A quality improvement project regarding family communication within critical care

Introduction: Communication is central to high quality critical care (CC)1 and caring for family members is integral to the care of critically ill patients. Communication within the CC frequently does not meet families' needs,2 impacts informed decisions making3 and can result in psychological morbidity for patients and their families.4 During the COVID-19 pandemic communication was challenging with restricted family visiting. As part of our recovery strategy we aim to ensure that frequent, high quality communication remains a key aspect of critical care. There is currently no guidance relating to the frequency of family communication within critical care. Objective(s): Our aim was to review the frequency of family communication during CC admissions admission and to develop our own internal standards. Method(s): A retrospective audit was conducted of 110 admissions to Guys and St Thomas' CC from November 2021 - February 202. We reviewed all routine family discussions documented in the medical notes. Data regarding the patient's length of stay, time to first communication from admission, frequency of communication throughout admission and grade of clinician leading the communication was collected. Family discussion regarding adverse incidents and admissions less than 24hrs were excluded. If multiple communications occurred on the same day, the most senior communication was included. To complement the audit a short survey of the consultants, regarding expectations and standards of practice of family communication was completed. Result(s): 99 patients were included within the audit and 13 responses to the survey (34% response). The mean length of stay for all patients was 14 days for survivors and 16.5 days for those who died. 32% of patients received a document family communication within 24hrs of admission, 34% did not have a documented communication within 72 hours of admission. 58.3% of consultants felt a family update should happen within 24hrs of admission and 84.7% of consultants reported that families should be updated once every 3 days. On average families received a documented family communication every 5.5 days of a CC admission. When focusing just on patients who died there was an increase in the frequency of communication to once every 3 days. 23% of all documented family discussions were consultant led with the number rising to 44% in non-survivors. The audit also showed that the longer a patient stayed within critical care the less frequently a family communication became. The survey indicated that the two biggest barriers to family communication is time pressures and appropriate space. Conclusion(s): We demonstrated that documented family communication was less frequent than expected. To ensure that family commination remains a key component of CC within our department we have adopted or own internal standard of providing families with an update once every 3 days. We are exploring the role of communication facilitators5 and seeking patient/family feedback also to improve family communication further.

Liposomal amphotericin B-the future.

Advances in medicine have led to a growing number of people with compromised or suppressed immune systems who are susceptible to invasive fungal infections. In particular, severe fungal infections are becoming increasingly common in ICUs, affecting people within and outside of traditional risk groups alike. This is exemplified by the emergence of severe viral pneumonia as a significant risk factor for invasive pulmonary aspergillosis, and the recognition of influenza-associated pulmonary aspergillosis and, more recently, COVID-19-associated pulmonary aspergillosis. The treatment landscape for haematological malignancies has changed considerably in recent years, and some recently introduced targeted agents, such as ibrutinib, are increasing the risk of invasive fungal infections. Consideration must also be given to the risk of drug-drug interactions between mould-active azoles and small-molecule kinase inhibitors. At the same time, infections caused by rare moulds and yeasts are increasing, and diagnosis continues to be challenging. There is growing concern about azole resistance among both moulds and yeasts, mandating continuous surveillance and personalized treatment strategies. It is anticipated that the epidemiology of fungal infections will continue to change and that new populations will be at risk. Early diagnosis and appropriate treatment remain the most important predictors of survival, and broad-spectrum antifungal agents will become increasingly important. Liposomal amphotericin B will remain an essential therapeutic agent in the armamentarium needed to manage future challenges, given its broad antifungal spectrum, low level of acquired resistance and limited potential for drug-drug interactions.

Optimizing the Interdisciplinary Design of Adaptive Platform Trials

Adaptive platform trials (APTs) are often complex clinical trials that, ideally, are well suited to answer the motivating clinical questions effectively and efficiently, with the motivating clinical questions and associated treatment arms expected to evolve over time as evidence accumulates. Recently, APTs have played a pivotal role in informing public health policy by efficiently generating compelling evidence regarding the effectiveness of therapies for COVID-19. For APTs to be maximally effective in informing future public health policy, they must be carefully tailored to address the right clinical questions, with the right balance of size, scope, rigor, and flexibility. The design process requires input from clinical and statistical domain experts and often includes input from trial implementation personnel, ethicists, and patient representatives. The design process is inherently iterative, with proposed designs evaluated through trial simulation, the identification of strengths and weaknesses of the proposed design, and revision by the team to address weaknesses. This iterative design process requires effective communication and collaboration between the statistical and clinical domain experts. This session is intended to present a current best practice in facilitating and enhancing the collaborative design process for APTs, including how best to present simulation-based trial performance to the design team and ensure effective interdisciplinary communication. The speakers have extensive experience in leading the design of APTs across multiple therapeutic areas, in both academic and industry settings. The session will begin with a brief presentation by Dr. Lewis on the basic structure of an APT and the tasks and challenges associated with the multidisciplinary design process. The subsequent discussion will be organized by the following themes: (1) considerations in the selection of the study population and primary outcome metric;(2) selecting treatment domains and factors to be compared;(3) trial simulation and communication of performance metrics to both statistical and non-statistical team members;and (4) defining and calibrating interim decision rules. Each of the 4 panel members will outline a recommended approach to facilitating 1 of the 4 design tasks, with examples drawn from their experience. The remaining time (15 min) will be available for a panel question-and-answer period. At the end of the session, the audience will have an understanding of the general organization of, and a process for facilitating, the design process for an adaptive platform trial. Panel Members Roger J Lewis, MD, PhD, is a Senior Physician in the Los Angeles County Department of Health Services, Professor of Emergency Medicine at the David Geffen School of Medicine at UCLA, and the Senior Medical Scientist at Berry Consultants, LLC, a group that specializes in innovative clinical trial design. He is also the former Chair of the Department of Emergency Medicine at Harbor-UCLA Medical Center. Dr. Lewis' expertise centers on adaptive and Bayesian clinical trials, including platform trials;translational, clinical, health services and outcomes research methodology;data and safety monitoring boards, and the oversight of clinical trials. Dr. Lewis was elected to membership in the National Academy of Medicine in 2009. He has authored or coauthored over 270 original research publications, reviews, editorials, and chapters. Dr. Lewis is a Past President of the Society for Academic Emergency Medicine (SAEM) and served on the Board of Directors for the Society for Clinical Trials. He is a fellow of the American College of Emergency Physicians, the American Statistical Association, and the Society for Clinical Trials. Juliana Tolles, MD, MHS, is an Assistant Professor of Emergency Medicine at the Harbor-UCLA Medical Center and the David Geffen School of Medicine at UCLA, and a Medical and Statistical Scientist at Berry Consultants, LLC. Her academic research interests include emergency medical services, resuscitation medicine, and trau a care. She has authored several reviews for Journal of the American Medical Association (JAMA) on statistical methodology and has lectured nationally on research methodology for the Society for Academic Emergency Medicine Advanced Research Methodology Evaluation and Design (ARMED) course. She is also a co-investigator for the Strategies to Innovate Emergency Clinical Care Trials (SIREN) network Southern California site. Kert Viele, PhD, is a Director and Senior Statistical Scientist with Berry Consultants, where he leads Berry Consultants' research enterprise. He is a leader in clinical trial implementation of Bayesian hierarchical modeling, with expertise in platform and basket trials as well as clinical trials incorporating the use of historical information. Prior to joining Berry Consultants in 2010, he was a faculty member at the University of Kentucky, where he received the Provost's Award for Outstanding Teaching and was an investigator for NSF and NIH-funded research. He has developed over 100 custom Bayesian adaptive clinical trials for clients in industry, government, and academia, and currently serves on several data safety monitoring boards for randomized clinical trials. A former editor of the journal Bayesian Analysis, Dr. Viele is also an author of FACTS (Fixed and Adaptive Clinical Trial Simulator), clinical trial simulation software currently licensed to multiple pharmaceutical, academic, and government organizations. William Meurer, MD, MS, is an Associate Professor of Emergency Medicine and Neurology at the University of Michigan Health System. In addition, he serves as a Medical and Statistical Scientist for Berry Consultants, LLC. He works to improve the care of patients with acute neurological disease both through his work on the acute stroke team and as a researcher. His work in the field focuses on the design of clinical trials with adaptive and flexible components. In addition, he is a principal investigator of the National Institutes of Neurological Disorders and Stroke (NINDS) Clinical Trials Methodology Course (http:// neurotrials.training) and a co-investigator in the clinical coordinating center of the Strategies to Innovate Emergency Care Clinical Trials (SIREN) network- also funded by NIH). He was a co-investigator on the Adaptive Designs Accelerating Promising Treatments into Trials (ADAPT-IT) project, as part of the FDA Advancing Regulatory Science initiative with NIH.

Collaborating In Times Of COVID: The Launch Of The National Wales COVID-19 Evidence Centre

Introduction. The COVID-19 pandemic has had a dramatic impact on the health and social care landscape, both in terms of service provision and citizen need. Responsive, evidence-based research is essential to develop and implement appropriate policies and practices that manage both the pandemic itself, and the impact COVID-19 has on other health and social care issues. To address this, the Wales COVID-19 Evidence Centre (WCEC) was launched in 2021 with the aim of providing the best available, up-to-date, and relevant evidence to inform health and care decision making across Wales. Methods. Funded by the Welsh Government, the WCEC comprises of a core team and several collaborating partner organizations, including Health Technology Wales, Wales Centre for Evidence- Based Care, Specialist Unit for Review Evidence Centre, SAIL Databank, Public Health Wales, Bangor Institute for Health & Medical Research in conjunction with Health and Care Economics Cymru, and the Public Health Wales Observatory. Over the last year, WCEC has developed its rapid review processes and methodology informed by best international practice and aims to provide around 50 reviews each year. WCEC works alongside various stakeholder groups from health and social care across Wales, and they form an integral part of the review process, from scoping to knowledge mobilization. Results. To date, the WCEC has produced reviews on a diverse range of COVID-19 topics, including transmission, vaccination uptake (barriers, facilitators and interventions), mental health and wellbeing, as well as face coverings and other preventative interventions. The topics have also covered a wide range of populations, from general public, to healthcare workers, to children. These reviews have been used to inform policy and decision-making, including the Welsh Government's Chief Medical Officer 21-day COVID-19 reviews. Conclusions. The WCEC has brought together multiple specialist centers with a diverse range of skills to produce timely reviews of the most up-to-date research to support decision makers across health and social care. These reviews have informed policy and decisionmaking across Wales.

RETHINKING STREETS WITH DISRUPTIVE FORCES: How new mobility and responses to COVID advance street design

Cities in the United States and globally have established goals and values aligning with SDGs that reflect a desire to mitigate climate change, promote equity, encourage social cohesion, improve safety, and promote physical activity. Cities control public space but most cities have prioritized private automobiles for decades. Cities have also been facing significant disruption in the norms in transportation over the last several decades. New technologies like transportation network companies (TNCs), e-scooters, and delivery apps shifted the way cities allocated public space for transportation. Autonomous vehicles pose a new challenge for considering how to design streets. And in 2020, a global pandemic shifted hubs and models of commerce in addition to typical methods of socializing while reducing travel to work. All of these disruptive forces yield moments to reconsider how to re-allocate public space for broader community uses that include a broader array of community residents. In this chapter, we will (1) identify the key values and goals within many cities based on SDGs, (2) describe the external disruptive forces affecting street design, (3) highlight a typology of case studies of rethinking streets under disruption, and (4) offer recommendations for rethinking streets to prioritize people to achieve key values. © 2022 selection and editorial matter, Yizhao Yang and Anne Taufen;individual chapters, the contributors.

Effect of COVID-19 infection and preventive public health measures on haemodynamics, activity and quality of life in patients with pulmonary arterial hypertension

Introduction & ObjectivesIn patients with pulmonary arterial hypertension (PAH), cardiopulmonary haemodynamics and exercise capacity relates to clinical outcomes, and exercise training improves cardiopulmonary function. Public health measures that limit physical activity have been widely enforced to reduce COVID-19 transmission. COVID-19 infection causes endothelial dysfunction, which is central to the pathophysiology of PAH. Here, we describe the temporal effects of UK government restriction measures on daily activity and quality of life (QoL) in patients with PAH and the effect of COVID-19 infection on cardiopulmonary haemodynamics and physical activity.MethodsPatients were enrolled in FIT-PH (NCT04078243) and implanted with remote monitoring devices that provided mean pulmonary artery pressure (mPAP), cardiac output (CO;CardioMEMS, Abbott), day/night heart rate (DHR/NHR), heart rate variability (HRV), and physical activity (PA;Medtronic LinQ). Data were transmitted and reviewed in accordance with established clinical protocols. Standard questionnaires were administered remotely to assess QoL (EmPHasis-10), anxiety (GAD-7), depression (PHQ-9) and collect dates of COVID-19 infection.ResultsFollowing a lockdown, mean activity was reduced compared to pre-lockdown levels (p<0.0001, n=26). QoL was reduced (p<0.01), whereas anxiety (p<0.001) and depression scores increased (p<0.001) compared to pre-lockdown levels. During lockdown measures, there was no change in mPAP, CO, DHR, NHR, or HRV. Of the cohort, 7 patients contracted COVID-19, leading to an decreased CO, increased mPAP and total pulmonary resistance. Consistent with observed changes in haemodynamics PA, HRV, DHR were reduced and NHR increased.ConclusionsIn this cohort of patients with PAH, protective health measures resulted in reduced daily activity and QoL and were associated with increased anxiety and depression indicators. COVID-19 infection resulted in acute changes to haemodynamics and physical activity.

A rapid review of innovations for attraction, recruitment and retention of social care workers, and exploration of factors influencing turnover within the UK context

Context: The UK social care sector has come under increased pressure to combat workforce shortages. With international recruitment of professionals impacted by Brexit and the COVID-19 pandemic, social care is in need of innovations to attract, recruit and retain staff. Objectives: This review aimed to identify (1) innovations to attract, recruit, and retain social workers (professionals working with children and adults to protect them from harm, often as case managers) and the wider social care workforce (workers providing direct practical support to children and adults with their daily activities) and (2) factors influencing staff turnover in the UK context. Method: Pre-defined inclusion criteria were developed using the SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type) framework. Searches were conducted across three databases and 32 key United Kingdom third sector and government organisations from 2001. In total, 1,835 citations were retrieved and 40 met the eligibility criteria (13 for social workers and 28 for social care workforce). Thematic analysis was used to explore the data and presented across two evidence maps. Findings: Evaluation evidence was only available for a small portion of innovations identified. Practice learning, fast-track graduate programmes, and apprenticeships may support the retention of social workers, while pre-employment training, national recruitment campaigns, care work ambassadors, and values-based recruitment could help attraction, recruitment, and retention of the wider social care workforce. Limitations: Most of the included studies were conducted pre-pandemic and mainly relied on descriptive and explorative methodologies. Implications: Future policy initiatives should include an evaluation strategy from the outset to develop a more extensive evidence base. Funding bodies should offer schemes supporting research in this area. © 2022 The Author(s).

Dietetic-led nutrition interventions provided to patients recovering from critical illness from COVID-19 in a large London teaching Hospital from March 2020 to April 2021

Critically-ill COVID-19 patients experience elevated metabolic response (1;2), alterations to gastrointestinal function and deficits in nutritional delivery throughout critical illness and the recovery phase. These contribute to a decline in nutritional status and poorer functional ability on step down to the ward (3) especially in those found to be malnourished on admission (4). The nutrition patients receive in their post Intensive Care Unit (ICU) phase of recovery is now considered equally as important as that received on the ICU, particularly for those already nutritionally compromised, frail or with sarcopenia (5). Guidelines produced by the British Dietetic Association (6) explicitly state the potential role of dietitians in nutritional recovery following COVID-19 critical illness. The aim of this study is to evaluate to role of the dietitian in the nutrition interventions provided patients with COVID-19 during ward-based rehabilitation following a critical care admission, making comparisons with these guidelines. Data was collected and analysed for adult patients with COVID-19 who left ICU during March 2020 to April 2021. Patients were followed from ICU step down to hospital discharge. The study was performed using a prospective observational methodology. Data was available on 177 patients. Demographics presented as mean (SD). ICU admission weight mean 89kg (20.9), BMI 30 kg/m2 (6.7), age 60 years old (12), 67% male, ward length of stay 11days (8.4) and total hospital stay 35.6days (21). 111 (63%) went home, 31 (18%) were transferred to another acute hospital and 27 (15%) discharged to rehabilitation hospital. On step down from ICU patients had lost 8.2kg (6.4) and 8.8% (6.9) weight loss and total stay loss of 9.3kg (6.8) and 9.8% loss (6.8). Guidelines(6) recommend supplemental use of enteral nutrition (EN) and/or high protein supplements to meet nutritional targets where required, enteral feeding tubes should not be removed without dietetic input and ensure community follow up is arranged when required. On discharge from ICU, 37 (21%) were exclusively on EN, 70 (40%) were on Supplementary EN and 68 (38%) needed Oral Nutritional Supplements (ONS). The majority of patients (90%) received dietetic interventions, all were seen within 48 hours of ICU step down and an average of 3 times (2.5). Those who required ENS received it for 6 days (5.5). Nasogastric tubes were removed without dietetic involvement in 58 (54%) patients. For the 107 patients that needed ENS, 34 (40%) used a high protein feed (6.3-7.5grams protein per 100ml), 24 (22%) a high energy feed (150 kcal per 100ml) and 12 (11%) concentrated feed (200 kcal per 100ml). 117 (66%) patients needed ONS over their admission with the majority (62%) using a compact high protein product. 125 (70%) patients needed dietetic follow up on discharge from hospital - 15 for continued EN (12%);68 ONS (54%);and 42 (34%) received healthy eating advice. This study demonstrated that 90% of patients who survived critical illness due to COVID-19 received individualised nutrition interventions from the dietitian to support rehabilitation. Due to the impact of the COVID-19 infection on the ability to eat and drink, EN and/or ONS were clinically appropriate throughout the duration of the ward stay. Dietetic provision met the recommended guidelines for nutrition support in hospital and facilitated further dietetic input on discharge. Feeding tubes were removed in half of patients without dietetic input which may have been premature in some cases and warrants further work on decision making. Patients lost weight over the ICU stay, but this was halted under dietetic-led care post ICU. References 7. Yu, P.J., Cassiere, H., DeRosa, S., et al. Hypermetabolism and Coronavirus Disease. JPEN 2019: 44(7), 1234-1236. 8. Whittle, J., Molinger, J., MacLeod, D. et al. Persistent hypermetabolism and longitudinal energy expenditure in critically ill patients with COVID-19. Critical Care 2020: 24(1) 1-4. 9. Zhu N, Zhang D et al. A novel coronavirus from patients with pneumonia in China. NEJ 2020:382, 727-33 10. Eden, T. and McAuliffe, S. Critical care nutrition and COVID-19: a cause of malnutrition not to be underestimated. BMJ NPH, 2021. 11. Singer P. Preserving the quality of life: nutrition in the ICU. Critical Care 2019: 23 (1) 1-5 12. Critical Care Specialist Group (CCSG) of the BDA Guidance on management of nutrition and dietetic services during the COVID-19 pandemic. 2020. (accessed 24.6.21)

Dietetic-led critical care nutrition interventions provided to critically ill patients with COVID-19 in a large London teaching hospital from March 2020 to April 2021

Many patients admitted to critical care with COVID-19 were at risk of malnutrition due to pre-existing chronic diseases associated with underlying poor nutritional intake and sarcopenia (1). Combined with increased energy expenditure and catabolism (2), alterations to gastrointestinal function and deficits in nutritional delivery during critical illness all risked declining nutritional status and subsequent poorer functional ability. International nutrition guidelines (3-6) recommend providing early enteral nutrition support using protocols. The UK and Australian versions created during the pandemic (3;4) recommend for individualised nutrition therapy by registered dietitians to anticipate and manage the complications commonly seen in these patients that can impact on the provision and type of nutrition support. The aim of this study is to evaluate the role of the dietitian in the nutrition interventions provided to patients with COVID-19 during critical illness and compare with recommended guidelines (3;4). Data was collected and analysed for adult patients with COVID-19 admitted to the intensive care units (ICU) requiring advanced respiratory support and enteral or parenteral nutrition support for longer than 48 hours during the period March 2020 to April 2021. Patients were followed from ICU admission to ward step down. Data was available for 453 critically ill patients. Demographic data presented as mean (SD);age 60 years old (12), 67% male, weight 84kg (20), BMI 29kg/m2 (6) for 20 ICU days (18), mortality of 55%. 167 patients (37%) were classified as high nutritional risk as determined by experienced critical care dietitians for whom nutritional requirements were individually determined by the dietitian within 24 hours of ICU admission. The remaining patients were seen within a mean of 72hrs. 99% (447/453) were enterally fed and the remaining received parenteral nutrition. Patients received on average 5.2 (4.5) dietetic interventions over the ICU stay, irrespective of nutritional risk. Reasons for dietetic interventions were adjustment of feed to account for calorie provision according to metabolic phase (74%);calories derived from sedation (55%);gastrointestinal dysfunction (32%);weaning from enteral nutrition to oral (32%);and renal, fluid and electrolyte adjustments (26%). A range of enteral feeds were used - the majority of patients (93%) received high protein (6.3-7.5grams protein per 100ml), concentrated (18.5%) (200 kcal per 100ml), peptide (9.5%) and protein supplementation (60%). On average those patients who survived lost 8.2kg (6.4) equating to 8.8% (6.9) of total weight over the ICU stay. A dietetic handover was provided for 100% of patients who transferred to the ward. In this study 100% of patients required dietetic input as their nutritional needs could not be met with protocol alone. A significant number were identified as nutritionally at risk, were prioritised as urgent and seen within the guideline timeframes. The dietitian was needed to tailor dietetic interventions to manage complications common in patients with COVID-19. They were also actively involved in adjusting nutrition interventions to facilitate patients’ nutritional recovery and rehabilitation. Patients lost weight over the ICU stay and all patients were handed over to ward dietitians for further dietetic management. References 1. Zhu N, Zhang D et al. A novel coronavirus from patients with pneumonia in China. NEJM 2020:382:727-33 2. Whittle, J., Molinger, J., MacLeod, D., et al. Persistent hypermetabolism and longitudinal energy expenditure in critically ill patients with COVID-19. Critical Care 2020: 24(1) 1-4. 3. Critical Care Specialist Group (CCSG) of the BDA Guidance on management of nutrition and dietetic services during the COVID-19 pandemic. 2020. (accessed 24.6.21) 4. Chapple, L. A. S., Fetterplace, K., Asrani, V., et al. Nutrition management for critically and acutely unwell hospitalised patients with coronavirus disease 2019 (COVID-19) in Australia and New Zealand. Nutrition & Dietetics,2020: 77(4), 426-436. 5. Barazzoni, R., Bischoff, S. C., Breda, J et al. ESPEN expert statements and practical guidance for nutritional management of individuals with SARS-CoV-2 infection. Clinical Nutrition, 2020: 39 (6), 1631-1638 6. Martindale, R., Patel, J. J., Taylor, B., et al. Nutrition Therapy in Critically Ill Patients with Coronavirus Disease (COVID-19). Journal of Parenteral and Enteral Nutrition. 2020: 44 (7), 1174-1184

LARGE VESSEL OCCLUSION STROKE IN A 17 YEAR OLD MALE WITH PAEDIATRIC INFLAMMATORY MULTI-SYSTEM SYNDROME ASSOCIATED WITH SARS-COV-2

Background: Paediatric Cov-2 infections have been less severe than in adults, however some have developed a newly defined syndrome, Paediatric Inflammatory Multisystem Syndrome associated with CoV-2 (PIMS -TS). Its presentation is variable and can cause multi-system involvement. It belongs to the common spectrum of pathogen-triggered hyperinflammatory states, including atypical Kawasaki disease. Case summary: 17 year old male of Ghanaian origin, with no significant past medical history, presented with a one-week history of general malaise, fevers and sore throat. He developed severe chest pain and cardiogenic shock, with a CRP of 200, raised troponin and global hypokinesia on echocardiogram with an ejection fraction of 20%. He was positive for SARS-CoV-2 antibodies (though PCR-antigen negative at admission) and fit the criteria for myocarditis secondary to PIMS-TS. He was treated for sepsis, commenced on IV methylprednisolone and needed intubation, sedation and cardiothoracic ICU level care. On weaning sedation after 3 days, he was found to have left middle cerebral artery syndrome with NIHSS 16. CT head and CT angiogram showed a left MCA ischaemic stroke, and a thrombus in the Sylvian MCA branch. This was treated with antiplatelets. His disease markers and motor deficits improved significantly, however he has cognitive impairment and low mood. Conclusion: PIMS-TS related LVO anterior circulation infarct is rare. It necessitates urgent recognition and multi-specialty involvement as currently management is not standardised. Axial DWI (A), ADC (B) MRI demonstrate large left MCA territory infarct. Axial MRA (C) shows occlusion of the left M2 branches, signal drop-out on SWI (D).

INTESTINAL SPIROCHETES ASSOCIATED WITH ASYMPTOMATIC COVID INFECTION

Purpose/Background: Intestinal spirochetosis has been described as a rare source of colitis caused by the organism Brachyspira pilosicoli. It is more commonly associated with an immunocompromised host, such as those with HIV or post transplant. Spirochetosis can also afflict the immunocompetent host. Hypothesis/Aim: We describe in this case report the diagnosis of intestinal spirochetosis via colonoscopy in an immunocompetent host. They presented with abdominal pain and diarrhea and tested positive for COVID-19. Methods/Interventions: A 60- year old man with history of unprotected intercourse with men but a negative infectious workup for HIV, HSV, gonorrhea and chlamydia presented after multiple weeks of abdominal pain and diarrhea. He reported no recent travels and had a negative colonoscopy 9 years prior. 6 weeks prior to his appointment in the colorectal office, he was in the ER with a CT scan demonstrating diffuse colitis and pulmonary changes consistent with COVID. He tested positive for the virus, despite a lack of symptoms. He followed up in the clinic with ongoing symptoms. An infections workup for GI pathogens, including ova and parasites, C diff, was negative. A colonoscopy was ordered. Results/Outcome(s): The colonoscopy did not reveal any evidence of colitis. Random biopsies of the entirety of the colon were taken. The pathology revealed spirochetes in the mucosa. He was treated with metronidazole with complete resolution of his symptoms. Limitations: This is limited by a single reported instance of a relatively rare entity and in this particular instance associated with COVID infection. Conclusions/Discussion: Intestinal spirochetosis represents an unusual cause of abdominal pain and diarrhea in humans. It has been more commonly associated with immunocompromised host or in certain regions of the world, such as the India and portions of Asia. This instance in an otherwise immunocompetent male with asymptomatic COVID infection represents a unique case. Its symptoms, diagnosis by colonoscopy, and cure with metronidazole reflect the traditional presentation, diagnostic modality and treatment pathway.

SHOULD WE BE TESTING FOR SPIROCHETOSIS IN COVID PATIENTS PRESENTING WITH PERSISTENT DIARRHEA? A CASE STUDY

Purpose/Background: In the US, intestinal spirochetosis (IS) as a cause of infectious colitis has mainly been described in the HIV positive population. This case describes IS in an HIV negative, COVID positive patient suggesting the need for a broader differential of chronic diarrhea in the COVID era. Hypothesis/Aim: To increase awareness of the need for a potentially broader differential of chronic diarrhea in the COVID era. Methods/Interventions: This is a case study describing an association between COVID and intestinal spirochetosis. Results/Outcome(s): Spirochetes, gram negative spiral-shaped flagellated bacteria, are best known for their ability to cause systemic disease in the form of Syphilis and Lyme Disease, but the genus Brachyspiraceae (Brachyspira aalborgi, Brachyspira pilosicoli) has also been described as both a commensal organism and an invasive pathogen causing intestinal spirochetosis (IS). IS in the US has largely been described in the MSM HIV population as a colitis presenting with abdominal pain and persistent diarrhea secondary to epithelial invasion with destruction of the intestinal brush border leading to malabsorption. IS remains an important part of the work up of infectious colitis in this population. In this case study, IS was diagnosed in an HIV negative, COVID positive patient whose COVID diagnosis coincided with the symptomatic presentation of IS suggesting that it is important to include IS in the differential diagnosis of chronic diarrhea in the COVID population regardless of HIV status. In this study, a 60 yo HIV negative MSM presented with abdominal pain x 3 weeks followed by persistent watery diarrhea refractory to imodium. No history of recent travel. No known infectious contacts. Prior colonoscopy 9 years prior to presentation WNL. After one episode of hematochezia, CT abd/pelvis was performed demonstrating colitis and COVID-related changes to the lung bases. Testing confirmed COVID infection, which was self-limited. Initial work up for infectious colitis was negative for gonorrhea, chlamydia, HIV, HSV, O+P, and C. Difficile. Colonoscopy was performed revealing no evidence of gross colitis. Histopathology demonstrated microscopic colitis w/ spirochete colonization of the intestinal epithelium (image 1). A course of metronidazole led to resolution of symptoms. Limitations: This is a descriptive study describing an association, but it does not imply causation. Conclusions/Discussion: Intestinal spirochetosis has been described as a cause of abdominal pain and refractory diarrhea in the US mainly in an immunosuppressed, HIV positive population. This case describes symptomatic intestinal spirochetosis in an HIV negative, COVID positive patient who hitherto COVID diagnosis had no risk factors for immunosuppression suggesting a link between COVID and IS. Further review is necessary to establish a true association, but this case suggests that IS should be considered during the work up of chronic diarrhea in COVID positive patients. (Figure Presented).

RNA Therapeutic Options to Manage Aberrant Signaling Pathways in Hepatocellular Carcinoma: Dream or Reality?

Despite the early promise of RNA therapeutics as a magic bullet to modulate aberrant signaling in cancer, this field remains a work-in-progress. Nevertheless, RNA therapeutics is now a reality for the treatment of viral diseases (COVID-19) and offers great promise for cancer. This review paper specifically investigates RNAi as a therapeutic option for HCC and discusses a range of RNAi technology including anti-sense oligonucleotides (ASOs), Aptamers, small interfering RNA (siRNA), ribozymes, riboswitches and CRISPR/Cas9 technology. The use of these RNAi based interventions is specifically outlined in three primary strategies, namely, repressing angiogenesis, the suppression of cell proliferation and the promotion of apoptosis. We also discuss some of the inherent chemical and delivery problems, as well as targeting issues and immunogenic reaction to RNAi interventions.

Therapeutic Underuse and Delay in Hepatocellular Carcinoma: Prevalence, Associated Factors, and Clinical Impact.

Prognosis of hepatocellular carcinoma (HCC) could be affected by lack of or delayed therapy. We aimed to characterize the prevalence, correlates, and clinical impact of therapeutic underuse and delay in patients with HCC. Patients with HCC diagnosed between 2010 and 2017 were analyzed from the United States National Cancer Database. Logistic regression analysis identified factors associated with no and delayed (>90 days after diagnosis) HCC treatment. Cox proportional hazards regression with landmark analysis assessed the association between therapeutic delay and overall survival (OS), accounting for immortal time bias. Of 116,299 patients with HCC, 24.2% received no treatment and 18.4% of treated patients had delayed treatment. Older age, Black, Hispanic, lower socioeconomic status, earlier year of diagnosis, treatment at nonacademic centers, Northeast region, increased medical comorbidity, worse liver dysfunction, and higher tumor burden were associated with no treatment. Among treated patients, younger age, Hispanic, Black, treatment at academic centers, West region, earlier tumor stage, and receipt of noncurative treatment were associated with treatment delays. In multivariable Cox regression with a landmark of 150 days, patients with and without treatment delays had similar OS (adjusted hazard ratio [aHR], 1.01; 95% confidence interval [CI], 0.98-1.04) with a median survival of 33.7 vs. 32.1 months, respectively. However, therapeutic delay was associated with worse OS in patients who had tumor, nodes, and metastases (TNM) stage 1 (aHR, 1.06; 95% CI, 1.01-1.11) or received curative treatment (aHR, 1.12; 95% CI, 1.05-1.18). Conclusion: One-fourth of patients with HCC receive no therapy and one-fifth of treated patients experience treatment delays. Both were associated with demographic, socioeconomic, and clinical characteristics of patients as well as facility type and region. The association between therapeutic delay and survival was stage and treatment dependent.

Bayesian modeling in COVID-19-disease modeling, therapeutics, and vaccines

COVID-19 efforts have dominated the headlines in 2020. These efforts have involved efforts across the medical and statistical spectrum, from modeling of the pandemic to the development of therapeutics to the testing of possible vaccines. Novel methodologies have been utilized, such as platform trials, Bayesian modeling of pandemic uncertainty, and Bayesian adaptive trials to facilitate timely vaccine delivery. In this session, we will present four real examples of Bayesian methods across this range of activities. These include the official modeling of the epidemic within Los Angeles County by the leader of the team, both design and execution of platforms trials within the COVID-19 pandemic, and the Bayesian Pfizer vaccine trial. All speakers confirmed. Roger Lewis is the leader of the COVID-19 epidemic modeling team for Los Angeles County, California, advising government officials on the progress of the epidemic and projecting future developments. He will discuss the Bayesian SEIR modeling performed for Los Angeles, including capturing uncertainty in the predictions and real-world issues in data collection and adjusting modeling in the presence of evolving medical care and government policies. Ben Saville will discuss therapeutic adaptive platform trials like PRINCIPLE and REMAP-CAP (focus on PRINCIPLE). Both trials are ongoing adaptive platform trials investigating multiple therapies for COVID- 19. PRINCIPLE is a UK national priority trial and is focused on ambulatory participants with suspected COVID-19 and a higher risk of morbidity (e.g. .50 years age with comorbidities). The trial is open-label and has co-primary endpoints of subject-reported time to recovery and hospitalization. REMAP-CAP includes both open-label and blinded interventions focused on hospitalized patients in the intensive care unit across eight countries. The primary endpoint is the number of organ support-free days, and includes multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Both trials use innovative Bayesian modeling that account for potential drift over time, with frequent interim analyses allowing early decisions of futility or superiority. Response-adaptive randomization is used to increase allocation to interventions with better observed outcomes, which can increase statistical power for finding effective therapies and result in better participant outcomes. Mark Fitzgerald will present some of the challenges of execution for the statistical analysis committee for a trial that is rapidly adapting to an ongoing pandemic, with a focus on REMAP-CAP. REMAP-CAP is an adaptive platform trial that explores the efficacy of interventions across a range of treatment domains, including the combinations across domains, that utilizes a novel endpoint: organ-support free days. The international effort combines data from five continents, evaluates thousands of treatment combinations, and rapidly evolves to accommodate information from external sources. The statistical analysis committee faces unique challenges in adjusting to rapid changes when combining data from disparate sources, updating models and reports to incorporate new design features, and producing results for public disclosure for closed domains or interventions, all while ensuring proper communication and maintaining trial integrity. Satrajit Roychoudhury will discuss the design of the Pfizer Bayesian adaptive vaccine trial. This trial incorporates multiple interim analyses, each based on achieving a sufficiently high Bayesian posterior probability of vaccine efficacy. The trial also incorporates early stopping for futility based on Bayesian predictive probabilities. In November 2020, the trial is currently ongoing. Additional information may be publicly available at the time of SCT 2021 that may be discussed, but this will depend on future events at time of submission.

The impact of sleep, physical activity and sedentary behaviour on symptoms of depression and anxiety before and during the COVID-19 pandemic in a sample of South African participants.

During lockdowns associated with the COVID-19 pandemic, individuals have experienced poor sleep quality and sleep regularity, changes in lifestyle behaviours, and heightened depression and anxiety. However, the inter-relationship and relative strength of those behaviours on mental health outcomes is still unknown. We collected data between 12 May and 15 June 2020 from 1048 South African adults (age: 32.76 ± 14.43 years; n = 767 female; n = 473 students) using an online questionnaire. Using structural equation modelling, we investigated how insomnia symptoms, sleep regularity, exercise intensity/frequency and sitting/screen-use (sedentary screen-use) interacted to predict depressive and anxiety-related symptoms before and during lockdown. We also controlled for the effects of sex and student status. Irrespective of lockdown, (a) more severe symptoms of insomnia and greater sedentary screen-use predicted greater symptoms of depression and anxiety and (b) the effects of sedentary screen-use on mental health outcomes were mediated by insomnia. The effects of physical activity on mental health outcomes, however, were only significant during lockdown. Low physical activity predicted greater insomnia symptom severity, which in turn predicted increased depressive and anxiety-related symptoms. Overall, relationships between the study variables and mental health outcomes were amplified during lockdown. The findings highlight the importance of maintaining physical activity and reducing sedentary screen-use to promote better sleep and mental health.