Critical care medicine is a natural environment for machine learning approaches to improve outcomes for critically ill patients as admissions to ICUs generate vast amounts of data. However, ...technical, legal, ethical, and privacy concerns have so far limited the critical care medicine community from making these data readily available. The Society of Critical Care Medicine and the European Society of Intensive Care Medicine have identified ICU patient data sharing as one of the priorities under their Joint Data Science Collaboration. To encourage ICUs worldwide to share their patient data responsibly, we now describe the development and release of Amsterdam University Medical Centers Database (AmsterdamUMCdb), the first freely available critical care database in full compliance with privacy laws from both the United States and Europe, as an example of the feasibility of sharing complex critical care data.
University hospital ICU.
Data from ICU patients admitted between 2003 and 2016.
We used a risk-based deidentification strategy to maintain data utility while preserving privacy. In addition, we implemented contractual and governance processes, and a communication strategy. Patient organizations, supporting hospitals, and experts on ethics and privacy audited these processes and the database.
AmsterdamUMCdb contains approximately 1 billion clinical data points from 23,106 admissions of 20,109 patients. The privacy audit concluded that reidentification is not reasonably likely, and AmsterdamUMCdb can therefore be considered as anonymous information, both in the context of the U.S. Health Insurance Portability and Accountability Act and the European General Data Protection Regulation. The ethics audit concluded that responsible data sharing imposes minimal burden, whereas the potential benefit is tremendous.
Technical, legal, ethical, and privacy challenges related to responsible data sharing can be addressed using a multidisciplinary approach. A risk-based deidentification strategy, that complies with both U.S. and European privacy regulations, should be the preferred approach to releasing ICU patient data. This supports the shared Society of Critical Care Medicine and European Society of Intensive Care Medicine vision to improve critical care outcomes through scientific inquiry of vast and combined ICU datasets.
Digital devices and wearables allow for the measurement of a wide range of health-related parameters in a non-invasive manner, which may be particularly valuable in pediatrics. Incorporation of such ...parameters in clinical trials or care as digital endpoint could reduce the burden for children and their parents but requires clinical validation in the target population. This study aims to determine the tolerability, repeatability, and reference values of novel digital endpoints in healthy children.
Apparently healthy children (n = 175, 46% male) aged 2-16 were included. Subjects were monitored for 21 days using a home-monitoring platform with several devices (smartwatch, spirometer, thermometer, blood pressure monitor, scales). Endpoints were analyzed with a mixed effects model, assessing variables that explained within- and between-subject variability. Endpoints based on physical activity, heart rate, and sleep-related parameters were included in the analysis. For physical-activity-related endpoints, a sample size needed to detect a 15% increase was calculated.
Median compliance was 94%. Variability in each physical activity-related candidate endpoint was explained by age, sex, watch wear time, rain duration per day, average ambient temperature, and population density of the city of residence. Estimated sample sizes for candidate endpoints ranged from 33-110 per group. Daytime heart rate, nocturnal heart rate and sleep duration decreased as a function of age and were comparable to reference values published in the literature.
Wearable- and portable devices are tolerable for pediatric subjects. The raw data, models and reference values presented here can be used to guide further validation and, in the future, clinical trial designs involving the included measures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Severe combined immunodeficiency (SCID) patients with an inactivating mutation in recombination activation gene 1 (RAG1) lack B and T cells due to the inability to rearrange immunoglobulin (Ig) and ...T-cell receptor (TCR) genes. Gene therapy is a valid treatment option for RAG-SCID patients, especially for patients lacking a suitable bone marrow donor, but developing such therapy has proven challenging. As a preclinical model for RAG-SCID, we used Rag1-/- mice and lentiviral self-inactivating (SIN) vectors harboring different internal elements to deliver native or codon-optimized human RAG1 sequences. Treatment resulted in the appearance of B and T cells in peripheral blood and developing B and T cells were detected in central lymphoid organs. Serum Ig levels and Ig and TCR Vβ gene segment usage was comparable to wild-type (WT) controls, indicating that RAG-mediated rearrangement took place. Remarkably, relatively low frequencies of B cells produced WT levels of serum immunoglobulins. Upon stimulation of the TCR, corrected spleen cells proliferated and produced cytokines. In vivo challenge resulted in production of antigen-specific antibodies. No leukemia development as consequence of insertional mutagenesis was observed. The functional reconstitution of the B- as well as the T-cell compartment provides proof-of-principle for therapeutic RAG1 gene transfer in Rag1-/- mice using lentiviral SIN vectors.
Proteasome inhibitor (PI) carfilzomib (CFZ) has activity superior to bortezomib (BTZ) and is increasingly incorporated in multiple myeloma (MM) frontline therapy and relapsed settings. Most MM ...patients ultimately experience PI-refractory disease, an unmet medical need with poorly understood biology and dismal outcome. Pharmacologic targeting of ABCB1 improved patient outcomes, including MM, but suffered from adverse drug effects and insufficient plasma concentrations. Proteomics analysis identified ABCB1 overexpression as the most significant change in CFZ-resistant MM cells. We addressed the functional role of ABCB1 overexpression in MM and observed significantly upregulated ABCB1 in peripheral blood malignant plasma cells (PCs) vs untreated patients' bone marrow PC. ABCB1 overexpression reduces the proteasome-inhibiting activity of CFZ due to drug efflux, in contrast to BTZ. Likewise, the cytotoxicity of established anti-MM drugs was significantly reduced in ABCB1-expressing MM cells. In search for potential drugs targeting ABCB1 in clinical trials, we identified the HIV protease inhibitors nelfinavir (NFV) and lopinavir (LPV) as potent functional modulators of ABCB1-mediated drug export, most likely via modulation of mitochondria permeability transition pore. NFV and LPV restored CFZ activity at therapeutically relevant drug levels and thus represent ready-to-use drugs to be tested in clinical trials to target ABCB1 and to re-sensitize PC to established myeloma drugs, in particular CFZ.
Novel digital endpoints gathered via wearables, small devices, or algorithms hold great promise for clinical trials. However, implementation has been slow because of a lack of guidelines regarding ...the validation process of these new measurements. In this paper, we propose a pragmatic approach toward selection and fit-for-purpose validation of digital endpoints. Measurements should be value-based, meaning the measurements should directly measure or be associated with meaningful outcomes for patients. Devices should be assessed regarding technological validity. Most importantly, a rigorous clinical validation process should appraise the tolerability, difference between patients and controls, repeatability, detection of clinical events, and correlation with traditional endpoints. When technically and clinically fit-for-purpose, case building in interventional clinical trials starts to generate evidence regarding the response to new or existing health-care interventions. This process may lead to the digital endpoint replacing traditional endpoints, such as clinical rating scales or questionnaires in clinical trials. We recommend initiating more data-sharing collaborations to prevent unnecessary duplication of research and integration of value-based measurements in clinical care to enhance acceptance by health-care professionals. Finally, we invite researchers and regulators to adopt this approach to ensure a timely implementation of digital measurements and value-based thinking in clinical trial design and health care. SIGNIFICANCE STATEMENT: Novel digital endpoints are often cited as promising for the clinical trial of the future. However, clear validation guidelines are lacking in the literature. This paper contains pragmatic criteria for the selection, technical validation, and clinical validation of novel digital endpoints and provides recommendations for future work and collaboration.
Summary
Background
Rosacea assessment and therapy monitoring can be challenging to standardize, as most clinical evaluation systems are prone to interobserver variability and not always validated. ...Therefore, objective, reliable and preferably noninvasive measurement tools are needed.
Objectives
To give insight into available noninvasive imaging techniques and biophysical methods in rosacea by performing a systematic review.
Methods
PubMed, Embase, Cochrane and Web of Science databases were searched until 1 September 2018 in accordance with PRISMA guidelines, to identify studies providing original data about objective noninvasive imaging and/or biophysical skin measurement techniques for diagnosis, assessing severity or therapy monitoring of adult patients with cutaneous facial rosacea. Risk of bias of included articles was assessed with the Cochrane Risk of Bias tool, Quality in Prognosis Studies tool, and the Newcastle–Ottawa Scale.
Results
A total of 78 studies were included, describing 14 imaging and biophysical methods. Widespread information about (sub)surface cutaneous morphology and functionality was obtained. Methodological study quality was relatively low and interstudy outcome variability was large. Several tools show promising value in research settings: for treatment follow‐up Demodex mites are countable with reflectance confocal microscopy, spectrometry can quantify erythema, and rosacea severity could be objectified with skin hydration‐ and transepidermal water loss measurements.
Conclusions
This systematic review describes the spectrum of noninvasive imaging and biophysical methods in rosacea assessment, giving multifaceted information about structure and properties of rosacea skin, especially useful for research purposes. Larger studies with good methodological quality are needed to create validated protocols for further implementation into research.
What's already known about this topic?
Rosacea is a chronic inflammatory skin disease with a variety of clinical manifestations.
Most clinical evaluation systems are subjective, not always validated, and subsurface skin processes remain unnoticed.
Currently, different types of noninvasive measurement tools are available for rosacea assessment and therapy monitoring, but a comprehensive overview is lacking.
What does this study add?
Seventy‐eight publications were included, describing 14 imaging and biophysical tools, providing a wide range of information about rosacea skin morphology and functionality.
Reflectance confocal microscopy and spectrometry are especially promising in therapy monitoring and skin barrier measurements for rosacea severity assessment.
Larger studies with better methodological quality are needed to create validated protocols for implementation into research.
Linked Comment: Tan. Br J Dermatol 2020; 182:10–11.
Plain language summary available online
The histologic examination of endoscopic biopsies or resection specimens remains a key step in the work-up of affected inflammatory bowel disease (IBD) patients and can be used for diagnosis and ...differential diagnosis, particularly in the differentiation of UC from CD and other non-IBD related colitides. The introduction of new treatment strategies in inflammatory bowel disease (IBD) interfering with the patients' immune system may result in mucosal healing, making the pathologists aware of the impact of treatment upon diagnostic features. The European Crohn's and Colitis Organisation (ECCO) and the European Society of Pathology (ESP) jointly elaborated a consensus to establish standards for histopathology diagnosis in IBD. The consensus endeavors to address: (i) procedures required for a proper diagnosis, (ii) features which can be used for the analysis of endoscopic biopsies, (iii) features which can be used for the analysis of surgical samples, (iv) criteria for diagnosis and differential diagnosis, and (v) special situations including those inherent to therapy. Questions that were addressed include: how many features should be present for a firm diagnosis? What is the role of histology in patient management, including search for dysplasia? Which features if any, can be used for assessment of disease activity? The statements and general recommendations of this consensus are based on the highest level of evidence available, but significant gaps remain in certain areas.
To evaluate whether immunomodulation can eliminate high sustained antibody levels, and thereby improve clinical outcome in classic infantile Pompe patients receiving enzyme replacement therapy (ERT) ...with recombinant human alpha-glucosidase (rhGAA).
Three patients (two cross-reactive immunologic material (CRIM) negative) with high sustained antibodies received a three-week treatment protocol with Rituximab and Bortezomib, followed by daily Rapamycin and monthly IVIG. Patients received 40 mg/kg/week rhGAA. Antibody titers were measured using ELISA. Neutralizing effects on cellular uptake were determined. Clinical efficacy was measured in terms of (ventilator-free) survival, reduction in left ventricular mass index (LVMI) and improvement in motor function.
Before immunomodulation anti-rhGAA antibody titers ranged from 1:156,250 to 1:781,250 and at last assessment from 1:31,250 to 1:156,250. Neutralizing effects of anti-rhGAA antibody titers (observed in two patients) disappeared. Infusion-associated reactions were no longer present. Immunomodulation resulted in substantial increases of aspartate transaminase, alanine transaminase, and creatine kinase levels. The two CRIM-negative patients who could walk at start of immunomodulation maintained their ability to walk; the patient who had lost this ability did not regain it.
To some extent, the immunomodulation protocol used in our study reduced antibody titers, but it did not eliminate them. Overall, there have been few reports on secondary immunomodulation, and various protocols have been applied. Future research should seek to identify the most successful immunomodulation protocol in patients with high sustained titers.
Abstract
Objective: This study examines the influence of patient demographics and peri- and postoperative (≪7 days) characteristics on the incidence of chronic thoracic pain 1 year after cardiac ...surgery. The impact of chronic thoracic pain on daily life is also documented. Methods: A prospective cohort study of 146 patients admitted to the intensive care unit after cardiac surgery via sternotomy was carried out. Pain scores (numeric rating scale 0-10) were recorded during the first 7 postoperative days. One year later, a questionnaire was used to evaluate the incidence in the 2 preceding weeks of chronic thoracic pain (numeric rating scale >0) associated with the primary surgery. Results: One year after surgery, 42 (35%) of the 120 responding patients reported chronic thoracic pain. Multivariate regression analysis of patient characteristics revealed that non-elective surgery, re-sternotomy, severe pain (numeric rating scale ≥4) on the third postoperative day, and female gender were all independent predictors of chronic thoracic pain. In addition, the chronic sufferers reported more sleep disturbances and more frequent use of analgesics than their cohorts. Conclusions: We have identified a number of factors correlated with persistent thoracic pain following cardiac surgery with sternotomy. Awareness of these predictors may be useful for further research concerning both the prevention and treatment of chronic thoracic pain, thereby potentially ameliorating the postoperative quality of life of a significant proportion of patients. Meanwhile, chronic thoracic pain should be discussed preoperatively with patients at risk so that they are truly informed about possible consequences of the surgery.
Aims
Optimizing D‐xylose transport in Saccharomyces cerevisiae is essential for efficient bioethanol production from cellulosic materials. We have used a gene shuffling approach of hexose (Hxt) ...transporters in order to increase the affinity for D‐xylose.
Methods and Results
Various libraries were transformed to a hexose transporter deletion strain, and shuffled genes were selected via growth on low concentrations of D‐xylose. This screening yielded two homologous fusion proteins (fusions 9,4 and 9,6), both consisting of the major central part of Hxt2 and various smaller parts of other Hxt proteins. Both chimeric proteins showed the same increase in D‐xylose affinity (8·1 ± 3·0 mmol l−1) compared with Hxt2 (23·7 ± 2·1 mmol l−1). The increased D‐xylose affinity could be related to the C terminus, more specifically to a cysteine to proline mutation at position 505 in Hxt2.
Conclusions
The Hxt2C505P mutation increased the affinity for D‐xylose for Hxt2, thus providing a way to increase D‐xylose transport flux at low D‐xylose concentration.
Significance and Impact of the Study
The gene shuffling protocol using the highly homologues hexose transporters family provides a powerful tool to enhance the D‐xylose affinity of Hxt transporters in S. cerevisiae, thus providing a means to increase the D‐xylose uptake flux at low D‐xylose concentrations.
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