Overcoming culture restriction for SARS-CoV-2 in human cells facilitates the screening of compounds inhibiting viral replication [Antiviral Agents]

xloma.fota13 shared this article with you from Inoreader Overcoming culture restriction for SARS-CoV-2 in human cells facilitates the screening of compounds inhibiting viral replication [Antiviral Agents] Via AAC Accepts: Articles Published Ahead of Print Efforts to mitigate the COVID-19 pandemic include screening of existing antiviral molecules that could be re-purposed to treat SARS-CoV-2 infections. Although SARS-CoV-2 replicates and propagates efficiently in African green monkey kidney (Vero) cells, antivirals such as nucleos(t)ide analogs (nucs) often show decreased activity in these cells due to inefficient metabolization. SARS-CoV-2 exhibits low viability in human cells in culture. Here, serial passages of a SARS-CoV-2 isolate (original-SARS2) in the human hepatoma cell clone Huh7.5 led to the selection of a variant (adapted-SARS2) with significantly improved infectivity in human liver (Huh7 and Huh7.5) and lung cancer cells (unmodified Calu-1 and A549). The adapted virus exhibited mutations in the spike protein, including a 9 amino acid deletion and 3 amino acid changes (E484D, P812R, and Q954H). E484D also emerged in Vero E6 cultured viruses that became viable in A549 cells. Original and adapted viru ses were susceptible to SR-B1 receptor blocking and adapted-SARS2 exhibited significantly less dependency of ACE2. Both variants were similarly neutralized by COVID-19 convalescent plasma but adapted-SARS2 exhibited increased susceptibility to exogenous type I interferon. Remdesivir inhibited original- and adapted-SARS2 similarly, demonstrating the utility of the system for the screening of nucs. Among the tested nucs, only remdesivir, molnupiravir and to a limited extent galidesivir, showed antiviral effect across human cell lines, whereas sofosbuvir, ribavirin, and favipiravir had no apparent activity. Analogously to the emergence of spike mutations in vivo, the spike protein is under intense adaptive selection pressure in cell culture. Our results indicate that the emergence of spike mutations will most likely not affect the activity of remdesivir. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole [Pharmacology]

xloma.fota13 shared this article with you from Inoreader External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole [Pharmacology] Via AAC Accepts: Articles Published Ahead of Print The antibiotic combination trimethoprim (TMP)-sulfamethoxazole (SMX) has a broad spectrum of activity and it is used for the treatment of numerous infections, but pediatric pharmacokinetic (PK) data are limited. We previously published population PK (popPK) models of oral TMP-SMX in pediatric patients based on sparse opportunistically collected data (POPS study, Antimicrob Agents Chemother 62:e01813-17, 2017, https://doi.org/10.1128/AAC.01813-17). We performed a separate PK study of oral TMP-SMX in infants and children with more traditional PK sample collection, and independently developed new popPK models of TMP-SMX using this external dataset. The POPS dataset and the External dataset were each used to evaluate both popPK models. The External TMP model had identical model and error structure as the POPS TMP model with typical values for PK parameters within 20%. The External SMX model did not identify the covariates in the POPS SMX model as significant. The External popPK models predicted higher exposures of TMP (median overprediction of 0.13 mg/L for the POPS dataset and 0.061 mg/L for the External dataset) and SMX (median overprediction of 1.7 mg/L and 0.90 mg/L) than the POPS TMP (median underprediction of 0.016 mg/L and 0.39 mg/L) and SMX (median underprediction of 1.2 mg/L and 14 mg/L) models. Nonetheless, both models supported TMP-SMX dose increases in infan ts and young children for more resistant pathogens with a minimum inhibitory concentration of 1 mg/L, although the required dose increase based on the External model is lower. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Traumatic ischemic injury in a top of the basilar distribution: a case report

xloma.fota13 shared this article with you from Inoreader Traumatic ischemic injury in a top of the basilar distribution: a case report Via Latest Results for BMC Neurology Abstract Background Top of the basilar syndrome is a rare, heterogeneous disorder that has previously only been described in the setting of acute ischemic stroke in predominantly elderly patients. We present the first reported case of traumatic brain injury (TBI) causing ischemia in a top of the basilar distribution. Case presentation A 19-year-old woman suffered an acute subdural hematoma and sustained hypoxemia after being struck by a motor vehicle. Neurosurgical evacuation of the hematoma was undertaken. Magnetic resonance imaging revealed ischemic injury in the midbrain and diencephalic structures fitting a top of the basilar distribution. No associated vascular injury was identified. The patient was eventually discharged in a state of persistent unresponsive wakefulness. Conclusions Ischemia in a top of the basilar distribution may occur in the setting of TBI. A high degree of clinical suspicion is required to identify this disorder. Further study of the complex inflammatory microenvironment and associated tissue perfusion dynamics in TBI are needed in order to elucidate the mechanisms underlying ischemic injury patterns, develop management paradigms and predict prognosis. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The frequency of cytomegalovirus non-ELR UL146 genotypes in neonates with congenital CMV disease is comparable to strains in the background population

xloma.fota13 shared this article with you from Inoreader The frequency of cytomegalovirus non-ELR UL146 genotypes in neonates with congenital CMV disease is comparable to strains in the background population Via BMC Infectious Diseases - Latest Articles Congenital cytomegalovirus disease (cCMV) is common and can be fatal or cause severe sequelae. Circulating strains of cytomegalovirus carry a high number of variable or disrupted genes. One of these is UL146, ... View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Episodic headache with spontaneous hypothermia reveal Shapiro’s syndrome variant with effectiveness of clonidine therapy

xloma.fota13 shared this article with you from Inoreader Episodic headache with spontaneous hypothermia reveal Shapiro's syndrome variant with effectiveness of clonidine therapy Via The Journal of Headache and Pain - Latest Articles Episodic headache with spontaneous hypothermia constitute an uncommon association and is not well recognized in the International Classification of Headache Disorders (ICHD-3). Spontaneous periodic hypothermia... View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cancers, Vol. 13, Pages 2100: BLBP Is Both a Marker for Poor Prognosis and a Potential Therapeutic Target in Paediatric Ependymoma

xloma.fota13 shared this article with you from Inoreader Cancers, Vol. 13, Pages 2100: BLBP Is Both a Marker for Poor Prognosis and a Potential Therapeutic Target in Paediatric Ependymoma Via Cancers Cancers, Vol. 13, Pages 2100: BLBP Is Both a Marker for Poor Prognosis and a Potential Therapeutic Target in Paediatric Ependymoma Cancers doi: 10.3390/cancers13092100 Authors: Durgagauri H. Sabnis Jo-Fen Liu Lucy Simmonds Sophie Blackburn Richard G. Grundy Ian D. Kerr Beth Coyle Paediatric ependymomas are aggressive, treatment-resistant tumours with a tendency towards relapse, consistent with a sub-population of therapy-resistant cancer stem cells. These cells are believed to derive from brain lipid binding protein (BLBP)-expressing radial glia, hence we proposed that BLBP may be a marker for ependymoma therapy resistance. BLBP protein expression correlated with reduced overall survival (OS) in patients from two trials (CNS9204, a chemotherapy-led infant trial—5 y OS 45% vs. 80%, p = 0.011—and CNS9904, a radiotherapy-led trial—OS 38% vs. 85%, p = 0.002). All ependymoma cell lines examined by qRT-PCR expressed BLBP, with expression elevated in stem cell-enriched neurospheres. Modulation of BLBP function in 2D and 3D assays, using either peroxisome proliferator activated receptor (PPAR) antagonists or BLBP's fatty acid substrate docosahexaneoic acid (DHA), potentiated chemotherapy response and reduced cell migration and invasion in ependymoma cell lines. BLBP is therefore an independent predictor of poor survival in paediatric ependymoma, and treatment with PPAR antagonists or DHA may represent effective novel therapies, preventing chemotherapy resistance and invasion in paediatric ependymoma patients. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cancers, Vol. 13, Pages 2099: De-Escalation of Therapy for Patients with Early-Stage Squamous Cell Carcinoma of the Anus

xloma.fota13 shared this article with you from Inoreader Cancers, Vol. 13, Pages 2099: De-Escalation of Therapy for Patients with Early-Stage Squamous Cell Carcinoma of the Anus Via Cancers Cancers, Vol. 13, Pages 2099: De-Escalation of Therapy for Patients with Early-Stage Squamous Cell Carcinoma of the Anus Cancers doi: 10.3390/cancers13092099 Authors: Eric Miller Jose Bazan The incidence of squamous cell carcinoma of the anus (SCCA) is increasing, particularly in the elderly, with increased mortality in this age group. While the current standard of care for localized SCCA remains chemoradiation (CRT), completion of this treatment can be challenging with risks for severe acute and late toxicity. It remains unclear if full course CRT is required for the management of early-stage SCCA or if de-escalation of treatment is possible without compromising patient outcomes. Alternative therapies include radiation therapy alone or local excision for appropriate patients. Modifying standard CRT may also reduce toxicity including the routine use of intensity-modulated radiation therapy for treatment delivery, modification of treatment volumes, and selection and dosing of concurrent systemic therapy agents. Finally, we provide an overview of currently accruing prospective trials focused on defining the role of de-escalation of therapy in patients with early-stage SCCA. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.