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Reframing remission in severe asthma:a conceptual framework for distinguishing disease activity versus damage
No full textRemission is emerging as a feasible treatment goal in moderate-to-severe asthma, driven by the success of biologic therapies in controlling inflammation and reducing exacerbations. Yet current definitions of remission-focused on symptom control, lung function, and corticosteroid reduction-lack precision, can only be ascertained retrospectively, and do not reflect the underlying mechanisms and pathology that drive disease progression. This gap limits the clinical applicability of these definitions and might obscure opportunities for early, disease-modifying intervention. In this Series paper, we propose a refined framework for understanding and reaching remission, centred on distinguishing modifiable disease activity from irreversible remodelling and comorbidity-related factors that contribute to disease burden. We introduce the concept of at-risk asthma as a crucial phase characterised by high disease activity and immune dysregulation, in which timely intervention might prevent irreversible airway and extrapulmonary damage and support long-term disease modification. We examine how symptoms, lung function impairment, and exacerbations can arise from distinct and overlapping mechanisms, underscoring the need for careful attribution in clinical assessment. We also outline four key pathophysiological domains-airway hyper-responsiveness, immune hyper-responsiveness, immune remodelling, and structural remodelling-and describe their temporal evolution and implications for treatment responsiveness. Finally, we present a domain-based strategy for assessment and intervention, linking targeted therapies to underlying mechanisms. This approach supports more personalised treatment decisions and redefines remission, not simply as the absence of symptoms, but as stabilisation of disease biology. As the field advances towards earlier intervention and more tailored application of biologics in at-risk asthma, such a framework could be essential to improve long-term outcomes and prevent overtreatment of irreversible disease.</p
Short- and long-term outcomes after venous resection during left-sided and total pancreatic resection:a nationwide cohort study
No full textBACKGROUND: Venous resection (VR) during left-sided pancreatic resection (LPR) is typically more challenging than during pancreatoduodenectomy, because the pancreatic head remains in situ. Theoretically, converting from LPR to total pancreatectomy (TP) could resolve this issue. This study compared clinical outcomes after LPR and TP with and without VR.METHODS: This nationwide retrospective study included all patients who underwent LPR for all indications or single-stage TP in the Netherlands from 2014 to 2019.RESULTS: One-thousand-seventy-five patients were analyzed: 996 underwent LPR and 79 TP. Twenty-eight (3%) LPRs were with VR (VR+), of which 17 wedge and 11 segmental resections. Of 21 (27%) TPs with VR, 11 were wedge and 10 segmental resections. In the LPR-group, VR+ was associated with a higher incidence of portomesenteric venous thrombosis (PVT) than VR- (3/28 vs. 5/968, p < 0.001), but not with major complications or mortality. Similarly, in the TP-group, higher rates of PVT were reported after VR+ (2/21 vs. 0/58, p = 0.004). The incidence of major complications and PVT were comparable between LPR-VR+ and TP-VR+, but postoperative mortality was higher in TP-VR+ (6/21 vs. 1/28 p = 0.032).CONCLUSION: Our findings suggest that, despite technical impediments of VR during LPR, switching to TP may not benefit patients.</p
Tacrolimus Pharmacokinetics in Pediatric Liver Transplant Recipients During the First Month After Transplantation
No full textIntroductionDespite dosing protocols and tight therapeutic drug monitoring (TDM), tacrolimus concentrations remain highly variable in pediatric liver transplant (LTx) recipients during the first month post-transplantation. The objective of this study was to describe weight-adjusted tacrolimus concentration-to-dose (C/D/kg) ratios and to identify physical, clinical, and laboratory parameters associated with interpatient pharmacokinetic (PK) variability in hospitalized children during the first month post-LTx.MethodsIn this single-center retrospective cohort study (January 2018–October 2021), we calculated C/D/kg ratios for 36 LTx recipients aged 0–2 years. Descriptive statistics and linear mixed models characterized changes in tacrolimus C/D/kg ratios over time, and we determined the percentage of concentrations within six predefined ranges (0–4, 4–6, 6–8, 8–10, 10–15, and > 15 μg/L).ResultsIn total, 524 trough concentrations of orally administered tacrolimus were analyzed. Tacrolimus C/D/kg ratios ranged from 0.19 to 0.75, demonstrating substantial interpatient variability. Time post-transplantation, alanine aminotransferase, aspartate aminotransferase, total bilirubin, coadministration of corticosteroids, spironolactone, fluconazole, fentanyl, amlodipine, flucloxacillin, and ciprofloxacin were significantly associated with interpatient variability (P < 0.05 for all). In the first week, 40.0% tacrolimus trough concentrations were below 4 μg/L, and using TDM the distribution shifted towards the therapeutic mid-range (6–10 μg/L).ConclusionTDM of tacrolimus is often not enough to obtain the concentrations in the therapeutic range. Identifying cofounders for variability a priori is essential for guiding efficient and accurate dosing, shifting the focus from reactive TDM towards better dosing strategies that improve PK predictions and ultimately improve therapy for pediatric LTx recipients
Cluster Analysis to Identify Distinct Asthma Phenotypes in the ATLANTIS Cohort
No full textBACKGROUND: Previous cluster analyses have identified subgroups of asthma. However, only a few studies included parameters of small airways dysfunction (SAD), or gene expression profiles reflecting underlying disease mechanisms. We aimed to identify clinically distinct asthma phenotypes, beyond GINA asthma severity, using available data from the ATLANTIS study which focused on identifying the prevalence of SAD in asthma and its role in asthma control, exacerbations and quality of life.METHODS: The ATLANTIS study included 773 asthma patients (mean age 44 years, 58% female, 76% never-smoker, GINA 1-5). Subjects were extensively characterized, including symptoms, parameters of large and small airways dysfunction, blood and sputum differential cell counts, and genome-wide gene expression profiling from nasal brushes. Clusters were generated using the Self-Organizing Map-Ward's method.RESULTS: Four distinct clusters were identified: A (N = 62; 8%) characterized by the most frequent exacerbations, lower post-bronchodilator FEV 1 % predicted, more small airways dysfunction, higher sputum and blood eosinophils, and high expression of asthma-related genes. B (N = 206; 27%) consisting of atopic patients with early-onset asthma, uncontrolled symptoms, and normal lung function and bronchial hyperresponsiveness, along with a high expression of asthma-related genes in the nasal epithelium. C (N = 277; 36%), predominantly male former smokers, with well-controlled asthma, mild obstructive lung disease, and relatively high neutrophil levels. D (N = 228; 29%), with normal lung function and low blood and sputum eosinophils. CONCLUSIONS: Four distinct clusters were identified, where the presence of SAD was associated with high type-2 inflammation, lower lung function, and frequent exacerbations. SAD may be a marker of poorly controlled asthma and should be considered as an important clinical trait.</p
Torque Teno Virus Loads and Leukocyte Populations in Stable Outpatient Solid Organ Transplant Recipients
No full textOBJECTIVES: Torque teno virus (TTV) is proposed as a biomarker of immune function, potentially aiding in personalized immunosuppressive dosing after solid organ transplantation. TTV is thought to replicate in leukocytes, particularly immature granulocytes. We primarily aimed to assess the association between immature granulocyte count and TTV load, while also exploring associations between TTV load and other leukocyte populations.METHODS: A total of 701 SOTR at 3 months post-transplantation were included from the TransplantLines Study for cross-sectional analyses. TTV load was measured by PCR assay (TTV R-GENE®, bioMérieux) and leukocytes were counted by a Sysmex XN hematology analyzer. Linear regression analyses were performed to assess associations.RESULTS: The mean age of the cohort was 57.0 ± 13.4 years, and 35.8% were female. In multivariable regression analyses, after adjusting for factors known to potentially influence TTV load, immature granulocyte count was positively associated with TTV load (st.β=0.45, p<0.001), while total granulocyte count was negatively associated (st.β=-0.39, p<0.001).CONCLUSION: These results provide evidence to support the theory that TTV replicates in immature granulocytes. The negative association with total granulocyte count suggests possible antiviral effects or altered granulocyte lifespan. These relationships may help clinical interpretation of TTV as a marker of immune function.</p
Helmet use in patients with severe traumatic brain injury:associations with Rotterdam CT score components, skull fractures, and cervical fractures
No full textBACKGROUND: Helmet use is widely accepted to reduce head injury severity by absorbing impact forces, but the specific effect on the presence of radiologically detected intracranial injuries remains unclear.OBJECTIVE: To examine the relationship between helmet use and Rotterdam CT score components, craniocervical fractures, and short-term mortality in cyclists and motorcyclists with severe TBI.METHOD: This is a secondary analysis of data from the BRAIN-PROTECT dataset, a prospective observational study of 2,589 subjects with severe traumatic brain injury in the Netherlands. Logistic regression analysis was used, with helmet use as the independent variable, and Rotterdam score components, craniocervical fractures, and 30-day mortality as outcome measures.RESULTS: Among 499 severe TBI patients analyzed (median age 43 years), helmet use significantly reduced epidural mass (OR 0.25, 95% CI 0.10-0.60, p = 0.008) and skull fractures (OR 0.37, 95% CI 0.25-0.56, p = 0.004). However, helmeted patients had higher odds of cervical fractures (OR 2.94, 95% CI 1.74-4.98, p = 0.004), which persisted after adjusting for age and motor GCS component. CONCLUSION: Among patients with severe TBI, those wearing helmets showed epidural mass lesions and skull fractures less frequently, but more often had cervical fractures than those not wearing helmets.</p
Engineering <i>Escherichia coli</i> for the production of saturated archaeal lipids
No full textArchaeal membrane phospholipids have a different chemical composition than the phospholipids found in bacteria and eukaryotes. Typically, in archaea, phospholipids consist of saturated isoprenoid chains that are ether-bonded to glycerol 1-phosphate whereas in bacteria and eukaryotes, the main phospholipids are fatty acyl chains ester-bonded to glycerol 3-phosphate. This distinct chemical structure of phospholipids is believed to play a crucial role in enabling archaea to survive extreme environments and energy-limited conditions. Escherichia coli has previously been engineered to synthesize archaeal phospholipids next to its endogenous bacterial phospholipids. Cells equipped with these mixed heterochiral membranes were found to be viable with some improvement in robustness. However, a complete biosynthetic pathway for the production of substantial amounts of saturated archaeal lipids has not yet been realized in E. coli. Here, we engineered E. coli for the production of saturated archaeal phospholipids by introducing next to the geranylgeranyl reductase (GGR) and ferredoxin (Fd) from Methanosarcina acetivorans, the pyruvate-ferredoxin oxidoreductase (PFOR) from E. coli to allow for an efficient reduction of Fd. This resulted in a strain where approximately 75 % of the produced archaeal lipids are partially or completely saturated. Importantly, E. coli cells containing this mixed heterochiral membrane showed improved resistance to both heat and cold shock as compared to native E. coli strain. This E. coli strain with saturated archaeal phospholipids can serve as a valuable model for further engineering to incorporate different types of more complex archaeal membrane lipids.</p
Characterizing mobility lifestyles in Finnish cities
No full textCar-centric urban development and car-dependent mobility practices are causing increasing harm to society and the environment. Achieving transformative changes in urban mobility requires a deeper understanding of citizens’ mobility lifestyles. This study investigates mobility lifestyles in three Finnish cities using public participation geographic information system (PPGIS) survey data from 3,260 participants. Cluster analysis identified six distinct lifestyle profiles based on travel attitudes and neighbourhood preferences. These profiles differ in travel behaviour, sociodemographic characteristics, residential locations, and perceived health and well-being.We identified three car-oriented and three sustainable mobility lifestyle profiles, indicating the coexistence of contrasting orientations within urban populations. Sustainable mobility lifestyles were more commonly associated with car-free attitudes, multimodal travel behaviour, younger age groups, lower income, and women. Attitudes towards active mobility, car use, and car ownership varied and were predictors of travel behaviour across profiles. However, mismatches between travel attitudes and behaviour were also observed, indicating that mobility choices may be caused by contextual factors. Neighbourhood preferences aligned partially with both sustainable and car-oriented profiles, suggesting nuanced associations with mobility behaviour.The findings advance understanding of the diverse motivations and conditions shaping everyday mobility practices. By revealing group-specific barriers and opportunities for behavioural change, the study provides actionable insights to support targeted interventions and sustainability transitions in urban mobility
