Impact of COVID-19 on the management of ureteric stones in the UK: the COVID Stones study

Introduction: In the COVIDStones study, we aimed to determine how management of ureteric stones changed during the COVID-19 pandemic in the United Kingdom. Materials and Methods: The COVID Stones study was a multi-centre retrospective study of consecutive adults diagnosed with CT-proven ureteric stone disease at 19 UK sites. We compared a pre-pandemic period (23/3/19 to 22/6/19) to a period during the pandemic (the 3-month period after the first SARS-CoV-2 case at individual sites). Results: 3755 patients were included (pre-pandemic = 1963 patients;pandemic = 1792 patients). Patients during the pandemic had significantly lower hospital admission rates (pre-pandemic = 54.2% vs pandemic = 46.6%, p<0.001), shorter length of stay (mean = 4.0 vs. 3.2 days, p=0.01), and higher rates of use of alpha-blockers (16.1% vs. 23.3%, p<0.001). In the cohort of patients who received interventional management (n=790 [44.1%] vs. n=686 [34.9%]), rates of ESWL (22.8% vs. 33.9%, p<0.001) were significantly higher;rates of ureteroscopy (56.7% vs. 47.7%, p<0.01) and stent insertion (67.9% vs. 54.5%, p>0.001) were lower;and there was no difference in rates of nephrostomy (p=0.76) during the pandemic. During the pandemic, there was no difference in success of primary treatment overall, including both non-interventional and interventional modalities (prepandemic= 73.8% vs. pandemic=76.2%, p=0.467), nor when stratified by treatment modality or stone size. Conclusions: Despite fewer invasive procedures performed during the pandemic, we demonstrated no difference in success of treatment, without an increase in adverse outcomes. This leads us to question whether the management of ureteric stones can be optimised further.

Efficacy and safety of the EMS Swiss LithoClast® Trilogy for PCNL: results of the European multicentre prospective study on behalf of European Section of UroTechnology.

PURPOSE: PCNL requires a lithotrite to efficiently break stones, and some devices include active suction to remove the fragments. We set out to determine the efficacy and safety of the Swiss LithoClast® Trilogy, in a prospective European multicentre evaluation and compared it to published stone clearance rates for Trilogy based on surface area (68.9 mm2/min) and using the 3D calculated stone volume (526.7 mm3/min). METHODS: Ten European centres participated in this prospective non-randomized study of Trilogy for PCNL. Objective measures of stone clearance rate, device malfunction, complications and stone-free rates were assessed. Each surgeon subjectively evaluated ergonomic and device effectiveness, on a 1-10 scale (10 = extremely ergonomic/effective) and compared to their usual lithotrite on a 1-10 scale (10 = extremely effective). RESULTS: One hundred and fifty seven PCNLs using Trilogy were included (53% male, 47% female; mean age 55 years, range 13-84 years). Mean stone clearance rate was 65.55 mm2/min or 945 mm3/min based on calculated 3D volume. Stone-free rate on fluoroscopy screening at the end of the procedure was 83%. Feedback for suction effectiveness was 9.0 with 9.1 for combination and 9.0 for overall effectiveness compared to lithotrite used previously. Ergonomic score was 8.1, the least satisfactory element. Complications included 13 (8.2%) Clavien-Dindo Grade II and 2 (1.3%) Grade III. Probe breakage was seen in 9 (5.7%), none required using a different lithotrite. CONCLUSIONS: We have demonstrated that Trilogy is highly effective at stone removal. From a user perspective, the device was perceived by surgeons to be highly effective overall and compared to the most commonly used previous lithotrite, with an excellent safety profile.

Fxr as a new therapeutic target for COVID-19

Background: Despite recent advances, the management of COVID19 is complicated by vaccine availability, the modest efficacy of existing treatments, and the potential for viral resistance. Therefore, there is a pressing need for new prophylactic and therapeutic agents. Modifying the expression of the SARS-CoV-2 entry receptor ACE2 could prevent viral infection and limit disease progression. Here, we identify that ACE2 expression is controlled by the transcription factor farnesoid X receptor (FXR) and demonstrate that ACE2 downregulation through FXR antagonism, using approved drugs, such as ursodeoxycholic acid (UDCA), could represent a novel therapeutic strategy to complement current approaches. Methods: Primary cholangiocyte, pulmonary and intestinal organoids were propagated using established protocols. Marker expression was assessed using singlecell RNA sequencing, QPCR, immunofluorescence and flow cytometry. FXR binding on DNA was assessed with chromatin immunoprecipitation. SARS-CoV-2 was isolated from bronchoalveolar lavage of a COVID19 patient. Viral load was measured via QPCR. Human livers not used for transplantation were perfused ex-situ using the metra (OrganOx) normothermic perfusion device. Serum ACE2 activity was measured with commercial kits. Patient data from the COVID-Hep and SECURE-Liver registries were compared using propensity score matching. Results: FXR activation directly upregulated ACE2 transcription in organoids from COVID19 affected tissues, including the biliary, gastrointestinal and respiratory systems. Conversely, FXR antagonism with z-guggulsterone or UDCA, had the opposite effect. Importantly, both drugs reduced susceptibility to SARS-CoV-2 infection in lung, cholangiocyte and gut organoids. Furthermore, systemic administration of UDCA in human organs perfused ex-situ downregulated ACE2 and reduced SARS-CoV-2 infection ex-vivo. Oral UDCA rapidly reduced serum ACE2 in vivo. Registry data showed a correlation between UDCA administration and better clinical outcomes in COVID19 patients, including hospitalisation, ICU admission, mechanical ventilation and death. Conclusion: We discovered FXR as a novel therapeutic target against SARS-CoV-2 and we identified approved FXR inhibitors which could be repurposed to potentially treat COVID19, paving the road for future clinical trials to validate these results.

Fxr antagonists as new agents for COVID19

Introduction The management of COVID19 is complicated by vaccine availability, the modest efficacy of existing treatments, and the potential for viral resistance. Therefore, there is a pressing need for new prophylactic and therapeutic agents. The viral receptor ACE2 is an ideal target as it is required for SARS-CoV-2 entry in host cells. Modifying ACE2 expression could prevent infection and/or limit disease progression. Nevertheless, the mechanisms controlling ACE2 expression remain elusive. Aims To identify pathways controlling the transcriptional regulation of ACE2, and exploit them to reduce SARS-CoV-2 infection. Methods Organoids from primary biliary, intestinal and pulmonary epithelia were derived and cultured as previously described. Single-cell RNA sequencing, QPCR, immunofluorescence and flow cytometry were used to assess marker expression. Chromatin immunoprecipitation was used to assess FXR binding on DNA. Bronchoalveolar lavage SARS-CoV-2 patient isolates were used for infection experiments. Human livers not used for transplantation were connected to the metra (OrganOx) normothermic perfusion device and perfused ex-situ using therapeutic doses of UDCA for 12 hours. ACE2 activity was measured following manufacturer's instructions. Patient data from the COVID-Hep and SECURE-Liver registries were compared using propensity score matching for sex, age and Child-Turcotte-Pugh score. Results We first demonstrated that cholangiocytes are susceptible to SARS-CoV-2 infection in vivo and in organoid culture. We then used cholangiocyte organoids to identify FXR as a transcriptional regulator of ACE2. We validated our results in pulmonary and intestinal organoids, showing that ACE2 regulation by FXR represents a broad mechanism present in multiple COVID19-affected tissues. We then demonstrated that approved FXR inhibitors, such as ursodeoxycholic acid (UDCA) and z-guggulsterone (ZGG), decrease ACE2 levels and reduce viral infection in vitro in primary biliary, intestinal and pulmonary organoids. We interrogated the impact of systemic UDCA administration in human livers perfused ex-situ, demonstrating reduced ACE2 levels and SARS-CoV-2 infection. Furthermore, we showed that commencing UDCA treatment lowers ACE2 levels in primary biliary cholangitis (PBC) patients. Finally, we identified a correlation between UDCA treatment and better clinical outcome in COVID-19 patients, including hospitalisation, ICU admission, mechanical ventilation and death, using registry data. Conclusion We identified FXR as a novel master regulator of ACE2 expression. Using a bench-to-bedside approach we combined in vitro, ex-vivo and patient data to demonstrate the efficacy of ACE2 downregulation against SARS-CoV-2 infection and identified approved and inexpensive drugs (UDCA, ZGG) which could be repurposed as prophylactic and therapeutic agents against SARS-CoV-2 infection, paving the road for future clinical trials.

The COVID stones collaborative: How has the management of ureteric stones changed during and after the COVID-19 pandemic? Rationale and study protocol

Background and objectives The coronavirus disease 2019 (COVID-19) pandemic is having a significant impact on healthcare delivery. As a result, management of patients with ureteric stones has likely been affected. We report our study protocol for the investigation of ureteric stone management during and after the COVID-19 pandemic. Material and methods The COVID Stones study is a multicenter national cohort study of the management and outcomes of patients with ureteric stones before, during, and after the COVID-19 pandemic in the United Kingdom. The study will consist of three data collection periods, pre-pandemic (“pre-COVID”), pandemic (“COVID”), and postpandemic (“post-COVID”). This will allow quantification of what “normal” was, how this has changed, and to capture any persisting changes in management. The primary outcome evaluating the success rate of the initial treatment decision will be assessed following a 6-month follow-up from the time of first presentation and will be performed for each recruited patient from each of the three data collection periods. This will allow comparison between both management and outcomes before, during, and after the pandemic. Conclusions We anticipate that this study will lead to an increased understanding of the impact of the outcomes of emergency management of ureteric stones following changes in clinical practice due to the COVID-19 pandemic health provision restrictions.