use. In our case the relationship between Covid-19 infection and TEN is not clear as the child had a history of Ibuprofen use that could be the culprit trigger. However, Covid-19 could still be the trigger in this case. It is worth reporting this case to keep in mind the wide spectrum of dermatological presentation in Covid-19 patients. Conclusion: Whether Covid 19 infection can trigger TEN in pediatrics patient is an important question that needs larger studies, yet it is worth reporting this case of possible correlation between Covid 19 and TEN in pediatrics.
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Suicide is defined as a fatal self-injurious act with some evidence of intent to die.1 Suicide occurs more often in older than in younger people, but is still one of the leading causes of death in the late childhood and adolescence. Every year, more than 1,00,000 people commit suicide in our country.1 Suicide accounts for 1.4% of all deaths, and is the 15th leading cause of death globally.2,3 Suicide is associated with an impulsive nature. Several risk factors concerning family structure and interactions have been linked to a suicidal behaviour. Direct conflicts with parents and siblings, Occupational status and social acceptance have a great impact, but so do the absence of communication and a lack of empathy.12 Interpersonal losses are also strongly associated with suicide cases. But in developing countries one of the major reason always remains unemployment and poverty. There are different rates of suicides and suicidal behaviour between males and females (among both adults and adolescents). While females more often have suicidal thoughts, males die by suicide more frequently.5 Hence, this study was planned with a purpose to know the magnitude and the socio-cultural factors of the problem of suicides, so that a sound prevention program could be suggested, planned and implemented for reducing the incidence of suicides.
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The COVID-19 pandemic, caused by SARS-CoV-2, has been the most significant global health crisis of the past century. The development of safe and effective vaccines has led to a reduction in COVID- 19-related hospitalizations and deaths;however, the clinical trials that led to US Food and Drug Administration Emergency Use Authorization and/or approval of the vaccines in the United States did not include individuals with inflammatory bowel disease (IBD). Because individuals with IBD are commonly treated with immunosuppressive medications, there had been concern for reduced vaccine efficacy in this population. This article provides an overview of the peer-reviewed literature addressing COVID-19 vaccination in individuals with IBD;details the perceptions of patients with IBD of COVID-19 vaccines, including how gastroenterologists can help to reduce vaccine hesitancy;and describes the humoral immune response to COVID-19 vaccines, with a majority of patients with IBD seroconverting following complete vaccination regardless of medication exposure. Additionally, low rates of IBD flare and similar rates of vaccine-related adverse events to those in the general population are described. Finally, the article provides current recommendations from the Centers for Disease Control and Prevention for COVID-19 vaccination in individuals with IBD.
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Introduction: Acute Respiratory Distress Syndrome (ARDS) became a leading cause of ICU admission since the COVID-19 outbreak. Refractory ARDS can benefit from Veno-Venous Extra Corporeal Membrane Oxygenation (VV ECMO). Amiodarone is used for treating cardiac arrhythmias and shockable cardiac arrest during cardiopulmonary resuscitation (CPR). Data about amiodarone under VV ECMO are still lacking. In a previous work led on a model of ARDS in pigs ongoing CPR, we showed a pharmacokinetics impairment of amiodarone under VV ECMO. We aimed to establish a PK modelling of amiodarone concentrations. Material and methods: Nonlinear mixed effects modelling approach was used to analyse plasma concentrations. Impact of VV ECMO on amiodarone pharmacokinetic profile were investigated. Using our final model, different dosing schemes for amiodarone (10 000 Monte Carlo simulations) were simulated in animals on ECMO VV. Results: A two-compartment model with first-order absorption and elimination was able to accurately describe amiodarone plasma concentrations. Interindividual variability was retained for clearance and central volume of distribution. Amiodarone PK parameters were influenced by the ECMO covariable. All parameters were well estimated. Goodness of fit plots comforted the accuracy of the model. Predicted-corrected visual predictive check of the final model was satisfactory. Simulated amiodarone exposure showed that amiodarone 600 mg bolus is required under VV ECMO to achieve similar AUC observed in the control group. Discussion/Conclusion: In our model of ARDS in pigs with cardiac arrest and benefiting from CPR and VV ECMO, a two-compartment model with first-order absorption and elimination was able to accurately describe amiodarone plasma concentrations. VV ECMO significantly modified both central distribution volume and amiodarone clearance. From Monte-Carlo simulation, we showed that a 2-fold increase of amiodarone doses should be considered to reach efficient drug exposure under VV ECMO.
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Background: There are no authorized or approved treatments in the US for COVID-19 in patients <12 years of age. SARS-CoV-2 neutralizing monoclonal antibodies bamlanivimab and etesevimab together (BAM+ETE) reduce COVID-19 related hospitalization and all-cause mortality in patients ≥12 years of age with mild to moderate COVID-19. Herein, we present the pharmacokinetic (PK), safety, and efficacy results from an open-label Phase III clinical trial addendum (BLAZE-1, NCT04427501) investigating weight-based dosing of BAM+ETE in pediatric patients at increased risk for severe COVID-19. Methods: A total of 91 pediatric patients (<18 years of age) were evaluated for PK. Pediatric patients weighing ≥40kg received 700mg BAM+1400mg ETE. Pediatric patients weighing less than 40kg received weight-based dosing to match the exposures observed in adults and adolescents (12 to <18 years of age) who received the authorized dose of 700mg BAM+1400mg ETE. Twenty additional adolescent patients (12 to <18 years of age) received BAM+ETE in controlled BLAZE-1 cohorts and were included in safety and efficacy analyses. All ambulatory patients had mild to moderate COVID-19 upon enrollment, at least one risk factor for severe COVID-19, and received treatment within 3 days of a positive SARS-CoV-2 test. The primary objective was to characterize the pharmacokinetics of weight-based dosing of BAM+ETE in pediatric patients. Results: Of the 111 pediatric patients who received BAM+ETE, the median age was 12 and age distribution was 12 to <18 (n=60), 6 to <12 (n=36), 2 to <6 (n=10), and 0 to <2 (n=5). Overall, 47.7% were female, 19.1% were Hispanic/Latino, and 62.4% were Black/African American. In patients receiving weight-based dosing, the AUC for both BAM and ETE in pediatric patients was similar (within 90% interval) to adults (Figure). For all pediatric patients, there were no reports of hospitalizations, serious adverse events, or deaths. At Day 7, pediatric patients had a change in viral load from baseline of-4.10 (normalized baseline viral load of 6.41) as compared to-3.65 (normalized baseline viral load of 6.75) in adult patients. The median time to complete symptom resolution was 5 days for all pediatric patients. Conclusion: The weight-based doses administered to pediatric patients provided similar drug exposures when compared to adult patients who received the authorized dose of 700 mg BAM+1400mg ETE. Treatment in pediatric patients was well-tolerated and resulted in favorable viral load reduction and symptom resolution.
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Background: HIV infection might accelerate aging process and people living with HIV (PLWH) have been observed to have a higher risk of severe COVID-19 outcomes. However, it is unclear whether the worse COVID-19 outcomes can be attributed to the accelerated aging process. This study aimed to examine: 1) the causal effect of HIV infection on severe COVID-19 outcomes;and 2) the threshold of age difference at which PLWH and non-HIV patients will have comparable COVID-19 outcomes. Methods: We identified COVID-19 positive adults between Jan 1, 2020, and Oct 18, 2021, from the U.S. National COVID Cohort Collaborative (N3C), a nationally-sampled electronic medical record repository. We identified PLWH by clinical diagnosis, drug exposure, and laboratory results. Among COVID-19 cases, PLWH were matched 1:1 to non-HIV persons using exact matching (by gender, race, and ethnicity) and propensity score matching (PSM) (by age, gender, race, ethnicity, and pre-COVID comorbidities). To determine age threshold, PLWH were matched to older non-HIV patients with an age differences between 1 to 15 years. We used conditional logistic regression for exact matched data and standard logistic regression for PSM data. Subgroup analyses stratified by CD4 counts (≥200 or CD4<200 cells/mm) were also conducted. Results: Among a total of 2,422,870 COVID-19 positive adults, we identified 15,188 PLWH. Among PLWH with CD4 data, 872 (14.03%) had CD4<200. Using exact match, PLWH had a significantly higher odds of COVID-19-associated hospitalization [OR: 1.95, 95%CI:(1.88,2.02)] or death [OR: 2.05, 95%CI:(1.90,2.22)] compared to non-HIV persons. By repeating PSM modeling with incrementally increasing ages, PLWH persistently had a higher risk of death compared to non-HIV persons until the age difference reached 6 years, while the threshold of age difference for the comparable hospitalization outcome extended to 14 years. Furthermore, when matching PLWH with CD4<200 with non-HIV persons, the threshold of age difference increased to 10 years for similar odds of mortality and at least 15 years for similar odds of hospitalization. PLWH with CD4≥200 more likely to be hospitalized, though had similar outcomes for death, than non-HIV persons. Conclusion: We find that the worse COVID-19 outcomes, among PWH may be potentially related to aging in HIV. Further investigation of the biological mechanisms at the intersections of HIV infection itself (eg, lower CD4 counts) and accelerated aging in HIV causing worse COVID-19 outcomes is needed.
ABSTRACT
Vimentin intermediate filament is involved in multiple steps of viral infection such as viral entry, trafficking and egress, as well as in various mechanisms of hyperinflammation such as the restraint of Treg cell functions and the activation of NLRP3 inflammasome. We evaluated a vimentin-binding small molecule compound ALD-R491 for its effects on cellular processes related to viral infection and for its efficacy in treating SARS-CoV2 infection in vitro and in vivo. In cultured cells, the compound could reduce endocytosis by 10%, endosomal trafficking by 40% and exosomal release by over 30%. In an infection system consisting of a lentiviral pseudotype bearing the SARS-CoV-2 spike protein and HEK293 cells over-expressing the human ACE2 receptor with multiplicity of infection (MOI) of 1, 10 and 100, the compound inhibited the infection up to a maximum of over 90%, with IC 50 < 50 nM, CC50 > 10 μM, and SI > 200. After oral administration of ALD-R491 in rats, the plasma concentration of the compound reached the peak (Tmax) at around 5 h with a half-life (T1/2) of about 5 h. The compound was widely distributed and enriched in tissues in vivo in rats with a volume of distribution (Vd) of over 2,000 ml/kg. The lung and the lymph nodes were among the tissues with high drug exposures. In rats receiving oral gavage of the compound at 30 mg/kg, the drug exposure in the lung and the lymph nodes maintained at levels over 1 μM from 1 h to 6 h after the oral dosing. In the syngeneic mouse tumor CT26 model, ALD-R491 was found to activate regulatory T cells (Tregs) in vivo and enhance de novo generation of Tregs in lymph nodes of the mice. In the Mouse-Adapted SARS-CoV2 model, aged mice (11-12 months) were used to provide a harder test of recovery from infection that reflects the severeness of COVID-19 in old patients. For therapeutic treatment, the mice were orally administered with the compound 24 h after the SARS-CoV2 infection once per day on Day 1, Day 2 and Day 4. At 10 mg/kg, ALD-R491 significantly reduced the body weight loss of the mice (p<0.01 on Day 5 post-infection). At both 3 mg/kg and 10 mg/kg, the compound significantly reduced the hemorrhagic score for the lungs (p<0.01 and p<0.05, respectively, on Day 5). These results indicate that vimentin intermediate filament is an effective host-directed antiviral target. Importantly, the vimentin-binding small molecule ALD-R491 impacts multiple aspects of SARS-CoV2 infection, has a favorable oral pharmacokinetics and a wide therapeutic window, and therefore may be a promising therapeutic candidate for treating COVID-19. Statement: Aluda Pharmaceuticals, Inc. has utilized the non-clinical and pre-clinical services program offered by the National Institute of Allergy and Infectious Diseases.