Effect of glucose variability on the mortality of adults aged 75 years and over during the first year of the COVID-19 pandemic.

BACKGROUND: To our knowledge, only one study has examined the association between glucose variability (GV) and mortality in the elderly population with diabetes. GV was assessed by HbA1c, and a J-shaped curve was observed in the relationship between HbA1c thresholds and mortality. No study of GV was conducted during the COVID-19 pandemic and its lockdown. This study aims to evaluate whether GV is an independent predictor of all-cause mortality in patients aged 75 years or older with and without COVID-19 who were followed during the first year of the COVID-19 pandemic and its lockdown measures. METHODS: This was a retrospective cohort study of 407,492 patients from the AGED-MADRID dataset aged 83.5 (SD 5.8) years; 63.2% were women, and 29.3% had diabetes. GV was measured by the coefficient of variation of fasting plasma glucose (CV-FPG) over 6 years of follow-up (2015-2020). The outcome measure was all-cause mortality in 2020. Four models of logistic regression were performed, from simple (age, sex) to fully adjusted, to assess the effect of CV-FPG on all-cause mortality. RESULTS: During follow-up, 34,925 patients died (14,999 women and 19,926 men), with an all-cause mortality rate of 822.3 per 10,000 person-years (95% confidence interval (CI), 813.7 to 822.3) (739 per 10,000; 95% CI 728.7 to 739.0 in women and 967.1 per 10,000; 95% CI 951.7 to 967.2 in men). The highest quartile of CV-FPG was significantly more common in the deceased group (40.1% vs. 23.6%; p < 0.001). In the fully adjusted model including dementia (Alzheimer's disease) and basal FPG, the odds ratio for mortality ranged from 1.88 to 2.06 in patients with T2DM and from 2.30 to 2.61 in patients with normoglycaemia, according to different sensitivity analyses. CONCLUSIONS: GV has clear implications for clinical practice, as its assessment as a risk prediction tool should be included in the routine follow-up of the elderly and in a comprehensive geriatric assessment. Electronic health records can incorporate tools that allow its calculation, and with this information, clinicians will have a broader view of the medium- and long-term prognosis of their patients.

External validation of three diabetes prediction scores in a Spanish cohort: does adding high risk for depression improve the validation of the FINDRISC score (FINDRISC-MOOD)?

OBJECTIVES: To evaluate the external validity of the FINDRISC, DESIR and ADA risk scores for the prediction of diabetes in a Spanish population aged >45 years and to test the possible improvement of FINDRISC by adding a new variable of high risk of depression when Patient Health Questionnaire-9 (PHQ-9) questionnaire score ≥10 (FINDRISC-MOOD). DESIGN: Prospective population-based cohort study. SETTING: 10 primary healthcare centres in the north of the city of Madrid (Spain). PARTICIPANTS: A total of 1242 participants without a history of diabetes and with 2-hour oral glucose tolerance test (OGTT) plasma glucose <200 mg/dL (<11.1 mmol/L) were followed up for 7.3 years (median) using their electronic health records (EHRs) and telephone contact. PRIMARY AND SECONDARY OUTCOME MEASURES: Diabetes risk scores (FINDRISC, DESIR, ADA), PHQ-9 questionnaire and 2-hour-OGTT were measured at baseline. Incident diabetes was defined as treatment for diabetes, fasting plasma glucose ≥126 mg/dL (≥7.0 mmol/L), new EHR diagnosis or self-reported diagnosis. External validation was performed according to optimal cut-off, sensitivity, specificity and Youden Index. Comparison between diabetes risk scores, including FINDRISC-MOOD (original FINDRISC score plus five points if PHQ-9 ≥10), was measured by area under the receiver operating characteristic curve (AUROC). RESULTS: During follow-up, 104 (8.4%; 95% CI, 6.8 to 9.9) participants developed diabetes and 185 had a PHQ-9 score ≥10. The AUROC values were 0.70 (95% CI, 0.67 to 0.72) for FINDRISC-MOOD and 0.68 (95% CI, 0.65 to 0.71) for the original FINDRISC. The AUROCs for DESIR and ADA were 0.66 (95% CI, 0.63 to 0.68) and 0.66 (95% CI, 0.63 to 0.69), respectively. There were no significant differences in AUROC between FINDRISC-MOOD and the other scores. CONCLUSIONS: The results of FINDRISC-MOOD were like those of the other risk scores and do not allow it to be recommended for clinical use.

Validation of diagnosis of acute myocardial infarction and stroke in electronic medical records: a primary care cross-sectional study in Madrid, Spain (the e-MADVEVA Study).

OBJECTIVES: To validate the diagnoses of acute myocardial infarction (AMI) and stroke recorded in electronic medical records (EMR) and to estimate the population prevalence of both diseases in people aged ≥18 years. DESIGN: Cross-sectional validation study. SETTING: 45 primary care centres. PARTICIPANTS: Simple random sampling of diagnoses of AMI and stroke (International Classification of Primary Care-2 codes K75 and K90, respectively) registered by 55 physicians and random age-matched and sex-matched sampling of the records that included in primary care EMRs in Madrid (Spain). PRIMARY AND SECONDARY OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values and overall agreement were calculated using the kappa statistic. Applied gold standards were ECGs, brain imaging studies, hospital discharge reports, cardiology reports and neurology reports. In the case of AMI, the ESC/ACCF/AHA/WHF Expert Consensus Document was also used. Secondary outcomes were the estimated prevalence of both diseases considering the sensitivity and specificity obtained (true prevalence). RESULTS: The sensitivity of a diagnosis of AMI was 98.11% (95% CI, 96.29 to 99.03), and the specificity was 97.42% (95% CI, 95.44 to 98.55). The sensitivity of a diagnosis of stroke was 97.56% (95% CI, 95.56 to 98.68), and the specificity was 94.51% (95% CI, 91.96 to 96.28). No differences in the results were found after stratification by age and sex (both diseases). The prevalence of AMI and stroke was 1.38% and 1.27%, respectively. CONCLUSION: The validation results show that diagnoses of AMI and stroke in primary care EMRs constitute a helpful tool in epidemiological studies. The prevalence of AMI and stroke was lower than 2% in the population aged over 18 years.

Clinical and Demographic Characteristics of Centenarians versus Other Age Groups Over 75 Years with Hip Fractures.

Objective: The primary objective was to describe the clinical characteristics, management, and outcomes of centenarians with fragility hip fracture and compare them to other age groups. The secondary objective was to determine the variables associated with length of stay, in-hospital mortality and 30-day mortality. Materials and Methods: This is a secondary analysis of the Spanish National Hip Fracture Registry. We included patients ≥75 years admitted for fragility hip fractures in 86 Spanish hospitals between 2017 and 2019, dividing the sample into four age groups. The variables studied were baseline characteristics, type of fracture, management, length of stay, in-hospital mortality and 30-day mortality. Results: We included 25,938 patients (2888 were 75-79 years old; 14,762 octogenarians; 8,035 nonagenarians and 253 centenarians). Of the centenarians, 83% were women, 33% had severe dementia, 9% had severe dependency and 36% lived in residential care homes. Six out of ten had intertrochanteric fracture. Length of hospital stay was 8.6 days; in-hospital mortality was 10.3% and 30-day mortality 20.9%. Older age groups had more women, severe functional dependency, severe dementia, intertrochanteric fracture, living in care facilities and being discharged to nursing care. They had less frequent early mobilization, osteoporosis treatment and discharge to rehabilitation units. In-hospital and 30-day mortality were higher with increasing age. In centenarians, time to surgery >48 hours was independently associated with length of stay (correlation coefficient 3.99 [95% CI: 2.35-5.64; p<0.001]) and anaesthetic risk, based on an ASA score of V, was related to 30-day mortality (ASA score II [OR 0.25, 95% CI: 0.09-0.70; p=0.009] and ASA score III [OR 0.43, 95% CI: 0.19-0.96; p=0.039]). Conclusion: Centenarians had different clinical characteristics, management and outcomes. Although centenarians had worse outcomes, nearly 4 out of 5 centenarians were alive one month after surgery.

Glycemic variability and all-cause mortality in a large prospective southern European cohort of patients with differences in glycemic status.

BACKGROUND: Few studies have analyzed the relationship between glucose variability (GV) and adverse health outcomes in patients with differences in glycemic status. The present study tests the hypothesis that GV predicts all-cause mortality regardless of glycemic status after simple adjustment (age and sex) and full adjustment (age, sex, cardiovascular disease, hypertension, use of aspirin, statins, GLP-1 receptor agonists, SGLT-2 inhibitors and DPP-4 inhibitors, baseline FPG and average HbA1c). METHODS: Prospective cohort study with 795 normoglycemic patients, 233 patients with prediabetes, and 4,102 patients with type 2 diabetes. GV was measured using the coefficient of variation of fasting plasma glucose (CV-FPG) over 12 years of follow-up. The outcome measure was all-cause mortality. RESULTS: A total of 1,223 patients (657 men, 566 women) died after a median of 9.8 years of follow-up, with an all-cause mortality rate of 23.35/1,000 person-years. In prediabetes or T2DM patients, the fourth quartile of CV-FPG exerted a significant effect on all-cause mortality after simple and full adjustment. A sensitivity analysis excluding participants who died during the first year of follow-up revealed the following results for the highest quartile in the fully adjusted model: overall, HR (95%CI) = 1.54 (1.26-1.89); dysglycemia (prediabetes and T2DM), HR = 1.41 (1.15-1.73); T2DM, HR = 1.36 (1.10-1.67). CONCLUSION: We found CV-FPG to be useful for measurement of GV. It could also be used for the prognostic stratification of patients with dysglycemia.

Improving hip fracture care in Spain: evolution of quality indicators in the Spanish National Hip Fracture Registry.

This study was carried out to analyze the evolution of the quality indicators in the Spanish National Hip Fracture Registry, after disseminating a series of recommendations based on available clinical practice guidelines to the participating hospitals. Six of the seven proposed quality indicators showed a significant improvement. PURPOSE: The Spanish National Hip Fracture Registry (RNFC) arises from the need to know the process and improve the quality of care. Our goal was to analyze the changes in the RNFC's quality indicators after an intervention based on disseminating specific recommendations among the participating hospitals, following available clinical practice guidelines. METHODS: Study comparing before and after performing an intervention in hospitals participating in the RNFC. Data from the hospitals that registered cases in 2017, and that kept registering cases in 2019. Seven quality indicators were chosen, and a standard to be achieved for each indicator was proposed. The intervention consisted in the dissemination of 25 recommendations with practical measures to improve each quality indicator, based on available clinical practice guidelines, by drafting and publishing a scientific paper and sending it via email and printed cards. Fulfilment of each quality indicator was measured after carrying out the intervention. RESULTS: Forty-three hospitals registered 2674 cases between January and May, 2017, and 8037 during 2019. The quality indicators chosen and the degree of compliance were (all with p<0.05): (1) surgery ≤48 h increased from 38.9 to 45.8%; (2) patients mobilised on the first postoperative day increased from 58.9 to 70.3%; (3) patients with anti-osteoporotic medication at discharge increased from 34.5 to 49.8%; (4) patients with calcium supplements at discharge increased from 48.7 to 62.8%; (5) patients with vitamin D supplements at discharge increased from 71.5 to 84.7%; (6) patients developing a grade >2 pressure ulcer during admission decreased from 6.5 to 5.0%; (7) patients able to move on their own at 1 month fell from 58.8 to 56.4%. More than 48% of hospitals improved the proposed indicators. CONCLUSION: Establishing quality indicators and standards and intervening through the dissemination of specific recommendations to improve these indicators achieved an improvement in hospital performance results on a national level.

[The Spanish National Hip Fractures Registry (RNFC) and the Minimum Basic Data Set (CMBD) are useful for research on hip fractures: comparison of two registries.] / El Registro Nacional de Fracturas de Cadera (RNFC) y el Conjunto Mínimo Básico de Datos son útiles para investigar sobre fracturas de cadera: comparación de ambos registros.

OBJECTIVE: National hip fracture registries have been established in several countries and recent publications show that the care process has been audited inspecting the representativeness according to quality standards. The aim of this study was to analyse if the Spanish National Hip Fracture Registry (RNFC) represents the Spanish population aged 75 and older admitted for hip fractures, and to compare its results regarding the care process with the national average, according to the National Inpatient register (Minimum Basic Dataset, CMBD). METHODS: The 2017-2018 National Minimum Basic Dataset (Conjunto Mínimo Básico de Datos, CMBD) was used as reference. For analysis, we included 83,110 cases from the CMBD and 21,130 from the RNFC. Eight common variables of both registries were selected for comparison. RESULTS: No significant differences were observed in the patient-related common variables (age, sex, type of fracture and fracture side), but statistically significant differences were found in the variables describing the care process (proportion of patients operated, deceased, surgical procedures and postoperative length of stay). CONCLUSIONS: The RNFC, designed as a convenience sample, is also representative of the population of patients aged 75 and older treated for hip fractures in Spain. However, there is a participation bias related to the professionals and the hospitals interested in voluntarily participating in a quality improvement program, which would explain the better results observed in the care process, compared to the national average as collected by the CMBD.

OBJETIVO: Los registros nacionales de fracturas de cadera se han establecido en varios países y publicaciones recientes muestran que el proceso de atención ha sido auditado para explorar su representatividad de acuerdo a estándares de calidad. El objetivo de este trabajo fue analizar si el Registro Nacional de Fracturas de Cadera (RNFC) es representativo de la población española de 75 o más años de edad ingresada por fractura de cadera, y comparar los resultados acerca del proceso asistencial con la media nacional según el Conjunto Mínimo Básico de Datos (CMBD). METODOS: Se empleó el CMBD de los años 2017-2018 como referencia. Para el análisis se incluyeron 83.110 casos del CMBD y 21.130 del RNFC. Se seleccionaron ocho variables comunes a ambos registros para ser comparadas. RESULTADOS: No se observaron diferencias significativas en las variables comunes paciente-dependientes (edad, sexo, tipo y lado de fractura), pero se hallaron diferencias significativas en las variables que describían el proceso asistencial (proporción de pacientes intervenidos, fallecidos, tipos de procedimiento quirúrgico y estancia postoperatoria). CONCLUSIONES: El RNFC, diseñado como muestra de conveniencia, es también representativa de la población de pacientes de 75 y más años, atendida por fractura de cadera en España. Sin embargo, existe un sesgo de participación relacionado con los profesionales y los hospitales interesados en participar voluntariamente en un programa voluntario de mejora de calidad que podría explicar los mejores resultados observados en el proceso asistencial, comparado con la media nacional según se recoge por el CMBD.

Differences in the baseline characteristics, management and outcomes of patients with hip fractures depending on their pre-fracture place of residence: the Spanish National Hip Fracture Registry (RNFC) cohort.

PURPOSE: One in four hip fracture patients comes from an aged care facility. This study aimed to compare the characteristics of these subjects with their community-dwelling counterparts at baseline, during hospitalization and 1-month post-fracture. METHODS: We analyzed data from a cohort of older adults admitted with hip fractures to 75 Spanish hospitals, collected prospectively in the Spanish National Hip Fracture Registry between 2016 and 2018. We classified participants according to pre-fracture residence: community dwellers vs. aged care facilities residents. We collected demographic records at baseline, along with variables relating to in-hospital evolution and discharge to geriatric rehabilitation units. Patients or relatives were interviewed at 1-month follow-up. RESULTS: Out of 18,262 patients, 4,422 (24.2%) lived in aged care facilities. Aged care facilities residents were older (median age: 89 vs. 86 years), less mobile (inability to walk independently: 20.8% vs. 9.4%) and had more cognitive impairment (Pfeiffer's SPMSQ > 3, 75.3% vs. 34.8%). They were more likely to receive conservative treatment (5.4% vs. 2.0%) and less likely to be mobilized early (58.2% vs. 63.0%). At discharge, they received less vitamin D supplements (68.5% vs. 72.4%), less anti-osteoporotic medication (29.3% vs. 44.3%), and were referred to geriatric rehabilitation units less frequently (5.4% vs. 27.5%). One-month post-fracture, 45% of aged care facilities residents compared to 28% of community dwellers experienced a severe gait decline. Aged care facilities residents had a higher one-month mortality (10.6% vs. 6.8%). CONCLUSION: Hip fracture patients from aged care facilities are more vulnerable than their community-dwelling peers and are managed differently both during hospitalization and at discharge. Gait decline is disproportionately higher among those admitted from aged care.

Tumor stem cells fuse with monocytes to form highly invasive tumor-hybrid cells.

The 'cancer cell fusion' theory is controversial due to the lack of methods available to identify hybrid cells and to follow the phenomenon in patients. However, it seems to be one of the best explanations for both the origin and metastasis of primary tumors. Herein, we co-cultured lung cancer stem cells with human monocytes and analyzed the dynamics and properties of tumor-hybrid cells (THC), as well as the molecular mechanisms beneath this fusion process by several techniques: electron-microscopy, karyotyping, CRISPR-Cas9, RNA-seq, immunostaining, signaling blockage, among others. Moreover, mice models were assessed for in vivo characterization of hybrids colonization and invasiveness. Then, the presence of THCs in bloodstream and samples from primary and metastatic lesions were detected by FACS and immunofluorescence protocols, and their correlations with TNM stages established. Our data indicate that the generation of THCs depends on the expression of CD36 on tumor stem cells and the oxidative state and polarization of monocytes, the latter being strongly influenced by microenvironmental fluctuations. Highly oxidized M2-like monocytes show the strongest affinity to fuse with tumor stem cells. THCs are able to proliferate, colonize and invade organs. THC-specific cell surface signature CD36+CD14+PANK+ allows identifying them in matched primary tumor tissues and metastases as well as in bloodstream from patients with lung cancer, thus functioning as a biomarker. THCs levels in circulation correlate with TNM classification. Our results suggest that THCs are involved in both origin and spread of metastatic cells. Furthermore, they might set the bases for future therapies to avoid or eradicate lung cancer metastasis.

[Spanish National Hip Fracture Registry (RNFC): First-year results and comparison with other registries and prospective multi-centric studies from Spain]. / Registro Nacional de Fracturas de Cadera (RNFC): resultados del primer año y comparación con otros registros y estudios multicéntricos españoles.

OBJECTIVE: The Spanish National Hip Fracture Registry (Registro Nacional de Fracturas de Cadera or RNFC) is a Spanish, prospective, multi- centric registry, commenced in 2017. The goal of this paper is to present the data from the first annual report and to compare them with autonomic registries and recent prospective multi-centric studies performed in Spain. METHODS: We included persons 75 years or older treated for fragility hip fractures in any of the centers participating in the RNFC between January and October 2017. The descriptive statistics of each variable used the mean (and standard deviation) or the median (and interquartile ranges) for the ordinal variables and the percentage for the categoric variables. A descriptive analysis of the casemix was performed and compared with available data from the aforementioned studies. RESULTS: The RNFC included 7.208 patients from 54 hospitals, with a mean age of 86.7 (SD 5.6) years; 75.4% were women, and 36.4% showed cognitive decline. Mean surgical delay was 75.7 (SD 63.6) hours, and length of stay averaged 10.9 (SD 6.7) days. Of the patients who lived at home (75.4%), less than half (37.0%) returned home at discharge. One-month mortality was 7.1%. Comparison with other studies showed important differences, especially regarding patients newly sent to nursing homes (7.7-29.4%) and with antiosteoporotic treatment at discharge (14.5-36.7%). CONCLUSIONS: The RNFC is the largest prospective database to date that offers data regarding the characteristics of patients hospitalized for hip fractures in Spain. Comparison with recent studies showed some important differences.

OBJETIVO: El Registro Nacional de Fracturas de Cadera (RNFC) es un registro español multicéntrico, prospectivo y continuo, que comenzó en 2017. El objetivo de este artículo fue presentar los datos del primer informe anual y compararlos con los registros autonómicos y los estudios multicéntricos realizados recientemente en España. METODOS: Se incluyeron las personas de 75 años o más atendidas con el diagnóstico de fractura de cadera por fragilidad en alguno de los hospitales participantes en el RNFC, entre enero y octubre de 2017. En el análisis estadístico se utilizó la media y desviación estándar o mediana y rangos intercuartílicos para las variables numéricas y los porcentajes para las variables categóricas. Se realizó un análisis descriptivo global de la casuística y se comparó con los datos disponibles de los estudios previos mencionados. RESULTADOS: Se registraron 7.208 personas de 54 hospitales, con una edad media de 86,7 años (DE 5,6). El 75,4% fueron mujeres y el 36,4% presentaron deterioro cognitivo previo. La demora quirúrgica media fue de 75,7 horas (DE 63,6) y la estancia media fue de 10,9 días (DE 6,7). De las personas que vivían en un domicilio antes de la fractura (75,4%), menos de la mitad (37,0%) volvieron a él tras el alta hospitalaria. Al mes, había fallecido el 7,1%. La comparación con los otros estudios mostró algunas diferencias importantes, sobre todo en la ubicación previa, en el porcentaje de pacientes institucionalizados de novo (7,7-29,4%) y en el porcentaje con tratamiento antiosteoporótico al alta (14,5-36,7%). CONCLUSIONES: El RNFC es la mayor base de datos prospectiva que aporta datos sobre el perfil de los pacientes hospitalizados por fractura de cadera en España. La comparación con otros estudios recientes muestra algunas diferencias importantes.

First proposal of quality indicators and standards and recommendations to improve the healthcare in the Spanish National Registry of Hip Fracture.

BACKGROUND: The Spanish National Hip Fracture Registry (or Registro Nacional de Fractura de Cadera, RNFC) is a database of hip fracture patients admitted to Spanish hospitals. Its goals include assessment and continuous improvement of the care process. OBJECTIVES: To (1) establish a series of indicators, (2) evaluate their initial fulfillment, (3) propose quality standards, (4) suggest recommendations to facilitate standards compliance, and (5) monitor the indicators. METHOD: The indicators fulfilled the criteria of (1) evaluating the process or outcome, (2) being clinically relevant for patients, (3) being modifiable through changes in healthcare practice, and (4) being considered important by the RNFC participants. The first quartile obtained by the group of hospitals in each of the respective variables was proposed as the standard. The Indicators Advisory Committee (IAC) elaborated a list of recommendations for each indicator, based on the available evidence. RESULTS: Seven indicators were chosen. These indicators (its baseline compliance vs. the standard to be reached, respectively) were: the proportion of patients receiving surgery within 48h (44% vs. 63%), mobilized the first postoperative day (56% vs. 86%), with antiosteoporotic medication at discharge (32% vs. 61%), with calcium supplements at discharge (46% vs. 77%), with vitamin D supplements at discharge (67% vs. 92%), who developed pressure ulcers during hospitalization (7.2% vs. 2.1%) and with independent mobility at 30 days (58% vs. 70%). The IAC has established 25 recommendations for improving care. CONCLUSION: The indicators and standards chosen are presented, as well as the list of recommendations. This process completes the first step to improve quality of care. The results will be evaluated 6 months after implementing the recommendations.

Pseudomonas aeruginosa colonization causes PD-L1 overexpression on monocytes, impairing the adaptive immune response in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is an endotoxin tolerance (ET)-related disease. Given that increased PD-L1 has been reported in ET, its expression and physiological effects on cystic fibrosis monocytes should be studied. METHODS: We analyzed the phenotype and ex vivo response of immune system cells in 32 patients with CF, 19 of them colonized by Pseudomonas aeruginosa. An in vitro model was developed of Pseudomonas aeruginosa colonization using purified lipopolysaccharides (LPS) from one of the most prevalent strains in patients with CF (a CF-adapted Pseudomonas aeruginosa ST395 clone). Changes in the immune response, including cytokine production and T-lymphocyte proliferation, as well as expression of PD-L1, were evaluated. RESULTS: PD-L1 was overexpressed in the monocytes of patients with CF compared with healthy volunteers, and levels of this immune checkpoint were associated with Pseudomonas aeruginosa colonization. In addition, patients with Pseudomonas aeruginosa colonization showed a patent ET status, including poor inflammatory response, reduced HLA-DR expression and T-lymphocyte proliferation impairment. PD-L1/PD-1 blocking assays reverted the impaired adaptive response. Ultimately, monocytes from healthy volunteers cultured in the presence of the clinically relevant strain of Pseudomonas aeruginosa or serum collected from patients with CF colonized by Pseudomonas aeruginosa reproduced the previous observed features. CONCLUSIONS: Pseudomonas aeruginosa colonization in patients with CF was associated with PD-L1 overexpression and impaired T cell response, and LPS from this pathogen induced the observed phenotype. Our findings open new avenues for the use of anti-PD-1/PD-L1 immunotherapy in patients with CF who are colonized by Pseudomonas aeruginosa.

Oxygen Saturation on Admission Is a Predictive Biomarker for PD-L1 Expression on Circulating Monocytes and Impaired Immune Response in Patients With Sepsis.

Sepsis is a pathology in which patients suffer from a proinflammatory response and a dysregulated immune response, including T cell exhaustion. A number of therapeutic strategies to treat human sepsis, which are different from antimicrobial and fluid resuscitation treatments, have failed in clinical trials, and solid biomarkers for sepsis are still lacking. Herein, we classified 85 patients with sepsis into two groups according to their blood oxygen saturation (SaO2): group I (SaO2 ≤ 92%, n = 42) and group II (SaO2 > 92%, n = 43). Blood samples were taken before any treatment, and the immune response after ex vivo LPS challenge was analyzed, as well as basal expression of PD-L1 on monocytes and levels of sPD-L1 in sera. The patients were followed up for 1 month. Taking into account reinfection and exitus frequency, a significantly poorer evolution was observed in patients from group I. The analysis of HLA-DR expression on monocytes, T cell proliferation and cytokine profile after ex vivo LPS stimulation confirmed an impaired immune response in group I. In addition, these patients showed both, high levels of PD-L1 on monocytes and sPD-L1 in serum, resulting in a down-regulation of the adaptive response. A blocking assay using an anti-PD-1 antibody reverted the impaired response. Our data indicated that SaO2 levels on admission have emerged as a potential signature for immune status, including PD-L1 expression. An anti-PD-1 therapy could restore the T cell response in hypoxemic sepsis patients with SaO2 ≤ 92% and high PD-L1 levels.

PD-L1 Overexpression During Endotoxin Tolerance Impairs the Adaptive Immune Response in Septic Patients via HIF1α.

Sepsis, among other pathologies, is an endotoxin tolerance (ET)-related disease. On admission, we classified 48 patients with sepsis into 3 subgroups according to the ex vivo response to lipopolysaccharide. This response correlates with the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the ET degree. Moreover, the ET-related classification determines the outcome of these patients. Programmed cell death-ligand 1 (PD-L1) expression on septic monocytes is also linked with ET status. In addition to the regulation of cytokine production, one of the hallmarks of ET that significantly affects patients with sepsis is T-cell proliferation impairment or a poor switch to the adaptive response. PD-L1/programmed cell death-1 (PD-1) blocking and knockdown assays on tolerant monocytes from both patients with sepsis and the in vitro model reverted the impaired adaptive response. Mechanistically, the transcription factor hypoxia-inducible factor-1α (HIF1α) has been translocated into the nucleus and drives PD-L1 expression during ET in human monocytes. This fact, together with patient classification according to the ex vivo lipopolysaccharide response, opens an interesting field of study and potential personalized clinical applications, not only for sepsis but also for all ET-associated pathologies.

Protocol for the BRECAR study: a prospective cohort follow-up on the impact of breast reconstruction timing on health-related quality of life in women with breast cancer.

INTRODUCTION: The completion of postmastectomy breast reconstruction (BR) in women with breast cancer can last from months to years, and to our knowledge, there is a lack of studies that analyse how the different types and times of reconstruction impact on the patient's quality of life and psychosocial adjustment.The primary aim of the BREast Cancer Reconstruction (BRECAR Study) is twofold. First, to describe health-related quality of life (HRQoL), overall satisfaction with surgery and psychological impact (body image, self-esteem, depression and anxiety) on women who will have undergone a mastectomy with planned BR, considering the varied timing of BR procedures (immediate BR (iBR), delayed BR (dBR) and two-stage BR (2sBR)). To measure the impact on surgical outcomes, we will obtain data prior to and after surgery (6-9 and at 18 months of follow-up). Second, to analyse sociodemographic, clinical and psychosocial factors associated with HRQoL, satisfaction with surgery and psychological impact. METHODS AND ANALYSIS: A prospective, observational, clinical cohort study of women diagnosed with breast cancer who have an indication for mastectomy treated at La Paz University Hospital (Madrid, Spain).Patients will be classified into one of three groups under conditions of routine clinical practice, based on the type of BR planned: the iBR group, the dBR group and the 2sBR group.Under typical clinical practice conditions, we will perform three visits: baseline visit (presurgery), V1 (6-9 months after diagnosis) and V2 (18 months after diagnosis). A sample size of 210 patients is estimated. ETHICS AND DISSEMINATION: The study protocol and informed consent form have been reviewed and approved by the Institutional Review Board of La Paz Hospital (no. PI-2036). Dissemination of results will be via journal articles and conference presentations.

Influenza vaccination in people with type 2 diabetes, coverage, predictors of uptake, and perceptions. Result of the MADIABETES cohort a 7years follow up study.

OBJECTIVES: We aim to determine influenza vaccination uptake among people with diabetes included in the MADIABETES cohort study in order to identify predictors of uptake and to analyze reasons for adherence and non-adherence with vaccination. METHODS: Using data from the MADIABETES Study we conducted a retrospective case record form based study without controls. We included outpatients with type 2 diabetes mellitus. Information was obtained from computerized clinical records and by telephone survey. The main dependent variables were influenza vaccination uptake in the year 2013 and the reason for receiving or refusing vaccination. RESULTS: Overall, 65.7% had received the influenza vaccine in 2013. The mean number of influenza vaccines received from 2007 to 2013 was 3.24 (SD1.15), although 19.23% had not received any influenza vaccine and 23.3% had been vaccinated against pneumococcus. The variables that increased the probability of being vaccinated were inclusion in the age-based recommendation (⩾60years), having a chronic respiratory disease, previous pneumococcal vaccination, higher number of visits to the general practitioner, higher number of influenza vaccines, and longer time since diabetes diagnosis. A higher mean glycated haemoglobin value in 2013 was associated with a reduced probability of vaccination. Most patients (90%) agreed to be vaccinated following their physician's advice because of their age or their chronic conditions. The most common reason for refusal among men was the belief that they were not at risk (41.6% vs. 29.79% in women); the most common reason for refusal among women was fear of adverse reactions (32.53% vs. 20.23% in men). CONCLUSIONS: The uptake of influenza vaccination among diabetic patients in the present study was below desirable levels. The main barrier to vaccination was lack of knowledge regarding the need for and risks and advantages of influenza vaccination. Healthcare professionals should educate and encourage influenza vaccination among people with diabetes.

Cardiovascular and all-cause mortality in patients with type 2 diabetes mellitus in the MADIABETES Cohort Study: Association with chronic kidney disease.

AIMS: To assess the prevalence of stage 3-5 chronic kidney disease (CKD) at baseline and to identify associated risk factors. To determine the effect of CKD and CKD stage according to estimated glomerular filtration rate (eGFR) and albuminuria categories on all-cause and cardiovascular mortality after a 5-year follow-up. METHODS: Prospective cohort study of 3443 outpatients with type 2 diabetes mellitus. RESULTS: The prevalence of CKD was 28.32% (95% CI, 26.84-29.86); and variables most strongly associated were: age >74 years (OR, 19.88; 95% CI, 12.89-30.68) and albuminuria (OR, 2.27; 95% CI, 1.72-3.00). During follow-up, 221 CKD patients (22.90%) died compared with 203 non-CKD patients (8.31%) (p<0.01). The adjusted HR of CKD for cardiovascular and all-cause mortality was 1.82 (95% CI, 1.36-2.44) and 2.11 (95% CI, 1.61-2.76) for those with LDL cholesterol =135 mg/dl, respectively. The adjusted HR of very-high-risk CKD for all-cause mortality was 4.44 (95% CI, 2.31-8.53) in aged <75 years and 1.80 (95% CI, 1.19-2.72) in aged ≥75 years. CONCLUSIONS: CKD at baseline is an independent risk factor for all-cause and cardiovascular mortality in the overall cohort, men and women, or in primary and secondary prevention of coronary heart disease. Albuminuria is an independent risk factor for all-cause and cardiovascular mortality only in primary prevention.

Validating prediction scales of type 2 diabetes mellitus in Spain: the SPREDIA-2 population-based prospective cohort study protocol.

INTRODUCTION: The incidence of type 2 diabetes mellitus (T2DM) is increasing worldwide. When diagnosed, many patients already have organ damage or advance subclinical atherosclerosis. An early diagnosis could allow the implementation of lifestyle changes and treatment options aimed at delaying the progression of the disease and to avoid cardiovascular complications. Different scores for identifying undiagnosed diabetes have been reported, however, their performance in populations of southern Europe has not been sufficiently evaluated. The main objectives of our study are: to evaluate the screening performance and cut-off points of the main scores that identify the risk of undiagnosed T2DM and prediabetes in a Spanish population, and to develop and validate our own predictive models of undiagnosed T2DM (screening model), and future T2DM (prediction risk model) after 5-year follow-up. As a secondary objective, we will evaluate the atherosclerotic burden of the population with undiagnosed T2DM. METHODS AND ANALYSIS: Population-based prospective cohort study with baseline screening, to evaluate the performance of the FINDRISC, DANISH, DESIR, ARIC and QDScore, against the gold standard tests: Fasting plasma glucose, oral glucose tolerance and/or HbA1c. The sample size will include 1352 participants between the ages of 45 and 74 years. ANALYSIS: sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio positive, likelihood ratio negative and receiver operating characteristic curves and area under curve. Binary logistic regression for the first 700 individuals (derivation) and last 652 (validation) will be performed. All analyses will be calculated with their 95% CI; statistical significance will be p<0.05. ETHICS AND DISSEMINATION: The study protocol has been approved by the Research Ethics Committee of the Carlos III Hospital (Madrid). The score performance and predictive model will be presented in medical conferences, workshops, seminars and round table discussions. Furthermore, the predictive model will be published in a peer-reviewed medical journal to further increase the exposure of the scores.