Reproduction of the Control Group in REMDACTA Trial Using the Millennial Medical Record, an Electric Health Record Database, in Japan

Objectives: Developing a control group of a clinical trial using real world data is desirable and ethically sound despite challenges pertaining to internal validity. To examine the internal validity, we reproduced the control group in a Randomized Controlled Trial (RCT) using Electric Health Record (EHR) data and evaluated the difference between the outcome of the original trial and that of the reproduced analysis. Method(s): We selected an RCT, REMDACTA trial, that was performed to evaluate the efficacy of tocilizumab plus remdesivir against placebo plus remdesivir in patients with severe COVID-19 pneumonia. We reproduced its control group (patients with severe COVID-19 pneumonia taking only remdesivir), using Japanese EHR data, Millennial Medical Record provided by Life Data Initiative. Target patients for the main analysis were those prescribed remdesivir within 2 days after admission and diagnosed with COVID-19 (defined by ICD-10 code, U07.1) and/or with COVID-19 pneumonia (defined by diagnosis name). Patients in the sub analysis included only those with COVID-19 pneumonia diagnosis. Among the target patients, those undergoing image inspection, oxygen administration, and not taking any medicines for pneumonia before the first remdesivir prescription were eligible for the analyses. Median length of stay was compared in the reproduced group and in REMDACTA trial. Result(s): The database included 676 and 110 target patients for the main and sub analyses, respectively. However, only 57 and 14 patients met the eligibility criteria for the main and sub analyses, respectively. The reduction in the number of patients is attributed to the criteria of image inspection and oxygen administration. Median length of stay in the reproduced group were 13 and 11 days in the main and sub analyses, respectively. In REMDACTA trial, 95% CI of median time was 11.0-16.0. Conclusion(s): We successfully reproduced the median time of the control group by EHR data.Copyright © 2023

Barriers to in-Person Focus Group Participation during the Third-Year of COVID-19 Pandemic: A Case Study of Colorectal Cancer (CRC) Screening in Underrepresented Groups

Objectives: In the process of conducting research to understand barriers to colorectal cancer (CRC) screening in underrepresented groups such as Blacks and Hispanics, it became evident that there were also barriers to recruitment in this population. This study assesses the challenges faced in recruitment of focus group participants regarding CRC screening practices among underrepresented groups. Since the COVID-19 pandemic, qualitative research participants have primarily been interviewed through online video or audio interactions. However, as restrictions on in-person interactions have been lifted, in-person focus groups are being increasingly considered. Method(s): The study investigators began recruitment through community health workers in August 2022, when COVID-19 vaccines were available for all adults (age>18 years). Eligible individuals were: age 45-75, Black or Hispanic, with Medicaid or no insurance, and no family history of CRC or diagnosis of certain colon-related diseases. We combined in-person and virtual recruitment strategies, including posting flyers in communities, advertising our study at health fairs, and on social media. Participants would receive a $50 gift card. Result(s): Fifty-five met the eligibility criteria among 144 respondents, and 45 subjects (29 women and 16 men) agreed to be contacted. An average of 2.5 attempts were made per eligible subject. Unfortunately, we were able to recruit only four women (3 Hispanic and one non-Hispanic black). Traveling to the research site was a barrier to participation. Many subjects (49%) requested virtual participation (online video or audio interactions);some declined because the topic was too sensitive (considered taboo), and eligible men were reluctant to participate in-person. Conclusion(s): The requirement of in-person participation affected our recruitment goals, suggesting that COVID-19 has shifted the preferences of research participants to virtual interaction. In response to the eligible participant preferences, the study protocol has been revised to re-contact patients and schedule virtual FG sessions.Copyright © 2023

Preliminary results from phase 2 of CC-92480- MM- 001: Mezigdomide plus dexamethasone in relapsed/refractory multiple myeloma (RRMM)

In phase 1 of CC-92480- MM- 001 (NCT03374085), the recommended phase 2 dose (RP2D) of mezigdomide plus dexamethasone (MEZI-d) was selected at 1 mg once daily for 21/28 days. Here we report preliminary results from the MEZI-d dose-expansion cohort in patients with heavily pretreated RRMM. Key eligibility criteria were: RRMM;>=3 prior lines of therapy;disease progression <=60 days of last myeloma therapy;refractoriness to lenalidomide/pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 monoclonal antibody. Oral mezigdomide 1 mg was given on days 1-21 of each 28-day cycle, plus weekly dexamethasone (40 mg;20 mg if >75 years of age). Primary objective was to evaluate efficacy (overall response rate [ORR]);secondary objectives included safety/tolerability and additional efficacy assessments. Pharmacodynamics was an exploratory objective. As of 16/Sep/2022, 101 patients had received MEZI-d at the RP2D. Median age was 67 (range 42-85) years, median time since initial diagnosis was 7.4 (1.1-37.0) years;39.6% of patients had plasmacytomas and 37/101 patients had high-risk cytogenetics (56/101 not evaluable). Median number of prior regimens was 6 (3-15);prior therapies included stem cell transplantation (77.2%) and anti-BCMA therapy (29.7%). All patients were refractory to last myeloma regimen and triple-class refractory. Median follow-up was 7.5 (0.5-21.9) months, with a median of 4 (1-20) cycles;10.0% of patients continued treatment;progressive disease was the main reason for discontinuation (60.4%). ORR was 40.6% for all patients. Whilst data are not mature yet, median PFS was 4.4 (95% CI 3.0-5.5) months and median duration of response was 7.6 (95% CI 5.4-9.5) months. ORR was 30.0% in patients with plasmacytomas (N = 40) and 50.0% in patients with prior anti-BCMA therapy (N = 30). Ninety-one (91.1%) patients experienced a grade 3/4 treatment-emergent adverse event (TEAE). Most frequent hematologic grade 3/4 TEAEs were neutropenia (75.2%), anaemia (35.6%), and thrombocytopenia (27.7%);34.7% of patients had grade 3/4 infections, including grade 3/4 pneumonia (15.8%) and COVID-19 (7.0%). Occurrence of other grade 3/4 non-hematologic TEAEs was generally low. Due to TEAEs, 76.2% and 29.7% of patients had mezigdomide dose interruptions and reductions, respectively;90.1% of patients discontinued mezigdomide. Mezigdomide induced substrate degradation and increases in activated and proliferating T cells in patients, including those directly refractory to pomalidomide-based therapies. MEZI-d had a manageable safety profile with encouraging efficacy in patients with triple-class refractory RRMM, including patients with prior BCMA-targeted therapies. These results strongly support the continued development of mezigdomide in MM, and especially in combination.

Identifying Clinical Subtypes of Long COVID: An Unsupervised Machine Learning Approach

Objectives: The symptoms of patients with post-acute COVID-19 syndrome are heterogenous, impact multiple systems, and are often non-specific. To better understand the symptomatic profile of this population, this study used real-world data and unsupervised machine learning techniques to identify distinct groupings of long COVID patients. Method(s): Children/adolescents (age 0-17) and adults (age 18-64 and >=65) with >=2 primary diagnoses for U09.9 "Post COVID-19 condition" from 10/01/2021 (ICD-10 code introduction) until 03/31/2022 were selected from Optum's de-identified Clinformatics Data Mart Database, with the first diagnosis deemed index. Included patients had >=1 diagnosis for COVID-19 at least 4 weeks before index and continuous enrollment during the 12 months prior to index. Diagnoses recorded +/-2 weeks from index that were not present prior to the initial COVID-19 diagnosis were captured and used as patient features for k-means clustering. Final cluster assignments were selected based on silhouette coefficient and clinical relevancy of groupings. Result(s): 3,587 patients met eligibility criteria, yielding three clusters. Concurrent symptom domains surrounding index included breathing, fatigue, pain, cognitive, and cardiovascular diagnoses. The first cluster (N=2,578, 71.8%) was characterized by patients with only a single symptom domain (33% breathing, 33% cardiovascular, 20% fatigue, 11% cognitive). The second cluster (N=651, 18.1%) all presented with breathing symptoms accompanied by one additional domain (cardiovascular 40%, fatigue 28%, pain 18%). The final cluster (N=358, 9.9%) experienced breathing symptoms accompanied by two additional domains (fatigue and cardiovascular 34%, cardiovascular and cognitive 34%). Cluster 3 was slightly older than clusters 1 or 2 (mean age 66 vs. 58 years, respectively). Conclusion(s): Unsupervised machine learning identified distinct groups of long COVID patients, which may help inform multidisciplinary care needs. Our analysis suggests that many patients with long COVID may experience symptoms from only a single domain, and multi-system illness may generally include breathing complications accompanied by fatigue and/or cardiovascular complications.Copyright © 2023

Characteristics of Patients Diagnosed with Long COVID: Early Findings from Real-World Data

Objectives: While persistent and relapsing symptoms of COVID-19 are increasingly documented, limited data exist on the post-acute population. The objective of this analysis is to identify the characteristics of patients diagnosed with long COVID using real-world data. Method(s): Children/adolescents (age 0-17) and adults (age 18-39, 40-64 and >=65) with >=2 primary diagnoses for U09.9 "Post COVID-19 condition" from 10/01/2021 (ICD-10 code introduction) until 03/31/2022 were selected from Optum's de-identified Clinformatics Data Mart Database, with the first diagnosis deemed index. Included patients had >=1 diagnosis for COVID-19 and continuous enrollment 12 months prior to index (baseline). To ensure alignment with most institutional definitions, >=4 weeks between initial COVID-19 infection and index was required. Diagnoses recorded +/-2 weeks from index that were not present prior to the initial COVID-19 diagnosis were summarized. Newly prescribed treatments and total medical costs were evaluated during the month following index (continuous enrollment required). Result(s): 3,587 patients met eligibility criteria (mean age 59.02, 57.56% female) with a median time from initial COVID-19 infection to long COVID diagnosis of 83 days (IQR: 46-201 days). The most common concurrent diagnoses included breathing complications such as dyspnea (20.38%) and respiratory failure (15.23%);malaise and fatigue (15.31%);symptoms related to cognitive functioning/anxiety (11.35%);and chest pain (7.67%). Children/adolescents had the highest prevalence of chest pain, while patients >=65 years of age had the highest prevalence of issues with coordination. The average total medical cost during the month following long COVID diagnosis was $4,267 (SD $14,662), with common prescriptions including albuterol (4.42%), prednisone (3.51%), and methylprednisolone (2.01%). Conclusion(s): This retrospective analysis confirms clinically documented symptoms of long COVID in a large, real-world population. Once more data become available, further research on the long term economic and clinical outcomes among patients diagnosed with post-acute COVID-19 syndrome are warranted.Copyright © 2023

Upskilling haematological services for WGS and germline assessments through a regional skin biopsy training programme

NHS England Genomics introduced whole genome sequencing (WGS) with standard-of- care (SoC) genetic testing for haemato-oncology patients who meet eligibility criteria, including patients with acute leukaemia across all ages, and exhausted SoC testing. Alongside, the role of germline mutations in haematological cancers is becoming increasingly recognised. DNA samples are required from the malignant cells (somatic sample) via a bone marrow aspirate, and from non-malignant cells (germline sample) for comparator analysis. Skin biopsy is considered the gold-standard tissue to provide a source of fibroblast DNA for germline analysis. Performing skin punch biopsies is not within the traditional skillset for haematology teams and upskilling is necessary to deliver WGS/germline testing safely, independently and sustainably. A teaching programme was designed and piloted by the dermatology and haematology teams in Sheffield and delivered throughout the NHS trusts in North East & Yorkshire Genomic Laboratory Hub. The training programme consisted of a 90-min session, slides, video and practical biopsy on pork belly or synthetic skin, designed to teach up to six students at one time. To disseminate best practice, the standard operating procedure and patient information used routinely in Sheffield were shared, to be adapted for local service delivery. From January 2021 to December 2022, 136 haematology staff from 11 hospitals, including 34 consultants, 41 registrars, 34 nurses and 8 physician associates, across the NEY GLH region completed the skin biopsy training programme. Feedback from the course was outstanding, with consistently high scores in all categories. Practical components of the course were especially valued;98.6% (71/72) trainees scored the practical element of the programme a top score of 5 out of 5, highlighting that despite the challenges of delivering face-to- face teaching due to COVID-19, teaching of practical skills was highly valued;training in this way could not have been replicated virtually. Costs of the programme have been approximately 16 000, including consultant input and teaching/educational materials. Recent support has been provided by a separately funded Genomic Nurse Practitioner (GNP), with succession planning for the GNP to take over leadership from the consultant dermatologist. Plans are in place to use the remaining budget to disseminate the programme nationally. Our training programme has shown that skin biopsy can be formally embedded into training for haematology consultants, trainees, nursing team, and physician associates. Delivery of training can be effective and affordable across regional GLHs with appropriate leadership and inter-speciality coordination, and ultimately sustainable with specialist nursing staff, including GNPs.

Evaluation of the Updated French Autorisation D'Acces Precoce (AAP) Early Access Authorization Pathway

Objectives: To evaluate products reviewed by the Transparency Committee (TC) of the Haute Authorite de Sante (HAS) under the Autorisation d'Acces Precoce (AAP) Early Access Authorization (EAA) pathway and investigate any trends. Method(s): All 97 AAP submissions are publicly available from HAS and were evaluated on or before January 4th, 2023. The TC's opinion was reviewed to obtain the outcome, decision date, therapeutic area, and reasons for rejection. Results were tabulated and descriptive statistics were compiled. Result(s): In total, 79 of the 97 (81%) submissions evaluated were approved for EAA, including renewals of previously granted authorization (6 of 79);18 were rejected. Of the 97 submissions, 35% were indicated for the treatment of solid cancers, 14% for haematological cancers, 10% for ultra-rare diseases, 10% for infectious diseases, 4% for rare diseases, 4% for autoimmune diseases, 4% for skin diseases, and 2% for weight management. Notable approved submissions including those indicated for rare diseases, cancer, autoimmune diseases, and COVID-19, with 93%, 90%, 75%, and 63% of these submissions being granted EAA, respectively. Across the 18 unsuccessful submissions, the main reasons cited for rejection were insufficient efficacy and safety data (78%), lack of innovation compared to existing treatment options (61%), the availability of existing treatment options (56%), and the treatment not being rare enough to qualify for special consideration (28%). Conclusion(s): Since its inception in July 2021, the AAP has proven to be a popular program. As awareness of the program grows and more information becomes available about its benefits and eligibility criteria, it is likely that the number of submissions will continue to increase. However, given the link between submission success and the quality of available data (including a data collection plan), it is recommended manufacturers provide robust evidence to bolster their submissions.Copyright © 2023

Updated Real-World Safety of the Pfizer-BioNTech COVID-19 Vaccine in Pregnancy: Data from the Organization of Teratology Information Specialists (OTIS) Pregnancy Registry

Purpose: Preliminary data indicate that pregnant women infected with COVID-19 are at increased risk of pregnancy complications (US Centers for Disease Control and Prevention, October 2022). Information on the real-world safety of COVID-19 vaccination in pregnancy is essential. We sought to describe preliminary results for pregnancy status among pregnancy registry participants enrolled in an ongoing safety study of the Pfizer-BioNTech COVID-19 vaccine to date. Method(s): This study uses data from the Organization of Teratology Information Specialists (OTIS) Pregnancy Registry as part of the Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) which enrolls pregnant women residing in the US or Canada. Data are captured through maternal interviews and the ion of medical records. The study population for this descriptive analysis includes Registry participants who met eligibility criteria on or after December 11, 2020, the date the US Food and Drug Administration granted emergency-use authorization for the Pfizer-BioNTech vaccine. The target sample size is 1,100 pregnant women who received any dose of the Pfizer-BioNTech vaccine from 30 days prior to the last menstrual period through the end of pregnancy, and 900 comparison women who received no COVID-19 vaccine in pregnancy. Result(s): Among pregnant women participating in the Registry between 11 December 2020 and 22 July 2022, 1,100/1,100 participants (100.0% of the target sample) were enrolled as part of the Pfizer-BioNTech COVID-19 vaccine exposure cohort, and 635/900 participants (70.6% of the target sample) were enrolled in the comparator cohort. As of 22 July 2022, 858 (78.0%) in the vaccine exposure cohort and 313 (34.8%) in the comparator cohort had completed pregnancies. Descriptive data indicated numerically similar percentages of pregnancies ending in at least one liveborn infant, spontaneous abortions, stillbirths, and elective terminations across the exposed cohort stratified by trimester of the earliest dose of the Pfizer-BioNTech COVID-19 vaccine received in pregnancy, and overall in the unexposed comparator cohort. Conclusion(s): Preliminary data have not identified any new safety concerns thus far for pregnant women who receive the Pfizer-BioNTech COVID-19 vaccine during pregnancy. Funding(s): This study was conducted as a collaboration between the University of California San Diego and Pfizer. Pfizer is the study sponsor.

Striking a match between FHIR-based patient data and FHIR-based eligibility criteria

Inputs and Outputs: The Strike-a-Match Function, written in JavaScript version ES6+, accepts the input of two datasets (one dataset defining eligibility criteria for research studies or clinical decision support, and one dataset defining characteristics for an individual patient). It returns an output signaling whether the patient characteristics are a match for the eligibility criteria.Purpose: Ultimately, such a system will play a "matchmaker" role in facilitating point of-care recognition of patient-specific clinical decision support.Specifications: The eligibility criteria are defined in HL7 FHIR (version R5) Evidence Variable Resource JSON structure. The patient characteristics are provided in an FHIR Bundle Resource JSON including one Patient Resource and one or more Observation and Condition Resources which could be obtained from the patient's electronic health record.Application: The Strike-a-Match Function determines whether or not the patient is a match to the eligibility criteria and an Eligibility Criteria Matching Software Demonstration interface provides a human-readable display of matching results by criteria for the clinician or patient to consider. This is the first software application, serving as proof of principle, that compares patient characteristics and eligibility criteria with all data exchanged using HL7 FHIR JSON. An Eligibility Criteria Matching Software Library at https://fevir.net/110192 provides a method for sharing functions using the same information model.

Beyond Articular Cartilage: A Systematic Review of the Extracellular Matrix in Other Components of the Osteoarthritic Joint

Background/Aims Traditionally viewed from the perspective of cartilage degeneration, osteoarthritis is increasingly seen as a disease of global joint dysfunction. Connective tissue extracellular matrix (ECM) is a crucial determinant of joint mechanobiology, providing cells with scaffolding, topographical cues, and a reservoir of soluble factors. While ECM dysregulation has been extensively studied in osteoarthritic cartilage, it remains poorly defined in other joint tissues. Here, we systematically review the composition, architecture, and remodelling of non-cartilage soft joint tissue ECM in human osteoarthritis and animal disease models. Methods A systematic search strategy was run through the MEDLINE, EMBASE and Scopus databases on 30 October 2020 and repeated on 1 October 2021. The search criteria included disease nomenclature, relevant tissues, as well as structural ECM components and architectural features. All papers were independently screened by two reviewers on the Covidence platform according to predefined eligibility criteria. Relevant clinical, demographic, and biological data were extracted from included studies, which were assessed for bias using the OHAT Risk of Bias Rating Tool for Human and Animal Studies. Results 148 of 8,156 identified studies met all eligibility criteria. 113 papers evaluated human osteoarthritis;of 35 animal studies, the most frequently used models involved surgical joint destabilisation in small mammals. ECM was best defined in menisci, ligaments, and synovium;fewer papers assessed skeletal muscles, tendons, and fat pads. Compared to the healthy joint, osteoarthritis is associated with qualitative and quantitative alterations in structural ECM components, most notably collagens and proteoglycans. In recent years, whole proteome sequencing has been employed to address these changes systematically. The mechanical properties of ECM change significantly in osteoarthritis in response to post-translational modifications, extensive calcification, and the marked loss of matrix organisation across the joint. Notably, some aspects of ECM remodelling in these tissues appear to precede discernible cartilage dysregulation. Similar ECM dysregulation is also observed in animal models, although intermodel variability in arthritogenic precipitant and the range of reported outcomes make comparisons difficult. Many studies are limited by significant bias, notably in the infrequent reporting of investigator blinding, and in the poor demographic matching of osteoarthritic and control patients. Encouragingly, the quality of methodology reporting and use of age-matched control populations have improved in recent years. Conclusion Current data provide compelling evidence of whole joint ECM changes in osteoarthritis and importantly suggest that these changes occur early in the disease process. How ECM dysfunction affects the behaviour of tissue-resident cells remains less well understood. Our work will support the design of disease-relevant biomaterials used to model osteoarthritis in vitro, helping to address this issue, by more accurately recreating the extracellular environment. Furthermore, the development of imaging modalities sensitive to connective tissue ECM changes warrants investigation from both diagnostic and prognostic perspectives.

Nirmatrelvir Use and Hospitalizations or Death in Individuals with Covid-19

Background: Nirmatrelvir/ritonavir (NMV/r) was granted Emergency Use Authorization in December 2021 for treatment of early symptomatic patients with mild to moderate COVID-19 at high risk of progression. However, its benefit is specific population subgroups remains unclear. Method(s): We used a matched cohort design to emulate a target trial within the VA COVID-19 Shared Data Resource database. Eligible individuals were those with at least two episodes of care in the VA in the last 2 years, who had a first confirmed SARS-CoV-2 infection between January 1 and August 31, 2022 and were free of hospitalization or death within 3 days of testing positive. Those hospitalized in the previous 60-days and those who received Molnupiravir after diagnosis were ineligible. Among the eligible individuals, we matched those prescribed NMV/r with those not prescribed NMV/r within 3 days of diagnosis. Controls were matched 1:1 on age (5-year blocks), race, sex, body mass index, Charlson Comorbidity Index, VA facility where NMV/r was prescribed, and vaccination status. Our primary outcome measure was hospitalization or death within 30 days of the index COVID-19 diagnosis date. Result(s): Among 90,432 persons with a confirmed first SARS-CoV-2 positive test, 68,236 persons met the eligibility criteria. Of those, 4,886 were prescribed NMV/r. Final primary analysis dataset included 4,148 matched pairs of NMV/r treated cases and controls. The incidence of hospitalization or death was significantly lower among those who were prescribed NMV/r overall (73 vs. 109 events;ARD [95% CI] -0.87 [-1.49 to -0.25]), for those older than 60 years (60 vs. 88 events;ARD [95% CI] -1.05 [-1.93 to -0.18]), for unvaccinated/incomplete primary series (ARD -1.88 [-3.54 to -0.22]), and those asymptomatic at baseline (ARD -1.96 [-3.00 to -0.92]). Those who were <60 years old, vaccinated with or without a booster, and those symptomatic at baseline did not experience a significant benefit. Conclusion(s): NMV/r use is associated with a modest but statistically significant reduction in hospitalization or death among previously uninfected, nonhospitalized population with COVID-19 who are at a high risk of progression to severe disease. The benefit is evident in older, unvaccinated, asymptomatic persons and those with certain comorbidities. But not in younger, vaccinated, and symptomatic persons.

Outcomes for Anti-CD19+ Chimeric Antigen Receptor T (CAR-T) Cell Therapy for Non Hodgkin Lymphoma (NHL) across a Large Community Transplant and Cellular Therapy Network

Background: The Sarah Cannon Transplant and Cellular Therapy Network (SCTCTN), which offers community access to transplant and cell therapy, implemented a coordinated approach to deliver CAR-T therapy through 5 programs. We conducted a retrospective review of clinical outcomes after FDA-approved anti-CD19+ CAR-T in B-cell NHL. Method(s): All patients referred for evaluation within SCTCTN were tracked in our prospective registry (Stafa-CT). We identified 110 patients who received FDA-approved anti-CD19+ CAR-T for NHL within the network between 12/10/2018 and 3/7/2022. All patients received care through standardized eligibility criteria, process, care pathways, toxicity management protocols, and a single quality plan. Result(s): The median age at referral was 60 years (range 23-82), 63% were male, the referral indication was diffuse large B-cell lymphoma (70%), mantle cell lymphoma (7%), follicular lymphoma (15%), or other B-NHL (8%). 35% had received a prior autologous transplant. The median time from referral to infusion was 143 days (range 89- 224), and from collection to infusion was 32 days. The infusion year was 2018 (1), 2019 (20), 2020 (31), 2021 (48), 2022 (10). The CAR-T cell products were Axi-cel (70), Tisa-cel (27), Brexu-cel (9), and Liso-cel (4). 16 patients (15%) were infused as outpatient, of which 10 patients were subsequently hospitalized at a median of 8 days (range 1-26) after infusion. Of the 94 patients (85%) infused as inpatient, the median length of stay was 15 days (range 6 to 85). Cytokine release syndrome (CRS) was observed in 78% with a median maximum grade 1. Maximum grade CRS was none, grade 1, grade 2, grade 3, grade 4, grade 5 in 22%, 36%, 32%, 7%, 2 % and <1%, respectively. The median times to onset and resolution of symptoms were day 3 and 8, respectively. Tocilizumab was administered to 39% for a median of 2 doses. Neurotoxicity was observed in 55% with a median maximum grade 1. Maximum grade neurotoxicity was none, grade 1, grade 2, grade 3, grade 4, grade 5 in 45%, 19%, 13%, 18%, 4 % and 0%, respectively. The median times to onset and resolution of symptoms were day 7 and 13, respectively. Neutropenia (<0.5/ muL) and thrombocytopenia (<20K/muL) at day 30 were reported in 11% and 12%, respectively. 18% required ICU stay. 37 deaths (34%) were reported from disease progression (23), infections (7, including 5 from COVID), CRS (2) and other causes (5).(Figure Presented) Conclusion(s): Administration of anti-CD19+ CAR-T is feasible in specialized community hospitals with outcomes similar to registrational clinical trials. Outpatient administration is feasible in selected patients, but subsequent hospitalization needs to be anticipated. CRS, neurotoxicity, cytopenias and infection remain challenges, while disease progression was the commonest cause of deathCopyright © 2023 American Society for Transplantation and Cellular Therapy

Prescribing of oral antibacterial drugs in primary care out-of-hours services: a scoping review

Introduction: The rapid spread of antimicrobial resistance (AMR), which causes a serious threat to both human health and the global economy, is primarily linked to the overuse and misuse of antibacterial drugs. The AMR crisis is significantly impacted by the use of antibacterial drugs in primary care (1). Within these settings, oral antibacterial drugs are considered one of the most frequently prescribed group of medicines. It has been claimed that within primary care, the proportion of antibacterial drug prescribing is higher outside the regular working hours (out-of-hours (OOH) services) compared to in-hours (IH) services (2). Aim(s): To identify the existing body of literature around oral antibacterial drug prescribing within primary care OOH services. Method(s): The scoping review was guided by the Joanna Briggs Institute manual and reported in accordance with the PRISMA-ScR. Seven electronic databases (Medline, Embase, Emcare, CINAHL, Scopus, Web of Science, and Cochrane Library) were systematically searched, and the results were screened against pre-defined eligibility criteria. Original and secondary analysis studies that addressed oral antibacterial prescribing in OOH primary care and were published in English were included. Titles and s were independently screened by three reviewers. A pre-piloted extraction form was used to extract relevant data. A narrative synthesis approach was used to summarise the results. Result(s): The initial search yielded 834 records. Upon screening, 28 publications fulfilled the eligibility criteria. Included studies originated from nine high-income countries, with the most frequent being the United Kingdom (six studies, 21.4%) followed by Belgium (five studies, 17.9%). Literature on antibacterial prescribing in OOH services was mostly from quantitative studies (23 studies, 82.14%), with only a few employing a qualitative design (five studies, 17.86%). Different themes and sub-themes were identified across these studies. The majority discussed antibacterial prescribing data in terms of the commonly prescribed medications and/or associated conditions. Eleven studies provided a comparison between IH and OOH settings. Seven studies reported the trends of prescribing over time;of these, three explored prescribing trends before and during COVID-19. The impact of intervention implementation on prescribing was investigated in two studies, an educational intervention in one study and the use of an interactive booklet in the other study. Four studies assessed the quality/appropriateness of prescribing either by adherence to guidelines or antibiotic prescribing quality indicators. Limited studies explored prescribing predictors and patients' expectations and satisfaction with OOH services. In contrast, qualitative studies focussed more on exploring prescribers' experiences, perspectives, behaviours, and the challenges they face during consultations within OOH settings which may influence their decision-making process. Of these, one study explored why patients consult OOH services and how they communicate their problems. Conclusion(s): This review shows the key areas around oral antibacterial prescribing in primary care OOH services. While there is a satisfactory number of published articles covering various areas within OOH, the use of different approaches to OOH across countries may confound the comparison of practice. A strength of this work is using three reviewers to screen identified records independently. Further research is needed to provide a better understanding of current practice in these settings and how it may be contributing to AMR.

Feasibility of an Automated Assessment to Measure Cognition and Mood in the Acute Stroke Setting

Introduction Over 50% of stroke survivors have cognitive impairment. National guidelines promote early cognitive testing however, current pen-and-paper based tests are not always appropriate, typically take place in hospital and are time costly for busy clinicians. This project aimed to create an easy-to-use cognitive assessment tool specifically designed for the needs of stroke survivors. We used a computerised doctor utilising automatic speech recognition and machine learning. Methods Patients are approached if they pass the eligibility criteria of having recent acute stroke/TIA, and do not have preexisting condition i.e dementia, severe aphasia Participants could speak to the digital doctor on the ward or at home via a web-version. Results Recruitment started on 8th December 2020;We have screened 614 people assessed for suspected acute stroke/TIA at Sheffield Teaching Hospitals. Of those we have recruited 71 participants (13 with TIA) Mean NIHSS of 4.5 and mean MoCA of 24.6. We will present initial results of factors affecting participant recruitment. We will also compare the mood and anxiety screening scores used in this study to those collected via the SNAPP database. Discussion Screening was adapted due to Covid pandemic and utilising remote consent and participa- tion allowed the project to continue.

High flow nasal oxygen (HFNO) in the treatment of COVID-19 infection of adult patients from - An emergency perspective: A systematic review and meta-analysis

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2, which was first discovered in Wuhan, China. The disease has grown into a global pandemic causing mild to moderate symptoms in most people. The disease can also exhibit serious illnesses, especially for patients with other chronic diseases such as cardiovascular diseases, diabetes, chronic respiratory disease, or cancer. In such cases of severe illness, high flow nasal oxygen (HFNO) has been used to provide oxygenation to COVID-19 patients. However, the efficiency of HFNO remains uncertain, prompting the conduction of this systematic review to evaluate the effectiveness of the therapy. A thorough search for relevant and original articles was carried out on five electronic databases, including ScienceDirect, PubMed, Cochrane Library, Embase, and Google Scholar. No time limitation was placed during the search as it included all the articles related to COVID-19 from 2019 to 2022. The search strategy utilized in this systematic review yielded 504 articles, of which only 10 met the eligibility criteria and were included. Our meta-analysis reveals that HFNO success rate was higher than HFNO failure rates (0.52 (95% CI;0.47, 0.56) and 0.48 (95% CI;0.44, 0.53), respectively), however, the difference was statistically insignificant. HFNO was associated with a significant decrease in mortality and intubation rates (0.28 (95% CI;0.19, 0.39) and 0.28 (95% CI;0.18, 0.41), respectively). Our statistical analysis has shown that significantly lower ROX index (5.07 +/- 1.66, p = 0.028) and PaO2/FiO2 (100 +/- 27.51, p = 0.031) are associated with HFNO failure, while a significantly lower respiratory rate (RR) (23.17 +/- 4.167, p = 0.006) is associated with HFNO success. No statistically significant difference was observed in SpO2/FiO2 ratio between the HFNO success and failure groups (154.23 +/- 42.74 vs. 124.025 +/- 28.50, p = 0.62, respectively). Based on the results from our meta-analysis, the success or failure of HFNO in treating COVID-19 adult patients remains uncertain. However, HFNO has been shown to be an effective treatment in reducing mortality and intubation rates. Therefore, HFNO can be recommended for COVID-19 patients but with close monitoring and should be carried out by experienced healthcare workers.Copyright © 2023 The Authors

Implementation of a clinical trial recruitment support system based on fast healthcare interoperability resources (FHIR) in a cardiology department

Background: Clinical Trial Recruitment Support Systems can booster patient inclusion of clinical trials by automatically analyzing eligibility criteria based on electronic health records. However, missing interoperability has hindered introduction of those systems on a broader scale. Purpose(s): Our aim was to develop a recruitment support system based on FHIR R4 and evaluate its usage and features in a cardiology department. Methods/Implementation: Clinical conditions, anamnesis, examinations, allergies, medication, laboratory data and echocardiography results were imported as FHIR resources. Trial study nurses and physicians were enabled to add new and edit trial information and input inclusion and exclusion criteria using a web-browser user interface in the hospital intranet. All information were recorded on the server side as the FHIR resources ResearchStudy and Group . Eligibility criteria linked by the logical operation OR were represented by using multiple FHIR Group resources for enrollment. On the client side, eligibility criteria were transformed to a tree-like structure (see Figure 1). Upon user demand, all hospitalized and ambulatory patients in the cardiology department were instantly screened for trial eligibility using the FHIR eligibility criteria on the existing patients' FHIR resources. Furthermore, study personal was able to manually edit trial status (i.e. ineligible, on-study, ..) of patients, which was implemented using the FHIR resource ResearchSubject . Result(s): This implementation of a CTRSS based on FHIR R4 was evaluated in clinical practice: Beginning from 1st April 2021 the application was used as an additional patient screening tool for the four trials CLOSUREAF, FAIR-HF2, SPRIRIT-HF and TORCH-PLUS of the German Centre for Cardiovascular Research. As the COVID-19 pandemic is prohibiting any proper comparison of patient inclusion rates, efficacy of the recruitment support system was tested by comparing the numbers of patients identified by the recruitment support system and enrolled in a trial to the actual number of enrolled patients irrespective of the screening method from 1st April 2021 to 23rd November 2021. The system was able to identify 52 of 55 patients included in those four clinical trials. Conclusion(s): Use of FHIR for defining eligibility criteria of clinical trials may facilitate interoperability and allow automatic screening for eligible patients at multiple sites of different healthcare providers in the future. Upcoming changes in FHIR should allow easier description of OR -linked eligibility criteria. (Figure Presented).

Real world evidence from a Breast Screening pilot for the underprivileged: Experiences from Bruhat Bengaluru Mahanagara Palike hospitals

Background: In India, less than 5% of women get routine screening for breast cancer due to lack of awareness and the absence of a coordinated national breast cancer screening programme. A community health initiative was launched by Niramai in collaboration with City Health officials in Bangalore as a pilot to increase awareness and make breast health screening available to all. Free breast cancer screening using AI powered Thermalytix test is being offered to all the underprivileged women walking into Bruhat Bengaluru Mahanagara Palike (BBMP) government hospitals from November 14, 2017 till today (after a break for 15 months during COVID). Material(s) and Method(s): This observational study was conducted in 22 BBMP-affiliated primary health centers where outpatient women over the age of 18 years and not pregnant were enrolled. The procedure included a briefing on camp procedures, taking patient consent, identification of eligible candidates, general health education, and conducting the Thermalytix test by a healthcare worker who was trained to use the Thermalytix software tool. Women were triaged using the output generated by Thermalytix 180. Those triaged as red were referred for further detailed imaging investigation in a district hospital using mammography, ultrasound and FNAC/biopsy. Result(s): A total of 6935 women underwent Thermalytix screening in 22 BBMP hospitals during Nov 2017 to July 2022. A total of 1687 participants were excluded from the analysis as they did not meet the eligibility criteria. The median age of the 5248 eligible participants was 42 years (range 18-86). Among them, 90 women (1.71%) had previously noticed a lump in their breast, 431 women (8.12%) had breast pain, 16 women had complained of nipple discharge, and 5 women had noticed skin discoloration. When screened, 62 (1.2%) women were detected with abnormalities and triaged positive by Thermalytix. Among them 11 women have so far gone through diagnostic investigations, of which 8 were radiologically positive and were recommended for histopathology correlation. The overall test positivity rate of Thermalytix in this cohort was 1.2% and positive predictive value with radiological positivity as reference was found to be 9/11 = 81.81%. Furhter histological analysis reported 1 DCIS and 8 benign fibroadenoma. The tests were conducted in screening camps and the average cost of conducting the test in the field came to around 6.5 USD per person. Conclusion(s): Thermalytix could be a potential automated screening tool for population-level screening in resource constrained settings. The portable equipment enabled easy movement across different PHCs. Since it is a privacy-aware test, there was less refusal to participate in the test. Community mobilization with the help of the local government health officials was crucial to ensure walk-ins. Conflict of interest: Ownership: yes Board of Directors: yes Corporate-sponsored Research: yesCopyright © 2022 Elsevier Ltd. All rights reserved

Emergency Department-based monoclonal antibody therapy for patients with mild to moderate COVID-19

Objectives: To describe the implementation of an ED-based program to offer monoclonal antibody therapy to patients with mild-moderate COVID-19 disease. Background(s): Monoclonal antibody therapy (MOAB) has recently emerged as a treatment for mild to moderate COVID-19, potentially preventing those with underlying conditions from progressing to severe illness and hospitalization. Further, as EDs are the primary point of health care access for many at-risk individuals, offering MOAB in the ED may increase availability of treatment options for patients from traditionally underserved communities. Method(s): A retrospective chart review was conducted of patients 12 years and above who received treatment in our urban, academic, community hospital. Patients 12 years and older were screened for eligibility during ED visits or during follow-up calls providing positive test results. Staff was trained on specific consent, infusion, monitoring, and documentation procedures adherent to MOAB administration under the Emergency Use Authorization. Patients were contacted following MOAB and queried regarding symptom resolution and healthcare utilization. Data regarding patient demographics, ED course, and 7-day unscheduled visits were collected. Result(s): In this ongoing quality improvement initiative, from December 2020 to March 2021, there were 26,229 patient encounters at the pilot ED site. 84 patients were provided MOAB, 87% Bamlanivimab and 13% Bamlanivimab/Etesevimab. Patients had a mean age of 52.3 years (SD 24.4);21% were 12-17 years of age and 37% were >65 years old. 52% were male. 33% self-reported as Caucasian, 19% Black, 18% Asian/Pacific Islander, 21% as other, and 9% were unknown. 17% identified as Latinx. 19% of patients were insured by Medicaid, 36% Medicare, 39% commercially insured, and 6% were uninsured. Patients had symptoms a median of 3 days prior to MOAB. After age (46%), the most commonly reported eligibility criteria was obesity (20%), followed by hypertension (11%) and immunocompromised state (11%). 74% of infusions were administered during nights and weekends. No infusion reactions occurred. 8% returned to an ED within 7 days of MOAB, 5% were hospitalized. No patients required ICU admission or died. Conclusion(s): ED-based MOAB has been safely implemented and may be an effective treatment for patients with mild to moderate COVID-19. Health-system wide expansion of this program may provide opportunities to offer this life-saving therapy to underserved populations with poor access to care.Copyright © 2023

Real-life prospective study on tocilizumab in severe COVID-19 infection

The outcomes of tocilizumab (recombinant monoclonal antibody inhibiting IL-6) in SARS-CoV-2 infection have been variable, with REMAP-CAP and RECOVERY being the largest trials to show benefits. In this prospective, observational study we compared tocilizumab plus standard care (dexamethasone) vs standard care alone in patients with severe COVID-19 infection. Eligibility criteria included patients (age >18 years) with radiological evidence of COVID-19 Pneumonia, PO2/FiO2 (PF) ratio of <300 mmHg and an inflammatory phenotype defined by raised CRP, IL-6 and Ferritin. The primary outcome was a composite of mechanical ventilation and death. A total of 36 patients were included in this study, 27 in the treatment group and 9 in the standard care group. The treatment arm received tocilizumab 8mg/kg (maximum 800mg) as a single infusion within the first 24 hours of respiratory deterioration (identified as worsening RR and PF ratio). Results showed significantly lower mortality rate in the tocilizumab group compared to standard care group (3% vs 33% respectively, p=0.013). Patients who received tocilizumab were also less likely to progress to mechanical ventilation, with only 3.7% of the treatment group requiring mechanical ventilation vs 44% in the control group (p=0.002). Our findings support the use of tocilizumab in severe COVID-19 infection when given early in respiratory deterioration. The predominant variant at the time of this study was the Alpha variant, and so further investigation is required into its effectiveness in newer variants. Limitations include small sample size.

Arrhythmia burden in COVID-19 patients from industrial workforce evaluated by remote patient monitoring technology

Introduction: Early reports from China estimated that overall cardiac arrhythmia prevalence in patients hospitalized for COVID-19 was 17%. A higher arrhythmia incidence (44%) was observed in patients admitted to intensive care unit. The industrial workforce was affected by COVID-19 to a great extent. A noteworthy proportion also suffered from cardiac abnormalities. Objective(s): To determine the incidence of arrhythmia in patients with COVID-19 among the industrial workforce using remote patient monitoring technology. Material(s) and Method(s): This was a retrospective, observational, descriptive study of the industrial workforce from Telangana State, India. Approval of the institutional ethics committee was obtained. The need for informed consent was waived off. Patients who tested positive for COVID-19 by RTPCR and aged above 18 years were eligible. The five-day recording of lead-2 ECG on Vigo Monitoring Solution (Connect Care India Pvt. Ltd) was collected and analysed. Brady-arrhythmia during day time, second degree AV block Type-2 (Mobitz II) during the day time, complete heart block, wide QRST, non-sustained ventricular tachycardia and sinus pause were considered "clinically significant". The other sub-types were defined as "clinically non-significant". The ECGs with regular sinus rhythm were interpreted as "normal". The prevalence of clinically significant, clinically non-significant and normal heart rhythm are described here. Result(s): Out of 240 COVID-19 patients who were on-board for remote monitoring, 216 (148 male and 68 female, mean age 51+/-15 years) met the eligibility criteria and only their ECG were analysed. Among them, 18 were known diabetics, 40 were hypertensive and 31 had both comorbidities. 112 were asymptomatic and 104 were symptomatic. The burden of arrhythmia was found clinically significant in 12 (5.6%) patients, clinically non-significant in 87 (40.4%) and normal among 117 (54%) out of 216 patients. Conclusion and Recommendation: The remote patient monitoring may be utilized as a tool for early screening of significant arrhythmia which are to be addressed immediately for better clinical outcome. These devices on being integrated into COVID-19 management strategies may contribute to patient satisfaction, emergency alerts, timely management, reducing mortality rate and enhancing the safety of healthcare providers.