Multinational Study Research Articles

Revascularization with BYCROSS atherectomy device- protocol of a prospective multicenter observational study

BackgroundThe BYCROSS™ device is a novel device intended for use in atherectomy of the peripheral arterial disease (PAD). With the BYCROSS™ atherectomy system, also prolonged calcifying lesions can be treated in a minimally invasive manner, which was previously reserved for bypass surgery. The aim of this study is to collect additional clinical data on safety and performance of the BYCROSS™ from patients undergoing revascularization of severely stenotic or occluded peripheral arterial vessels with the BYCROSS™.Methods and designThis is an investigator-initiated national prospective multicenter observational study in patients with PAD. Sixty patients (20 per center) with PAD with stenosis higher than 80% or complete occlusion (de novo or recurrent stenosis) of vessels below the aortic bifurcation (min 3 mm vessel diameter) will be recruited. Three vascular surgery centers are participating in the study. The primary efficacy endpoint is procedural success, defined as passage of the occlusion through the BYCROSS device, and safety outcomes, explicated as freedom from device-related serious adverse events (SADEs). Secondary endpoints include primary and secondary patency rates, change in Rutherford classification, and freedom from amputation at 3 and 12 months.DiscussionThe BYCROSS atherectomy system may be a novel device for the minimally invasive treatment of prolonged calcified lesions previously reserved for bypass surgery. This national prospective multicenter observational study could represent another step in demonstrating the efficancy and safety of this device for treatment of PAD.Trial registration#DRKS00029947 (who.int).Protocol approval id#22–0047(Ethics Committee at Ludwig-Maximilians-University Munich).

COVID-19 illness severity and 2-year prevalence of physical symptoms: an observational study in Iceland, Sweden, Norway and Denmark.

Although the persistence of physical symptoms after SARS-CoV-2 infection is a major public health concern, evidence from large observational studies beyond one year post diagnosis remain scarce. We aimed to assess the prevalence of physical symptoms in relation to acute illness severity up to more than 2-years after diagnosis of COVID-19. This multinational study included 64,880 adult participants from Iceland, Sweden, Denmark, and Norway with self-reported data on COVID-19 and physical symptoms from April 2020 to August 2022. We compared the prevalence of 15 physical symptoms, measured by the Patient Health Questionnaire (PHQ-15), among individuals with or without a confirmed COVID-19 diagnosis, by acute illness severity, and by time since diagnosis. We additionally assessed the change in symptoms in a subset of Swedish adults with repeated measures, before and after COVID-19 diagnosis. During up to 27 months of follow-up, 34.5% participants (22,382/64,880) were diagnosed with COVID-19. Individuals who were diagnosed with COVID-19, compared to those not diagnosed, had an overall 37% higher prevalence of severe physical symptom burden (PHQ-15 score ≥15, adjusted prevalence ratio [PR] 1.37 [95% confidence interval [CI] 1.23-1.52]). The prevalence was associated with acute COVID-19 severity: individuals bedridden for seven days or longer presented with the highest prevalence (PR 2.25 [1.85-2.74]), while individuals never bedridden presented with similar prevalence as individuals not diagnosed with COVID-19 (PR 0.92 [0.68-1.24]). The prevalence was statistically significantly elevated among individuals diagnosed with COVID-19 for eight of the fifteen measured symptoms: shortness of breath, chest pain, dizziness, heart racing, headaches, low energy/fatigue, trouble sleeping, and back pain. The analysis of repeated measurements rendered similar results as the main analysis. These data suggest an elevated prevalence of some, but not all, physical symptoms during up to more than 2 years after diagnosis of COVID-19, particularly among individuals suffering a severe acute illness, highlighting the importance of continued monitoring and alleviation of these targeted core symptoms. This work was mainly supported by grants from NordForsk (COVIDMENT, grant number 105668 and 138929) and Horizon 2020 (CoMorMent, 847776). See Acknowledgements for further details on funding.

The implication of a translational triage tool in mass casualty incidents: part three: a multinational study, using validated patient cards

BackgroundMass casualty incidents (MCI) pose significant challenges to existing resources, entailing multiagency collaboration. Triage is a critical component in the management of MCIs, but the lack of a universally accepted triage system can hinder collaboration and lead to preventable loss of life. This multinational study uses validated patient cards (cases) based on real MCIs to evaluate the feasibility and effectiveness of a novel Translational Triage Tool (TTT) in primary triage assessment of mass casualty victims.MethodsUsing established triage systems versus TTT, 163 participants (1575 times) triaged five patient cases. The outcomes were statistically compared.ResultsTTT demonstrated similar sensitivity to the Sieve primary triage method and higher sensitivity than the START primary triage system. However, the TTT algorithm had a lower specificity compared to Sieve and higher over-triage rates. Nevertheless, the TTT algorithm demonstrated several advantages due to its straightforward design, such as rapid assessment, without the need for additional instrumental interventions, enabling the engagement of non-medical personnel.ConclusionsThe TTT algorithm is a promising and feasible primary triage tool for MCIs. The high number of over-triages potentially impacts resource allocation, but the absence of under-triages eliminates preventable deaths and enables the use of other personal resources. Further research involving larger participant samples, time efficiency assessments, and real-world scenarios is needed to fully assess the TTT algorithm's practicality and effectiveness in diverse multiagency and multinational contexts.

Estimating the Burden of Venous and Arterial Thrombotic Events in Hospitalized Adults with COVID-19; A National Multicenter Cohort Study

Background: Patients infected with Coronavirus Disease 2019 (COVID-19) have clinical and laboratory features consistent with a hypercoaguable state, particularly in more severely ill patients that require hospitalization. However, estimates of thrombotic complications in this high risk population vary widely. A geographic representative cohort to explore the rates of thrombotic events in patients hospitalized with COVID-19 in the United States would be useful to better understand the burden of thrombosis in this population. We aimed to assess the rates of venous and arterial thrombosis events during hospitalization in patients with COVID-19 in a national multicenter cohort study. Methods: We conducted a retrospective cohort study of hospitalized patients diagnosed with COVID-19 from January 1 2020 to January 2023. IRB approval was obtained at each site. Inclusion criteria included adults (> 21 years), hospitalized for >1 day and laboratory confirmation of polymerase chain reaction testing of severe acute respiratory syndrome coronavirus 2. Data were extracted by participating centers in a pre-specified instrument from the electronic medical record at each institution and pooled prior to analysis. Data sources included manual extraction by study investigators in 7 sites and electronic extraction based on billing codes at one site (Cleveland Clinic). Primary outcome was venous thrombotic events, including deep vein thrombosis (DVT), pulmonary embolism (PE). Unusual sites including splanchnic vein thrombosis and cerebral venous thrombosis were included if objectively demonstrated on imaging. Arterial thrombotic events including ischemic stroke, acute coronary syndrome were included as secondary outcomes. Data are presented as proportions, with binomial 95% confidence intervals (CI). Results: We included 33,769 patients from eight medical centers across the United States. Participating hospitals included all four census regions from the North East (Beth Israel Deaconess Medical Center, MA (n=1021) Rochester Regional Hospital, NY (n=99)), South (John Hopkins Medical Institute, ML (n=334); Baycare Health System, FL (n=3734), MidWest (Cleveland Clinic Foundation, OH (n=25467); Henry Ford Health System, MI (973); University of Illinois, IL (1192)) and West (University of California, CA (n=613)). (Figure) Of the total 33,433 hospitalized patients with COVID-19 included, 1684 patients developed a venous thrombotic event during the index hospitalization (5.0%, 95% CI 4.8-5.2) and 261 developed an arterial thrombotic event (0.8%, 95% CI, 95% CI 0.7-0.9). Rates of venous events by individual sites ranged from 2.6-8% and arterial events from 0.3-6.6%. Conclusion: In this national multicenter cohort study that included academic and community hospitals from all four US census regions, we estimated the rates of VTE were over five times more frequent than arterial events in hospitalized patients with COVID-19. Accurate estimates of thrombotic rates and trends can help plan targeted interventions related to strategies around thromboprophylaxis interventions and resource allocation for future surges of COVID-19 cases.

Prognostic Features of CD9 in Childhood Acute Lymphoblastic Leukemia - a Retrospective Analysis of a Nation-Wide Multicenter Study in China

Background and objectives: The outcomes of children with acute lymphoblastic leukemia (ALL) have been incrementally improved with risk-directed chemotherapy but therapy responses remain heterogeneous in clinically defined risk groups. Parameters with added prognostic values are therefore warranted to refine the current risk stratification system and inform appropriate management. CD9, a cell surface protein presented on malignant lymphoblasts, may have such predictive characteristics as shown by our previous single-center study conducted in Hong Kong (Leung et al, Leukemia, 2020). This study aims to determine the precise prognostic features of CD9 in a nation-wide, multicenter childhood ALL cohort in China, and deliver algorithms for identification of patients who may benefit from early interventions. Study design and outcome measures: This multicenter cohort study included childhood ALL patients (aged <18 years) enrolled into the Chinese Children Cancer Group (CCCG)-ALL-2015 study from January 2015 to December 2019, with 7,640 patients from 20 tertiary hospitals in China treated with a uniform protocol. A total of 3,781 subjects (49.5%) from 16 sites had flow cytometry data on lymphoblast CD9 at diagnosis. The final study cohort comprised 3,395 B-ALL and 386 T-ALL patients with a median follow-up of 53.9 months. The primary outcomes were 5-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) for patients with CD9 + or CD9 - phenotypes (positivity defined by the presence of ≥20% CD9 + blasts evaluated through a univariate analysis demonstrating the highest odds for adverse events or relapse at this cut-off). The secondary outcomes were 5-year OS, EFS, and CIR rates of CD9 + and CD9 - patients after inclusion of known prognostic factors, including risk assignment, cytogenetic anomalies, and minimal residual disease (MRD) status. Survival benefits of CD9 + subjects from treatment intensification or hematopoietic stem cell transplantation (HSCT) were analyzed. Results: CD9 was expressed in 88.5% of B-ALL and 27.9% of T-ALL cases. It conferred a dismal EFS (82.1% vs. 89.3%, P=0.001) and a higher CIR (15.5% vs. 7.8%, P<0.001) in B-ALL but not T-ALL patients. The prognostic impact of CD9 is much more prominent in subjects with adverse presenting features or poor early treatment responses, as best exemplified in those assigned to the intermediate/high-risk arms (EFS: 72.8% vs. 83.2%, P=0.028; CIR: 23.1% vs. 10.2%, P=0.003) or those with positive MRD at day 19 (EFS: 65.2% vs. 82.0%, P=0.053; CIR: 30.3% vs. 9.7%, P=0.007). The adverse impact of CD9 is confined to specific cytogenetics, including BCR-ABL1 (CIR: 39.5% vs. 0%, P=0.019) and normal karyotype (CIR: 15.0% vs. 6.8%, P=0.034). In multivariate analyses, CD9 remains an independent factor predicting event-free survival (HR=1.917, P=0.001) and relapse (HR=2.208, P<0.001). The time to and site of relapse did not differ between CD9 + and CD9 - patients. For CD9 + patients with MRD at the end of induction, treatment upstaging only benefited initial low-risk subjects. HSCT at first remission did not improve the outcomes of high-risk subjects with a CD9 + phenotype. Conclusions: This is the largest study to evaluate the significance of CD9 in childhood ALL. We confirmed the results of our previous single-center study with this multicenter national study. CD9 positivity is definitively associated with a higher relapse probability particularly for patients with intermediate/high risk diseases, MRD positivity or specific cytogenetic background. BCR-ABL1 + patients with a CD9 - phenotype had excellent outcomes and HSCT may not be required. Whereas MRD + patients who were CD9 + had poor outcomes, and therefore should have early interventions with innovative treatments to reduce the risk of relapse. With these, we propose to incorporate CD9 into the diagnostic immunophenotyping panel to inform risk stratification and management of childhood ALL.

Comparison of Alloimmunization in Pregnant People with Sickle Cell Disease Receiving Chronic Versus on-Demand Transfusions: A Multinational Study

Introduction Despite exceptional maternal morbidity and mortality risk, people with sickle cell disease (SCD) lack firm indications for chronic transfusion therapy (CTT) during pregnancy. Alloimmunization may cause hemolytic transfusion reactions and can limit the safety of future blood transfusions; thus it is a rationale for restricting CTT during pregnancy. Little data quantifies this risk. The 2020 American Society of Hematology (ASH) Guidelines for SCD TransfusionSupport recommend CTT in some pregnancies, but adoption in clinical practice is unknown. This study's purpose is to use a large two-center SCD pregnancy cohort to describe alloimmunization rates in SCD pregnancies treated with CTT vs on-demand transfusion (ODT) and to determine the fraction of SCD pregnancies meeting the ASH Guideline to initiate CTT in pregnancy. Methods We reviewed SCD pregnancies delivered at Mt. Sinai Hospital, Toronto (1990-2017) and Johns Hopkins Hospital (2000-2021). We collected data on transfusions and SCD complications before and during pregnancy, delivery, and fetal outcomes. Analyses classified subjects and pregnancies as receiving CTT or ODT. We defined CTT as pregnancies treated with scheduled, prophylactic transfusions; ODT as pregnancies transfused as-needed, including no transfusions. Sinai routinely matched transfusions for Rh and K antigens while Hopkins matched Rh only. Both centers provided extended matching if an alloantibody was detected. The first analysis included singleton pregnancies to primigravida subjects. We compared new alloantibody development, SCD complications, and pregnancy outcomes in CTT vs. ODT groups and in genotype stratified groups. We used Chi-squared and Wilcoxon rank-sum tests for categorical and continuous variables; p < .05 was significant. The second analysis included all cohort pregnancies and identified which met criteria for CTT per ASH Transfusion Guidelines which advise CTT for (A) severe SCD complications before or during pregnancy here defined by acute chest syndrome (ACS) or pain requiring acute care in the year before or during pregnancy, any history of venous thromboembolism (VTE), stroke, or multi-organ failure or (B) features of high-risk pregnancy, defined by multiple gestation, pre-eclampsia, gestational hypertension, cardiac comorbidities, or preterm labor history. Results Among 145singleton, primigravida pregnancies, more received ODT than CTT (119 ODT vs 26 CTT). Among ODT subjects 46/119 received at least one transfusion during pregnancy. CTT subjects had more severe SCD than ODT subjects before pregnancy (Table 1). During pregnancy, SCD severity did not differ (Table 2). Before pregnancy, 18 subjects were alloimmunized and did not differ by treatment group (6/26 CTT vs 12/119 ODT, p=0.07). During pregnancy, six subjects developed an alloantibody and did not differ by treatment group (1/26 CTT vs 5/119 ODT, p=0.93). Half (3/6) had a history of alloimmunization before pregnancy (1 CTT vs 2 ODT, p=0.27) and three did not (0 CTT vs 3 ODT, p=0.27). All subjects with new antibodies during pregnancy and historic alloimmunization developed anti-K antibodies (1 CTT, 2 ODT) at both sites. Those without alloimmunization history developed anti-Jkantibodies (3 ODT) at Sinai. In the secondary analysis, we included 299 pregnancies to 203 subjects. Among them, 249 pregnancies (83%) met at least one ASH Guideline criteria for initiating CTT. This included all CTT pregnancies (61/61, 39 subjects) and 79% of ODT pregnancies (188/238, 164 subjects), 46% of which received at least one transfusion during pregnancy (86/188). Conclusions In this SCD pregnancy cohort, alloimmunization rates were low and did not differ between those treated with CTT versus ODT. As alloimmunization events were inconsistent with institutional matching practices, new antibody development may be attributable to transfusions from outside hospitals or pregnancy-associated alloimmunization. Antigen matching per ASH Transfusion Guidelines avoids C, E, K and Jk alloimmunization. Scheduled transfusions may reduce emergency transfusion which increases alloimmunization risk. Finally, all CTT and 79% of ODT pregnancies met ASH Guideline criteria for CTT in pregnancy, however the cohort predates ASH Guideline publication. Guideline adherence may lead to increased use of CTT during pregnancy. More discriminating tools are needed to inform CTT use in SCD pregnancy.

Patient Characteristics and Diagnostic Journey of Thrombotic Microangiopathy Associated with a Trigger: A Real-World, Retrospective, Multi-National Study

Introduction Thrombotic microangiopathy (TMA) is characterized by thrombocytopenia, microangiopathic hemolytic anemia and microthrombi leading to ischemic tissue injury and organ damage. Disease emergence is unpredictable and in some cases TMA manifests in relation to a trigger, including autoimmune disease, infection, malignant hypertension, pregnancy, transplantation and drugs. In this study, we characterized the patient diagnostic journey of TMA associated with a trigger using real-world data. Methods Data were drawn from the Adelphi aHUS Disease Specific Programme, a cross-sectional survey of physicians and their patients with TMA associated with a trigger (data collected August-December 2022) from Australia, France, Germany, Italy, Spain, the UK and the USA. This analysis included physician-reported patient data and all patients had TMA associated with a trigger diagnosed by a physician. Analyses were conducted with all triggers combined, and by trigger type. Results Overall, 321 patients with TMA associated with a trigger were included; the top 5 most frequent triggers were infection (19.0%), drug (15.0%), autoimmune disease (14.6%), malignancy (13.7%) and solid organ transplantation (10.6%). Demographics, clinical characteristics and route to diagnosis are provided for all patients in the Table.At the point of survey, 53.6% of patients were female and the median age (interquartile range [IQR]) was 47.0 (33.5-59.0) years. Overall, 7/312 (2.2%) and 16/309 (5.2%) patients had a family history of TMA or kidney disease, respectively, although these proportions were higher in patients with TMA triggered postpartum (2/18 [11.1%] and 4/18 [22.2%]). The most common ethnicity was White/Caucasian (199/280 [71.1%]), however this varied across triggers; lowest in malignant severe hypertension (12/24 [50.0%]) and highest in bone marrow transplantation (21/25 [84.0%]). At first presentation to a healthcare professional (HCP), the most common symptom/complication was hemolytic anemia (208/312 [66.7%]), yet other common symptoms/complications varied across triggers (e.g. 24/45 [53.3%] patients with TMA triggered by an autoimmune disease presented with fatigue, and 17/29 [58.6%] and 14/29 [48.3%] patients with TMA triggered by malignant hypertension presented with kidney damage and proteinuria, respectively). At first diagnosis of TMA associated with a trigger, 125/315 (39.7%) and 44/315 (14.0%) patients had severe or life-threatening TMA, respectively; further, 260/277 (93.9%) patients had a platelet count outside the normal range, 101/115 (87.8%) patients had a lactate dehydrogenase level > 1.5 × the upper limit of normal, and the median (IQR) serum creatinine level among all patients was 2.9 mg/dL (1.8-4.0). Across all triggers, the first consulting HCP at symptom onset was most often a nephrologist (23.4%), general practitioner (GP; 21.8%) or emergency room (ER)/intensive care unit (ICU) physician (21.2%), while the first diagnosing HCP of TMA associated with a trigger was most often a nephrologist (38.6%), hematologist (24.9%), or hematologist-oncologist (22.4%). In 249 patients with available data, the median duration from symptom onset to TMA diagnosis was 6.0 days (IQR, 0-30.0 days). Conclusion In this study, severe or life-threatening TMA associated with a trigger was reported at the point of diagnosis for over half of the patients. An increased awareness of the clinical characteristics, symptoms and complications of TMA associated with a trigger by HCPs, particularly GPs who were frequently the first consulting HCP, is key to facilitating early diagnosis and timely referral to TMA experts/multi-disciplinary teams and optimizing patient management. Study/medical writing support funder: Alexion, AstraZeneca Rare Disease, Boston, MA, USA.

Standardising personalised diabetes care across European health settings: A person-centred outcome set agreed in a multinational Delphi study.

Standardised person-reported outcomes (PRO) data can contextualise clinical outcomes enabling precision diabetes monitoring and care. Comprehensive outcome sets can guide this process, but their implementation in routine diabetes care has remained challenging and unsuccessful at international level. We aimed to address this by developing a person-centred outcome set for Type 1 and Type 2 diabetes, using a methodology with prospects for increased implementability and sustainability in international health settings. We used a three-round questionnaire-based Delphi study to reach consensus on the outcome set. We invited key stakeholders from 19 countries via purposive snowball sampling, namely people with diabetes (N = 94), healthcare professionals (N = 65), industry (N = 22) and health authorities (N = 3), to vote on the relevance and measurement frequency of 64 previously identified clinical and person-reported outcomes. Subsequent consensus meetings concluded the study. The list of preliminary outcomes was shortlisted via the consensus process to 46 outcomes (27 clinical outcomes and 19 PROs). Two main collection times were recommended: (1) linked to a medical visit (e.g. diabetes-specific well-being, symptoms and psychological health) and (2) annually (e.g. clinical data, general well-being and diabetes self management-related outcomes). PROs are often considered in a non-standardised way in routine diabetes care. We propose a person-centred outcome set for diabetes, specifically considering psychosocial and behavioural aspects, which was agreed by four international key stakeholder groups. It guides standardised collection of meaningful outcomes at scale, supporting individual and population level healthcare decision making. It will be implemented and tested in Europe as part of the H2O project.

Transcranial Doppler Screening of Children with Sickle Cell Disease for a Large, Multinational Interventional Study: Experience from the Phase 3 HOPE-Kids 2 Trial Investigating the Effect of Voxelotor Treatment on Transcranial Doppler Flow Velocity

Introduction: Transcranial Doppler (TCD) ultrasound is an effective screening tool for identifying children with sickle cell disease (SCD) who are at high risk of stroke. Implementing TCD screening, along with appropriate therapies, for the purpose of primary stroke prevention in resource-constrained settings remains challenging. HOPE-KIDS 2 (NCT04218084) is an ongoing, phase 3, multicenter, double-blind, placebo-controlled trial of voxelotor in children with SCD and elevated arterial cerebral blood flow (measured by time-averaged maximum of the mean velocity [TAMMV]). Our aim is to describe the findings from successful implementation of a standardized TCD screening protocol that was conducted in a multinational setting. Methods: The purpose of HOPE-KIDS 2 is to evaluate the effect of voxelotor treatment on reducing the risk of stroke in participants aged 2 to <15 years with SCD who have conditional TAMMV (170 to <200 cm/s) at baseline. Children aged 2 to <15 years with SCD (HbSS/HbSβ 0) were screened after local sonographers were trained and certified on standardized TCD examination protocol, using the same model of Multi-Dop T digital machine (Compumedics DWL, Germany). TCD assessments were sent for central quality review and interpretation by 2 independent reviewers. STOP criteria were used to classify stroke risk: normal, <170 cm/s; conditional, 170 to <200 cm/s; or abnormal, ≥200 cm/s. Patient baseline characteristics, including clinical measurements of markers of anemia and hemolysis, were measured during study screening. The reasons for patient screen failure were summarized. Results: Between Nov 2020 and Feb 2023, 708 participants consented at 29 sites in Nigeria (n=250; 5 sites), Kenya (n=241; 4 sites), Egypt (n=145; 4 sites), Ghana (n=28; 2 sites), the US (n=17; 8 sites), Italy (n=9; 3 sites), Oman (n=9; 1 site), Saudi Arabia (n=8; 1 site), and the UK (n=1; 1 site). Of these patients, 92.1% (652/708) completed TCD screening examinations (mean [SD] age 7.6 [3.24] years; range 2.0-14.0 years; 50.8% male; 23.0% receiving hydroxyurea). Of the patients who completed TCD screening, the mean (SD) TAMMV was 163.0 (31.26) cm/s, and 47.1% (307/652) had conditional TCD at baseline (29.0% low conditional, 18.1% high conditional). The main reason for screen failure was index TAMMV outside of conditional range (abnormal, n=39 [6.0%]; normal, n=306 [46.9%]). Elevated TAMMV on screening TCD was more common in younger children (2 to ≤8 years vs >8 to <15 years); patients aged 2-8 years comprised 66.8% and 82.1% of the conditional and abnormal TCD categories, respectively. There were 39 assessments that required adjudication, but only 9 were deemed unreadable. Of all patients screened, 36.2% (236/652) fulfilled eligibility criteria for randomization; the characteristics at screening of these patients are summarized (Table). The mean (SD) Hb level and TAMMV at screening for randomly assigned patients was 7.7 (1.06) g/dL and 182.7 (7.53) cm/s, respectively. Conclusions: Clinical sites for the HOPE-KIDS 2 study successfully implemented a standardized, local TCD screening protocol supported by central quality review. For a large interventional trial aimed at reducing the risk of stroke in children with SCD, African and Middle Eastern sites presented relatively few limitations with respect to participant screening.

Treatment Patterns in Patients with Mantle Cell Lymphoma: Updated Report of the Asia-Pacific Multinational Retrospective Registry Study

I ntroduction We conducted a multinational, multicenter retrospective registry study to better define the treatment patterns and survival outcomes of newly diagnosed patients with mantle cell lymphoma (MCL) in the Asia-Pacific region. Methods Data were collected from newly diagnosed MCL patients between January 2008 and September 2019 from 27 hospitals in Asian countries, including China, Malaysia, Japan, Singapore, South Korea, Taiwan, and Thailand. The first interim analysis with 191 patients was previously reported. An updated analysis of 381 patients was performed at the data cutoff date of June 20, 2023. Results The median age was 62 years (range, 26-90), and 282 patients were male (74.0%). The majority of the patients had stage 3 or 4 disease (n = 329, 87.1%). Based on the MIPI score, 20.7% (n = 139) were classified as high-risk, while 39.4% (n = 150) were classified as high-risk according to the IPI. The most frequently administered 1 st line regimen was R-CHOP or R-CHOP-like regimens (n = 177, 46.5%), followed by cytarabine-containing regimens (n = 113, 29.7%), including R-Hyper-CVAD (n = 78), and bendamustine-rituximab (n = 27, 6.3%). There was a significant difference in the treatment pattern between young (age < 65, n = 210) versus elderly patients (age ≥ 65, n = 171). A higher proportion of elderly patients received R-CHOP or R-CHOP-like regimens (n = 98, 57.3%) while cytarabine-containing regimens were more frequently administered in young patients (n = 97, 46.2%). The treatment response to 1st line regimens was available in 349 patients. The overall response rate (ORR) and the complete response (CR) rate among these patients were 91.1% and 57.9%, respectively. The response rates (ORR/CR rate) for each regimen were as follows; 91.4%/49.1% for R-CHOP or R-CHOP-like regimens, 93.5%/67.3% for cytarabine-containing regimens, and 96.2%/76.9% for bendamustine-rituximab (BR). With a median follow-up duration of 82.6 months, the median progression-free survival (PFS) was 40.6 months, and the median overall survival (OS) was 86.8 months (Figure). The median PFS was 35.2 months for R-CHOP or R-CHOP-like regimens, 65.8 months for cytarabine-containing regimens, and 57.9 months for BR. The role of upfront ASCT was evaluated in pts who are < 65 years old and achieved at least partial response (PR) to 1 st line treatment (n = 181). No significant differences were observed in baseline characteristics between patients who received upfront ASCT (n = 48) and those who did not (n = 133). There were no significant differences in PFS and OS between the ASCT and non-ASCT groups, with a 5-year PFS rate of 56.3% vs. 48.9% ( P = 0.190) and a 5-year OS rate of 82.1% vs. 76.1% ( P = 0.069), respectively. The role of maintenance treatment was evaluated in patients who achieved PR or better to 1 st line treatment and did not experience disease progression within 3 months after completion of 1 st line treatment (n = 293). A significantly higher proportion of patients in the non-maintenance group (n = 270) was classified as a high-risk group according to the MIPI score compared with those who received rituximab maintenance (n = 23) (20.3% vs. 0.0%, P = 0.043). Rituximab maintenance was associated with significantly better PFS and OS compared with no maintenance group, with a 5-year PFS rate of 67.7% vs. 42.0% ( P = 0.015) and 5-year OS rate of 88.4% vs. 66.7% ( P = 0.008). A total of 192 patients were treated with 2 nd line regimens. The most frequently administered 2 nd line regimen was cytarabine-based chemotherapy (n = 47, 24.5%), followed by ibrutinib (n = 46, 24.0%) and BR (n = 32, 16.7%). The ORR and the CR rate among these patients were 75.5% and 43.4%, respectively. The median 2 nd PFS was 16.8 months. Conclusion Our study demonstrated that the majority of patients with MCL in the Asia-Pacific region were treated with rituximab-based regimens in the contemporary era. However, R-CHOP or R-CHOP-like regimens are still the most commonly used 1 st line treatment. The rate of upfront ASCT and usage of rituximab maintenance was relatively low, and there was no significant difference in survival outcomes according to upfront ASCT. Although rituximab maintenance was associated with improved survival, patients without maintenance treatment had a higher proportion of high-risk patients in the current study. Our contemporary real-world analysis showed improved survival outcomes compared to previous studies.

Ibrutinib As First Line Therapy in Chronic Lymphocytic Leukemia Patients over 80 Years Old: A Retrospective Real-Life Multicenter Italian Cohort

Background: Although CLL primarily affects older adults (median age 71 years), limited data exist about the outcomes of adults who are ≥80 years old because they are under-enrolled in clinical trials. Methods: We performed a multicenter national study enrolling consecutive treatment-naïve CLL patients ≥80 years at the time of frontline CLL therapy, treated with ibrutinib. Kaplan-Meier analyses were used to plot progression-free survival (PFS) and overall survival (OS). Results: Our study included 79 patients with CLL who were aged ≥80 years at the time of frontline CLL therapy starting between 1/2014 and 3/2021; the clinical features of these patients are summarized in Table 1. A total of 13 (16.5%) patients achieved a nodal clinical response (CR; bone marrow evaluation was not performed), 58 (73.4%) a partial response (PR) or PR + lymphocytosis (PR+L), 3 (3.8%) a stable disease (SD), and 5 (6.3%) were not evaluated since they early withdrew ibrutinib. Discontinuation because of progressive disease (PD) occurred in 9 cases (11%), whereas discontinuation due to toxicity in 11 patients (13.9%). The most common grade >3 adverse events (AEs) were infections (25.5%), neutropenia (10.1%), and anemia (2.5%). Eighteen patients (22.8%) experienced cardiovascular events: 9 (11%) had atrial fibrillation (AF), 5 hypertension (6%), 3 heart failure (3%), and 1 acute coronary syndrome (1%). All cases of AF and hypertension were of grade 2. Patients with AF received anticoagulation and no thrombotic stroke were recorded. Bleeding events were observed in 27 (34.2%) patients but were mild, of grade 1-2 in 24 and grade 3 in 3. Patients who received anticoagulants or anti-platelets drugs did not experienced a significantly higher rate of hemorrhagic events than those not assuming anticoagulation. Secondary malignancies were reported in 6 patients (7.8%) and Richter's transformation in five. Temporary drug withdrawal (7-30 days) occurred in 33 patients (41.8%): in 17 (21.5%) due to infections, 5 (6.3%) cardiovascular events, 10 (12.7%) hemorrhagic events, and 4 (5.1%) hematologic toxicity. Ibrutinib was permanently discontinued in 26 patients (32%): in 9 with PD (Richter's syndrome, 5), 6 with secondary malignancies, 5 with infections, 3 with cardiac failure, 2 due to severe bleeding and a sudden death was reported in 1. After a median follow-up of 24 months, the median PFS was 49.3 months (95% CI 39.9-58.7) and the median OS 51.8 (95% CI 50.1-53.5). Age, sex, creatinine clearance, Binet stage, del17p, TP53 and IGHV mutational status did not significantly impact PFS. Conversely, CIRS >6 was associated with a significantly shorter PFS (median PFS: 33.1 months, 95% CI 25.3-40.9 vs. not reached, p=0.016). A significantly longer PFS (p=0.03) was observed in the 46 patients who never discontinued ibrutinib or stopped the drug for less than 7 days (median PFS 66.3 months, 95% CI 50.5-82.1) compared to those with a transient treatment discontinuation, between 7 and 30 days, (median PFS; 32.7 months, 95% CI 23.2-42.3) (Figure 1). Sex, creatinine clearance, Binet stage, IGHV, del17p, and TP53 mutational status, as well as CIRS, did not significantly impact OS. Conversely, a trend toward a statistically significant longer OS (P=0.07) was observed for patients who discontinued ibrutinib <7 days (67.2 months, 95% CI 43.5-90.9) compared with those who discontinued for 7-30 days (51.8 months, 95% CI 34.4-69.2). Conclusions: To our knowledge, this is the largest real-world study examining treatment-naive elderly patients receiving ibrutinib as first-line therapy. Ibrutinib represents a suitable therapeutic choice even for patients aged >80 years with comorbidities. In this setting of patients, the drug was well tolerated and no new side effects were recorded.

Burnout syndrome among rheumatologists and rheumatology fellows in Arab countries: an ArLAR multinational study.

Burnout is frequent among physicians and seems to be underestimated among rheumatologists. To estimate the frequency of burnout in a sample of rheumatologists practising in the Arab countries and determine its associated factors. This was a descriptive cross-sectional study conducted by the Arab League of Associations for Rheumatology (ArLAR research group) using an anonymous electronic questionnaire set up on the Google Forms platform. All Arab rheumatologists and rheumatology fellows were invited to participate in the spring of 2022 via ArLAR social media accounts, societies' WhatsApp groups, and mass emails. Burnout was defined by at least one positive domain of the Maslach Burnout Inventory (MBI) (Emotional exhaustion, Depersonalization, and Personal accomplishment). The final score was correlated to socio-demographic factors using a multivariable binary logistic regression. The study included 445 rheumatologists and rheumatology fellows with an average age of 45.2years (SD 11.5); 61.8% were men. The frequency of burnout among rheumatologists was 61.3% and was driven by low personal accomplishment scores (58.1%). Younger age (OR 1.92 (95%CI 1.20-3.08)), dissatisfaction with the specialty (OR 2.036 (95% CI 1.20-3.46)), and low income (OR 2.26 (95% CI 1.01-5.10)) were associated with burnout. The frequency of burnout in a sample of rheumatologists in Arab countries is very high, driven by low personal accomplishment scores and associated with a low income, dissatisfaction with the specialty and younger age. Some associated factors might be modifiable, thus reducing the burden of burnout on rheumatologists and on the healthcare system. Key Points • The frequency of burnout in a sample of Arab rheumatologists was 61.3% according to the MBI. • The score was mainly driven by low personal accomplishment scores (58.1%). • Younger age, dissatisfaction with the specialty, and low income were associated with burnout. • Acting upon modifiable risk factors would help reducing the burden of burnout on rheumatologists and on the healthcare system.

Multi-national observational study to assess quality of life and treatment preferences in patients with Crohn's perianal fistulas.

Patients with Crohn's disease (CD) are at risk of developing complications such as perianal fistulas. Patients with Crohn's perianal fistulas (CPF) are affected by fecal incontinence (FI), bleeding, pain, swelling, and purulent perianal discharge, and generally face a higher treatment burden than patients with CD without CPF. To gain insights into the burden of illness/quality of life in patients with CPF and their treatment preferences and satisfaction. This cross-sectional observational study was conducted in patients with CD aged 21-90 years via a web-enabled questionnaire in seven countries (April-August 2021). Patients were recruited into three cohorts: Cohort 1 included patients without perianal fistulas; cohort 2 included patients with perianal fistulas without fistula-related surgery; and cohort 3 included patients with perianal fistulas and fistula-related surgery. Validated patient-reported outcome measures were used to assess quality of life. Drivers of treatment preferences were measured using a discrete choice experiment (DCE). In total, 929 patients were recruited (cohort 1, n = 620; cohort 2, n = 174; cohort 3, n = 135). Short Inflammatory Bowel Disease Questionnaire scores were worse for patients with CPF (cohorts 2 and 3) than for those with CD without CPF (cohort 1): Mean score 3.8 and 3.7 vs 4.1, respectively, (P < 0.001). Similarly, mean Revised FI and FI Quality of Life scores were worse for patients with CPF than for those with CD without CPF. Quality of Life with Anal Fistula scores were similar in patients with CPF with or without CPF-related surgery (cohorts 2 and 3): Mean score 41 and 42, respectively. In the DCE, postoperative discomfort and fistula healing rate were the most important treatment attributes influencing treatment choice: Mean relative importance 35.7 and 24.7, respectively. The burden of illness in CD is significantly higher for patients with CPF and patients rate lower postoperative discomfort and higher healing rates as the most desirable treatment attributes.

Age- and sex-based heterogeneity in coronary artery plaque presence and burden in familial hypercholesterolemia: A multi-national study

ObjectivesIndividuals with familial hypercholesterolemia (FH) are at an increased risk for coronary artery disease (CAD). While prior research has shown variability in coronary artery calcification (CAC) among those with FH, studies with small sample sizes and single-center recruitment have been limited in their ability to characterize CAC and plaque burden in subgroups based on age and sex. Understanding the spectrum of atherosclerosis may result in personalized risk assessment and tailored allocation of costly add-on, non-statin lipid-lowering therapies. We aimed to characterize the presence and burden of CAC and coronary plaque on computed tomography angiography (CTA) across age- and sex-stratified subgroups of individuals with FH who were without CAD at baseline. MethodsWe pooled 1,011 patients from six cohorts across Brazil, France, the Netherlands, Spain, and Australia. Our main measures of subclinical atherosclerosis included CAC ranges (i.e., 0, 1–100, 101–400, >400) and CTA-derived plaque burden (i.e., no plaque, non-obstructive CAD, obstructive CAD). ResultsNinety-five percent of individuals with FH (mean age: 48 years; 54% female; treated LDL-C: 154 mg/dL) had a molecular diagnosis and 899 (89%) were on statin therapy. Overall, 423 (42%) had CAC=0, 329 (33%) had CAC 1–100, 160 (16%) had CAC 101–400, and 99 (10%) had CAC >400. Compared to males, female patients were more likely to have CAC=0 (48% [n = 262] vs 35% [n = 161]) and no plaque on CTA (39% [n = 215] vs 26% [n = 120]). Among patients with CAC=0, 85 (20%) had non-obstructive CAD. Females also had a lower prevalence of obstructive CAD in CAC 1–100 (8% [n = 15] vs 18% [n = 26]), CAC 101–400 (32% [n = 22] vs 40% [n = 36]), and CAC >400 (52% [n = 16] vs 65% [n = 44]). Female patients aged 50–59 years were less likely to have obstructive CAD in CAC >400 (55% [n = 6] vs 70% [n = 19]). ConclusionIn this large, multi-national study, we found substantial age- and sex-based heterogeneity in CAC and plaque burden in a cohort of predominantly statin-treated individuals with FH, with evidence for a less pronounced increase in atherosclerosis among female patients. Future studies should examine the predictors of resilience to and long-term implications of the differential burden of subclinical coronary atherosclerosis in this higher risk population.

Development and validation of a clinical prediction model for 90-day venous thromboembolism risk following total hip and total knee arthroplasty: a multinational study

BackgroundThe risk of venous thromboembolism (VTE) following total hip arthroplasty (THA) and total knee arthroplasty (TKA) is 1.0% to 1.5%, despite uniform thromboprophylaxis. ObjectivesTo develop and validate a prediction model for 90-day VTE risk. MethodsA multinational cohort study was performed. For model development, records were used from the Oxford Royal College of General Practitioners Research and Surveillance Centre linked to Hospital Episode Statistics and Office of National Statistics UK routine data. For external validation, data were used from the Danish Hip and Knee Arthroplasty Registry, the National Patient Registry, and the National Prescription Registry. Binary multivariable logistic regression techniques were used for development. ResultsIn the UK data set, 64 032 THA/TKA procedures were performed and 1.4% developed VTE. The prediction model consisted of age, body mass index, sex, cystitis within 1 year before surgery, history of phlebitis, history of VTE, presence of varicose veins, presence of asthma, history of transient ischemic attack, history of myocardial infarction, presence of hypertension and THA or TKA. The area under the curve of the model was 0.65 (95% CI, 0.63-0.67). Furthermore, 36 169 procedures were performed in the Danish cohort, of whom 1.0% developed VTE. Here, the area under the curve was 0.64 (95% CI, 0.61-0.67). The calibration slope was 0.92 in the validation study and 1.00 in the development study. ConclusionThis clinical prediction model for 90-day VTE risk following THA and TKA performed well in both development and validation data. This model can be used to estimate an individual’s risk for VTE following THA/TKA.

Adherence to PKU guidelines among patients with phenylketonuria: A cross-sectional national multicenter survey-based study in Argentina, Brazil, and Mexico

ObjectiveTo characterize adherence to Phenylketonuria (PKU) management practices among PKU patients treated at reference sites around Argentina, Brazil, and Mexico. MethodsThis is a retrospective, observational, multicenter, and multinational survey-based study using aggregate data. From an initial list of 40 sites, 22 clinicians expressed interest in completing the survey, with 20 clinicians from 20 unique sites fulfilling all the study criteria. The Survey contained 28 questions, including respondent's clinic characteristics, clinic PKU treatment recommendations, and patient adherence to clinic recommendations. Survey was available in local languages, and the respondents were asked to consult their clinic records to complete their responses. Adherence was assessed by target blood phenylalanine (Phe), target blood testing frequency, and clinic visits. ResultsA total of 1077 (out of 1377) actively managed PKU patients (seen in the clinic in the last 3 years) from 13 clinics in Brazil, six in Argentina, and one in Mexico were analyzed. Upper blood Phe target was set over 360 μMol/L in 70% of the clinics for adult patients. Around 40% of the patients >30 years old had Phe blood tests done twice a year or less, with 60% of the clinics recommending semestral visits for adults <30 years old. Twice a month was the most common frequency of visits for <1 year old. The COVID-19 pandemic was a disruptor for frequency of visits and exams. ConclusionsThese results show that there is still room for improvement in terms of adherence, namely in adults and older children. More efforts must be made to educate patients and healthcare professionals about the importance of treatment adherence, accompanied by public policies that expand access to pharmacological and dietary treatment with diversity and quality to improve adherence to adequate blood Phe levels.

Association between public health policies on alcohol and worldwide cancer, liver disease and cardiovascular disease outcomes

The long-term impact of alcohol-related public health policies (PHPs) on disease burden is unclear. We aimed to assess the association between alcohol-related PHPs and alcohol-related health consequences. We conducted an ecological multi-national study including 169 countries. We collected data on alcohol-related PHPs from the WHO Global Information System of Alcohol and Health 2010. Data on alcohol-related health consequences between 2010-2019 were obtained from the Global Burden of Disease database. We classified PHPs into five items, including criteria for low, moderate, and strong PHP establishment. We estimated an alcohol preparedness index (API) using multiple correspondence analysis (0 lowest and 100 highest establishment). We estimated an incidence rate ratio (IRR) for outcomes according to API using adjusted multilevel generalized linear models with a Poisson family distribution. The median API in the 169 countries was 54 [IQR 34.9-76.8]. The API was inversely associated with alcohol use disorder (AUD) prevalence (IRR 0.13; 95% CI 0.03-0.60; p= 0.010), alcohol-associated liver disease (ALD) mortality (IRR 0.14; 95% CI 0.03-0.79; p= 0.025), mortality due to neoplasms (IRR 0.09; 95% CI 0.02-0.40; p= 0.002), alcohol-attributable hepatocellular carcinoma (HCC) (IRR 0.13; 95% CI 0.02-0.65; p= 0.014), and cardiovascular diseases (IRR 0.09; 95% CI 0.02-0.41; p= 0.002). The highest associations were observed in the Americas, Africa, and Europe. These associations became stronger over time, and AUD prevalence was significantly lower after 2 years, while ALD mortality and alcohol-attributable HCC incidence decreased after 4 and 8 years from baseline API assessment, respectively (p <0.05). The API is a valuable instrument to quantify the robustness of alcohol-related PHP establishment. Lower AUD prevalence and lower mortality related to ALD, neoplasms, alcohol-attributable HCC, and cardiovascular diseases were observed in countries with a higher API. Our results encourage the development and strengthening of alcohol-related policies worldwide. We first developed an alcohol preparedness index, an instrument to assess the existence of alcohol-related public policies for each country. We then evaluated the long-term association of the country's alcohol preparedness index in 2010 with the burden of chronic liver disease, hepatocellular carcinoma, other neoplasms, and cardiovascular disease. The strengthening of alcohol-related public health policies could impact long-term mortality rates from cardiovascular disease, neoplasms, and liver disease. These conditions are the main contributors to the global burden of disease related to alcohol use. Over time, this association has not only persisted but also grown stronger. Our results expand the preliminary evidence regarding the importance of public health policies in controlling alcohol-related health consequences.

Characteristics of COVID-19 Infections and Severe Outcomes in a Multinational Study in Latin America During the Circulation Period of the Delta Variant in the Pediatric Population

Abstract Background SARS-CoV-2 infection had specific characteristics in the pediatric population described in previous studies. These clinical features included specific COVID-19 presentation, antibiotic usage, and predictors of disease severity. In addition to patient related factors, external influences could affect COVID-19 outcomes. The features of children with COVID-19 of five Latin American countries were described. Study participants were members of the Prevencionistas e Infectólogos para Cáncer Pediátrico en América Latina (PRINCIPAL) Network of the Global Infectious Diseases Program at St Jude Children's Research Hospital. This study aims to analyze the differences between patients with non-severe and severe disease when the circulation of the Delta variant was predominant, and few children had received SARS-CoV-2 vaccines. Methods This is a retrospective, observational, multinational study that included children with a confirmed diagnosis of COVID-19 between January 2021 and January 2022. Epidemiological, clinical, and treatment characteristics are described and compared between patients with severe and non-severe disease. Frequencies and percentages are presented as well as median and interquartile ranges (IQR). Comparisons were made using the chi-squared test for proportions and the Wilcoxon test for nonparametric quantitative variables. Results 745 patients were included. Patients had a median age of 51 (13-139) months, 194 (26%) had comorbidities, and 701 (94%) presented with symptomatic disease. Fever was present in 524 (74.8%) patients, respiratory symptoms in 550 (78.5%), followed by gastrointestinal manifestations in 218 (31.1%). X-ray findings were abnormal in 175/362 patients, with interstitial infiltrates being the most common finding, 123 (70.7%). Almost a third of patients (29%) received an antibiotic; ceftriaxone was most frequently prescribed in 123/216 cases. Of 745 patients, 526 (70.8%) were hospitalized, of which 165 (31.4%) required PICU admission. Patients presenting with severe disease and requiring PICU admission we more likely to have a comorbidity, 128 (22%) vs. 66 (40%), p&amp;lt;0.001. Mucocutaneous findings or adenitis were more frequently described in severe cases, 19 (11.5) vs. 18 (5.0%), p=0.007. Regarding laboratory results, low lymphocytes 2445 vs. 1676 (p&amp;lt;0.001) and low platelets 294,000 vs. 250,000 (p=0.0002) were most common in patients with severe disease. The proportion of patients with lymphocytopenia was also higher in those with severe disease, 39% vs. 52% p= 0.010. Not surprisingly, antibiotic usage (broad and narrow spectrum) was higher in patients admitted to the PICU (32 vs. 16.5%) p=0.001, despite no significant difference in the frequency of bacterial coinfection (5.56% vs. 9.7% p=0.081) when compared to patients with non-severe disease. Specific treatment strategies were more frequent in PICU patients (39.1% vs. 72.1%) p&amp;lt;0.001, and steroids were the most frequently used drug, 35.2% vs. 70.7% (p&amp;lt;0.001). Table 1. Conclusions Regardless of the variant, COVID-19 is an important cause of hospitalization in children. Fever, respiratory and gastrointestinal symptoms are the most frequent manifestations in children. Despite the low frequency of bacterial coinfection, a high proportion of antibiotic usage is described. Compared to recent publications, mucocutaneous involvement, lower lymphocyte and platelet counts, and higher inflammatory markers were more frequently found in admissions to the PICU. Currently, with higher vaccine coverage and more comprehensive knowledge of the disease, optimization of pediatric COVID-19 management is expected, especially concerning antibiotic use. It is essential to continue multicenter surveillance of the behavior of COVID-19 in the pediatric population.

A O04 Prevalence and risk factors for malignant nodal involvement in early oesophago-gastric cancer: Initial results from the CONGRESS study (endosCopic resectiON, esophaGectomy or gastrectomy foR Early oeSophagogastric cancerS)

Abstract Background Controversy remains surrounding the optimal management of patients with T1N0 early oesophago-gastric (OG) cancer. Current guidelines recommend consideration of radical surgery for T1b disease because of the greater risk of nodal metastasis. However, data to accurately predict risk for individual patients is sparse; individual units may see only low numbers of patients with early stage disease. The endosCopic resectiON, esophaGectomy or gastrectomy foR Early oeSophagogastric cancerS (CONGRESS) study was a retrospective multinational study which aimed to characterise the impact of different management strategies, including endoscopic resection (ER) and radical surgery, for early OG cancer on a large scale. Methods An international multicentre retrospective study was performed. Inclusion criteria were all patients diagnosed with T1N0 OG cancer from 2015 to 2022. Led by local and regional collaborators, centralised anonymised data capture was used to record diagnostic, demographic, treatment, and outcome data. Histopathological outcomes for surgical resection specimens were compared to pre-operative staging and diagnostic data. Statistical analysis was performed to assess the association between patient demographic and histological data, and presence of malignant nodal disease. Results A total of 1,509 patients from 26 centres were recorded, with a median 33 months (range 0-194) follow-up from diagnosis. Initial T stage at diagnosis was T0 266/1509 (17.6%), unspecified T1 375/1509 (24.9%), T1a 319/1509 (21.1%), T1b 204/1509 (13.5%), TX 313/1509 (20.7%). Of 436 patients who underwent surgical resection, the risk of nodal metastasis for each clinically or endoscopically staged depth of invasion was T0: 5/31 (16.1%), unspecified T1: 37/193 (19.2%), T1a: 7/73 (9.6%) T1b: 21/137 (15.3%). No histological or patient factors were significantly associated with presence of positive nodes in the surgical resection specimen. Conclusions The risk of nodal metastases in this real-world contemporary dataset suggests a higher rate of nodal metastasis than reported in some series. Tumour depth alone is a poor predictor of nodal positivity. Further work is required to determine which patients might benefit from an organ-preserving versus resective treatment approach.

Exploring the long-term seroprevalence of SARS-CoV-2 antibodies in infants born to women with clinical or laboratory-confirmed COVID-19

IntroductionInfants are at a higher risk of severe illness with COVID-19 infection compared to older children. While COVID-19 vaccination is not recommended for young infants, they can acquire maternally-derived anti-SARS-CoV-2 antibodies passively through the placenta and breastmilk. We described the persistence of infection-induced maternal antibodies in infant circulation at 9–12 months of age. MethodologyThis was a cross-sectional study nested within the INTERCOVID multinational cohort study. For each COVID positive pregnant woman, two unmatched consecutive COVID negative pregnant women were enrolled between April and September 2020. Women with a positive PCR test, radiographic signs consistent with COVID-19, or at least 2 predefined symptoms of COVID-19 were considered as COVID positive. For this nested cross-sectional study, all COVID positive and either one of the COVID negative participants recruited from the Aga Khan University, Pakistan were approached 9–12 months after delivery, and maternal and infant sera were collected for antibody detection. ResultsAltogether, 83 mothers provided consent, of whom 32 (38.6 %) were COVID positive and 51 (61.4 %) were COVID negative during pregnancy. Anti-SARS-CoV-2 antibodies were present in 13 (41 %) infants born to COVID positive and 19 (39 %) infants born to COVID negative mothers (p = 0.87). The presence of reactive antibodies in infants at follow-up was associated with maternal antibodies at follow-up (OR:9.50, 95 % CI:2.03–44.42; p = 0.004). COVID infection occurred in 3 (6 %) infants born to COVID negative mothers while no infant born to a COVID positive mother had a history of infection (p = 0.27). ConclusionThe presence of reactive anti-SARS-CoV-2 antibodies in infants at 9–12 months of age is associated with maternal seropositivity 9–12 months after delivery rather than maternal infection during pregnancy. Further studies are required to validate these findings and assess whether passive immunity in infants is protective against COVID-19 infection.