Complejo Hospitalario Torrecárdenas

The aim of this study was to investigate 28-day mortality after COVID-19 diagnosis in the European kidney replacement therapy population. In addition, we determined the role of patient characteristics, treatment factors, and country on mortality risk with the use of ERA-EDTA Registry data on patients receiving kidney replacement therapy in Europe from February 1, 2020, to April 30, 2020. Additional data on all patients with a diagnosis of COVID-19 were collected from 7 European countries encompassing 4298 patients. COVID-19–attributable mortality was calculated using propensity score–matched historic control data and after 28 days of follow-up was 20.0% (95% confidence interval 18.7%–21.4%) in 3285 patients receiving dialysis and 19.9% (17.5%–22.5%) in 1013 recipients of a transplant. We identified differences in COVID-19 mortality across countries, and an increased mortality risk in older patients receiving kidney replacement therapy and male patients receiving dialysis. In recipients of kidney transplants ≥75 years of age, 44.3% (35.7%–53.9%) did not survive COVID-19. Mortality risk was 1.28 (1.02–1.60) times higher in transplant recipients compared with matched dialysis patients. Thus, the pandemic has had a substantial effect on mortality in patients receiving kidney replacement therapy, a highly vulnerable population due to underlying chronic kidney disease and a high prevalence of multimorbidity. The aim of this study was to investigate 28-day mortality after COVID-19 diagnosis in the European kidney replacement therapy population. In addition, we determined the role of patient characteristics, treatment factors, and country on mortality risk with the use of ERA-EDTA Registry data on patients receiving kidney replacement therapy in Europe from February 1, 2020, to April 30, 2020. Additional data on all patients with a diagnosis of COVID-19 were collected from 7 European countries encompassing 4298 patients. COVID-19–attributable mortality was calculated using propensity score–matched historic control data and after 28 days of follow-up was 20.0% (95% confidence interval 18.7%–21.4%) in 3285 patients receiving dialysis and 19.9% (17.5%–22.5%) in 1013 recipients of a transplant. We identified differences in COVID-19 mortality across countries, and an increased mortality risk in older patients receiving kidney replacement therapy and male patients receiving dialysis. In recipients of kidney transplants ≥75 years of age, 44.3% (35.7%–53.9%) did not survive COVID-19. Mortality risk was 1.28 (1.02–1.60) times higher in transplant recipients compared with matched dialysis patients. Thus, the pandemic has had a substantial effect on mortality in patients receiving kidney replacement therapy, a highly vulnerable population due to underlying chronic kidney disease and a high prevalence of multimorbidity. Editor’s NoteThis is one of several articles we think you will find of interest that are part of our special issue of Kidney International addressing the challenges of dialysis and transplantation during the COVID-19 pandemic. Please also find additional material in our commentaries and letters to the editor sections. We hope these insights will help you in the daily care of your own patients. This is one of several articles we think you will find of interest that are part of our special issue of Kidney International addressing the challenges of dialysis and transplantation during the COVID-19 pandemic. Please also find additional material in our commentaries and letters to the editor sections. We hope these insights will help you in the daily care of your own patients. Since the initial outbreak in Wuhan, China, in December 2019, coronavirus disease 2019 (COVID-19) has spread rapidly across the world, prompting a global pandemic. The disease—caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus—causes pneumonia, but also affects other organs. According to the European Centre for Disease Prevention and Control, the number of reported COVID-19 cases in the European Union (EU) is 2783 (range 281–6648) per million general population (pmp), representing 0.28% (range 0.03%–0.66%) of the EU population, with variation in numbers depending on governmental control measures, definition of cases, and testing capacity.1European Centre for Disease Prevention and ControlCOVID-19 situation update for the EU/EEA and the UK.https://www.ecdc.europa.eu/en/cases-2019-ncov-eueeaDate accessed: June 9, 2020Google Scholar Mortality due to the SARS-CoV-2 virus is high compared with most other viral infections. Although a case fatality rate of 2.3% was reported from China,2Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention.JAMA. 2020; 323: 1239-1242Crossref PubMed Scopus (12778) Google Scholar the average rate is 11.7% (range 0.6%–18.9%) in the EU general population.1European Centre for Disease Prevention and ControlCOVID-19 situation update for the EU/EEA and the UK.https://www.ecdc.europa.eu/en/cases-2019-ncov-eueeaDate accessed: June 9, 2020Google Scholar Among hospitalized patients in United Kingdom suffering from severe COVID-19, the case fatality rate reaches 26%.3Docherty A.B. Harrison E.M. Green C.A. et al.Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol.medRxiv. 2020; 04: 20076042Google Scholar Patients treated with kidney replacement therapy (KRT; either dialysis or kidney transplantation) represent a vulnerable population. Under normal circumstances, age-standardized cardiovascular and noncardiovascular mortality rates in dialysis patients are already 8.8 and 8.1 times higher than in the general population, respectively,4de Jager D.J. Grootendorst D.C. Jager K.J. et al.Cardiovascular and noncardiovascular mortality among patients starting dialysis.JAMA. 2009; 302: 1782-1789Crossref PubMed Scopus (593) Google Scholar and compared with their age- and sex-matched counterparts in the general population, kidney transplant recipients experience a 30%–50% reduced life expectancy.5ERA-EDTA RegistryERA-EDTA Registry Annual Report 2017. 2019.https://www.era-edta.org/en/registry/publications/annual-reports/#2017Google Scholar It may be expected that COVID-19 causes substantial mortality in both dialysis and kidney transplant populations due to their underlying chronic kidney disease and a high prevalence of comorbid conditions such as diabetes mellitus and cardiovascular disease. In transplant recipients, the potential effect of their long-term use of immunosuppression is a matter of debate. Some argue they may be at greater risk of severe infection because of their impaired immune system,6Coates P.T. Wong G. Drueke T. et al.Early experience with COVID-19 in kidney transplantation.Kidney Int. 2020; 97: 1074-1075Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar whereas others speculate that immunosuppressive therapy may be protective as it might address the COVID-19–induced cytokine storm.7Tay M.Z. Poh C.M. Rénia L. et al.The trinity of COVID-19: immunity, inflammation and intervention.Nat Rev Immunol. 2020; 20: 363-374Crossref PubMed Scopus (2942) Google Scholar Although no deaths were reported among 5 COVID-19 cases on hemodialysis in a single Chinese center,8Wang R. Liao C. He H. et al.COVID-19 in hemodialysis patients: a report of 5 cases.Am J Kidney Dis. 2020; 76: 141-143Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar several case series from Italy (n = 41, n = 94),9Scarpioni R. Manini A. Valsania T. et al.Covid-19 and its impact on nephropathic patients: the experience at Ospedale “Guglielmo da Saliceto” in Piacenza.G Ital Nefrol. 2020; 37: 4Google Scholar,10Alberici F. Delbarba E. Manenti C. et al.A report from the Brescia Renal COVID Task Force on the clinical characteristics and short-term outcome of hemodialysis patients with SARS-CoV-2 infection.Kidney Int. 2020; 98: 20-26Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar Spain (n = 36),11Goicoechea M. Sánchez Cámara L.A. Macías N. et al.COVID-19: clinical course and outcomes of 36 maintenance hemodialysis patients from a single center in Spain.Kidney Int. 2020; 98: 27-34Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar and the United States (n = 59)12Valeri A.M. Robbins-Juarez S.Y. Stevens J.S. et al.Presentation and outcomes of patients with ESKD and COVID-19.J Am Soc Nephrol. 2020; 31: 1409-1415Crossref PubMed Scopus (258) Google Scholar with varying follow-up suggest a high mortality in the dialysis population with rates ranging from 29% to 41%. Preliminary reports in transplant recipients seem to suggest a somewhat lower mortality, with estimates ranging from 13% (n = 15) in the United States to 25% in Italy (n = 20).13Mohan S. Early description of coronavirus 2019 disease in kidney transplant recipients in New York.J Am Soc Nephrol. 2020; 31: 1150-1156Crossref PubMed Scopus (191) Google Scholar, 14Banerjee D. Popoola J. Shah S. et al.COVID-19 infection in kidney transplant recipients.Kidney Int. 2020; 97: 1076-1082Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar, 15Alberici F. Delbarba E. Manenti C. et al.A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia.Kidney Int. 2020; 97: 1083-1088Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar The largest study to date is from Spain, reporting on a group of 868 KRT patients (67% dialysis patients and 33% transplant patients) with a mortality rate of 23%.16Sánchez-Álvarez J.E. Fontán M.P. Martín C.J. et al.Status of SARS-CoV-2 infection in patients on renal replacement therapy. Report of the COVID-19 Registry of the Spanish Society of Nephrology (SEN).Nefrologia. 2020; 40: 272-278PubMed Google Scholar Risk estimates from studies with small sample sizes are known to suffer from inaccuracy due to random variation. In addition, because some of the above-mentioned samples were derived from in-hospital populations, the estimates reflect risk in a selected group of more severely ill patients and may not be generalizable to the broader KRT patient population. Moreover, most of these studies, including the largest one, used the case fatality rate as a measure of mortality, which is often calculated while the individual outcome (recovery or death) is known only for a proportion of infected patients.17Natale F. Ghio D. Tarchi D. Goujon A. Conte A. COVID-19 cases and case fatality rate by age.https://ec.europa.eu/knowledge4policy/publication/covid-19-cases-case-fatality-rate-age_enDate accessed: June 9, 2020Google Scholar To date, large population-based studies on mortality in the KRT population with complete follow-up information are lacking. Therefore, the first aim of the present study was to investigate the COVID-19 attributable mortality 28 days after diagnosis in European dialysis and kidney transplant recipients with the use of historic cohorts of prevalent dialysis and transplant patients without COVID-19. The second aim was to compare mortality between dialysis and transplant patients with COVID-19. Finally, we aimed to determine the role of patient characteristics, KRT treatment-related factors, and country as risk factors for death in both groups. From February 1, 2020, to April 30, 2020, a total of 4298 KRT patients were diagnosed with COVID-19, of which 3285 (76.4%) were on dialysis—3160 on hemodialysis and 125 on peritoneal dialysis—and 1013 (23.6%) were living with a functioning transplant (Table 1). The majority of dialysis patients diagnosed with COVID-19 originated from France (49.6%) and Spain (29.7%). In dialysis patients, the median age at COVID-19 diagnosis was 71.7 years (interquartile range [IQR] 60.6–80.5), ranging from 63.2 years in Romania to 74.0 years in Spain. Two-thirds were ≥65 years of age, almost two-thirds were male, almost half suffered from either diabetes mellitus (25.5%) or hypertension/renovascular disease (RVD) (21.2%) as primary renal disease (PRD), and 96.2% were on hemodialysis. Sufficient numbers of transplant patients with COVID-19 were available from France (50.5%) and Spain (49.5%). Transplant recipients were younger than those on dialysis (P < 0.001), with a median age of 60.9 years (IQR 51.1–69.4) and 37.3% being ≥65 years. Similarly to dialysis patients, 65.4% were male (P = 0.23), however, the share of patients with diabetes mellitus (12.8%) and hypertension/RVD (10.6%) as PRD was lower.Table 1Characteristics of KRT patients diagnosed with COVID-19, by treatment modality and countryDialysisTransplantAllHDPDAustriaFrench-speaking part of BelgiumaData on patients younger than 20 years were not included.FranceRomaniaSpainSwitzerlandThe NetherlandsAllFranceSpainNo. of patients32853160125441401631270976871371013512501Age at diagnosis, yr, median (IQR)71.7 (60.6–80.5)71.8 (60.8–80.6)70.2 (59.4–78.5)71.8 (62.8–81.3)71.2 (57.9–78.5)72 (60.8–81.2)63.2 (52.7–70.2)74 (63–81.2)73.7 (59.6–81.9)73.4 (61–81.5)60.9 (51.1–69.4)59.6 (49.9–67.9)62.5 (52.3–70.9) 0–199 (0.3)8 (0.3)1 (0.8)0 (0)NA3 (0.2)1 (0.4)5 (0.5)0 (0)0 (0)8 (0.8)4 (0.8)4 (0.8) 20–44225 (6.8)215 (6.8)10 (8.0)2 (4.5)11 (7.9)127 (7.8)26 (9.6)46 (4.7)7 (8.0)6 (4.4)128 (12.6)80 (15.6)48 (9.6) 45–64854 (26.0)817 (25.9)37 (29.6)10 (22.7)41 (29.3)401 (24.6)123 (45.6)222 (22.7)22 (25.3)35 (25.5)499 (49.3)263 (51.4)236 (47.1) 65–74857 (26.1)823 (26.0)34 (27.2)15 (34.1)34 (24.3)429 (26.3)82 (30.4)245 (25.1)16 (18.4)36 (26.3)260 (25.7)115 (22.5)145 (28.9) ≥751340 (40.8)1297 (41.0)43 (34.4)17 (38.6)54 (38.6)671 (41.1)38 (14.1)458 (46.9)42 (48.3)60 (43.8)118 (11.6)50 (9.8)68 (13.6)Sex Male2077 (63.2)1993 (63.1)84 renal disease modality of KRT median of starting treatment of starting treatment coronavirus disease kidney replacement not peritoneal are as n or median are country was only it had dialysis or transplant patients with on patients younger than 20 years were not of starting treatment in a COVID-19, coronavirus disease kidney replacement not peritoneal disease. are as n or median are country was only it had dialysis or transplant patients with COVID-19. 1, 2020, COVID-19 cases of all prevalent patients on dialysis range and of those living with a functioning range with dialysis and transplant patients without COVID-19, those with COVID-19 were years The proportion of male patients was with more among dialysis patients, and more among transplant recipients In both dialysis and transplant patients with COVID-19 were more patients with diabetes mellitus as PRD and days after COVID-19 diagnosis, of hemodialysis patients and of 125 patients on peritoneal dialysis had that in the dialysis group as a had 28 days after diagnosis, with of deaths on the of In transplant recipients, of 1013 had after 28 28-day of death of was to that in the dialysis with of deaths on the of 28 the to that most of the deaths due to COVID-19 had this with the expected mortality in the matched control group of dialysis patients without COVID-19, the COVID-19 attributable mortality was 20.0% and mortality risk was (95% confidence interval times higher in dialysis patients diagnosed with COVID-19 In transplant recipients diagnosed with COVID-19, the attributable mortality was 19.9% the expected mortality in the matched control mortality is lower in transplant patients compared with dialysis patients, their mortality risk was (95% times higher compared with their matched control patients 1). that the mortality risk in transplant recipients with COVID-19 was higher compared with the selected group of dialysis patients that be matched In dialysis patients, the of mortality by age substantial differences across age with 28-day mortality in patients ≥75 years of age as high as (Table The risk of death in was in patients with hypertension/RVD as PRD had the of death by diabetes mellitus and The 28-day of death was in those treated with peritoneal dialysis and in hemodialysis patients. were substantial differences in mortality across the 7 it was in the and in Romania identified higher age and male as risk factors for 28-day mortality in COVID-19 dialysis patients (Table for all available dialysis patients in Romania and France had a lower mortality risk than those in The of death by age and PRD is in and the COVID-19–attributable mortality is in of death in and risk factors in dialysis patients with of death 28 days (95% (95% for age was for and the for was for age and the for primary renal disease was for age, and the for of KRT was for age, and the for treatment modality was for age, of KRT and and the for country was for age, and of KRT for age was for and the for was for age and the for primary renal disease was for age, and the for of KRT was for age, and the for treatment modality was for age, of KRT and and the for country was for age, and of KRT at COVID-19 diagnosis, renal disease of KRT Spain this was of dialysis modality The confidence COVID-19, coronavirus disease kidney replacement peritoneal The for age was for and the for was for age and the for primary renal disease was for age, and the for of KRT was for age, and the for treatment modality was for age, of KRT and and the for country was for age, and of KRT Spain this was of dialysis in a of death among dialysis patients and transplant patients with coronavirus disease 2019 by confidence confidence COVID-19, coronavirus disease kidney replacement peritoneal disease. In kidney transplant recipients, the of mortality by age group a high 44.3% of death in those ≥75 years of age, which for almost half of the patients (Table The of death was in and in and in patients suffering from diabetes mellitus as PRD by hypertension/RVD and in those with The of death was higher in Spain than in France In only higher age was identified as a risk for 28-day mortality (Table The of death by age and PRD is in and the COVID-19–attributable mortality is in of death in and risk factors in transplant patients with of death 28 days (95% (95% for age was for and the for was for age and the for primary renal disease was for age, and the for of KRT and of transplant was for age, and and the for country was for age, and of KRT transplantation in for age was for and the for was for age and the for primary renal disease was for age, and the for of KRT and of transplant was for age, and and the for country was for age, and of KRT transplantation in at COVID-19 diagnosis, renal disease of KRT of transplantation confidence COVID-19, coronavirus disease kidney replacement peritoneal The for age was for and the for was for age and the for primary renal disease was for age, and the for of KRT and of transplant was for age, and and the for country was for age, and of KRT transplantation in in a confidence COVID-19, coronavirus disease kidney replacement peritoneal disease. In this we present complete population-based data on more than KRT patients by COVID-19 collected and renal in We report the of death at 28 days after diagnosis and risk factors in dialysis patients from 7 European countries and in transplant recipients from 2 European In both the dialysis and the transplant of patients had by 28 days after matched that transplant recipients had a higher risk of death compared with their dialysis in dialysis patients higher age, male and country as risk factors, whereas in transplant recipients only higher age was with an increased risk of The data suggest that the of diagnosed COVID-19 in the KRT population was as of the prevalent dialysis population and of those living on a functioning were by COVID-19, this disease to had a greater impact on the KRT population compared to the general Centre for Disease Prevention and ControlCOVID-19 situation update for the EU/EEA and the UK.https://www.ecdc.europa.eu/en/cases-2019-ncov-eueeaDate accessed: June 9, 2020Google Scholar which may be due to their older age, or the of more our COVID-19 patients were from population-based they may not represent all KRT patients with COVID-19. The majority of are or and not not of a general or a patients may not and may testing in dialysis more during the of the this is the case for hemodialysis patients their dialysis center a times a The of patients with COVID-19 were lower in patients on peritoneal dialysis and in transplant We speculate that in these testing may to the and more severe cases, and our data for these populations represent a group of patients. This is by the high number of transplant recipients on the of diagnosis This may our that transplant patients are at higher risk of death than dialysis patients of propensity the other being may more of a while the infection than an the cytokine P.T. Wong G. Drueke T. et al.Early experience with COVID-19 in kidney transplantation.Kidney Int. 2020; 97: 1074-1075Abstract Full Text Full Text PDF PubMed Scopus (44) Google M.Z. Poh C.M. Rénia L. et al.The trinity of COVID-19: immunity, inflammation and intervention.Nat Rev Immunol. 2020; 20: 363-374Crossref PubMed Scopus (2942) Google Scholar Although the risk of COVID-19 was in KRT patients, 28-day mortality in COVID-19 patients the mortality that may be expected for KRT patients of propensity on the historic control on the 28-day of death due to COVID-19 by age in the general population is lacking. data on the rate in the general population to in and to for those years of G. G. S. rate and characteristics of patients in to COVID-19 in 2020; 323: Google Scholar data from Spain higher and COVID-19, no COVID-19 a accessed: June 9, 2020Google Scholar This may suggest that mortality from COVID-19 in the dialysis population age 71.7 is times higher and in transplant patients age 60.9 times compared with patients with COVID-19 of in dialysis and transplant patients will an important role in this substantial mortality, but our data did not on this We however, in that in both the dialysis and the transplant almost of patients COVID-19 at to 28 days after diagnosis, the that a substantial number of may not admitted to the care to their high risk of In both dialysis and transplant patients with COVID-19, higher age the most important risk for mortality in our The that male was a risk in dialysis patients with COVID-19 is of It in the general population and also the increased cardiovascular mortality in compared with on dialysis without Jager D.J. M. et al.Cardiovascular and noncardiovascular mortality among and starting J Am Soc Nephrol. PubMed Scopus Google Scholar studies disease to be a risk in dialysis F. Delbarba E. Manenti C. et al.A report from the Brescia Renal COVID Task Force on the clinical characteristics and short-term outcome of hemodialysis patients with SARS-CoV-2 infection.Kidney Int. 2020; 98: 20-26Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar We did not to but PRD be as a for In our the estimates of the additional risk by diabetes mellitus and hypertension/RVD did suggest a in an additional effect of PRD on of age not be as a of In dialysis patients with COVID-19, we that the of death across Although it is we not to from that because of the variation may be to in the of COVID-19 cases a of varying testing differences in the of and the to for and This study reports data from renal that aim to complete data with the in and this it to reporting on patient populations with COVID-19, renal the of impaired testing from of cases, of the of care of or not reporting to the KRT treatment will to an of This is to be small for hemodialysis patients, but it may be more important for peritoneal dialysis patients and transplant recipients, more severe cases were The of this by varying testing may across countries and using data as a we had no to additional information on patient and treatment characteristics that be important to the outcome of COVID-19 patients on Finally, this study the number of COVID-19 patients on KRT to date, it may suffer from of in an to The COVID-19 pandemic has had a substantial effect on mortality in all of KRT patients by the in KRT patients and in transplant It is that in the hemodialysis may as important of It is of that in the and control in and be to to the of their patients and the to their as as in this and studies on of COVID-19 in KRT patients are

Increased age and female sex are suggested risk factors for drug-induced hepatotoxicity (DILI). We studied the influence of these variables on the propensity to develop DILI, as well as its clinical expression and outcome. All cases of DILI submitted to the Spanish Registry between April 1994 and August 2007 were analyzed. Six hundred three DILI cases (310 men; mean age, 54 years) showed a similar sex distribution, reaching two peaks in the 40- to 49-year-old and 60- to 69-year-old age groups. No cases were recorded in the 20- to 29-year-old group. Patients aged > or =60 years accounted for 46% of the cases, with a male predominance (158 males, 118 females; P= 0.009), as opposed to younger patients. Older age was independently associated with cholestatic type of injury (odds ratio for an age interval for 1 year: 1.024 [95% confidence interval: 1.010-1.038]; male/female ratio, 1:2; P = 0.001) and younger age with hepatocellular damage (odds ratio: 0.983 [95% confidence interval: 0.972-0.994]; female/male ratio, 1:2; P = 0.002). In the mixed group, no age effect was evident. Outcome with fulminant liver failure/liver transplantation was more frequently encountered in women (P < 0.01). conclusion: Neither older age nor female sex are predisposing factors to overall DILI. However, older age is a determinant for cholestatic damage with a male predominance, whereas younger age is associated with cytolytic damage and a female overrepresentation. Women distinctly exhibit the worst outcome. Knowledge of these phenotypic associations could guide differential diagnosis and attribution of causality in DILI.

A chronic adverse reaction may occur in some instances of drug-induced liver injury (DILI), even despite drug cessation. In our study, we obtained records from a Spanish registry and evaluated cases of DILI with biochemical evidence of long-term damage. Chronic outcome was defined as a persistent biochemical abnormality of hepatocellular pattern of damage more than 3 months after drug withdrawal or more than 6 months after cholestatic/mixed damage. Data on 28 patients with a chronic clinical evolution (mean follow-up 20 months) between November 1995 and October 2005 were retrieved (18 female; overall mean age 55 yr) and accounted for 5.7% of total idiosyncratic DILI cases (n = 493) submitted to the registry. The main drug classes were cardiovascular and central nervous system (28.5% and 25%, respectively), which, in contrast, represented only 9.8% and 13%, respectively, of all DILI cases. The most frequent causative drugs were amoxicillin-clavulanate (4 of 69 cases), bentazepam (3 of 7 cases), atorvastatin (2 of 7 cases), and captopril (2 of 5 cases). Patients with cholestatic/mixed injury (18 of 194 cases [9%]) were more prone to chronicity than patients with hepatocellular injury (10 of 240 cases; P < .031). In the case of chronic hepatocellular injury, 3 patients progressed to cirrhosis and 2 to chronic hepatitis. In the cholestatic/mixed group, liver biopsy indicated cirrhosis in 1 patient and ductal lesions in 3 patients. In conclusion, cholestatic/mixed type of damage is more prone to become chronic while, in the hepatocellular pattern, the severity is greater. Cardiovascular and central nervous system drugs are the main groups leading to chronic liver damage.

BACKGROUND: Diabetes is a growing public health problem. Diabetic kidney disease (DKD) is the most prevalent chronic renal disease and the major cause of end-stage renal failure worldwide, predominantly due to the increase of Type 2 diabetes associated with obesity. The intimate mechanisms leading to the development and progression of renal injury in DKD are not well understood, but current knowledge indicates that its pathogenesis is multifactorial, where the immune response and inflammation appear to be relevant factors. SUMMARY: This review summarizes the role of relevant inflammatory molecules and pathways that participate in the development of DKD. Likewise, we focused on the new therapeutic approaches based on anti-inflammatory effects of different drugs. Key Messages: This new pathogenic perspective of DKD as an inflammatory condition leads to novel horizons, such as the potential role of inflammatory signaling pathways and their downstream products as emerging biomarkers and promising therapeutic targets.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are indicated in type 2 diabetes and obesity for their high efficacy in controlling glycaemia and inducing body weight loss, respectively. Patients may develop gastrointestinal adverse events (GI AEs), namely nausea, vomiting, diarrhoea and/or constipation. To minimize their severity and duration, healthcare providers (HCPs) and patients must be aware of appropriate measures to follow while undergoing treatment. An expert panel comprising endocrinologists, nephrologists, primary care physicians, cardiologists, internists and diabetes nurse educators convened across virtual meetings to reach a consensus regarding these compelling recommendations. Firstly, specific guidelines are provided about how to reach the maintenance dose and how to proceed if GI AEs develop during dose-escalation. Secondly, specific directions are set about how to avoid/minimize nausea, vomiting, diarrhoea and constipation symptoms. Clinical scenarios representing common situations in daily practice, and infographics useful to guide both HCPs and patients, are included. These recommendations may prevent people with T2D and/or obesity from withdrawing from GLP-1 RAs treatment, thus benefitting from their superior effect on glycaemic control and weight loss.

The impact of the adequacy of empirical therapy on outcome for patients with bloodstream infections (BSI) is key for determining whether adequate empirical coverage should be prioritized over other, more conservative approaches. Recent systematic reviews outlined the need for new studies in the field, using improved methodologies. We assessed the impact of inadequate empirical treatment on the mortality of patients with BSI in the present-day context, incorporating recent methodological recommendations. A prospective multicenter cohort including all BSI episodes in adult patients was performed in 15 hospitals in Andalucía, Spain, over a 2-month period in 2006 to 2007. The main outcome variables were 14- and 30-day mortality. Adjusted analyses were performed by multivariate analysis and propensity score-based matching. Eight hundred one episodes were included. Inadequate empirical therapy was administered in 199 (24.8%) episodes; mortality at days 14 and 30 was 18.55% and 22.6%, respectively. After controlling for age, Charlson index, Pitt score, neutropenia, source, etiology, and presentation with severe sepsis or shock, inadequate empirical treatment was associated with increased mortality at days 14 and 30 (odds ratios [ORs], 2.12 and 1.56; 95% confidence intervals [95% CI], 1.34 to 3.34 and 1.01 to 2.40, respectively). The adjusted ORs after a propensity score-based matched analysis were 3.03 and 1.70 (95% CI, 1.60 to 5.74 and 0.98 to 2.98, respectively). In conclusion, inadequate empirical therapy is independently associated with increased mortality in patients with BSI. Programs to improve the quality of empirical therapy in patients with suspicion of BSI and optimization of definitive therapy should be implemented.

BACKGROUND: Penicillin is no longer the most commonly prescribed beta-lactam, and the pattern of reactions has changed. We studied the diagnostic value of skin testing in penicillin-allergic subjects from a population where benzylpenicillin is not now the most frequently used beta-lactam. METHODS: Patients with a history of immediate allergic reactions to penicillins were studied with: skin tests with major and minor determinants of benzylpenicillin (BPO/MDM), amoxicillin, and ampicillin; in vitro determination of specific IgE; and controlled administration for those with a positive history but negative skin and in vitro tests. A reaction was considered immediate when symptoms appeared within a maximum of 1 h after drug intake. RESULTS: After testing, 290 patients (71% having anaphylaxis and 29% having urticaria) proved to be allergic. Amoxicillin was involved in 64.8% and benzylpenicillin in 2.8% of the patients. Skin test positivity to at least one determinant appeared in 70% of cases, amoxicillin being the most frequent. The overall sensitivity decreased markedly when only BPO and MDM were considered. In 13.1% of patients, the diagnosis was established by in vitro test and in 16.9% by controlled administration. Of the 290 patients, 42.1% were positive to determinants generated from benzylpenicillin and 57.9% were selective responders. CONCLUSIONS: Sensitivity of skin tests to BPO was lower than reported, being partly replaced by minor determinants, mostly amoxicillin. The incorporation of additional reagents and the development of new tests are required, and these will probably change as the patterns of consumption vary.

Continuous subcutaneous apomorphine infusion (CSAI) is, at present, an alternative option for advanced Parkinson's disease (PD) with motor fluctuations. We studied the evolution of patients with PD and severe motor fluctuations long-term treated with CSAI. We reviewed data from 82 patients with PD (mean age, 67 +/- 11.07; disease duration, 14.39 +/- 5.7 years) and severe motor fluctuations referred to 35 tertiary hospitals in Spain. These patients were long-term treated (for at least 3 months) with CSAI and tolerated the procedure without serious side effects. We compared the baseline data of these 82 patients (before CSAI) with those obtained from the last follow-up visit of each patient. The mean follow-up of CSAI was 19.93 +/- 16.3 months. Mean daily dose of CSAI was 72.00 +/- 21.38 mg run over 14.05 +/- 1.81 hours. We found a statistically significant reduction in off-hours, according to self-scoring diaries (6.64 +/- 3.09 vs. 1.36 +/- 1.42 hours/day, P < 0.0001), total and motor UPDRS scores (P < 0.0001), dyskinesia severity (P < 0.0006), and equivalent dose of antiparkinsonian therapy (1,405 +/- 536.7 vs. 800.1 +/- 472.9 mg of levodopa equivalent units P < 0.0001). CSAI is an effective option for patients with PD and severe fluctuations, poorly controlled by conventional oral drug treatment.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) is associated with significant morbidity and mortality. Several aspects of clinical management have been shown to have significant impact on prognosis. The objective of the study was to identify evidence-based quality-of-care indicators (QCIs) for the management of SAB, and to evaluate the impact of a QCI-based bundle on the management and prognosis of SAB. METHODS: A systematic review of the literature to identify QCIs in the management of SAB was performed. Then, the impact of a bundle including selected QCIs was evaluated in a quasi-experimental study in 12 tertiary Spanish hospitals. The main and secondary outcome variables were adherence to QCIs and mortality. Specific structured individualized written recommendations on 6 selected evidence-based QCIs for the management of SAB were provided. RESULTS: A total of 287 and 221 patients were included in the preintervention and intervention periods, respectively. After controlling for potential confounders, the intervention was independently associated with improved adherence to follow-up blood cultures (odds ratio [OR], 2.83; 95% confidence interval [CI], 1.78-4.49), early source control (OR, 4.56; 95% CI, 2.12-9.79), early intravenous cloxacillin for methicillin-susceptible isolates (OR, 1.79; 95% CI, 1.15-2.78), and appropriate duration of therapy (OR, 2.13; 95% CI, 1.24-3.64). The intervention was independently associated with a decrease in 14-day and 30-day mortality (OR, 0.47; 95% CI, .26-.85 and OR, 0.56; 95% CI, .34-.93, respectively). CONCLUSIONS: A bundle orientated to improving adherence to evidence-based QCIs improved the management of patients with SAB and was associated with reduced mortality.

UNLABELLED: Individual vulnerability to drug-induced liver injury (DILI) might result from deficiencies in the detoxification process, which determines the level of exposure to the reactive metabolite. We evaluated whether a genetically determined reduction in the ability to detoxify electrophilic compounds, such as that expected among individuals with glutathione S-transferase (GST) null genotypes, might play a role in determining the risk for DILI and its clinical expression. Genomic DNA from 154 patients (74 men, 80 women; mean age, 53 years) with a diagnosis of DILI as assessed with the Council for International Organizations of Medical Science scale and 250 sex- and age-matched healthy controls were analyzed. A multiplex polymerase chain reaction-based method was used to detect GSTM1 and GSTT1 gene deletions. Carriers of double GSTT1-M1 null genotypes had a 2.70-fold increased risk of developing DILI compared with noncarriers (odds ratio 2.70, 95% confidence interval 1.45-5.03; P = 0.003). The odds ratio for DILI patients receiving antibacterials, and NSAIDs were 3.52 (P = 0.002), and 5.61 (P = 0.001), respectively. Patients with amoxicillin-clavulanate hepatotoxicity (n = 32) had a 2.81-fold increased risk (P = 0.037). Patients classified by the combined GSTT1 and GSTM1 null genotypes did not differ with regard to the type of injury, clinical presentation, or outcome, except for the predominance of women in the combined null genotype (P < 0.001). CONCLUSION: The double-null genotype for GSTT1 and GSTM1 might play a role in determining the susceptibility to develop DILI, as a general mechanism that occurs regardless of the type of drug involved, and predominantly in women.

BACKGROUND: Evaluation of peritoneal metastases by computed tomography (CT) scans is challenging and has been reported to be inaccurate. METHODS: A multi-institutional prospective observational registry study of patients with peritoneal carcinomatosis from colorectal cancer was conducted and a subset analysis was performed to examine peritoneal cancer index (PCI) based on CT and intraoperative exploration. RESULTS: Fifty-two patients (mean age 52.6 ± 12.4 years) from 16 institutions were included in this study. Inaccuracies of CT-based assessment of lesion sizes were observed in the RUQ (P = 0.004), LLQ (P < 0.0005), RLQ (P = 0.003), distal jejunum (P = 0.004), and distal ileum (P < 0.0005). When CT-PCI was classified based on the extent of carcinomatosis, 17 cases (33%) were underestimations, of which, 11 cases (21%) were upstaged from low to moderate, 4 cases (8%) were upstaged from low to severe, and 2 cases (4%) were upstaged from moderate to severe. Relevant clinical discordance where an upstage occurred to severe carcinomatosis constituted a true inaccuracy and was observed in six cases (12%). CONCLUSIONS: The actual clinical impact of inaccuracies of CT-PCI was modest. CT-PCI will remain as a mandatory imaging tool and may be supplemented with other tools including positron emission tomography scan or diagnostic laparoscopy, in the patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Healthcare workers are vulnerable to adverse mental health impacts of the COVID-19 pandemic. We assessed prevalence of mental disorders and associated factors during the first wave of the pandemic among healthcare professionals in Spain. All workers in 18 healthcare institutions (6 AACC) in Spain were invited to web-based surveys assessing individual characteristics, COVID-19 infection status and exposure, and mental health status (May 5 – September 7, 2020). We report: probable current mental disorders (Major Depressive Disorder-MDD- [PHQ-8≥10], Generalized Anxiety Disorder-GAD- [GAD-7≥10], Panic attacks, Posttraumatic Stress Disorder –PTSD- [PCL-5≥7]; and Substance Use Disorder –SUD-[CAGE-AID≥2]. Severe disability assessed by the Sheehan Disability Scale was used to identify probable “disabling” current mental disorders. 9,138 healthcare workers participated. Prevalence of screen-positive disorder: 28.1% MDD; 22.5% GAD, 24.0% Panic; 22.2% PTSD; and 6.2% SUD. Overall 45.7% presented any current and 14.5% any disabling current mental disorder. Workers with pre-pandemic lifetime mental disorders had almost twice the prevalence than those without. Adjusting for all other variables, odds of any disabling mental disorder were: prior lifetime disorders (TUS: OR=5.74; 95%CI 2.53-13.03; Mood: OR=3.23; 95%CI:2.27-4.60; Anxiety: OR=3.03; 95%CI:2.53-3.62); age category 18-29 years (OR=1.36; 95%CI:1.02-1.82), caring “all of the time” for COVID-19 patients (OR=5.19; 95%CI: 3.61-7.46), female gender (OR=1.58; 95%CI: 1.27-1.96) and having being in quarantine or isolated (OR= 1.60; 95CI:1.31-1.95). One in seven Spanish healthcare workers screened positive for a disabling mental disorder during the first wave of the COVID-19 pandemic. Workers reporting pre-pandemic lifetime mental disorders, those frequently exposed to COVID-19 patients, infected or quarantined/isolated, female workers, and auxiliary nurses should be considered groups in need of mental health monitoring and support. Los profesionales sanitarios son vulnerables al impacto negativo en salud mental de la pandemia COVID-19. Evaluamos la prevalencia de trastornos mentales y factores asociados durante la primera oleada de la pandemia en sanitarios españoles. Se invitó a todos los trabajadores de 18 instituciones sanitarias españolas (6 CCAA) a encuestas en línea evaluando características individuales, estado de infección y exposición a COVID-19 y salud mental (5 Mayo – 7 Septiembre, 2020). Reportamos: probables trastornos mentales actuales (Trastorno depresivo mayor TDD [PHQ-8≥10], Trastorno de ansiedad generalizada TAG [GAD-7≥10], Ataques de pánico, Trastorno de estrés postraumático TEP [PCL-5≥7]; y Trastorno por uso de sustancias TUS [CAGE-AID≥2]. La interferencia funcional grave (Escala de Discapacidad de Sheehan) identificó los probables trastornos “discapacitantes”. Participaron 9.138 sanitarios. Prevalencia de cribado positivo: 28,1% TDD; 22,5% TAG, 24,0% Pánico; 22,2% PTE; y 6,2% TUS. En general, el 45,7% presentó algún trastorno mental actual y el 14,5% algún trastorno discapacitante. Los sanitarios con trastornos mentales previos tuvieron el doble de prevalencia que aquellos sin patología mental previa. Ajustando por todas las variables, el trastorno mental incapacitante se asoció positivamente con: trastornos previos (TUS: OR=5.74; 95%CI 2.53-13.03; Ánimo: OR=3.23; 95%CI:2.27-4.60; Ansiedad: OR=3,03; IC 95%: 2,53-3,62); edad 18-29 años (OR=1,36; IC 95%: 1,02-1,82); atender “siempre” a pacientes COVID-19 (OR=5,19; IC 95%: 3,61-7,46), género femenino (OR=1,58; IC 95%: 1,27-1,96) y haber estado en cuarentena o aislado (OR=1,60; IC 95%: 1,31-1,95). Uno de cada 7 sanitarios españoles presentaron un probable trastorno mental discapacitante durante la primera oleada de COVID-19. Aquéllos con trastornos mentales alguna vez antes de la pandemia, los que están expuestos con frecuencia a pacientes con COVID-19, los infectados o en cuarentena / aislados, las mujeres y las enfermeras auxiliares deben considerarse grupos que necesitan seguimiento y apoyo de su salud mental.

BACKGROUND: Chronic kidney disease (CKD) is a public health problem worldwide. We aimed to estimate the CKD prevalence in Spain and to examine the impact of the accumulation of cardiovascular risk factors (CVRF). MATERIAL AND METHODS: We performed a nationwide, population-based survey evaluating 11,505 individuals representative of the Spanish adult population. Information was collected through standardised questionnaires, physical examination, and analysis of blood and urine samples in a central laboratory. CKD was graded according to current KDIGO definitions. The relationship between CKD and 10CVRF was assessed (age, hypertension, general obesity, abdominal obesity, smoking, high LDL-cholesterol, low HDL-cholesterol, hypertriglyceridaemia, diabetes and sedentary lifestyle). RESULTS: Prevalence of CKD was 15.1% (95%CI: 14.3-16.0%). CKD was more common in men (23.1% vs 7.3% in women), increased with age (4.8% in 18-44 age group, 17.4% in 45-64 age group, and 37.3% in ≥65), and was more common in those with than those without cardiovascular disease (39.8% vs 14.6%); all P<.001. CKD affected 4.5% of subjects with 0-1CVRF, and then progressively increased from 10.4% to 52.3% in subjects with 2 to 8-10CVRF (P trend <.001). CONCLUSIONS: CKD affects one in seven adults in Spain. The prevalence is higher than previously reported and similar to that in the United States. CKD was particularly prevalent in men, older people and people with cardiovascular disease. Prevalence of CKD increased considerably with the accumulation of CVRF, suggesting that CKD could be considered as a cardiovascular condition.

BACKGROUND: The diagnosis of IgE-mediated immediate reactions to penicillins can be supported by in vivo or in vitro tests using classical benzylpenicillin determinants. The wide variety of beta-lactams and the description of new specificities requires a re-evaluation of the different tests available. The objective was to evaluate the diagnostic capacity of Pharmacia CAP System RAST FEIA amoxicilloyl c6 (AXO) and benzylpenicilloyl c1 (BPO) in patients with a documented IgE-mediated penicillin allergy. METHODS: We studied 129 patients in five groups. Groups 1, 2, and 3 had developed an immediate reaction after penicillin treatment. Group 1 (n=19) were skin test positive to amoxicillin (AX) and/or BPO and/or minor determinant mixture (MDM); group 2 (n=29) were skin test positive to AX but negative to BPO and MDM; and group 3 (n=26) were skin test negative to all determinants, the diagnosis being confirmed by a previous repetitive history or controlled administration. Two control groups, one with nonimmediate reactions -- group 4 (n=25) -- and one with good tolerance to penicillin -- group 5 (n=30) -- were included. All samples were analyzed in vitro for AXO and BPO, and the results compared to the in vivo diagnosis. RESULTS: AX was the drug most often involved. In group 1, 53% were in vitro positive for AXO and 68% for BPO, but 74% had at least one positive test result. In group 2, only 10% had a positive in vitro test to BPO compared to 41% to AXO. In group 3, 42% had positive BPO and/or AXO in vitro tests. In the control groups 4 and 5, the negative in vitro results for AXO were 96% and 100%, and for BPO 100% and 97%, respectively. A positive correlation between specific IgE levels and the time interval from the reaction to the evaluation was found only for group 3. CONCLUSIONS: This in vitro assay is beneficial for evaluating subjects allergic to beta-lactams. It is necessary to test for specific IgE to AXO in addition to BPO in patients with immediate allergic reactions after AX. The combination of in vivo and in vitro tests for estimating IgE antibodies to penicillins is important because of the existence of patients with a positive history but negative skin test.

BACKGROUND: Although several studies have investigated the influence of diet on asthma in schoolchildren, none of them has evaluated how obesity can modify this effect. A study was undertaken to evaluate the association of various foods and a Mediterranean diet with the prevalence of asthma and rhinoconjunctivitis, adjusting for obesity and exercise. METHODS: A cross-sectional study was performed in 20 106 schoolchildren aged 6-7 years from eight Spanish cities. Using the ISAAC phase III questionnaire, parents reported chest and nose symptoms, food intake, weight, height and other factors, including exercise. A Mediterranean diet score was developed. A distinction was made between current occasional asthma (COA) and current severe asthma (CSA). RESULTS: Independent of the amount of exercise, each Mediterranean score unit had a small but protective effect on CSA in girls (adjusted OR 0.90, 95% CI 0.82 to 0.98). Exercise was a protective factor for COA and rhinoconjunctivitis in girls and boys (the more exercise, the more protection). Obesity was a risk factor for CSA in girls (adjusted OR 2.35, 95% CI 1.51 to 3.64). Individually, a more frequent intake (1-2 times/week and>or=3 times/week vs never/occasionally) of seafood (adjusted ORs 0.63 (95% CI 0.44 to 0.91) and 0.53 (95% CI 0.35 to 0.80)) and cereals (adjusted OR 0.56 (95% CI 0.30 to 1.02) and 0.39 (95% CI 0.23 to 0.68)) were protective factors for CSA, while fast food was a risk factor (adjusted ORs 1.64 (95% CI 1.28 to 2.10) and 2.26 (95% CI 1.09 to 4.68)). Seafood (adjusted ORs 0.74 (95% CI 0.60 to 0.92) and 0.67 (95% CI 0.53 to 0.85)) and fruit (adjusted ORs 0.76 (95% CI 0.60 to 0.97) and 0.71 (95% CI 0.57 to 0.88)) were protective factors for rhinoconjunctivitis. CONCLUSIONS: A Mediterranean diet has a potentially protective effect in girls aged 6-7 years with CSA. Obesity is a risk factor for this type of asthma only in girls.

Amoxicillin-clavulanate (AC) hepatotoxicity has been reported to exhibit a higher predominance of cholestatic types of damage, especially in males. However, the determinants of its clinical expression are unknown. This study prospectively evaluated the profile of AC hepatotoxicity. Data on all cases of hepatotoxicity reported to the Spanish Registry attributed to AC and assessed as definite or probable on the Council for International Organizations of Medical Sciences (CIOMS) scale were collated and compared to published case series. Hepatotoxicity related to amoxicillin-clavulanate was identified in 69 patients (36 males; mean age 56 years) representing 14% of all cases of hepatotoxicity submitted to the Registry. There was an overall sex distribution and the predominant pattern of lesion was hepatocellular (36%) which occurred at a shorter duration of treatment (P < .03). Mean time lapse between therapy initiation and jaundice onset was 16 days. Late onset of symptoms following end of treatment occurred in half the cases. Multiple logistic regression analysis identified advancing age as the factor associated with the development of cholestatic/mixed type of injury (odds ratio for an age interval for 1 year: 1.045 [95% CI = 1.013-1.078; P = .005). An unfavorable outcome was seen in 7% of patients. In conclusion, age is the most important determinant in the biochemical expression of AC hepatotoxicity; younger age is associated with cytolytic damage and shorter treatment duration, whereas cholestatic/mixed type of damage is related to older age and prolonged AC therapy.

The objective of these guidelines is to ensure efficient and effective clinical practice. The panel of experts who produced this consensus document developed a research protocol based on a review of the literature. The prevalence of allergic reactions to iodinated contrast media (ICM) is estimated to be 1:170 000, that is, 0.05%-0.1% of patients undergoing radiologic studies with ICM (more than 75 million examinations per year worldwide). Hypersensitivity reactions can appear within the first hour after administration (immediate reactions) or from more than 1 hour to several days after administration (nonimmediate or delayed reactions). The risk factors for immediate reactions include poorly controlled bronchial asthma, concomitant medication (eg, angiotensin-converting enzyme inhibitors, ß-blockers, and proton-pump inhibitors), rapid administration of the ICM, mastocytosis, autoimmune diseases, and viral infections. The most common symptoms of immediate reactions are erythema and urticaria with or without angioedema, which appear in more than 70% of patients. Maculopapular rash is the most common skin feature of nonimmediate reactions (30%-90%). Skin and in vitro tests should be performed for diagnosis of both immediate and nonimmediate reactions. The ICM to be administered will therefore be chosen depending on the results of these tests, the ICM that induced the reaction (when known), the severity of the reaction, the availability of alternative ICM, and the information available on potential ICM cross-reactivity. Another type of contrast media, gadolinium derivatives, is used used for magnetic resonance imaging. Although rare, IgE-mediated reactions to gadolinium derivatives have been reported.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are gaining acceptance as treatment for selected patients with colorectal cancer with peritoneal carcinomatosis (CRCPC). Tremendous variations exist in the HIPEC delivery. METHODS: The American Society of Peritoneal Surface Malignancies (ASPSM) examined the overall survival in patients with CRCPC who underwent a complete cytoreduction and HIPEC with Oxaliplatin vs. Mitomycin C (MMC), stratifying them by the Peritoneal Surface Disease Severity Score (PSDSS). RESULTS: Median overall survival (OS) of 539 patients with complete cytoreduction was 32.6 months, 32.7 months for the MMC group and 31.4 months for the Oxaliplatin group (P = 0.925). However, when stratified by PSDSS, median OS rates in PSDSS I/II patients were 54.3 months in those receiving MMC vs. 28.2 months in those receiving oxaliplatin (P = 0.012), whereas in PSDSS III/IV patients, median OS rates were 19.4 months in those receiving MMC vs. 30.4 months in those receiving Oxaliplatin (P = 0.427). CONCLUSION: These data suggest that MMC might be a better agent for HIPEC delivery than Oxaliplatin in patients with CRCPC, favorable histologies and low burden of disease (PSDSS I/II) undergoing complete cytoreduction. Prospective studies are warranted, which stratify patients by their PSDSS and randomize them to HIPEC with MMC vs. Oxaliplatin.

Heterozygous missense and splice-site mutations in the tau gene have been previously identified in familial frontotemporal dementia with autosomal dominant inheritance. Here we report a Spanish kindred in which two brothers born from a third-degree consanguineous marriage were both affected with atypical progressive supranuclear palsy. A homozygous deletion at codon 296 (delN296) was identified in one of the affected siblings. Among the heterozygous carriers, two members with probable Parkinson's disease were identified, but none of heterozygotes developed atypical parkinsonism. The delN296 mutation lies in the sequence corresponding to the second tubulin-binding repeat of tau protein and affects one asparagine residue absolutely conserved in other species. This finding indicates that homozygous mutations in the tau gene may also cause hereditary tauopathies.

BACKGROUND: Most studies show a steep increase in asthma prevalence in the last decades, although few studies had applied the same methodology. Recent reports point out the possibility that the epidemic has come to an end. We have studied the prevalence of asthma in a very large sample of children, repeating the study eight years apart. METHODS: Repeated cross-sectional studies using the International Study of Asthma and Allergies in Childhood (ISAAC) protocol in a sample of Spanish schoolchildren 6-7 (parent-reported) and 13-14 (self-reported) years old in 1994-95 (phase I) and 2002-2003 (phase III). The number of participants was 42 417 in phase I and 42 813 in phase III. The participation rate was over 87% (13-14 years) and 70% (6-7 years). RESULTS: The prevalence of wheezing in the previous year in children aged 13-14 years was 9.0 and 9.3% for boys and 9.6 and 9.2% for girls for phases I and III, respectively. Children 6-7 years of age showed a substantial increase in wheezing in the previous year (7.0 and 10.7% for boys and 5.3 and 8.2% for girls). Other symptoms and severity indexes followed the same patterns. CONCLUSIONS: In the last 8 years, the prevalence of asthma has not changed in 13-14-year-old Spanish children but has increased substantially in 6-7-year olds.