Use of Living Systematic Reviews (LSRS) Beyond COVID-19

Objectives: A LSR is a systematic review that is continually updated, incorporating new evidence as it becomes available. They are conducted in research areas where new evidence is constantly emerging on diagnostic methods, treatments, and outcomes. The objective of this study was to understand the current application of LSRs across research areas. Method(s): Embase, MEDLINE, and the Cochrane Database of Systematic Reviews were searched to identify LSRs. Only the most recent update of a LSR was included. Data regarding the indication, intervention, methods, frequency of updates, and funding were extracted. Result(s): Of the 1,243 records identified, 126 LSRs were included for analysis. The first LSR was published in 2015, with a significant increase in the number of LSRs published starting in 2020, coinciding with the COVID-19 pandemic. The most common indication represented by LSRs was COVID-19 (72%), followed by oncology (10%). Other indications with LSRs included chronic pain, traumatic brain injury, and skin disorders, among others. While most oncology LSRs identified interventional randomized-controlled trials (RCTs) (85%), only 54% of COVID-19 LSRs were restricted to interventional studies, including a combination of RCTS and real-world observational studies. Oncology LSRs included common cancers such as prostate, renal, or multiple myeloma. Of the reviews that reported update frequency, 28% planned monthly, 12% yearly, and 12% weekly updates. Only 46% of LSRs were registered. The majority of LSRs were funded by government or research organizations. Objectives of LSRs varied, with most stating the need to maintain up-to-date databases;however, several studies used LSRs to facilitate network meta-analysis or mixed treatment comparisons. Conclusion(s): While LSRs were introduced over five years ago, their frequency increased during the COVID-19 pandemic. Apart from COVID-19, LSRs are commonly used in oncology settings. LSRs provide high-level, relevant, and up-to-date evidence, making them a useful tool for clinical and real-world research.Copyright © 2023

COVID-associated pernio: Mechanistic insights to an abortive, seronegative SARS-CoV-2 infection

Introduction: SARS-CoV-2 replicates primarily in the airways but generates a systemic immune response mediated by Type I interferons (IFN-I). Pernio is a rare skin manifestation of disorders characterized by excessive IFN-I signalling. Although pernio increased in incidence during the pandemic, the relationship to SARS-CoV-2 remains controversial. Because of the pivotal nature of interferons in COVID-19 outcomes, pernio offers a window to investigate the biology underlying host resiliency to SARS-CoV-2 infection. Method(s): To further assess COVID-associated pernio, we characterized clinical samples from affected patients across 4 waves of the pandemic and investigated mechanistic feasibility in a rodent model. Patients were followed longitudinally with banking of blood and tissue. Golden hamsters were mock-treated or intra-nasally infected with SARS-CoV-2 and harvested at 3-and 30-days post-infection. Result(s): In affected tissue, immunophenotyping utilizing multiplex immunohistochemistry profiled a robust IFN-1 signature characterized by plasmacytoid dendritic cell activation. Viral RNA was detectable in a subset of cases using in situ hybridization for the SARS-CoV-2 S gene transcript. Profiling of the systemic immune response did not reveal a durable type 1 interferon signature. Consistent with previous literature, antibody and T-cell specific responses to SARS-CoV-2 were not detected. Nasopharyngeal SARS-CoV-2 inoculation in hamsters resulted in rapid dissemination of viral RNA and the generation of an IFN-I response that were both detectable in the paws of infected animals. Conclusion(s): Our data support a durable local IFN signature, with direct evidence of viral SARS-CoV-2 RNA in acral skin and suggest that COVID-associated pernio results from an abortive, seronegative SARS-CoV-2 infection.

Of Vaccine and Hesitancy

Vaccinated individuals-like Tolstoy's happy families-are all alike;each unvaccinated individual is hesitant for her own reason. Irrational and unreasonable conspiracy theories about COVID-19 and its vaccine abound among the anti-vaxxers. Contrary to popular belief, however, conspiracy theories are not the main driver of vaccine hesitancy. Whether an individual remains hesitant about receiving a COVID19 vaccine may depend on personal beliefs, informed by a background that is a totality of, for example, race (and its historical past), gender, education, life experience, and information consumption. This individualized background then forms a value system that informs the personal decision-making process as to whether to receive a COVID19 vaccine.

e-Prescription: what are the benefits and challenges for general practitioners and community pharmacists

Background: Since May 2020, the Australian Government has implemented e-prescription to provide convenience and choice to patients, improve efficiency of prescribing and dispensing medications, reduce errors, and minimise use of paper prescriptions. e-Prescriptions are digital prescriptions with a unique QR code which pharmacists could scan for the relevant information to provide patients with the prescribed medications. In the current COVID-19 pandemic environment, this initiative also provides an opportunity to protect community members and healthcare providers from exposure to infectious diseases by contributing to the telehealth services. However, there are mixed opinions amongst GPs and pharmacists about the switch to digital services. Anecdotally, there are also differences in the challenges in e-prescription faced by rural and metropolitan healthcare providers. Aims/Objective: Our study aims to explore the potential benefits, barriers and enablers of e-prescription to GPs and pharmacists in metropolitan Sydney by identifying challenges to and perceptions of its implementation. Findings will be compared with those of a similar study conducted in rural NSW. Method(s): This MBBS student research project is a qualitative study using semi-structured interviews with 10 GPs and 10 pharmacists, recruited via professional networks and social media, to explore their experiences and views about e-prescription. Their responses will be audio-recorded, transcribed and thematically analysed. More interviews will be conducted to reach data saturation if necessary. Findings will be compared with those of the study conducted by the Bathurst Rural Clinical School in 2021. Finding(s): Ethics approval for this project is pending. Data collection is planned to start in May for 2 months. Preliminary results will be presented at this conference. Implications: Findings may facilitate the implementation of e-prescription either through raised awareness of new technology or identification of areas for improvement. Further research to address any barriers that prevent providers from using e-prescription can improve patient care.

CARDIAC MANIFESTATIONS OF MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN AT A TERTIARY REFERRAL CHILDREN'S HOSPITAL

Background: Since the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a new multisystem inflammatory syndrome in children (MIS-C) has been described amongst patients with recent past SARS-CoV-2 infection. The primary objective of this study is to describe a single center experience in relation to cardiac manifestations of MIS-C in an ethnically diverse pediatric population. Methods: We conducted a retrospective chart review of pediatric patients less than 21 of age meeting MIS-C criteria who presented to a tertiary care children's hospital from May 2020 to March 2021. Results: Seventy-eight patients diagnosed with MIS-C (average age 9.7 +/- 4.6 years, 57% male) were included in this study (60 Hispanic, 9 non-Hispanic White, 7 Black, and 1 American Indian). The most common presenting symptoms were nausea and vomiting (76%), abdominal pain (71%), appetite changes (69%), fatigue (64%), and conjunctivitis (63%). The average length of intensive care unit stay was 2.5 days while average total hospitalization was 7.3 days. Forty-nine patients (62%) underwent echocardiography. Of those evaluated, there was systolic dysfunction in 45% with an average ejection fraction of 48%, diastolic dysfunction in 14%, valvular disease in 53%, coronary involvement in 16%, and pericardial effusion in 22%. Electrocardiogram was completed on 37 patients (47%) which revealed heart block in 23% and arrhythmia in 3%. Troponin T was elevated in 32% and pro-BNP was elevated in 89%. Ninety-five percent of patients received immunomodulators during their hospitalization, while 94% received methylprednisolone, 59% received intravenous immunoglobulin, and 19% received Anakinra. There was one mortality. Conclusion: The results of this retrospective study contribute to a growing knowledge base in the literature that MIS-C can exhibit a wide spectrum of cardiac manifestations further underscoring the importance of thorough cardiac workup and regular outpatient follow-up in patients diagnosed with MIS-C.

Precision medicine in renal transplantation: Structural biology of HLA defines allelic binding of cardinal pathogenic viruses in transplantation

Purpose: The incidence, clearance and clinical expression of viremia post-Tx are heterogeneous, complicating prediction, prognosis and therapy. We postulated that variation viral presentation related to HLA type may inform understanding, and we used in silico methods to assess the MHC-peptide binding affinity for three important phylogenetically distinct viruses (SARS-CoV-2, CMV and BKV). Methods: Carrier frequencies for 11 HLA genes (HLA-A, B, C;DRB1, DRB3/4/5, DQA1, DQB1, DPA1, DPB1) were determined by NGS in 1150 renal transplant recipients. All FASTA-formatted viral protein sequence data from the NCBI RefSeq database were kmerized into 8-12 mers. Using netMHCpan, MHC-peptide binding affinities were predicted and affinity scores <500nM were included in the HLA allele rankings Results: A total of 206 Class I HLA alleles identified in 1150 patients exhibited population frequencies ranging from 0.09% to 30%. Within this repertoire, peptide binding varied dramatically identifying low-and high-affinity alleles for each of the three viral proteomes. Alleles with lowest binding propensity were specific to each virus (e.g. HLA-B∗46:01 for SARS-CoV-2, HLA-B∗51:05 for CMV and HLA-B∗15:08 for BKV). In contrast, alleles with the highest binding propensity were remarkably uniform for all 3 viruses (e.g. HLA-A∗02:11 top for all three virus proteomes). Sequence signatures for HLA isoforms in the same allele group defined high or low binding characteristics, the difference being conferred by as little as a single amino acid within the peptide binding region (e.g. HLA-B∗15:08 vs B∗15:03). Carrier rates for predicted SARS-CoV-2 susceptibility/resistance genes in the transplant population were observed to be similar to global population carrier rates (Fig 1). Conclusions: Evaluation of peptide binding provides a unique insight into viral recognition. If confirmed in our current proof-of-principle study comparing sequence and outcome in a large Canadian population, this data may offer a vital biomarker to define risk and treatment within conventional virological patient strata following transplant. (Figure Presented).

Who is a good death for?

This essay introduces the Critical Intervention forum focused on the question “Who is a good death for?” The eight contributions in this Critical Intervention forum use art, prose, performance, and critical analysis to explore this guiding question. Dying well should be for everyone, but as the contributors observe, accomplishing a good death is complicated by context, geography, relationships, politics, and ideology. © 2021 University of California Press. All rights reserved.

Explainable Data Analytics for Disease and Healthcare Informatics

With advancements in technology, huge volumes of valuable data have been generated and collected at a rapid velocity from a wide variety of rich data sources. Examples of these valuable data include healthcare and disease data such as privacy-preserving statistics on patients who suffered from diseases like the coronavirus disease 2019 (COVID-19). Analyzing these data can be for social good. For instance, data analytics on the healthcare and disease data often leads to the discovery of useful information and knowledge about the disease. Explainable artificial intelligence (XAI) further enhances the interpretability of the discovered knowledge. Consequently, the explainable data analytics helps people to get a better understanding of the disease, which may inspire them to take part in preventing, detecting, controlling and combating the disease. In this paper, we present an explainable data analytics system for disease and healthcare informatics. Our system consists of two key components. The predictor component analyzes and mines historical disease and healthcare data for making predictions on future data. Although huge volumes of disease and healthcare data have been generated, volumes of available data may vary partially due to privacy concerns. So, the predictor makes predictions with different methods. It uses random forest With sufficient data and neural network-based few-shot learning (FSL) with limited data. The explainer component provides the general model reasoning and a meaningful explanation for specific predictions. As a database engineering application, we evaluate our system by applying it to real-life COVID-19 data. Evaluation results show the practicality of our system in explainable data analytics for disease and healthcare informatics. © 2021 ACM.

Impact of SARS-COV-2 on the clinical outcomes and placental pathology of pregnant women and their infants: a systematic review

Pregnant women are susceptible to viral infections due to physiological changes such as cell-mediated immunity. No severe adverse pregnancy or neonatal outcomes have been consistently reported in 2019 novel coronavirus disease (COVID-19) positive pregnancy cases. There are controversies around the role of COVID-19 in pregnancy. A systematic review was conducted to examine clinical maternal and neonatal clinical outcomes. Studies were included if they reported SARS-CoV-2 infection among pregnant women and/or COVID-19 positive neonates as validated by positive antibody testing or viral testing using polymerase chain reaction . Case series, case reports, case-control studies, and comparative studies were included. Eight hundred and thirty-seven records were identified, resulting in 525 records for level I screening. Forty-one were included after full-text review. Results suggest elevated rates of intensive care unit (ICU) admission, gestational diabetes, preeclampsia, C-sections, pre-term birth, and C-reactive protein (CRP) in comparison to pregnant women without SARS-CoV-2. Careful monitoring of pregnancies with SARS-CoV-2 is recommended.

SARS-CoV-2-associated ‘covid toes:’ multiplex immunofluorescent characterization of pathophysiology

Coincident with the start of the COVID-19 pandemic, dermatologists worldwide have reported an uncharacteristic increase in pernio or chilblains (aka ‘COVID toes’). However, the lack of systemic illness, low PCR positivity and lack of consistent seroconversion have led some authors to postulate an epiphenomenon. SARS-CoV-2 spike protein has been identified in a limited number of skin biopsies in few publications, yet there remain conflicting reports regarding other SARS-CoV-2 associated proteins, the presence or absence of viral RNA, and a unifying pathophysiology. In cooperation with the COVID Human Genome Effort, our “COVID toes” biobank was established to identify both the genetic and immunologic basis and provide clinically relevant insights into targeted therapeutics. As of March 2021, we have enrolled 96 patients, creating a prospective biorepository with clinical data, saliva, serial blood collection, and skin biopsies. Here we aim to comprehensively investigate the conflicting findings, detail the inflammatory response, and identify the source of interferon signaling with multiplex immunofluorescence (IFA) and the RNAscope fluorescent assay to detect viral mRNA. Median patient age was 17 (range 2 – 72) and 44/96 (46%) were male. Preliminary IFA results demonstrate detection of SARS-CoV-2 components, robust MxA detection and plasmacytoid dendritic cell (pDC) colocalization, identifying PDCs as the likely primary source of IFN-I production and implicates an excessive localized IFN-I response in affected patients.

Characteristics of mild to moderate COVID-19 infection from an urban ambulatory COVID-19 clinic-a guide to triage patients in the clinic

Introduction:Since the start of the pandemic, COVID-19 has spread rapidly. It presents with flu-like symptoms and can cause serious complications in high-risk individuals. Here, we discuss the presentation of COVID-19 infection in an ambulatory setting. Method:Data was collected from all patients who visited the COVID-19 clinic from 03/11/2020- 06/14/2020. Testing was done based on the CDC guidelines at the time using a PCR method. Medical records were reviewed and captured on a RedCap database. Statistical analysis was performed using both univariate and bivariate analysis using Fischer's exact test with 2-sided p values. All analyses were done in person with a high predictive valve per CDC guidelines for testing, and not in general population. Results:Of the 2471 total evaluated patients, 846 (34.2%) were positive for COVID-19. The mean age was 43.4 years (SD+/-15.4), 60.1% were female and 48.4% were Black. There was known exposure to COVID-19 in 58.7% of all people tested, and amongst those with exposure, 33.3% were positive. Hospitalization occurred in 101 patients (11.1%), with a median number of days from testing to hospitalization of 2 (range 0-25) and the median length of stay of 6 days (range 1-51). A total of 22 patients (23.4% of hospitalized patients) required ICU admission and 10 patients died. The overall death rate of patients presenting to COVID clinic was 0.4%, or 1.2% amongst those who tested positive. When compared to patients without COVID-19 infection, the symptoms significantly associated with COVID-19 positivity included anosmia, subjective fever, change in taste, anorexia, objective fever, myalgias, cough, chills and fatigue (Figure 1). No significant differences were noted in other presenting symptoms and vital signs. An increased risk for COVID-19 infection was seen in diabetics [OR 1.39, CI1.09-1.77]. Whereas, individuals with lung disease, asthma and malignancy were not associated with increased risk of COVID-19 infection. No statistically significant association with COVID-19 infection was found in individuals with hypertension, heart failure, COPD, HIV, CKD, ESRD and immunocompromised state. Discussion:Blacks and females had the highest infection rates. Most patients with mild to moderate disease did not require hospitalization. The hospitalization rate was 11.1%, while the death rate for patients who visited COVID-19 clinic was <1%. This suggests there is a broad gap in mortality of those who are very ill and require hospitalization to those who remain ambulatory. The above data could assist health care professionals perform a targeted review of systems and co-morbidities, allowing for appropriate patient triage.

Investigating placental pathologies in pregnant women with and without sars-cov-2: A systematic review and meta-analysis

Background: There is a need to understand if SARS-CoV-2 has the capacity to contribute to diseases of the placenta. Placental pathology results are conflicting, with some evidence suggesting specific placental pathology findings induced by SARS-CoV-2. Patberg et al found that cases were more likely to display evidence of mural fibrin deposition [32.5% (25/77) vs. 3.6% (2/56)] and villitis of unknown etiology (VUE) [20.8% (16/77) vs. 7.1% (4/56)] in comparison to controls. In contrast, He et al reported no significant differences in individual or group gross or microscopic pathological features. A systematic review was conducted in light of the conflicting evidence. Methods: MEDLINE including Epub Ahead of Print, In-Process & Other Non-Indexed Citations (1946-November 17, 2020) and Embase (1980-November 17, 2020) databases were searched. Case series, case-control and cohort studies of asymptomatic and symptomatic pregnant women, who tested positive for SARS-CoV-2 on admission, as validated by laboratory confirmed positive antibody testing or using real-time reverse-transcriptasepolymerase chain reaction (rRT-PCR) were included. Literature reviews, systematic reviews, editorials, conference abstracts, and commentaries were excluded. The primary endpoints were any placental pathology syndromes, as identified by the Amsterdam placental workshop group consensus. Results: Six hundred and twenty-seven articles records were identified, resulting in 481 records for level I screening. After full-text screening (n=41), there were 12 eligible studies remaining for narrative synthesis. Eight (67%) were conducted in the United States. Five (42%) were case control studies, four (33%) case series, and three (25%) retrospective or prospective cohort studies. In total, 507 pregnant women with SARS-CoV-2 who had complete placental pathology reports were examined, in comparison to 18 035 controls. Documented placental pathologies from all studies included: chorioamnionitis (73/507,14%);fetal vascular malperfusion (54/507,11%);maternal vascular malperfusion (42/507, 8%);and chronic villitis and/or chronic deciduitis (124/507, 24%). In contrast, 43% (7791/18035) controls demonstrated any feature of maternal vascular malperfusion;53% (9624/18035) fetal vascular malperfusion;and 37% chronic inflammatory pathology with both low-grade chronic villitis and chronic deciduitis with plasma cells (6739/18035). Conclusion: Our findings demonstrate higher prevalence of placental pathologies in controls than cases;however, further investigation through a meta-analysis is warranted to determine if pregnant women with versus without SARSCoV-2 are at a higher risk of having placental pathologies, while considering maternal comorbidities including hypertensive diseases, diabetes and obesity.

Healthcare workers with COVID-19 infection: Experience from a designated COVID-19 clinic

Background: Healthcare workers (HCW) are at the frontline of the COVID- 19 pandemic, risking infection through hospital contacts. Data regarding predisposing factors in the healthcare field is limited. In this study, we characterized presenting symptoms, occupation and hospitalizations for HCW who tested COVID-19 positive. Methods: This is a retrospective study of HCW who presented for screening to a designated COVID-19 clinic at the largest hospital in Washington, DC between 3/13/20 - 5/28/20. Variables extracted included profession, exposure, presenting symptoms, past medical history and outcomes. Univariate analysis was performed using Fischer's exact tests, with significance defined as p < 0.05. IRB approval was obtained. Results: There were a total of 881 HCW who presented for COVID-19 testing: 316 (35.8%) tested positive;216 (68.4%) were female, mean age was 39. Cough was the most common presenting symptom (92.7%), followed by subjective fever (63.3%), myalgia (57.9%), and chills (46.8%)(Fig 1). RNs [110 (34.8%)] and physicians [39 (12.3%)] accounted for nearly 50% of cases. Hospitalizations occurred in 22(6.9%);2(0.6%) died from COVID-19. See Fig 2 for symptoms associated with hospitalizations. African Americans (OR 4.52, CI95 1.54-12.50), and those with hypertension (3.14, 1.32-7.23) and obesity (2.98, 1.25-6.89) were more likely to be hospitalized. Conclusion: HCW remain at risk for COVID-19 infection with respiratory and constitutional symptoms as the most common presentation. RNs were among the most affected. This study supports other reports that African Americans and those with pre-existing comorbidities have greater morbidity with COVID-19 - we have documented that these inequities are also prevalent amongst HCW. This should be considered when testing for and implementing practices to avoid risk of COVID-19 among HCW. (Figure Presented).