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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.
Comparison of Lysis and Amplification Methodologies for Optimal 16S rRNA Gene Profiling for Human and Mouse Microbiome Studies.
When conducting sequence-based analysis of microbiome samples, it is important to accurately represent the bacterial communities present. The aim of this study was to compare two commercially available DNA isolation and PCR amplification approaches to determine their impact on the taxonomic composition of microbiome samples following 16S rRNA gene sequencing. A well-established 16S rRNA gene profiling approach, which was widely used in the Human Microbiome Project (HMP), was compared with a novel alkaline degenerative technique that utilizes alkaline cell lysis in combination with a degenerate pool of primers for nucleic acid extraction and PCR amplification. When comparing these different approaches for the microbiome profiling of human and mouse fecal samples, we found that the alkaline-based method was able to detect greater taxonomic diversity. An in silico analysis of predicted primer binding against a curated 16S rRNA gene reference database further suggested that this novel approach had the potential to reduce population bias found with traditional methods, thereby offering opportunities for improved microbial community profiling.
The cingulum: anatomy, connectivity and what goes beyond
For over half a century, the cingulum has been the subject of neuroanatomical and therapeutic investigations owing to its wide range of functions and involvement in various neurological and psychiatric diseases. Recent clinical studies investigating neurosurgical techniques targeting the cingulum, like deep brain stimulation of the anterior cingulate cortex and cingulotomy, have further boosted interests in this central ‘hub’ as a target for chronic intractable pain. Proper targeting within the cingulum is essential to achieve sufficient pain relief. Despite the cingulum being the centre of research for over a century, its structural and functional organization remains a subject to debate, consequently complicating neurosurgical targeting of this area. This study aims to review anatomical and connectivity data of the cingulum from a clinical perspective in order to improve understanding of its role in pain. For the current study, a systematic literature search was performed to assess the anatomy and functional and structural connectivity of the cingulate bundle and cortex. These outcomes focus on MRI and PET data. Articles were searched within the PubMed database, and additional articles were found manually through reviews or references cited within the articles. After exclusion, 70 articles remained included in this analysis, with 50, 29 and 10 studies describing human, monkey and rat subjects, respectively. Outcomes of this analysis show the presence of various anatomical models, each describing other subdivisions within the cingulum. Moreover, connectivity data suggest that the cingulate bundle consists of three distinct fibre projections, including the thalamocortical, cingulate gyrus and anterior frontal and posterior parietal projections. Further, the cingulum is responsible for a variety of functions involved in chronic pain, like sensory processing, memory, spatial functioning, reward, cognition, emotion, visceromotor and endocrine control. Based on the current outcomes, it can be concluded that the cingulum is a central ‘hub’ for pain processing, because it is a melting pot for memory, cognition and affect that are involved in the complex phenomenon of pain experience, memory, spatial functioning, reward, cognition, emotion, visceromotor and endocrine control. Variability in anatomical and connectivity models complicate proper and standardized neurosurgical targeting, consequently leading to clinicians often being reluctant on stimulation and/or lesioning of the cingulum. Hence, future research should be dedicated to the standardization of these models, to allow for optimal targeting and management of patients with chronic intractable pain.
Ultrafast optical and passive acoustic mapping characterization of nanoscale cavitation nuclei based on gas vesicle proteins
Genetically encodable gas-filled particles, known as gas vesicles (GVs), have shown promise as a biomolecular contrast agent for ultrasound imaging and have the potential to be used as cavitation nuclei for ultrasound therapy. In this study, we used passive acoustic mapping techniques to characterize GV-seeded cavitation, utilizing 0.5 and 1.6 MHz ultrasound insonation over peak rarefactional pressures ranging from 100 to 2200 kPa. We found that GVs produce cavitation for the duration of the first applied pulse, up to at least 5000 cycles, but that bubble activity diminishes rapidly over subsequent pulses. At 0.5 MHz, the frequency content of cavitation emissions was predominantly broadband in nature, while at 1.6 MHz, narrowband content at harmonics of the main excitation frequency dominated. Simulations and high-speed camera imaging suggest that the received cavitation emissions come not from individual GVs but instead from the coalescence of GV-released gas into larger bubbles during the applied ultrasound pulse. These results will aid the future development of GVs as cavitation nuclei in ultrasound therapy.