Early infection risk in patients with systemic lupus erythematosus treated with rituximab or belimumab from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR): a prospective longitudinal study

Background: Patients with systemic lupus erythematosus (SLE) are at an increased risk of infection relative to the general population. We aimed to describe the frequency and risk factors for serious infections in patients with moderate-to-severe SLE treated with rituximab, belimumab, and standard of care therapies in a large national observational cohort. Method(s): The British Isles Lupus Assessment Group Biologics Register (BILAG-BR) is a UK-based prospective register of patients with SLE. Patients were recruited by their treating physician as part of their scheduled care from 64 centres across the UK by use of a standardised case report form. Inclusion criteria for the BILAG-BR included age older than 5 years, ability to provide informed consent, a diagnosis of SLE, and starting a new biological therapy within the last 12 months or a new standard of care drug within the last month. The primary outcome for this study was the rate of serious infections within the first 12 months of therapy. Serious infections were defined as those requiring intravenous antibiotic treatment, hospital admission, or resulting in morbidity or death. Infection and mortality data were collected from study centres and further mortality data were collected from the UK Office for National Statistics. The relationship between serious infection and drug type was analysed using a multiple-failure Cox proportional hazards model. Finding(s): Between July 1, 2010, and Feb 23, 2021, 1383 individuals were recruited to the BILAG-BR. 335 patients were excluded from this analysis. The remaining 1048 participants contributed 1002.7 person-years of follow-up and included 746 (71%) participants on rituximab, 119 (11%) participants on belimumab, and 183 (17%) participants on standard of care. The median age of the cohort was 39 years (IQR 30-50), 942 (90%) of 1048 patients were women and 106 (10%) were men. Of the patients with available ethnicity data, 514 (56%) of 911 were White, 169 (19%) were Asian, 161 (18%) were Black, and 67 (7%) were of multiple-mixed or other ethnic backgrounds. 118 serious infections occurred in 76 individuals during the 12-month study period, which included 92 serious infections in 58 individuals on rituximab, eight serious infections in five individuals receiving belimumab, and 18 serious infections in 13 individuals on standard of care. The overall crude incidence rate of serious infection was 117.7 (95% CI 98.3-141.0) per 1000 person-years. Compared with standard of care, the serious infection risk was similar in the rituximab (adjusted hazard ratio [HR] 1.68 [0.60-4.68]) and belimumab groups (1.01 [0.21-4.80]). Across the whole cohort in multivariate analysis, serious infection risk was associated with prednisolone dose (>10 mg;2.38 [95%CI 1.47-3.84]), hypogammaglobulinaemia (<6 g/L;2.16 [1.38-3.37]), and multimorbidity (1.45 [1.17-1.80]). Additional concomitant immunosuppressive use appeared to be associated with a reduced risk (0.60 [0.41-0.90]). We found no significant safety signals regarding atypical infections. Six infection-related deaths occurred at a median of 121 days (IQR 60-151) days from cohort entry. Interpretation(s): In patients with moderate-to-severe SLE, rituximab, belimumab, and standard immunosuppressive therapy have similar serious infection risks. Key risk factors for serious infections included multimorbidity, hypogammaglobulinaemia, and increased glucocorticoid doses. When considering the risk of serious infection, we propose that immunosupppressives, rituximab, and belimumab should be prioritised as mainstay therapies to optimise SLE management and support proactive minimisation of glucocorticoid use. Funding(s): None.Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

A systems immunology study comparing innate and adaptive immune responses in adults to COVID-19 mRNA and adenovirus vectored vaccines.

Identifying the molecular mechanisms that promote optimal immune responses to coronavirus disease 2019 (COVID-19) vaccination is critical for future rational vaccine design. Here, we longitudinally profile innate and adaptive immune responses in 102 adults after the first, second, and third doses of mRNA or adenovirus-vectored COVID-19 vaccines. Using a multi-omics approach, we identify key differences in the immune responses induced by ChAdOx1-S and BNT162b2 that correlate with antigen-specific antibody and T cell responses or vaccine reactogenicity. Unexpectedly, we observe that vaccination with ChAdOx1-S, but not BNT162b2, induces an adenoviral vector-specific memory response after the first dose, which correlates with the expression of proteins with roles in thrombosis with potential implications for thrombosis with thrombocytopenia syndrome (TTS), a rare but serious adverse event linked to adenovirus-vectored vaccines. The COVID-19 Vaccine Immune Responses Study thus represents a major resource that can be used to understand the immunogenicity and reactogenicity of these COVID-19 vaccines.

Refusal to walk post COVID -19 in a child with cerebral palsy and rehabilitation intervention

Musculoskeletal manifestation in child with cerebral palsy post COVID-19 can present with refusal to walk and rehabilitation can facilitate recovery. He is a 4-year-old boy with spastic bilateral cerebral palsy gross motor function classification system level 4 presented to the outpatient rehabilitation consult 3 weeks after COVID-19 infection with refusal to walk. He had 2 days of fever and was relatively well. Subsequently, he refused to stand or walk after 1 week from the onset of fever. During clinical examination, he was uncooperative and refused weight bearing on left lower limb which was kept in a flexed hip and knee position. Further investigation was conducted which included left lower limb X-ray and inflammatory markers. All investigations were reported normal. Child was given a provisional diagnosis of post COVID-19 myalgia. Oral analgesic was prescribed to children for pain control. He was enrolled in a multidisciplinary rehabilitation programme with the aim for gradual return to walking. Exercise prescription included gentle stretching to prevent contractures. Child was put on supported standing with gradual increase time. Play therapy was included to encourage child's participation. He was able to return to his previous walking status after 10 sessions of therapy.Early rehabilitation intervention with strategy to identify the complications in a child with disability post COVID-19 infection may leverage the recovery in this special group.

A systems immunology study comparing innate and adaptive immune responses in adults to COVID-19 mRNA (BNT162b2/mRNA-1273) and adenovirus vectored vaccines (ChAdOx1-S) after the first, second and third doses (preprint)

We longitudinally profiled immune responses in 102 adults who received BNT162b2 (Pfizer-BioNTech) or ChAdOx1-S (Oxford-AstraZeneca) as their primary vaccinations. Bloods were collected pre-vaccination, 1-7 days after the 1st, 2nd and 3rd doses (BNT162b2 or mRNA-1273) to assess innate and early adaptive responses, and ~28 days after the 2nd and 3rd doses to assess immunogenicity. Using a multi-omics approach including RNAseq, cytokine multiplex assay, proteomics, lipidomics, and flow cytometry we identified key differences in the immune responses induced by the ChAdOx1-S and BNT162b2 vaccines that were correlated with subsequent antigen-specific antibody and T cell responses or vaccine reactogenicity. We observed that vaccination with ChAdOx1-S but not BNT162b2 induced a memory-like response after the first dose, which was correlated with the expression of several proteins involved in complement and coagulation. The COVID-19 Vaccine Immune Responses Study (COVIRS) thus represents a major resource to understand the immunogenicity and reactogenicity of these COVID-19 vaccines.

“I depend on her for everything”: A mixed-methods analysis of the role of home care workers caring for medically and socially complex patients during the COVID-19 pandemic

Background: The devastating impact of the COVID-19 pandemic on long-term care facilities has illustrated the need for quality home-based care. Home care workers (HCWs) have played critical roles in meeting the medically and socially complex needs of homebound adults during COVID-19, yet their essential work is often undervalued and understudied. Our purpose was to explore the association between patients' medical and social circumstances and HCW services during COVID-19. Methods: In this mixed-methods study, we collected demographic and clinical data and performed a thematic analysis of medical records from 53 homebound patients with HCWs in a home-based primary care program in New York City. We ed unstructured clinical notes from 12/1/19 - 12/31/20 into a priori and emergent categories, including patient medical and social risk and changes to HCW responsibilities. Core themes were identified via team meeting discussions. Results: Of the 53 patients, 24.5% died during the initial COVID surge, 34% lived alone, and 41.5% had 24-hour HCWs. 50.9% of the patients lived with dementia and the mean Elixhauser Comorbidity Index was 3.66. Three themes emerged from our analysis: 1) Among this high-risk, high-need population, patients with certain risks (i.e. dementia diagnosis, living alone) had more intense and dynamic medical and social needs than others, 2) Patient medical status and risk factors influenced HCW tasks in meeting patient needs, such as managing progressing dementia behaviors or helping food-insecure patients obtain food, and 3) The combined effect of COVID-19 and HCW disruptions (i.e. unstable schedules, aide turnover) created difficult situations for patients and their caregivers, including increased risk of hospitalization and nursing home placement. Conclusions: During COVID-19, HCWs were essential in meeting the existing and new needs of homebound older adults. HCW disruptions were particularly challenging for patients who had more complex medical and social needs, leading to risk of hospitalization. This analysis can inform policies to better integrate HCWs on medical teams, further develop HCW training to identify social as well as medical risks, and address workforce shortages to expand access to adequate HCW services for homebound older adults and their caregivers.

Spatial Temporal Analysis of 40,000,000,000,000 Internet Darkspace Packets

The Internet has never been more important to our society, and understanding the behavior of the Internet is essential. The Center for Applied Internet Data Analysis (CAIDA) Telescope observes a continuous stream of packets from an unsolicited darkspace representing 1/256 of the Internet. During 2019 and 2020 over 40,000,000,000,000 unique packets were collected representing the largest ever assembled public corpus of Internet traffic. Using the combined resources of the Supercomputing Centers at UC San Diego, Lawrence Berkeley National Laboratory, and MIT, the spatial temporal structure of anonymized source-destination pairs from the CAIDA Telescope data has been analyzed with GraphBLAS hierarchical hypersparse matrices. These analyses provide unique insight on this unsolicited Internet darkspace traffic with the discovery of many previously unseen scaling relations. The data show a significant sustained increase in unsolicited traffic corresponding to the start of the COVID19 pandemic, but relatively little change in the underlying scaling relations associated with unique sources, source fan-outs, unique links, destination fan-ins, and unique destinations. This work provides a demonstration of the practical feasibility and benefit of the safe collection and analysis of significant quantities of anonymized Internet traffic.

Supercomputing Enabled Deployable Analytics for Disaster Response

First responders and other forward deployed essential workers can benefit from advanced analytics. Limited network access and software security requirements prevent the usage of standard cloud based microservice analytic platforms that are typically used in industry. One solution is to precompute a wide range of analytics as files that can be used with standard preinstalled software that does not require network access or additional software and can run on a wide range of legacy hardware. In response to the COVID-19 pandemic, this approach was tested for providing geo-spatial census data to allow quick analysis of demographic data for better responding to emergencies. These data were processed using the MIT SuperCloud to create several thousand Google Earth and Microsoft Excel files representative of many advanced analytics. The fast mapping of census data using Google Earth and Microsoft Excel has the potential to give emergency responders a powerful tool to improve emergency preparedness. Our approach displays relevant census data (total population, population under 15, population over 65, median age) per census block, sorted by county, through a Microsoft Excel spreadsheet (xlsx file) and Google Earth map (kml file). The spreadsheet interface includes features that allow users to convert between different longitude and latitude coordinate units. For the Google Earth files, a variety of absolute and relative colors maps of population density have been explored to provide an intuitive and meaningful interface. Using several hundred cores on the MIT SuperCloud, new analytics can be generated in a few minutes. © 2021 IEEE.

How to Help the Elderly Cope with Death and Dying during the Pandemic? The Moral Dilemma of Hong Kong Christians

Christian faith has been a crucial influence on the cultural and ethical formation of Hong Kong since the 17th century, and many hospitals and institutions for elderly palliative care are associated with Christian churches. However, the past one and a half year have been a challenge because of the global covid-19 pandemic. The situation has been particularly difficult for the elderly facing their death as well as for their family members. This paper therefore investigates the concept of a "good death" in Christian ethics and how Christians should practice the ethic of care during the pandemic. The author contends that we should not ignore the great physical and mental needs of these elderly people and their families in the name of public health concerns.

Fast Mapping onto Census Blocks

Pandemic measures such as social distancing and contact tracing can be enhanced by rapidly integrating dynamic location data and demographic data. Projecting billions of longitude and latitude locations onto hundreds of thousands of highly irregular demographic census block polygons is computationally challenging in both research and deployment contexts. This paper describes two approaches labeled "simple" and "fast". The simple approach can be implemented in any scripting language (Matlab/Octave, Python, Julia, R) and is easily integrated and customized to a variety of research goals. This simple approach uses a novel combination of hierarchy, sparse bounding boxes, polygon crossing-number, vectorization, and parallel processing to achieve 100,000,000+ projections per second on 100 servers. The simple approach is compact, does not increase data storage requirements, and is applicable to any country or region. The fast approach exploits the thread, vector, and memory optimizations that are possible using a low-level language (C++) and achieves similar performance on a single server. This paper details these approaches with the goal of enabling the broader community to quickly integrate location and demographic data.

Effect of SARS and COVID-19 outbreaks on urology practice and training.

INTRODUCTION: The objective was to investigate the changes in urology practice during coronavirus disease 2019 (COVID-19) pandemic with a perspective from our experience with severe acute respiratory syndrome (SARS) in 2003. METHODS: Institutional data from all urology centres in the Hong Kong public sector during the COVID-19 pandemic (1 Feb 2020-31 Mar 2020) and a non-COVID-19 control period (1 Feb 2019-31 Mar 2019) were acquired. An online anonymous questionnaire was used to gauge the impact of COVID-19 on resident training. The clinical output of tertiary centres was compared with data from the SARS period. RESULTS: The numbers of operating sessions, clinic attendance, cystoscopy sessions, prostate biopsy, and shockwave lithotripsy sessions were reduced by 40.5%, 28.5%, 49.6%, 44.8%, and 38.5%, respectively, across all the centres reviewed. The mean numbers of operating sessions before and during the COVID-19 pandemic were 85.1±30.3 and 50.6±25.7, respectively (P=0.005). All centres gave priority to cancer-related surgeries. Benign prostatic hyperplasia-related surgery (39.1%) and ureteric stone surgery (25.5%) were the most commonly delayed surgeries. The degree of reduction in urology services was less than that during SARS (47.2%, 55.3%, and 70.5% for operating sessions, cystoscopy, and biopsy, respectively). The mean numbers of operations performed by residents before and during the COVID-19 pandemic were 75.4±48.0 and 34.9±17.2, respectively (P=0.002). CONCLUSION: A comprehensive review of urology practice during the COVID-19 pandemic revealed changes in every aspect of practice.

Enhancing departmental preparedness for COVID-19 using rapid-cycle in-situ simulation.

In response to coronavirus disease 2019 (COVID-19), a rapid-cycle in-situ simulation (ISS) programme was developed to facilitate identification and resolution of systems-based latent safety threats. The simulation involved a possible COVID-19 case in respiratory failure, using a mannequin modified to aerosolize phosphorescent secretions. Thirty-six individuals participated in five ISS sessions over 6 weeks, and a further 20 individuals observed these sessions. Debriefing identified latent safety threats from four domains: personnel, personal protective equipment, supply/environment and communication. These threats were addressed and resolved in later iterations. Ninety-four percent of participants felt more prepared to care for a potential case of COVID-19 after the ISS.