T Cell Homeostasis Disturbances in a Cohort of Long-Term Elite Controllers of HIV Infection.

Elite controllers (ECs) are people living with HIV (PLWH) able to control HIV replication without antiretroviral therapy and have been proposed as a model of a functional HIV cure. Much evidence suggests that this spontaneous control of HIV has a cost in terms of T cell homeostasis alterations. We performed a deep phenotypic study to obtain insight into T cell homeostasis disturbances in ECs maintaining long-term virologic and immunologic control of HIV (long-term elite controllers; LTECs). Forty-seven PLWH were included: 22 LTECs, 15 non-controllers under successful antiretroviral therapy (onART), and 10 non-controllers not receiving ART (offART). Twenty uninfected participants (UCs) were included as a reference. T cell homeostasis was analyzed by spectral flow cytometry and data were analyzed using dimensionality reduction and clustering using R software v3.3.2. Dimensionality reduction and clustering yielded 57 and 54 different CD4 and CD8 T cell clusters, respectively. The offART group showed the highest perturbation of T cell homeostasis, with 18 CD4 clusters and 15 CD8 clusters significantly different from those of UCs. Most of these alterations were reverted in the onART group. Interestingly, LTECs presented several disturbances of T cell homeostasis with 15 CD4 clusters and 13 CD8 clusters different from UC. Moreover, there was a specific profile of T cell homeostasis alterations associated with LTECs, characterized by increases in clusters of naïve T cells, increases in clusters of non-senescent effector CD8 cells, and increases in clusters of central memory CD4 cells. These results demonstrate that, compared to ART-mediated control of HIV, the spontaneous control of HIV is associated with several disturbances in CD4 and CD8 T cell homeostasis. These alterations could be related to the existence of a potent and efficient virus-specific T cell response, and to the ability to halt disease progression by maintaining an adequate pool of CD4 T cells.

A specific natural killer cells phenotypic signature associated to long term elite control of HIV infection.

Elite controllers (ECs) are an exceptional group of people living with HIV (PLWH) that control HIV replication without therapy. Among the mechanisms involved in this ability, natural killer (NK)-cells have recently gained much attention. We performed an in-deep phenotypic analysis of NK-cells to search for surrogate markers associated with the long term spontaneous control of HIV. Forty-seven PLWH (22 long-term EC [PLWH-long-term elite controllers (LTECs)], 15 noncontrollers receiving antiretroviral treatment [ART] [PLWH-onART], and 10 noncontrollers cART-naïve [PLWH-offART]), and 20 uninfected controls were included. NK-cells homeostasis was analyzed by spectral flow cytometry using a panel of 15 different markers. Data were analyzed using FCSExpress and R software for unsupervised multidimensional analysis. Six different subsets of NK-cells were defined on the basis of CD16 and CD56 expression, and the multidimensional analysis revealed the existence of 68 different NK-cells clusters based on the expression levels of the 15 different markers. PLWH-offART presented the highest disturbance of NK-cells homeostasis and this was not completely restored by long-term ART. Interestingly, long term spontaneous control of HIV (PLWH-LTEC group) was associated with a specific profile of NK-cells homeostasis disturbance, characterized by an increase of CD16dimCD56dim subset when compared to uninfected controls (UC) group and also to offART and onART groups (p < 0.0001 for the global comparison), an increase of clusters C16 and C26 when compared to UC and onART groups (adjusted p-value < 0.05 for both comparisons), and a decrease of clusters C10 and C20 when compared to all the other groups (adjusted p-value < 0.05 for all comparisons). These findings may provide clues to elucidate markers of innate immunity with a relevant role in the long-term control of HIV.

PRPH2-Related Retinal Dystrophies: Mutational Spectrum in 103 Families from a Spanish Cohort.

PRPH2, one of the most frequently inherited retinal dystrophy (IRD)-causing genes, implies a high phenotypic variability. This study aims to analyze the PRPH2 mutational spectrum in one of the largest cohorts worldwide, and to describe novel pathogenic variants and genotype-phenotype correlations. A study of 220 patients from 103 families recruited from a database of 5000 families. A molecular diagnosis was performed using classical molecular approaches and next-generation sequencing. Common haplotypes were ascertained by analyzing single-nucleotide polymorphisms. We identified 56 variants, including 11 novel variants. Most of them were missense variants (64%) and were located in the D2-loop protein domain (77%). The most frequently occurring variants were p.Gly167Ser, p.Gly208Asp and p.Pro221_Cys222del. Haplotype analysis revealed a shared region in families carrying p.Leu41Pro or p.Pro221_Cys222del. Patients with retinitis pigmentosa presented an earlier disease onset. We describe the largest cohort of IRD families associated with PRPH2 from a single center. Most variants were located in the D2-loop domain, highlighting its importance in interacting with other proteins. Our work suggests a likely founder effect for the variants p.Leu41Pro and p.Pro221_Cys222del in our Spanish cohort. Phenotypes with a primary rod alteration presented more severe affectation. Finally, the high phenotypic variability in PRPH2 hinders the possibility of drawing genotype-phenotype correlations.

Fibroblast growth factor 23 independently predicts adverse outcomes after an acute coronary syndrome.

AIMS: Abnormalities of mineral metabolism (MM) have been related to cardiovascular disorders. There are no reports on the prognostic role of MM after an acute coronary syndrome (ACS). We aim to assess the prognostic role of MM after an ACS. METHODS AND RESULTS: Plasma levels of components of MM [fibroblast growth factor 23 (FGF23), calcidiol, parathormone, klotho, and phosphate], high-sensitivity C-reactive protein, and N-terminal-pro-brain natriuretic peptide were measured in 1190 patients at discharge from an ACS. The primary outcome was a combination of acute ischaemic events, heart failure (HF) and death. Secondary outcomes were the separate components of the primary outcome. Age was 61.7 ± 12.2 years, and 77.1% were men. Median follow-up was 5.44 (3.03-7.46) years. Two hundred and ninety-four patients developed the primary outcome. At multivariable analysis FGF23 (hazard ratio, HR 1.18 [1.08-1.29], P < 0.001), calcidiol (HR 0.86 [0.74-1.00], P = 0.046), previous coronary or cerebrovascular disease, and hypertension were independent predictors of the primary outcome. The predictive power of FGF23 was homogeneous across different subgroups of population. FGF23 (HR 1.45 [1.28-1.65], P < 0.001) and parathormone (HR 1.06 1.01-1.12]; P = 0.032) resulted as independent predictors of HF. FGF23 (HR 1.21 [1.07-1.37], P = 0.002) and calcidiol (HR 0.72 [0.54-0.97), P = 0.028) were independent predictors of death. No biomarker predicted acute ischaemic events. FGF23 predicted independently the primary outcome in patients with estimated glomerular filtration rate > 60 mL/min/1.73 m2 . CONCLUSIONS: FGF23 and other components of MM are independent predictors of HF and death after an ACS. This effect is homogeneous across different subgroups of population, and it is not limited to patients with chronic kidney disease.

Androgen receptor polyQ alleles and COVID-19 severity in men: A replication study.

BACKGROUND: Ample evidence indicates a sex-related difference in severity of COVID-19, with less favorable outcomes observed in men. Genetic factors have been proposed as candidates to explain this difference. The polyglutamine (polyQ) polymorphism in the androgen receptor gene has been recently described as a genetic biomarker of COVID-19 severity. OBJECTIVE: To test the association between the androgen receptor polyQ polymorphism and COVID-19 severity in a large cohort of COVID-19 male patients. MATERIALS AND METHODS: This study included 1136 male patients infected with SARS-CoV-2 as confirmed by positive PCR. Patients were retrospectively and prospectively enrolled from March to November 2020. Patients were classified according to their severity into three categories: oligosymptomatic, hospitalized and severe patients requiring ventilatory support. The number of CAG repeats (polyQ polymorphism) at the androgen receptor was obtained by PCR and patients were classified as either short (<23 repeats) or long (≥23 repeats) allele carriers. The association between polyQ alleles (short or long) and COVID-19 severity was assessed by Chi-squared (Chi2 ) and logistic regression analysis. RESULTS: The mean number of polyQ CAG repeats was 22 (±3). Patients were classified as oligosymptomatic (15.5%), hospitalized (63.2%), and severe patients (21.3%) requiring substantial respiratory support. PolyQ alleles distribution did not show significant differences between severity classes in our cohort (Chi2 test p > 0.05). Similar results were observed after adjusting by known risk factors such as age, comorbidities, and ethnicity (multivariate logistic regression analysis). DISCUSSION: Androgen sensitivity may be a critical factor in COVID-19 disease severity. However, we did not find an association between the polyQ polymorphism and the COVID-19 severity. Additional studies are needed to clarify the mechanism underlying the association between androgens and COVID-19 outcome. CONCLUSIONS: The results obtained in our study do not support the role of this polymorphism as biomarker of COVID-19 severity.

Radiaciones ionizantes en trabajadores sanitarios: función tiroidea y niveles de riesgo de exposición laboral / Ionizing radiation in healthcare workers: thyroid function and risk levels of occupational exposure

Introducción: Uno de los sectores donde más se emplean las radiaciones ionizantes es el sanitario. Existen evidencias que sugieren que la exposición a radiaciones ionizantes podría relacionarse con alteraciones en las hormonas tiroideas. Objetivos: Analizar la posible asociación de alteraciones de hormonas tiroideas con la exposición a radiaciones ionizantes en trabajadores sanitarios según la clasificación actual con mayor probabilidad de riesgo (PER A) y menor probabilidad de riesgo (PER B), y la influencia de otros factores asociados, así como, valorar las dosimetrías personales en función de la exposición laboral en distintas zonas de trabajo según el nivel de riesgo. Material y Métodos: Estudio retrospectivo comparativo de valores de TSH, T3 y T4 en trabajadores expuestos (PER A y/o PER B) y un grupo control. Finalmente, se realizó una comparación de valores de dosimetrías personales respecto a zonas de trabajo con distintos niveles de exposición. Resultados: se halla un ligero aumento de los valores de TSH en los trabajadores PER B (2,6 ± 1,4) y PER A (2,7 ± 1,3), frente a no PER (2,4 ± 1,5) sin alcanzar significación estadística. Se ha encontrado diferencia estadísticamente significativa en las dosis quinquenales individuales de los trabajadores en relación a los niveles de exposición laboral con valores de 0,1 ± 0,3 en la zona de exposición baja y de 0,9 ± 1,4 en la zona de exposición media/alta. Conclusiones: Se evidencia la relación entre exposición laboral a radiaciones ionizantes y los valores individuales dosimétricos en trabajadores sanitarios expuestos, por lo que parece conveniente considerar también las zonas de trabajo de cara a las medidas preventivas realizadas en los trabajos con riesgo de exposición a radiaciones ionizantes. (AU)

Introduction: One of the sectors with the highest rates of use of ionizing radiations is the healthcare system. There is some evidence to suggest that exposure to ionizing radiations could be associated with alterations in thyroid hormone levels. Objectives: To analyze a possible association between the levels of thyroid hormones and the occupational exposure to ionizing radiation in healthcare workers according to the current classification of PER A (with more probability of risk of exposure) and PER B (with less probability of risk of exposure), plus the influence of other factors. To analyze the values of personal dosimeters according to the occupational exposure in the different areas of work and level of risk. Material and Methods: Retrospective comparative study of TSH, T3 and T4 in exposed healthcare workers (PER A and PER B) and control group, working from 2014 to 2019. Levels of personal dosimeters were compared in the areas classified according to the level of risk of exposure. Results: No statistically significant relationship was found between the levels of thyroid hormones and the occupational exposure to radiation in PER A, PER B, though higher levels of TSH were found in the exposed groups PER B (2,6 ± 1,4) and PER A (2,7 ± 1,3) compared to TSH levels in the control group (2,4 ± 1,5). There is a statistically significant difference between the individual five-year dose of healthcare workers and the levels of occupational exposure, with values in the areas classified according to the level of exposure with values of 0,1 ± 0,3 in the low exposure area and 0,9 ± 1,4 in the medium/high exposure area. Conclusions: There is a relationship between occupational exposure to ionizing radiations and the individual dosimetric values, thus areas of work should be considered when designing preventive measures in healthcare workers exposed to ionizing radiations. (AU)

Estimation of recurrent atherosclerotic cardiovascular event risk in patients with established cardiovascular disease: the updated SMART2 algorithm.

AIMS: The 10-year risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events in patients with established ASCVD can be estimated with the Secondary Manifestations of ARTerial disease (SMART) risk score, and may help refine clinical management. To broaden generalizability across regions, we updated the existing tool (SMART2 risk score) and recalibrated it with regional incidence rates and assessed its performance in external populations. METHODS AND RESULTS: Individuals with coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysms were included from the Utrecht Cardiovascular Cohort-SMART cohort [n = 8355; 1706 ASCVD events during a median follow-up of 8.2 years (interquartile range 4.2-12.5)] to derive a 10-year risk prediction model for recurrent ASCVD events (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular mortality) using a Fine and Gray competing risk-adjusted model. The model was recalibrated to four regions across Europe, and to Asia (excluding Japan), Japan, Australia, North America, and Latin America using contemporary cohort data from each target region. External validation used data from seven cohorts [Clinical Practice Research Datalink, SWEDEHEART, the international REduction of Atherothrombosis for Continued Health (REACH) Registry, Estonian Biobank, Spanish Biomarkers in Acute Coronary Syndrome and Biomarkers in Acute Myocardial Infarction (BACS/BAMI), the Norwegian COgnitive Impairment After STroke, and Bialystok PLUS/Polaspire] and included 369 044 individuals with established ASCVD of whom 62 807 experienced an ASCVD event. C-statistics ranged from 0.605 [95% confidence interval (CI) 0.547-0.664] in BACS/BAMI to 0.772 (95% CI 0.659-0.886) in REACH Europe high-risk region. The clinical utility of the model was demonstrated across a range of clinically relevant treatment thresholds for intensified treatment options. CONCLUSION: The SMART2 risk score provides an updated, validated tool for the prediction of recurrent ASCVD events in patients with established ASCVD across European and non-European populations. The use of this tool could allow for a more personalized approach to secondary prevention based upon quantitative rather than qualitative estimates of residual risk.

High SARS-CoV-2 viral load is associated with a worse clinical outcome of COVID-19 disease.

COVID-19 severity and progression are determined by several host and virological factors that may influence the final outcome of SARS-CoV-2-infected patients. The objective of this work was to determine a possible association between viral load, obtained from nasopharyngeal swabs, and the severity of the infection in a cohort of 448 SARS-CoV-2-infected patients from a hospital in Madrid during the first outbreak of the pandemic in Spain. To perform this, we clinically classified patients as mild, moderate and severe COVID-19 according to a number of clinical parameters such as hospitalization requirement, need of oxygen therapy, admission to intensive care units and/or death. Also, Ct values were determined using SARS-CoV-2-specific oligonucleotides directed to ORF1ab. Here we report a statistically significant association between viral load and disease severity, a high viral load being associated with worse clinical prognosis, independently of several previously identified risk factors such as age, sex, hypertension, cardiovascular disease, diabetes, obesity and lung disease (asthma and chronic obstructive pulmonary disease). The data presented here reinforce viral load as a potential biomarker for predicting disease severity in SARS-CoV-2-infected patients. It is also an important parameter in viral evolution since it relates to the numbers and types of variant genomes present in a viral population, a potential determinant of disease progression.

Overcoming PLK1 inhibitor resistance by targeting mevalonate pathway to impair AXL-TWIST axis in colorectal cancer.

New therapeutic targets are revolutionizing colorectal cancer clinical management, opening new horizons in metastatic patients' outcome. Polo Like Kinase1 (PLK1) inhibitors have high potential as antitumoral agents, however, the emergence of drug resistance is a major challenge for their use in clinical practice. Overcoming this challenge represents a hot topic in current drug discovery research. BI2536-resistant colorectal cancer cell lines HT29R, RKOR, SW837R and HCT116R, were generated in vitro and validated by IG50 assays and xenografts models by the T/C ratio. Exons 1 and 2 of PLK1 gene were sequenced by Sanger method. AXL pathway, Epithelial-to-Mesenchymal transition (EMT) and Multidrug Resistance (MDR1) were studied by qPCR and western blot in resistant cells. Simvastatin as a re-sensitizer drug was tested in vitro and the drug combination strategies were validated in vitro and in vivo. PLK1 gene mutation R136G was found for RKOR. AXL pathway trough TWIST1 transcription factor was identified as one of the mechanisms involved in HT29R, SW837R and HCT116R lines, inducing EMT and upregulation of MDR1. Simvastatin was able to impair the mechanisms activated by adaptive resistance and its combination with BI2536 re-sensitized resistant cells in vitro and in vivo. Targeting the mevalonate pathway contributes to re-sensitizing BI2536-resistant cells in vitro and in vivo, raising as a new strategy for the clinical management of PLK1 inhibitors.

Tasa de ultrafiltración horaria ajustada a peso corporal y mortalidad en hemodiálisis / Ultrafiltration rate adjusted to body weight and mortality in hemodialysis patients

Antecedentes y objetivo: La mortalidad de los pacientes en hemodiálisis es alta. Una tasa de ultrafiltración horaria ajustada por peso (UFR/W) elevada se ha asociado con episodios de hipotensión arterial y con mayor riesgo de muerte y/o eventos cardiovasculares. Material y métodos: Hemos evaluado la asociación entre UFR/W y mortalidad en 215 pacientes en hemodiálisis prevalentes seguidos durante 28 ± 6,12 meses. Se estimaron características clínicas basales y UFR/W media a lo largo del seguimiento. Resultados: La UFR/W media fue 9,0 ± 2,4 y los terciles 7,1 y 10,1 mL/kg/h. Se categorizó a la población en función del tiempo que habían estado con UFR/W igual o superior a los puntos de corte descritos en la literatura como relacionados con mayor mortalidad (10,0 mL/kg/h y 13,0 mL/kg/h). Los pacientes con mayor UFR/W fueron más jóvenes, con mayor ganancia de peso interdiálisis y porcentaje de reducción de peso, pero con menor peso seco, inicial y final. Durante el seguimiento, fallecieron 46 (21,4%) personas de las cuales la mayoría eran > 70 años, diabéticas o con enfermedad cardiovascular. No hubo diferencias en la mortalidad entre los grupos de UFR/W ni en la UFR/W entre los fallecidos y no fallecidos. En comparación con estudios previos donde describieron la asociación entre UFR/W y mortalidad, en nuestra población había más prevalencia de medicación protectora cardiovascular y no se observaron UFR/W tan altas. Conclusión: En nuestro medio, la UFR/W más elevada se observó en pacientes más jóvenes y de menor peso y no se asoció con mayor mortalidad. (AU)

Background and aims: Mortality among hemodialysis patients remains high. An elevated ultrafiltration rate adjusted by weight (UFR/W) has been associated with hypotension and higher risk of death and/or cardiovascular events. Methods: We evaluated the association between UFR/W and mortality in 215 hemodialysis patients. The mean follow-up was 28 ± 6.12 months. We collected patientś baseline characteristics and mean UFR/W throughout the follow-up. Results: Mean UFR/W was 9.0 ± 2,4 and tertiles 7.1 y 10.1 mL/kg/h. We divided our population according to the percentage of sessions with UFR/W above the limits described in the literature associated with increased mortality (10.0 mL/kg/h and 13.0 mL/kg/h). Patients with higher UFR/W were younger, with higher interdialytic weight gain and weight reduction percentage but lower dry, pre and post dialysis weight. Throughout the follow-up, 46 (21.4%) patients died, the majority over 70 years old, diabetic or with cardiovascular disease. There were neither differences regarding mortality between groups nor differences in UFR/W among patients who died and those who did not. Contrary to previous studies, we did not find an association between UFR/W and mortality, maybe due to a higher prevalence in the use of cardiovascular protection drugs and lower UFR/W. Conclusions: The highest UFR/W were observed in younger patients with lower weight and were not associated with an increased mortality. (AU)

Time to a Negative SARS-CoV-2 PCR Predicts Delayed Return to Work After Medical Leave in COVID-19 Infected Health Care Workers.

OBJECTIVE: To investigate whether HCWs return to work (RTW) after COVID-19 was associated with time to a negative viral detection test. METHODS: To evaluate the association of RTW with an undetectable RT-PCR adjusting for different factors. RESULTS: Three hundred seventy-five HCWs who required medical leave for COVID-19 at a hospital in Madrid. Multivariable analyses confirmed the association of delayed RTW with interval to negative PCR (ORadj 1.12, 95% CI 1.08, 1.17) as well as age, sex, and nursing staff and clinical support services compared to physicians. A predictive model based on those variables is proposed, which had an area under the receiver operating curve of 0.82. CONCLUSIONS: Delayed RTW was associated with longer interval to a negative RT-PCR after symptom onset, adjusting for occupational category, age, and sex.

Urinary Cyclophilin A as Marker of Tubular Cell Death and Kidney Injury.

Background: Despite the term acute kidney injury (AKI), clinical biomarkers for AKI reflect function rather than injury and independent markers of injury are needed. Tubular cell death, including necroptotic cell death, is a key feature of AKI. Cyclophilin A (CypA) is an intracellular protein that has been reported to be released during necroptosis. We have now explored CypA as a potential marker for kidney injury in cultured tubular cells and in clinical settings of ischemia-reperfusion injury (IRI), characterized by limitations of current diagnostic criteria for AKI. Methods: CypA was analyzed in cultured human and murine proximal tubular epithelial cells exposed to chemical hypoxia, hypoxia/reoxygenation (H/R) or other cell death (apoptosis, necroptosis, ferroptosis) inducers. Urinary levels of CypA (uCypA) were analyzed in patients after nephron sparing surgery (NSS) in which the contralateral kidney is not disturbed and kidney grafts with initial function. Results: Intracellular CypA remained unchanged while supernatant CypA increased in parallel to cell death induction. uCypA levels were higher in NSS patients with renal artery clamping (that is, with NSS-IRI) than in no clamping (NSS-no IRI), and in kidney transplantation (KT) recipients (KT-IRI) even in the presence of preserved or improving kidney function, while this was not the case for urinary Neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, higher uCypA levels in NSS patients were associated with longer surgery duration and the incidence of AKI increased from 10% when using serum creatinine (sCr) or urinary output criteria to 36% when using high uCypA levels in NNS clamping patients. Conclusions: CypA is released by kidney tubular cells during different forms of cell death, and uCypA increased during IRI-induced clinical kidney injury independently from kidney function parameters. Thus, uCypA is a potential biomarker of kidney injury, which is independent from decreased kidney function.

Programa de intervención de gestión de edad y cambios de hábitos en un hospital terciario de Madrid / Program of age management and changes of habits in a tertiary hospital in Madrid

Objetivos: La edad media de los trabajadores europeos sanitarios es cada vez mayor, con unas elevadas demandas físicas y psíquicas, lo que repercute en su calidad de vida. Parece necesario realizar intervenciones sobre la salud y bienestar. Valorar si se mejora la calidad de vida percibida de trabajadores sanitarios tras una intervención y si es más eficaz en función de variables como el puesto de trabajo. Material y Métodos: estudio de intervención prospectivo; población: trabajadores iguales o mayores de 45 años que trabajan en un hospital terciario; métodos: programa “Gestión de la edad y cambio de hábitos”, variables: cuestionario SF-12, CSF-12 Y CSM-12 y variables personales y laborales. Resultados: tras la intervención sólo se observa un aumento significativo de CSM-12 en trabajadores administrativos en comparación con las categorías profesionales de tipo sanitario (53,6± 6,85 vs 47,5±7,92, p=0,036). Conclusiones: los programas de intervención sobre gestión de edad en los lugares de trabajo pueden ser de utilidad (AU)

Objectives: The average age of European health workers is increasing, with high physical and mental demands, which affects their quality of life. Health and wellness interventions seem necessary. To assess whether the perceived quality of life of health workers is improved after an intervention and whether it is more effective depending on variables such as the job. Material and Methods: prospective intervention study; population: workers equal to or older than 45 years who work in a tertiary hospital; methods: “Age management and change of habits” program, variables: SF-12 questionnaire, CSF-12 and CSM-12 and personal and work variables. Results: after the intervention, a significant increase in CSM-12 was only observed in administrative workers compared to the professional categories of health type (53.6 ± 6.85 vs 47.5 ± 7.92, p = 0.036). Conclusions: intervention programs about age management at the workplaces could be useful (AU)

Ultrafiltration rate adjusted to body weight and mortality in hemodialysis patients.

BACKGROUND AND AIMS: Mortality among hemodialysis patients remains high. An elevated ultrafiltration rate adjusted by weight (UFR/W) has been associated with hypotension and higher risk of death and/or cardiovascular events. METHODS: We evaluated the association between UFR/W and mortality in 215 hemodialysis patients. The mean follow-up was 28 ±â€¯6.12 months. We collected patients' baseline characteristics and mean UFR/W throughout the follow-up. RESULTS: Mean UFR/W was 9.0 ±â€¯2,4 and tertiles 7.1 y 10.1 mL/kg/h. We divided our population according to the percentage of sessions with UFR/W above the limits described in the literature associated with increased mortality (10.0 ml/kg/h and 13.0 mL/kg/h). Patients with higher UFR/W were younger, with higher interdialytic weight gain and weight reduction percentage but lower dry, pre and post dialysis weight. Throughout the follow-up, 46 (21.4%) patients died, the majority over 70 years old, diabetic or with cardiovascular disease. There were neither differences regarding mortality between groups nor differences in UFR/W among patients who died and those who did not. Contrary to previous studies, we did not find an association between UFR/W and mortality, maybe due to a higher prevalence in the use of cardiovascular protection drugs and lower UFR/W. CONCLUSIONS: The highest UFR/W were observed in younger patients with lower weight and were not associated with an increased mortality.

Impact of the antibiotic-cargo from MSNs on Gram-positive and Gram-negative bacterial biofilms.

Mesoporous silica nanoparticles (MSNs) are promising drug nanocarriers for infection treatment. Many investigations have focused on evaluating the capacity of MSNs to encapsulate antibiotics and release them in a controlled fashion. However, little attention has been paid to determine the antibiotic doses released from these nanosystems that are effective against biofilm during the entire release time. Herein, we report a systematic and quantitative study of the direct effect of the antibiotic-cargo released from MSNs on Gram-positive and Gram-negative bacterial biofilms. Levofloxacin (LVX), gentamicin (GM) and rifampin (RIF) were separately loaded into pure-silica and amino-modified MSNs. This accounts for the versatility of these nanosystems since they were able to load and release different antibiotic molecules of diverse chemical nature. Biological activity curves of the released antibiotic were determined for both bacterial strains, which allowed to calculate the active doses that are effective against bacterial biofilms. Furthermore, in vitro biocompatibility assays on osteoblast-like cells were carried out at different periods of times. Albeit a slight decrease in cell viability was observed at the very initial stage, due to the initial burst antibiotic release, the biocompatibility of these nanosystems is evidenced since a recovery of cell viability was achieved after 72 h of assay. Biological activity curves for GM released from MSNs exhibited sustained patterns and antibiotic doses in the 2-6 µg/mL range up to 100 h, which were not enough to eradicate biofilm. In the case of LVX and RIF first-order kinetics featuring an initial burst effect followed by a sustained release above the MIC up to 96 h were observed. Such doses reduced by 99.9% bacterial biofilm and remained active up to 72 h with no emergence of bacterial resistance. This pioneering research opens up promising expectations in the design of personalized MSNs-based nanotherapies to treat chronic bone infection.

Low Intracellular Water, Overhydration, and Mortality in Hemodialysis Patients.

BACKGROUND: In hemodialysis patients, extracellular water (ECW) overload predicts all-cause and cardiovascular mortality. The primary aim of the present study was to analyze changes in post-dialysis (i.e., following removal of excess ECW) ECW, intracellular water (ICW), and the overhydration (OH) parameter over time. Additionally, the association of these parameters with mortality was explored. PATIENTS AND METHODS: Prospective study of prevalent hemodialysis patients (n = 124) followed for a median of 20 (interquartile range (IQR) 8-31) months. In three visits, inflammation (C-reactive protein) and post-dialysis fluid status (bioimpedance, BIS) were assessed. RESULTS: During follow-up, the overhydration (OH) parameter increased (-0.696 ± 1.6 vs. 0.268 ± 1.7 L; p = 0.007) at the expense of a decrease in intracellular water (ICW) (19.90 ± 4.5 vs. 18.72 ± 4.1 24 L; p = 0.006) with a non-significant numerical increase in ECW/ICW ratio (0.795 ± 0.129 vs. 0.850 ± 0.143; p = 0.055). Baseline ICW positively correlated with muscle mass and energy intake and negatively with C-reactive protein and it was lower in those who died than in survivors (15.09 ± 2.36 vs. 18.87 ± 4.52 L; p = 0.004). In Kaplan-Meier analysis, patients with low baseline ICW (≤17 L) and high ECW/ICW ratio (≥0.84) were at an increased risk of death. Baseline ICW was also associated with the risk of death in adjusted Cox proportional hazards models (HR 0.62 (0.40-0.98) p = 0.04). CONCLUSIONS: In hemodialysis patients, the post-dialysis OH parameter increased over time while ICW decreased, without changes in ECW. Low baseline post-dialysis ICW correlated with muscle wasting and inflammation and was an independent risk factor for mortality.

A Prospective Randomized Trial Comparing the Functional Results of Buddy Taping Versus Closed Reduction and Cast Immobilization in Patients With Fifth Metacarpal Neck Fractures.

PURPOSE: Although fifth metacarpal neck fractures are typically treated nonsurgically, most often with closed reduction and orthosis immobilization, cast immobilization may not improve outcomes compared with buddy taping without reduction. The aim of this study was to compare functional outcomes of buddy taping versus reduction and cast immobilization in patients with fifth metacarpal neck fractures. METHODS: Adult patients with acute fifth metacarpal neck fractures with less than 70º volar angulation and without rotational deformity were randomly assigned to be treated either with buddy taping or a cast after closed reduction. The primary outcome was the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire score at 9 weeks. Secondary outcomes included the DASH score at 3 weeks and 1 year, range of motion of the metacarpophalangeal joint, pain, grip strength, return to work, radiographic angulation, and complication rate. RESULTS: We recruited 72 patients between August 2016 and January 2018. After 3 weeks, the DASH score was significantly lower for patients treated with buddy taping (19.7 ± 19.7) compared with cast immobilization (44.6 ± 15.0). At 9 weeks, clinical outcomes in the buddy taping group were better in terms of range of motion and DASH score, with a mean difference of 6.3 points, which did not exceed the minimally clinically important difference. There were more complications in the cast immobilization group. Fracture angulation after reduction was followed by a loss of reduction at 3 weeks' follow-up and equivalent residual radiographic volar angulation was observed at 3 and 9 weeks after injury in both groups. Duration of time off from work was 28 days shorter with buddy taping compared with cast treatment. CONCLUSIONS: There is no benefit to reduction and orthosis immobilization of fifth metacarpal neck fractures with an initial angulation less than 70°. Use of buddy taping and early mobilization had good clinical results as well as significant improvement in time lost from work. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I.

Gender, Albuminuria and Chronic Kidney Disease Progression in Treated Diabetic Kidney Disease.

BACKGROUND: Women are reported to have a lower incidence of renal replacement therapy, despite a higher prevalence of chronic kidney disease (CKD). AIM: To analyze diabetic kidney disease (DKD) progression in men and women. METHODS: Prospective cohort: n = 261, 35% women, new consecutive nephrology DKD referrals. RESULTS: Women smoked less and better complied with the dietary phosphate and sodium restrictions. Despite a less frequent nephrology referral, women had lower baseline albuminuria. Over a 30 ± 10-month follow-up, albuminuria decreased in women and the estimated glomerular filtration rate (eGFR) loss was slower than in men. However, the percentage of rapid progressors was similar in both sexes. The best multivariate model predicting rapid progression in men (area under curve (AUC) = 0.92) and women differed. Albuminuria and fractional excretion of phosphate (FEphosphate) were part of the men multivariable model, but not of women. The AUC for the prediction of rapid progression by albuminuria was higher in men than in women, and the albuminuria cut-off points also differed. In women, there was a higher percentage of rapid progressors who had baseline physiological albuminuria. CONCLUSIONS: Female DKD differs from male DKD: albuminuria was milder and better responsive to therapy, the loss of eGFR was slower and the predictors of rapid progression differed from men: albuminuria was a better predictor in men than in women. Lifestyle factors may contribute to the differences.

Profilin is a marker of severity in allergic respiratory diseases.

BACKGROUND: The capacity of profilin to induce allergic symptoms in patients with respiratory allergy has been questioned. In this sense, the aim of this study was to investigate the correlation between profilin exposure and induction of symptoms in a prospective case-control study. METHODS: The concentration of profilin as well as pollen levels in the air was measured. A diary score of symptoms was collected from allergic patients. Seventy-nine individuals were included in the study; fifty cases and 28 controls were positive or negative to profilin, respectively. Conjunctival and bronchial provocation tests were performed with purified profilin (Pho d 2) in a subgroup of cases and controls. RESULTS: Profilin was detected in the environment on 133 days (maximum peak of 0.56 ng/m3 ). A positive correlation between profilin and pollen count of Olea and Poaceae was observed (ρ = 0.24; P < .001). Intensity of total, nasal and ocular symptoms was statistically higher in cases than in controls (P < .001). The risk of suffering symptoms, measured by the percentage of patients who presented any of the symptoms each day, was also higher in cases than in controls. The provocation test was positive in 95% of bronchial and 90% of conjunctival challenges in cases, and negative in all controls. CONCLUSIONS: Profilin was detected in the environment and had the ability to induce a specific allergen response. Patients sensitized to this panallergen showed more symptoms and were more likely to have symptoms. Therefore, sensitization to profilin seems to be a marker of severity in patients with rhinoconjunctivitis and asthma mediated by pollen.

Comparison of impulse oscillometry and spirometry for detection of airway hyperresponsiveness to methacholine, mannitol, and eucapnic voluntary hyperventilation in children.

BACKGROUND: Forced expiratory maneuvers are usually difficult in young children. Impulse oscillometry (IOS) requires no active cooperation, is noninvasive, rapid, and easy to perform. This study aimed to compare IOS indexes and forced expiratory volume in 1 second (FEV1) in children for the assessment of bronchial hyperreactivity to methacholine, mannitol, and eucapnic voluntary hyperventilation (EVH). MATERIALS: Children aged 3-14 years (mean 10.0 ± 3.1) with symptoms suggestive of asthma were recruited. IOS measurements were taken before spirometry. Methacholine, mannitol, and EVH tests were performed without a specific order. RESULTS: We included 190 children, whose mean age was 10.0 ± 3.1 years. Changes in FEV1 correlated significantly with variation in IOS indexes (P < .05). The indexes with the greatest discriminative capacity were Z5, R5, and X5. Optimal cut-offs were: for methacholine tests, ≧22% in R5, ≧82% for reactance area (AX), and ≦41% for X5; for the mannitol test, ≧18% in R5, ≧40% in AX, and ≦21% for X5. In the EVH test, ≧23% for R5, ≧40% for AX, and a fall of 29% for X5. When using the optimal cut-off points obtained from IOS, the mean number of steps and doses required for methacholine and mannitol tests to induce significant bronchoconstriction were significantly lower compared with spirometry ( P < .05). CONCLUSIONS: The effectiveness of R5, X5, and AX indexes were comparable to FEV1 in assessing bronchial obstruction during bronchial challenge testing. Therefore, IOS may be useful in assessing bronchial obstruction in children who cannot reliably perform spirometric maneuvers during bronchial challenge testing.