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.

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.

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.

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.

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.

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.

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.

Criteria for classification of protein-energy wasting in dialysis patients: impact on prevalence.

Malnutrition is highly prevalent in dialysis patients and associated with poor outcomes. In 2008, protein-energy wasting (PEW) was coined by the International Society of Renal Nutrition and Metabolism (ISRNM), as a single pathological condition in which undernourishment and hypercatabolism converge. In 2014, a new simplified score was described using serum creatinine adjusted for body surface area (sCr/BSA) to replace a reduction of muscle mass over time in the muscle wasting category. We have now compared PEW-ISRNM 2008 and PEW-score 2014 to evaluate the prevalence of PEW and the risk of death in 109 haemodialysis patients. This was a retrospective analysis of cross sectional data with a median prospective follow-up of 20 months. The prevalence of PEW was 41 % for PEW-ISRNM 2008 and 63 % for PEW-score 2014 (P <0·002). Using PEW-score 2014: twenty-nine patients (27 %) had severe malnutrition (PEW-score 2014 0-1) and forty (37 %) with moderate malnutrition (score 2). Additionally, thirty-three (30 %) patients had mild wasting and only seven patients (6 %) presented a normal nutritional status. sCr/BSA correlated with lean total mass (R 0·46. P<0·001). A diagnosis of PEW according to PEW-score 2014, but not according to PEW-ISRNM 2008, was significantly associated with short-term mortality (P=0·0349) in univariate but not in multivariate analysis (P=0·069). In conclusion, the new PEW-score 2014 incorporating sCr/BSA identifies a higher number of dialysis PEW patients than PEW-ISRNM 2008. Whereas PEW-score-2014 provides timelier and therefore more clinically relevant information, its association with early mortality needs to be confirmed in larger studies.

Effect of ciprofloxacin in the ultrastructure and development of biofilms formed by rapidly growing mycobacteria.

BACKGROUND: The aim of this study was to analyze the effect of ciprofloxacin at different times on the development and behavior of intrinsic autofluorescence, covered area, thickness and cell viability in a biofilm formed by non-pigmented rapidly growing mycobacteria (NPRGM).Confocal laser scanning microscopy and image analysis were used to study the behavior of ciprofloxacin on biofilms. RESULTS: Thickness was the most affected parameter, although some species showed changes in other parameters. At the same time, we also measured the minimum inhibitory concentration and the minimum biofilm eradication concentration (MBEC). An increase in MBEC was observed in all the strains, M. peregrinum being the species that presented the highest increase. CONCLUSIONS: This study help us to understand better how mycobacterial biofims can be affected by ciprofloxacin.

Cortisol levels are associated with mortality risk in hemodialysis patients.

BACKGROUND: End-stage renal disease (ESRD) conveys high mortality risk by complex mechanisms not fully elucidated but possibly linked to hormonal abnormalities, including cortisol. Whereas a high serum cortisol level has recently been linked with increased mortality in the general population, there is scarce information on the clinical associates and prognostic value of cortisol levels in ESRD. PATIENTS AND METHODS: Prospective study of prevalent hemodialysis patients (n = 75), mostly non-diabetic (76%), where cortisol levels were assessed and patients were afterwards followed for a median of 20 (interquartile range (IQR) 8 - 31) months. RESULTS: Cortisol levels were negatively correlated with plasma sodium (Rho = -0.26. p < 0.025) and positively correlated with C-reactive protein (CRP; Rho = 0.26, p = 0.027). The association with CRP remained independent of multiple confounders. Baseline cortisol levels of those who died were higher than of those who survived (19.8 ± 6.9 vs. 15.3 ± 5.7 mcg/dL, p = 0.0083). Kaplan-Meier analysis showed that patients with cortisol levels within the highest tertile (≥ 18 mcg/dL) were at increased risk of death. Cortisol was associated with risk of death both in crude and adjusted Cox proportional hazards models (HR 1.09 (1.021 - 1.167) p = 0.011; and 1.16 (1.027 - 1.309), p = 0.01, respectively)). CONCLUSIONS: High serum concentrations of cortisol were associated with a state of inflammation and independently identified a subgroup of chronic hemodialysis patients at a high mortality risk.

Patient-prosthesis mismatch in patients undergoing bioprosthetic aortic valve implantation increases risk of reoperation for structural valve deterioration.

OBJECTIVES: Patient-prosthesis mismatch has been identified as a risk factor for mortality after aortic valve replacement and for structural valve deterioration (SVD) in patients receiving a bioprosthetic aortic valve. The aim of the present study was to compare the incidence of aortic valve bioprosthesis replacement for SVD in patients with mismatch to a population without mismatch. METHODS: Three hundred eighty-seven adult patients who underwent aortic valve replacement with a bioprosthesis from 1974 to 2009 were retrospectively reviewed. Mismatch was considered to be present if the anticipated indexed effective orifice area was <0.70 cm(2) /m(2) . The median follow-up period was 7.2 years. Follow-up was 97% complete. RESULTS: Patient-prosthesis mismatch was present in 12% of the study population (n = 47). Ten-year freedom from reoperation for aortic bioprosthesis replacement was 74.3 ± 3.2%. During follow-up, 111 patients underwent reoperation for aortic bioprosthesis replacement. Causes of aortic bioprosthesis replacement were SVD of the bioprosthesis (n = 96), paravalvular leak (n = 10), and acute endocarditis (n = 5). According to unadjusted Kaplan-Meier analysis, patients with mismatch had a higher incidence of aortic bioprosthesis replacement for SVD when compared with patients without mismatch (log rank test: p 0.05). This result was confirmed by multivariable Cox regression analysis, which identified two independent predictors of aortic bioprosthesis replacement for SVD: patients' age (hazard ratio (HR) 0.967) and patient-prosthesis mismatch (HR 2.161). CONCLUSION: Patients suffering from mismatch were twice as likely to undergo reoperation for aortic bioprosthesis replacement for SVD than those without mismatch.

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.

Autofluorescence as a tool for structural analysis of biofilms formed by nonpigmented rapidly growing mycobacteria.

The structure of biofilms formed by seven nonpigmented rapidly growing mycobacteria, including saprophytes and opportunistic species, was analyzed. Analysis included amount of covered surface, thickness, cell viability, and presence of intrinsic autofluorescence at different times using confocal laser scanning microscopy and image analysis. Autofluorescence was detected inside and outside cells of all mycobacteria.

Dynamic ultrasound assessment of medial meniscal subluxation in knee osteoarthritis.

OBJECTIVE: Although clinical reports have described medial meniscal subluxation (MMS) in knee OA, few controlled studies have used dynamic US to examine the potential impact of MMS on OA. The aim of this study was to assess MMS in patients with knee OA and in asymptomatic controls by US in different weight-bearing positions. METHODS: In a cross-sectional controlled study, MMS was evaluated by US in 33 symptomatic OA knees and in 13 control knees in supine neutral and unipodal weight-bearing positions. The reproducibility of US in this setting was assessed and the US measurements were compared between patients and controls. RESULTS: MMS was observed more frequently in OA knees than in controls in the unipodal weight-bearing position both before (P = 0.014) and after (P = 0.035) walking 50 m. In both OA and control knees, an increase in MMS was observed in the unipodal weight-bearing positions compared with the supine neutral position, but this increase was greater in OA knees than in controls (P < 0.001). CONCLUSION: Our findings confirm clinical observations that the medial meniscus undergoes significant subluxation in knee OA. The degree of subluxation is greater in weight-bearing than in non-weight-bearing positions. Dynamic US is a reproducible method for the assessment of MMS.

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.

Prevalence of disability in a composite ≥75 year-old population in Spain: a screening survey based on the International Classification of Functioning.

BACKGROUND: The prevalence and predictors of functional status and disability of elderly people have been studied in several European countries including Spain. However, there has been no population-based study incorporating the International Classification of Functioning, Disability and Health (ICF) framework as the basis for assessing disability. The present study reports prevalence rates for mild, moderate, and severe/extreme disability by the domains of activities and participation of the ICF. METHODS: Nine populations surveyed in previous prevalence studies contributed probabilistic and geographically defined samples in June 2005. The study sample was composed of 503 subjects aged ≥75 years. We implemented a two-phase screening design using the MMSE and the World Health Organization-Disability Assessment Schedule 2nd edition (WHO-DAS II, 12 items) as cognitive and disability screening tools, respectively. Participants scoring within the positive range of the disability screening were administered the full WHO-DAS II (36 items; score range: 0-100) assessing the following areas: Understanding and communication, Getting along with people, Life activities, Getting around, Participation in society, and Self-care. Each disability area assessed by WHO-DAS II (36 items) was reported according to the ICF severity ranges (No problem, 0-4; Mild disability, 5-24; Moderate disability, 25-49; Severe/Extreme disability, 50-100). RESULTS: The age-adjusted disability prevalence figures were: 39.17 ± 2.18%, 15.31 ± 1.61%, and 10.14 ± 1.35% for mild, moderate, and severe/extreme disability, respectively. Severe and extreme disability prevalence in mobility and life activities was three times higher than the average, and highest among women. Sex variations were minimal, although life activities for women of 85 years and over had more severe/extreme disability as compared to men (OR = 5.15 95% CI 3.19-8.32). CONCLUSIONS: Disability is highly prevalent among the Spanish elderly. Sex- and age-specific variations of disability are associated with particular disability domains.

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.

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.

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.

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.