Acute or chronic irreversible respiratory failure may occur in patients undergoing pneumonectomy. Aim of this study was to determine transcriptome expression changes after experimental pneumonectomy ...in swine model. Experimental left pneumonectomy was performed in five pigs under general anaesthesia. Both the resected and the remaining lung, after 60 post-operative completely uneventful days, underwent genome-wide bulk RNA-Sequencing (RNA-Seq).
Histological analysis showed dilation of air spaces and rupture of interalveolar septa. In addition, mild inflammation, no fibrosis, radial stretch of the bronchus, strong enlargement of airspaces and thinning of the blood supply were observed. Bioinformatic analyses of bulk RNA-Seq data identified 553 Differentially Expressed Genes (DEGs) at adjusted P-value below 0.001, between pre- and post-pneumonectomy. The top 10 up-regulated DEGs were Edn1, Areg, Havcr2, Gadd45g, Depp1, Cldn4, Atf3, Myc, Gadd45b, Socs3; the top 10 down-regulated DEGs were Obscn, Cdkn2b, ENSSSCG00000015738, Prrt2, Amer1, Flrt3, Efnb2, Tox3, Znf793, Znf365. Leveraging digital cytometry tools, no difference in cellular abundance was found between the two experimental groups, while the analysis of cell type-specific gene expression patterns highlighted a striking predominance of macrophage-specific genes among the DEGs. DAVID-based gene ontology analysis showed a significant enrichment of "Extrinsic apoptotic signaling pathway" (FDR q = 7.60 × 10
) and "Response to insulin" (FDR q = 7.60 × 10
) genes, along with an enrichment of genes involved as "Negative regulators of DDX58/IFIH1 signaling" (FDR q = 7.50 × 10
) found by querying the REACTOME pathway database. Gene network analyses indicated a general dysregulation of gene inter-connections.
This translational genomics study highlighted the existence both of individual genes, mostly dysregulated in certain cellular populations (e.g., macrophages), and gene-networks involved in pulmonary reaction after left pneumonectomy. Their involvement in lung homeostasis is largely supported by previous studies, carried out both in humans and in other animal models (under homeostatic or disease-related conditions), that adopted candidate-gene approaches. Overall, the present findings represent a preliminary assessment for future, more focused, studies on compensatory lung adaptation, pulmonary regeneration and functional reload.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is an acute need for research to acquire high-quality information on the use of medicines in pregnancy, both in terms of appropriateness and safety. For this purpose, the Italian Medicines ...Agency established a Network for Monitoring Medication use in pregnancy (MoM-Net) through the conduction of population-based studies using administrative data available at regional level. This paper aimed to describe the experiences and challenges within the network. MoM-Net currently involves eight regions and several experts from public and academic institutions. The first study conducted aimed to identify drug use before, during and after pregnancy investigating specific therapeutic categories, analysing regional variability and monitoring drug use in specific subpopulations (i.e. foreign women/multiple pregnancies). Aggregated demographic, clinical, and prescription data were analysed using a distributed network approach based on common data model. The study population included all women delivering during 2016–2018 in the participating regions (
n
= 449,012), and corresponding to 59% of deliveries in Italy. Seventy-three per cent of the cohort had at least one drug prescription during pregnancy, compared to 57% before and 59% after pregnancy. In general, a good adherence to guidelines for pregnant women was found although some drug categories at risk of inappropriateness, such as progestins and antibiotics, were prescribed. A strong variability in the use of drugs among regions and in specific subpopulations was observed. The MoM-Net represents a valuable surveillance system on the use of medicines in pregnancy, available to monitor drug categories at high risk of inappropriateness and to investigate health needs in specific regions or subpopulations.
Purpose
Diffuse large B‐cell lymphoma (DLBCL) is an aggressive lymphoma often refractory to currently available treatments (immuno‐chemotherapy/autologous‐stem‐cell‐transplantation‐ASCT). Recently, ...new cell therapies have been approved for patients failing two conventional treatments, CAR‐T (Chimeric‐Antigen‐Receptor‐T‐cell), committing payers in planning and implementing their use. We aim to define, using Real World Data (RWD), a reproducible procedure that allows identification of CAR‐T target population for DLBCL.
Methods
Through the linking of electronic healthcare datasets (EHD), we identified patients with non‐Hodgkin's Lymphoma (NHL), resident in Lazio region (2010–2015), aged ≥20 years. DLBCL patients were followed using pathological anatomy (PA) reports, up to 3 years. To be defined as relapsed after two treatment lines, patients must have had new chemotherapy and/or NHL hospitalization after ASCT or at the end of the second chemotherapy. The incident rate of second relapse (R2‐rate) was extended to the population without PA reports.
Result
NHL incident patients were 7384, 68% presented a PA report and, 29% of these had DLBCL codes. Patients who relapsed after two treatment lines were 47 (39%) in the subgroup of patients who received ASCT and 138 (41%) in that with second chemotherapy treatment. Patients in the two subgroups were very different in terms of age and comorbidity. The annual incident number of DLBCL was estimated to be 329 which multiplied by R2‐rate (13.7%) gives 45 patients per year eligible for CAR‐T.
Discussion
This study shows how RWD allows the identification of a target population with new advanced therapies. This approach is rigorous, transparent and verifiable over time.
Purpose
To analyse the drug use pattern in women with psoriasis before, during and after pregnancy.
Methods
All children born (2009‐2016) in a central Italian region (Lazio) to mothers with a ...diagnosis of psoriasis were identified. Drug use patterns (biologicals, systemic, and topical), and discontinuation and switching of drug therapies before, during, and after pregnancy were studied. Findings were compared with data from a population exposed to similar drug therapies (eg, antirheumatic drugs).
Results
Among 3499 deliveries by women affected by psoriasis, 1876 (53.6%) were diagnosed with this condition before the Last Menstrual Period (LMP). Of these, 525 (27.9%) had at least one drug prescription for psoriasis therapy during 6 months before LMP. For each class of drugs considered, there was a general decrease in its use during pregnancy. Considering the two trimesters preceding LMP and the three trimesters of pregnancy, the following percentages of prescriptions were observed: from 10.5% to 0% for biologicals, 7.2% to 2.5% for the conventional systemic drugs, and 51.1% to 9.4% for the topical treatments. After delivery, previous treatments were resumed. Similar results were observed for rheumatoid arthritis, a chronic condition.
Conclusions
Majority of drugs come with warnings regarding potential embryo‐fetotoxicity, which might play a role in the decision to continue treatments during pregnancy. According to our study pregnancy appears to have a significant influence on drug prescriptions of different pharmacological treatments for psoriasis.
Importance: Since the beginning of the Coronavirus Disease-19 (COVID-19) pandemic, Severe Acute Respiratory Syndrome-CoV-2 (SARS-CoV-2) infection has been a serious challenge for immune-compromised ...patients with immune-mediated inflammatory diseases (IMIDs). Objective: Our aim was to investigate the impact of COVID-19 in terms of risks of infection, hospitalization and mortality in a cohort of patients with rheumatoid arthritis (RA), psoriasis (PSO) or inflammatory bowel disease (IBD). Furthermore, we studied the impact of SARS-CoV-2 infection on the prescribed drug regimen in these patients. Methods: Through the record linkage between health information systems, a cohort of patients, ≥18 years old, assisted in the Lazio region and who had suffered from immune-mediated inflammatory diseases (RA, PSO, IBD) between 2007 and 2019, was identified. The risk of infection, hospitalization or mortality for COVID-19, was assessed by logistic regression models, and reported in an Odds Ratio (ORs; CI 95%), adjusting for sex, age and the Charlson Comorbidity Index. We also estimated these risks separately by IMID and in the subgroup of prevalent biologic drug users. We investigated deferral of biological treatments in the study population by comparing the prevalence of weekly use of biologicals (2019–2020) before and during the pandemic periods. Findings: Within the 65,230 patients with IMIDs, the cumulative incidence for COVID-19 was 303/10,000 ab. In this cohort of patients, we observed a significantly higher risk of SARS-CoV-2 infection than the general population: OR = 1.17 (95% CI 1.12–1.22). The risk was higher even considering separately each disease and in the subgroup of prevalent biologic drug users. This last subgroup of patients showed a higher risk of death related to COVID-19 (OR 1.89; 95% CI 1.04–3.33) than the general population. However, no differences in terms of risks of hospitalization or death related to COVID-19 were recorded in patients with the IMIDs. Comparing the 2019–2020 prevalence of weekly biological drug treatments in prevalent biologic drug users, we found a decrease (−19.6%) during the lockdown, probably due to pandemic restrictions. Conclusions and Relevance: Patients with IMIDs seem to have a higher risk of SARS-CoV2 infection. However, other than for patients with prevalent biologic drug treatment, no significant differences in terms of hospitalization and mortality were reported compared to the general populations; further investigation is warranted on account of unmeasured confounding. In addition, during the lockdown period, the COVID-19 emergency highlighted a lower use of biologic drugs; this phenomenon requires strict pharmacological monitoring as it could be a proxy of forthcoming long-term clinical progression.
The goal of post-transplant immunosuppressive drug therapy is to prevent organ rejection while minimizing drug toxicities. In clinical practice, a multidrug approach is commonly used and involves ...drugs with different mechanisms of action, including calcineurin inhibitors (CNI) (tacrolimus or cyclosporine), antimetabolite (antimet) (mycophenolate or azathioprine), inhibitors of mechanistic target of rapamycin (mTOR) (sirolimus or everolimus), and/or steroids. Although evidence based on several randomized clinical trials is available, the optimal immunosuppressive therapy has not been established and may vary among organ transplant settings. To improve the knowledge on this topic, a multiregional research network to Compare the Effectiveness and Safety of Immunosuppressive drugs in Transplant patients (CESIT) has been created with the financial support of the Italian Medicines Agency. In this article, we describe the development of this network, the framework that was designed to perform observational studies, and we also give an overview of the preliminary results that we have obtained. A multi-database transplant cohort was enrolled using a common data model based on healthcare claims data of four Italian regions (Lombardy, Veneto, Lazio, and Sardinia). Analytical datasets were created using an open-source tool for distributed analysis. To link the National Transplant Information System to the regional transplant cohorts, a semi-deterministic record linkage procedure was performed. Overall, 6,914 transplant patients from 2009–19 were identified: 4,029 (58.3%) for kidney, 2,219 (32.1%) for liver, 434 (6.3%) for heart, and 215 (3.1%) for lung. As expected, demographic and clinical characteristics showed considerable variability among organ settings. Although the triple therapy in terms of CNI + antimet/mTOR + steroids was widely dispensed for all settings (63.7% for kidney, 33.5% for liver, 53.3% for heart, and 63.7% for lung), differences in the active agents involved were detected. The CESIT network represents a great opportunity to study several aspects related to the use, safety, and effectiveness of post-transplant maintenance immunosuppressive therapy in real practice.
Abstract
Background
Very scanty evidence is available on factors influencing the choice of immunosuppressive drug therapy after kidney transplantation.
Methods
An Italian multiregional real-world ...study was conducted integrating national transplant information system and claims data. All patients undergoing kidney transplantation for the first time during 2009–2019 (incident patients) were considered. Multilevel logistic models were used to estimate Odds Ratio (OR) and corresponding 95% Confidence intervals. Factors with statistically significance were identified as characteristics associated with treatment regimens: cyclosporin-CsA vs tacrolimus-Tac and, within the latter group, mTOR inhibitors vs mycophenolate-MMF.
Results
We identified 3,622 kidney patients undergoing transplantation in 17 hospitals located in 4 Italian regions, 78.3% was treated with TAC-based therapy, of which 78% and 22% in combination with MMF and mTOR, respectively. For both comparison groups, the choice of immunosuppressive regimens was mostly guided by standard hospital practices. Only few recipient and donor characteristics were found associated with specific regimen (donor/receipt age, immunological risk and diabetes).
Conclusions
The choice of post-renal transplant immunosuppressive therapy seems to be mostly driven by standard Centre practices, while only partially based on patient’s characteristics and recognized international guidelines.
Background
In immunosuppression after transplantation, several multi-drug approaches are used, involving calcineurin inhibitors (
CNI: tacrolimus-TAC or cyclosporine-CsA
), antimetabolites (
antiMs
...), mammalian target of rapamycin inhibitors (
mTORis
), and corticosteroids. However, data on immunosuppressive therapy by organ and its space–time variability are lacking.
Methods
An Italian multicentre observational cohort study was conducted using health information systems. Patients with incident transplant during 2009–2019 and resident in four regions (Veneto, Lombardy, Lazio, and Sardinia) were enrolled. The post-transplant immunosuppressive regimen was evaluated by organ, region, and year.
Results
The most dispensed regimen was triple-drug therapy for the kidneys tacrolimus (TAC) + antiM + corticosteroids = 41.5% and heart cyclosporin + antiM + corticosteroids = 36.6% and double-drug therapy for liver recipients (TAC + corticosteroids = 35.4%). Several differences between regions and years emerged with regard to agents and the number of drugs used.
Conclusion
A high heterogeneity in immunosuppressive therapy post-transplant was found. Further studies are needed in order to investigate the reasons for this variability and to evaluate the risk–benefit profile of treatment schemes adopted in clinical practice.
Metabolic Endotoxemia Initiates Obesity and Insulin Resistance
Patrice D. Cani 1 2 ,
Jacques Amar 3 ,
Miguel Angel Iglesias 1 ,
Marjorie Poggi 4 ,
Claude Knauf 1 ,
Delphine Bastelica 4 ,
Audrey M. ...Neyrinck 2 ,
Francesca Fava 5 ,
Kieran M. Tuohy 5 ,
Chantal Chabo 1 ,
Aurélie Waget 1 ,
Evelyne Delmée 2 ,
Béatrice Cousin 6 ,
Thierry Sulpice 7 ,
Bernard Chamontin 3 ,
Jean Ferrières 3 ,
Jean-François Tanti 8 ,
Glenn R. Gibson 5 ,
Louis Casteilla 6 ,
Nathalie M. Delzenne 2 ,
Marie Christine Alessi 4 and
Rémy Burcelin 1
1 Institute of Molecular Medicine, I2MR Toulouse, France
2 Unité Pharmacokinetics, Metabolism, Nutrition, and Toxicology-73/69, Université catholique de Louvain, Brussels, Belgium
3 Institut National de la Santé et de la Recherche Médicale (INSERM) 558, Toulouse, France
4 INSERM U 626, Marseille, France
5 Food Microbial Sciences Unit, Department of Food Biosciences, University of Reading, Reading, U.K
6 Unité Mixte de Recherche 5241, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France
7 Physiogenex S.A.S., Labège Innopole, France
8 INSERM U 568, Nice, France
Address correspondence and reprint requests to Rémy Burcelin, I2MR U858, IFR 31, Hôpital Rangueil, BP 84225, Toulouse 31432
Cedex 4, France. E-mail: burcelin{at}toulouse.inserm.fr
Abstract
Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking
an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide
(LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively,
on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times,
a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing
microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion
of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar
extent as in high-fat–fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride
content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14
mutant mice resisted most of the LPS and high-fat diet–induced features of metabolic diseases. This new finding demonstrates
that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that
the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration
could be a potent strategy for the control of metabolic diseases.
IKK, inhibitor of κB kinase
IL, interleukin
LPS, lipopolysaccharide
PAI, plasminogen activator inhibitor
TLR4, toll-like receptor 4
TNF, tumor necrosis factor
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 24 April 2007. DOI: 10.2337/db06-1491.
P.D.C., J.A., and M.A.I. contributed equally to this article.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted April 13, 2007.
Received October 24, 2006.
DIABETES
Implant-related osteomyelitis is a severe and deep infection of bone that arises and develops all around an implant. Staphylococcus aureus is the first cause of osteomyelitis, whether implant-related ...or not. Bone is an optimal substratum for S. aureus, since this bacterium expresses various adhesins by which can adhere to bone proteins and to the biomaterial surfaces coated with the proteins of the host extracellular matrix. S. aureus is able not only to colonize bone tissues, but also to invade and disrupt them by entering bone cells and inducing cell death and osteolysis. Here we illustrate the pathogenetic mechanisms that can explain how the osteomyelitis sets in and develops around an implant.
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