Intermediate Results of the Research for Percutaneous and Surgical Treatment for Left Anterior Descending Artery Chronic Total Occlusion

Objective: Is to find out which revascularization methods have less of risk factors and complications after the surgery and long-term period. Method(s): From January 2018 to December 2019 were operated 134 patients with LAD CTO. 48 of them underwent MIDCAB: 36 (75%) males and 12 (25%) females;aged 58.7 +/-8.7;7 (14.6%) with previous diabetes;10 (20.8%) with previous PCI of LAD with drug-eluting stent. In the PCI group there were 86 patients: 52 (60.5%) males and 34 (39.5%) females;aged 64.8 +/-8.3;23 (26.7%) with previous diabetes. Result(s): Hospital mortality was 0 (0%) in MIDCAB unlike 1 (1.2%) in PCI. Myocardial infarction was 0 (0%) in both the groups. In MIDCAB the number of conversions to onpump and sternotomy was 0 (0%), there were 6 (12.5%) pleuritis with pleural puncture and 3 (6.2%) with long wound-aches. The hospitalization period was 10.7+/-2.9 days for MIDCAB and 9.9 +/-3.9 days for PCI. In the PCI group 2.0 +/-1.0 drug-eluting stents were used. In-hospital costs were higher for PCI 3809 unlike 3258 for MIDCAB. After one year in MIDCAB group died 2 (4.2%) patients, from noncardiac causes. In PCI group died 3 (3.5%) patients, all from cardiac causes. Because of pandemic COVID-19 were checked only 48 patients by angiography and general clinical examination: 25 after MIDCAB and 23 after PCI. 5 patients have a graft failure, caused by surgical mistakes. 4 patients have stents restenosis and 1 has LAD's reocclusion. Conclusion(s): Both methods of revascularization for LAD CTO are demonstrated similar results. EuroSCORE II (P = 0.008) and glomerular filtrating rate (P = 0.004) are significant potential risk factors for mortality in both groups, age is potential risk factor for graft failure (P = 0.05). Dyslipidemia is significant risk factor for LAD restenosis in PCI group (P = 0.02). MIDCAB is associated with lower incidence of revascularization repeat and in-hospital mortality in the literature data and it costs lower than PCI for LAD CTO as our study has shown.

Re-vaccination against SARS-COV2 in allogeneic HSCT patients: Repeated primary vaccines doses increases seroconversion rates

Patients undergoing treatment for haematological malignancies have been shown to have reduced antibody responses to vaccination against SARS-COV2. This is particularly important in patients who have undergone allogeneic haemopoietic stem cell transplantation (HSCT), in whom there is limited data about vaccine efficacy. In this retrospective single-centre analysis, we present data on serologic responses following one, two, three or four doses of either Pfizer-BioNTech (PB), AstraZeneca (AZ) or Moderna (MU) SARS-CoV- 2 vaccines from a series of 75 patients who have undergone allogeneic HSCT within 2 years from the time they were revaccinated. The seroconversion rates following post-HSCT vaccination were found to be 50.7%, 78%, 79% and 83% following the first, second, third and fourth primary post -HSCT vaccine doses, respectively. The median time from allograft to first revaccination was 145 days (range 79-700). Our findings suggest that failure to respond to the first SARS-CoV- 2 vaccine post-HSCT was associated with the presence of acute GVHD (p = 0.042) and treatment with rituximab within 12 months of vaccination (p = 0.019). A statistical trend was observed with the presence of chronic GVHD and failure to seroconvert following the second (p = 0.07) and third (p = 0.09) post-HSCT vaccine doses. Patients who had received one or more SARS-CoV- 2 vaccines prior to having an allogeneic stem cell transplant were more likely to demonstrate a positive antibody response following the first dose of revaccination against Sars-CoV- 2 (p = 0.019) and retained this seropositivity following subsequent doses. The incidence of confirmed COVID-19 diagnosis among this cohort at the time of analysis was 16%. 17% of these were hospitalised and there was one recorded death (8%) secondary to COVID-19 in a patient who was 15.7 months post allogeneic transplant. In summary, this study suggests that despite the initial low seroconversion rates observed postallogeneic transplant, increasing levels of antibody response are seen post the second primary vaccine dose. In addition, there seems to be lower risk of mortality secondary to COVID-19 in this vaccinated population, compared to what was reported in the earlier phases of the pandemic prior to use of SARS-COV2 vaccination. This adds support to the widely adopted policy of early full revaccination with repeat of primary vaccine doses and boosters post-HSCT to reduce mortality in this population. Finally, we have identified rituximab use and active GVHD as potential risk factors influencing serological responses to SARS-COV2 vaccination and further work should focus on further characterising this risk and optimum dosing schedule both pre-and post-transplant.

Use of metolazone as an adjunct therapy to loop diuretics in diuretic resistant acute decompensation of heart failure: A systematic review and meta-analysis: Metolazone in diuretic resistant AHF: A Meta-Analysis

Introduction: Loop diuretics are the first-line treatment for volume overload in acute decompensation of congestive heart failure (AHF). Loop diuretic resistance is common due to pharmacologic tachyphylaxis. Therefore, thiazide and thiazide-like diuretics are often used as add-on therapy to combine two different pharmacologic mechanisms. This systemic review and meta-analysis aimed to synthesize the current evidence on the efficacy and safety of metolazone and other thiazide-like diuretics in AHF. Method(s): PRISMA guidelines were followed in conducting this systematic review. PubMed, Scopus, PubMed Central, and Embase databases were searched using relevant keywords for studies published before 5 Jan 2022. and title screening was performed, followed by full-text screening using the Covidence software. Data were extracted, and analysis was done using Cochrane Review Manager (RevMan v5.1). The results were reported in odds ratio and mean difference with 95% confidence intervals. Result(s): Out of 2999 studies identified by database search, eight studies met the inclusion criteria (2 RCTs and 6 cohort studies). Pooled analysis using a random-effects model showed no difference in mean difference among the metolazone group and control group for 24 hours total urine output (MD 69.32, 95% CI -638.29 to 776.94;n = 551;I2 = 84%), change in urine output in 24 hours (MD -284.09, 95% CI -583.99 to 15.81;n = 345;I2 = 0%), 48 hours total urine output (MD -465.62, 95% CI -1302.22 to 370.99;n = 242;I2 = 0%) and urine output at 72 hours (MD -13.24, 95% CI -90.88 to 64.40;n = 205;I2 = 0%). However, studies with furosemide only in the comparator arm, 24 hours of total urine outcome favored metolazone (MD 692.70, 95% CI 386.59 to 998.82;n = 334;I2 = 0%). There was no difference between the two groups in the rate of adverse events, loss of weight, mortality, or readmission rates. Conclusion(s): Metolazone therapy in diuretic resistant AHF may improves urine output and facilitates achieving a net negative balance. Thus, metolazone and thiazide-like diuretics can be used as add-on therapy in acute decompensation of heart failure, especially in diuretic resistance.Copyright © 2023 The Author(s)

Oncolytic virus TG6002 safety and activity after intrahepatic artery administration in patients with liverdominant metastatic colorectal cancer

The TG6002.03 trial is a dose-escalation phase 1 clinical trial of TG6002 infusion via the hepatic artery in patients with liver-dominant colorectal cancer metastases. TG6002 is an engineered Copenhagen strain oncolytic Vaccinia virus, deleted of thymidine kinase and ribonucleotide reductase to enhance tumor selective viral replication and expressing FCU1, an enzyme converting the non-cytotoxic prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). In this trial, patients with advanced unresectable liver-dominant metastatic colorectal cancer who had failed previous oxaliplatin and irinotecan-based chemotherapy were treated with up to 2 cycles of TG6002 infusion 6 weeks apart via the hepatic artery on day 1 combined with oral 5-FC on days 5 to 14 (where day 1 = TG6002 infusion). TG6002 infusion was performed over 30 minutes via selective catheterization of the hepatic artery proper. 5-FC oral dosing was 50mg/kg x4 daily. Blood was sampled for TG6002 pharmacokinetics and 5-FC and 5-FU measurements. Sampling of liver metastases was performed at screening and on day 4 or day 8 for virus detection and 5-FC and 5-FU quantification. In total, 15 patients (median age 61 years, range 37-78) were treated in 1 UK centre and 2 centres in France and received a dose of TG6002 of 1 x 106 (n=3), 1 x 107 (n=3), 1 x 108 (n=3), or 1 x 109 pfu (n=6). Fourteen of the 15 patients received a single cycle of treatment, including one patient who did not received 5-FC, and one patient received two cycles. TG6002 was transiently detected in plasma following administration, suggesting a strong tissue selectivity for viral replication. In the highest dose cohort, a virus rebound was observed on day 8, concordant with replication time of the virus. In serum samples, 5-FU was present on day 8 in all patients with a high variability ranging from 0.8 to 1072 ng/mL and was measurable over several days after initiation of therapy. Seven of the 9 patients evaluable showed the biodistribution of the virus in liver lesions by PCR testing on day 4 or day 8. Translational blood samples showed evidence for T-cell activation and immune checkpoint receptor-ligand expression. At 1 x 109 pfu, there was evidence for T-cell proliferation and activation against tumour-associated antigens by ELISpot and for immunogenic cell death. In terms of safety, a total of 34 TG6002-related adverse events were reported, of which 32 were grade 1-2 and 2 were grade 3. The maximum tolerated dose was not reached, and a single dose-limiting toxicity was observed consisting of a myocardial infarction in a context of recent Covid-19 infection in a 78-year-old patient. These results indicate that TG6002 infused via the hepatic artery in combination with oral 5-FC was well tolerated, effectively localized and replicated in the tumor tissues, expressed its therapeutic payload and showed anti-tumoral immunological activity.

Incidence of heparin resistance and heparin failure in patients receiving extracorporeal membrane oxygenation - an exploratory retrospective analysis

Objectives: Unfractionated heparin (UFH) remains the anticoagulation of choice at most centres for patients receiving extracorporeal membrane oxygenation (ECMO). One disadvantage of UFH relies on its individual dosing requirement to achieve target values. In this context heparin resistance has been described, defined as doses exceeding 35,000 IU UFH/d. However, the incidence of heparin resistance and its association with thromboembolic complications despite anticoagulation within target ranges remains unknown. Method(s): This retrospective study included adults receiving venovenous (VV) and venoarterial (VA) ECMO, or extracorporeal CO2-removal (ECCO2R) between 2010 and May 2022. The primary outcome was the incidence of heparin resistance (>35,000 IU of UFH/d). Secondary outcomes were heparin failure (thromboembolic complications despite anticoagulation within target ranges) and survival. A multivariable poisson regression model was fitted to analyse the effect of heparin resistance, COVID-19 and ECMO type on the incidence rate of thromboembolic events. Result(s): Of 197 included patients, 33 (16.8%) had heparin resistance. Patients with COVID-19 (n=51) had a higher rate of heparin resistance compared to nonCOVID-19 patients (37% vs. 9.6%, P<0.001). Thromboembolic complications occurred at a rate of 5.89/100 ECMO days. There was a significant effect of COVID-19 (incidence rate ratio (IRR) 2.12, 95% confidence interval (CI) 1.4 to 3.3, P<0.001) and ECMO type (VA ECMO: IRR 2.35;95% CI 1.43 to 3.87, P<0.001;ECCO2R: IRR 2.63, 95% CI 1.37 to 4.9, P=0.003;reference VV ECMO) on incidence rate of thromboembolic events, but not of heparin resistance (IRR 1.11, 95% CI 0.7 to 1.76, P=0.7). ECMO duration was longer (25d (IQR 11-33) vs. 8d (IQR 4-18), P<0.001) in patients with heparin resistance, but hospital survival did not differ (23 (70%) vs. 91 (57%), P=0.2). Conclusion(s): The study revealed a high incidence of heparin failure in ECMO patients, especially in those with COVID-19. Heparin resistance had no effect on the incidence rate of thromboembolic events, whereas our data suggest an increased risk in patients with COVID19, VA ECMO and ECCO2R.

Perinatal SARS-CoV-2 infection and vaccination: new insight

Cumulative data regardingCOVID-19 infection during pregnancy have demonstrated the ability of SARS-CoV-2 to infect the placenta. However, the mechanisms of SARS-CoV-2 placental viral entry are yet to be defined. SARS-CoV-2 infects cells by binding to the ACE2 receptor. However, SARS-CoV-2 cell entry also requires co-localization of spike protein cleavage by the serine protease TMPRSS2. However, the co-expression of ACE2 and TMPRSS2 in placental cells is debated, raising the question of whether potential non-canonical molecular mechanismsmay be involved in SARS-CoV-2 placental cells' viral entry. Although published data regarding the ability of the SARS-CoV- 2 to infect the fetus are contradicting, the placenta appears to be an immunological barrier to active SARS-CoV-2 infection and vertical transmission;however, the mechanism is unclear. Our experiments demonstrated the ability of the SARS-CoV-2 virus to directly infect the placenta and induce transcriptomic responses in COVID-positive mothers. These transcriptomic responses were characterized by differential expression of specific mRNAs and miRNAs associated with SARS-CoV-2 infection, with induction of specific placental miRNAs that can inhibit viral replication. Failure in such mechanisms may be associated with vertical transmission. Since the start of the COVID-19 pandemic, the COVID-19 mRNA vaccines have been widely used to reduce the morbidity and mortality of SARS-CoV-2 infection. Historically, non-live vaccines have not caused any harm to pregnant mothers;however, it is unclear whether our current understanding of the effects of non-live vaccines serves as a reliable precedent owing to the novel technology used to create these mRNA vaccines. Since there are no definitive data on the possible biodistribution of mRNA vaccines to the placenta, the likelihood of vaccine mRNA reaching the fetus remains uncertain. Little has been reported on the tissue localization of the lipid nanoparticles (LNPs) after intramuscular (IM) administration of the mRNA vaccine. The biodistribution of LNPs containing the mRNA vaccine has been investigated in animal models but not humans. In the murine model, the vaccine LNPs were rapidly disseminated to several organs, including the heart, liver, kidney, lung, and spleen, following IM administration. However, no traditional pharmacokinetic or biodistribution studies have been performed with the mRNA vaccines, including possible biodistribution to breast milk or the placenta.

Unique vascular complication following extended VV-ECMO support

Objectives: To present an unusual complication related to prolonged ECMO support in a patient with COVID19 induced acute respiratory syndrome (ARDS). Method(s): Clinical chart review of the care process after obtaining the informed consent from the patient. Result(s): A 48-year-old female with COVID-19 infection during second wave of pandemic in August 2021 progressed to severe ARDS. She was put on VV-ECMO support after failing conventional therapy for refractory hypoxemia. Her cannulation configuration included a 25 F venous drainage cannula in the right femoral vein and a 21 F venous return cannula in the right Internal Jugular (IJ) vein. Cannulations were performed using the ;Seldinger technique;under USG guidance, and no difficulties or complications were reported. Her hospital course was notable for delirium, and intermittent bleeding from the cannula sites. After 80 days of support, she showed adequate respiratory improvement which allowed ECMO decannulation. She continued to show improvement, and was eventually discharged after 102 days of total hospital stay. During her 6 weeks follow-up clinic visit a palpable thrill was noted at the jugular ECMO cannula site. A CT angiogram of the neck demonstrated a large venous varix connecting the right IJ and the left common carotid artery with filling from the left common carotid artery. ECMO cannulation site complications such as aneurysm, clots, infections and stenosis are well known. What was unusual in this case is the nature of the aneurysm given that there were no arterial procedures performed on the left side of the neck. She was managed by an ;Amplatzer plug;to the carotid artery at the level of the connection to the varix without any complications. Conclusion(s): Longer duration of ECMO support needs careful follow-up for timely recognition and management of vascular complications. (Figure Presented).

Clinical characteristics, complications, and outcomes of severe COVID-19 ARDS patients supported by ECMO and triaged for lung transplantations

Objectives: More than 200 patients have benefited from lung transplantation who failed to recover from COVID-19-induced acute respiratory distress (ARDS) with conventional ventilatory support and/ or extracorporeal membrane oxygenation support (ECMO) in USA. We aim to share our experience and lessons learned at our institute through this case series. Method(s): After IRB approval, we performed a retrospective chart review and identified 37 patients who received ECMO for COVID-19 induced ARDS between May 2020 through January 2022. Out of these, 12 received a formal consultation from the transplant team. We studied patient characteristics, interventions during ECMO support, and evaluation outcomes. Result(s): Most of our patients had single organ failure i.e., lung, except for two who required dialysis after ECMO initiation. Six out of the 12 patients received bilateral lung transplant. One patient received the transplant before ECMO initiation. However, the patient required two runs of ECMO after the transplant due to postop complications from suspected COVID19 reinfection and deceased on postoperative day 101. All the patients after transplant had an expedited recovery except one who required prolonged hospitalization before starting physical therapy. The median length of hospital stay for the transplant group was 148 (89- 194) days and for the non-transplant group was 114 (58-178) days. The 30-day survival rate was 100% for the transplant group. At a median follow-up of 207 (0- 456) days after discharge, 5(83.3%) patients in the transplant group and 3(50%) patients in the nontransplant group were alive. In the non-transplant group, 4 patients received ECMO support for more than 75 days and at last follow-up 2 were alive and functioning well without needing new lungs. This asks for an objective prospective study to define the timeline of irreversibility of the lung injury. Conclusion(s): Lung transplantation is a viable salvage option in patients with COVI-19 induced irreversible lung injury. However, the irreversibility of the lung injury and the timing of lung transplant remains to be determined case-by-case. (Figure Presented).

Membrane dysfunction in patients with severe COVID-19 treated with venovenous extracorporeal membrane oxygenation - analysis from a pooled data from a single centre

Objectives: It is well known that severe COVID-19 is associated with complex immunological and inflammatory dysregulation. Both these physiopathological events translate to a high risk of major thrombotic or hemorrhagic events. In patients treated with venovenous extracorporeal membrane oxygenation (VVECMO), membrane dysfunction might affect systemic oxygenation and limit its duration-expectancy. This study aimed to assess the possible causes of extracorporeal membrane failure in COVID-19 patients and its impact on outcome. Method(s): Retrospective, single-center, observational case-control study involving adult COVID-19 patients admitted to an ECMO referral centre in a tertiary university hospital. All patients required VVECMO for acute respiratory failure, including 48 cases who needed one or more extracorporeal membrane exchanges and 45 controls (no membrane exchange). These two groups were compared for demographic characteristics, severity of the disease using validated scores (SAPS II and SOFA), duration of ECMO run, coagulation assessment, cumulative anticoagulation dose, associated complications, and outcomes (ICU and hospital mortality). Result(s): Most patients were males (71.0%) and younger than 50 years (79.5%). Median ECMO run duration was significantly longer in the case group (35.0 vs 14.0 days, p <0.001), as well as ICU length-of-stay (45.5 vs 28 days, p <0.001). Membrane exchange tended to be associated with sepsis (56% vs 33%, p=0.037), major hemorrhage (58% vs 43%, p=0.022), heparin-induced thrombocytopenia (25% vs 9%, p=0.054), higher D-dimer title (17.36 ng/dL vs 7.5 ng/dL, p=0.07) and lower platelet counts (133.000/muL vs 154.000/muL). Median SAPS II (32.0 vs 33.0, p=0.20) and the mortality (27% vs 24%, p >0.99) were similar between these groups. Conclusion(s): In patients with SARS-CoV-2 pneumonia and severe hypoxemia treated with VVECMO support the emergence of infection, coagulopathy and inflammation were associated with high risk of membrane dysfunction. No impact on mortality could be confirmed from these data. Anticoagulation monitoring and dosing strategies should be reinforced to promote membrane protection.

Outcomes of cancer patients with Covid-19 admitted to the Intensive Care Unit: A retrospective study

Introduction: Active cancer increases the odds of death among patients with COVID-19.1 Cancer patients may be at increased risk of complications and mortality from COVID-19 owing to the systemic effects of malignancy, immune suppression after chemotherapy, treatment-related complications and presence of co-morbidities.2 They may develop serious complications necessitating ICU admission. In a meta-analysis, the pooled mortality in cancer patients with COVID-19 admitted to an ICU was 60.2%.3 Our hospital is a tertiary referral cancer centre, and the ICU admitted cancer patients with Covid-19 throughout the pandemic. Objective(s): To determine the 30-day in-hospital mortality of adult cancer patients with Covid-19 admitted to the ICU. We also aimed to determine the factors associated with mortality in cancer patients with Covid-19. Method(s): After approval from the Institutional Ethics Committee, data of all cancer patients (age = 16 years) with Covid-19 admitted to the ICU between March 2020 and March 2021 were retrieved from the hospital records. In case of multiple ICU admissions, data from the first admission was recorded. Data recorded included demographic details, type of cancer (solid, haematological), surgical status, APACHE-II and SOFA scores, C-reactive protein, and interventions in ICU. The primary outcome was 30-day in-hospital mortality. Data were analysed using Man-Whitney test and chi-square test. A multivariable regression analysis was carried out to determine factors associated with mortality. Result(s): Data of 127 cancer patients with Covid-19 was analysed. The median [interquartile range, IQR] age was 55 (43-62) years, and there were 50 females (39.3%). Comorbidities were present in 46 (36%) patients, the commonest being diabetes (29 patients) and hypertension (31 patients). The median [IQR] APACHE-II and SOFA scores were 15[8-20] and 4[2-7], respectively. Overall, 62/127 patients died, and 30-day hospital mortality was 49%. There were 30 patients with haematological malignancy and 97 with solid tumours with 30-day in-hospital mortality rates of 46.7% and 49.5%, respectively;p = 0.84). Amongst patients with solid tumours, there was no difference in mortality in surgical patients compared to non-surgical patients (43.3% vs. 52.2%;p = 0.42). Table 1 summarises the parameters and interventions in survivors and non-survivors. On multivariable analysis, only the change in SOFA score from Day 1 to Day 3 was independently associated with outcome (Odds ratio 1.36 (95% confidence interval 1.01-1.84, p-0.04). Conclusion(s): In patients with cancer and Covid-19 and age =16 years admitted to our ICU, the crude 30-day hospital mortality was 47%. There was no association of mortality with cancer type or surgical status. The only independent predictor of mortality was progression of organ failure. Cancer patients with Covid-19 have a reasonable outcome and should be given a trial of intensive care.

SARS-CoV-2 Reinfection Rate: A Systematic Review and Meta-analysis

Backgrounds: Reinfection among COVID-19 patients is still a challenging issue in the medical literature. Therefore, the current meta-analysis was conducted to estimate the pooled incidence rate of reinfection among COVID-19 patients. Material(s) and Method(s): A comprehensive search was conducted in PubMed, Web of Science, and Scopus databases from July 1 to October 1, 2021. Original studies which estimated the incidence rate of COVID-19 reinfection were included. CASP (Critical Appraisal skills program) was used to assess the quality of studies. Data were analyzed by STATA statistical software Version 15 (StataCorp, College Station, TX, USA). Finding(s): A total of 3803 articles were found, of which 16 articles remained after title, , and full text screening. The minimum and maximum incidence rates of reinfection were 0.001 and 0.73%, respectively. The pooled estimated incidence rate of COVID-19 reinfection was 0.11% (95% confidence interval: 0.02-0.20, p< .001, I2 = 100.0). The highest pooled estimated incidence rate of reinfection was observed in people <50 years old (0.14%) (95% CI: 0.001-0.34, p<.001, I2 = 100). Regarding the time elapsed after the first infection, the highest reinfection rate occurred four months after the first infection (0.12%) (95% CI: 0.001-0.27, p< .001, I2 = 100). Conclusion(s): The incidence rate of reinfection among COVID-19 patients is expected to be high. However, it seems that the influence of factors including the age of patients and the time elapsed after the first infection must be considered.Copyright A© 2023, TMU Press.

An Emerging Role of Interferon Targeted Therapy in Mucocutaneous Sle: A Prospective Real-World Evaluation of Anifrolumab for Refractory Cutaneous Lupus

Background/Aims Advances in rational drug design and recent clinical trials are leading to emergence of a range of novel therapies for SLE and therapeutic options in clinical practice are expected to broaden rapidly. The optimal real-world place of emerging and established agents will be guided by understanding their differential efficacy on specific SLE manifestations as well as efficacy for more resistant disease. Anifrolumab, a type-I interferon receptor blocking monoclonal antibody, showed efficacy in SLE in phase III trials with a notable effect on mucocutaneous disease although specific lesion subtypes and chroncicity were not explored. Severe refractory mucocutaneous SLE such as scarring discoid lesions are an important and common clinical challenge in current practice. We therefore prospectively evaluated the real-world efficacy and quality of life impact of anifolumab for active mucocutaneous SLE, recalcitrant to multiple biologic and immunosuppressant therapies. Methods Seven patients commenced anifrolumab (300mg by monthly iv infusion) following application to the manufacturer's early access programme (NCT 04750057). Prior biologic therapies were discontinued at least 5 half-lives in advance. Mucocutaneous disease activity was captured by Cutaneous Lupus Disease Area and Severity Index (CLASI) activity score and medical photography. Patient reported health-related quality of life comprising the Dermatology Life Quality Index (DLQI);Lupus-QoL and EQ5D-5L were evaluated at baseline, three and six months. Results Seven female patients with active mucocutaneous SLE (Discoid LE n=5, chilblain LE n=1, subacute cutaneous LE n=1) and median disease duration of 17 years were evaluated. Median baseline CLASI activity score was 17 (range 10-26;higher scores indicating severe disease). Median number of previously failed therapies was 7 and included rituximab in 6/7, belimumab in 2/7 and thalidomide in 4/7. Rapid resolution of scale and erythema in DLE was established within 1 month of anifrolumab treatment. Improvements to chilblain lupus were evident by three months. CLASI activity score was improved >=75% in all patients at 3 months. Clinical responses were associated with significant improvements in DLQI (p<0.001) and EQ5D-VAS (p=0.002) by three months. Lupus-QoL trended toward improvement across all domains but most strongly for fatigue (p=0.01) and pain (p=0.002) by 6 months. One patient discontinued treatment after 4 months due to polydermatomal shingles complicated by sensorineural hearing loss. Infection coincided with background prednisolone dose >15mg daily, recent COVID-19 infection and new on-treatment hypogammaglobulinaemia (IgG <5g/L). Prolonged aciclovir treatment was required for lesion resolution. Conclusion We report rapid real-world efficacy and quality of life impact of anifrolumab on highly refractory mucocutaneous SLE, which exceeded that anticipated from existing clinical trial data. Findings suggest a unique role for emerging interferon targeting therapies in management of mucocutaneous SLE but emphasize need for enhanced VZV precautions among higher risk patients.

Scientific debrief: cirrhosis

Globally, hepatitis C (26%), alcohol (24%), and hepatitis B (23%) contribute almost equally to the global burden of cirrhosis. The contribution from nonalcoholic fatty liver disease (8%) is small but increasing. Patients with acutely decompensated cirrhosis have a dismal prognosis and frequently progress to acuteon-chronic liver failure, which is characterised by hepatic and extrahepatic organ failure, Cardiovascular alterations including portal hypertension trigger the formation of portocaval shunts and varices. Systemic under filling and arterial hypotension is compensated by vasoconstriction but might decline into a state of aggravated portal hypertension and cirrhotic cardiomyopathy, leading to a hyperdynamic state, microvascular dysfunction and reduced organ perfusion culminating in decompensation. The immune system is dysfunctional showing a contrary co-existence of immune paralysis and immune overstimulation leading to secondary infections and inflammatory response syndrome aggravating cardiovascular alterations but also initiating tissue injury and metabolic alteration. This transition from compensated to decompensated cirrhosis is characterised by the occurrence of ascites, variceal bleeding and/or hepatic encephalopathy or organ failures (in the case of ACLF. Precipitating events for ACLF vary between Western countries (bacterial infection, alcohol intake) and Eastern countries (flare of HBV, superimposed HAV or HEV). In the majority of patients, systemic inflammation is a major driver of progression from compensated to decompensated cirrhosis. Once the first episode of AD develops, systemic inflammation follows a chronic course, with transient periods of aggravation due to proinflammatory precipitants or bursts of bacterial translocation resulting in repeated episodes of AD. The multistate model describing the clinical outcomes of decompensated cirrhosis has been well validated. State 3 is defined by the occurrence of variceal bleeding alone, state 4 by any single non-bleeding event, state 5 by any 2 or more events and the late decompensate state by any event with organ failures either with or without ACLF. 5-year mortality across states from 3 to 5 is in the order of, respectively: 20%, 30%, 88%. With late decompensation mortality ranges between 60 and 80% at 1 year. Cirrhosis is increasingly common and morbid. Optimal utilisation of therapeutic strategies to prevent and control the complications of cirrhosis are central to improving clinical and patient-reported outcomes. Aetiology-focused therapies that can prevent cirrhosis and its complications. These include anti-viral therapies, psychopharmacological therapy for alcohol-use disorder, management of hepatic encephalopathy (HE), ascites, hepatorenal syndrome, non-pain symptoms of cirrhosis including pruritis, muscle cramps, sexual dysfunction and fatigue, and reduce the risk of hepatocellular carcinoma. New disease-modifying agents are expected to be identified in the next few years by systematic drug repurposing and the development of novel molecules currently undergoing pre-clinical or early clinical testing. COVID-19 continues to pose a significant healthcare challenge throughout the world. Comorbidities including diabetes and hypertension are associated with a significantly higher mortality risk. Cirrhosis is associated with an increased risk of all-cause mortality in COVID-19 infection compared to non-cirrhotic patients. Patients with cirrhosis should be considered for targeted public health interventions to prevent COVID-19 infection, such as shielding and prioritisation of vaccination.

Liver injury in patients with COVID-19 who received dexamethasone monotherapy

Introduction: Liver injury is frequently seen in coronavirus disease 2019 (COVID-19), and it has been reported to be associated with the severity of COVID-19. The direct action of the virus, cytokine storm, coagulation abnormalities, drug-induced, etc. are considered to be the causes of liver injury, and antiviral agents against COVID-19 and steroids used as anti-inflammatory agents have also been reported to contribute to the appearance of liver injury. In Japan, remdesivir, dexamethasone (Dex), baricitinib, etc. are used as therapeutic agents for COVID-19, but there is still not enough evidence about the frequency of liver injury as an adverse event. Aims & Methods: This study aimed to clarify the influence of Dex monotherapy for liver injury in COVID-19 with respiratory failure. We examined 171 patients with COVID-19 with liver injury in the respiratory failure groups and the nonrespiratory failure groups and investigated 41 patients with moderate COVID-19 with respiratory failure who received Dex monotherapy in the liver injury group and the nonliver injury group at the time before treatment. Result(s): The respiratory failure group had 64% more liver damage than the non-respiratory failure group, was older, had more men, and had significantly more complications of lifestyle-related diseases such as hypertension and diabetes. Obesity was more common in the liver injury group prior to Dex monotherapy, and the liver CT value was significantly lower than in the non-liver injury group. Liver injury worsened in 41% of patients after Dex monotherapy, but there was no significant difference in the frequency before Dex monotherapy between the liver injury group and the non-liver injury group, and the degree of liver injury was mild in all cases, improving in 38% of the liver injury group. Conclusion(s): Dex monotherapy was a safe treatment for moderate COVID-19 with respiratory failure, which frequently resulted in liver injury.

A Case Report of Ivermectin-Induced Liver Failure

Introduction: Ivermectin is an antiparasitic medication that is primarily metabolized by the liver. During the COVID-19 pandemic, researchers demonstrated that Ivermectin successfully inhibited the replication of SARS-COV-2 in vivo, but current research has failed to demonstrate clinical benefit for treatment of COVID-19. Despite this, misinformation campaigns have misled patients to ingest Ivermectin at concentrations meant for domestic animals. Here, we present a case of acute liver failure secondary to the use of Ivermectin. Case Description/Methods: A 61-year-old man with medical history of ischemic cardiomyopathy with last echocardiogram showing ejection fraction at 21%, atrial fibrillation on warfarin for oral anticoagulation, and previously treated Hepatitis C presented with generalized weakness and yellowish discoloration of the skin worsening over the last two weeks. The patient denied significant alcohol use, acetaminophen use, or illicit drugs. He admitted to injecting himself with two doses of weight-based horse ivermectin, for COVID prophylaxis, two weeks prior to his presentation. Physical exam was pertinent for scleral icterus and hepatomegaly with no abdominal tenderness. Initial labs revealed elevated liver chemistries in a mixed pattern (Figure 1). Acute hepatitis panel, HSV, and CMV were negative. Hepatitis C antibodies were positive, but the patient was in sustained virologic response. Full workup for chronic liver disease was unremarkable. Ultrasound revealed hepatosplenomegaly with patent portal and hepatic vasculature. Subsequently, the patient developed hepatic encephalopathy along with his coagulopathy, raising concern for acute hepatic failure. The patient was transferred to the ICU and started on NAcetylcysteine, rifaximin, and supportive care. The patient recovered well and fortunately did not require liver transplant. Discussion(s): While the FDA recommends against the use of Ivermectin for COVID-19, many continue to inappropriately consume it. Ivermectin-induced liver failure is a rare but deadly side effect. Given our patient's rapid onset of symptoms post-self injection of Ivermectin, his liver injury was presumed to be related to Ivermectin. The drug interaction between Ivermectin and warfarin had worsened the patients coagulopathy. Physicians should be aware of the ways Ivermectin overdose may clinically present to avoid delayed treatment. This case demonstrates the detriments of perpetuation of medical misinformation to care.

What is the new normal? Frequency of monitoring after COVID-19

Background: Recommended frequency of HIV plasma viral load (VL) monitoring is 6 monthly, but published data suggest a low risk of virological failure with longer monitoring intervals. National COVID-19 'lockdowns' necessitated much reduced VL monitoring. We hypothesised that many people living with HIV (PLWH) may have remained on extended monitoring intervals. Method(s): We interrogated laboratory data for all HIV VL performed in our service for the period 1/1/2018 to 31/12/2022. As COVID-19 lockdowns principally affected face-to-face clinical care during Q2 and Q3 2020, we considered two 27-month periods of 1/1/2018 to 31/3/2020 (P1) and 1/10/2020 to 31/12/2022 (P2). Within each period, PLWH were eligible for inclusion if there were at least two VL results. The last two monitoring visits of the period were used for analyses. An extended monitoring interval was defined as 34 weeks or more. Result(s): 1302 PLWH were monitored during P1 at a mean frequency of 1.97 VL per annum, and 1370 in P2 at 1.76 pa. The proportion of PLWH with VL <200 copies/mL rose from 92.9% in P1 to 96.0% in P2 (p<0.001). The proportion suppressed to <50 copies/mL rose from 76.4% to 86.2% (p<0.001). Of those PLWH with VL <200 copies/mL at initial visit, 9.9% had an extended monitoring interval to the subsequent visit in P1, and 23.0% in P2 (p<0.001). However, within P2, 4.7% of those with an extended monitoring interval had VL >=200 copies/mL at subsequent visit compared with 0.8% of those with standard interval (p<0.001). Conclusion(s): Virological monitoring intervals have become significantly longer in the period since the COVID-19 lockdowns. Viral suppression across all PLWH has improved. However, extended follow-up intervals were associated with increased risk of virological failure, even in the setting of prior suppression. This study was not able to determine the reasons for extended monitoring intervals (e.g. active shared decision vs. suboptimal attendance). Further research is required in order to develop criteria for safe extension of monitoring intervals.

Uncontrolled Acromegaly Resulting in the Need for LVAD as Bridge to Heart Transplant

Introduction: Acromegaly is an uncommon pituitary disorder with an incidence of six per million persons. While hypertension is often encountered in these patients, heart failure rarely is seen with an incidence rate under 10%. We describe a case of an individual who was diagnosed with acromegaly after an acute exacerbation of heart failure with subsequent management requiring an LVAD to perform Transsphenoidal Surgery (TSS). Case Description: 37-year-old male otherwise healthy initially presented to an emergency room and was found to be in acute heart failure exacerbation. Concerning acromegaly features included macrognathia, enlarged hands and feet, swollen phalanges, widened spacing of teeth, and frontal bossing. IGF-1 level was found 455 ng/mL. MRI showed a 10mm macroadenoma. A right heart catheterization showed elevated filling pressures. Cardiac MRI showed no defects or enhancement. Endomyocardial biopsy showed no inflammatory infiltrates or evidence of infiltrative diseases. Patient had an ejection fraction of 15% corroborated by cardiac MRI along with the presence of aortic root dilatation and mitral regurgitation. The patient started on 0.5mg of Cabergoline twice weekly and 120mg weekly Lanreotide injections. Patient stabilized with plans for further close monitoring and outpatient neurosurgical evaluation. The COVID-19 pandemic and insurance gaps led the patient to spend two years off his medicines and he was unable to be seen by his medical team. Patient was seen by our system after recurrent hospitalizations for heart failure at our sister hospital, AICD was unable to be placed due to the patient's anatomy, he was placed on wearable cardiac defibrillator and required milrinone infusion for progression to end-stage heart failure with cardiac cachexia. At our institution, the patient was evaluated for Orthotopic Heart Transplant (OHT) but due to active GH secreting macroadenoma there was concern for OHT failure without TSS. Decision was made to utilize LVAD as Bridge-to-Transplant for OHT so the patient could be stabilized and safely undergo TSS. The patient tolerated surgeries well and is currently on the active transplant list. Discussion(s): Heart failure is an uncommon presentation of severe acromegaly requiring multidisciplinary management. We describe a case of a patient who initially presented with heart failure too unstable for surgery. Due to the COVID-19 pandemic the patient's disease progressed resulting in end-stage heart failure requiring LVAD placement for further treatment. We would like to draw attention to the use of LVAD placement in acromegalic patients who develop severe cardiovascular disease who are not candidates for OHT.Copyright © 2023

Understanding Patient Experiences with Overactive Bladder

INTRODUCTION AND OBJECTIVE: Overactive bladder (OAB) is highly prevalent, affecting millions of Americans, and poses a significant symptom burden. The purpose of this study was to understand patient experiences with OAB and the impact of these experiences on OAB treatment. METHOD(S): People with symptoms of OAB were recruited from a tertiary care clinic and from an online health research portal to complete semi-structured interviews regarding their OAB experiences. The interviews were recorded, transcribed, coded, and inductively analyzed to identify emerging themes. RESULT(S): We performed 19 interviews and identified several key themes central to the patient experience, including symptom impact and severity, knowledge, stigma, self-efficacy, and regret. We considered these themes along the following stages of the patient's OAB journey. Symptom Development and Awareness: The routine of self-care is insidious and normalized, making realization of a lifestyle that is centered around voiding less obvious to patients, leading to a delay of care-seeking. Participants noted restrictions on all aspects of life. Adjectives used to describe symptom impact included "annoyance, depression, humiliation and desperation." Care-Seeking: Participants expressed coping behaviors during onset and gradual worsening of symptoms, however many recounted a "sentinel event" that heightened their severity perception and served as a cue to action. Routine primary care visit screenings and friend recommendations were additional cues to action. Reasons for careseeking delay included lack of OAB knowledge, stigma, and embarrassment. Experiences with Therapy: Participants recognized that treatment outcomes depended on their engagement. Some individuals regretted their lack of self-advocacy and self-efficacy. Participants highlighted internal barriers (forgetfulness, doubting treatment effectiveness) and external barriers (comorbidities, COVID- 19) to therapy adherence. Among those with high self-efficacy, fear of treatment failure, calendar tools, and social support networks facilitated treatment compliance (Figure 1). CONCLUSION(S): Living with OAB affects patients physically, mentally, and socially. Gaining a better understanding of OAB experiences can help physicians tailor their practice to meet patients' needs.

Outcomes following application of high flow nasal cannula and non-invasive ventilation during the second COVID-19 wave in Singapore

Introduction: COVID-19 pneumonia can result in significant morbidity and mortality in affected individuals. Our audit aims to study the respiratory outcomes of patients with COVID-19 pneumonia following the use of HFNC and NIV during the second wave of the pandemic. Method(s): We analysed the outcomes of 94 patients admitted to a tertiary combined HDU/ICU with severe COVID-19 pneumonia requiring non-invasive support between July and December 2021. Result(s): 94 patients were admitted during the study period. ICU mortality rate was 22% (21/94), total in-hospital mortality was 38% (36/94). HFNC was used as first line respiratory support in 58/94 cases, of which 39.6% required intubation. Of those patients who failed HFNC, time to intubation was significantly higher in those patients who passed away than those who were intubated and survived (mean 6.08 days vs 2.86 days, p < 0.05 one sided T-test). In all patients, very late intubation defined as intubation > 5d post admission to ICU, occurred in 6/41 patients, of which the mortality rate was 100%. ROX score performed at 12 h post intubation was unable to discriminate those who succeeded with HFNC and those who required intubation (mean ROX 7.24 vs 7.9, p > 0.05). NIV was used in combination with HFNC pre-intubation in 5/23 HFNC cases with 100% mortality rate. Extubation failure rates were low (5/94) and use of tracheostomy was uncommon (4/94;all 4 survived ICU stay, 3 eventually died in hospital). Conclusion(s): HFNC failure with prolonged use of HFNC and use of multiple non-invasive device strategies before intubation was associated with a high risk of mortality. Conventional measurements of HFNC failure in the form of a 12 h ROX score could not assist the clinician in predicting those patients at risk of HFNC failure.

A Randomized Trial on Early Therapy in Covid-19 High-Risk Outpatients in Omicron Era

Background: Antivirals and monoclonal antibodies (mAbs) were approved for early treatment of COVID-19 based on data from trials conducted in unvaccinated people before the Omicron era. The comparative effectiveness of different treatments is unknown. We present the results of the interim analysis of MONET trial (EudraCT: 2021-004188-28). Method(s): In this ongoing multicenter, open-label, phase 4 trial, we randomly assigned, in a 1:1:1 ratio, non-hospitalized patients with early symptomatic Covid-19 (<=5 days after symptoms onset) and >=1 risk factor for disease progression, to receive 500 mg of intravenous sotrovimab (SOT) or 600 mg of intramuscular tixagevimab/cilgavimab (TIX/CIL) or oral 5-days course of NMV/r 300/100 mg BID. Primary outcome was hospitalization or death for any cause within 29 days after randomization, reported as cumulative incidence per 100 (95% CI), and P-value calculated by Fisher's exact test. Inflammatory marker (CRP, d-dimer, and neutrophils-to-lymphocytes ratio) and antibody level (serum anti-S IgG and anti-N IgG) analysed by mixed linear regression with random intercept and P-values for time trend calculated by ANOVA-style test with Bonferroni correction. Result(s): Prespecified interim analysis, including 400 patients (SOT =133, TIX/ CIL=130, NMV/r=137) enrolled from Mar 4 to Nov 16, 2022 (Fig.1A). Overall, 5 pts (3/5 immunosuppressed) had disease progression leading to hospitalization [1.25% (95% CI 0.4%-2.89%)], 1 in SOT (0.75%, 95% CI 0.01%-4.1%), 4 in TIX/CIL (3.08%, 95% CI 0.84%-7.69%) and none in NMV/r arm (P=0.030). No deaths or ICU admissions were observed. Among the hospitalized pts, 3 were infected with BA.2 (1 SOT, 2 TIX/CIL), one with BA.4/5, and one BQ.1.1 (both TIX/ CIL). No serious adverse events and no kidney or liver toxicity were reported. Temporal trend of inflammation markers was similar in the three arms, and their estimates are shown in Fig.1B. Kinetics of antibody was reported in Fig.1C. The plot shows a rapid increase of anti-S in both mAb arm and a linear increase of IgG in the NMV/r arm. Anti-N IgG kinetics was similar in the three arms. Conclusion(s): By these data the overall cumulative risk of clinical failure in mild Covid-19 occurring in the Omicron era is low. The hypothesis that differences in clinical progression among the three arms could be related to different activity against the Omicron subvariant observed in vitro should be further investigated. Type of treatment does not seem to influence the development of the natural antibody response.