Relationship between Pain, Physical Activity, and Quality of Life in Patients with Haemophilia a and Haemophilia B

Introduction: The extended half-life (EHL) registry was established in 2016 to ascertain the long-term outcomes in patients with HaemophiliaA(HA) and B(HB) receiving replacement therapy. The aim was to quantify disease burden and quality of life at baseline and after switching to EHLs. Method(s): The study is a prospective, observational cohort study that enrolled patients switching EHLs or on standard replacement therapy after informed consent following local ethics approval and was registered at www.clinicaltrials.gov (NCT02938156). The study was paused during the COVID pandemic. Here the baseline results are presented for pain, activity and quality of life and their correlations. Pain evaluation was assessed through the brief pain inventory (BPI) 7-day recall, quality of life by EuroQol-5 Dimension (EQ5D5L) and physical activity through the international physical activity questionnaire (IPAQ). The BPI assess severity of pain and the interference with activities. IPAQ assess physical activity undertaken across a comprehensive set of domains. Three levels of physical activity are used to classify the populations: 'low', 'moderate', and ' high'. Result(s): A total of 231 HA and 97 HB were included in the analysis, of whom 231 had switched to EHL products and 96 were on standard replacement therapy. The levels of Physical Activity were similar between Haemophilia types, with approximately 46%, 32% and 22% of patients reporting high, moderate, and low physical activity, respectively. BPI mean (+/-SD) severity score in HA was 2.86 (+/-2.1), HB 3.24 (+/-2.0);interference score HA 3.22 (+/-2.8), HB 3.09 (+/-2.5), mean EQ5D5L visual analogue scale (VAS) for HA 72.92 (+/-15.5) and HB 71.10 (+/-18.2). Within instruments, IPAQ sub-scores and BPI average scores were highly correlated. Between instruments, the strongest linear correlations were seen between theVAS and the BPI scores (R=-0.59, p< 0.0001, n=206 for the average interference score, R=-0.57, p< 0.0001, n=208 for the average pain severity, v.s. the VAS). Correlations between the IPAQ total score and either VAS or BPI scores were weaker, even when limiting to patients with moderate or high activity and using a log scale given the skewed distribution of the IPAQ summary measure. Discussion/Conclusion: The study demonstrates for the first time a strong correlation between pain and quality of life, and weaker correlation between physical activity and quality of life.

Biomarkers in COVID-19: Association with disease severity and outcomes

Background: In coronavirus disease 2019 (COVID-19) the need for intervention increases with disease severity and a risk prediction model that incorporates biomarkers would be beneficial for identifying patients for treatment escalation. Aim(s): To investigate biomarkers changes associated with disease severity and outcomes (mortality, thrombosis). Method(s): COVID-19 patients were sampled between April 15 and May 31 2020. Disease severity was assessed by World Health Organization (WHO) ordinal scale. 132 systemic biomarkers were investigated by routine and multiplex assays and statistical analysis performed to characterise the biomarker profile of COVID-19 patients associated with disease severity, duration, survival and thrombosis. Result(s): The study enrolled 150 COVID-19 positive adults and 16 healthy volunteers. The average age was 64 years, 59% were male, 85% had co-morbidities, 33% had a thrombotic event, and 13% died. A cross comparative analysis of biomarkers identified 13 biomarkers common to severity, mortality and thrombosis with significant correlation;including endothelial dysfunction (VWF, tPA, TFPI), hypercatabolism (low albumin, Hb, FXIII) and inflammatory response (IL-8, Osteopontin). Similarly, 14 biomarkers associated with severity and mortality included pro-inflammatory cytokines and their receptors (sTNFRII, STNFRI, sIL2a, IL6, MIP1a), neutrophils (elevated WBC, Neutrophils, TIMP1) and tissue remodelling (SCGF, EG3A). Nine biomarkers common across severity and thrombosis were angiogenesis (VEGF, LYVE1, Follistatin), acute phase response (SAP, AGP) and clot formation (Fibrinogen and PAPs). Conclusion(s): The biomarker profile associated with poorer outcomes indicates an inflammatory response, endothelial cell disruption, hypercoagulability and hypercatabolism. This study has identified several biomarkers that may be useful indicators of disease severity and progression. Further work is needed to determine how these may be used to direct clinical management. (Figure Presented).

A pilot, open-label, phase II clinical trial of nebulised recombinant tissue-plasminogen activator in patients with COVID-19 acute respiratory distress syndrome: The PACA trial

Background: Alveolar fibrin deposition and pulmonary microthrombi are pathophysiological features of COVID-19- induced respiratory failure. Nebulised thrombolysis offers locally targeted therapy with potentially lower bleed risk than systemic administration. Aim(s): To investigate the safety and potential for clinical efficacy of nebulised recombinant tissue plasminogen activator (rt-PA) for improving oxygenation in patients hospitalised with COVID-19 complicated by mild to severe acute respiratory distress syndrome (ARDS). Method(s): Patients hospitalised with severe COVID-19 and a PaO2/ FiO2 (P/F) ratio of <300 (units), requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received 40-60 mg per day of rt-PA, dosed for <=14 days in a phase II, open-label, single-centre pilot study. Efficacy was assessed via improved oxygenation. Safety was assessed by treatment-related serious adverse event bleeding and reduction of fibrinogen to <1.0-1.5 g/L. Result(s): Nine (Cohort 1 [C1];6/9 IMV, 3/9 NIRS) and 26 adults (Cohort 2 [C2];12/26 IMV, 14/26 NIRS) received nebulised rt-PA alongside standard of care. Matched historical controls (HC) (n = 18) were used for comparison in C1. Mean P/F ratio increased in both C1 groups from baseline (BL) to end of study (EOS) (rt-PA;154.4 to 298.8 vs. HC;154.1 to 211.6);a linear mixed effect model confirmed higher P/F ratios in the rt-PA group. Among C2 groups, greater improvements in mean P/F ratio from BL to EOS were seen in the NIRS group (NIRS;125.5 to 239.4 vs. IMV;120.3 to 188.2). Four potentially treatment-related bleeds were reported;no clinically significant fibrinogen reductions were observed. Lower mortality was observed in the C1 rt-PA group (11.1%) vs. the HC group (55.6%) and in the C2 NIRS group (21.4%) vs. the IMV group (41.7%). Conclusion(s): Nebulised rt-PA is well-tolerated, improves oxygenation in patients with COVID-19- related ARDS, and merits a randomised controlled trial to confirm efficacy and potentially identify a subgroup of interest.

Deployment of Medibot in Medical Field

During this pandemic situation most of the people's health are in the need of medicine and doctors suggestions to improve and protect their health. Also, have seen many such cases where many people have been infected by COVID. To reduce the physical contact and help the people from the spread of diseases the proposed methodology is to implement the medibot in hospitals. A medical bot is a Chatbot which uses NLP (Natural Language Processing) by text-format. The medibot is supported by AI and Deep Learning for Medical Diagnostics. The goal of the project is to create a medibot that overcomes the proposed methodology. There were many people who could not meet the doctors for simple problems such as cold and fever. To reduce these cases will implement the medibot. This medibot can communicate with the patients and understand the symptoms, it will also give them medicines. © 2022 IEEE.

The link between inflammation, coagulation and endothelium damage in COVID-19: Evidence from an exploratory crosssectional study

Background: Increasing evidence suggests that endothelial activation and dysfunction contribute to COVID-19 pathogenesis by altering vessel integrity, promoting pro-coagulative and inflammatory state. Aims: 1. Investigate changes in coagulation, inflammation and endothelium associated with the progression and severity of COVID-19, as well as their correlation to survival and/or occurrence of venous thromboembolic events (VTE). 2. Explore potential new biomarkers to predict COVID-19 severity. Methods: Samples were collected from COVID-19 patients after appropriate consent. Disease severity was assessed with WHO ordinal scale on day of sampling. In addition to routine haematology, biochemistry and coagulation analysis, additional analysis spanning coagulation, endothelium, platelet, inflammatory biomarkers by conventional assays and multiplex immuno-assays were undertaken. Results: Participants included 151 COVID-19 patients aged 18 years and greater, 16 healthy volunteers and 9 non-COVID-19 ICUcontrols. COVID-19 patients were categorised in 7 groups based on severity and time from symptom onset and the data also provides mortality and VTE rates (Table 1). The biomarker profile of hospitalised COVID-19 patients demonstrated an increase in plasma levels of cytokines, inflammatory, soluble endothelial cell markers and markers of coagulation activation when compared to the ambulatory group (Figure 1). Significantly higher levels of inflammatory markers (CRP, WBC, fibrinogen, serum amyloid P, alpha 1 acid glycoprotein) were observed in patients with VTE and in the non-survivors group. Interestingly, the same trend was seen for coagulation (FVIII, VWF) and fibrinolysis markers (D-dimer, TFPI, t-PA) with higher levels in the VTE and non-survivors group. In addition, higher plasma levels of endothelial markers (ICAM-1, angiopoietin, TIE-2, LYVE-1, syndecan) were observed in severe COVID-19 when compared to non-COVID-19 ICU-controls. (Figure Presented) Conclusions: Our study provides evidence of a strong, global inflammatory response in COVID-19 patients. The elevation of circulating markers suggests significant endothelial cell activation/dysfunction and a possible cause for the pro-coagulant phenotype observed in these patients.

Hyper acute dialysis access pathway (HADAP)-undertaking creation of arteriovenous fistulae in the renal ward

Introduction: The impetus to apply the lean method to creation of arteriovenous fistulae came with the pandemic restricting access to theatres. Here we present HADAP implemented in a dedicated procedure room in the Renal ward. Method: Between April and September 2020, 44 patients underwent ward-based arteriovenous fistula operations with no more than 3 people in the room - surgeon, runner and patient. The parameters assessed were duration of operation, complications, patency, patient and surgeon feedback and financial implications. Results: The service was predominantly registrar-led who created 91% of the fistulae. 95% operations were completed successfully with a 2- week primary patency of 73% and no surgical site infections. 40% of the procedures were radiocephalic fistulae. 14% procedures required surgical assistance by the runner. The average operating time reduced from 90 minutes for the first 10 cases to 50 minutes for the last 9. A structured questionnaire showed positive feedback from both patients and surgeons (4-5 out of 5). This service has cleared potentially 9 main theatre lists for more complex procedures. Conclusions: Our study demonstrates the successful implementation of a novel operating environment allowing expedited care for renal failure patients. It has enhanced our ability to deliver a dialysis access program despite the challenges of COVID.

LATE-BREAKING AND COVID-19 ORAL COMMUNICATION SESSION ABSTRACTS

FLT180a is an investigational gene therapy medicinal product candidate intended for treating HB patients. It includes a novel synthetic capsid, AAVS3, with a higher liver transduction efficiency than wild type AAV, and a codon optimised F9 gene with a gain of function mutation. To assess the safety and efficacy of a single systemic adminis-tration of FLT180a in adult patients with HB. Phase 1/2, multi- centre, ongoing, open- label and long- term follow- up study assessing FLT180a dose levels in an escalating/descending adaptive design, to identify a dose that consistently normalises FIX activity (50- 150%). Participants have severe or moderately severe HB and are negative for neutralis-ing AAVS3 antibodies. Pre- emptive immunosuppression is given to mitigate vector related transaminitis and associated reduction in FIX expression. Ten patients with severe HB have been treated across 4 dose levels, with week 3 FIX activity levels ranging between 24 and 168%. The first two patients, receiving the 4.5e11vg/Kg dose, have stable, therapeutic, FIX activity levels through week 104. No patient has had a bleeding episode requiring FIX concentrates. The most common drug related serious adverse event was transient transaminitis (in four patients) requiring supplemental immunosup-pression. FIX activity levels above 150% have been observed, which were individually assessed for risk of thrombosis, and one patient is being treated with DOACs. Refinement of the immunosuppression regimen for the latest three patients (9.75e11 vg/kg dose) prevented transaminitis during the critical phase (4- 16 weeks). FLT180a achieves clinically meaningful, dura-ble FIX activity levels in patients with HB, associated with in-dependence from FIX replacement therapy and zero treated bleeds. Transient transaminitis was largely averted by prophy-lactic immunosuppression. A dose between 7.5 to 9.75e11vg/Kg can potentially create sustained, normal FIX activity levels in patients with severe HB.