Clinical Characteristics and Efficacy of Adalimumab and Low-Dose Methotrexate Combination Therapy in Patients With Vogt–Koyanagi–Harada Disease

This retrospective study investigated the clinical characteristics and efficacy of adalimumab and low-dose methotrexate combination therapy in patients with Vogt–Koyanagi–Harada disease who were treated at Hiroshima University from February 2012 to May 2021. The patients' demographics, clinical features at administration of immunosuppressive therapy, steroid-sparing immunosuppressive therapy, side effects, and relapses were recorded. The efficacies of steroid-sparing immunosuppressive therapy (methotrexate, cyclosporine A, adalimumab, and adalimumab and methotrexate combination therapy) were analyzed. Among 62 patients, the median age at diagnosis was 47 years and the median duration of uveitis was 51 months. Systemic corticosteroid therapy was administered to 93.5% of patients (n = 58). Thirty-four patients (54.8%) were treated with steroid-sparing immunosuppressive therapy. Methotrexate and cyclosporine A were administered to 12 and 22 patients, respectively; relapse occurred in 50.0% and 22.7% of the patients, respectively. Discontinuation of cyclosporine A was required in 63.6% of patients because of side effects. Adalimumab was administered to 14 patients. Recurrence occurred in 11 patients, requiring methotrexate concomitantly. The mean dose of methotrexate at inflammatory quiescence after side effect-related dose decrease was 8.0 mg/week (0.13 mg/kg). The median duration of combination therapy without recurrence was 20 months. There were no serious adverse events during adalimumab therapy. A high relapse rate was observed in patients receiving methotrexate; a high rate of side effects requiring discontinuation was observed in patients receiving Cyclosporine A. Patients with late-stage Vogt–Koyanagi–Harada disease may achieve better control with adalimumab and methotrexate combination therapy.

Trends of Clinical Outcomes of Patients with Advanced Hepatocellular Carcinoma Treated with First-line Sorafenib in Randomized Controlled Trials

Background: Sorafenib has consistently served as the control arm in multiple RCTs evaluating novel therapies for advanced HCC for more than a decade. Analyzing trends in clinical outcomes of patients treated with sorafenib for the same indication over time offers the opportunity for unique insight into the evolution of clinical trial conduct and potential non-drug factors impacting outcomes. Methods: We identified RCTs in patients with treatment-naïve advanced HCC where sorafenib was compared to another systemic therapy or placebo. We extracted trial-level demographic, clinicopathologic, and outcome data (OS, progression-free survival (PFS), objective response rate (ORR) and duration of therapy). Sample-weighted linear regression was used to identify temporal trends with significance set at p0.05. Results: Sixteen RCTs (9 phase III and 7 phase II) enrolling 4086 patients treated with sorafenib were included in the analysis. Included trials enrolled patients from 2005-2019. OS has significantly improved by 4.5 months from 2005-2019 (p=0.048) over time. Thirteen studies provided data on PFS using RECIST 1.1, with no significant change over time (p=0.69). ORR assessed by RECIST 1.1 has significantly improved by 6.0% over time (p=0.003). Median duration of therapy with sorafenib has decreased by 53% since the enrollment of the first clinical trial in 2005, from 23.1 weeks to 12.2 weeks (p=0.0037). There was no significant change in patient demographics were identified over time to explain the OS findings. Conclusion: The median OS of patients with advanced HCC treated with sorafenib has improved significantly over 15 years. At the same time, the median duration of therapy with sorafenib has decreased. The reason for these findings was not explained by changing demographics of patients enrolled in these trials and has implications for ongoing clinical trials.

Prolonged Viral Shedding in Vertically Acquired SARS-CoV-2 Infection in Preterm Infants–Shedding Versus Infectivity

The reported median duration of viral shedding after infection with SARS-CoV2 is between 12 and 20 days. It is now established that infected individuals can continue to shed viral ribonucleic acid (RNA) without shedding live virus. This has implications for quarantine and infection control practices. COVID in the acute phase seems to be milder in children, and the duration of viral RNA shedding is shorter in children compared to adults. SARS-CoV-2 infections in the newborn period is rare. Little is known about the duration of viral shedding in preterm infants with vertically acquired SARS-CoV-2. 3 of the 4 preterm infants cared for at our center had prolonged shedding up to 34 days with live viral shedding not seen beyond the second week when tested in 3 of them.

Non-tuberculous Mycobacterial Infection of the Musculoskeletal System Detected at Two Tertiary Medical Centres in Henan, China, 2016–2020

Non-tuberculous mycobacterial (NTM) infection of the musculoskeletal system is rare but poses a grave threat to public health. These infections yield non-specific symptoms that remain undetected until the development of the later stages of the disease. In this study, we performed a retrospective review of 25 cases of musculoskeletal NTM infection at two tertiary medical centres over a 5-year period to determine the clinical features and improve the current clinical diagnosis and treatment. The most common mycobacterial species detected were Mycobacterium fortuitum in eleven patients, Mycobacterium abscessus in eight patients, Mycobacterium houstonense in three patients, Mycobacterium avium in two patients, and Mycobacterium smegmatis in one patient. The sites of infection included the limbs and joints, most commonly the knee (ten patients) and foot (six patients). The median duration from the onset of symptoms to diagnosis was 2.5 months (0.8–13.5 months). Deep sinus tracts extending to the surgical site were observed in 60% of the patients (15/25), and granulomatous inflammation and granulomatous inflammation with necrosis occurred in 60% of the patients (15/25). All patients underwent surgical treatment for infection control, and all patients, except one, received antimycobacterial therapy based on drug sensitivity assays. The median duration of the antimicrobial chemotherapy was 5 months (range: 3–20 months). At the final follow-up, 24 patients presented with absence of recurrence and one patient succumbed owing to heart failure after debridement. Our findings highlight the importance of vigilance and improvements in the diagnostic methods for musculoskeletal NTM infection. Aggressive surgical treatment and antimycobacterial drug treatment can help achieve satisfactory results.

COVID-19 testing, timeliness and positivity from ICMR’s laboratory surveillance network in India: Profile of 176 million individuals tested and 188 million tests, March 2020 to January 2021

Background The Indian Council of Medical Research set up a pan-national laboratory network to diagnose and monitor Coronavirus disease 2019 (COVID-19). Based on these data, we describe the epidemiology of the pandemic at national and sub-national levels and the performance of the laboratory network. Methods We included surveillance data for individuals tested and the number of tests from March 2020 to January 2021. We calculated the incidence of COVID-19 by age, gender and state and tests per 100,000 population, the proportion of symptomatic individuals among those tested, the proportion of repeat tests and test positivity. We computed median (Interquartile range—IQR) days needed for selected surveillance activities to describe timeliness. Results The analysis included 176 million individuals and 188 million tests. The overall incidence of COVID-19 was 0.8%, and 12,584 persons per 100,000 population were tested. 6.1% of individuals tested returned a positive result. Ten of the 37 Indian States and Union Territories accounted for about 75.6% of the total cases. Daily testing scaled up from 40,000 initially to nearly one million in March 2021. The median duration between symptom onset and sample collection was two (IQR = 0,3) days, median duration between both sample collection and testing and between testing and data entry were less than or equal to one day. Missing or invalid entries ranged from 0.01% for age to 0.7% for test outcome. Conclusion The laboratory network set-up by ICMR was scaled up massively over a short period, which enabled testing a large section of the population. Although all states and territories were affected, most cases were concentrated in a few large states. Timeliness between the various surveillance activities was acceptable, indicating good responsiveness of the surveillance system.

Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients

Chimeric antigen receptor (CAR) T cells targeting the CD19 antigen are effective in treating adults and children with B-cell malignancies. Place-of-care manufacturing may improve performance and accessibility by obviating the need to cryopreserve and transport cells to centralized facilities. Here we develop an anti-CD19 CAR (CAR19) comprised of the 4-1BB co-stimulatory and TNFRSF19 transmembrane domains, showing anti-tumor efficacy in an in vivo xenograft lymphoma model. CAR19 T cells are manufactured under current good manufacturing practices (cGMP) at two disparate clinical sites, Moscow (Russia) and Cleveland (USA). The CAR19 T-cells is used to treat patients with relapsed/refractory pediatric B-cell Acute Lymphocytic Leukemia (ALL; n = 31) or adult B-cell Lymphoma (NHL; n = 23) in two independently conducted phase I clinical trials with safety as the primary outcome (NCT03467256 and NCT03434769, respectively). Probability of measurable residual disease-negative remission was also a primary outcome in the ALL study. Secondary outcomes include complete remission (CR) rates, overall survival and median duration of response. CR rates are 89% (ALL) and 73% (NHL). After a median follow-up of 17 months, one-year survival rate of ALL complete responders is 79.2% (95%CI 64.5‒97.2%) and median duration of response is 10.2 months. For NHL complete responders one-year survival is 92.9%, and median duration of response has not been reached. Place-of-care manufacturing produces consistent CAR-T cell products at multiple sites that are effective for the treatment of patients with B-cell malignancies.

Medicine treatment of glaucoma in Australia 2012–2019: prevalence, incidence and persistence

ObjectiveMedical therapy can halt or significantly slow the progression of glaucoma if medicines are used in accordance with the guidelines. We used dispensing claims for a 10% sample of all Australians dispensed publicly subsidised glaucoma medicines to determine the prevalence and incidence of glaucoma medicine treatment and to examine treatment persistence between July 2012 and June 2019.MethodsWe estimated incidence and prevalence per 10 000 population for Australian financial years (1 July to 30 June). We defined prevalence as at least one dispensing of any glaucoma medicine and incidence as a dispensing of any glaucoma medicine with no previous dispensing during the preceding 12 months. We estimated duration of treatment for a cohort initiating glaucoma medicines and used Kaplan-Meier methods to estimate the proportion of people persisting on treatment at 6, 12, 18 and 36 months after initiation. We stratified analyses by the number of repeats prescribed at initiation, age, sex and medicine class.ResultsPrevalence remained stable over the study period at around 180/10 000 people/year; incidence was also stable around 36/10 000/year. Among 34 900 people initiating glaucoma medicines, 37.0% remained on treatment at 6 months from initiation, 29.8% at 12 months and 19.2% at 36 months. Median duration of treatment was 13.2 months (IQR: 2.5—not reached) for people initiating prostaglandin analogues and less than 3 months for those initiating other medicine classes.ConclusionPrevalence and incidence of glaucoma treatment have not changed in Australia over the past decade. Persistence to treatment increased with age but remained poor throughout the study period.

Addition of Salvage Immunotherapy to Targeted Therapy in Patients with Metastatic Renal Cell Carcinoma

There have been significant advances in the treatment of metastatic renal cell carcinoma (mRCC), with immunotherapy (IO)-based combinations as the standard-of-care treatment in the front-line setting. IO in this setting is paired with another IO agent or with a vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (TKI). One IO/IO combination and four IO/TKI combinations are currently approved. However, the role of the salvage IO in patients with disease progression on TKI monotherapy is uncertain. Here, we present a case series of five patients who were on single-agent TKI therapy for treatment-refractory mRCC and upon disease progression had an IO agent added to their TKI. The median duration of TKI monotherapy was 11.2 months (range, 1.7–31.1 months), and the median duration of response after the addition of IO was 4 months (range, 2.8–10.5 months). Although IO salvage therapy has a plausible rationale, this case series did not show a clear benefit to this approach. Further clinical trials are needed to determine the clinical utility of IO salvage therapy in mRCC.

Abstract 10412: Duration of Interruptions in Chest Compressions Increases with Increasing Number of Interventions During Cardiac Arrest

Introduction: The American Heart Association recommends limiting chest compression interruptions to ≤10 seconds because prolonged interruptions are detrimental to survival in cardiac arrest. Determining the causes of interruptions is important to structure teams to minimize interruption time. This study sought to determine 1) whether performing more interventions during an interruption increases interruption time and 2) whether the time into the resuscitation in which the interruption occurs affects the duration of the interruption. Hypothesis: We hypothesize that the median duration of an interruption increases as the number of interventions increases and that the median duration of an interruption increases if it occurs later in the resuscitation. Methods: In January 2018 our Emergency Department (ED) began video recording all cardiac arrest resuscitations. These videos are reviewed by a committee of physicians, nurses, technicians, and research staff, and specific data points are confirmed by a physician. The duration of each interruption and cause of each intervention performed during each interruption was recorded. Results: A total of 122 patients with 798 chest compression interruptions from January 2018 to December 2020 were included in our analysis. Median age was 78 years and 44% were female. The median duration of interruptions was 13 seconds (interquartile range [IQR]: 10, 18) when no interventions were performed, 12 seconds (IQR: 8, 18) with 1 intervention, 17 seconds (IQR: 12, 26) with 2 interventions, and 19 seconds (IQR: 13, 24) with 3 or 4 interventions (p<0.0001). The median duration of interruptions was 14 seconds (IQR: 10, 22) in the first quartile of resuscitation length, 14 seconds (IQR: 10, 20) in quartile 2, 14 seconds (IQR: 10, 24) in quartile 3, and 11 seconds (IQR: 8, 18) in quartile 4 (p=0.0058). Conclusions: Our findings demonstrate that the median duration of chest compression interruptions increases as the number of interventions performed during that interruption increases. Additionally, interruption duration was shortest when the interruption was performed later in the resuscitation. These findings suggest that interruptions in chest compressions can be minimized by performing fewer tasks during the interruption.

Abstract 11781: Association of Rapid Response Teams With Hospital Mortality in Medicare Patients

Background: Rapid response teams (RRT) have been promoted as a strategy to reduce unexpected hospital deaths, as they are designed to evaluate and treat patients experiencing sudden decline. However, evidence to support their effectiveness in reducing in-hospital mortality remains uncertain. Methods: Using data from 56 hospitals participating in Get With The Guidelines Resuscitation linked to Medicare, we calculated annual rates of case-mix adjusted mortality for each hospital during 2000-2014. We constructed a hierarchical interrupted time series model to determine whether implementation of a RRT was associated with a reduction in mortality that was larger than expected based on pre-implementation trends alone. Results: Over the study period, the median annual number of Medicare admissions across study hospitals was 5214 (range: 408-18,398). The median duration of the pre-implementation period was 7.6 years comprising ~2.5 million admissions, and the median duration of the post-implementation period was 7.2 years comprising ~2.6 million admissions. Before implementation of RRTs, hospital mortality was already decreasing by 2.7% annually (Figure). Implementation of RRTs was not associated with change in mortality in the initial year of implementation (RR for model intercept: 0.98; 95% CI 0.94-1.02; P= 0.30) or in the mortality trend over time (RR for model slope: 1.01 per-year; 95% CI 0.99-1.02; P =0.30). Within individual hospitals, a RRT was associated with a significantly lower than expected mortality at 4 (7.1%) of hospitals, and significantly higher than expected mortality at 2 (3.6%), when compared to pre-implementation trends. Conclusion: Among a diverse sample of U.S. hospitals, we found that the implementation of a RRT was not associated with a significant reduction in hospital mortality. Given their prevalence in most U.S. hospitals, further studies are needed to understand best practices in composition, design, and implementation of RRTs.