Residual N-acetyl-α-glucosaminidase activity in fibroblasts correlates with disease severity in patients with mucopolysaccharidosis type IIIB

Background: Mucopolysaccharidosis type IIIB (MPS IIIB) is a rare genetic disorder in which the deficiency of the lysosomal enzyme N-acetyl-α-glucosaminidase (NAGLU) results in the accumulation of heparan sulfate (HS), leading to progressive neurocognitive deterioration. In MPS IIIB a wide spectrum of disease severity is seen. Due to a large allelic heterogeneity, establishing genotype-phenotype correlations is difficult. However, reliable prediction of the natural course of the disease is needed, in particular for the assessment of the efficacy of potential therapies. Methods: To identify markers that correlate with disease severity, all Dutch patients diagnosed with MPS IIIB were characterised as either rapid (RP; classical, severe phenotype) or slow progressors (SP; non-classical, less severe phenotype), based on clinical data. NAGLU activity and HS levels were measured in patients’ fibroblasts after culturing at different temperatures. Results: A small, though significant difference in NAGLU activity was measured between RP and SP patients after culturing at 37 °C (p < 0.01). Culturing at 30 °C resulted in more pronounced and significantly higher NAGLU activity levels in SP patients (p < 0.001) with a NAGLU activity of 0.58 nmol.mg-1.hr-1 calculated to be the optimal cut-off value to distinguish between the groups (sensitivity and specificity 100 %). A lower capacity of patients’ fibroblasts to increase NAGLU activity at 30 °C could significantly predict for the loss of several disease specific functions. Conclusion: NAGLU activity in fibroblasts cultured at 30 °C can be used to discriminate between RP and SP MPS IIIB patients and the capacity of cells to increase NAGLU activity at lower temperatures correlates with disease symptoms

Health status and psychological outcomes after trauma: A prospective multicenter cohort study

Introduction Survival after trauma has considerably improved. This warrants research on non-fatal outcome. We aimed to identify characteristics associated with both short and long-term health status (HS) after trauma and to describe the recovery patterns of HS and psychological outcomes during 24 months of follow-up. Methods Hospitalized patients with all types of injuries were included. Data were collected at 1 week 1, 3, 6, 12, and 24 months post-trauma. HS was assessed with the EuroQol-5D-3L (EQ-5D3L) and the Health Utilities Index Mark 2 and 3 (HUI2/3). For the screening of symptoms of post-traumatic stress, anxiety and depression, the Impact of Event Scale (IES) and the Hospital Anxiety and Depression Scale (HADS) subscale anxiety (HADSA) and subscale depression (HADSD) were used. Recovery patterns of HS and psychological outcomes were examined with linear mixed model analyses. Results A total of 4,883 patients participated (median age 68 (Interquartile range 53–80); 50% response rate). The mean (Standard Deviation (SD)) pre-injury EQ-5D-3L score was 0.85 (0.23). One week post-trauma, mean (SD) EQ-5D-3L, HUI2 and HUI3 scores were 0.49 (0.32), 0.61 (0.22) and 0.38 (0.31), respectively. These scores significantly improved to 0.77 (0.26), 0.77 (0.21) and 0.62 (0.35), respectively, at 24 months. Most recovery occurred up until 3 months. At long-term follow-up, patients of higher age, with comorbidities, longer hospital stay, lower extremity fracture and spine injury showed lower HS. The mean (SD) scores of the IES, HADSA and HADSD were respectively 14.80 (15.80), 4.92 (3.98) and 5.00 (4.28), respectively, at 1 week post-trauma and slightly improved over 24 months post-trauma to 10.35 (14.72), 4.31 (3.76) and 3.62 (3.87), respectively. Discussion HS and psychological symptoms improved over time and most improvements occurred within 3 months post-trauma. The effects of severity and type of injury faded out over time. Patients frequently reported symptoms of post-traumatic stress. Trial registration ClinicalTrials.gov identifier: NCT02508675

Patient-reported scar quality of donor-sites following split-skin grafting in burn patients: Long-term results of a prospective cohort study

Background: Skin grafting is the current gold standard for treatment of deeper burns. How patients appraise the donor-site scar is poorly investigated. The aim of this study was to evaluate long-term patient-reported quality of donor-site scars after split skin grafting and identify possible predictors. Methods: A prospective cohort study was conducted. Patients were included in a Dutch burn centre during one year. Patient-reported quality of donor-site scars and their worst burn scar was assessed at 12 months using the Patient and Observer Scar Assessment Scale (POSAS). Mixed model analyses were used to identify predictors of scar quality. Results: This study included 115 donor-site scars of 72 patients with a mean TBSA burned of 11.2%. The vast majority of the donor-site scars (84.4%) were rated as having at least minor differences with normal skin (POSAS item score ≥2) on one or more scar characteristics and the

Course of scar quality of donor sites following split skin graft harvesting: Comparison between patients and observers

There exists little to no data on the development of donor-site scars that remain after split skin graft harvesting. The objectives of this study were to (a) examine changes in characteristics of donor-site scar quality over time and (b) assess the agreement between patient-reported and observer-reported donor-site scar quality in a burn population. A prospective cohort study was conducted including patients who underwent split skin grafting for their burn injury. Patients and observers completed the Patient and Observer Scar Assessment Scale (POSAS) for the first harvested donor site at 3 and 12 months post-surgery. This study included 80 patients with a median age of 34 years. At 3 months post-surgery, the patients scored the POSAS items itch and color as most deviant from normal skin, both improved between 3 and 12 months (3.1 vs 1.5 and 5.0 vs 3.5, respectively [P <.001]). Other scar characteristics did not show significant change over time. The patients' overall opinion score improved from 3.9 to 3.2 (P <.001). Observers rated the items vascularization and pigmentation most severe, only vascularization improved significantly between both time points. Their overall opinion score decreased from 2.7 to 2.3 (P <.001). The inter-observer agreement between patients and observers was considered poor (ICC < 0.4) at both time points. Results of current study indicate that observers underestimate the impact of donor-site scars. This has to b

A transcriptionally distinct CXCL13+CD103+CD8+ T-cell population is associated with B-cell recruitment and neoantigen load in human cancer

The chemokine CXCL13 mediates recruitment of B cells to tumors and is essential for the formation of tertiary lymphoid structures (TLSs). TLSs are thought to support antitumor immunity and are associated with improved prognosis. However, it remains unknown whether TLSs are formed in response to the general inflammatory character of the tumor microenvironment, or rather, are induced by (neo)antigen-specific adaptive immunity. We here report on the finding that the transforming growth factor beta (TGFβ)-dependent CD103+CD8+ tumor-infiltrating T-cell (TIL) subpopulation expressed and produced CXCL13. Accordingly, CD8+ T cells from peripheral blood activated in the presence of TGFβ upregulated CD103 and secreted CXCL13. Conversely, inhibition of TGFβ receptor signaling abrogated CXCL13 production. CXCL13+CD103+CD8+ TILs correlated with B-cell recruitment, TLSs, and neoantigen burden in six cohorts of human tumors. Altogether, our findings indicated that TGFβ plays a non-canonical role in coordinating immune responses against human tumors and suggest a potential role for CXCL13+CD103+CD8+ TILs in mediating B-cell recruitment and TLS formation in human tumors

Recurrent differentiated thyroid cancer: Towards personalized treatment based on evaluation of tumor characteristics with PET (THYROPET Study): Study protocol of a multicenter observational cohort study

Background: After initial treatment of differentiated thyroid carcinoma (DTC) patients are followed with thyroglobulin (Tg) measurements to detect recurrences. In case of elevated levels of Tg and negative neck ultrasonography, patients are treated 'blindly' with Iodine-131 (131I). However, in up to 50% of patients, the post-therapy scan reveals no 131I-targeting of tumor lesions. Such patients derive no benefit from the blind therapy but are exposed to its toxicity. Alternatively, iodine-124 (124I) Positron Emission Tomography/Computed Tomography (PET/CT) has become available to visualize DTC lesions and without toxicity. In addition to this, 18F-fluorodeoxyglucose (18F-FDG) PET/CT detects the recurrent DTC phenotype, which lost the capacity to accumulate iodine. Taken together, the combination of 124I and 18F-FDG PET/CT has potential to stratify patients for treatment with 131I.Methods/Design: In a multicenter prospective observational cohort study the hypothesis that the combination of 124I and 18F-FDG PET/CT can avoid futile 131I treatments in patients planned for 'blind' therapy with 131I, is tested.One hundred patients planned for 131I undergo both 124I and 18F-FDG PET/CT after rhTSH stimulation. Independent of the outcome of the scans, all patients will subsequently receive, after thyroid hormone withdrawal, the 131I therapy. The post 131I therapeutic scintigraphy is compared with the outcome of the 124I and 18F-FDG PET/CT in order to evaluate the diagnostic value of the combined PET modalities.This study primary aims to reduce the number of futile 131I therapies. Secondary aims are the nationwide introduction of 124I PET/CT by a quality assurance and quality control (QA/QC) program, to correlate imaging outcome with histopathological features, to compare 124I PET/CT after rhTSH and after withdrawal of thyroid hormone, and to compare 124I and 131I dosimetry.Discussion: This study aims to evaluate the potential value of the combination of 124I and 18F-FDG PET/CT in the prevention of futile 131I therapies in patients with biochemically suspected recurrence of DTC. To our best knowledge no studies addressed this in a prospective cohort of patients. This is of great clinical importance as a futile 131I is a costly treatment associated with morbidity and therefore should be restricted to those likely to benefit from this treatment.Trial registration: Clinicaltrials.gov identifier: NCT01641679

Vuurwerkletsel in Zuidwest-Nederland rond de jaarwisseling 2017-2018

OBJECTIVE: To report the number of patients with firework-related injuries treated in December 2017 and January 2018 in a hospital in the south-west Netherlands trauma region, and to provide details about the types of firework used and the specific injuries. DESIGN: A prospective multicentre cohort study (NTR6793). METHODS: Patients of all ages with firework-related injuries were eligible for inclusion. The injury had to have been sustained between 1 December 2017 and 31 January 2018, and treated at a hospital in the south-west Netherlands trauma region (approximately 2.5 million inhabitants). Data were extracted from patients' medical files and additional information was obtained from patient interviews. RESULTS: Fifty-four patients were included. The majority were male (93%) and the median age was 15 years. Twenty-five (46%) patients were bystanders and 12 (22%) were injured by illegal fireworks. Fifty patients were injured by bangers (n=22) or decorative fireworks (n=28). The patients had a total of 79 injuries, of which 29 (37%) were localised to the upper extremity and 19 (24%) to the eyes. Most upper extremity injuries were burns (69%), primarily partial thickness. Of the eye injuries, 14 were caused by blunt trauma, seven by chemical trauma, and one by penetrating trauma. Three patients sustained indirect firework-related injuries. CONCLUSION: Between 1 December 2017 and 31 January 2018 in the south-west Netherlands trauma region mainly teenage males and bystanders sustained firework-related injuries. Most injuries were upper extremity burns and eye injuries, mainly due to legal fireworks and bangers or decorative fireworks. The extent of the sample indicatDoel Een volledig overzicht geven van het aantal vuurwerkslachtoffers dat in december 2017 en januari 2018 behandeld werd in een ziekenhuis in de traumaregio Zuidwest-Nederland, het gebruikte soort vuurwerk en de specifieke letsels. Opzet Een prospectieve, multicentrische cohortstudie (NTR6793). Methode Patiënten van alle leeftijden met vuurwerkletsel kwamen in aanmerking voor inclusie. Het letsel moest zijn ontstaan in de periode 1 december 2017-31 januari 2018 en zijn behandeld in een ziekenhuis in de traumaregio Zuidwest-Nederland (circa 2,5 miljoen inwoners). Gegevens werden verzameld vanuit het patiëntendossier en aanvullende gegevens werden verkregen tijdens een interview. Resultaten Er werden 54 patiënten geïncludeerd. Het overgrote deel betrof mannen (93%) en de mediane leeftijd was 15 jaar. 25 gewonden (46%) waren omstander en 12 mensen (22%) raakten gewond door illegaal vuurwerk. Van de 54 patiënten raakten er 50 gewond door knalvuurwerk (n = 22) of siervuurwerk (n = 28). De 54 geïncludeerde patiënten hadden 79 letsels; het letsel was 29 keer (37%) gelokaliseerd aan armen of handen en 19 keer (24%) aan de ogen. Letsel aan de arm of hand bestond voornamelijk uit brandwonden (69%), met name tweedegraads. Oogletsel werd 14 keer door stomp inwerkend geweld veroorzaakt, 7 keer door chemisch letsel en 1 keer werd het oog gepenetreerd. Er raakten 3 patiënten indirect gewond door vuurwerk. Conclusie In de traumaregio Zuidwest-Nederland raakten in de 2 maanden rond de jaarwisseling 2017-2018 vooral minderjarige mannen en omstanders gewond. Slachtoffers liepen met name brandwonden aan armen of handen of oogletsel op. De verwondingen waren met name het gevolg van legaal knal- en siervuurwerk. Door de omvang van de steekproef lijken de studiebevindingen goed te extrapoleren naar het gehele land

Synthetic Nanoparticles for Vaccines and Immunotherapy

The immune system plays a critical role in our health. No other component of human physiology plays a decisive role in as diverse an array of maladies, from deadly diseases with which we are all familiar to equally terrible esoteric conditions: HIV, malaria, pneumococcal and influenza infections; cancer; atherosclerosis; autoimmune diseases such as lupus, diabetes, and multiple sclerosis. The importance of understanding the function of the immune system and learning how to modulate immunity to protect against or treat disease thus cannot be overstated. Fortunately, we are entering an exciting era where the science of immunology is defining pathways for the rational manipulation of the immune system at the cellular and molecular level, and this understanding is leading to dramatic advances in the clinic that are transforming the future of medicine.1,2 These initial advances are being made primarily through biologic drugs– recombinant proteins (especially antibodies) or patient-derived cell therapies– but exciting data from preclinical studies suggest that a marriage of approaches based in biotechnology with the materials science and chemistry of nanomaterials, especially nanoparticles, could enable more effective and safer immune engineering strategies. This review will examine these nanoparticle-based strategies to immune modulation in detail, and discuss the promise and outstanding challenges facing the field of immune engineering from a chemical biology/materials engineering perspectiveNational Institutes of Health (U.S.) (Grants AI111860, CA174795, CA172164, AI091693, and AI095109)United States. Department of Defense (W911NF-13-D-0001 and Awards W911NF-07-D-0004