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Expanding the OMOP Common Data Model to Support Perinatal Research in Network Studies.
OBJECTIVES: The Observational Medical Outcomes Partnership common data model (OMOP-CDM) is a useful tool for large-scale network analysis but currently lacks a structured approach to pregnancy episodes. We aimed to develop and implement a perinatal expansion for the OMOP-CDM to facilitate perinatal network research. METHODS: We collaboratively developed a perinatal expansion with input from domain experts and stakeholders to reach consensus. The structure and vocabularies followed the OMOP-CDM ontological framework principles. We tested the expansion using SIDIAP and Norwegian databases. We developed a diagnostics package for quality control assessment and conducted a descriptive analysis on the captured perinatal data mapped to the OMOP-CDM. RESULTS: The perinatal expansion consists of a pregnancy table and an infant table, each with required and optional variables incorporated into standardized vocabularies. Quality assessment of the perinatal expansion table in SIDIAP and Norwegian databases demonstrated accurate capture of perinatal characteristics. Descriptive analysis measured the number of pregnancies (SIDIAP: 646 530; Norway: 746 671), pregnancy outcomes (e.g., 0.5% stillbirths in SIDIAP and 0.4% in Norway), gestational length (median [IQR] in days, SIDIAP: 273 [56-280]; Norway: 280 [273-286]), number of infants (Norway: 758 806), and birth weight (median [IQR] in grams, Norway: 3520 [3175-3860)], among other relevant variables. DISCUSSION AND CONCLUSION: We developed and implemented a perinatal expansion that captures important variables for perinatal research and allows interoperability with existing tables in the OMOP-CDM, which is expected to facilitate future network studies. The publicly available diagnostics package enables testing the implementation of the extension table and the quality and completeness of available data on pregnancy and pregnancy-related outcomes in databases mapped to the OMOP CDM.
Aligning, autoencoding and prompting large language models for novel disease reporting
Given radiology images, automatic radiology report generation aims to produce informative text that reports diseases. It can benefit current clinical practice in diagnostic radiology. Existing methods typically rely on large-scale medical datasets annotated by clinicians to train desirable models. However, for novel diseases, sufficient training data are typically not available. We propose a prompt-based deep learning framework, i.e., PromptLLM, to align, autoencode, and prompt the (large) language model to generate reports for novel diseases accurately and efficiently. Our method includes three major steps: (1) aligning visual images and textual reports to learn general knowledge across modalities from diseases where labeled data are sufficient, (2) autoencoding the LLM using unlabeled data of novel diseases to learn the specific knowledge and writing styles of the novel disease, and (3) prompting the LLM with learned knowledge and writing styles to report the novel diseases contained in the radiology images. Through the above three steps, with limited labels on novel diseases, we show that PromptLLM can rapidly learn the corresponding knowledge for accurate novel disease reporting. The experiments on COVID-19 and diverse thorax diseases show that our approach, utilizing 1% of the training data, achieves desirable performance compared to previous methods. It shows that our approach allows us to relax the reliance on labeled data that is common to existing methods. It could have a real-world impact on data analysis during the early stages of novel diseases. Our code and data are available at https://github.com/ai-in-health/PromptLLM.
MAIT cells protect against sterile lung injury.
Mucosal-associated invariant T (MAIT) cells, the most abundant unconventional T cells in the lung, can exhibit a wide range of functional responses to different triggers via their T cell receptor (TCR) and/or cytokines. Their role, especially in sterile lung injury, is unknown. Using single-cell RNA sequencing (scRNA-seq), spectral analysis, and adoptive transfer in a bleomycin-induced sterile lung injury, we found that bleomycin activates murine pulmonary MAIT cells and is associated with a protective role against bleomycin-induced lung injury. MAIT cells drive the accumulation of type 1 conventional dendritic cells (cDC1s), limiting tissue damage in a DNGR-1-dependent manner. Human scRNA-seq data revealed that MAIT cells were activated, with increased cDC populations in idiopathic pulmonary fibrosis patients. Thus, MAIT cells enhance defense against sterile lung injury by fostering cDC1-driven anti-fibrotic pathways.
Patient and parent perspectives on being invited to join a trial of night-time only versus full-time bracing for adolescent idiopathic scoliosis : a qualitative study.
AIMS: The Bracing Adolescent Idiopathic Scoliosis (BASIS) study is a randomized controlled non-inferiority pragmatic trial of 'full-time bracing' (FTB) compared to 'night-time bracing' (NTB) for the treatment of adolescent idiopathic scoliosis (AIS). We anticipated that recruiting patients to BASIS would be challenging, as it is a paediatric trial comparing two markedly different bracing pathways. No previous studies have compared the experiences of AIS patients treated with FTB to those treated with NTB. This qualitative study was embedded in BASIS to explore families' perspectives of BASIS, to inform trial communication, and to identify strategies to support patients treated in a brace. METHODS: Semi-structured interviews were conducted with parents (n = 26) and young people (n = 21) who had been invited to participate in BASIS at ten of the 22 UK paediatric spine services in hospitals recruiting to BASIS. Audio-recorded interviews were transcribed and analyzed thematically. RESULTS: Families viewed their interactions with BASIS recruiters positively, but were often confused about core aspects of BASIS, such as the aims, expectations of bracing, and the process of randomization. Participants typically expressed a preference for NTB, but recruiters may have framed NTB more favourably. Patients and parents reported challenges wearing a brace, such as physical discomfort, feelings of self-consciousness, difficulty participating in physical activities, and strain on financial resources to support brace use. Patients in FTB reported more pronounced challenges. While families valued health professional support, they felt there was a lack of social, emotional, and school support, and relied on online resources, as well private counselling services to address this need. CONCLUSION: The findings informed the development of resources and strategies, including guidance for schools and the recommendations in this paper, to support patients to wear NTB and FTB as prescribed. The results indicated opportunities for recruiters to enhance trial communication in ways that could improve informed consent and recruitment to BASIS, and inform future trials of bracing.
Impact of the COVID-19 pandemic on paediatric patients with cancer in low-income, middle-income and high-income countries: protocol for a multicentre, international, observational cohort study.
INTRODUCTION: Childhood cancers are a leading cause of non-communicable disease deaths for children around the world. The COVID-19 pandemic may have impacted on global children's cancer services, which can have consequences for childhood cancer outcomes. The Global Health Research Group on Children's Non-Communicable Diseases is currently undertaking the first international cohort study to determine the variation in paediatric cancer management during the COVID-19 pandemic, and the short-term to medium-term impacts on childhood cancer outcomes. METHODS AND ANALYSIS: This is a multicentre, international cohort study that will use routinely collected hospital data in a deidentified and anonymised form. Patients will be recruited consecutively into the study, with a 12-month follow-up period. Patients will be included if they are below the age of 18 years and undergoing anticancer treatment for the following cancers: acute lymphoblastic leukaemia, Burkitt lymphoma, Hodgkin lymphoma, Wilms tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas and neuroblastomas. Patients must be newly presented or must be undergoing active anticancer treatment from 12 March 2020 to 12 December 2020. The primary objective of the study was to determine all-cause mortality rates of 30 days, 90 days and 12 months. This study will examine the factors that influenced these outcomes. χ2 analysis will be used to compare mortality between low-income and middle-income countries and high-income countries. Multilevel, multivariable logistic regression analysis will be undertaken to identify patient-level and hospital-level factors affecting outcomes with adjustment for confounding factors. ETHICS AND DISSEMINATION: At the host centre, this study was deemed to be exempt from ethical committee approval due to the use of anonymised registry data. At other centres, participating collaborators have gained local approvals in accordance with their institutional ethical regulations. Collaborators will be encouraged to present the results locally, nationally and internationally. The results will be submitted for publication in a peer-reviewed journal.
Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic.
INTRODUCTION: Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality. METHODS: Prospective cohort study in 109 institutions in 41 countries. INCLUSION CRITERIA: children <18 years who were newly diagnosed with or undergoing active treatment for acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, retinoblastoma, Wilms tumour, glioma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma and neuroblastoma. Of 2327 cases, 2118 patients were included in the study. The primary outcome measure was all-cause mortality at 30 days, 90 days and 12 months. RESULTS: All-cause mortality was 3.4% (n=71/2084) at 30-day follow-up, 5.7% (n=113/1969) at 90-day follow-up and 13.0% (n=206/1581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3-11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68); p<0.001), lower middle income (OR 3.32 (95% CI 1.96 to 5.61); p<0.001) and upper middle income (OR 3.49 (95% CI 2.02 to 6.03); p<0.001) country status and chemotherapy (OR 0.55 (95% CI 0.36 to 0.86); p=0.008) and immunotherapy (OR 0.27 (95% CI 0.08 to 0.91); p=0.035) within 30 days from MDT plan. Multivariable analysis revealed laboratory-confirmed SARS-CoV-2 infection (OR 5.33 (95% CI 1.19 to 23.84); p=0.029) was associated with 30-day mortality. CONCLUSIONS: Children with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer.
Use of oxygen-loaded nanobubbles to improve tissue oxygenation: Bone-relevant mechanisms of action and effects on osteoclast differentiation.
Gas-loaded nanobubbles have potential as a method of oxygen delivery to increase tumour oxygenation and therapeutically alleviate tumour hypoxia. However, the mechanism(s) whereby oxygen-loaded nanobubbles increase tumour oxygenation are unknown; with their calculated oxygen-carrying capacity being insufficient to explain this effect. Intra-tumoural hypoxia is a prime therapeutic target, at least partly due to hypoxia-dependent stimulation of the formation and function of bone-resorbing osteoclasts which establish metastatic cells in bone. This study aims to investigate potential mechanism(s) of oxygen delivery and in particular the possible use of oxygen-loaded nanobubbles in preventing bone metastasis via effects on osteoclasts. Lecithin-based nanobubbles preferentially interacted with phagocytic cells (monocytes, osteoclasts) via a combination of lipid transfer, clathrin-dependent endocytosis and phagocytosis. This interaction caused general suppression of osteoclast differentiation via inhibition of cell fusion. Additionally, repeat exposure to oxygen-loaded nanobubbles inhibited osteoclast formation to a greater extent than nitrogen-loaded nanobubbles. This gas-dependent effect was driven by differential effects on the fusion of mononuclear precursor cells to form pre-osteoclasts, partly due to elevated potentiation of RANKL-induced ROS by nitrogen-loaded nanobubbles. Our findings suggest that oxygen-loaded nanobubbles could represent a promising therapeutic strategy for cancer therapy; reducing osteoclast formation and therefore bone metastasis via preferential interaction with monocytes/macrophages within the tumour and bone microenvironment, in addition to known effects of directly improving tumour oxygenation.
Postpartum-specific vital sign reference ranges
The majority of maternal deaths occur in the postpartum period (57% in the United States), compared with the antenatal and intrapartum periods. However, maternal deaths in the postpartum period have not been studied as extensively as the antenatal and intrapartum periods. Venous thromboembolism, hemorrhage, sepsis, and gestational hypertensive disorders are the leading causes of death during postpartum. Little data exists describing normal postpartum vital signs. This study aimed to estimate maternal postpartum vital sign ranges.
Activation-induced thrombospondin-4 works with thrombospondin-1 to build cytotoxic supramolecular attack particles.
Cytotoxic attack particles released by CTLs and NK cells include diverse phospholipid membrane and glycoprotein encapsulated entities that contribute to target cell killing. Supramolecular attack particles (SMAPs) are one type of particle characterized by a cytotoxic core enriched in granzymes and perforin surrounded by a proteinaceous shell including thrombospondin (TSP)-1. TSP-4 was also detected in bulk analysis of SMAPs released by CTLs; however, it has not been investigated whether TSP-4 contributes to distinct SMAP types or the same SMAP type as TSP-1 and, if in the same type of SMAP, whether TSP-4 and TSP-1 cooperate or compete. Here, we observed that TSP-4 expression increased upon CD8+ T cell activation while, surprisingly, TSP-1 was down-regulated. Correlative Light and Electron Microscopy and Stimulated Emission Depletion microscopy localized TSP-4 and TSP-1 in SMAP-containing multicore granules. Superresolution dSTORM revealed that TSP-4 and TSP-1 are usually enriched in the same SMAPs while particles with single-positive shells are rare. Retention Using Selective Hooks assays showed that TSP-4 localizes to the lytic granules faster than TSP-1 and promotes its accumulation therein. TSP-4 contributed to direct CTL-mediated killing, as previously shown for TSP-1. TSP-4 and TSP-1 were both required for latent SMAP-mediated cell killing, in which released SMAPs kill targets after removal of the CTLs. Of note, we found that chronic lymphocytic leukemia (CLL) cell culture supernatants suppressed expression of TSP-4 in CTL and latent SMAP-mediated killing. These results identify TSP-4 as a functionally important component of SMAPs and suggest that SMAPs may be targeted for immune suppression by CLL.
Upadacitinib for Induction of Remission in Paediatric Crohn's Disease: An International Multicentre Retrospective Study.
BACKGROUND: There are scarce data available on upadacitinib in children with Crohn's disease (CD). AIM: To evaluate the effectiveness and safety of upadacitinib as an induction therapy in paediatric CD. METHODS: This was a multicentre retrospective study between 2022 and 2024 of children treated with upadacitinib for induction of remission of active CD conducted in 30 centres worldwide affiliated with the IBD Interest and Porto group of the ESPGHAN. We recorded demographic, clinical and laboratory data and adverse events (AEs) at week 8 post-induction. The analysis of the primary outcome was based upon the intention-to-treat (ITT) principle. RESULTS: We included 100 children (median age 15.8 [interquartile range 14.3-17.2]). All were previously treated with biologic therapies including 89 with ≥ 2 biologics. At the end of the 8-week induction period, we observed clinical response, clinical remission and corticosteroid- and exclusive enteral nutrition-free clinical remission (CFR) in 75%, 56% and 52%, respectively. By the end of induction, 68% had achieved normalisation of C-reactive protein, and 58% had faecal calprotectin (FC)
Reduced organ damage accumulation in adult patients with SLE on anifrolumab plus standard of care compared to real-world external controls
Objectives: Anifrolumab is approved for the treatment of systemic lupus erythematosus (SLE). We aimed to determine if anifrolumab plus standard of care (SOC) was associated with reduced organ damage accumulation in adult patients with moderately to severely active SLE compared to real-world (RW) external controls from the University of Toronto Lupus Clinic (UTLC) cohort who received SOC only. Methods: Patients who initiated 300 mg anifrolumab in the TULIP (Treatment of Uncontrolled Lupus via the Interferon Pathway) trials were included in the anifrolumab arm; key eligibility criteria were applied to the UTLC to create the RW SOC arm. Propensity score and censoring weighting were used to account for baseline confounding and loss to follow-up. The primary endpoint was change in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score from baseline to week 208, and the secondary endpoint was time to first SDI score increase. Results: 354 patients were included in the anifrolumab arm, and 561 patients were included in the RW SOC arm. Following weighting, mean change in SDI was 0.416 points lower (95% CI: −0.582, −0.249; P < .001) in the anifrolumab arm than in the RW SOC arm. Patients in the anifrolumab arm were 59.9% less likely (hazard ratio: 0.401; 95% CI: 0.213, 0.753, P = .005) to experience an increase in SDI within 208 weeks. Conclusions: Patients who received anifrolumab accumulated significantly less organ damage after 208 weeks than patients who received RW SOC. The addition of anifrolumab to SOC is effective at preventing and/or delaying organ damage in patients with moderately to severely active SLE.
Protocol for the femoroacetabular impingement trial (FAIT) : a multi-centre randomised controlled trial comparing surgical and non-surgical management of femoroacetabular impingement
Aims: Femoroacetabular Junction Impingement (FAI) describes abnormalities in the shape of the femoral head-neck junction, or abnormalities in the orientation of the acetabulum. In the short term, FAI can give rise to pain and disability, and in the long-term it significantly increases the risk of developing osteoarthritis. The Femoroacetabular Impingement Trial (FAIT) aims to determine whether operative or non-operative intervention is more effective at improving symptoms and preventing the development and progression of osteoarthritis. Methods: FAIT is a multicentre superiority parallel two-arm randomised controlled trial comparing physiotherapy and activity modification with arthroscopic surgery for the treatment of symptomatic FAI. Patients aged 18 to 60 with clinical and radiological evidence of FAI are eligible. Principal exclusion criteria include previous surgery to the index hip, established osteoarthritis (Kellgren-Lawrence ≥ 2), hip dysplasia (centre-edge angle < 20°), and completion of a physiotherapy programme targeting FAI within the previous 12 months. Recruitment will take place over 24 months and 120 patients will be randomised in a 1:1 ratio and followed up for three years. The two primary outcome measures are change in hip outcome score eight months post-randomisation (approximately six-months post-intervention initiation) and change in radiographic minimum joint space width 38 months post-randomisation. ClinicalTrials.gov: NCT01893034. Cite this article: Bone Joint Res 2014;3:321-7.
National COVID Cohort Collaborative data enhancements: a path for expanding common data models.
OBJECTIVE: To support long COVID research in National COVID Cohort Collaborative (N3C), the N3C Phenotype and Data Acquisition team created data designs to aid contributing sites in enhancing their data. Enhancements include long COVID specialty clinic indicator; Admission, Discharge, and Transfer transactions; patient-level social determinants of health; and in-hospital use of oxygen supplementation. MATERIALS AND METHODS: For each enhancement, we defined the scope and wrote guidance on how to prepare and populate the data in a standardized way. RESULTS: As of June 2024, 29 sites have added at least one data enhancement to their N3C pipeline. DISCUSSION: The use of common data models is critical to the success of N3C; however, these data models cannot account for all needs. Project-driven data enhancement is required. This should be done in a standardized way in alignment with common data model specifications. Our approach offers a useful pathway for enhancing data to improve fit for purpose. CONCLUSION: In this initiative, we rapidly produced project-specific data modeling guidance and documentation in support of long COVID research while maintaining a commitment to terminology standards and harmonized data.
Effect of nirmatrelvir/ritonavir (Paxlovid) on hospitalization among adults with COVID-19: An electronic health record-based target trial emulation from N3C.
BACKGROUND: Nirmatrelvir with ritonavir (Paxlovid) is indicated for patients with Coronavirus Disease 2019 (COVID-19) who are at risk for progression to severe disease due to the presence of one or more risk factors. Millions of treatment courses have been prescribed in the United States alone. Paxlovid was highly effective at preventing hospitalization and death in clinical trials. Several studies have found a protective association in real-world data, but they variously used less recent study periods, correlational methods, and small, local cohorts. Their estimates also varied widely. The real-world effectiveness of Paxlovid remains uncertain, and it is unknown whether its effect is homogeneous across demographic strata. This study leverages electronic health record data in the National COVID Cohort Collaborative's (N3C) repository to investigate disparities in Paxlovid treatment and to emulate a target trial assessing its effectiveness in reducing severe COVID-19 outcomes. METHODS AND FINDINGS: This target trial emulation used a cohort of 703,647 patients with COVID-19 seen at 34 clinical sites across the United States between April 1, 2022 and August 28, 2023. Treatment was defined as receipt of a Paxlovid prescription within 5 days of the patient's COVID-19 index date (positive test or diagnosis). To emulate randomization, we used the clone-censor-weight technique with inverse probability of censoring weights to balance a set of covariates including sex, age, race and ethnicity, comorbidities, community well-being index (CWBI), prior healthcare utilization, month of COVID-19 index, and site of care provision. The primary outcome was hospitalization; death was a secondary outcome. We estimated that Paxlovid reduced the risk of hospitalization by 39% (95% confidence interval (CI) [36%, 41%]; p < 0.001), with an absolute risk reduction of 0.9 percentage points (95% CI [0.9, 1.0]; p < 0.001), and reduced the risk of death by 61% (95% CI [55%, 67%]; p < 0.001), with an absolute risk reduction of 0.2 percentage points (95% CI [0.1, 0.2]; p < 0.001). We also conducted stratified analyses by vaccination status and age group. Absolute risk reduction for hospitalization was similar among patients that were vaccinated and unvaccinate, but was much greater among patients aged 65+ years than among younger patients. We observed disparities in Paxlovid treatment, with lower rates among black and Hispanic or Latino patients, and within socially vulnerable communities. This study's main limitation is that it estimates causal effects using observational data and could be biased by unmeasured confounding. CONCLUSIONS: In this study of Paxlovid's real-world effectiveness, we observed that Paxlovid is effective at preventing hospitalization and death, including among vaccinated patients, and particularly among older patients. This remains true in the era of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron subvariants. However, disparities in Paxlovid treatment rates imply that the benefit of Paxlovid's effectiveness is not equitably distributed.