PHIRI: lessons for an extensive reuse of sensitive data in federated health research.

BACKGROUND: The extensive and continuous reuse of sensitive health data could enhance the role of population health research on public decisions. This paper describes the design principles and the different building blocks that have supported the implementation and deployment of Population Health Information Research Infrastructure (PHIRI), the strengths and challenges of the approach and some future developments. METHODS: The design and implementation of PHIRI have been developed upon: (i) the data visiting principle-data does not move but code moves; (ii) the orchestration of the research question throughout a workflow that ensured legal, organizational, semantic and technological interoperability and (iii) a 'master-worker' federated computational architecture that supported the development of four uses cases. RESULTS: Nine participants nodes and 28 Euro-Peristat members completed the deployment of the infrastructure according to the expected outputs. As a consequence, each use case produced and published their own common data model, the analytical pipeline and the corresponding research outputs. All the digital objects were developed and published according to Open Science and FAIR principles. CONCLUSION: PHIRI has successfully supported the development of four use cases in a federated manner, overcoming limitations for the reuse of sensitive health data and providing a methodology to achieve interoperability in multiple research nodes.

Has the COVID-19 pandemic changed existing patterns of non-COVID-19 health care utilization? A retrospective analysis of six regions in Europe.

BACKGROUND: Resilience of national health systems in Europe remains a major concern in times of multiple crises and as more evidence is emerging relating to the indirect effects of the COVID-19 pandemic on health care utilization (HCU), resulting from de-prioritization of regular, non-pandemic healthcare services. Most extant studies focus on regional, disease specific or early pandemic HCU creating difficulties in comparing across multiple countries. We provide a comparatively broad definition of HCU across multiple countries, with potential to expand across regions and timeframes. METHODS: Using a cross-country federated research infrastructure (FRI), we examined HCU for acute cardiovascular events, elective surgeries and serious trauma. Aggregated data were used in forecast modelling to identify changes from predicted European age-standardized counts via fitted regressions (2017-19), compared against post-pandemic data. RESULTS: We found that elective surgeries were most affected, universally falling below predicted levels in 2020. For cardiovascular HCU, we found lower-than-expected cases in every region for heart attacks and displayed large sex differences. Serious trauma was the least impacted by the COVID-19 pandemic. CONCLUSION: The strength of this study comes from the use of the European Population Health Information Research Infrastructure's (PHIRI) FRI, allowing for rapid analysis of regional differences to assess indirect impacts of events such as pandemics. There are marked differences in the capacity of services to return to normal in terms of elective surgery; additionally, we found considerable differences between men and women which requires further research on potential sex or gender patterns of HCU during crises.

Delayed treatment in breast cancer patients during the COVID-19 pandemic: a population health information research infrastructure (PHIRI) case study.

BACKGROUND: The indirect impact of the coronavirus disease 2019 pandemic on healthcare services was studied by assessing changes in the trend of the time to first treatment for women 18 or older who were diagnosed and treated for breast cancer between 2017 and 2021. METHODS: An observational retrospective longitudinal study based on aggregated data from four European Union (EU) countries/regions investigating the time it took to receive breast cancer treatment. We compiled outputs from a federated analysis to detect structural breakpoints, confirming the empirical breakpoints by differences between the trends observed and forecasted after March 2020. Finally, we built several segmented regressions to explore the association of contextual factors with the observed changes in treatment delays. RESULTS: We observed empirical structural breakpoints on the monthly median time to surgery trend in Aragon (ranging from 9.20 to 17.38 days), Marche (from 37.17 to 42.04 days) and Wales (from 28.67 to 35.08 days). On the contrary, no empirical structural breakpoints were observed in Belgium (ranging from 21.25 to 23.95 days) after the pandemic's beginning. Furthermore, we confirmed statistically significant differences between the observed trend and the forecasts for Aragon and Wales. Finally, we found the interaction between the region and the pandemic's start (before/after March 2020) significantly associated with the trend of delayed breast cancer treatment at the population level. CONCLUSIONS: Although they were not clinically relevant, only Aragon and Wales showed significant differences with expected delays after March 2020. However, experiences differed between countries/regions, pointing to structural factors other than the pandemic.

Federated causal inference based on real-world observational data sources: application to a SARS-CoV-2 vaccine effectiveness assessment.

INTRODUCTION: Causal inference helps researchers and policy-makers to evaluate public health interventions. When comparing interventions or public health programs by leveraging observational sensitive individual-level data from populations crossing jurisdictional borders, a federated approach (as opposed to a pooling data approach) can be used. Approaching causal inference by re-using routinely collected observational data across different regions in a federated manner, is challenging and guidance is currently lacking. With the aim of filling this gap and allowing a rapid response in the case of a next pandemic, a methodological framework to develop studies attempting causal inference using federated cross-national sensitive observational data, is described and showcased within the European BeYond-COVID project. METHODS: A framework for approaching federated causal inference by re-using routinely collected observational data across different regions, based on principles of legal, organizational, semantic and technical interoperability, is proposed. The framework includes step-by-step guidance, from defining a research question, to establishing a causal model, identifying and specifying data requirements in a common data model, generating synthetic data, and developing an interoperable and reproducible analytical pipeline for distributed deployment. The conceptual and instrumental phase of the framework was demonstrated and an analytical pipeline implementing federated causal inference was prototyped using open-source software in preparation for the assessment of real-world effectiveness of SARS-CoV-2 primary vaccination in preventing infection in populations spanning different countries, integrating a data quality assessment, imputation of missing values, matching of exposed to unexposed individuals based on confounders identified in the causal model and a survival analysis within the matched population. RESULTS: The conceptual and instrumental phase of the proposed methodological framework was successfully demonstrated within the BY-COVID project. Different Findable, Accessible, Interoperable and Reusable (FAIR) research objects were produced, such as a study protocol, a data management plan, a common data model, a synthetic dataset and an interoperable analytical pipeline. CONCLUSIONS: The framework provides a systematic approach to address federated cross-national policy-relevant causal research questions based on sensitive population, health and care data in a privacy-preserving and interoperable way. The methodology and derived research objects can be re-used and contribute to pandemic preparedness.

Genetic Engineering of Donor Pig for the First Human Cardiac Xenotransplantation: Combatting Rejection, Coagulopathy, Inflammation, and Excessive Growth.

PURPOSE OF REVIEW: The first successful pig to human cardiac xenotransplantation in January 2022 represented a major step forward in the fields of heart failure, immunology, and applied genetic engineering, using a 10-gene edited (GE) pig. This review summarizes the evolution of preclinical modelling data which informed the use of each of the 10 genes modified in the 10-GE pig: GGTA1, Β4GalNT2, CMAH, CD46, CD55, TBM, EPCR, CD47, HO-1, and growth hormone receptor. RECENT FINDINGS: The translation of the 10-GE pig from preclinical modelling to clinical compassionate xenotransplant use was the culmination of decades of research combating rejection, coagulopathy, inflammation, and excessive xenograft growth. Understanding these 10 genes with a view to their combinatorial effects will be useful in anticipated xenotransplant clinical trials.

Comprehensive Evaluation of the Impact of Sociodemographic Inequalities on Adverse Outcomes and Excess Mortality During the Coronavirus Disease 2019 (COVID-19) Pandemic in Mexico City.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic in Mexico City has been sharp, as several social inequalities at all levels coexist. Here we conducted an in-depth evaluation of the impact of individual and municipal-level social inequalities on the COVID-19 pandemic in Mexico City. METHODS: We analyzed suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases, from the Mexico City Epidemiological Surveillance System from 24 February 2020 to 31 March 2021. COVID-19 outcomes included rates of hospitalization, severe COVID-19, invasive mechanical ventilation, and mortality. We evaluated socioeconomic occupation as an individual risk, and social lag, which captures municipal-level social vulnerability, and urban population density as proxies of structural risk factors. Impact of reductions in vehicular mobility on COVID-19 rates and the influence of risk factors were also assessed. Finally, we assessed discrepancies in COVID-19 and non-COVID-19 excess mortality using death certificates from the general civil registry. RESULTS: We detected vulnerable groups who belonged to economically unfavored sectors and experienced increased risk of COVID-19 outcomes. Cases living in marginalized municipalities with high population density experienced greater risk for COVID-19 outcomes. Additionally, policies to reduce vehicular mobility had differential impacts modified by social lag and urban population density. Finally, we report an under-registry of COVID-19 deaths along with an excess mortality closely related to marginalized and densely populated communities in an ambulatory setting. This could be attributable to a negative impact of modified hospital admission criteria during the pandemic. CONCLUSIONS: Socioeconomic occupation and municipality-wide factors played a significant role in shaping the course of the COVID-19 pandemic in Mexico City.

Awake prone positioning and oxygen therapy in patients with COVID-19: the APRONOX study.

BACKGROUND: The awake prone positioning strategy for patients with acute respiratory distress syndrome is a safe, simple and cost-effective technique used to improve hypoxaemia. We aimed to evaluate intubation and mortality risk in patients with coronavirus disease 2019 (COVID-19) who underwent awake prone positioning during hospitalisation. METHODS: In this retrospective, multicentre observational study conducted between 1 May 2020 and 12 June 2020 in 27 hospitals in Mexico and Ecuador, nonintubated patients with COVID-19 managed with awake prone or awake supine positioning were included to evaluate intubation and mortality risk through logistic regression models; multivariable and centre adjustment, propensity score analyses, and E-values were calculated to limit confounding. RESULTS: 827 nonintubated patients with COVID-19 in the awake prone (n=505) and awake supine (n=322) groups were included for analysis. Fewer patients in the awake prone group required endotracheal intubation (23.6% versus 40.4%) or died (19.8% versus 37.3%). Awake prone positioning was a protective factor for intubation even after multivariable adjustment (OR 0.35, 95% CI 0.24-0.52; p<0.0001, E=2.12), which prevailed after propensity score analysis (OR 0.41, 95% CI 0.27-0.62; p<0.0001, E=1.86) and mortality (adjusted OR 0.38, 95% CI 0.26-0.55; p<0.0001, E=2.03). The main variables associated with intubation among awake prone patients were increasing age, lower baseline peripheral arterial oxygen saturation/inspiratory oxygen fraction ratio (P aO2 /F IO2 ) and management with a nonrebreather mask. CONCLUSIONS: Awake prone positioning in hospitalised nonintubated patients with COVID-19 is associated with a lower risk of intubation and mortality.

COnVIDa: COVID-19 multidisciplinary data collection and dashboard.

Since the first reported case in Wuhan in late 2019, COVID-19 has rapidly spread worldwide, dramatically impacting the lives of millions of citizens. To deal with the severe crisis resulting from the pandemic, worldwide institutions have been forced to make decisions that profoundly affect the socio-economic realm. In this sense, researchers from diverse knowledge areas are investigating the behavior of the disease in a rush against time. In both cases, the lack of reliable data has been an obstacle to carry out such tasks with accuracy. To tackle this challenge, COnVIDa (https://convida.inf.um.es) has been designed and developed as a user-friendly tool that easily gathers rigorous multidisciplinary data related to the COVID-19 pandemic from different data sources. In particular, the pandemic expansion is analyzed with variables of health nature, but also social ones, mobility, etc. Besides, COnVIDa permits to smoothly join such data, compare and download them for further analysis. Due to the open-science nature of the project, COnVIDa is easily extensible to any other region of the planet. In this way, COnVIDa becomes a data facilitator for decision-making processes, as well as a catalyst for new scientific researches related to this pandemic.

Exploring the rationale for thermotherapy in COVID-19.

Increased transmissibility of the pandemic severe acute respiratory coronavirus 2 (SARS-CoV-2) has been noted to occur at lower ambient temperatures. This is seemingly related to a better replication of most respiratory viruses, including SARS-CoV-2, at lower-than-core body temperatures (i.e., 33 °C vs 37 °C). Also, intrinsic characteristics of SARS-CoV-2 make it a heat-susceptible pathogen. Thermotherapy has successfully been used to combat viral infections in plants which could otherwise result in great economic losses; 90% of viruses causing infections in plants are positive-sense single-stranded ribonucleic acid (+ssRNA) viruses, a characteristic shared by SARS-CoV-2. Thus, it is possible to envision the use of heat-based interventions (thermotherapy or mild-temperature hyperthermia) in patients with COVID-19 for which moderate cycles (every 8-12 h) of mild-temperature hyperthermia (1-2 h) have been proposed. However, there are potential safety and mechanistic concerns which could limit the use of thermotherapy only to patients with mild-to-moderate COVID-19 to prevent disease progression rather than to treat patients who have already progressed to severe-to-critical COVID-19. Here, we review the characteristics of SARS-CoV-2 which make it a heat-susceptible virus, potential host mechanisms which could be enhanced at higher temperatures to aid viral clearance, and how thermotherapy could be investigated as a modality of treatment in patients with COVID-19 while taking into consideration potential risks.

Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor Responses.

Immune checkpoint blockade has shown anti-cancer efficacy, but requires systemic administration of monoclonal antibodies (mAbs), often leading to adverse effects. To avoid toxicity, mAbs could be expressed locally in tumors. We developed adeno-associated virus (AAV) and Semliki Forest virus (SFV) vectors expressing anti-programmed death ligand 1 (aPDL1) mAb. When injected intratumorally in MC38 tumors, both viral vectors led to similar local mAb expression at 24 h, diminishing quickly in SFV-aPDL1-treated tumors. However, SFV-aPDL1 induced >40% complete regressions and was superior to AAV-aPDL1, as well as to aPDL1 mAb given systemically or locally. SFV-aPDL1 induced abscopal effects and was also efficacious against B16-ovalbumin (OVA). The higher SFV-aPDL1 antitumor activity could be related to local upregulation of interferon-stimulated genes because of SFV RNA replication. This was confirmed by combining local SFV-LacZ administration and systemic aPDL1 mAb, which provided higher antitumor effects than each separated agent. SFV-aPDL1 promoted tumor-specific CD8 T cells infiltration in both tumor models. In MC38, SFV-aPDL1 upregulated co-stimulatory markers (CD137/OX40) in tumor CD8 T cells, and its combination with anti-CD137 mAb showed more pronounced antitumor effects than each single agent. These results indicate that local transient expression of immunomodulatory mAbs using non-propagative RNA vectors inducing type I interferon (IFN-I) responses represents a potent and safe approach for cancer treatment.

Polymorphic variation of hypoxia inducible factor-1 A (HIF1A) gene might contribute to the development of knee osteoarthritis: a pilot study.

BACKGROUND: Osteoarthritis (OA) is a multifactorial degenerative condition of the whole joint with a complex pathogenesis whose development and progression is significantly mediated by interactions between the joint cartilage and articular tissues, particularly, proinflammatory mediators and oxidative stress, which results in cartilage deterioration and subchondral bone destruction. HIF-1 alpha regulates oxygen homeostasis in hypoxic tissues such as joint cartilage; efficiency of transcriptional activity of the HIF1A gene is strongly influenced by the presence of polymorphic variants. Given the loss of articular cartilage and with intention to restore damaged tissue, WISP-1 participates in the development of subchondral bone; further, its expression is highly increased in chondrocytes of OA patients. The aim of this study was to evaluate gene frequencies of HIF1A and WISP1 polymorphisms in Mexican patients suffering from knee OA. METHODS: We determined HIF1A rs11549465 (P582S), rs11549467 (A588T), and rs2057482 (C191T), and WISP1 rs2929970 (A2364G) polymorphisms in 70 Mexican patients with knee OA and compare them to those present in 66 ethnically matched healthy controls. Genotyping for these polymorphisms was performed by Real-Time PCR using TaqMan probes. RESULTS: Gene frequencies exhibited a significant increase of the CC genotype of rs11549465 polymorphism in knee OA patients as compared with those present in controls (P = 0.003 OR = 5.7, 95% CI = 1.7-21.6); CT genotype and T allele showed decreased frequency in the knee OA group vs. the controls (P = 0.003 OR = 0.2, CI = 0.05-0.6; and P = 0.004 OR = 0.2, CI = 0.05-0.65, respectively). Allele frequencies of the other polymorphic variants were similar in both patients and controls. CONCLUSIONS: These results suggest that the presence of the rs11549465 SNP (HIF1A) plays a role protective in the loss of articular cartilage in our population, and offers the possibility to further study the molecular mechanisms within cartilage and subchondral bone.

Approach to interstitial lung disease associated with systemic sclerosis-A survey to pulmonologists and rheumatologists in Colombia.

INTRODUCTION: Interstitial lung disease is a leading cause of mortality in patients with systemic sclerosis. Currently, there is a lack of consensus regarding screening, rescreening, diagnosis, and follow-up practices in interstitial lung disease associated with systemic sclerosis (SSc-ILD) in Colombia. METHODS: A structured survey focused on clinical practices in patients with SSc-ILD was conducted. Members of the Asociación Colombiana de Neumología y Cirugía de Tórax (Asoneumocito) and the Asociación Colombiana de Reumatología (Asoreuma) were invited to participate from March 2023 to May 2023. RESULTS: We surveyed 51 pulmonologists and 44 rheumatologists. Overall, 51.6% reported having access to multidisciplinary team discussion in ILD. Among the 95 participants, 78.9% would routinely perform a high-resolution computed tomography scan of the chest once a diagnosis of systemic sclerosis was established. This practice is more frequent among rheumatologists (84.1%) than among pulmonologists (74.5%). Approximately half of the participants would rescreen patients annually with computed tomography scan (56.8%) if baseline images were negative. Spirometry (81.1%), diffusing capacity of the lung for carbon monoxide (80.0%), and 6-min walk test (55.8%) were the most frequently performed tests upon diagnosis of systemic sclerosis. During follow-up, participants would consider repeating pulmonary function tests mostly every 6 months. CONCLUSIONS: Screening of SSc-ILD is high among pulmonologists and rheumatologists. Decision-making on diagnosis and follow-up is similar between specialties, but there are variations in their frequency and indications. Further research is needed to evaluate how to adapt recommendations for assessing SSc-ILD in different settings.

Statistical Considerations for the Design and Analysis of Pragmatic Trials in Aging Research.

Pragmatic trials aim to assess intervention efficacy in usual patient care settings, contrasting with explanatory trials conducted under controlled conditions. In aging research, pragmatic trials are important designs for obtaining real-world evidence in elderly populations, which are often underrepresented in trials. In this review, we discuss statistical considerations from a frequentist approach for the design and analysis of pragmatic trials. When choosing the dependent variable, it is essential to use an outcome that is highly relevant to usual medical care while also providing sufficient statistical power. Besides traditionally used binary outcomes, ordinal outcomes can provide pragmatic answers with gains in statistical power. Cluster randomization requires careful consideration of sample size calculation and analysis methods, especially regarding missing data and outcome variables. Mixed effects models and generalized estimating equations (GEEs) are recommended for analysis to account for center effects, with tools available for sample size estimation. Multi-arm studies pose challenges in sample size calculation, requiring adjustment for design effects and consideration of multiple comparison correction methods. Secondary analyses are common but require caution due to the risk of reduced statistical power and false-discovery rates. Safety data collection methods should balance pragmatism and data quality. Overall, understanding statistical considerations is crucial for designing rigorous pragmatic trials that evaluate interventions in elderly populations under real-world conditions. In conclusion, this review focuses on various statistical topics of interest to those designing a pragmatic clinical trial, with consideration of aspects of relevance in the aging research field.

A comprehensive review of hip arthroscopy techniques and outcomes.

Transforming the orthopedic landscape, hip arthroscopy pioneers a minimally invasive surgical approach for diagnosing and addressing hip pathologies. With its origins dating back to Burman's 1931 cadaveric study, this groundbreaking technique gained clinical relevance in 1939 through Takagi's report. However, the 1980s marked the actual emergence of hip arthroscopy for treating a wide range of hip disorders. Now, a staple in modern orthopedics, hip arthroscopy empowers patients with previously undiagnosed and untreated hip conditions, enabling them to obtain relief and reclaim their lives. By employing a compact camera and specialized tools, surgeons expertly navigate the hip joint, performing procedures from excising loose bodies and mending labral tears to addressing femoroacetabular impingement and tackling other intricate issues. This innovative approach has dramatically elevated patients' quality of life, allowing them to embrace targeted treatments and resume daily activities without resorting to lifestyle alterations.

Role of Renal Venous Oxygen Pressure for Renal Function Monitoring After Related Living-Donor Kidney Transplantation: Cohort Study.

BACKGROUND: Monitoring of renal function after kidney transplantation (KT) is performed by measuring serum creatinine (SCr), urine volumes (UV), and glomerular filtration rate (GFR). Other methods based on oxygen metabolism, such as the renal venous oxygen pressure (PrvO2), may be useful. The aim of this study was to explore the correlation between PrvO2 and SCr, UV, and GFR 5 days after KT (SCr5, UV5, and GFR5, respectively). METHODS: We conducted a prospective cohort study in adults scheduled for living donor KT. A venous blood sample was taken from the renal vein after declamping the renal artery, and blood gas determinations were made. Correlation analyses between PrvO2 and SCr5, UV5, and GFR5 were done by calculating Spearman's correlation coefficient with generalized linear models (GLM). A Spearman's correlation analysis was performed between the percentage decrease in SCr (%ΔSCr) and PrvO2. A GLM was also performed to determine the association of PrvO2 with slow graft function (SGF). RESULTS: The study included 42 patients, of whom 67% were men. The median age was 31 years (IQR, 27-43.5). PrvO2 was negatively correlated with SCr5 (ρ = -0.53, P = .003), and positively correlated with GFR5 (ρ = 0.49, P = .001) and %ΔSCr (ρ = 0.47, P = .002). A higher PrvO2 was associated with an increase in GFR in univariable (ß = 1.24, 95% CI, 0.56-1.93, P = .001) and multivariable (ß = 1.24, 95% CI, 0.53-1.94, P = .001) analyses. No association was found between PrvO2 and SGF. CONCLUSION: PrvO2 could be used to monitor renal function in the first 5 days after related living-donor KT, given its good correlation with SCr and GFR.

Fine structure processing improves telephone speech perception in cochlear implant users.

The objective of this study was to compare telephone speech perception and subjective preferences in cochlear implant users with two different speech-processing strategies: high-definition continuous interleaved sampling (HDCIS) and fine structure processing (FSP). A randomized double-blind study was designed for intra-individual comparison of HDCIS and FSP. Twenty-five post-lingually deafened patients with either the PulsarCI(100) or SonataTI(100) and Opus2 acoustic processor were tested consecutively with both coding strategies, assigned in a random order. Disyllabic word speech perception was tested 6 weeks after each fitting under the following conditions: landline use with (LWN) and without (LWoN) background noise, mobile use with (MWN), and without (MWoN) background noise and mobile use with a Bluetooth magnetic field transmitter necklace (MB). Changes in health-related quality of life (QoL) were assessed using the Glasgow Benefit Inventory (GBI) and Faber's questionnaire. Personal preferences between strategies were surveyed upon completion of the study. All subjects included in this study performed better with FSP in the landline tests. There was an improvement of 11.5 % in LWN use (p = 0.014; CI 95 % = 3-20 %) and 10 % in LWoN use (p = 0.001; CI 95 % = 5-15 %). MWoN showed an improvement of 6.3 % with FSP (p = 0.03; CI 95 % = 0-13 %). MB tests showed an improvement of 11 % with FSP (p < 0.05; CI 95 % = 1.5-22 %). Quality of life was significantly better using FSP. Eighty-four percent of participants preferred FSP. The FSP speech coding strategy improved the speech recognition of cochlear implant users when using the telephone compared to HDCIS. Cochlear implantation with FSP coding improved QoL.