FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome

Prevention of SARS-CoV-2 entry in cells through the modulation of viral host receptors, such as ACE2, could represent a new therapeutic approach complementing vaccination. However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We demonstrate that FXR antagonists, including the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA), downregulate ACE2 levels, and reduce susceptibility to SARS-CoV-2 infection in lung, cholangiocyte and gut organoids. We then show that therapeutic levels of UDCA downregulate ACE2 in human organs perfused ex situ and reduce SARS-CoV-2 infection ex vivo. Finally, we perform a retrospective study using registry data and identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection, including hospitalisation, ICU admission and death. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that this approach could be beneficial for reducing SARS-CoV-2 infection, thereby paving the road for future clinical trials.

Human embryonic stem cell-derived cardiomyocytes express SARS-CoV-2 host entry proteins: screen to identify inhibitors of infection

Patients with cardiovascular comorbidities are more susceptible to severe infection with SARS-CoV-2, known to directly cause pathological damage to cardiovascular tissue. We outline a screening platform using human embryonic stem cell-derived cardiomyocytes, confirmed to express the protein machinery critical for SARS-CoV-2 infection, and a pseudotyped virus system. The method has allowed us to identify benztropine and DX600 as novel inhibitors of SARS-CoV-2 infection.

Implementation of the IPACK (Infiltration between the Popliteal Artery and Capsule of the Knee) block into a multimodal analgesic pathway for total knee replacement / 대한마취과학회지

BACKGROUND@#The Infiltration between the Popliteal Artery and Capsule of the Knee (IPACK) block is a new anesthesiologist- administered analgesic technique for controlling posterior knee pain that has not yet been well studied in total knee arthroplasty (TKA) patients. We compared pain outcomes in TKA patients before and after implementation of the IPACK with the hypothesis that patients receiving IPACK blocks will report lower pain scores on postoperative day (POD) 0 than non-IPACK patients.@*METHODS@#With Institutional Review Board approval, we retrospectively reviewed data for consecutive TKA patients by a single surgeon 4 months before (PRE) and after (POST) IPACK implementation. All TKA patients received adductor canal catheters and peri-operative multimodal analgesia. The primary outcome was pain on POD 0. Other outcomes were daily pain scores, opioid consumption, ambulation distance, length of stay, and adverse events within 30 days.@*RESULTS@#Post-implementation, 48/50 (96%) of TKA patients received an IPACK block, and they were compared with 32 patients in the PRE group. On POD 0, the lowest pain score (median [10th–90th percentiles]) was significantly lower for the POST group compared to the PRE group (0 [0–4.3] vs. 2.5 [0–7]; P = 0.003). The highest patient-reported pain scores on any POD were similar between groups with no differences in other outcomes.@*CONCLUSIONS@#Within a multimodal analgesic protocol, addition of IPACK blocks decreased the lowest pain scores on POD 0. Although other outcomes were unchanged, there may be a role for new opioid-sparing analgesic techniques, and changing clinical practice change can occur rapidly.

Implementation of the IPACK (Infiltration between the Popliteal Artery and Capsule of the Knee) block into a multimodal analgesic pathway for total knee replacement / 대한마취과학회지

BACKGROUND: The Infiltration between the Popliteal Artery and Capsule of the Knee (IPACK) block is a new anesthesiologist- administered analgesic technique for controlling posterior knee pain that has not yet been well studied in total knee arthroplasty (TKA) patients. We compared pain outcomes in TKA patients before and after implementation of the IPACK with the hypothesis that patients receiving IPACK blocks will report lower pain scores on postoperative day (POD) 0 than non-IPACK patients. METHODS: With Institutional Review Board approval, we retrospectively reviewed data for consecutive TKA patients by a single surgeon 4 months before (PRE) and after (POST) IPACK implementation. All TKA patients received adductor canal catheters and peri-operative multimodal analgesia. The primary outcome was pain on POD 0. Other outcomes were daily pain scores, opioid consumption, ambulation distance, length of stay, and adverse events within 30 days. RESULTS: Post-implementation, 48/50 (96%) of TKA patients received an IPACK block, and they were compared with 32 patients in the PRE group. On POD 0, the lowest pain score (median [10th–90th percentiles]) was significantly lower for the POST group compared to the PRE group (0 [0–4.3] vs. 2.5 [0–7]; P = 0.003). The highest patient-reported pain scores on any POD were similar between groups with no differences in other outcomes. CONCLUSIONS: Within a multimodal analgesic protocol, addition of IPACK blocks decreased the lowest pain scores on POD 0. Although other outcomes were unchanged, there may be a role for new opioid-sparing analgesic techniques, and changing clinical practice change can occur rapidly.