Lipid and protein ingested before carbohydrate reduce postprandial hyperglycemia. We tested feasibility, safety and clinical efficacy of manipulating the sequence of nutrient ingestion in patients ...with type 2 diabetes (T2D). After a 4-week run-in, 17 T2D patients were randomized to either a control diet (CD) or to an experimental diet (ED) allowing the consumption of high-carbohydrate foods only after high-protein and high-fat foods at each main meal (lunch+dinner). Both diets were accurately followed and neutral on arterial blood pressure, plasma lipids and indices of hepatic and kidney function. After 8 weeks, in spite of a similar reduction of body weight (ED -1.9 95% confidence interval (-3.4/-0.4)kg, P<0.03; CD -2.0 (-3.6/-0.5)kg, P<0.02) and waist circumference (ED -2.9 (-4.3/-1.5)cm, P<0.002; CD -3.3 (-5.9/-0.7)cm, P<0.02), the ED only was associated with significant reductions of HbA1c (-0.3 (-0.50/-0.02)%, P<0.04), fasting plasma glucose (-1.0 (-1.8/-0.3)mmol l(-1), P<0.01), postprandial glucose excursions (lunch -1.8 (-3.2/-0.4)mmol l(-1), P<0.01; dinner: -1.0 (-1.9/-0.1)mmol l(-1), P<0.04) and other indices of glucose variability (s.d.: -0.5 (-0.7/-0.2)mmol l(-1), P<0.02; Coefficient of variation: -6.6 (-10.4/-2.7)%, P<0.02). When compared with the CD, the ED was associated with lower post-lunch glucose excursions (P<0.02) and lower glucose coefficients of variation (P<0.05). Manipulating the sequence of nutrient ingestion might reveal a rapid, feasible, economic and safe strategy for optimizing glucose control in T2D.
A growing number of international initiatives (e.g. EU‐ADR, Sentinel, OMOP, PROTECT and VAESCO) are based on the combined use of multiple healthcare databases for the conduct of active surveillance ...studies in the area of drug and vaccine safety. The motivation behind combining multiple healthcare databases is the earlier detection and validation, and hence earlier management, of potential safety issues. Overall, the combination of multiple healthcare databases increases statistical sample size and heterogeneity of exposure for postmarketing drug and vaccine safety surveillance, despite posing several technical challenges. Healthcare databases generally differ by underlying healthcare systems, type of information collected, drug/vaccine and medical event coding systems and language. Therefore, harmonization of medical data extraction through homogeneous coding algorithms across highly different databases is necessary. Although no standard procedure is currently available to achieve this, several approaches have been developed in recent projects. Another main challenge involves choosing the work models for data management and analyses whilst respecting country‐specific regulations in terms of data privacy and anonymization. Dedicated software (e.g. Jerboa) has been produced to deal with privacy issues by sharing only anonymized and aggregated data using a common data model. Finally, storage and safe access to the data from different databases requires the development of a proper remote research environment. The aim of this review is to provide a summary of the potential, disadvantages, methodological issues and possible solutions concerning the conduct of postmarketing multidatabase drug and vaccine safety studies, as demonstrated by several international initiatives.
IntroductionSafe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was ...granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections.Methods and analysisBRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed.Ethics and disseminationThe study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals.Trial registration numberEUPAS30280.
COVID-19 case fatality rate in hospitalized patients varies across countries and studies. Reliable estimates, specific for age, sex, and comorbidities, are needed to monitor the epidemic, to compare ...the outcome in different settings, and to correctly design trials for COVID-19 interventions. The aim of this study was to provide population-based survival curves of hospitalized COVID-19 patients.
A cohort study was conducted in three areas of Northern Italy, heavily affected by SARS-CoV-2 infection (Lombardy and Veneto Regions, and Reggio Emilia province), using a loco-regional COVID-19 surveillance system, linked to hospital discharge databases. We included all patients testing positive for SARS-CoV-2 RNA by RT-PCR on nasopharyngeal/throat swab samples who were hospitalized from 21 February to 21 April 2020. Kaplan-Meier survival estimates were calculated at 14 and 30 days for death in any setting, stratifying by age, sex, and the Charlson Index.
Overall, 42,926 hospitalized COVID-19 patients were identified. Patients' median age was 69 years (IQR: 57-79), 62.6% were males, and 6.0% had a Charlson Index ≥3. Survival curves showed that 22.0% (95% CI 21.6-22.4) of patients died within 14 days and 27.6% (95% CI 27.2-28.1) within 30 days from hospitalization. Survival was higher in younger patients and in females. The negative impact of comorbidities on survival was more pronounced in younger age groups.
The high fatality rate observed in the study (28% at 30 days) suggests that studies should focus on death as primary endpoint during a follow-up of at least one month.
Abstract
After its successful campaign of measurements beyond the Polar Arctic Circle, the PolarquEEEst experiment measured the cosmic charged particle rate at sea level in a latitude interval ...between 35
$$^{\circ }$$
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N and 82
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N. In this paper, these measurements are described and the corresponding results are discussed.
The eruption of the Hunga-Tonga volcano in the South Pacific Ocean on January 15, 2022, at about 4:15 UTC, generated a violent explosion, which created atmospheric pressure disturbances in the form ...of Rayleigh-Lamb waves detected all over the globe. Here we discuss the observation of the Hunga-Tonga shock-wave performed at the Ny-Ålesund Research Station on the Spitsbergen island, by the detectors of the PolarquEEEst experiment and their ancillary sensors. Online pressure data as well as the results of dedicated offline analysis are presented and discussed in details. Results include wave arrival times, wave amplitude measurements and wave velocity calculation. We observed five passages of the shock wave with a significance larger than 3 Formula: see text and an amplitude up to 1 hPa. The average propagation velocity resulted to be (308 ± 0.6) m/s. Possible effects of the atmospheric pressure variation associated with the shock-wave multiple passages on the cosmic-ray rate at ground level are also investigated. We did not find any significant evidence of this effect.
Purpose: This research aimed to develop and validate a META-algorithm combining individual immune-mediated inflammatory disease (IMID)-specific algorithms to identify the exact IMID indications for ...incident biological drug users from claims data within the context of the Italian VALORE project. Methods and Patients: All subjects with at least one dispensing of TNF-alpha inhibitors, anti-interleukin agents, and selective immunosuppressants approved for IMTDs were identified from claims databases of Latium region in Italy (observation period: 2010-2020). Validated coding algorithms for identifying individual IMIDs from claims databases were found from published literature and combined into a META-algorithm. Positive predictive value (PPV), sensitivity (Se), negative predictive value (NPV), specificity (Sp), and accuracy (Acc) were estimated for each indication against the electronic therapeutic plans (ETPs) of the Latium region as the reference standard. Lastly, the frequency of the indication of use across individual biologic drugs was compared with that reported in three other Italian regions (Lombardy, Apulia, and the Veneto region). Results: In total, 9755 incident biological drug users with a single IMID indication were identified. Using the newly developed META-algorithm, an indication of use was detected in 95% (n=9255) of the total cohort. The estimated Acc, Se, Sp, PPV, and NPV, against the reference standard were as follows: 0.96, 0.86, 0.97, 0.82, and 0.98 for Crohn's disease, 0.96, 0.80, 0.98, 0.85, and 0.97 for ulcerative colitis, 0.93, 0.76, 0.99, 0.95, and 0.92 for rheumatoid arthritis, 0.97, 0.75, 0.99, 0.85, and 0.98 for spondylarthritis, and 0.91, 0.92, 0.91, 0.88, and 0.94 for psoriatic arthritis/psoriasis, respectively. Additionally, no substantial difference was observed in the frequency of indication of use by active ingredient among Latium and the other three Italian regions included in the study. Conclusion: The newly developed META-algorithm demonstrated high validity estimates in the Italian claims data and was capable of discriminating with good performance among the most frequent IMID indications. Plain Language Summary: In the claims database, the lack of information on the indication of use represents a well-known limitation for the conduct of observational studies. This study was conducted to develop and validate a META-algorithm that accurately identifies the exact indication for the use of biological drugs in treating various immune-mediated inflammatory diseases. Using claims databases from the Latium region, we developed and validated a META-algorithm. The META-algorithm combines disease-specific algorithms for different immune-mediated inflammatory diseases (ie, Crohn's disease, ulcerative colitis, rheumatoid arthritis, spondyloarthritis, psoriasis, and psoriatic arthritis) and was tested against a reference standard (electronic therapeutic plans of the Lazio region). The META-algorithm reported high validity estimates and was able to distinguish with a good performance among the most frequent IMIDs as indications for use. Applying this META-algorithm may facilitate post-marketing surveillance of biological drugs such as TNF-alpha inhibitors, anti-interleukin, and selective immunosuppressants in specific therapeutic areas in an Italian setting. Keywords: immune-mediated inflammatory diseases, biological drugs, validation, claims data, META-algorithm, indication for use
Andrea Spini,1 Luca L'Abbate,2 Ylenia Ingrasciotta,1 Giorgia Pellegrini,1 Massimo Carollo,1 Valentina Ientile,2 Olivia Leoni,3 Martina Zanforlini,4 Domenica Ancona,5 Paolo Stella,5 Anna Cavazzana,6 ...Angela Scapin,6 Sara Lopes,7 Valeria Belleudi,7 Gianluca Trifirò1 1Department of Diagnostics and Public Health, University of Verona, Verona, Italy; 2Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy; 3Lombardy Regional Centre of Pharmacovigilance and Regional Epidemiologic Observatory, Milan, Italy; 4Azienda Regionale per l'Innovazione e gli Acquisti, S.p.A, Milan, Italy; 5Apulian Regional Health Department, Bari, Italy; 6Azienda Zero, Regione Veneto, Italy; 7Department of Epidemiology, Lazio Regional Health Service, Rome, ItalyCorrespondence: Gianluca Trifirò, Department of Diagnostics and Public Health, University of Verona, P. le L.A. Scuro 10, Verona, 37134, Italy, Tel +39 045 802 7679, Email gianluca.trifiro@univr.it
The experimental investigation of Heavy Ion reactions at Fermi energies requires an accurate measurement of observables, such as linear momentum and energy of the detected particles. In order to ...address this problem, dedicated and flexible correlator arrays are useful tools to be coupled with 4π detectors. One of these arrays is FARCOS, presently under construction at the INFN Sezione di Catania and Laboratori Nazionali del Sud (LNS).
High-cholesterol and high-fat diets alter biochemical composition and anti-oxidant properties of high-density lipoproteins (HDL) in animals. Whether this occurs in humans is unknown. Therefore, we ...examined the effect of a short-term elevation in dietary cholesterol and fat intake on HDL composition in healthy subjects.
In a randomized, crossover clinical trial, 14 healthy young volunteers followed a 14-day low-cholesterol/low-fat diet (LChF) and a 14-day isocaloric high-cholesterol/high-fat diet (HChF) in a random order. After each diet, we measured HDL concentrations of hydroxyeicosatetraenoic acids (HETE), hydroxyoctadecadienoic acids (HODE), and haptoglobin, as well as serum amyloid A (SAA) and paroxonase-1 activity (PON-1). HDL concentrations of 15-HETE (+254%, p = 0.002), 5-HETE (+116%, p = 0.004), 13-HODE (+102%, p = 0.049), and SAA levels (+75%, p = 0.007) were significantly higher after the HChF than after the LChF. Furthermore, haptoglobin was marginally increased (+32%, p = 0.091) while PON-1 activity was unaffected (−16%, p = 0.366) by the HChF.
In healthy subjects, a short-term elevation in dietary cholesterol and fat intake increases HDL lipid hydroperoxide content (15-HETE, 5-HETE, 13-HODE) and SAA levels, which are key features of dysfunctional HDL. This is the first study showing that a physiologic manipulation of dietary cholesterol and fat intake affects HDL lipidome and proteome in healthy subjects independently of weight changes.
NCT02549144.
•HDL lose their anti-atherosclerotic properties under pathological conditions.•High dietary cholesterol and fat increases HDL lipid hydroperoxide content and SSA levels.•These alterations in HDL lipidome and proteome are key features of dysfunctional HDL.•Changes in HDL biochemical composition induced by the diet may increase the risk of atherosclerotic disease.
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