Dried blood spot (DBS) sample analysis for drug and metabolomic profiling in oncology clinical trials: Cost-effective decentralized sampling modality for precision Oncology

The COVID19 pandemic accelerated opportunities for innovation within the decentralization process of clinical trials with opportunities for implementation of patient-centric workflows for efficiency and cost-reduction. Decentralized sample collection, particularly whole blood using dried blood spots (DBS) provides the ideal mechanism for patient driven sample collection with ease of access to sample generation, drug level assessments and metabolomic prMegofiling, providing longitudinal real-time measure of drug specific pharmacodynamic readout for safety and efficacy. In this study, we report the development of a protocol for the capture and comprehensive profiling of metabolomics using dried blood spots from a cohort of 49 healthy volunteer donors. Using liquid chromatography combined with mass spectrometric (UPLC-MS/MS) methods an untargeted metabolomic approach resulted in the identification of >800 biochemicals of which a significant subset was found to be presented in corresponding matched plasma (from whole blood) samples. The biochemicals identified from the DBS samples included metabolites that were part of the lipid, amino acid, nucleotide, peptide, cofactors, carbohydrate and energy super pathways. A significant number of metabolites identified in the DBS samples were xenobiotics including those representing the biotransformation products of drugs. The overall metabolite profiles were analyzed for precision and accuracy of measure, variability in performance and dynamic range to establish benchmarks for evaluation. An additional cohort with a longitudinal sampling as part of the protocol provided the reproducibility of the analytic method for inter-day variability of metabolite performance over time. Although metabolomic profiles varied between individuals from a population perspective, there was minimal variation observed within individuals when samples were profiled longitudinally over several weeks. Thus, the protocols for DBS collection and the corresponding capture of a large set of metabolites with reproducible performance provides an opportunity for its implementation in oncological clinical trials as part of a de-centralized clinical trial solution.

Stimulation of the ssRNA virus immune receptor, Toll-like receptor 7, on megakaryocytes increases thrombopoesis

Background: TLR7/8 are immune receptors expressed in megakaryocytes which detects single-stranded RNA viruses such as SARS-CoV- 2. There is increasing evidence that in addition to raised platelet counts, severe infection with SARS-CoV- 2 increases the risk of venous, arterial and microvascular coagulation. Aim(s): To determine if ssRNA viruses are capable of increasing thrombopoeisis through direct interaction with megakaryocytes. Method(s): Cells were incubated with and without Gardiquimod (GDQ), a specific agonist of TLR7/8 in cord blood derived (CBMKs) and mouse bone marrow derived megakaryocytes (mMKs). TLR7/8-/- iPSC derived megakaryocytes (iPSC-MKs) were produced using CRISPR Cas9 editing of iPSCs and forward programming using an doxycyclin inducible cassette. GFP labelled SARS-CoV- 2 virus was incubated with the TLR7/8-/- iPSC- MKs and wild-type iPSC-MKs. Result(s): Incubation with GDQ increased platelet production in CBMKs and mMKs, and increased platelet function. Increased platelet counts were seen in mice treated with GDQ, and mice infected with influenza. Incubation with GDQ induced increased expression of IL1beta in the parental iPSC-MKs, however in the TLR7-/- and TLR7/8-/- MKs, no increased expression was observed. There was a significant increase in platelet production from the parental iPSC-MKs in response to incubation with GDQ, which was not seen in the TLR7-/- and TLR7/8-/- MKs. Incubation of the GFP-labelled SARS-CoV- 2 virus with wild-type MKs did not lead to a significant increase in fluorescence. Only very low level viral sequences were found in the cells post-incubation demonstrating that penetration within the MKs is unlikely to be of significance. Studies are ongoing to ascertain whether SARS-CoV- 2 induces outside in signalling leading to changes in transcription within the MKs (such as elevation of IL1beta). Conclusion(s): TLR7/8 agonists, including ssRNA genome viruses, increase platelet production and functionality from megakaryocytes. SARS-CoV- 2 does not appear to penetrate and significantly replicate within MKs, however incubation with megakaryocytes did show elevated expression of IL1beta. (Figure Presented).

PULSERIDER-ASSISTED TREATMENT OF INTRACRANIAL ANEURYSMS IN THE STERLING REGISTRY

Introduction PulseRider (Cerenovus, Irvine, CA) is an adjunctive neck bridging device designed to aid in coiling of wide neck bifurcation intracranial aneurysms. We present outcomes of PulseRider assisted coil embolization of brain aneurysms in routine clinical practice included in the STERLING registry. Materials and Methods STERLING (NCT03642639) is a prospective, global registry of endovascular treatment of intracranial aneurysms with Galaxy and MicrusFrame coils (Cerenovus, Irvine, CA). PulseRider cases from STERLING were included in this interim analysis. Primary outcome measures were core-lab assessed modified Raymond-Roy (mRR) occlusion at final procedural angiogram, and where available, at 6 months (+/-3 months) or 1 year (COVID allowed window: -3 months/+1.5 years). Safety outcomes were procedureand device-related adverse events. Results Seventeen subjects (mean age 64.4 ± 8.69 years, 12 female) were treated with the PulseRider device. All cases were unruptured and two were retreatments of previously coiled aneurysms. All aneurysms had saccular morphology, 14/ 15 (93.3%) were wide neck and 13/15 (86.7%) were at a bifurcation. Target aneurysm locations included basilar artery (6/15, 40.0%), MCA bifurcation (4/15, 26.7%), ACA (3/15, 20%), ICA terminus (1/15, 6.7%), and M2 (distal to bifurcation, 1/15, 6.7%), with a mean parent vessel diameter of 2.65 ± 0.440mm. PulseRider was successfully implanted with the ability to retain the coil mass in all cases. Mean packing density was 29.7 ± 11.32%. Adequate occlusion (mRR I or II) was achieved in 86.7% (13/15) cases immediately post procedure, 100% (3/3) at 6 moths, and 75% (3/4) at 1 year. There were no intraprocedural ruptures, no symptomatic thromboembolic events, and no device related SAEs through the maximum follow up. 87.5% (7/8) subjects had mRS 0-2 at 1 year. There were no aneurysm retreatments. Conclusion In this interim analysis of the ongoing STERLING registry, treatment of intracranial aneurysms with the PulseRider device in conjunction with embolization using Galaxy and MicrusFrame coils showed excellent safety outcomes and high rates of adequate occlusion and good clinical outcome.

Managed Wildfire: A Strategy Facilitated by Civil Society Partnerships and Interagency Cooperation

Federal land managers in the United States are permitted to manage wildfires with strategies other than full suppression under appropriate conditions to achieve natural resource objectives. However, policy and scientific support for “managed wildfire” appear insufficient to support its broad use. We conducted case studies in northern New Mexico and southwestern Utah to examine how managers and stakeholders navigated shifting barriers and opportunities to use managed wildfire from 2018 to 2021. The use of managed wildfire was fostered through an active network of civil society partnerships in one case, and strong interagency cooperation and existing policies and plans in the other. In both, the COVID-19 pandemic, drought, and agency direction curtailed recent use. Local context shapes wildfire response strategies, yet centralized decision-making and policy also can enable or constrain them. Future research could refine the understanding of social factors in incident decision-making, and evaluation of risks and tradeoffs in wildfire response. Implications Managers and stakeholders seeking to restore fire’s ecological roles in their own landscapes through the use of managed wildfires could use these findings to cultivate supportive local environments for their objectives. Both case studies offer examples of how managed wildfires may be facilitated through civil society partnerships and interagency cooperation. Networks of civil society and agency partners can encourage policy change at multiple levels through concerted efforts over time, particularly by building a larger case through localized examples of collaborative projects and a body of regionally relevant scientific evidence. Strong interagency cooperation on both mitigation and response can also foster an environment of mutual understanding, even given differing missions and mandates for managed wildfire. Management implications Federal wildfire response must consider multiple objectives that may compete across scales, social-ecological contexts, and timeframes. These include minimizing negative impacts on human values, responding to immediate risks of fire exposure, managing land sustainably under longer timeframes;and meeting accomplishment targets, such as acres of hazardous fuels reduction, ecological restoration, and other resource objectives. Federal wildfires and land managers are permitted to manage wildfires for natural resource objectives but face challenges of ambiguous terminology, conflicting policies, drought, increasing numbers of homes in wildlands, and unanticipated events, such as the COVID-19 pandemic. Conditions, opportunities, and barriers to manage wildfire vary substantially by locality and are dependent on local actors, yet also subject to higher-level changes in policy direction. Beyond improved risk analytics and decision support tools, enabling social and internal institutional conditions may also facilitate opportunities for use of managed wildfire. Social science can provide evidence and frameworks including concrete lessons learned, expanded use of after-action reviews, process monitoring, briefings with leadership, and science application through boundary-spanning organizations. © 2022 Taylor & Francis Group, LLC.

STROKE CARE QUALITY BETWEEN 2017- 2020: OBSERVATIONAL DATA FROM THE AUSTRALIAN STROKE CLINICAL REGISTRY

Background and aims: National clinical quality registries facilitate reliable monitoring of stroke care by providing local hospital teams with data on their performance compared to national benchmarks. We aimed to assess changes in stroke care over time from public hospitals participating in the Australian Stroke Clinical Registry (AuSCR). Methods: AuSCR stroke quality care indicators were compared between 2017 and 2020, using a matched-hospital design. Analyses were limited to adults with stroke or transient ischaemic attack admitted to hospitals contributing ≥30 episodes each year during the study period. Descriptive statistics and linear tests for trend were used to assess changes in quality indicators across years. Results: Among 47 eligible hospitals, admissions increased from 13,508 (2017) to 18,139 (2020). Overall, half were aged ≥75 years, 45% were female, and 59% had a severe stroke (no differences by year). Between 2017 and 2020, improvements were observed for: endovascular retrieval (+8%;P<0.001), hyperacute antithrombotics (+6%;P<0.001), mobilisation during admission (+3%;P<0.001), swallow screen/assessment within 4 hours (+12%;P<0.001), discharge care planning (+11%;P<0.001), and discharge secondary prevention medications (+10%;P<0.001). However, delivery of thrombolysis remained unchanged (-1%;P=0.07), door-toneedle within 60 minutes decreased (-6%;P=0.008), and access to stroke unit care declined in 2020 (76% 2019 vs 72% 2020;P<0.001). Conclusion: Improvements in many indicators of quality stroke care have been observed within Australian hospitals participating in a national registry. Declines in timeliness to thrombolysis and access to stroke units in 2020 represent a likely consequence of the COVID-19 pandemic that requires national action.

The Impact of COVID-19 on Social Work Practice in Canada: A Comparison of Urban and Rural Contexts

Social workers involved in child maltreatment investigations faced considerable challenges during the COVID-19 pandemic. Interactions with children and families carried new restrictions and risks, which resulted in changes in practice. We conducted a two-phase, mixed-methods study which examined the impact of the COVID-19 pandemic on social workers who work with maltreated children from both urban and rural areas across Canada. More specifically, we examined changes in service delivery, as well as perceptions of safety, stress, worry, and how support differed between urban and rural social workers. Fifty social workers (62% urban, 38% rural) responded to the Phase 1 survey, disseminated in May 2020, with 34 (76% urban, 24% rural) responding to the Phase 2 survey in November 2020. Quantitative and qualitative data revealed that rural social workers reported more worry, stress and a greater need for mental health support, in addition to receiving less support than urban social workers during the first wave of COVID-19 cases. However, during the second wave of cases, urban social workers reported more stress, a greater need for mental health support, and receiving less support than rural social workers. Additional research is needed to further uncover the nature of the differences between rural and urban social workers, and to identify the prolonged effects of the COVID-19 pandemic on social workers. © 2021. All Rights Reserved.

Glycosuria induced hypernatremia secondary to COVID-19

Case Report The purpose of this study is to describe a case study of possible glycosuria-induced hypernatremia in a patient hospitalized with COVID-19 acute respiratory distress syndrome. Methods Used Case study and literature review Summary of Results A 55-year-old man with a past medical history of non-insulin-dependent type II diabetes and hypertension developed hypernatremia, glycosuria, and acute kidney injury in the setting of COVID-19 pneumonia after resolution of diabetic ketoacidosis. The patient was initially admitted with a positive SARS-COVID-19 screening, a creatinine of 1.1 mg/dL (0.5-1.2) with glycosuria, and sodium of 137 mmol/L (136-145). Seventeen days into his hospital admission for severe acute respiratory distress syndrome, he developed hypernatremia (147 mmol/L). Over the subsequent twenty-two days, the patient continued to have hypernatremia up to 153 mmol/L refractory to treatment. In addition, the patient had persistent glycosuria and an elevated creatinine of 2.3 mg/dL (greater than thirty percent above his baseline). His total fluid balance was +1444 mL during this phase of hospitalization. The patient's electrolyte derangements concomitant with his worsening renal function suggests possible Fanconi syndrome. We hypothesize this is secondary to COVID-19. Conclusion COVID-19 has been shown to be associated with renal dysfunction, including acute tubular injury, such as membranous nephropathy and Fanconi syndrome. Experimental data have suggested that COVID-19 can infect renal proximal tubular cells via the Angiotensin Converting Enzyme 2 with subsequent development of incomplete Fanconi syndrome preceding acute kidney injury. Studies have also shown that glycosuria, proteinuria, pyuria, and hematuria may occur with COVID-19 regardless of comorbidities. We concluded our patient developed refractory hypernatremia secondary to glycosuria induced incomplete Fanconi syndrome due to COVID- 19.

Iatrogenic opioid withdrawal syndrome in the intensive care unit: A case report

Purpose of Study Describe possible iatrogenic opioid withdrawal syndrome in a mechanically ventilated and sedated COVID-19 patient. Methods Used Case study Summary of Results A 41-year-old man presented with acute hypoxic respiratory failure due to COVID-19 requiring mechanical ventilation and high dose sedation with fentanyl over several days. Past medical history included type 2 diabetes, hypertension, rheumatoid arthritis on immunosuppressive medications, gout, and morbid obesity. The patient received an IV fentanyl infusion over fifteen days of approximately 50,000 mcg of fentanyl IV. The patient had frequent episodes of hypertension, delirium, and agitation while weaning from this sedation protocol. The CAM-ICU score and vital signs were used to assess for possible opioid withdrawal. Post-extubation, he received fentanyl at 10 micrograms per hour for three days to limit withdrawal symptoms. Discussion Approximately one-fourth of mechanically ventilated patients who received opioid infusions experience iatrogenic opioid withdrawal syndrome. Opioid withdrawal syndrome in an intubated and sedated patient can be challenging to identify. Classical diagnostic criteria outlined in the DSM-V include three or more of the following: dysphoric mood, nausea, vomiting, muscle aches, lacrimation, rhinorrhea, pupillary dilation, piloerection, sweating, diarrhea, yawning, fever, and insomnia. Relying on these symptoms in intubated and sedated patients with complex medical pathologies can confound the results of identifying and adequately treating Iatrogenic Opioid Withdrawal Syndrome. This case emphasizes the importance of judicious sedation in the intensive care setting and using bedside scales, such as the CAM-ICU score and autonomic changes in vital signs, to assess patients for withdrawal.

Gaisbock in 2021

Case Report The purpose of the study is to explore the possible diagnosis of Gaisbock in a patient with long-standing erythrocytosis and hypertension. Methods Used Case Study Summary of Results A 40-year-old Caucasian man with obesity was admitted with recurrent leg swelling and increasing oxygen requirements two weeks after hospitalization with COVID-19 pneumonia. Upon review of the patient's history, he was found to have untreated hypertension over several medical encounters and an erythrocytosis spanning ten years. Recent medical history included a diagnosis of deep vein thrombosis (DVT) in the same leg two and a half months prior and was treated with Xarelto. The patient reported a history of low testosterone for 12 years. However, he had not used any testosterone supplementation for the last nine months. He reported daytime fatigue, frequent bouts of nighttime awakenings, and frequent snoring. The patient never had a sleep study or used a CPAP. The patient used half a can of chewing tobacco daily for thirteen years, and he smoked one pack per day for ten years but quit 12 years ago. He worked strenuous jobs in the construction industry most of his life. On this admission, the patient's lab work was notable for hemoglobin of 18.7 gm/dL (13.7-17.5) and a normal erythropoietin level of 5.7 MIU/mL (2.6-18.5) without thrombocytosis or leukocytosis and a positive factor V Leiden mutation. His blood pressure was 132/91 mmHg. On review of previous records, the patient was found to have consistently elevated hemoglobin The patient had a stocky, ruddy appearance without hepatosplenomegaly. Conclusion Erythrocytosis can be categorized as primary, secondary, or relative. Patients with relative erythrocytosis have a decreased plasma volume with a relative increase in hemoglobin. Additionally, elevated hemoglobin levels have been associated with hypertension. Gaisbock's syndrome, first described in 1905, is characterized by hypertension and erythrocytosis without splenomegaly, leukocytosis, or thrombocytosis. It is associated with mild obesity, elevated blood pressure, and increased blood viscosity, which may explain why these patients often develop cardiovascular complications. Patients with relative erythrocytosis are at a higher risk for thromboembolic complications. In this case, Gaisbock's syndrome was suspected because the patient had had a stocky, plethoric appearance with persistently elevated hemoglobin and blood pressure with a normal erythropoietin level. Gaisbock's syndrome establishes a relationship between benign erythrocytosis, hypertension, and an increased risk for cardiovascular events. (Table Presented).

Antiplatelet therapy and covid-19 outcomes in patients with stable coronary artery disease

Introduction: Severe COVID-19 can cause acute respiratory distress syndrome (ARDS), with pulmonary pathology composed of platelet microthrombi. Antiplatelet agents have been investigated as a treatment in ARDS, but without clear evidence of benefit. The decision on antiplatelet use in patients with COVID-19 and coronary artery disease (CAD) is key. Hypothesis: We assessed the hypothesis that increased use of antiplatelet therapy was associated with no worse clinical outcomes in COVID-19 among adults with stable CAD. Methods: We performed a retrospective cohort study of patients who presented with COVID-19 to two New York City hospitals from March 3 to May 15, 2020. Patients were separated into groups based on antiplatelet use, including no outpatient antiplatelet use, monotherapy, and dual antiplatelet therapy (DAPT). Outcomes and complications were compared among the groups, using propensity scoring with inverse probability of treatment weighting. Results: This study included 315 patients with stable CAD and COVID-19. Patients on no outpatient antiplatelet therapy were significantly older and more likely to be taking anticoagulation, while patients on DAPT had the highest rates of diabetes and chronic kidney disease. The most prescribed antiplatelet in the cohort was aspirin (72.1%) followed by clopidogrel (22.5%). There was no difference in COVID-19 admission mortality between the DAPT and monotherapy groups (DAPT 27.9%, monotherapy 27.2%, p=NS). Patients on DAPT had decreased rates of venous thromboembolism compared to monotherapy (DAPT 0.0%, monotherapy 6.4%, p=0.01), and bleeding rates were similar. The rate of home monotherapy continuation in hospital was 79.9%, with the most common reasons for discontinuation being hemorrhage, anemia, and thrombocytopenia. No outpatient antiplatelet use was a high-risk group, with the highest rates of intensive care admissions, intubations and mortality. Conclusions: In conclusion, we found no difference in COVID-19 outcomes for CAD patients on DAPT compared to those on monotherapy. There were decreased clotting complications in patients on more antiplatelet therapy, while bleeding rates were similar. No outpatient antiplatelet use was found to be a high-risk group in COVID-19.

Towards predicting COVID-19 trends: Feature engineering on social media responses

During the course of this pandemic, the use of social media and virtual networks have been at an all-time high. Individuals have used social media to express their thoughts on matters related to the pandemic. It is difficult to predict current trends based on historic case data because trends are more connected to social activities which can lead to the spread of coronavirus. So, it's important for us to derive meaningful information from social media as it is widely used. Therefore, we grouped tweets by common keywords, found correlations between keywords and daily COVID-19 statistics and built predictive modeling. The features correlation analysis was very effective, so trends were predicted very well. A RMSE score of 0.0425504, MAE of 0.03295105 and RSQ of 0.5237014 in relation to daily cases. In addition, we found a RMSE score of0.07346836, MAE of 0.0491152 and RSQ 0.374529 in relation to daily deaths. © 2021 Information Systems for Crisis Response and Management, ISCRAM. All rights reserved.

"more than learning": Teaching and learning ethics within an electrical engineering undergraduate capstone course

How learning is conceptualized and negotiated within the engineering undergraduate curriculum is affected by the theory of learning implicit in the design of the curriculum. The shift to online learning due to restrictions brought about by the COVID-19 pandemic provides the opportunity to make visible aspects of the curriculum that were previously hidden. The paper presents evidence of student learning relating to ethics found in student assignments submitted in partial fulfillment of a capstone course that forms part of the undergraduate program for Electrical Engineering at the University of Cape Town. Evidence of student learning will be linked to three distinct theories of learning that are presented and contrasted as metaphors: A theory of learning that assumes transference and is acquisition-based;a theory of learning that assumes transference by means of participation within a community and a theory of learning that is activity-centered and aims to be transformative. Each of these theories will be linked to particular teaching approaches and assessment strategies. The learning theories provide a frame to examine evidence of student learning relating to ethics in a particular context. This process justifies an expanded conception of learning relating to ethics in engineering. © 2021 South African Institute of Electrical Engineers. All rights reserved.

Additional cost in personal protective equipment to NHS services during COVID-19: a review of the expense incurred by Aneurin Bevan Healthboards Maxillofacial unit over a one-year period to meet current clinical guidelines.

COVID-19 has led to increased levels of personal protective equipment (PPE) in surgical specialties. Aneurin Bevan Healthboard Oral and Maxillofacial unit sees approximately 2,808 patients per annum and to meet current guidelines this added PPE is estimated to cost an extra £32,292. Whilst this helps improve safety for clinicians and patients, we also recommend that evidence is regularly reviewed to assess what PPE is justified at different stages of viral prevalence.