Health Data Re-Identification: Assessing Adversaries and Potential Harms.

Sharing biomedical data for research can help to improve disease understanding and support the development of preventive, diagnostic, and therapeutic methods. However, it is vital to balance the amount of data shared and the sharing mechanism chosen with the privacy protection provided. This requires a detailed understanding of potential adversaries who might attempt to re-identify data and the consequences of their actions. The aim of this paper is to present a comprehensive list of potential types of adversaries, motivations, and harms to targeted individuals. A group of 13 researchers performed a three-step process in a one-day workshop, involving the identification of adversaries, the categorization by motivation, and the deduction of potential harms. The group collected 28 suggestions and categorized them into six types, each associated with several of six distinct harms. The findings align with previous efforts in structuring threat actors and outcomes and we believe that they provide a robust foundation for evaluating re-identification risks and developing protection measures in health data sharing scenarios.

Rapid Deployment of a Pseudonymization Service in a Distributed Research Data Infrastructure - Lessons Learned.

The SARS-CoV-2 pandemic highlighted the importance of fast, collaborative research in biomedicine. Within the ORCHESTRA consortium, we rapidly deployed a pseudonymization service with minimal training and maintenance efforts under time-critical conditions to support a complex, multi-site research project. Over two years, the service was deployed in 13 sites across 11 countries to register more than 10,000 study participants and 15,000 biosamples. In this work, we present lessons learned as part of this process. Most importantly, we learned that common challenges can be overcome by creatively utilizing widely available tools and that having a dedicated partner to manage software rollout and pre-configure software packages for each site fosters the effective implementation.

A Scalable Pseudonymization Tool for Rapid Deployment in Large Biomedical Research Networks: Development and Evaluation Study.

Background: The SARS-CoV-2 pandemic has demonstrated once again that rapid collaborative research is essential for the future of biomedicine. Large research networks are needed to collect, share, and reuse data and biosamples to generate collaborative evidence. However, setting up such networks is often complex and time-consuming, as common tools and policies are needed to ensure interoperability and the required flows of data and samples, especially for handling personal data and the associated data protection issues. In biomedical research, pseudonymization detaches directly identifying details from biomedical data and biosamples and connects them using secure identifiers, the so-called pseudonyms. This protects privacy by design but allows the necessary linkage and reidentification. Objective: Although pseudonymization is used in almost every biomedical study, there are currently no pseudonymization tools that can be rapidly deployed across many institutions. Moreover, using centralized services is often not possible, for example, when data are reused and consent for this type of data processing is lacking. We present the ORCHESTRA Pseudonymization Tool (OPT), developed under the umbrella of the ORCHESTRA consortium, which faced exactly these challenges when it came to rapidly establishing a large-scale research network in the context of the rapid pandemic response in Europe. Methods: To overcome challenges caused by the heterogeneity of IT infrastructures across institutions, the OPT was developed based on programmable runtime environments available at practically every institution: office suites. The software is highly configurable and provides many features, from subject and biosample registration to record linkage and the printing of machine-readable codes for labeling biosample tubes. Special care has been taken to ensure that the algorithms implemented are efficient so that the OPT can be used to pseudonymize large data sets, which we demonstrate through a comprehensive evaluation. Results: The OPT is available for Microsoft Office and LibreOffice, so it can be deployed on Windows, Linux, and MacOS. It provides multiuser support and is configurable to meet the needs of different types of research projects. Within the ORCHESTRA research network, the OPT has been successfully deployed at 13 institutions in 11 countries in Europe and beyond. As of June 2023, the software manages data about more than 30,000 subjects and 15,000 biosamples. Over 10,000 labels have been printed. The results of our experimental evaluation show that the OPT offers practical response times for all major functionalities, pseudonymizing 100,000 subjects in 10 seconds using Microsoft Excel and in 54 seconds using LibreOffice. Conclusions: Innovative solutions are needed to make the process of establishing large research networks more efficient. The OPT, which leverages the runtime environment of common office suites, can be used to rapidly deploy pseudonymization and biosample management capabilities across research networks. The tool is highly configurable and available as open-source software.

Multisectoral action to address noncommunicable diseases: lessons from three country case studies.

Introduction: Multisectoral action is a central component of the global response to the rising prevalence of non-communicable diseases (NCDs). In this paper we aimed to unpack the definition of multisectoral action and provide an overview of the historical context, challenges, and recommendations alongside three country case studies: salt reduction in the UK, tobacco legislation in Nigeria, and regulation of edible oils in Iran. Methods: We used an iterative review process to select three country case studies from a list of 20 potential cases previously identified by WHO. At our third round of review we unanimously agreed to focus on salt reduction in the UK, tobacco regulation in Nigeria, and edible oil regulation in Iran as these represented rich cases on diverse risk factors from three different world regions that we felt offered important lessons. We conducted literature reviews to identify further data for each case study. Results: Across the three studies a number of important themes emerged. We found that multisectoral approaches demand the often difficult reconciliation of competing and conflicting values and priorities. Across our three chosen cases, commercial interests and free trade agreements were the most common obstacles to successful multisectoral strategies. We found that early consultative stakeholder engagement and strong political and bureaucratic leadership were necessary for success. Discussion: The complex multi-rooted nature of NCDs requires a multisectoral approach, but the inevitable conflicts that this entails requires careful navigation.

Molecular mechanisms of ischemia and glutamate excitotoxicity.

Excitotoxicity is classically defined as the neuronal damage caused by the excessive release of glutamate, and subsequent activation of excitatory plasma membrane receptors. In the mammalian brain, this phenomenon is mainly driven by excessive activation of glutamate receptors (GRs). Excitotoxicity is common to several chronic disorders of the Central Nervous System (CNS) and is considered the primary mechanism of neuronal loss of function and cell death in acute CNS diseases (e.g. ischemic stroke). Multiple mechanisms and pathways lead to excitotoxic cell damage including pro-death signaling cascade events downstream of glutamate receptors, calcium (Ca2+) overload, oxidative stress, mitochondrial impairment, excessive glutamate in the synaptic cleft as well as altered energy metabolism. Here, we review the current knowledge on the molecular mechanisms that underlie excitotoxicity, emphasizing the role of Nicotinamide Adenine Dinucleotide (NAD) metabolism. We also discuss novel and promising therapeutic strategies to treat excitotoxicity, highlighting recent clinical trials. Finally, we will shed light on the ongoing search for stroke biomarkers, an exciting and promising field of research, which may improve stroke diagnosis, prognosis and allow better treatment options.

GLP-1 Increases Circulating Leptin Levels in Truncal Vagotomized Rats.

GLP-1 is a gastro-intestinal hormone acting within the gut/brain axis for energy balance regulation. We aimed to evaluate the role of the vagus nerve in whole-body energy homeostasis and in mediating GLP-1 effects. For this, rats submitted to truncal vagotomy and sham-operated controls underwent a comprehensive evaluation, including eating behavior, body weight, percentage of white (WAT) and brown adipose tissue (BAT), resting energy expenditure (REE) and acute response to GLP-1. Truncal vagotomized rats had significantly lower food intake, body weight, body weight gain, WAT and BAT, with a higher BAT/WAT ratio, but no significant difference in REE when compared to controls. Vagotomized rats also had significantly higher fasting ghrelin and lower glucose and insulin levels. After GLP-1 administration, vagotomized rats depicted a blunted anorexigenic response and higher plasma leptin levels, as compared to controls. However, in vitro stimulation of VAT explants with GLP-1 resulted in no significant changes in leptin secretion. In conclusion, the vagus nerve influences whole-body energy homeostasis by modifying food intake, body weight and body composition and by mediating the GLP-1 anorectic response. The higher leptin levels in response to acute GLP-1 administration observed after truncal vagotomy suggest the existence of a putative GLP-1-leptin axis that relies on the integrity of gut-brain vagal pathway.

Proteostasis networks in aging: novel insights from text-mining approaches.

Aging is a topic of paramount importance in an increasingly elderly society and has been the focus of extensive research. Protein homeostasis (proteostasis) decline is a hallmark in aging and several age-related diseases, but which specific proteins and mechanisms are involved in proteostasis (de)regulation during the aging process remain largely unknown. Here, we used different text-mining tools complemented with protein-protein interaction data to address this complex topic. Analysis of the integrated protein interaction networks identified novel proteins and pathways associated to proteostasis mechanisms and aging or age-related disorders, indicating that this approach is useful to identify previously unknown links and for retrieving information of potential novel biomarkers or therapeutic targets.

Bacillary layer detachment in serpiginous-like choroiditis of presumed intraocular tuberculosis: Report of two cases.

Purpose: To describe the presence of bacillary layer detachment (BALAD) in serpiginous-like choroiditis (SLC) in presumed intraocular tuberculosis. Observations: Clinical and multimodal imaging including fundus photography, fundus autofluorescence, and spectral domain and enhanced-deep imaging optical coherence tomography (OCT) of two cases of SLC in presumed intraocular tuberculosis. Two patients (26 and 38-year-old woman) presented with unilateral, decreased vision of acute onset. They were diagnosed with SLC in presumed intraocular tuberculosis, and OCT revealed splitting of the ellipsoid zone, resembling BALAD. All two patients showed complete resolution after treatment with antitubercular therapy (ATT). Conclusions and Importance: BALAD appears in the acute stage of SLC in presumed intraocular tuberculosis and resolves rapidly at the beginning of ATT.

The role of NAD metabolism in neuronal differentiation.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD) metabolism is involved in redox and non-redox reactions that regulate several processes including differentiation of cells of different origins. Here, the role of NAD metabolism in neuronal differentiation, which remains elusive so far, was investigated. MATERIAL AND METHODS: A protein-protein interaction network between neurotrophin signaling and NAD metabolic pathways was built. Expression of NAD biosynthetic enzymes in SH-SY5Y cells during retinoic acid (RA)/brain derived neurotrophic factor (BDNF) differentiation, was evaluated. The effects of NAD biosynthetic enzymes QPRT and NAPRT inhibition in neurite outgrowth, cell viability, NAD availability and histone deacetylase (HDAC) activity, were analyzed in RA- and BDNF-differentiated cells. RESULTS: Bioinformatics analysis revealed the interaction between NAD biosynthetic enzyme NMNAT1 and NTRK2, a receptor activated by RA/BDNF sequential treatment. Differences were found in the expression of NAD biosynthetic enzymes during neuronal differentiation, namely, increased QPRT gene expression along the course of RA/BDNF treatment and NAPRT protein expression after a 5-day treatment with RA. QPRT inhibition in BDNF-differentiated SH-SY5Y cells resulted in less neuritic length per cell, decreased expression of the neuronal marker ß-III Tubulin and also decreased NAD+ levels and HDAC activity. NAPRT inhibition had no effect in neuritic length per cell, NAD+ levels and HDAC activity. Of note, NAD supplementation along with RA, but not with BDNF, resulted in considerable cell death. CONCLUSIONS: Taken together, our results show the involvement of NAD metabolism in neuronal differentiation, specifically, the importance of QPRT-mediated NAD biosynthesis in BDNF-associated SH-SY5Y differentiation and suggest additional roles for NAPRT beyond NAD production in RA-differentiated cells.

An International Comparison of Baseline Characteristics of Patients Undergoing Initiation of Anti-VEGF Therapy for DME.

BACKGROUND AND OBJECTIVE: Diabetic macular edema (DME) is a leading cause of vision loss worldwide. The object of this study is to compare global differences of baseline characteristics of patients undergoing initiation of anti-vascular endothelial growth factor (VEGF) therapy for DME. PATIENTS AND METHODS: This multicenter, cross-sectional study included diabetic patients with foveal-involving retinal edema secondary to DME as documented by fundus exam and optical coherence tomography who were undergoing initiation of intravitreal anti-VEGF drugs. Variables were collected to find possible risk factors and to create an epidemiological profile of DME patients undergoing initiation of anti-VEGF agents. RESULTS: Nine hundred two patients were selected. Mean age was 62.4 (±11) years, 49.7% were Caucasians, 57.6% were male, and 96% had type two diabetes with an average disease duration of 181.7 months ± 113 months. Of the patients included, 74.7% suffered from hypertension, 26.6% from cardiovascular disease, 12.1% from cerebrovascular disease, 12.8% from peripheral vascular disease, and 12.8% from renal insufficiency. Best-corrected visual acuity (BCVA) was 65 (±20) Early Treatment Diabetic Retinopathy Study letters, central subfield thickness was 364 (±162) µm, cube volume 11.1 ± 3.1 mm3, cube average thickness 328.8 µm ± 61 µm, and 63.9% had nonproliferative diabetic retinopathy. Comparison between U.S. versus international patients, and patients with BCVA 70 letters or less versus more than 70 letters were performed, significant differences were acknowledged, and risk factors were recognized. CONCLUSION: There were key differences in the epidemiologic profile between patients presenting with DME in the U.S. and internationally. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e300-e310.].