Treatment of chronic or relapsing COVID-19 in immunodeficiency

BACKGROUND: Patients with some types of immunodeficiency can suffer chronic or relapsing infection with SARS-CoV-2. This leads to morbidity and mortality, infection control challenges and the risk of evolution of novel viral variants. Optimal treatment for chronic COVID-19 is unknown. OBJECTIVE: To characterise a cohort of patients with chronic or relapsing COVID-19 disease and to record treatment response. METHODS: We conducted a UK physician survey to collect data on underlying diagnosis and demographics, clinical features and treatment response of immune deficient patients with chronic (at least 21 days) or relapsing (at least two episodes) of COVID-19. RESULTS: We identified 31 cases with a median age of 49 years. Underlying immune deficiency was characterised by antibody deficiency with absent or profoundly reduced peripheral B cells; prior anti-CD20 therapy and X-linked agammaglobulinemia were most common. Clinical features of COVID-19 were similar to the general population, but the median duration of symptomatic disease was 64 days (maximum 300 days) and individual patients experienced up to five episodes of illness. Remdesivir monotherapy (including when given for prolonged courses up to 20 days) was associated with sustained viral clearance in 7/23 (30.4%) clinical episodes whereas the combination of remdesivir with convalescent plasma or anti-SARS-CoV-2 monoclonal antibodies resulted in viral clearance in 13/14 (92.8%) episodes. Patients receiving no therapy did not clear SARS-CoV-2. CONCLUSIONS: COVID-19 can present as a chronic or relapsing disease in patients with antibody deficiency. Remdesivir monotherapy is frequently associated with treatment failure, but the combination of remdesivir with antibody-based therapeutics holds promise

Cross-platform expression profiling demonstrates that SV40 small tumor antigen activates Notch, Hedgehog, and Wnt signaling in human cells

BACKGROUND: We previously analyzed human embryonic kidney (HEK) cell lines for the effects that simian virus 40 (SV40) small tumor antigen (ST) has on gene expression using Affymetrix U133 GeneChips. To cross-validate and extend our initial findings, we sought to compare the expression profiles of these cell lines using an alternative microarray platform. METHODS: We have analyzed matched cell lines with and without expression of SV40 ST using an Applied Biosystems (AB) microarray platform that uses single 60-mer oligonucleotides and single-color quantitative chemiluminescence for detection. RESULTS: While we were able to previously identify only 456 genes affected by ST with the Affymetrix platform, we identified 1927 individual genes with the AB platform. Additional technical replicates increased the number of identified genes to 3478 genes and confirmed the changes in 278 (61%) of our original set of 456 genes. Among the 3200 genes newly identified as affected by SV40 ST, we confirmed 20 by QRTPCR including several components of the Wnt, Notch, and Hedgehog signaling pathways, consistent with SV40 ST activation of these developmental pathways. While inhibitors of Notch activation had no effect on cell survival, cyclopamine had a potent killing effect on cells expressing SV40 ST. CONCLUSIONS: These data show that SV40 ST expression alters cell survival pathways to sensitize cells to the killing effect of Hedgehog pathway inhibitors

Rivastigmine: the advantages of dual inhibition of acetylcholinesterase and butyrylcholinesterase and its role in subcortical vascular dementia and Parkinson’s disease dementia

Nagaendran Kandiah,1,2 Ming-Chyi Pai,3,4 Vorapun Senanarong,5 Irene Looi,6,7 Encarnita Ampil,8 Kyung Won Park,9 Ananda Krishna Karanam,10 Stephen Christopher11 1Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, 2Duke-NUS, Graduate Medical School, Singapore; 3Division of Behavioral Neurology, Department of Neurology, 4Alzheimer’s Disease Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 5Division of Neurology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 6Clinical Research Centre, 7Department of Medicine, Hospital Seberang Jaya, Penang, Malaysia; 8Department of Neurology and Psychiatry, Faculty of Medicine and Surgery, University of Santo Tomas, Manila, Philippines; 9Department of Neurology and Cognitive Disorders and Dementia Center, Institute of Convergence Bio-Health, Dong-A University College of Medicine, Busan, Republic of Korea; 10Novartis Healthcare Private Limited, Hyderabad, India; 11Novartis (Singapore) Pte. Ltd., Singapore Abstract: Several studies have demonstrated clinical benefits of sustained cholinesterase inhibition with rivastigmine in Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD). Unlike donepezil and galantamine that selectively inhibit acetylcholinesterase (AChE; EC 3.1.1.7), rivastigmine is a unique cholinesterase inhibitor with both AChE and butyrylcholinesterase (BuChE; EC 3.1.1.8) inhibitory activity. Rivastigmine is also available as transdermal patch that has been approved by the US Food and Drug Administration for the treatment of mild, moderate, and severe AD as well as mild-to-moderate PDD. In this review, we explore the role of BuChE inhibition in addition to AChE inhibition with rivastigmine in the outcomes of cognition, global function, behavioral symptoms, and activities of daily living. Additionally, we review the evidence supporting the use of dual AChE-BuChE inhibitory activity of rivastigmine as a therapeutic strategy in the treatment of neurological disorders, with a focus on the role of rivastigmine in subcortical dementias such as vascular dementia (VaD) and PDD. Toward this objective, we performed a literature search in PubMed and Ovid with limits to articles published in the English language before June 2016. The available evidence from the literature suggests that the dual inhibition of AChE and BuChE may afford additional therapeutic potential of rivastigmine in subcortical dementias (subcortical VaD and PDD) with benefits on cognition and behavioral symptoms. Rivastigmine was found to specifically benefit executive dysfunction frequently observed in subcortical dementias; however, large randomized clinical studies are warranted to support these observations. Keywords: acetylcholinesterase, BuChE genotype, butyrylcholinesterase, Parkinson’s disease dementia, rivastigmine, subcortical vascular dementi

Treatment of chronic or relapsing COVID-19 in immunodeficiency

BACKGROUND: Patients with some types of immunodeficiency can suffer chronic or relapsing infection with SARS-CoV-2. This leads to morbidity and mortality, infection control challenges and the risk of evolution of novel viral variants. Optimal treatment for chronic COVID-19 is unknown. OBJECTIVE: To characterise a cohort of patients with chronic or relapsing COVID-19 disease and to record treatment response. METHODS: We conducted a UK physician survey to collect data on underlying diagnosis and demographics, clinical features and treatment response of immune deficient patients with chronic (at least 21 days) or relapsing (at least two episodes) of COVID-19. RESULTS: We identified 31 cases with a median age of 49 years. Underlying immune deficiency was characterised by antibody deficiency with absent or profoundly reduced peripheral B cells; prior anti-CD20 therapy and X-linked agammaglobulinemia were most common. Clinical features of COVID-19 were similar to the general population, but the median duration of symptomatic disease was 64 days (maximum 300 days) and individual patients experienced up to five episodes of illness. Remdesivir monotherapy (including when given for prolonged courses up to 20 days) was associated with sustained viral clearance in 7/23 (30.4%) clinical episodes whereas the combination of remdesivir with convalescent plasma or anti-SARS-CoV-2 monoclonal antibodies resulted in viral clearance in 13/14 (92.8%) episodes. Patients receiving no therapy did not clear SARS-CoV-2. CONCLUSIONS: COVID-19 can present as a chronic or relapsing disease in patients with antibody deficiency. Remdesivir monotherapy is frequently associated with treatment failure, but the combination of remdesivir with antibody-based therapeutics holds promise

Efficacy and safety of Bimagrumab in sporadic inclusion body myositis : long-term extension of RESILIENT

ObjectiveTo assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM).MethodsParticipants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety.ResultsBetween November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had >= 1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [ n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively).ConclusionExtended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint.Classification of EvidenceThis study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, welltolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.Neurological Motor Disorder