Inhalation therapy in the next decade : Determinants of adherence to treatment in asthma and COPD

Peer reviewedPublisher PD

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Inner strut morphology is the key parameter in producing highly porous and mechanically stable poly(ε-caprolactone) scaffolds via selective laser sintering

Selective laser sintering (SLS) is an established method to produce dimensionally accurate scaffolds for tissue engineering (TE) applications, especially in bone. In this context, the FDA-approved, biodegradable polymer poly (ε-caprolactone) (PCL) has been suggested as a suitable scaffold material. However, PCL scaffold mechanical stability – an attribute of particular importance in the field of bone TE – was not considered as a primary target for SLS process parameters optimization so far. Here, we investigated the influence of SLS process parameters on the sintered scaffolds with the aim of producing highly porous (>70% porosity) PCL scaffolds with sub-mm geometrical features for bone TE. Specifically, we studied the influence of laser power, beam compensation and laser beam diameter on the dimensional accuracy and mechanical stiffness of the produced PCL scaffolds. We found that the ratio between the diameter of the molten cross-section within scaffold struts and the outer strut diameter (including partially sintered particles) depended on the SLS process parameters. By maximizing this ratio, the mechanical stability could be optimized. The comparison with in silico predictions of scaffold me-chanical stiffness revealed that the diameter of the molten cross-section within struts and not the strut diameter controlled the mechanical behaviour of the scaffold. These observations should be considered when evaluating the quality of the sintering process based on dimensional accuracy, especially for features <1 mm. Based on these findings, we suggested an approach to evaluate the sintering outcome and to define SLS process parameters that enable the production of highly porous scaffolds that are both dimensionally accurate and mechanically stable. Moreover, the cytocompatibility of PCL scaffolds was evaluated by elution tests with primary human mesen-chymal stromal cells. No evidence of cytotoxicity was found in any of the investigated scaffolds, confirming the suitability of SLS as production technique of PCL scaffolds for bone TE over a wide range of SLS process parameters

Diabetes and cancer: A critical appraisal of the pathogenetic and therapeutic links

Diabetes and cancer represent two common, multifactorial, chronic and potentially fatal diseases, not infrequently co-diagnosed in the same patient. Epidemiological data demonstrate significant increases of the cancer incidence in patients with obesity and diabetes, which is more evident for certain site-specific cancers. Although there is increasing evidence that strongly indicates an augmented risk of cancer in diabetic patients, several confounding factors complicate the ability to precisely assess the risk. Mainly in insulin-resistant states (such as in type 2 diabetes mellitus and in metabolic syndrome), direct associations between obesity-related hyperinsulinemia and increasing circulating insulin-like growth factor-1 (IGF-1) levels have been implicated as key factors in the mechanisms involved in carcinogenesis. Whilst anti-diabetic drugs can increase the cancer risk, anti-proliferative drugs may cause diabetes or aggravate pre-existing diabetes. Additionally, an increasing number of targeted anti-cancer therapies may interfere with the pathways shared by IGF-1 and insulin receptors, showing a adverse effect on glucose metabolism through various mechanisms. Although there is a requirement for large-scale randomized evidence, the present review summarizes the majority of the epidemiological association studies between diabetes and various types of cancer, discussing the pathophysiological mechanisms that may be involved in promoting carcinogenesis in diabetes and the potential impact of different anti-diabetic therapies on cancer risk

Neutrophil CD64 expression: a reliable diagnostic marker of infection in advanced cancer patients?

Infection and sepsis are major health problems in cancer patients. There is a need for the identification and validation of biomarkers to improve their early diagnosis and treatment. Emerging evidence showed that neutrophil CD64 is a highly sensitive and specific marker for systemic infection and sepsis in critically ill patients with various diseases but data on patients bearing solid tumors are still lacking. Using a dedicated flow cytometric assay we evaluated neutrophil CD64 expression in patients with advanced cancer without active infections to verify if it could be utilized as a reliable biomarker of early infections also in oncologic patients

3D Silicon Microstructures: A New Tool for Evaluating Biological Aggressiveness of Tumor Cells

In this work, silicon micromachined structures (SMS), consisting of arrays of 3- μ m-thick silicon walls separated by 50- μm-deep, 5- μ m-wide gaps, were applied to investigate the behavior of eight tumor cell lines, with different origins and biological aggressiveness, in a three-dimensional (3D) microenvironment. Several cell culture experiments were performed on 3D-SMS and cells grown on silicon were stained for fluorescence microscopy analyses. Most of the tumor cell lines recognized in the literature as highly aggressive (OVCAR-5, A375, MDA-MB-231, and RPMI-7951) exhibited a great ability to enter and colonize the narrow deep gaps of the SMS, whereas less aggressive cell lines (OVCAR-3, Capan-1, MCF7, and NCI-H2126) demonstrated less penetration capability and tended to remain on top of the SMS. Quantitative image analyses of several fluorescence microscopy fields of silicon samples were performed for automatic cell recognition and count, in order to quantify the fraction of cells inside the gaps, with respect to the total number of cells in the examined field. Our results show that higher fractions of cells in the gaps are obtained with more aggressive cell lines, thus supporting in a quantitative way the observation that the behavior of tumor cells on the 3D-SMS depends on their aggressiveness level

Upward convergence in employment and socioeconomic factors

The report investigates upward socioeconomic and employment-related convergence using a set of 21 indicators, most of which are part of the Social Scoreboard of the European Pillar of Social Rights. The report is organised in three main parts: first, upward convergence is investigated at the European level, with a distinction made between countries that are in the euro zone and those that are not. Next, some selected indicators are investigated at the regional level, and factors influencing convergence are discussed. Finally, the role of two possible policy initiatives – the European unemployment insurance (EUI) scheme and the European minimum wage (EMW) policy – are discussed and assessed in terms of how well they promote convergence