Evaluation and in vivo efficacy study of pyrano[3,2‐c]quinoline analogues as TNF‐α inhibitors

A series of pyrano[3,2 c]quinoline was evaluated for its in vivo efficacy as TNF‐α inhibitor using LPS, phosphodiesterase (PDE)‐4, and CIA assays in different mice/rat models. The synthesis was performed using one‐pot multicomponent condensation between 2,4‐dihydroxy‐1‐methylquinoline, malononitrile, and diverse un(substituted) aromatic aldehydes. In vivo efficacy of the title compounds was evaluated using LPS assay in BALB/c mice, PDE4 inhibition in ketamine–xylazine‐induced anesthetize SD rats, and CIA assay was performed in DBA/1J mice as per the standard literature protocols. The outcome of the study revealed that compound 4v was found to be most promising candidate of the series. It was efficacious with 48.8 ± 13.0% inhibition of TNF‐α release at 100 mg/kg p.o., in the LPS assay in Balb/c mice model. It was effective in PDE4 assay in ketamine–xylazine‐induced anesthetize SD rats with duration of 38.3 ± 4.5 min for reversal of anesthetic effect and also showed significant inhibition of PDE4 in salbutamol treated U937 cell assay. It was also abolished TNF‐α induced phosphorylation and degradation of IκBα. Ultimately, its effect on CIA‐related bone and cartilage damage was found statistically similar to Enbrel.     

Hello,can you hear me? Orthopaedic clinic telephone consultations in the COVID-19 era- a patient and clinician perspective

BACKGROUNDThe coronavirus disease 2019 (COVID-19) pandemic has resulted in seismic changes in healthcare delivery. As a result of this, hospital footfall required to be reduced due to increased risk of transmission of infection. To ensure patients can safely access healthcare, we introduced orthopaedic clinic telephone consultations in our busy district general hospital.AIMTo investigate patients’ and clinicians’ perspective of telephone consultations during COVID-19, and whether this method of consultation could be a viable option in the post- pandemic future. METHODSThis is a single centre, prospective study conducted in a busy National Health Service district general hospital. In May 2020, 100 non- consecutive adult patients were contacted by independent investigators within 48 h of their orthopaedic clinic telephone consultation to complete a telephone satisfaction questionnaire. The questions assessed satisfaction regarding various aspects of the consultation including overall satisfaction and willingness to use this approach long term. Satisfaction and perspective of 25 clinicians conducting these telephone consultations was also assessed via an online survey tool.RESULTS93% of patients were overall satisfied with telephone consultations and 79% were willing to continue this method of consultation post- pandemic. Patients found telephone consultations to reduce personal cost and inconvenience associated with attending a hospital appointment. 72% of clinicians reported overall satisfaction with this service and 80% agreed that telephone consultations should be used in the future. The majority found it less laborious in time and administration in comparison to face to face consultations. Patients and clinicians expressed their desire for video consultations as a method of further improving their experience with remote consultations.CONCLUSIONOur study has shown that telephone consultations are a safe and rapid method of adaptation to the COVID-19 pandemic, achieving the aim of reducing hospital footfall. This method of consultation has resulted in immense clinician and patient satisfaction. Our findings suggest that this tool has benefits in post pandemic healthcare delivery. It has also highlighted that telephone consultations can act as a steppingstone to the introduction of the more complex platform of video consulting.     

Therapeutic plasma exchange in the management of sepsis and multiple organ dysfunction syndrome: A report of three cases

Sepsis with multi organ dysfunction syndrome (MODS) is the most common cause of death in patients in noncoronary intensive care units. Currently, there are no specific treatments that reduce mortality in patients with sepsis and MODS. We report three patients who received therapeutic plasma exchange (TPE) for sepsis with MODS who completely recovered. The first patient, a 3‐year‐old male presented with Methicillin‐resistant Staphylococcus aureus‐associated respiratory, renal, coagulation, hepatic, and neurologic dysfunction. After 5 TPEs, the patient fully recovered. The second patient was a 36‐year‐old pregnant female who developed MODS at 22 weeks of gestation. She had developed respiratory, hepatic, renal, cardiovascular, neurologic, and coagulation dysfunction following pneumonia and concurrent urinary tract infection resulting in an intrauterine fetal demise. After 8 TPEs, the patient was discharged home with only mild residual hepatic dysfunction. The third patient, a 50‐year‐old female with a history of seizure disorder, was found unresponsive in over 100°F heat and diagnosed with Staphylococcus aureus‐associated MODS. Her respiratory, coagulation, neurologic, renal, and hepatic systems were affected. The patient underwent 6 TPEs after which she had marked improvement. In conclusion, TPE may be an effective adjunct therapy in MODS by possibly removing toxic mediators and replacing deficient factors using donor plasma. J. Clin. Apheresis 29:127–131, 2014. © 2013 Wiley Periodicals, Inc.     

Screening for Inhibition of Vibrio cholerae VipA-VipB Interaction Identifies Small-Molecule Compounds Active against Type VI Secretion

The type VI secretion system (T6SS) is the most prevalent bacterial secretion system and an important virulence mechanism utilized by Gram-negative bacteria, either to target eukaryotic cells or to combat other microbes. The components show much variability, but some appear essential for the function, and two homologues, denoted VipA and VipB in Vibrio cholerae, have been identified in all T6SSs described so far. Secretion is dependent on binding of an α-helical region of VipA to VipB, and in the absence of this binding, both components are degraded within minutes and secretion is ceased. The aim of the study was to investigate if this interaction could be blocked, and we hypothesized that such inhibition would lead to abrogation of T6S. A library of 9,600 small-molecule compounds was screened for their ability to block the binding of VipA-VipB in a bacterial two-hybrid system (B2H). After excluding compounds that showed cytotoxicity toward eukaryotic cells, that inhibited growth of Vibrio, or that inhibited an unrelated B2H interaction, 34 compounds were further investigated for effects on the T6SS-dependent secretion of hemolysin-coregulated protein (Hcp) or of phospholipase A₁ activity. Two compounds, KS100 and KS200, showed intermediate or strong effects in both assays. Analogues were obtained, and compounds with potent inhibitory effects in the assays and desirable physicochemical properties as predicted by in silico analysis were identified. Since the compounds specifically target a virulence mechanism without affecting bacterial replication, they have the potential to mitigate the virulence with minimal risk for development of resistance.     

Impact of COVID-19 on U.S. and Canadian neurologists’ therapeutic approach to multiple sclerosis: a survey of knowledge,attitudes, and practices

Journal of Neurology - To report the understanding and decision-making of neuroimmunologists and their treatment of patients with multiple sclerosis (MS) during the early stages of the SARS-CoV-2...     

A Survey of Practices in the United States Regarding Hepatitis C Screening in Pregnant Women

PurposeHepatitis C virus (HCV) cases have increased in the past decade, with many cases in pregnant patients. However, recommendations for HCV screening during pregnancy vary by professional organization.MethodsPrenatal care providers were surveyed via e-mail about factors affecting choice of HCV screening.FindingsA total of 86 completed surveys were received. Providers using risk-based screening valued guidance from obstetrics and gynecology societies and risk for vertical transmission. Providers using universal screening valued availability of curative treatment in addition to guidance from the Centers for Disease Control and Prevention/infectious diseases societies and obstetrics and gynecology societies.ImplicationsThe results highlight the need for consensus guidelines on HCV screening as a part of prenatal care.