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

Effect of upadacitinib on inflammatory markers and clinical outcomes in patients with Crohn's disease in the phase 3, U-EXCEL, U-EXCEED, and U-ENDURE studies

Background: Improvement in clinical outcomes and normalisation of objective markers of inflammation, high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP), are considered treatment targets per STRIDE-II guidelines.1 We evaluated the effect of the oral selective Janus kinase inhibitor upadacitinib (UPA) on changes in hs-CRP, FCP, and clinical outcomes in patients with Crohn's disease (CD). Method(s): In 2 phase 3, randomized, double-blind, placebo-controlled induction studies (U-EXCEL, NCT03345849;U-EXCEED, NCT03345836), patients with moderate-to-severe CD received 12-week treatment with UPA 45 mg (UPA45) once daily (QD) or placebo (PBO). Patients with clinical response to UPA45 were rerandomised in U-ENDURE (NCT03345823) to receive 52-week maintenance treatment with UPA 30 mg QD (UPA30), UPA 15 mg QD (UPA15), or PBO. Endpoints included marker normalisation (hs-CRP <= 5 mg/L, FCP <= 250 mug/g) in patients with elevated baseline marker levels, normal marker and clinical remission by Crohn's Disease Activity Index (CDAI < 150) or very soft/liquid stool frequency (SF)/abdominal pain score (APS) (average daily SF <= 2.8 and average daily APS <= 1, neither greater than baseline), and >= 50% reduction from baseline in marker values with a decrease of at least 100 points in CDAI from baseline. Median changes from baseline in marker levels were also evaluated. Non-responder imputation with no special data handling for missing data due to COVID-19 was used. Result(s): Of 1021 enrolled patients, 645 (63.2%) had elevated hs-CRP (> 5 mg/L) and 750 (73.5%) had elevated FCP (> 250 mug/g) levels at baseline. Significantly greater proportions of patients with elevated baseline marker levels achieved normalisation with UPA compared with PBO at week 12 (Fig 1A/B) and week 52 (Fig 2A/B;nominal P < .001 for all). Decreases in marker levels from baseline with UPA were observed as early as week 2 and were significantly greater than with PBO through week 12 (Fig 1C) and week 52 (Fig 2C;nominal P < .001 for all). Patients achieved clinical endpoints and improvements in markers at significantly higher rates with UPA45 vs PBO at week 12 (Fig 1D-F) and with UPA15 and UPA30 vs PBO at week 52 (Fig 2D-F;P < .001 for all). The safety profile of UPA in CD was previously reported and no new safety concerns were identified. Conclusion(s): Improvements in clinical endpoints and normalisation of objective markers of inflammation were achieved as early as week 2 with UPA45 induction and sustained with UPA15 and UPA30 maintenance therapy in patients with CD. Median changes in hs-CRP and FCP with UPA support continued improvement of inflammation up to week 52 .

Efficacy of risankizumab induction and maintenance therapy by baseline Crohn's disease location: Post hoc analysis of the Phase 3 ADVANCE, MOTIVATE, and FORTIFY studies

Background and Aim: In patients with Crohn's disease (CD), disease location affects treatment outcomes.1 This post hoc analysis assessed the efficacy of risankizumab (RZB), an interleukin-23 p19 inhibitor, by disease location. Method(s): In the ADVANCE (NCT03105128) and MOTIVATE (NCT03104413) studies, patients with moderately to severely active CD and intolerance or inadequate response to conventional and/or biologic therapy (ADVANCE) or to biologic therapy (MOTIVATE) received intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients achieving clinical response to IV RZB induction were re-randomized in a maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or SC PBO (i.e. withdrawal) for 52 weeks. This post hoc analysis included patients who received RZB 600 mg IV in either ADVANCE or MOTIVATE and patients who received RZB 360 mg SC in FORTIFY. Clinical and endoscopic outcomes were evaluated in patient subgroups stratified by CD location at baseline (ileal only, colonic only, ileal-colonic) using nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19. Result(s): At Week 12, significantly greater proportions of patients receiving RZB 600 mg IV achieved the co-primary endpoints of CD Activity Index (CDAI)-based clinical remission and endoscopic response compared with PBO in the colonic only (n = 190) and ileal-colonic (n = 252) subgroups (P < 0.001). At Week 12, statistically higher proportions of RZB-treated patients achieved the composite endpoint of CDAI clinical remission and endoscopic response, as well as endoscopic remission, in the colonic only and ileal-colonic subgroups compared with PBO (P < 0.001). At Week 52, significantly greater proportions of patients receiving RZB 360 mg SC achieved the co-primary endpoints of CDAI clinical remission and endoscopic response, composite CDAI clinical remission and endoscopic response, and endoscopic remission, compared with withdrawal (PBO SC) in the colonic only (n = 59) and ileal-colonic (n = 67) subgroups (P <= 0.05;Fig. 1a-1d). In patients with endoscopic remission after 12 weeks of IV RZB (Week 0 of maintenance), significantly more RZB-treated patients achieved sustained endoscopic remission at Week 52 compared with withdrawal (PBO SC) in the colonic only and ileal-colonic subgroups (P <= 0.01;Fig. 1e). At Weeks 12 and 52, efficacy rates were numerically lower in ileal-only CD relative to colonic-only and ileal-colonic CD. Results for ileal-only CD are limited by the small number of patients in this subgroup (induction, 85;maintenance, 15). Conclusion(s): RZB induction and maintenance therapy was effective in patients with moderately to severely active CD, with greater benefits observed in patients with any colonic involvement.

A study of machine translation for Vietnamese and Korean on the TED Talks 2020 corpus

Vietnam has achieved impressive economic growth in the last two decades. It becomes a worth investing country in the area. Consequently, the need of understanding foreign investors from different countries (S. Korea in specific) is an essential issue. Therefore, building an automatic machine translation system with high precision is a necessary solution, especially during the COVID-19 pandemic, where keeping distance is the best way to avoid spreading the virus. As a result, this research presents some experimental results on the TED Talks 2020 dataset for the task Korean - Vietnamese and Vietnamese - Korean machine translation with the purpose of providing an overview of the dataset and a deep learning machine translation model for the problem. © 2022 IEEE.

POST-VACCINATION SYMPTOMS AFTER A THIRD DOSE OF SARS-COV-2 MRNA VACCINATION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Background:Symptoms after SARS-CoV-2 primary vaccination among patients with inflammatory bowel disease (IBD) are generally similar to the general population,although symptoms after the second dose are more frequent and severe than after the first dose.Postvaccination symptoms after a 3rd mRNA vaccine dose in the predominantly immune-compromised IBD population is unknown.Methods:Adults with IBD participating in the prospective Coronavirus Risk Associations and Longitudinal Evaluation in IBD (CORALE-IBD) vaccine registry who received a 3rd mRNA vaccine dose were asked to complete a detailed symptom survey 1 week after vaccination.Symptoms were assessed across 11 organ systems,and graded as mild,moderate,or severe,or requiring hospitalization.“Severe+” referred to those with severe symptoms or who required hospitalization.We stratified by age (<or> 50 years) given prior distinct symptom profiles after dose 2 (D2).We also evaluated whether severe+ symptoms after D2 predicted severe+ symptoms after dose 3 (D3).Results:We included 524 participants (70% female, mean age 45 years) who received a 3rd mRNA vaccine through October 11, 2021.Most had Crohn's disease (71%), and 89% were on biologic therapies.Most (58%) had received primary vaccination with BNT562b2,and only 3.5% reported prior COVID infection at the time of initial vaccination.Overall, 97% of subjects received a 3rd dose with the same mRNA vaccine as in their initial series with the remainder receiving the other mRNA vaccine type.No participants received a 3rd dose with the Ad26.CoV.2 (J&J) vaccine. Overall, 41% reported symptoms after a 3rd dose,with symptoms generally more frequent and severe among those <55 years (Table).The most frequent postvaccination symptom was injection site pain (39%).Common systemic symptoms included fatigue/malaise (34%),headache (23%),and muscle, bone or joint symptoms (13%).These were all less frequent after D3 than after D2 (Figure).Gastrointestinal symptoms were reported by 8.8%, which was slightly more frequent than after D2 (7.8%).Among those with postvaccination symptoms, the proportion with severe symptoms after D3 was lower than D2 for fatigue/ malaise, headache, dizziness and lightheadedness, fever/chills, and rheumatologic symptoms, but was slightly higher than D2 for gastrointestinal symptoms.Severe+ symptoms were seen in 17% after D2 and in 14% after D3. Of those with severe+ symptoms after D2, 34% had severe+ symptoms after D3.In contrast, about 22% had severe+ symptoms after D3 but did not report severe+ symptoms after D2.Conclusion:The frequency and severity of symptoms after a 3rd mRNA vaccine dose are generally similar or lower than those after a second dose.Furthermore, prior severe+ symptoms after D2 do not necessarily predict severe+ symptoms after D3. Further evaluation of postvaccination gastrointestinal symptoms in this population is warranted. (Figure Presented) (Table Presented)

PATIENTS WITH INFLAMMATORY BOWEL DISEASE HAVE IMPAIRED HUMORAL BUT PRESERVED CELLULAR RESPONSES TO SARS-COV-2 MRNA VACCINATION

Background: Vaccine-induced protection against SARS-CoV-2 infection is predominantly mediated by humoral immunity;protection against disease progression is primarily determined by cellular immunity. Patients with inflammatory bowel disease (IBD) have high rates of post-vaccination anti-Spike IgG [IgG(S)] seroconversion, but postvaccination immune responses relative to non-IBD controls have not been well described. We aimed to assess post-vaccination humoral (antibody) and cellular (T-cell) responses in IBD relative to healthcare worker (HCW) controls. Methods: We evaluated IBD patients enrolled in a US registry referred from 26 centers at 2, 8, and 16 weeks after completing 2 doses of SARSCoV- 2 mRNA vaccination and compared results to non-IBD non-immunosuppressed HCW participating in a parallel study. We analyzed plasma antibodies to the receptor binding domain of the viral spike protein using the SARS-CoV-2 IgG-II assay (Abbott Labs, Abbott Park, IL);IgG(S) > 50 AU/mL was defined as positive. Those with prior COVID were excluded. We also performed T-cell clonal analysis by T-cell receptor (TCR) immunosequencing at 8 weeks (Adaptive Biotechnologies, Seattle, WA). The breadth (number of unique sequences to a given protein) and depth (relative abundance of all the unique sequences to a given protein) of the T-cell clonal response were quantified using reference datasets. Analyses were adjusted for age, sex and vaccine type. Results: Overall, 1805 subjects were included (IBD n=1074 (65% Crohn's disease, 35% ulcerative colitis);HCW n=731). Age and sex were similar between both cohorts;Hispanic ethnicity and Asian race were less common among IBD than HCW (Table). Vaccine type included BNT162b2 (Pfizer) (75% of IBD, 98% of HCW) and the remainder mRNA-1274 (Moderna). IBD treatments included anti- TNF (46%), other biologics (33%), other immune suppressing therapy (9%), and no immune suppression (12%). Postvaccination antibody levels were lower among IBD than HCW both before and after adjusting for vaccine type (p<0.0001 each timepoint;Figure). After further restricting the IBD cohort to those on no immune-suppressive therapies, antibodies remained lower in IBD vs HCW at 2w (p=0.008) and 8w (p<0.0001), but not 16w (p=0.07). Among 321 subjects with available whole cell samples at 8 weeks (IBD n=163, HCW =158), Spikespecific TCR responses were similar between IBD and HCW for both clonal breadth and depth in both unadjusted and adjusted analyses;sub-analyses of those on biologics yielded similar results. Conclusion: Patients with IBD have dampened humoral responses, but similar cellular responses, after SARS-CoV-2 mRNA vaccination relative to HCW. These findings suggest a potentially greater risk of infection, but not of disease progression, among those with IBD, and should be considered to help guide booster dosing strategies for the IBD population. (Figure Presented) (Figure Presented) Figure: Post-vaccination immune responses: (A) Antibody responses are lower in IBD relative to non-IBD healthcare workers at 2, 8, and 16 weeks (p<0.0001 at each timepoint). In contrast, post-vaccination Spike-specific T-cell receptor clonal breadth (B1) and clonal depth (B2) at 8 weeks are similar in IBD compared to healthcare workers.

Efficacy of risankizumab induction and maintenance therapy by baseline Crohn's Disease location: Post hoc analysis of the phase 3 ADVANCE, MOTIVATE, and FORTIFY studies

Background: In Crohn's disease (CD), disease location affects treatment outcomes.1 This post hoc analysis assessed the efficacy of risankizumab (RZB), an interleukin 23 p19 inhibitor, by disease location. Methods: In ADVANCE (NCT03105128) and MOTIVATE (NCT03104413), patients with moderately to severely active CD and intolerance or inadequate response to conventional and/or biologic therapy (ADVANCE) or to biologic therapy (MOTIVATE) received intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients achieving clinical response to IV RZB induction were re-randomised in a maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or SC PBO (ie, withdrawal) for 52 weeks. This post hoc analysis included patients who received RZB 600 mg IV in either ADVANCE or MOTIVATE and patients who received RZB 360 mg SC in FORTIFY. Clinical and endoscopic outcomes were evaluated in patient subgroups stratified by CD location at baseline (ileal only, colonic only, ileal-colonic) using non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19. Results: At week 12, significantly greater proportions of patients receiving RZB 600 mg IV achieved the co-primary endpoints CD Activity Index (CDAI) clinical remission and endoscopic response vs PBO in the colonic only (n = 190) and ileal-colonic (n = 252) subgroups (P < .001;Figure 1A-1B). At week 12, statistically higher proportions of RZB-treated patients achieved the composite endpoint CDAI clinical remission and endoscopic response, as well as endoscopic remission in the colonic only and ileal-colonic subgroups vs PBO (P < .001;Figure 1C-1D). At week 52, significantly greater proportions of patients receiving RZB 360 mg SC achieved the co-primary endpoints CDAI clinical remission and endoscopic response, composite CDAI clinical remission and endoscopic response, and endoscopic remission vs withdrawal (PBO SC) in the colonic only (n = 59) and ileal-colonic (n = 67) subgroups (P ≤ .05;Figure 2A-2D). In patients with endoscopic remission after 12 weeks of IV RZB (week 0 of maintenance), significantly more RZB-treated patients achieved sustained endoscopic remission at week 52 vs withdrawal (PBO SC) in the colonic only and ileal-colonic subgroups (P ≤ .01;Figure 2E). At weeks 12 and 52, efficacy rates were numerically lower in ileal only CD relative to colonic only and ileal-colonic CD. Results for ileal only CD are limited by the small number of patients in the subgroup (induction, n = 85;maintenance, n = 15). Conclusion: RZB induction and maintenance therapy was effective in patients with moderately to severely active CD with greater benefits observed in patients with any colonic involvement.

Secure Inference via Deep Learning as a Service without Privacy Leakage

Cloud computing plays an important role in many applications today. There is a lot of machine learning as a service that provides models for users' prediction online. However, in many problems which involve healthcare or finances, the privacy of the data that sends from users to the cloud server needs to be considered. Machine learning as a service application does not only require accurate predictions but also ensures data privacy and security. In this paper, we present a novel secure protocol that ensures to compute a scalar product of two real number vectors without revealing the origin of themselves. The scalar product is the most common operation that used in the deep neural network so that our proposed protocol can be used to allow a data owner to send her data to a cloud service that hosts a deep model to get a prediction of input data. We show that the cloud service is capable of applying the neural network to make predictions without knowledge of the user's original data. We demonstrate our proposed protocol on an image benchmark dataset MNIST and an real life application dataset - COVID-19. The results show that our model can achieve 98.8% accuracy on MNIST and 95.02% on COVID-19 dataset with very simple network architecture and nearly no reduction in accuracy when compares with the original model. Moreover, the proposed system can make around 120000 predictions per hour on a single PC with low resources. Therefore, they allow high throughput, accurate, and private predictions. © 2021 IEEE.

Gastrointestinal symptoms in patients with inflammatory bowel disease after SARS-CoV-2 mRNA vaccination

Introduction: In the SARS-CoV2 mRNA vaccine trials, post-vaccination gastrointestinal (GI) symptoms were reported in 10-20% of participants. These symptoms could be perceived as inflammatory bowel disease (IBD) flare which could lead to patient anxiety, and unnecessary tests or treatment. We aimed to assess GI symptoms after SARS-CoV2 mRNA vaccination in patients with IBD relative to non-IBD healthcare workers (HCW). Methods: We assessed GI symptoms in adults with IBD and HCW at baseline and after each dose of a SARS-CoV-2 mRNA vaccine. We analyzed patient-reported IBD-specific disease activity (PRO2) after each dose (stool frequency (SF) and rectal bleeding for ulcerative colitis (UC), SF and abdominal pain for Crohn's disease (CD)). We also compared the frequency, severity, and duration of postvaccination GI symptoms in IBD patients compared to HCW. Severity was defined by impact on daily activities (mild, did not interfere;moderate, some interference;severe, prevented routine activity;extreme, required hospitalization). Severe and extreme were combined and designated as severe+. Duration was classified as<2 days, 2-7 days, or>7 days. Results: Post-vaccination GI symptoms were assessed after dose 1 (D1) (1391 IBD, 933 HCW) and dose 2 (D2) (1271 IBD, 884 HCW) (Table). About 60% of IBD and>99% of HCW received the BNT162b vaccine (Pfizer);the remainder received mRNA-1273 (Moderna). New GI symptoms after D1 were more frequent among IBD than HCW (6.0% vs 2.9%, p=0.001) but not after D2 (12.1% vs 12.7%, p=NS). Relative to HCW, IBD patients reported more diarrhea (3.8% vs. 1% (p<0.001) after D1 and 7.5% vs 4.2% (p=0.003) after D2) and abdominal pain (2.2% vs. 0.4% (p=0.001) after D1 and 6.2% vs 3% (p=0.002) after D2). Severe1 symptoms were noted in 1.5% IBD and 0.3% HCW (p=NS) after D1 and in 3.3% IBD and 0.1% HCW (p<0.001) after D2 (Figure 1). Longer GI symptom duration was more common in IBD than HCW after D1 (2.1% vs 0.5%, p=0.002) and D2 (5.4% vs. 2.1%, p<0.001). Among 423 CD and 300 UC patients with PRO2 data, 71%, 68%, and 65% of CD and 86%, 86%, and 83% of UC were in clinical remission at baseline, after D1, and after D2, respectively. Conclusion: The frequency of GI symptoms in IBD was greater than HCW after D1, but similar after D2. More severe and longer duration of GI symptoms were noted in a small number of IBD patients. Reassuringly, the mRNA vaccines do not seem to increase the risk of a disease flare in the vast majority of IBD patients.

Association of antiplatelet and anticoagulation therapy with dialysis-requiring AKI in critically ill patients with COVID-19

Background: Critically ill patients with COVID-19 have a high incidence of thrombotic complications and dialysis-requiring acute kidney injury (AKI-D). COVID-19 hypercoagulability has been implicated as a possible contributor to AKI-D. Our hypothesis is that pre-existing antiplatelet (APT) or anticoagulation therapy (ACT) is associated with a lower incidence of AKI-D in critically ill patients with COVID-19. Methods: Records of patients with COVID-19 admitted to the ICU from March 13th -April 1st 2020 were reviewed. Exclusion criteria included ESRD status, and ICU discharge or death prior to 14 days of follow-up. Groups were divided based on APT or ACT prior to ICU admission. AKI-D was defined as initiation of renal replacement therapy (RRT) of any kind during the 14 days. Groups were compared using 2-tailed Fisher's exact test and unpaired t tests. Results: A total of 149 records were reviewed, and 98 patients were included (47 died and 4 discharged). Twenty-three patients (23.5%) were on APT or ACT and 39 (40%) required RRT. Table 1 compares characteristics by study group. Hypertension and cardiac conditions were significantly different between groups. Twelve (52%) of patients on APT or ACT required RRT and 27 (36%) not on either required RRT (p=0.22). Conclusions: Pre-existing APT or ACT was not associated with AKI-D in critically ill patients with COVID-19 and 2 weeks of follow up. Our study confirmed a high incidence of AKI-D but was limited by significant differences in cardiac conditions between study groups. Future larger studies examining this association in groups with comparable cardiac conditions are needed.

A novel approach to spinal anaesthesia to avoid aerosol-generating procedures in a patient with COVID-19 presenting for laser prostate surgery.

General anaesthesia involves aerosol-generating procedures which, in the context of the coronavirus 2019 (COVID-19) pandemic, increases the risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) transmission from patients to staff. This risk can be minimised by performing spinal or regional anaesthesia instead of general anaesthesia where possible. We report the successful management of a patient utilising spinal anaesthesia in a patient with COVID-19 undergoing urgent holmium laser enucleation of prostate for symptomatic benign prostatic hyperplasia. A combination of bupivacaine, diamorphine and midazolam was administered intrathecally which provided adequate anaesthesia despite the prolonged surgical duration. Nebulised lidocaine was also given to prevent coughing during the procedure. This report demonstrates that it is possible and safe to use spinal anaesthesia to perform prolonged surgical procedures that are normally conducted under general anaesthesia using a combination of intrathecal adjuncts to facilitate effective block duration. In addition, the novel use of nebulised lidocaine for its antitussive effects in a patient with COVID-19 is highlighted.