Estimated Annual Healthcare Costs After Acute Pulmonary Embolism: Results From a Prospective Multicentre Cohort Study

OBJECTIVE: Patients surviving acute pulmonary embolism (PE) necessitate long-term treatment and follow-up. However, the chronic economic impact of PE on European healthcare systems remains to be determined. METHODS AND RESULTS: We calculated the direct cost of illness during the first year after discharge for the index PE, analyzing data from a multicentre prospective cohort study in Germany. Main and accompanying readmission diagnoses were used to calculate DRG-based hospital reimbursements; anticoagulation costs were estimated from the exact treatment duration and each drug's unique national identifier; and outpatient post-PE care costs from guidelines-recommended algorithms and national reimbursement catalogues. Of 1017 patients enrolled at 17 centres, 958 (94%) completed ≥ 3-month follow-up; of those, 24% were rehospitalized (0.34 [95% CI 0.30-0.39] readmissions per PE survivor). Age, coronary artery, pulmonary and kidney disease, diabetes, and (in the sensitivity analysis of 837 patients with complete 12-month follow-up) cancer, but not recurrent PE, were independent cost predictors by hurdle gamma regression accounting for zero readmissions. Estimated rehospitalization cost was €1138 (95% CI 896-1420) per patient. Anticoagulation duration was 329 (IQR 142-365) days, with estimated average per-patient costs of €1050 (median 972; IQR 458-1197); costs of scheduled ambulatory follow-up visits amounted to €181. Total estimated direct per-patient costs during the first year after PE ranged from €2369 (primary analysis) to €2542 (sensitivity analysis). CONCLUSIONS: By estimating per-patient costs and identifying cost drivers of post-PE care, our study may inform decisions concerning implementation and reimbursement of follow-up programmes aiming at improved cardiovascular prevention. (Trial registration number: DRKS00005939)

'Which treatment do you believe you received?' A randomised blinding feasibility trial of spinal manual therapy

BACKGROUND Blinding is essential for mitigating biases in trials of low back pain (LBP). Our main objectives were to assess the feasibility of blinding: (1) participants randomly allocated to active or placebo spinal manual therapy (SMT), and (2) outcome assessors. We also explored blinding by levels of SMT lifetime experience and recent LBP, and factors contributing to beliefs about the assigned intervention. METHODS A two-parallel-arm, single-centre, placebo-controlled, blinding feasibility trial. Adults were randomised to active SMT (n = 40) or placebo SMT (n = 41). Participants attended two study visits for their assigned intervention, on average seven days apart. The primary outcome was participant blinding (beliefs about assigned intervention) using the Bang blinding index (BI) at two study visits. The Bang BI is arm-specific, chance-corrected, and ranges from - 1 (all incorrect beliefs) to 1 (all correct beliefs), with 0 indicating equal proportions of correct and incorrect beliefs. Secondary outcomes included factors contributing to beliefs about the assigned intervention. RESULTS Of 85 adults screened, 81 participants were randomised (41 [51%] with SMT lifetime experience; 29 [39%] with recent LBP), and 80 (99%) completed follow-up. At study visit 1, 50% of participants in the active SMT arm (Bang BI: 0.50 [95% confidence interval (CI), 0.26 to 0.74]) and 37% in the placebo SMT arm (0.37 [95% CI, 0.10 to 0.63]) had a correct belief about their assigned intervention, beyond chance. At study visit 2, BIs were 0.36 (0.08 to 0.64) and 0.29 (0.01 to 0.57) for participants in the active and placebo SMT arms, respectively. BIs among outcome assessors suggested adequate blinding at both study visits (active SMT: 0.08 [- 0.05 to 0.20] and 0.03 [- 0.11 to 0.16]; placebo SMT: - 0.12 [- 0.24 to 0.00] and - 0.07 [- 0.21 to 0.07]). BIs varied by participant levels of SMT lifetime experience and recent LBP. Participants and outcome assessors described different factors contributing to their beliefs. CONCLUSIONS Adequate blinding of participants assigned to active SMT may not be feasible with the intervention protocol studied, whereas blinding of participants in the placebo SMT arm may be feasible. Blinding of outcome assessors seemed adequate. Further methodological work on blinding of SMT is needed. TRIAL REGISTRATION NUMBER NCT05778396

Effect of local epidural application of methylprednisolone acetate on time to ambulation in non-ambulatory dogs with thoracolumbar intervertebral disc disease: A prospective randomised, blinded control trial

BACKGROUND: The objective of this study was to analyse the potential benefit of the epidural application of steroids on time to ambulation in non-ambulatory dogs affected by intervertebral disc disease (IVDD) treated with decompressive surgery. METHODS: This prospective, randomised, blinded control trial involved 41 dogs with thoracolumbar disc extrusion, which were randomly allocated into two groups. In the control group, saline was locally applied after surgical decompression of the spinal cord (n = 23). In the treatment group (n = 18), local epidural application of methylprednisolone acetate (1 mg/kg) was used. Ambulation time was the primary outcome measure, defined as the ability to take 10 independent steps. RESULTS: The median number of days to ambulation was 7 days (range: 1‒17 days) for the control group and 3 days (range: 1‒8 days) for the treatment group. One dog from the treatment group developed discospondylitis and abscess formation. LIMITATIONS: The study's heterogeneity in dog breeds, ages and pre-existing health conditions could affect the generalisability of the findings. CONCLUSION: Epidural methylprednisolone acetate applied locally at the time of surgery may accelerate recovery in dogs following IVDD surgery

Quality of technology integration matters: positive associations with students’ behavioral engagement and digital competencies for learning

Despite extensive research on technology's potential to enhance teaching, large-scale studies often report mixed or negative impacts of technology use at school on student learning achievements. This ambiguity is often attributed to previous large-scale studies focusing more on the frequency rather than the quality of technology integration in the classroom. To further investigate this issue, our study developed the Technology Integration Quality Scale (TIQS) to measure students' perceptions of technology integration across different dimensions of teaching quality: support for learning, classroom management, individualized teaching, and cognitive activation. Using a sample of 2,281 students from 29 upper secondary schools in Switzerland, we validated the TIQS through exploratory and confirmatory factor analyses. We also employed cluster-robust structural equation modelling to examine how both the frequency and perceived quality of technology integration predict students’ self-assessed digital competencies and behavioral engagement for learning. The results show that quality explains considerably more variance than the frequency of technology integration in promoting both students' behavioral engagement and digital competencies for learning. However, for digital competencies, quantity also explains a substantial amount of variance. By simultaneously considering multiple dimensions of teaching quality, the frequency of technology use and two output variables, this study contributes to the existing research by offering a more nuanced perspective on the impact of technology integration. Furthermore, interaction effects between the independent variables highlight the need to further explore the relationships between different dimensions of teaching quality, which could also contribute to the development of the theory of generic teaching quality

Individual variability of neural computations underlying flexible decisions

The ability to flexibly switch our response to external stimuli according to contextual information is critical for successful interactions with a complex world. Context-dependent computations are necessary across many domains1–3, yet their neural implementations remain poorly understood. Here we developed a novel behavioral task in rats to study context-dependent selection and accumulation of evidence for decision-making4−6. Under assumptions supported by both monkey and rat data, we first show mathematically that this computation can be supported by three dynamical solutions, and all networks performing the task implement a combination of these solutions. These solutions can be identified and tested directly with experimental data. We further show that existing electrophysiological and modeling data are compatible with the full variety of possible combinations of these solutions, suggesting that different individuals could use different combinations. To study variability across individual subjects, we developed automated, high-throughput methods to train rats on our task, and we trained many subjects on it. Consistent with theoretical predictions, neural and behavioral analyses revealed substantial heterogeneity across rats, despite uniformly good task performance. Our theory further predicts a specific link between behavioral and neural signatures, which was robustly supported in the data. In summary, our results provide a new experimentally-supported theoretical framework to analyze individual variability in biological and artificial systems performing flexible decision-making tasks, they open the door to cellular-resolution studies of individual variability in higher cognition, and they provide insights into neural mechanisms of context-dependent computation more generally

Updated EANO Guideline on Rational Molecular Testing of Gliomas, Glioneuronal, and Neuronal Tumors in Adults for Targeted Therapy Selection - Update 1

The standard of care for adult patients with gliomas, glioneuronal, and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a major part of the standard treatment; however, the predictive significance of most of the targets for treatment in systemic cancer is less well-established in central nervous system tumors. In 2023 the European Association for NeuroOncology (EANO) Guideline Committee presented evidence-based recommendations for rational testing of molecular targets for targeted treatments. From all targets reviewed, only testing for BRAF V600E mutations was of proven clinical benefit; despite regulatory approvals for tumor agnostic treatment of NTRK gene fusions and high tumor mutational burden (TMB) for patients with adult brain tumors, the evidence of clinical benefit for adult patients was still limited. This guideline has a modular structure, allowing regular updating of individual sections and adding new ones. The present version (Update 1) presents a review of the rationale of testing for PTEN, H3F3A, MTAP, RET and IDH, and presents an update of the text on TMB high and mismatch repair deficiency. It also presents an overview of the therapeutic yield of routine next-generation sequencing for mutations and fusion detection. The Supplemental File II accompanying this version contains an in-depth review of all targets, whereas, in the main manuscript, the final recommendations of the revised and new targets are presented. Updates will be made on a regular basis

Developmental anatomy of the thalamus, perinatal lesions, and neurological development

The thalamic nuclei develop before a viable preterm age. GABAergic neuronal migration is especially active in the third trimester. Thalamic axons meet cortical axons during subplate activation and create the definitive cortical plate in the second and third trimesters. Default higher-order cortical driver connections to the thalamus are then replaced by the maturing sensory networks, in a process that is driven by first-order thalamic neurons. Surface electroencephalographic activity, generated first in the subplate and later in the cortical plate, gradually show oscillations based on the interaction of the cortex with thalamus, which is controlled by the thalamic reticular nucleus. In viable newborn infants, in addition to sensorimotor networks, the thalamus already contributes to visual, auditory, and pain processing, and to arousal and sleep. Isolated thalamic lesions may present as clinical seizures. In addition to asphyxia and stroke, infection and network injury are also common. Cranial ultrasound can be used to classify neonatal thalamic injuries based on functional parcelling of the mature thalamus. We provide ample illustration and a detailed description of the impact of neonatal focal thalamic injury on neurological development, and discuss the potential for neuroprotection based on thalamocortical plasticity

Gastroesophageal reflux disease is associated with a more severe interstitial lung disease in systemic sclerosis in the EUSTAR cohort

OBJECTIVES Gastroesophageal reflux disease (GERD) is frequent in systemic sclerosis (SSc) and could predict progression of interstitial lung disease (ILD). We aimed to analyse (1) the prevalence of GERD among SSc-ILD patients, (2) its association with disease characteristics and (3) predictive factors for ILD progression in SSc-ILD patients with GERD. METHODS SSc patients from the EUSTAR database with ILD were included. GERD was labeled as present if reflux/dysphagia was reported at the baseline visit or before. Disease characteristics of patients with and without GERD were compared at baseline. ILD progression was defined as relative FVC decline ≥10% or relative FVC decline between 5-9% in association with relative DLCO decline of ≥ 15% over 12±3 months of follow-up. Prognostic factors for ILD progression, overall survival and progression-free survival in SSc-ILD patients with GERD were tested by multivariable Cox regression. RESULTS 5462 SSc-ILD patients were included, 4400 (80.6%) had GERD. Patients with GERD presented more frequently with diffuse cutaneous SSc (OR: 1.44 [1.22-1.69], p < 0.001) and more severe lung involvement with lower FVC (85.8±22.1 vs 90.2±20.1, p < 0.001), lower DLCO (60.8±19.7 vs 65.3±20.6, p < 0.001) and worse performance at the 6-minute walking test. Female sex (HR: 1.39 [1.07-1.80], p = 0.012) and older age (HR: 1.02 [1.01-1.03], p < 0.001) independently predicted ILD progression in SSc-ILD patients with GERD. CONCLUSION SSc-ILD patients with GERD appear to suffer from a more severe SSc disease. In this population, female sex may be considered as risk factor for ILD progression

Sex Differences in Patient-rated Outcomes After Lumbar Spinal Fusion for Degenerative Disease

Study design Heterogeneous data collection via a mix of prospective, retrospective, and ambispective methods. Objective To evaluate the effect of biological sex on patient-reported outcomes after spinal fusion surgery for lumbar degenerative disease. Summary of background data Current literature suggests sex differences regarding clinical outcome after spine surgery may exist. Substantial methodological heterogeneity and limited comparability of studies warrants further investigation of sex-related differences in treatment outcomes. Methods We analyzed patients who underwent spinal fusion with or without pedicle screw insertion for lumbar degenerative disease included within a multinational study, comprising patients from 11 centers in 7 countries. Absolute values and change scores (change from pe-operative baseline to post-operative follow-up) for 12-month functional impairment (Oswestry disability index [ODI]) and back and leg pain severity (numeric rating scale [NRS]) were compared between male and female patients. Minimum clinically important difference (MCID) was defined as > 30% improvement. Results Six-hundred-sixty (59%) of 1115 included patients were female. Female patients presented with significantly baseline ODI (51.5 ± 17.2 vs. 47.8 ± 17.9, P<0.001) and back pain (6.96 ± 2.32 vs. 6.60 ± 2.30, P=0.010) and leg pain (6.49 ± 2.76 vs. 6.01 ± 2.76, P=0.005). At 12-months, female patients still reported significantly higher ODI (22.76 ± 16.97 vs. 20.50 ± 16.10, P=0.025), but not higher back (3.13 ± 2.38 vs. 3.00 ± 2.40, P=0.355) or leg pain (2.62 ± 2.55 vs. .34 ± 2.43, P=0.060). Change scores at 12 months did not differ significantly among male and female patients in ODI (∆ 1.31, 95% CI -3.88-1.25, P=0.315), back (∆ 0.22, 95% CI -0.57-0.12, P=0.197) and leg pain (∆ 0.16, 95% CI -0.56-0.24, P=0.439). MCID at 12-months was achieved in 330 (77.5%) male patients and 481 (76.3%) female patients (P=0.729) for ODI. Conclusion Both sexes experienced a similar benefit from surgery in terms of relative improvement in scores for functional impairment and pain. Although female patients reported a higher degree of functional impairment and pain preoperatively, at 12 months only their average scores for functional impairment remained higher than those for their male counterparts, while absolute pain scores were similar for female and male patients

Undetectable pre-radical cystectomy circulating tumour DNA status predicts improved oncological outcomes

OBJECTIVE To assess recurrence-free survival (RFS) in patients with undetectable tumour-informed circulating tumour DNA (ctDNA) before radical cystectomy (RC) and evaluate if those who converted from detectable to undetectable ctDNA status after RC have similar RFS outcomes as those with persistently undetectable ctDNA status. PATIENTS AND METHODS Patients who underwent RC had prospectively and longitudinally collected tumour-informed ctDNA analyses during 2021-2023. ctDNA status was informed from the pre-RC specimen. The minimal residual disease (MRD) window was defined as the initial 90 days after RC. RFS was evaluated using the Kaplan-Meier method. Cox regression analysis was performed to find predictors of disease recurrence. RESULTS The cohort included 135 patients with 647 ctDNA analyses. The median (interquartile range [IQR]) age was 71 (63-77) years. Over a median (IQR) follow-up of 11 (7-18) months, 41 patients (30%) had a recurrence. Pre-RC undetectable ctDNA status was found in 54 patients (40%). The RFS rates at 6, 12, and 21 months were 98%, 93%, and 82%, respectively. Of 77 patients with undetectable ctDNA status at the MRD window available for conversion dynamics analysis, 43 had persistently undetectable ctDNA status (both at pre-RC and MRD window) and 31 converted from pre-RC detectable to MRD undetectable status (conversion group). The persistently undetectable group had significantly better RFS than the conversion group (log-rank, P < 0.001), with 12-month RFS rates of 97% vs 51%, and 18-month RFS rates of 88% vs 51%, respectively. On Cox multivariate analysis, only the conversion group status predicted disease recurrence. CONCLUSIONS Patients with undetectable pre-RC ctDNA status have a favourable prognosis and may be candidates for treatment de-escalation. Those with persistently undetectable ctDNA had superior RFS compared to the conversion group. Pre-RC ctDNA status should be incorporated into trials examining ctDNA use in clinical decision-making