Quantifying caregiver workload during the COVID-19 pandemic using ambient intelligence

Introduction: The COVID-19 pandemic has increased caregiver workload [1]. It is unclear how this workload is distributed across patients with varying presentations. Ambient intelligence (AmI) utilizes neural networks to monitor multiple data points in video feeds, and automatically tracks various aspects of human movement [2]. AmI was used to examine the workload of healthcare staff in relation to temporal and patient characteristics on a COVID ward at a major metropolitan hospital. Method(s): Sensors were deployed in patient rooms on a COVID ward to detect caregiver visits at 5-min intervals. Electronic medical records were used to identify variables hypothesized to contribute to visits. Result(s): 5514 h across 55 patients (mean age 72, range 17-98) were analyzed. The primary reason for admission was medical in 45 cases (81.8%), psychiatric in 8 cases (14.5%) and surgical in 2 cases (3.6%). Medical emergency (MET) calls occurred in 21 (38.2%) cases. As summarized in Fig. 1, visitation was lowest between 0000 and 0400 (27.3 +/- 1.1 min/hour (min/hr)) and highest between 1200 and 1600 (65.5 +/- 1.3 min/hr). The mean +/- SE visitation spent with medical, psychiatric, and surgical patients was 51.7 +/- 0.6, 38.8 +/- 1.3, and 33.7 +/- 3.9 min/hr respectively (p < 0.005). Overall lowest visitation was in surgical patients between 0400 and 0800 (4.5 +/- 4.5 min/hr). Mean +/- SE visitation were 66.7 +/- 4.6 min/hr in the three hours preceding and following MET calls compared to 50.2 +/- 0.5 min/hr in periods without MET calls (p < 0.005). There was no difference in visitation time between patients with respiratory symptoms and those without (50.7 +/- 0.9 vs 48.8 +/- 0.7 min/hr, p = 0.1). Conclusion(s): AmI can help quantify patient workload, potentially improving staff planning. Further studies comparing healthcare attendance between patients on COVID wards and non-COVID wards may provide insight into the impact of unique factors associated with the pandemic.

Definitive Management of Cervical Cancer Patients at an Urban Institution During the COVID-19 Pandemic - Brachytherapy Treatment During the Surge

Purpose: Locally advanced cervical cancer was defined by an international consensus panel as a high priority malignancy during the COVID-19 pandemic, recommending prompt initiation of definitive treatment and completion of treatment (PMID 32563593). The objective of this study was to study the clinical outcomes of patients (pts) with cervical cancer treated with definitive chemoradiation (CRT) and brachytherapy (BT) at our institution in 2019 (pre-COVID) and in 2020 (peri-COVID). Material(s) and Method(s): This was a retrospective cohort study of pts with FIGO Stage IB2-IVA cervical cancer at our institutions from 1/1/2019 to 12/31/2020. Pts received CRT followed by intracavitary brachytherapy (IC) with two operative insertions one week apart, or interstitial (IS) BT with one operative insertion. BT treatment was planned using image-guided CT or MR delineation. Pre-COVID was defined by initiation of CRT in 1/2019-12/2019, and peri-COVID was defined by initiation in 1/2020-10/2020. Process changes peri-COVID included limited on-site staff (e.g., minimal OR staff, no trainees, remote physics team), universal implementation of COVID-19 testing prior to surgery, and CT instead of MR-delineation based treatment. Outcomes of interest were time to treatment initiation and completion and differences in treatment planning modality or dosimetry. Fisher's exact and Mann Whitney U tests were used with significance p<0.05. Result(s): Thirty-one pts were included, with 18 patients undergoing treatment pre-COVID and 13 peri-COVID. The median age at diagnosis pre-COVID was 57.7 (range 23-77) and for peri-COVID, 45.5 (range 28-62, p=0.06). There were no differences in non-English speaking pts (44% vs 59%, p=0.71) or uninsured pts (11% vs 33%, p=0.184) between the two cohorts. Median time to initiation of treatment from biopsy diagnosis was 52 days (range 13-209) in 2019 and for peri-COVID, 55.5 (range 20-173, p=0.71). During COVID, four pts had delayed initiation to treatment >100 days: two related to fertility, and one due to fear of COVID-19. For this pt, tumor size progressed from 2.3 cm to 4.2 cm maximal dimension. One pt treated in 2020 tested positive following treatment and did not require hospital admission. All pts except one completed CRT with RT: 25 pts pelvic RT (45 Gy), 3 pelvic and para-aortic RT (45 Gy with 57.5 Gy concomitant boost to nodes), 8 pts pelvic RT (45Gy) with sequential parametrial boost (50.4-59.4 Gy) using IMRT with no dose differences between pre and peri-COVID (Table 1). No pts required treatment breaks and the median overall treatment time was 50 days (range 31-85) in 2019 vs 50 days (range 43-63) in 2020 (p=0.710). Conclusion(s): Despite the significant burden of the COVID-19 pandemic on our health care system, all cervical cancer pts receiving CRT met standard of care including CRT and BT within the recommended time frame with no significant differences in dosimetric treatment parameters pre- and peri-COVID. Delays in treatment initiation of treatment initiation were seen in 30% of pts in the peri-COVID period, suggesting that patients may have had increased barriers to access care. More follow-up is needed to determine how the Covid pandemic impacted cervical cancer outcome measures. Copyright © 2022

Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice.

The portfolio of SARS-CoV-2 small molecule drugs is currently limited to a handful that are either approved (remdesivir), emergency approved (dexamethasone, baricitinib, paxlovid, and molnupiravir), or in advanced clinical trials. Vandetanib is a kinase inhibitor which targets the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), as well as the RET-tyrosine kinase. In the current study, it was tested in different cell lines and showed promising results on inhibition versus the toxic effect on A549-hACE2 cells (IC50 0.79 µM) while also showing a reduction of >3 log TCID50/mL for HCoV-229E. The in vivo efficacy of vandetanib was assessed in a mouse model of SARS-CoV-2 infection and statistically significantly reduced the levels of IL-6, IL-10, and TNF-α and mitigated inflammatory cell infiltrates in the lungs of infected animals but did not reduce viral load. Vandetanib also decreased CCL2, CCL3, and CCL4 compared to the infected animals. Vandetanib additionally rescued the decreased IFN-1ß caused by SARS-CoV-2 infection in mice to levels similar to that in uninfected animals. Our results indicate that the FDA-approved anticancer drug vandetanib is worthy of further assessment as a potential therapeutic candidate to block the COVID-19 cytokine storm.

PO40 Presentation Time: 4:45 PM: Definitive Management of Cervical Cancer Patients at an Urban Institution During the COVID-19 Pandemic - Brachytherapy Treatment During the Surge

Purpose: Locally advanced cervical cancer was defined by an international consensus panel as a high priority malignancy during the COVID-19 pandemic, recommending prompt initiation of definitive treatment and completion of treatment (PMID 32563593). The objective of this study was to study the clinical outcomes of patients (pts) with cervical cancer treated with definitive chemoradiation (CRT) and brachytherapy (BT) at our institution in 2019 (pre-COVID) and in 2020 (peri-COVID). Materials and Methods: This was a retrospective cohort study of pts with FIGO Stage IB2-IVA cervical cancer at our institutions from 1/1/2019 to 12/31/2020. Pts received CRT followed by intracavitary brachytherapy (IC) with two operative insertions one week apart, or interstitial (IS) BT with one operative insertion. BT treatment was planned using image-guided CT or MR delineation. Pre-COVID was defined by initiation of CRT in 1/2019-12/2019, and peri-COVID was defined by initiation in 1/2020-10/2020. Process changes peri-COVID included limited on-site staff (e.g., minimal OR staff, no trainees, remote physics team), universal implementation of COVID-19 testing prior to surgery, and CT instead of MR-delineation based treatment. Outcomes of interest were time to treatment initiation and completion and differences in treatment planning modality or dosimetry. Fisher's exact and Mann Whitney U tests were used with significance p<0.05. Results: Thirty-one pts were included, with 18 patients undergoing treatment pre-COVID and 13 peri-COVID. The median age at diagnosis pre-COVID was 57.7 (range 23-77) and for peri-COVID, 45.5 (range 28-62, p=0.06). There were no differences in non-English speaking pts (44% vs 59%, p=0.71) or uninsured pts (11% vs 33%, p=0.184) between the two cohorts. Median time to initiation of treatment from biopsy diagnosis was 52 days (range 13-209) in 2019 and for peri-COVID, 55.5 (range 20-173, p=0.71). During COVID, four pts had delayed initiation to treatment >100 days: two related to fertility, and one due to fear of COVID-19. For this pt, tumor size progressed from 2.3 cm to 4.2 cm maximal dimension. One pt treated in 2020 tested positive following treatment and did not require hospital admission. All pts except one completed CRT with RT: 25 pts pelvic RT (45 Gy), 3 pelvic and para-aortic RT (45 Gy with 57.5 Gy concomitant boost to nodes), 8 pts pelvic RT (45Gy) with sequential parametrial boost (50.4-59.4 Gy) using IMRT with no dose differences between pre and peri-COVID (Table 1). No pts required treatment breaks and the median overall treatment time was 50 days (range 31-85) in 2019 vs 50 days (range 43-63) in 2020 (p=0.710). Conclusions: Despite the significant burden of the COVID-19 pandemic on our health care system, all cervical cancer pts receiving CRT met standard of care including CRT and BT within the recommended time frame with no significant differences in dosimetric treatment parameters pre- and peri-COVID. Delays in treatment initiation of treatment initiation were seen in 30% of pts in the peri-COVID period, suggesting that patients may have had increased barriers to access care. More follow-up is needed to determine how the Covid pandemic impacted cervical cancer outcome measures.

Author Correction: A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Host Kinase CSNK2 is a Target for Inhibition of Pathogenic SARS-like ß-Coronaviruses.

Inhibition of the protein kinase CSNK2 with any of 30 specific and selective inhibitors representing different chemotypes, blocked replication of pathogenic human, bat, and murine ß-coronaviruses. The potency of in-cell CSNK2A target engagement across the set of inhibitors correlated with antiviral activity and genetic knockdown confirmed the essential role of the CSNK2 holoenzyme in ß-coronavirus replication. Spike protein endocytosis was blocked by CSNK2A inhibition, indicating that antiviral activity was due in part to a suppression of viral entry. CSNK2A inhibition may be a viable target for the development of anti-SARS-like ß-coronavirus drugs.

Genomewide CRISPR knockout screen identified PLAC8 as an essential factor for SADS-CoVs infection.

Zoonotic transmission of coronaviruses poses an ongoing threat to human populations. Endemic outbreaks of swine acute diarrhea syndrome coronavirus (SADS-CoV) have caused severe economic losses in the pig industry and have the potential to cause human outbreaks. Currently, there are no vaccines or specific antivirals against SADS-CoV, and our limited understanding of SADS-CoV host entry factors could hinder prompt responses to a potential human outbreak. Using a genomewide CRISPR knockout screen, we identified placenta-associated 8 protein (PLAC8) as an essential host factor for SADS-CoV infection. Knockout of PLAC8 abolished SADS-CoV infection, which was restored by complementing PLAC8 from multiple species, including human, rhesus macaques, mouse, pig, pangolin, and bat, suggesting a conserved infection pathway and susceptibility of SADS-CoV among mammals. Mechanistically, PLAC8 knockout does not affect viral entry; rather, knockout cells displayed a delay and reduction in viral subgenomic RNA expression. In a swine primary intestinal epithelial culture (IEC) infection model, differentiated cultures have high levels of PLAC8 expression and support SADS-CoV replication. In contrast, expanding IECs have low levels of PLAC8 expression and are resistant to SADS-CoV infection. PLAC8 expression patterns translate in vivo; the immunohistochemistry of swine ileal tissue revealed high levels of PLAC8 protein in neonatal compared to adult tissue, mirroring the known SADS-CoV pathogenesis in neonatal piglets. Overall, PLAC8 is an essential factor for SADS-CoV infection and may serve as a promising target for antiviral development for potential pandemic SADS-CoV.

Host kinase CSNK2 is a target for inhibition of pathogenic β-coronaviruses including SARS-CoV-2 (preprint)

Inhibition of the protein kinase CSNK2 with any of 30 specific and selective inhibitors representing different chemotypes, blocked replication of pathogenic human and murine {beta}-coronaviruses ({beta}-CoV). The potency of in-cell CSNK2A target engagement across the set of inhibitors correlated with antiviral activity and genetic knockdown confirmed the essential role of the CSNK2 holoenzyme in {beta}-CoV replication. Spike protein uptake was blocked by CSNK2A inhibition, indicating that antiviral activity was due in part to a suppression of viral entry. CSNK2A inhibition may be a viable target for development of new broad spectrum anti-{beta}-CoV drugs.

Human factors and performance: Reducing errors and improving safety

While companies employ a variety of tactics to reduce workplace incidents, behavioral-based programs have proven highly effective-particularly because such programs ensure that safety becomes a collective responsibility shared by all employees. However, training managers and their employees on the fundamentals of behavior-based programs such as the Siemens Energy Human Performance (HuP) program has proven challenging during the global COVID-19 pandemic. Training that traditionally was done in person, where people could interact and discuss root causes of accidents in the same room, had to be replaced with virtual training sessions. This paper reviews the key facets of the HuP program, which includes safety training, raising awareness of employees' susceptibility to human error, and how to design management systems as well as to promote behaviors to prevent safety incidents. It also reviews common practices in the program-including Stop Work authority, Safety Walk & Talks, daily toolboxes, and rapid risk assessment-and how they are being consolidated into one virtual training curriculum. People bring their own personal mix of skills, knowledge, experience, attitudes, motivation, habits, and personality to their jobs-and to each task that they routinely perform. The novelty of the HuP approach is that it empowers workers to recognize where errors occur, use the proper tools to change their habits, and then contribute equally to their own safety and operational excellence, rather than relying on written policies and discipline. The efforts focus on safety within and outside the company. © 2021, Society of Petroleum Engineers

The uclpartners proactive care frameworks-optimising cvd prevention post covid. innovation to restore and improve care in the high-risk conditions and prevent heart attacks and strokes at scale

Introduction COVID-19 has disrupted pathways of care for over 12 months. Primary care has transformed dramatically with much care being provided remotely. The COVID surges and vaccination programme have reduced capacity further. People with conditions such as hypertension, cardiovascular disease and diabetes depend on regular review and treatment optimisation to keep them well. There is a high risk that continued disruption to proactive care will drive an increase in exacerbations and complications. It is likely this will drive further waves of demand for urgent care over the coming months in primary care, in emergency departments and in hospital admissions. Methods The team of GPs & pharmacists at UCLPartners, with patient and public support, developed proactive care frameworks for six conditions including atrial fibrillation, hypertension, high cholesterol and type 2 diabetes mellitus. The frameworks focus on the 'how to' of delivering care in the new world of primary care post COVID-19. They are built on 4 principles: virtual where appropriate, use of the wider workforce, step change in self-management, and use of digital resources. For each condition, the frameworks include: risk stratification tools;pathways that support remote care and deploy staff such as healthcare assistants and social prescribers to systematically support education, self-management and lifestyle change;scripts, protocols and training to guide these staff in consultations;digital tools;and resources to support treatment optimisation. The frameworks include clinical and project management support for local pathway adaptation and implementation. Results The frameworks have gained wide traction in primary care across England. There have been over 2,700 downloads of the search/stratification tools with evidence of implementation in several regions. In the UCLP geography, North East London and North Central London have adopted the frameworks for roll out across 475 GP practices and 2.8 million people. NHSEngland has now adopted the Frameworks as a key part of the NHS@Home programme with plans to support at scale national roll out. Evaluation is being commissioned. Conclusions The UCLPartners Proactive Care Frameworks provide systematic, evidence-based support to restore services post COVID: stratifying so that higher risk patients can be prioritised and workload managed;maximising remote care;optimising personalisation and support for self-care. By using a population health management approach together with comprehensive resources to support clinical management in real world primary care, the frameworks provide a platform not just to restore services but to optimise treatment and outcomes in the high-risk conditions for CVD. The widespread national traction the frameworks are gaining suggests that despite the pandemic, this brings an opportunity to deliver the NHS Long Term Plan ambitions for CVD prevention and prevent 150,000 heart attacks, strokes and cases of dementia.

Safe management of placental adhesive disorders in regional Australia during COVID-19

The incidence of placental adhesive disorders has been increasingly identified as a consequence of rising caesarean sections. Management of these cases is well established using a multidisciplinary team. This case highlights the challenges of delivering safe obstetric care for these women in regional Australia during COVID-19 pandemic restrictions. Patient 'P' was a G8P5 who had 5 previous caesarean sections. She presented late in her pregnancy for routine obstetric care to a rural antenatal clinic. She was identified as high risk and referred to the nearest regional unit for specialist obstetric evaluation. A routine obstetric ultrasound raised concerns of the presence of a placenta accreta, and a subsequent MRI confirmed these findings. Urgent referral to a tertiary centre was made. Further investigations at a tertiary centre concluded the presence of a major placental adhesive disorder requiring MDT input. The delivery of her baby and management of the placenta percreta were difficult with an estimated blood loss of 3800 mLs. This case demonstrates safe obstetric care for high-risk women in regional Australia despite government imposed restrictions in response to COVID-19. This was achieved by utilising best practice guidelines in a collaborative framework between regional healthcare facilities and major tertiary centres. This approach allowed for timely multidisciplinary review and planning of a complex caesarean section including hysterectomy. Finally, this case demonstrated positive obstetric outcomes which can be achieved through appropriate antenatal surveillance, effective communication, team work and tertiary centre support for regional hospitals managing complex cases.

Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine, and Pyronaridine: In Vitro Activity against SARS-CoV-2 and Potential Mechanisms.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) is a newly identified virus that has resulted in over 2.5 million deaths globally and over 116 million cases globally in March, 2021. Small-molecule inhibitors that reverse disease severity have proven difficult to discover. One of the key approaches that has been widely applied in an effort to speed up the translation of drugs is drug repurposing. A few drugs have shown in vitro activity against Ebola viruses and demonstrated activity against SARS-CoV-2 in vivo. Most notably, the RNA polymerase targeting remdesivir demonstrated activity in vitro and efficacy in the early stage of the disease in humans. Testing other small-molecule drugs that are active against Ebola viruses (EBOVs) would appear a reasonable strategy to evaluate their potential for SARS-CoV-2. We have previously repurposed pyronaridine, tilorone, and quinacrine (from malaria, influenza, and antiprotozoal uses, respectively) as inhibitors of Ebola and Marburg viruses in vitro in HeLa cells and mouse-adapted EBOV in mice in vivo. We have now tested these three drugs in various cell lines (VeroE6, Vero76, Caco-2, Calu-3, A549-ACE2, HUH-7, and monocytes) infected with SARS-CoV-2 as well as other viruses (including MHV and HCoV 229E). The compilation of these results indicated considerable variability in antiviral activity observed across cell lines. We found that tilorone and pyronaridine inhibited the virus replication in A549-ACE2 cells with IC50 values of 180 nM and IC50 198 nM, respectively. We used microscale thermophoresis to test the binding of these molecules to the spike protein, and tilorone and pyronaridine bind to the spike receptor binding domain protein with K d values of 339 and 647 nM, respectively. Human Cmax for pyronaridine and quinacrine is greater than the IC50 observed in A549-ACE2 cells. We also provide novel insights into the mechanism of these compounds which is likely lysosomotropic.

Swine acute diarrhea syndrome coronavirus replication in primary human cells reveals potential susceptibility to infection.

Zoonotic coronaviruses represent an ongoing threat, yet the myriads of circulating animal viruses complicate the identification of higher-risk isolates that threaten human health. Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a newly discovered, highly pathogenic virus that likely evolved from closely related HKU2 bat coronaviruses, circulating in Rhinolophus spp. bats in China and elsewhere. As coronaviruses cause severe economic losses in the pork industry and swine are key intermediate hosts of human disease outbreaks, we synthetically resurrected a recombinant virus (rSADS-CoV) as well as a derivative encoding tomato red fluorescent protein (tRFP) in place of ORF3. rSADS-CoV replicated efficiently in a variety of continuous animal and primate cell lines, including human liver and rectal carcinoma cell lines. Of concern, rSADS-CoV also replicated efficiently in several different primary human lung cell types, as well as primary human intestinal cells. rSADS-CoV did not use human coronavirus ACE-2, DPP4, or CD13 receptors for docking and entry. Contemporary human donor sera neutralized the group I human coronavirus NL63, but not rSADS-CoV, suggesting limited human group I coronavirus cross protective herd immunity. Importantly, remdesivir, a broad-spectrum nucleoside analog that is effective against other group 1 and 2 coronaviruses, efficiently blocked rSADS-CoV replication in vitro. rSADS-CoV demonstrated little, if any, replicative capacity in either immune-competent or immunodeficient mice, indicating a critical need for improved animal models. Efficient growth in primary human lung and intestinal cells implicate SADS-CoV as a potential higher-risk emerging coronavirus pathogen that could negatively impact the global economy and human health.

A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures.

Coronaviruses are prone to transmission to new host species, as recently demonstrated by the spread to humans of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic1. Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures2,3. SARS-CoV-2 cannot infect wild-type laboratory mice owing to inefficient interactions between the viral spike protein and the mouse orthologue of the human receptor, angiotensin-converting enzyme 2 (ACE2)4. Here we used reverse genetics5 to remodel the interaction between SARS-CoV-2 spike protein and mouse ACE2 and designed mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA), a recombinant virus that can use mouse ACE2 for entry into cells. SARS-CoV-2 MA was able to replicate in the upper and lower airways of both young adult and aged BALB/c mice. SARS-CoV-2 MA caused more severe disease in aged mice, and exhibited more clinically relevant phenotypes than those seen in Hfh4-ACE2 transgenic mice, which express human ACE2 under the control of the Hfh4 (also known as Foxj1) promoter. We demonstrate the utility of this model using vaccine-challenge studies in immune-competent mice with native expression of mouse ACE2. Finally, we show that the clinical candidate interferon-λ1a (IFN-λ1a) potently inhibits SARS-CoV-2 replication in primary human airway epithelial cells in vitro-both prophylactic and therapeutic administration of IFN-λ1a diminished SARS-CoV-2 replication in mice. In summary, the mouse-adapted SARS-CoV-2 MA model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN-λ1a as a treatment for human COVID-196.

Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the novel viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV) potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 µM). Weaker activity is observed in Vero E6 cells (EC50 = 1.65 µM) because of their low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase of SARS-CoV-2. In mice infected with the chimeric virus, therapeutic RDV administration diminishes lung viral load and improves pulmonary function compared with vehicle-treated animals. These data demonstrate that RDV is potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for treatment of COVID-19.