Clinical Validation of Digital Healthcare Solutions: State of the Art, Challenges and Opportunities.

Digital health technologies (DHTs) at the intersection of health, medical informatics, and business aim to enhance patient care through personalised digital approaches. Ensuring the efficacy and reliability of these innovations demands rigorous clinical validation. A PubMed literature review (January 2006 to July 2023) identified 1250 papers, highlighting growing academic interest. A focused narrative review (January 2018 to July 2023) delved into challenges, highlighting issues such as diverse regulatory landscapes, adoption issues in complex healthcare systems, and a plethora of evaluation frameworks lacking pragmatic guidance. Existing frameworks often omit crucial criteria, neglect empirical evidence, and clinical effectiveness is rarely included as a criterion for DHT quality. The paper underscores the urgency of addressing challenges in accreditation, adoption, business models, and integration to safeguard the quality, efficacy, and safety of DHTs. A pivotal illustration of collaborative efforts to address these challenges is exemplified by the Digital Health Validation Center, dedicated to generating clinical evidence of innovative healthcare technologies and facilitating seamless technology transfer. In conclusion, it is necessary to harmonise evaluation approaches and frameworks, improve regulatory clarity, and commit to collaboration to integrate rigorous clinical validation and empirical evidence throughout the DHT life cycle.

Elevated Prostaglandin E2 Synthesis Is Associated with Clinical and Radiological Disease Severity in Cystic Fibrosis.

Background: Previous studies found high but very variable levels of tetranor-PGEM and PGDM (urine metabolites of prostaglandin (PG) E2 and PGD2, respectively) in persons with cystic fibrosis (pwCF). This study aims to assess the role of cyclooxygenase COX-1 and COX-2 genetic polymorphisms in PG production and of PG metabolites as potential markers of symptoms' severity and imaging findings. Methods: A total of 30 healthy subjects and 103 pwCF were included in this study. Clinical and radiological CF severity was evaluated using clinical scoring methods and chest computed tomography (CT), respectively. Urine metabolites were measured using liquid chromatography/tandem mass spectrometry. Variants in the COX-1 gene (PTGS1 639 C>A, PTGS1 762+14delA and COX-2 gene: PTGS2-899G>C (-765G>C) and PTGS2 (8473T>C) were also analyzed. Results: PGE-M and PGD-M urine concentrations were significantly higher in pwCF than in controls. There were also statistically significant differences between clinically mild and moderate disease and severe disease. Patients with bronchiectasis and/or air trapping had higher PGE-M levels than patients without these complications. The four polymorphisms did not associate with clinical severity, air trapping, bronchiectasis, or urinary PG levels. Conclusions: These results suggest that urinary PG level testing can be used as a biomarker of CF severity. COX genetic polymorphisms are not involved in the variability of PG production.

Upregulation of Platelet-Activating Factor Receptor Expression and Lyso-Platelet-Activating Factor Isoforms in Human Nasal Polyp Tissues.

BACKGROUND: The Platelet-Activating Factor (PAF)/receptor (PAFR) system is involved in asthma and allergic rhinitis; however, its role in chronic rhinosinusitis (CRS) is still unclear. This study aimed to assess the expression of PAFR and the concentration of Lyso-PAF isoforms in the nasal polyps (NP) of patients suffering from CRS with/without comorbidities such as asthma and NSAID-exacerbated respiratory disease (N-ERD) compared to healthy nasal mucosa (NM) from control subjects. METHODS: NM (n = 8) and NP tissues were obtained from patients undergoing surgery for septal deviation/turbinate hypertrophy or endoscopic sinus surgery, respectively. Three phenotypes were studied: CRSwNP with no asthma (n = 6), CRSwNP with non-steroidal anti-inflammatory drug (NSAID)-tolerant asthma (n = 6), and CRSwNP with NSAID-exacerbated respiratory disease (n = 6). PAFR protein and mRNA were assessed via immunochemistry, immunofluorescence, Western blot, and real-time quantitative PCR. Lyso-PAF isoforms (C16, C18, and C18:1) were quantified via mass spectrometry. RESULTS: PAFR protein was expressed in the NM and NP, concretely in epithelial cells and submucosal glands. Compared to NM, PAFR mRNA expression was higher in all NP phenotypes (p < 0.05) while all Lyso-PAF isoform concentrations were higher in the NP from asthmatic patients (p < 0.05). Lyso-PAF C16 and C18 concentrations were higher in the NP from asthmatic patients than in the NP from patients without asthma. CONCLUSIONS: The PAF/PAFR system could play a pathophysiological role in CRSwNP pathogenesis.

Effect of Obesity on the Expression of Genes Associated with Severe Asthma-A Pilot Study.

Asthma is a complex condition resulting from the interaction of genes and environment. Obesity is a risk factor to develop asthma and contributes to poor response to asthma therapy and severity. The aim of the study was to evaluate the effect of obesity on the expression levels of genes previously associated with severe asthma. Three groups of subjects were studied: non-obese asthmatics (NOA), obese asthma patients (OA), and non-asthmatic obese subjects (O). Previously reported overexpressed (IL-10, MSR1, PHLDA1, SERPINB2, and CD86) and underexpressed genes (CHI3L1, CPA3, IL-8, and PI3) in severe asthma were analyzed by RT-qPCR in peripheral blood mononuclear cells (PBMCs). In the overexpressed genes, obesity significantly decreased the expression of MSR1 and PHLDA1 and had no effects on CD86, IL-10, and SERPINB2. In underexpressed genes, obesity did not affect PI3, CHI3L1, and IL-8 and significantly reduced CPA3 expression. The results of this study show that obesity should be included among the known factors that can contribute toward modifying the expression of genes associated with asthma and, in particular, severe asthma.

Effect of MP-AzeFlu compared to monotherapy on COX-2, PGE2 , and EP2 gene expression in upper airway mucosa.

MP-AzeFlu (intranasal fluticasone and azelastine) has been widely studied and has demonstrated efficacy in Allergic rhinitis with a superior effect compared to these drugs administered individually; however, the mechanism by which MP-AzeFlu produces this improved clinical effect has not yet been fully explained. In this study, we investigated the effect of MP-AzeFlu and fluticasone propionate (FP) on arachidonic acid metabolism as measured by changes in regulation of cyclooxygenase (COX) isoforms, prostaglandin (PG) D2 , PGE2 , PGE2 receptor (EP) 2, and EP3. Expression of these key inflammation markers was assessed through an in vitro model of upper airway inflammation using fibroblasts derived from both healthy and inflamed upper airway mucosa. Both MP-AzeFlu and FP inhibited interleukin-1ß-induced COX-2 messenger RNA (mRNA) and protein expression and PGE2 secretion in vitro. MP-AzeFlu and FP both upregulated EP2 mRNA expression, though neither upregulated EP2 protein expression. This downregulation of COX-2 and PGE2 coupled with upregulation of EP2 receptor expression reinforces the anti-inflammatory effect of MP-AzeFlu in upper airway inflammation.

Mechanisms by which dupilumab normalizes eicosanoid metabolism and restores aspirin-tolerance in AERD: A hypothesis.

Aspirin-exacerbated respiratory disease (AERD) is associated with overproduction of proinflammatory cysteinyl leukotrienes (CysLTs), defective generation of anti-inflammatory prostaglandin E2 (PGE2), and reduced expression of the EP2 receptor for PGE2. Reduced PGE2 synthesis results from the downregulation of inducible COX-2. Because PGE2 signaling via EP2 inhibits the 5-lipoxygenase/leukotriene C4 synthase-dependent pathway, the deficient levels of both PGE2 and EP2 likely contribute to the excessive baseline production of cysteinyl leukotrienes in patients with AERD compared with in patients with aspirin-tolerant asthma. The COX-2 pathway is regulated by an autocrine metabolic loop involving IL-1ß, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. Previous studies reported that this metabolic loop is dysregulated in patients with AERD. When the downexpressed EP2 receptor is normalized, the entire loop returns to its normal function. Cotreatment of airway cells from healthy subjects with IL-4 and IFN-γ induces alterations in the metabolic loop similar to those seen in patients with AERD. In these patients, IL-4, which is produced in excess in airways of patients with AERD, likely contributes to the alteration of normal functioning of the autocrine metabolic loop involving IL-1ß, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. We hypothesized that by blocking IL-4 action, dupilumab normalizes EP2 expression and restores the normal functioning of the COX-2 pathway autocrine metabolic loop, thereby normalizing the synthesis of PGE2 and restoring aspirin tolerance.

Differences in Inflammatory Cytokine Profile in Obesity-Associated Asthma: Effects of Weight Loss.

Obesity and asthma are associated with systemic inflammation maintained by mediators released by adipose tissue and lung. This study investigated the inflammatory serum mediator profile in obese subjects (O) (n = 35), non-obese asthma (NOA) patients (n = 14), obese asthmatics (OA) (n = 21) and healthy controls (HC) (n = 33). The effect of weight loss after bariatric surgery (BS) was examined in 10 OA and 31 O subjects. We analyzed serum markers including leptin, adiponectin, TGF-ß1, TNFR2, MCP-1, ezrin, YKL-40, ST2, IL-5, IL-9, and IL-18. Compared with HC subjects, the O group showed increased levels of leptin, TGF-ß1, TNFR2, MCP-1, ezrin, YKL-40, and ST2; the OA group presented increased levels of MCP-1, ezrin, YKL-40, and IL-18, and the NOA group had increased levels of ezrin, YKL-40, IL-5, and IL-18. The higher adiponectin/leptin ratio in NOA with respect to OA subjects was the only significant difference between the two groups. IL-9 was the only cytokine with significantly higher levels in OA with respect to O subjects. TNFR2, ezrin, MCP-1, and IL-18 concentrations significantly decreased in O subjects after BS. O, OA, and NOA showed distinct patterns of systemic inflammation. Leptin and adiponectin are regulated in asthma by obesity-dependent and -independent mechanisms. Combination of asthma and obesity does not result in significant additive effects on circulating cytokine levels.

Reference Gene Validation for RT-qPCR in PBMCs from Asthmatic Patients with or without Obesity.

Obesity is known to impair the efficacy of glucocorticoid medications for asthma control. Glucocorticoid-induced gene expression studies may be useful to discriminate those obese asthmatic patients who present a poor response to glucocorticoids. The expression of genes of interest is normalized with respect to reference genes (RGs). Ideally, RGs have a stable expression in different samples and are not affected by experimental conditions. The objective of this work was to analyze suitable RGs to study the role of glucocorticoid-induced genes in obese asthmatic patients in further research. The gene expression of eight potential RGs (GUSB, B2M, POLR2A, PPIA, ACTB, GAPDH, HPRT1, and TBP) was assessed with reverse transcription-quantitative polymerase chain reaction in peripheral blood mononuclear cells (PBMCs) from asthmatic, obese asthmatic, and healthy individuals. Their stability was analyzed using four different algorithms-BestKeeper, ΔCt, geNorm, and NormFinder. geNorm analysis recommended the use of a minimum of three genes for normalization. Moreover, intergroup variation due to the treatment was calculated by NormFinder, which found that B2M was the gene that was least affected by different treatments. Comprehensive rankings indicated GUSB and HPRT1 as the best RGs for qPCR in PBMCs from healthy and asthmatic subjects, while B2M and PPIA were the best for obese asthmatic subjects. Finally, our results demonstrated that B2M and HPRT1 were the most stable RGs among all groups, whereas ACTB, TBP, and GAPDH were the worst shared ones.

Adenosine Signaling in Mast Cells and Allergic Diseases.

Adenosine is a nucleoside involved in the pathogenesis of allergic diseases. Its effects are mediated through its binding to G protein-coupled receptors: A1, A2a, A2b and A3. The receptors differ in the type of G protein they recruit, in the effect on adenylyl cyclase (AC) activity and the downstream signaling pathway triggered. Adenosine can produce both an enhancement and an inhibition of mast cell degranulation, indicating that adenosine effects on these receptors is controversial and remains to be clarified. Depending on the study model, A1, A2b, and A3 receptors have shown anti- or pro-inflammatory activity. However, most studies reported an anti-inflammatory activity of A2a receptor. The precise knowledge of the adenosine mechanism of action may allow to develop more efficient therapies for allergic diseases by using selective agonist and antagonist against specific receptor subtypes.

Asthma and Obesity: Two Diseases on the Rise and Bridged by Inflammation.

Asthma and obesity are two epidemics affecting the developed world. The relationship between obesity and both asthma and severe asthma appears to be weight-dependent, causal, partly genetic, and probably bidirectional. There are two distinct phenotypes: 1. Allergic asthma in children with obesity, which worsens a pre-existing asthma, and 2. An often non allergic, late-onset asthma developing as a consequence of obesity. In obesity, infiltration of adipose tissue by macrophages M1, together with an increased expression of multiple mediators that amplify and propagate inflammation, is considered as the culprit of obesity-related inflammation. Adipose tissue is an important source of adipokines, such as pro-inflammatory leptin, produced in excess in obesity, and adiponectin with anti-inflammatory effects with reduced synthesis. The inflammatory process also involves the synthesis of pro-inflammatory cytokines such as IL-1ß, IL-6, TNFα, and TGFß, which also contribute to asthma pathogenesis. In contrast, asthma pro-inflammatory cytokines such as IL-4, IL-5, IL-13, and IL-33 contribute to maintain the lean state. The resulting regulatory effects of the immunomodulatory pathways underlying both diseases have been hypothesized to be one of the mechanisms by which obesity increases asthma risk and severity. Reduction of weight by diet, exercise, or bariatric surgery reduces inflammatory activity and improves asthma and lung function.

Role of microRNAs in inflammatory upper airway diseases.

MicroRNAs (miRNAs) are a conserved family of small endogenous noncoding RNA molecules that modulate post-transcriptional gene expression in physiological and pathological processes. miRNAs can silence target mRNAs through degradation or inhibition of translation, showing their pivotal role in the pathogenesis of many human diseases. miRNAs play a role in regulating immune functions and inflammation and are implicated in controlling the development and activation of T and B cells. Inflammatory chronic upper airway diseases, such as rhinitis and rhinosinusitis, are spread all over the world and characterized by an exaggerated inflammation involving a complex interaction between immune and resident cells. Until now and despite allergy, little is known about their etiology and the processes implicated in the immune response and tuning inflammation of these diseases. This review highlights the knowledge of the current literature about miRNAs in inflammatory chronic upper airways diseases and how this may be exploited in the development of new clinical and therapeutic strategies.

Role of the Cyclooxygenase Pathway in the Association of Obstructive Sleep Apnea and Cancer.

The objective of this review is to examine the findings that link obstructive sleep apnea (OSA) with cancer and the role played by the cyclooxygenase (COX) pathway in this association. Epidemiological studies in humans suggest a link between OSA and increased cancer incidence and mortality. Studies carried out in animal models have shown that intermittent hypoxia (IH) induces changes in several signaling pathways involved in the regulation of host immunological surveillance that results in tumor establishment and invasion. IH induces the expression of cyclooxygenase 2 (COX-2) that results in an increased synthesis of prostaglandin E2 (PGE2). PGE2 modulates the function of multiple cells involved in immune responses including T lymphocytes, NK cells, dendritic cells, macrophages, and myeloid-derived suppressor cells. In a mouse model blockage of COX-2/PGE2 abrogated the pro-oncogenic effects of IH. Despite the fact that aspirin inhibits PGE2 production and prevents the development of cancer, none of the epidemiological studies that investigated the association of OSA and cancer included aspirin use in the analysis. Studies are needed to investigate the regulation of the COX-2/PGE2 pathway and PGE2 production in patients with OSA, to better define the role of this axis in the physiopathology of OSA and the potential role of aspirin in preventing the development of cancer.

Integrated mRNA and microRNA transcriptome profiling during differentiation of human nasal polyp epithelium reveals an altered ciliogenesis.

BACKGROUND: Human adult basal stem/progenitor cells (BSCs) obtained from chronic rhinosinusitis with nasal polyps (CRSwNP) when differentiated in an air-liquid interface (ALI) usually provide a pseudostratified airway epithelium with similar abnormalities than original in vivo phenotype. However, the intrinsic mechanisms regulating this complex process are not well defined and their understanding could offer potential new therapies for CRSwNP (incurable disease). METHODS: We performed a transcriptome-wide analysis during in vitro mucociliary differentiation of human adult BSCs from CRSwNP, compared to those isolated from control nasal mucosa (control-NM), in order to identify which key mRNA and microRNAs are regulating this complex process in pathological and healthy conditions. RESULTS: A number of genes, miRs, biological processes, and pathways were identified during mucociliary differentiation of both CRSwNP and control-NM epithelia, and notably, we have demonstrated for the first time that genetic transcriptional program responsible of ciliogenesis and cilia function is significantly impaired in CRSwNP epithelium, presumably produced by an altered expression of microRNAs, particularly of those miRs belonging to mir-34 and mi-449 families. CONCLUSIONS: This study provides for the first time a novel insight into the molecular basis of sinonasal mucociliary differentiation, demonstrating that transcriptome related to ciliogenesis and cilia function is significantly impaired during differentiation of CRSwNP epithelium due to an altered expression of microRNAs.

Riesgo cardiovascular en la disminución leve-moderada de la tasa de filtrado glomerular, diabetes y enfermedad coronaria en un área del sur de Europa / Cardiovascular risk in mild to moderately decreased glomerular filtration rate, diabetes and coronary heart disease in a southern European region

INTRODUCCIÓN Y OBJETIVOS: Se considera que los individuos con disminución leve-moderada de la tasa de filtrado glomerular estimada (TFGe, 30-59ml/min/1,73 m2) están en alto riesgo de enfermedad cardiovascular (ECV). Ningún estudio ha comparado este riesgo con TFGe 30-59, diabetes mellitus (DM) y enfermedad coronaria (EC) en regiones con baja incidencia de EC. MÉTODOS: Se realizó un estudio de cohortes retrospectivo en 122.443 individuos de 60-84 años de una región de baja incidencia de EC con creatinina determinada entre el 1 de enero de 2010 y 31 de diciembre de 2011. Se identificaron los ingresos por EC (infarto de miocardio, angina de pecho) o ECV (EC, accidente cerebrovascular o accidente isquémico transitorio) hasta el 31 de diciembre de 2013 según registros electrónicos. Se estimaron las tasas de incidencia y la subdistribution hazard ratio (sHR) ajustadas mediante regresión de Cox considerando los riesgos competitivos en individuos con TFGe 30-59, DM y EC o combinaciones, respecto a individuos sin estas afecciones. RESULTADOS: La mediana de seguimiento fue de 38,3 [intervalo intercuartílico, 33,8-42,7] meses. Las sHR de EC de los individuos con TFGe 30-59, DM, TFGe 30-59 más DM, EC previa, EC más DM y EC más TFGe 30-59 más DM fueron, respectivamente, 1,34 (IC95%, 1,04-1,74), 1,61 (IC95%, 1,36-1,90), 1,96 (IC95%, 1,42-2,70), 4,33 (IC95%, 3,58-5,25), 7,05 (IC95%, 5,80-8,58) y 7,72 (IC95%, 5,72-10,41), y las sHR de ECV, 1,25 (IC95%, 1,06-1,46), 1,56 (IC95%, 1,41-1,74), 1,83 (IC95%, 1,50-2,23), 2,86 (IC95%, 2,48-3,29), 4,54 (IC95%, 3,93-5,24) y 5,33 (IC95%, 4,31-6,60). CONCLUSIONES: Los individuos de 60-84 años con TFGe 30-59, de modo similar que la DM, presentaron un riesgo de ingreso por EC y ECV un 50% inferior que aquellos con EC previa. Una TFGe 30-59 no aparece como equivalente de riesgo coronario. Debe priorizarse un tratamiento más intensivo del riesgo cardiovascular de los individuos con EC y DM o TFGe 30-59 más DM

INTRODUCTION AND OBJECTIVES: Individuals with mild to moderately decreased estimated glomerular filtration rate (eGFR=30-59 mL/min/1.73 m2) are considered at high risk of cardiovascular disease (CVD). No studies have compared this risk in eGFR=30-59, diabetes mellitus (DM), and coronary heart disease (CHD) in regions with a low incidence of CHD. METHODS: We performed a retrospective cohort study of 122 443 individuals aged 60-84 years from a region with a low CHD incidence with creatinine measured between January 1, 2010 and December 31, 2011. We identified hospital admissions due to CHD (myocardial infarction, angina) or CVD (CHD, stroke, or transient ischemic attack) from electronic medical records up to December 31, 2013. We estimated incidence rates and Cox regression adjusted subdistribution hazard ratio (sHR) including competing risks in patients with eGFR=30-59, DM and CHD, or combinations, compared with individuals without these diseases. RESULTS: The median follow-up was 38.3 [IQR, 33.8-42.7] months. Adjusted sHR for CHD in individuals with eGFR=30-59, DM, eGFR=30-59 plus DM, previous CHD, CHD plus DM, and CHD plus eGFR=30-59 plus DM, were 1.34 (95%CI, 1.04-1.74), 1.61 (95%CI, 1.36-1.90), 1.96 (95%CI, 1.42-2.70), 4.33 (95%CI, 3.58-5.25), 7.05 (5.80-8.58) and 7.72 (5.72-10.41), respectively. The corresponding sHR for CVD were 1.25 (95%CI, 1.06-1.46), 1.56 (95%CI, 1.41-1.74), 1.83 (95%CI, 1.50-2.23), 2.86 (95%CI, 2.48-3.29), 4.54 (95%CI, 3.93-5.24), and 5.33 (95%CI, 4.31-6.60). CONCLUSIONS: In 60- to 84-year-olds with eGFR=30-59, similarly to DM, the likelihood of being admitted to hospital for CHD and CVD was about half that of individuals with established CHD. Thus, eGFR=30-59 does not appear to be a coronary-risk equivalent. Individuals with CHD and DM, or eGFR=30-59 plus DM, should be prioritized for more intensive risk management

The Association between Loneliness and Health Related Quality of Life (HR-QoL) among Community-Dwelling Older Citizens.

Background: This study aimed to assess the association between loneliness and Health-Related Quality of Life (HR-QoL) among community-dwelling older citizens in five European countries. We characterize loneliness broadly from an emotional and social perspective. Methods: This cross-sectional study measured loneliness with the 6-item De Jong Gierveld Loneliness Scale and HR-QoL with the 12-Item Short-Form Health Survey. The association between loneliness and HR-QoL was examined using multivariable linear regression models. Results: Data of 2169 citizens of at least 70 years of age and living independently (mean age = 79.6 ± 5.6; 61% females) were analyzed. Among the participants, 1007 (46%) were lonely; 627 (29%) were emotionally and 575 (27%) socially lonely. Participants who were lonely experienced a lower HR-QoL than participants who were not lonely (p ≤ 0.001). Emotional loneliness [std-ß: -1.39; 95%-CI: -1.88 to -0.91] and social loneliness [-0.95; -1.44 to -0.45] were both associated with a lower physical HR-QoL. Emotional loneliness [-3.73; -4.16 to -3.31] and social loneliness [-1.84; -2.27 to -1.41] were also both associated with a lower mental HR-QoL. Conclusions: We found a negative association between loneliness and HR-QoL, especially between emotional loneliness and mental HR-QoL. This finding indicates that older citizens who miss an intimate or intense emotional relationship and interventions targeting mental HR-QoL deserve more attention in policy and practice than in the past.

Immune-Mediated Mechanisms in Cofactor-Dependent Food Allergy and Anaphylaxis: Effect of Cofactors in Basophils and Mast Cells.

Cofactors may explain why in some cases food ingestion leads to anaphylaxis while in others elicits a milder reaction or tolerance. With cofactors, reactions become more severe and/or have a lower allergen threshold. Cofactors are present in up to 58% of food anaphylaxis (FAn). Exercise, NSAIDs, and alcohol are the most frequently described, although the underlying mechanisms are poorly known. Several hypotheses have suggested the influence of these cofactors on basophils and mast cells (MCs). Exercise has been suggested to enhance MC activation by increasing plasma osmolarity, redistributing blood flow, and activating adenosine and eicosanoid metabolism. NSAIDs' cofactor effect has been related with cyclooxygenase inhibition and therefore, prostaglandin E2 (PGE2) production. Indeed, overexpression of adenosine receptor 3 (A3) gene has been described in NSAID-dependent FAn; A3 activation potentiates FcϵRI-induced MC degranulation. Finally, alcohol has been related with an increase of histamine levels by inhibition of diamino oxidase (DAO) and also with and increase of extracellular adenosine by inhibition of its uptake. However, most of these mechanisms have limited evidence, and further studies are urgently needed. In conclusion, the study of the immune-related mechanisms involved in food allergic reactions enhanced by cofactors is of the utmost interest. This knowledge will help to design both tailored treatments and prophylactic strategies that, nowadays, are non-existent.

Cardiovascular risk in mild to moderately decreased glomerular filtration rate, diabetes and coronary heart disease in a southern European region.

INTRODUCTION AND OBJECTIVES: Individuals with mild to moderately decreased estimated glomerular filtration rate (eGFR=30-59 mL/min/1.73 m2) are considered at high risk of cardiovascular disease (CVD). No studies have compared this risk in eGFR=30-59, diabetes mellitus (DM), and coronary heart disease (CHD) in regions with a low incidence of CHD. METHODS: We performed a retrospective cohort study of 122 443 individuals aged 60-84 years from a region with a low CHD incidence with creatinine measured between January 1, 2010 and December 31, 2011. We identified hospital admissions due to CHD (myocardial infarction, angina) or CVD (CHD, stroke, or transient ischemic attack) from electronic medical records up to December 31, 2013. We estimated incidence rates and Cox regression adjusted subdistribution hazard ratio (sHR) including competing risks in patients with eGFR=30-59, DM and CHD, or combinations, compared with individuals without these diseases. RESULTS: The median follow-up was 38.3 [IQR, 33.8-42.7] months. Adjusted sHR for CHD in individuals with eGFR=30-59, DM, eGFR=30-59 plus DM, previous CHD, CHD plus DM, and CHD plus eGFR=30-59 plus DM, were 1.34 (95%CI, 1.04-1.74), 1.61 (95%CI, 1.36-1.90), 1.96 (95%CI, 1.42-2.70), 4.33 (95%CI, 3.58-5.25), 7.05 (5.80-8.58) and 7.72 (5.72-10.41), respectively. The corresponding sHR for CVD were 1.25 (95%CI, 1.06-1.46), 1.56 (95%CI, 1.41-1.74), 1.83 (95%CI, 1.50-2.23), 2.86 (95%CI, 2.48-3.29), 4.54 (95%CI, 3.93-5.24), and 5.33 (95%CI, 4.31-6.60). CONCLUSIONS: In 60- to 84-year-olds with eGFR=30-59, similarly to DM, the likelihood of being admitted to hospital for CHD and CVD was about half that of individuals with established CHD. Thus, eGFR=30-59 does not appear to be a coronary-risk equivalent. Individuals with CHD and DM, or eGFR=30-59 plus DM, should be prioritized for more intensive risk management.