International forum. an investigation of iron status in blood donors

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Bacteria tracking by in vivo magnetic resonance imaging

Background: Different non-invasive real-time imaging techniques have been developed over the last decades to study bacterial pathogenic mechanisms in mouse models by following infections over a time course. In vivo investigations of bacterial infections previously relied mostly on bioluminescence imaging (BLI), which is able to localize metabolically active bacteria, but provides no data on the status of the involved organs in the infected host organism. In this study we established an in vivo imaging platform by magnetic resonance imaging (MRI) for tracking bacteria in mouse models of infection to study infection biology of clinically relevant bacteria. Results: We have developed a method to label Gram-positive and Gram-negative bacteria with iron oxide nano particles and detected and pursued these with MRI. The key step for successful labeling was to manipulate the bacterial surface charge by producing electro-competent cells enabling charge interactions between the iron particles and the cell wall. Different particle sizes and coatings were tested for their ability to attach to the cell wall and possible labeling mechanisms were elaborated by comparing Gram-positive and -negative bacterial characteristics. With 5-nm citrate-coated particles an iron load of 0.015 ± 0.002 pg Fe/bacterial cell was achieved for Staphylococcus aureus. In both a subcutaneous and a systemic infection model induced by iron-labeled S. aureus bacteria, high resolution MR images allowed for bacterial tracking and provided information on the morphology of organs and the inflammatory response. Conclusion: Labeled with iron oxide particles, in vivo detection of small S. aureus colonies in infection models is feasible by MRI and provides a versatile tool to follow bacterial infections in vivo. The established cell labeling strategy can easily be transferred to other bacterial species and thus provides a conceptual advance in the field of molecular MRI.<br

Properdin binds independent of complement activation in an in vivo model of anti-glomerular basement membrane disease

Properdin is the only known positive regulator of complement activation by stabilizing the alternative pathway convertase through C3 binding, thus prolonging its half-life. Recent in vitro studies suggest that properdin may act as a specific pattern recognition molecule. To better understand the role of properdin in vivo, we used an experimental model of acute anti-glomerular basement membrane disease with wild-type, C3-and properdin knockout mice. The model exhibited severe proteinuria, acute neutrophil infiltration and activation, classical and alternative pathway activation, and progressive glomerular deposition of properdin, C3 and C9. Although the acute renal injury was likely due to acute neutrophil activation, we found properdin deposition in C3-knockout mice that was not associated with IgG. Thus, properdin may deposit in injured tissues in vivo independent of its main ligand C3.Peer reviewe

Mutation of friezes

We study mutations of Conway–Coxeter friezes which are compatible with mutations of cluster-tilting objects in the associated cluster category of Dynkin type A. More precisely, we provide a formula, relying solely on the shape of the frieze, describing how each individual entry in the frieze changes under cluster mutation. We observe how the frieze can be divided into four distinct regions, relative to the entry at which we want to mutate, where any two entries in the same region obey the same mutation rule. Moreover, we provide a combinatorial formula for the number of submodules of a string module, and with that a simple way to compute the frieze associated to a fixed cluster-tilting object in a cluster category of Dynkin type A in the sense of Caldero and Chapoton

Large-scale identification and characterization of alternative splicing variants of human gene transcripts using 56 419 completely sequenced and manually annotated full-length cDNAs

We report the first genome-wide identification and characterization of alternative splicing in human gene transcripts based on analysis of the full-length cDNAs. Applying both manual and computational analyses for 56 419 completely sequenced and precisely annotated full-length cDNAs selected for the H-Invitational human transcriptome annotation meetings, we identified 6877 alternative splicing genes with 18 297 different alternative splicing variants. A total of 37 670 exons were involved in these alternative splicing events. The encoded protein sequences were affected in 6005 of the 6877 genes. Notably, alternative splicing affected protein motifs in 3015 genes, subcellular localizations in 2982 genes and transmembrane domains in 1348 genes. We also identified interesting patterns of alternative splicing, in which two distinct genes seemed to be bridged, nested or having overlapping protein coding sequences (CDSs) of different reading frames (multiple CDS). In these cases, completely unrelated proteins are encoded by a single locus. Genome-wide annotations of alternative splicing, relying on full-length cDNAs, should lay firm groundwork for exploring in detail the diversification of protein function, which is mediated by the fast expanding universe of alternative splicing variants

Validation of a Step Detection Algorithm during Straight Walking and Turning in Patients with Parkinson’s Disease and Older Adults Using an Inertial Measurement Unit at the Lower Back

INTRODUCTION Inertial measurement units (IMUs) positioned on various body locations allow detailed gait analysis even under unconstrained conditions. From a medical perspective, the assessment of vulnerable populations is of particular relevance, especially in the daily-life environment. Gait analysis algorithms need thorough validation, as many chronic diseases show specific and even unique gait patterns. The aim of this study was therefore to validate an acceleration-based step detection algorithm for patients with Parkinson's disease (PD) and older adults in both a lab-based and home-like environment. METHODS In this prospective observational study, data were captured from a single 6-degrees of freedom IMU (APDM) (3DOF accelerometer and 3DOF gyroscope) worn on the lower back. Detection of heel strike (HS) and toe off (TO) on a treadmill was validated against an optoelectronic system (Vicon) (11 PD patients and 12 older adults). A second independent validation study in the home-like environment was performed against video observation (20 PD patients and 12 older adults) and included step counting during turning and non-turning, defined with a previously published algorithm. RESULTS A continuous wavelet transform (cwt)-based algorithm was developed for step detection with very high agreement with the optoelectronic system. HS detection in PD patients/older adults, respectively, reached 99/99% accuracy. Similar results were obtained for TO (99/100%). In HS detection, Bland-Altman plots showed a mean difference of 0.002 s [95% confidence interval (CI) -0.09 to 0.10] between the algorithm and the optoelectronic system. The Bland-Altman plot for TO detection showed mean differences of 0.00 s (95% CI -0.12 to 0.12). In the home-like assessment, the algorithm for detection of occurrence of steps during turning reached 90% (PD patients)/90% (older adults) sensitivity, 83/88% specificity, and 88/89% accuracy. The detection of steps during non-turning phases reached 91/91% sensitivity, 90/90% specificity, and 91/91% accuracy. CONCLUSION This cwt-based algorithm for step detection measured at the lower back is in high agreement with the optoelectronic system in both PD patients and older adults. This approach and algorithm thus could provide a valuable tool for future research on home-based gait analysis in these vulnerable cohorts

Dutch Oncology COVID-19 consortium:Outcome of COVID-19 in patients with cancer in a nationwide cohort study

Aim of the study: Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). To identify risk factors associated with a worse outcome of COVID-19, a nationwide registry was developed for patients with cancer and COVID-19. Methods: This observational cohort study has been designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a nationwide collaboration of oncology physicians in the Netherlands. A questionnaire has been developed to collect pseudonymised patient data on patients' characteristics, cancer diagnosis and treatment. All patients with COVID-19 and a cancer diagnosis or treatment in the past 5 years are eligible. Results: Between March 27th and May 4th, 442 patients were registered. For this first analysis, 351 patients were included of whom 114 patients died. In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) were independent risk factors for a fatal outcome of COVID-19. In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥65 years). Conclusion: The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to severe acute respiratory syndrome coronavirus 2, whereas treatment adjustments and prioritising vaccination, when available, should also be considered

To continue or not to continue? Antipsychotic medication maintenance versus dose-reduction/discontinuation in first episode psychosis: HAMLETT, a pragmatic multicenter single-blind randomized controlled trial

BACKGROUND: Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition-a finding that was not replicated in another recently published long-term study. METHODS/DESIGN: The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3-6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years. DISCUSSION: The HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration and when to taper off medication after remission of a FEP. Moreover, it may provide patient characteristics associated with safe dose reduction with a minimal risk of relapse. TRIAL STATUS: Protocol version 1.3, October 2018. The study is active and currently recruiting patients (since September 2017), with the first 200 participants by the end of 2019. We anticipate completing recruitment in 2022 and final assessments (including follow-up 3.5 years after phase one) in 2026. TRIAL REGISTRATION: European Clinical Trials Database, EudraCT number 2017-002406-12. Registered 7 J

Clinical features and predictors for disease natural progression in adults with Pompe disease: A nationwide prospective observational study

Background: Due partly to physicians' unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults, and mapped out the distribution and severity of muscle weakness, and the sequence of involvement of the individual muscle groups. Furthermore, we defined the natural disease course and identified prognostic factors for disease progression. Methods. We conducted a single-center, prospective, observational study. Muscle strength (manual muscle testing, and hand-held dynamometry), muscle function (quick motor function test), and pulmonary function (forced vital capacity in sitting and supine positions) were assessed every 3-6 months and analyzed using repeated-measures ANOVA. Results: Between October 2004 and August 2009, 94 patients aged between 25 and 75 years were includ