Convalescent Plasma Treatment of Severe Covid-19 Cases in the Bronx, Ny

Junior Physician Investigator Award Recipient Purpose of study Severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2) is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Convalescent plasma obtained from recovered persons was used for previous respiratory pandemics. Convalescent plasma with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) antibodies (CCP) was proposed as an option that may hold promise as treatment for COVID-19. Our aim was to retrospectively evaluate the efficacy of CCP treatment of patients with severe to life-threatening COVID-19 hospitalized at Montefiore Medical Center (MMC) in the Bronx, NY between April 13 to May 4, 2020. Methods used We administered CCP as part of the Mayo Clinic expanded access investigational new drug (IND) program for hospitalized patients. We compared the mortality and clinical outcome of 73 patients with COVID-19 who received 200 mL of CCP with a Spike protein IgG titer >=1:2,430 (median 1:47,385) within 72 hours of admission to 1:1 propensity score-matched controls. Matching criteria for controls were age, sex, body mass index, race, ethnicity, comorbidities, week of admission, oxygen requirement, D-dimer, lymphocyte counts, corticosteroids, and anticoagulation use (figure 1). We additionally measured Spike protein IgG and neutralizing antibody titer in CCP and pre- and post-transfusion Spike protein IgG, IgM and IgA titer in CCP recipients. The primary outcome was all-cause mortality at day 28 post-CCP. The secondary outcomes were improvement in oxygenation status or mortality at day 28 post-CCP. Exploratory outcomes were associations between pre-CCP SARS-CoV-2 antibody titers and mortality at day 28. Summary of results There was no difference in mortality or oxygenation between CCP recipients and controls at day 28. When stratified by age, compared to matched controls, CCP recipients < 65 years had 4-fold lower mortality and 4-fold lower deterioration in oxygenation or mortality at day 28 (figure 2, 3). There was no association between CCP IgG or neutralizing antibody titer and clinical outcome. For CCP recipients, pre-transfusion Spike protein IgG, IgM and IgA titers were associated with mortality at day 28 in univariate analyses but not in multivariable analyses. Pre-transfusion Spike protein IgG titer was significantly correlated with Ddimer and detected viral load measured by cycle threshold (Ct) value of nasopharyngeal SARS-CoV-2 reverse-transcriptase- polymerase-chain-reaction (figure 4). No adverse effects of CCP were observed. Conclusions We report that CCP administration within 72 hours of hospitalization demonstrated a possible signal of reduced mortality in patients < 65 years. Pre-transfusion IgG titer may be a proxy for disease severity that may be useful in identifying those who are more likely to respond to CCP. Data from controlled trials is needed to validate this finding and establish the effect of ageing on CCP efficacy. (Figure Presented).

High-Cited Papers in Global COVID-19 Vaccine Research

Aim and Background: The coronavirus disease 2019 (Covid-19) virus pandemic is still ravaging the world with its ongoing resurgence and the continuous mutation, suggesting the need for continuous research on safe and effective novel vaccines. Presently several types of vaccines have been developed and emerged in the global market to control COVID-19 virus. Consequently, the knowledge and information on COVID-19 have been expanding at a high level. Researchers need to gain relevant knowledge regarding the different vaccines;however scattered information makes this process time-consuming and laborious. The present study aimed to evaluate the characteristics and trends in global COVID-19 vaccine high-cited literature using bibliometric and visualizations methods and offer some directions and suggestions for future research. Methodology: Studies published between December 2019 and 22 Nov 2022 on COVID-19 vaccines were retrieved from the Scopus database. From the 16026 studies retrieved, 406 were identified as high-cited papers (HCPs) having received 100 or more citations. From the 406 HCPs, information about publications outputs, countries, institutions, journals, keywords, and citation counts was identified. Data analysis and visualization were conducted using Microsoft Excel, VOSviewer and Bibliometrix R software. Result(s): The 406 global HCPs on COVID-19 vaccines research were identified in Scopus database since Dec 2019 till 30 Nov 2022 using a search strategy, which received 123614 citations, averaging 304.17 citations per publication (CPP). An external funding was received by 53.20% (216 publications), which were cited 76107 times (with an average of 352.35 CPP). The 7086 authors from 694 organizations affiliated to 76 countries and publishing in 121 journals were involved in global COVID-19 vaccine research. The most productive countries were USA (n=213), U.K (n=91), China (n=36) and Germany (n=35). The most impactful countries in terms of citations per paper (CPP) and relative citation index (RCI) were South Africa (794.68 and 2.61), Germany (507.11 and 1.67), U.K. (396.59 and 1.30) and Spain (367.5 and 1.121). The most productive organizations were University of Oxford, U.K., Imperial College London, U.K. (n=25 each), Center for Disease Control and Prevention (CDC), USA and Tel Aviv University (n=19 each) and the most impactful organizations were University of Cambridge, U.K (783.4 and 2.57), Emory University, USA (780.1 and 2.56), John Hopkins Bloomberg School of Public Health, USA (702.67 and 2.31) and National Institute of Allergy and Infectious Diseases. USA (676.41 and 2.22). The most productive authors were A.J. Pollard (n=16) and T. Lambe (n=14) (of University of Oxford), O. Tureci and P.R. Dormitzer (n=12 each) (of BioNTechSE, Germany) and the most impactful were D. Cooper (1239.22 and 4.07), K.J. Janseu (1228.11 and 4.03) (BioNTechSE, Germany, K.A. Swanson (987.0 and 3.24) (University of Oxford, U.K.) and P.R. Dormitzer (983 and 3.23) (BioNTechSE, Germany). The most productive journals were New England Journal of Medicine (n=53), The Lancet (n=28), Nature (n=22) and JAMA (N=17). The most impactful journals (as per citations per paper) were New England Journal of Medicine (613.15), Lancet (496.39), Human Vaccines and Immunotherapeutics (369.67) and Nature (360.64). Among population age groups, the major focus was on adults (51.48%) and Middle Aged (39.16%). Among publication types, the major focus was Clinical Studies (26.85%), Epidemiology (22.66%) and Genetics (21.92%). The most significant keywords by frequency of appearances were "Covid-19" (n=388), "Covid-19 Vaccines" (n=357), "Vaccination" (n=221), "Prevention and Control" (n=181) and "Vaccine Immunogenicity" (n=133), Conclusion(s): The HCPs in COVID-19 vaccine research was done mainly by the authors and institutions of high-income Countries (HIC) and was published in high-impact medical journals. Our research has identified the leading countries, institutions, journals, hotspots and development trend in the field that could provide the foundati n for further investigations. The bibliometric analysis will help the clinicians to rapidly identify the potential collaborative partners, identify significant studies, and research topics within their domains of COVID-19 vaccines.Copyright Author (s) 2023.

Efficacy of low dose whole-lung irradiation for the treatment of moderate to severe COVID-19 pneumonia: Meta-analysis.

Objective To systematically evaluate the efficacy of low dose whole-lung irradiation in COVID-19 pneumonia based on the present evidence. Methods All literature related to the application of low dose whole-lung irradiation in COVID-19 pneumonia were retrieved from Pubmed, Embase, the Cochrane Library, Web of Science, Google scholar, Scoupus, CNKI, Wanfang database, VIP database until May 2022. Two researchers independently screened the literature. For the literature that met the inclusion criteria, both data extraction and literature quality evaluation were blinded. Revman 5.3 software was used for statistical analysis. Results A total of 5 controlled clinical trials involving 194 patients met the inclusion criteria. No statistically significant differences were detected in the low dose whole-lung irradiation group compared with the best supportive care group for clinical recovery rates, intubation rates, radiographic improvement rates and 28 d-overall survival. Conclusions In patients of COVID-19 pneumonia, low dose whole-lung irradiation conferred no significant benefit to clinical outcomes. Currently, the routine use of low dose whole-lung irradiation for the treatment of moderate to severe COVID-19 pneumonia is not recommended.Copyright © Chinese Medical Journals Publishing House Co.Ltd. All Rights Reserved.

Barriers to Accessing Essential Medicines in Nephrology and Related Non-Communicable Diseases: A Scoping Review

Introduction: Access to safe, effective, quality, and affordable essential medicines (EM) for all is one of the World Health Organization's Sustainable Development Goals for health. However, access to EM for the treatment of non-communicable diseases (NCDs) is lacking in many low-income (LICs) and lower-middle income countries (LMICs). Chronic kidney disease (CKD) is often a downstream consequence of other NCDs, such as diabetes (DM) and cardiovascular disease (CVD), further exacerbating the economic burden on healthcare systems and societies. In nephrology, access to EM is especially important to reduce the risk of CKD progression because kidney replacement therapy is unavailable or cost-prohibitive in many regions of the world. As members of the International Society of Nephrology (ISN) Emerging Leaders Program 2021 cohort, we conducted a scoping review to assess the breadth of evidence regarding EMs for management of CKD and related NCDs, with identification of barriers to EM access as one of our main aims. Method(s): We included English-language articles of any study design that addressed barriers to accessing essential medicines in populations with CKD (all stages, causes, and ages), CVD, hypertension, and/or DM. All ISN geographical regions and World Bank income categories were considered. We searched MEDLINE, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials to May 2021. Titles and abstracts were screened, and full texts were retrieved for potentially relevant publications. Each full-text article was assessed for inclusion. For included articles, data extraction was performed with a standardized form using Covidence software. Each step was performed by one reviewer and checked by a 2nd reviewer. Applying an ecological model, barriers were categorized as occurring at the national/health policy level, regional level, organization level, provider level, or patient level. Result(s): Ninety-six publications addressed barriers to access to essential medicines, including LICs (16 articles), LMICs (43 articles), upper-middle income countries (25 articles), high-income countries (10 articles), plus 21 articles which did not specify countries. Most publications assessed barriers at the health policy-level, which included high EM prices in the setting of current patent laws;lack of effective systems for public procurement of EM, resulting in large out-of-pocket household expenditure for medicines in LIC/LMIC;inefficient distribution systems with multiple price mark-ups;and lack of regulatory systems, giving rise to counterfeit medications. Regional-level barriers included lack of governance of supply chain logistics, lack of regional coordination, and poor transportation infrastructure, especially in rural settings. Organization-level barriers included medication stock-outs at facilities, and health care worker shortages. Provider-level barriers included irrational prescribing, lack of CKD identification, and poor communication with patients. Patient-level barriers included poverty, informational barriers/health literacy, and negative perception of generic medicines (Figure). [Formula presented] Conclusion(s): Barriers to accessing EM exist at several levels, particularly the health system-level, and affect LICs and LMICs disproportionately. This scoping review serves as an initial step towards designing implementation studies to address barriers to improve EM access. Conflict of interest Potential conflict of interest: MMMY has a consultancy agreement with George Clinical and served on a CKD advisory board sponsored by AstraZenecaCopyright © 2023

Awake Prone Positioning in Covid-19: A Review of Prospective Clinical Trials

PURPOSE/HYPOTHESIS: Coronavirus disease 2019 (COVID-19) may result in hypoxemic respiratory failure and death similar to acute respiratory distress syndrome (ARDS). Based on its known efficacy in ARDS, prone positioning (PP) was used to manage intubated patients with severe COVID-19 lung disease. Though less supported by evidence, awake prone positioning (APP) was also trialed in non-intubated patients with COVID-19 to preserve resources and optimize outcomes. The primary available evidence included in recent reviews on APP in COVID-19 were the resultant retrospective single group studies that showed mixed findings. While such designs expedite results, a risk of bias weakens their application. With emerging research, this focused review evaluated APP in COVID-19 based on prospective trials that included a comparison group. NUMBER OF SUBJECTS: Not applicable. MATERIALS AND METHODS: PubMed and CINAHL databases were searched through June 10, 2022 with the following strategy: [(SARS-COV-2) OR (COVID-19) OR (coronavirus)] AND [(prone) OR (proning) OR (prone positioning)]. Prospective studies investigating APP in non-intubated adults with COVID-19 compared to usual care were included. Quality of evidence was determined by the Cochrane Risk of Bias tool with recommendations made using the GRADE approach. RESULT(S): Seven articles evaluating APP in a combined total of 2604 participants (66% male, mean age: 59.8 yrs, BMI: 29.0) with mild to moderate hypoxemic respiratory failure were included. Participant characteristics were heterogeneous and the duration of proning ranged from 4 to 16 hrs/d. APP was associated with improved oxygenation;however, only one study reported a lower incidence of intubation. No effect was noted on mortality or length of stay (LOS). Adverse events were rare but APP was associated an initial worsening outcome in one instance. Lack of blinding and protocol heterogeneity were identified risks of bias. CONCLUSION(S): APP may improve oxygenation in non-intubated individuals with mild to moderate COVID-19 lung disease as compared to usual care;however, prospective controlled trials do not support a positive effect on intubation, LOS, or mortality. The lack of transference in contrast to PP in intubated patients suggests that the primary benefit of PP may be minimizing ventilator-induced lung injury. Alternatively, benefits of APP may be reserved in select individuals as patient characteristics and proning protocols may influence the response. Though serious adverse events were not reported, the potential for skin breakdown and brachial plexus injuries are noted in ventilated patients with the proning times necessary for benefit. Given these findings, the value of immobilizing awake patients in prone should be questioned and alternate active interventions investigated. CLINICAL RELEVANCE: The routine application of APP in COVID-19 lung disease to improve clinical outcomes is not supported by current literature. Based on the GRADE approach, a weak recommendation against using APP was determined. Future studies should investigate if optimal protocols matched to potential responders improve the value of APP in COVID-19.

The study of the quality control of clinical research related to the prevention and treatment by traditional Chinese medicine

The scientific research on prevention and control of coronavirus disease 2019 (COVID-19) has been a major and urgent task, of which clinical trials occupy a pivotal position in the entire prevention and control system. 204 relative clinical trials of traditional Chinese medicine (TCM) have been registered on Chinese Clinical Trial Registry. Through the analysis of all online public protocols of registered trials, it is found that the clinical studies of TCM in China showed lack of research foundation, tight time and heavy tasks, difficult clinical implementation, and disturbance by changes of the epidemic status. Based on these characteristics, this paper put forward several thoughts and suggestions on the quality management and design improvement for clinical trials of TCM preventing and treating COVID-19, in order to improve the quality of clinical trials in China, provide effective supports for the public health decision-making on the epidemic, and also give a reference for the prevention and control of epidemics in the future. Copyright © 2023 West China University of Medical Science. All rights reserved.

ISHAM 2022 Congress Abstracts

The proceedings contain 542 papers. The topics discussed include: risk factors associated with oropharyngeal candidiasis in COVID-19 patients: a case control study;diagnosis of fungal infections in animals: combining the old and the new to maximize results;genetics andgenomics of Malassezia species;diversity and hybridization in Malassezia furfur;the human pathobiont Malassezia furfur secreted protease MFSAP1 regulates cell dispersal and exacerbates skin inflammation;challenges in diagnosing and management of invasive fungal infections during the pandemic;Cryptococcus QPCR assays: the future for routine mycology labs and clinical trials dealing with cryptococcosis;epidemiology of myotic keratitis in developing countries;proteomics in fungal keratitis research: a road map to personalized treatment;incidence of mixed fungal infections in post-COVID-19 outbreak of mucormycosis;talaromycosis in HIV-negative patients: challenges and counter-measures;and evaluation of new tools for the diagnosis of histoplasmosis.

Mutagenicity of N-Hydroxycytidine and Monlnupiravir in E. Coli and Mammalian Cell Cultures

Molnupiravir (MOV) has received FDA's Emergency Use Authorization for the treatment of COVID-19, which is caused by SARS-CoV-2 infection. MOV is a prodrug of the ribonucleoside analog, Nhydroxycytidine (NHC). Upon phosphorylation, NHC incorporates into nascent viral RNA during replication triggering “catastrophic” mutation of the viral genome. However, NHC can also enter the deoxy-ribonucleotide pool, become incorporated into DNA, and cause DNA mutations. In nonclinical safety assessments, MOV was positive (i.e., mutagenic) in the Ames assay but negative in regulatory in vitro and in vivo micronucleus assays. Multiple in vitro studies conducted in bacteriophages, bacteria, fungi, and mammalian cells have reported that NHC can induce DNA mutations, mainly A:T>G:C transitions. We used a recently developed error-corrected wholegenome sequencing technique for detecting mutations induced by MOV and NHC in cultures of E. coli, mouse L5178YTk+/-, and human TK6 cells. Treatment of bacterial and mammalian cultures (for 4 hours and 5 days, respectively) with either MOV or NHC increased mutation frequencies in a dose-dependent manner in all three models. The majority of induced mutations were A:T>G:C, consistent with the type of mutation caused by incorporation of dNHC opposite to dA in the first round of DNA replication and incorporation of dG opposite to dNHC in the subsequent round(s) of DNA replication. Trinucleotide mutational signatures in MOV/NHC-treated cells were similar in mouse and human cells and different from the background spontaneous mutational signatures in parental cell cultures. The specific mutational signature was evident in mammalian cells exposed to NHC concentrations comparable to those observed in the plasma of human subjects who received clinical doses of MOV. This data indicates more well-controlled rodent and clinical studies of MOV/NHC-induced mutagenicity should be done in the interest of public health safety.

Combining cell therapy and extracorporeal membrane oxygenation for Acute Respiratory Distress Syndrome: Back to no future?

Introduction: After more than 50 years of research we are yet to develop an effective treatment for the Acute Respiratory Distress Syndrome (ARDS). This stands in contrast to the advances made in supportive care, a prime example of which is the maturation of Extracorporeal Membrane Oxygenation (ECMO). While technologies such as ECMO 'buy time' for recovery, the identification of a therapy remains crucial to improving outcomes. Recently, mesenchymal stem cells (MSCs) have shown promise as a novel treatment.1 Importantly, cell therapy may represent a means to overcome the hurdles associated with successful pharmacological intervention in ARDS. Little is known about the interaction between cell therapy and ECMO. This is a deficiency, given that those receiving ECMO for ARDS are among the most severely ill and therefore most likely to benefit. This programme of work was designed to close that gap. Objectives: Using a translational pipeline, our objective was to assess the safety and efficacy of MSCs during ECMO for ARDS. Methods: We employed several diverse methods to address our objectives, including an ex-vivo ECMO simulation, complex sheep models of ARDS and ARDS and venovenous ECMO, systematic review methodology, and unsupervised machine learning techniques. Results: In our ex-vivo model, we were the first to demonstrate potential harms associated with MSC therapy during ECMO.2 When 40 × 10∧6 clinical-grade human MSCs (Cynata Therapeutics Ltd., Australia) were added to fresh whole human blood and subjected to extracorporeal circulation using commercial components, oxygenator and pump performance was severely impaired within 4 hours. These experiments also demonstrated benefits associated with MSCs, including trends toward lower inflammatory cytokine concentrations and less neutrophil activation.3 To validate our findings, we sought to test hMSCs in a clinicallyrelevant sheep model. At the outset we undertook a systematic review of existing pre-clinical models of ARDS and ECMO.4 This has since produced an international collaborative effort to characterise pre-clinical models of ECMO across a range of indications. We subsequently described a 'double-hit' model of ARDS which combines oleic acid and intra-tracheal E. coli lipopolysaccharide. Using cluster analysis, we showed that this model shares qualitative similarities with the 'hypo-inflammatory' phenotype identified in clinical cohorts [Millar JE et al. Physiological Reports 2021. In Press]. Finally, in a 24-hour model, combining our novel injury method, VV-ECMO, and best practice ventilatory and supportive care, we performed a controlled trial of intra-tracheal hMSC therapy5 [Editorial: Del Sorbo L, Fan E. AJRCCM 2020]. This study showed that hMSCs reduce histological evidence of lung injury and ameliorate shock. However, hMSC-mediated impairment of oxygenator function was evident again. Conclusion: This work addresses a gap in our understanding of cell therapy in critical illness. The findings are of direct clinical relevance, highlighting the potential harms of cell therapy during extracorporeal circulation. With a recent explosion in the number of registered clinical trials of MSCs for severe COVID-19 in mind, the use of MSCs during ECMO cannot be recommended.

BEST PRACTICES FOR THE PROVISION OF VIRTUAL CARE IN IBD AND BEYOND: A SYSTEMATIC REVIEW OF CURRENT GUIDELINES

Background: Telemedicine has emerged as a feasible adjunct to in-person care in multiple clinical contexts, including inflammatory bowel disease (IBD), and its role has expanded in the context of the COVID-19 pandemic. However, there exists a general paucity of information surrounding best practice recommendations for conducting specialty or disease-specific virtual care. Aims: The purpose of this study was to systematically review existing best practice guidelines for conducting telemedicine encounters, both in general and specific to patients with IBD. Methods: A systematic review of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) of existing guidelines for the provision of virtual care was performed. Data was synthesized using the Synthesis Without Meta-Analysis (SWiM) guideline, and the AGREE II tool was used to evaluate quality of evidence Results: A total of 60 studies providing guidance for virtual care encounters were included;52% of these were published during the COVID-19 pandemic. No gastroenterology-specific guidelines were found. The majority (95%) of provider guidelines specified a type of virtual encounter to which their guidelines applied. Of included studies, 65% provided guidance regarding confidentiality/security, 58% discussed technology/setup, and 56% commented on patient consent. 31 studies also provided guidance to patients or caregivers. Overall guideline quality was poor. Conclusions: General best practices for successful telemedicine encounters include ensuring confidentiality and consent, preparation prior to a visit, and clear patient communication. Future studies should aim to objectively assess the efficacy of existing clinician practices in order to further optimize the provision of virtual care for specific populations, such as patients with IBD. (Table Presented) .

SYSTEMATIC LITERATURE REVIEW on the SCREENING and PROPHYLAXIS of CHRONIC and OPPORTUNISTIC INFECTIONS

Background: Opportunistic and chronic infections can arise in the context of treatment used for Autoimmune Rheumatic Diseases (ARDs). Although it is recognized that screening procedures and prophylactic measures must be followed, clinical practice is largely heterogeneous, with relevant recommendations not currently developed or disparately located across the literature. Objectives: To conduct a systematic literature review (SLR) focusing on the screening and prophylaxis of opportunistic and chronic infections in ARDs. This is preparatory work done by members of the respective EULAR task force (TF). Methods: Following the EULAR standardised operating procedures, we conducted an SLR with the following 5 search domains;1) Infection: infectious agents identifed by a scoping review and expert opinion (TF members), 2) Rheumatic Diseases: all ARDs, 3) Immunosuppression: all immunosuppressives/immunomodulators used in rheumatology, 4) Screening: general and specifc (e.g mantoux test) terms, 5) Prophylaxis: general and specifc (e.g trimethop-rim) terms. Articles were retrieved having the terms from domains 1 AND 2 AND 3, plus terms from domains 4 OR 5. Databases searched: Pubmed, Embase, Cochrane. Exclusion criteria: post-operative infections, pediatric ARDs, not ARDs (e.g septic arthritis), not concerning screening or prophylaxis, Covid-19 studies, articles concerning vaccinations and non-Εnglish literature. Quality of studies included was assessed as follows: Newcastle Ottawa scale for non-randomized controlled trials (RCTs), RoB-Cochrane tool for RCTs, AMSTAR2 for SLRs. Results: 5641 studies were initially retrieved (Figure 1). After title and screening and removal of duplicates, 568 full-text articles were assessed for eligibility. Finally, 293 articles were included in the SLR. Most studies were of medium quality. Reasons for exclusion are shown in Figure 1. Results categorized as per type of microbe, are as follows: For Tuberculosis;evidence suggests that tuberculin skin test (TST) is affected by treatment with glucocorticoids and conventional synthetic DMARDs (csDMARDs) and its performance is inferior to interferon gamma release assay (IGRA). Agreement between TST and IGRA is moderate to low. Conversion of TST/IGRA occurs in about 10-15% of patients treated with biologic DMARDs (bDMARDs). Various prophylactic schemes have been used for latent TB, including isoniazide for 9 months, rifampicin for 4 months, isoniazide/rifampicin for 3-4 months. For hepatitis B (HBV): there is evidence that risk of reactivation is increased in patients positive for hepatitis B surface antigen. These patients should be referred for HBV treatment. Patients who are positive for anti-HBcore antibodies, are at low risk for reactivation when treated with glucocorticoids, cDMARDs and bDMARDs but should be monitored periodically with liver function tests and HBV-viral load. Patients treated with rituximab display higher risk for HBV reactivation especially when anti-HBs titers are low. Risk for reactivation in hepatitis C RNA positive patients, treated with bDMARDs is low. However, all patients should be referred for antiviral treatment and monitored periodically. For pneumocystis jirovecii: prophylaxis with trimeth-oprim/sulfamethoxazole (alternatively with atovaquone or pentamidine) should be considered in patients treated with prednisolone: 15-30mg/day for more than 4 weeks. Few data exist for screening and prophylaxis from viruses like E B V, CMV and Varicella Zoster Virus. Expert opinion supports the screening of rare bugs like histoplasma and trypanosoma in patients considered to be at high risk (e.g living in endemic areas). Conclusion: The risk of chronic and opportunistic infections should be considered in all patients prior to treatment with immunosuppressives/immunomod-ulators. Different screening and prophylaxis approaches are described in the literature, partly determined by individual patient and disease characteristics. Collaboration between different disciplines is important.

Palliative care interventions for people who use substances during communicable disease outbreaks: a scoping review

Objectives When resources are strained during communicable disease outbreaks, novel palliative care interventions may be required to optimally support people who use substances with life-limiting illnesses. Therefore, we asked the question, € what is known about communicable disease outbreaks, palliative care and people who use substances?', such as palliative care interventions that can improve the quality of life of patients with life-limiting illnesses. Design We conducted a scoping review that involved comprehensive searches in six bibliographic databases from inception to April 2021 (Medline ALL (Medline and Epub Ahead of Print and In-Process and Other Non-Indexed Citations), Embase Classic+Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trial, PsycInfo all from the OvidSP platform, Scopus from Elsevier) and grey literature searches. We included English and French records about people ≥18 years old with life-limiting illnesses who use substances during communicable disease outbreaks. We identified, summarised and presented the findings about palliative care interventions in figures, tables and narrative descriptions. Results We identified 32 records about palliative care interventions for people who use substances during communicable disease outbreaks. The majority focused on palliative care for people who use substances with AIDS during HIV epidemics (n=27, 84.4%), and approximately half were published in the USA (n=15, 46.9%). Most common substances used were alcohol (n=18, 56.3%), opioids (n=14, 43.8%) and cocaine (n=10, 31.3%). Four groups of palliative care interventions were identified: (1) symptom management (n=20, 62.5%), (2) psychosocial support (n=15, 46.9%), (3) advance care planning (n=8, 25.0%) and (4) healthcare provider training (n=6, 18.8%). Conclusions Beyond studies on HIV epidemics, there is limited knowledge about palliative care interventions for people who use substances during communicable disease outbreaks. Research and guidance are needed about how best to provide palliative care to this population with complex needs including in resource-limited countries. Protocol Buchman DZ, Ding P, Lo S, et al. Palliative care for people who use substances during communicable disease epidemics and pandemics. BMJ Open 2021;11: e053124

Abstracts 8th PCNE Working Symposium 'Navigating Research on Pharmaceutical Care'

The proceedings contain 62 papers. The topics discussed include: key stakeholders' experiences with the implementation of medication reviews in community pharmacies: a systematic review;screening for patients with hepatitis C in Swiss community pharmacies: a pilot study;effect of a pharmacist-led intervention on the quality of drug treatment;impact of pharmacist-led medication reconciliation on healthcare utilization: a controlled clinical trial;development and psychometric validation of the CONTACT-patient-centered care questionnaire;co-creation of an intervention to increase medication safety among vulnerable migrants;implementation fidelity of a pharmacist-led transitional pharmaceutical care program: process evaluation of the march study;management of acute upper respiratory infections during the COVID-19 pandemic: challenges for community pharmacies;continuity of care after hospital discharge in type 2 diabetic polymorbid patients;and pharmacy owners' views and experiences with the implementation of medication reviews in German community pharmacies: a qualitative study.

Kratom-induced Liver Failure and Death: A Case Report

Introduction: Kratom (mitragynine speciosa) is a tree native to Southeast Asia that has both opioid, stimulant, and other unknown properties. It is currently legal in the United States and used for therapeutic and recreational purposes. There is a dearth of literature on kratom’s effects on the body. At least half of reported kratom exposures resulted in a serious medical outcome, including death (1). In contrast, there are no controlled clinical trials on safety and efficacy of kratom as a treatment (2). Case: A 32-year-old Caucasian, currently unemployed, unmarried, mother of two children presented intubated to the MICU from an outside hospital with acute fulminant hepatic failure in the setting of significant kratom use. The patient also presented febrile with intracranial hemorrhage, cerebral edema, GI bleeding, acute renal failure, and diffuse intravascular coagulation. Psychiatry was consulted for potential liver transplant candidacy. Her previous history included six years of opioid use and transition to kratom 1-2 years prior to admission, with recent ingestion up to twenty-five times the patient’s usual amount (up to 125mg). Pertinent positive labs included elevated troponin (0.4), transaminitis ( >11,000), elevated PT/PTT (99/52), D-dimer ( >20), hematuria, pyuria, serum ferritin, prolonged QTc (514), and hypoglycemia. Pertinent negatives included unrevealing serum ethanol, phosphatidylethanol, viral hepatitis, HIV, COVID-19, EBV, CMV, other viral panels, acetaminophen level, toxicology screen, and EEG. Imaging revealed interstitial pulmonary edema and diffuse cerebral edema. Given lack of published information on kratom, the team emergently listed the patient for liver transplant despite significant concern for kratom use disorder. Over the course of three days, the patient’s mental status and labs continued to worsen, ultimately resulting in death. Interventions pursued included dialysis, mechanical ventilation, intracranial pressure monitoring with pressure optimization, anticonvulsant therapy, antibiotic therapy, N-acetylcysteine, and other routine MICU care. Due to relatively unremarkable health before ingestion, lack of other significant events, and severe rapid decline, multidisciplinary team consensus cause of death was due to kratom ingestion causing “acute liver failure with hepatic coma”. Discussion: This case report will go into further detail on kratom by analyzing kratom’s mechanism of action, therapeutic use, known side effects including addictive potential, effects on the liver including acute fulminant injury, and current laws and regulations surrounding kratom in the United States with relevance to public health. This is relevant to psychiatrists in the general consult, transplant, and addictions services. References: 1. Post S, Spiller HA, Chounthirath T, Smith GA. Kratom exposures reported to United States poison control centers: 2011–2017. Clinical Toxicology. 2019 57:10,847-854. DOI:10.1080/15563650.2019.1569236 2. Prozialeck W. Update on the Pharmacology and Legal Status of Kratom. J of the AOA. 2016, 116, 802-809. DOI: https://doi.org/10.7556/jaoa.2016.156

VITAMIN C NEPHROTOXICITY IN A COVID-19 PATIENT: A CASE REPORT

BACKGROUND AND AIMS: During the time of the COVID-19 pandemic, multiple treatment options have been investigated, even though their efficacy and secondary effects remain insufficiently known. We report the case of a vitamin C induced oxalate nephropathy in a COVID-19 patient with preexisting chronic kidney disease (CKD) resulting in irreversible acute renal failure. Vitamin C, also known as ascorbic acid, has been used as an anti-inflammatory therapy for COVID-19, but review of the literature shows similar cases of acute kidney injury (AKI), raising concern. METHOD: We report the case of a 73-year-old Caucasian woman admitted for hyperthermia and digestive disorders. She had recently started a first-line chemotherapy for multiple myeloma with partial response. She also displayed preexisting stage 4 CKD (eGFR 18.50 mL/min/1.73 m2 using CKD-EPI) of unknown aetiology. She was tested positive for SARS-CoV2 by nasopharyngeal swab and soon transferred to the intensive care unit. She received intravenous corticosteroids using dexamethasone 6 g/24 h for 10 days and a piperacillin + tazobactam probabilistic antibiotherapy. She also received high doses (15 g/24 h) of vitamin C for three consecutive days. No monoclonal antibodies were prescribed due to a previous vaccination with a positive serology upon admission. Although the patient recovered from respiratory tract infection, her kidney function progressively deteriorated with serum creatinine levels rising up to 8.06 g/dL, leading to her admission in our nephrology department. The patient was initially treated with high doses of diuretics for anasarca and an abdominal CT excluded urinary tract obstruction with normal kidney size and aspect. Urinary analysis showed protein to creatinine (p/c) ratio of 1348 g/g, and presence of urinary light chains. Her monoclonal spike was measured at 2.3 g/L and her kappa/lambda fraction was 1.74. Intermittent haemodialysis was initiated, and a kidney biopsy was performed. RESULTS: Histology revealed hundreds of intratubular calcium oxalate crystals, with severe and diffuse acute tubular necrosis and interstitial edema. There was no amyloidosis, no sign of active glomerular disease and no interstitial fibrosis. Immunofluorescence (IgA, IgG, IgM, C1Q, C3, kappa and lambda) was negative. We concluded to oxalate nephropathy. After a 2-month follow-up, the patient remains dialysis dependent. Vitamin C is a precursor of oxalate and has been shown to cause secondary oxaluria, particularly with high-dose regimens in patients with altered renal function. Given the histological findings evocative of acute oxalate nephropathy, the accountability of high doses of vitamin C should be considered. No other cause of hyperoxaluria was identified in our patient beside broad spectrum antibiotic use, which could decrease intestinal bacterial oxalate degradation. In particular, there was no malabsorption The limitation of our report is the unknown cause of preexisting CKD;therefore, we cannot rule out preexisting hyperoxaluria. Also, no dosage of serum vitamin C and oxalate levels were performed during follow-up. Finally, our patient had other possible causes AKI, such as recent SARS-CoV2 infection, or linked to multiple myeloma, but these were considered unlikely given the proper haematological response to treatment and non-evocative biopsy. The rationale for vitamin C use in COVID-19 is based on in vitro studies showing its antioxidant, anti-inflammatory, anticoagulant and immune modulatory properties. There lack large clinical studies, and the literature shows conflicting results. Multiple cases of acute oxalate nephropathy were described. CONCLUSION: Vitamin C is an anti-inflammatory treatment used in COVID-19 that can lead to secondary hyperoxaluria with significant and irreversible AKI. Due to the severity of AKI in patients with preexisting CKD, we believe renal function should be considered before using high doses of vitamin C. Larger controlled trials are needed both to establish the clinical benefit of vitamin C and further describe its potential ephrotoxicity.

Interventions for immune augmentation against SARScoV-2 virus infection via heterologous immunity, active immunity, passive immunity, and immunotherapy: A meta-analysis

Background: In this meta-analysis we evaluated strategies on augmentation of host immunity against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. Method: We searched clinical trials registered at the National Institutes of Health by 30 November 2020, and conducted analyses on inoculated population, involved immunological processes, source of injected components, and trial phases. We then searched PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials for their corresponding reports. A bivariate random-effects meta-analysis was used to derive the pooled estimate of seroconversion and adverse events (AEs). Results: A total of 540,269 participants were enrolled in 225 identified trials. The working mechanisms included heterologous immunity, active immunity, passive immunity, and immunotherapy. A total of 2,565 healthy adults from 10 clinical trials were included for meta-analyses. The odd ratio (OR) was 90.82 for kinetics of serologic responses to anti-SARS-CoV-2 antibody IgG titer (95% CI =36.1-228.49;p < 0.00001). The pooled ORs were 2.57 for solicited systemic AEs (95%CI =1.57-4.21;p = 0.0002), 5.72 for solicited local AEs (95% CI=2.59-12.67;p < 0.0001), and 2.08 for unsolicited systemic events (95% CI=1.42-3.05;p = 0.0002), compared to placebo or conservative treatment. Conclusion: Among all immune-augmentative interventions, a paradigm shift to vaccines providing active immunity was observed. The efficacy of these interventions was promising although systemic adverse events were noted.

Prevalence of dyspnea and/or chest pain persistence at mid-term after COVID-19 infection: A systematic review and meta-analysis

Introduction: COVID-19 is a recent infection that affects the whole world. Symptoms such as dyspnea and/or chest pain may persist in some people after the acute infection phase. However, the extent of this phenomenon is not yet well known. Purpose: To determine the prevalence of dyspnea and/or chest pain at least at one month after COVID-19 infection diagnosis. Methods: EMBASE, Ovid MEDLINE in-process and other nonindexed citations, and Ovid MEDLINE (between 1948 and January 15, 2021), and EBM Reviews-Cochrane Central Register of Controlled Trials and EBM Reviews-Cochrane Database of Systematic Reviews (between 2005 and January 15, 2021) were searched for a combination of keywords related to the type of exposure (COVID-19 infection) and to the type of outcomes (dyspnea persistence and/or chest pain persistence at least one month after COVID-19 infection diagnosis). Two independent reviewers selected studies of any design and in any language, using original data. Descriptive and quantitative information was extracted from each selected study and study quality was also assessed. We estimated prevalence in percentage and 95% Cis for each outcome, using a random-effects model. Statistical heterogeneity across the studies was calculated by the I2 statistic to quantify inconsistencies between studies. To assess the potential for publication bias, we visually inspected funnel plots and added the Egger's regression test p-value for funnel symmetry. Results: After an exhaustive screening of 1287 citations in title and , 31 studies were reviewed from entire article and 10 studies with 2004 patients were finally selected for meta-analysis. Interrater agreements were very high (0.91 and 1 respectively for the two selection steps). The pooled dyspnea persistence prevalence from 10 studies was of 39%;95% Ci [29%-49%], p<0.01, I2=91%, Egger's regression test p=0.19. The pooled chest pain persistence prevalence from 6 studies was of 18%;95% Ci [11%-24%], p<0.01, I2=89%, Egger's regression test p=0.12). Conclusion: Dyspnea and/or chest pain persistence prevalences after COVID-19 infection diagnosis are unexpectedly high, at least at one month. We have to take into account high heterogeneity due to subjects characteristics, various COVID-19 infection severities and study methodologies but there were no statistical argument for a publication bias. Nevertheless, this phenomenon requires more research to determine the long-term prevalence of these symptoms persistence and the mechanisms involved.

Creating a chinese herbal medicine database to support a clinical trial for suspected COVID-19

Purpose: Chinese herbal medicine (CHM) is a common therapy and is used alongside conventional medicine in some Chinese and Taiwanese hospitals. While a few trials are published outside of the US examining CHM's impact on coronaviruses, in the United States, before a trial can begin, the Food and Drug Administration requires evidence of safety and effectiveness for each herb to be used. Methods: This project is a literature review of articles needed to pursue prospective controlled research in Chinese Herbal Medicine. We are following the template of a group of NIH-funded researchers who completed a successful botanical application to the Federal Drug Administration (Ritenbaugh et al, 2012). We first received from our expert herbal collaborators a list of the 60 most necessary single herbs needed to treat expected COVID-19 cases. Next, we developed a database to place herbs into the required categories: pharmacology, toxicology, interactions with biomedical drugs, and previous human experience. We searched HerbMed Pro, Natural Medicine, PubMed, Chinese Traditional Herb Database, and the textbook Chinese Herbal Medicine: Materia Medica and Formulas & Strategies v 4 (Bensky et al, 2013. Eastland Press). During the research, systematic reviews and meta-analysis resources were primarily considered. The primary targets included COVID-, viral infection-, and influenzarelated articles as well. Results: All categories in the database have been completed by the authors and we are currently double-checking each other's work. Conclusion: Students are learning what categories of information are necessary to conduct research in the United States, as well as deepening their understanding of evidence-based medicine and integrative medicine. This database will be used to support federal funding for a prospective controlled trial.