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The aim of this study is to analyze the life habits and personal factors associated with an increased SARS-CoV-2 risk in a university environment with in-person lectures during the COVID-19 pandemic. There are no previous longitudinal studies that have analyzed behavioral and personal factors with the risk of SARS-CoV-2 infection on an entire university population. A cohort study was conducted in the three campuses of the University of Navarra between August 24th 2020 and May 30th 2021, including 14,496 students and employees. 10,959 participants were finally included. Descriptive and multivariate adjusted models were performed using Cox regression. A total of 1,032 (9.4%) participants were diagnosed with COVID-19 (879 students, 153 employees), almost 50% living with their family. COVID-19 was associated with living in college or residence (HR:1.96 CI 95% 1.45 to 2.63), motor transportation (HR:1.36 CI 95% 1.14 to 1.62), South American origin (HR:1.41 CI 95% 1.17 to 1.69) and belonging to Madrid’s campus (HR:3.15 CI 95% 2.50 to 3.97). In conclusion, international students, especially from Latin America, mostly lived in university apartments or shared flats and cohabited with 4-11 people. Living in a big city (Madrid), was a significant risk factor.

Background Breast implant capsule development and behavior are mainly determined by implant surface combined with other external factors such as intraoperative contamination, radiation or concomitant pharmacologic treatment. Thus, there are several diseases: capsular contracture, breast implant illness or Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL), that have been correlated with the specific type of implant placed. This is the first study to compare all major implant and texture models available in the market on the development and behave of the capsules. Through a histopathological analysis, we compared the behavior of different implant surfaces and how different cellular and histological properties give rise to different susceptibilities to develop capsular contracture among these devices. Methods A total of 48 Wistar female rats were used to implant 6 different types of breast implants. Mentor®, McGhan®, Polytech polyurethane®, Xtralane®, Motiva® and Natrelle Smooth® implants were employed; 20 rats received Motiva®, Xtralane® and Polytech polyurethane®, and 28 rats received Mentor®, McGhan® and Natrelle Smooth® implants. The capsules were removed five weeks after the implants placement. Further histological analysis compared capsule composition, collagen density and cellularity. Results High texturization implants showed the highest levels of collagen and cellularity along the capsule. However, polyurethane implants capsules behaved differently regarding capsule composition, with the thickest capsules but fewer collagen and myofibroblasts than expected, despite being generally considered as a macrotexturized implant. Nanotextured implants and microtextured implants histological findings showed similar characteristics and less susceptibility to develop a capsular contracture compared with smooth implants. Conclusions This study shows the relevance of the breast implant surface on the definitive capsules’ development, since this is one of the most differentiated factors that determine the incidence of capsular contracture and probably other diseases like BIA-ALCL. A correlation of these findings with clinical cases will help to unify implant classification criteria based on their shell and their estimated incidence of capsule-associated pathologies. Up to this point, the establishment of additional groups is recommended as nanotexturized implants seem to behave differently to pure smooth surfaces and polyurethane implants present diverse features from macro- or microtextured implants. No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

COVID-19 patients elicit strong responses to the nucleocapsid (N) protein of SARS-CoV-2 but binding antibodies are also detected in prepandemic individuals, indicating potential crossreactivity with common cold human coronaviruses (HCoV) and questioning its utility in seroprevalence studies. We investigated the immunogenicity of the full-length and shorter fragments of the SARS-CoV-2 N protein, and the crossreactivity of antibodies with HCoV. We identified a C-terminus region in SARS-CoV2 N of minimal sequence homology with HCoV that was more specific for SARS-CoV-2 and highly immunogenic. IgGs to the full-length SARS-CoV-2 N also recognized N229E N, and IgGs to HKU1 N recognized SARS-CoV-2 N. Crossreactivity with SARS-CoV-2 was stronger for alpha- rather than beta-HCoV despite having less sequence identity, revealing the importance of conformational recognition. Higher preexisting IgG to OC43 N correlated with lower IgG to SARS-CoV-2 N in rRT-PCR negative individuals, reflecting less exposure and indicating a potential protective association. Antibodies to SARS-CoV-2 N were higher in patients with more severe and longer duration of symptoms and in females. IgGs remained stable for at least 3 months, while IgAs and IgMs declined faster. In conclusion, N protein is a primary target of SARS-CoV-2-specific and HCoV crossreactive antibodies, both of which may affect the acquisition of immunity to COVID-19.

Background: Debridement, antibiotic agents, and implant retention (DAIR) is a currently accepted approach for the treatment of early prosthetic joint infections (PJI). The success of a DAIR procedure has shown variable results throughout the published literature. Scoring systems such as the Kidney, Liver, Index surgery, Cemented prosthesis, and C-reactive protein value (KLIC) score for the selection of patients that are likely to benefit from DAIR have proved to be helpful in decision making. Our study aims to further validate the KLIC score using a large external multicentric cohort and to evaluate other risk factors for failure. Patients and Methods: A retrospective analysis of patients with an early acute PJI who were treated with DAIR and recorded in a database of eight Spanish university hospitals was performed. According to pre-operative variables of the KLIC study, patients were categorized into five groups: group A, =2 points; group B, 2.5-3.5 points; group C, 4-5 points; group D, 5.5-6.5 points; and group E, =7 points. Failure rates were compared between groups at 60 days and after 60 days of DAIR. Further variables for risk of failure were also analyzed. Results: A total of 455 patients with early acute PJI were included in the analyses. At 60 days, patients presenting with pre-operative elevated C-reactive protein serum levels, Staphylococcus aureus, and polymicrobial infections were associated with failure. Failure rates recorded were 12% for group A (n = 210), 18% for group B (n = 83), 26% for group C (n = 89), 24% for group D (n = 66), and 0% for group E (n = 7). Univariable analysis between consecutive groups of the KLIC score showed no differences for failure before 60 days of the DAIR procedure. Scheduled surgery and having the procedure performed by a specialized unit were also identified as important factors for DAIR success. Conclusions: Our results suggest the KLIC score was not useful for predicting failure in our cohort. Furthermore, our results indicate a specialized unit should conduct DAIR procedures.

Background Excessive inflammation is pathogenic in the pneumonitis associated with severe COVID-19. Neutrophils are among the most abundantly present leukocytes in the inflammatory infiltrates and may form neutrophil extracellular traps (NETs) under the local influence of cytokines. NETs constitute a defense mechanism against bacteria, but have also been shown to mediate tissue damage in a number of diseases. Research Question Could NETs and their tissue-damaging properties inherent to neutrophil-associated functions play a role in the respiratory failure seen in patients with severe COVID-19, and how does this relate to the SARS-CoV-2 viral loads, IL-8 (CXCL8) chemokine expression, and cytotoxic T-lymphocyte infiltrates? Study Design and Methods Sixteen lung biopsy samples obtained immediately after death were analyzed methodically as exploratory and validation cohorts. NETs were analyzed quantitatively by multiplexed immunofluorescence and were correlated with local levels of IL-8 messenger RNA (mRNA) and the density of CD8+ T-cell infiltration. SARS-CoV-2 presence in tissue was quantified by reverse-transcriptase polymerase chain reaction and immunohistochemistry analysis. Results NETs were found in the lung interstitium and surrounding the bronchiolar epithelium with interindividual and spatial heterogeneity. NET density did not correlate with SARS-CoV-2 tissue viral load. NETs were associated with local IL-8 mRNA levels. NETs were also detected in pulmonary thrombi and in only one of eight liver tissues. NET focal presence correlated negatively with CD8+ T-cell infiltration in the lungs. Interpretation Abundant neutrophils undergoing NETosis are found in the lungs of patients with fatal COVID-19, but no correlation was found with viral loads. The strong association between NETs and IL-8 points to this chemokine as a potentially causative factor. The function of cytotoxic T-lymphocytes in the immune responses against SARS-CoV-2 may be interfered with by the presence of NETs.

Thromboprophylaxis with low molecular weight heparin in hospitalized patients with COVID-19 is mandatory, unless contraindicated. Given the links between inflammation and thrombosis, the use of higher doses of anticoagulants could improve outcomes. We conducted an open-label, multicenter, randomized, controlled trial in adult patients hospitalized with nonsevere COVID-19 pneumonia and elevated D-dimer. Patients were randomized to therapeutic-dose bemiparin (115 IU/kg daily) versus standard prophylaxis (bemiparin 3,500 IU daily), for 10 days. The primary efficacy outcome was a composite of death, intensive care unit admission, need of mechanical ventilation support, development of moderate/severe acute respiratory distress, and venous or arterial thrombosis within 10 days of enrollment. The primary safety outcome was major bleeding (International Society on Thrombosis and Haemostasis criteria). A prespecified interim analysis was performed when 40% of the planned study population was reached. From October 2020 to May 2021, 70 patients were randomized at 5 sites and 65 were included in the primary analysis; 32 patients allocated to therapeutic dose and 33 to standard prophylactic dose. The primary efficacy outcome occurred in 7 patients (22%) in the therapeutic-dose group and 6 patients (18%) in the prophylactic-dose (absolute risk difference 3.6% [95% confidence interval [CI], –16% –24%]; odds ratio 1.26 [95% CI, 0.37–4.26]; p = 0.95). Discharge in the first 10 days was possible in 66 and 79% of patients, respectively. No major bleeding event was registered. Therefore, in patients with COVID-19 hospitalized with nonsevere pneumonia but elevated D-dimer, the use of a short course of therapeutic-dose bemiparin does not appear to improve clinical outcomes compared with standard prophylactic doses. Trial Registration: ClinicalTrials.gov NCT04604327.

In December 2019, an outbreak of severe acute respiratory syndrome associated to SARS-CoV2 was reported in Wuhan, China. To date, little is known on histopathological findings in patients infected with the new SARS-CoV2. Lung histopathology shows features of acute and organising diffuse alveolar damage. Subtle cellular inflammatory infiltrate has been found in line with the cytokine storm theory. Medium-size vessel thrombi were frequent, but capillary thrombi were not present. Despite the elevation of biochemical markers of cardiac injury, little histopathological damage could be confirmed. Viral RNA from paraffin sections was detected at least in one organ in 90% patients.

BackgroundSpain is one of the countries most heavily affected by the COVID-19 pandemic. As in other countries such as UK and USA, nursing homes have been an important human reservoir for the virus and the population with the highest mortality worldwide. The presence of asymptomatic carriers within nursing homes is one of the factors that could provoke new outbreaks during the relaxing of lockdown measures.MethodsWe developed a high-throughput protocol for RNA extraction of patient samples based on silane magnetic beads in multi-well plates. The sensitivity, specificity and reproducibility rates were assessed using positive and negative clinical samples from the Clinica Universidad de Navarra, Spain. We utilized the protocol to test a pilot cohort of 138 residents and 87 staff from a nursing home in Northern Navarre, Spain.FindingsOur protocol showed high sensitivity (100%), specificity (96·0%) and linear correlation with PCR cycle threshold values obtained with a standard testing kit (R2 = 0·807, p=3E-05). Testing of 225 individuals from the nursing home revealed 63 residents (46%) and 14 staff (16%) positive for SARS-CoV-2. Only 18 of the positive residents (28·6%) were symptomatic at time of testing. During follow-up, 6 PCR-negative symptomatic residents were retested and resulted positive. One-month mortality among positive residents was higher than in negative residents (15·9% vs 1·3%), regardless of age or comorbidities.InterpretationRapid silane bead-based RNA extraction expanded the testing capabilities and COVID-19 patients were promptly identified. Personal and public health measures were enacted to avoid spreading and tighten clinical surveillance. The ability to easily adapt the technical capabilities of academic research centers to large-scale testing for SARS-CoV-2 could provide an invaluable tool for ensuring a safe lifting of lockdown in countries with high numbers of cases.FundingEuropean Molecular Biology Organization and Genomics Unit, Cima Universidad de Navarra.

Background Ivermectin inhibits the replication of SARS-CoV-2 in vitro at concentrations not readily achievable with currently approved doses. There is limited evidence to support its clinical use in COVID-19 patients. We conducted a Pilot, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of a single dose of ivermectin reduce the transmission of SARS-CoV-2 when administered early after disease onset. Methods Consecutive patients with non-severe COVID-19 and no risk factors for complicated disease attending the emergency room of the Clínica Universidad de Navarra between July 31, 2020 and September 11, 2020 were enrolled. All enrollments occurred within 72 h of onset of fever or cough. Patients were randomized 1:1 to receive ivermectin, 400 mcg/kg, single dose (n = 12) or placebo (n = 12). The primary outcome measure was the proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day 7 post-treatment. The primary outcome was supported by determination of the viral load and infectivity of each sample. The differences between ivermectin and placebo were calculated using Fisher's exact test and presented as a relative risk ratio. This study is registered at ClinicalTrials.gov: NCT04390022. Findings All patients recruited completed the trial (median age, 26 [IQR 19-36 in the ivermectin and 21-44 in the controls] years; 12 [50%] women; 100% had symptoms at recruitment, 70% reported headache, 62% reported fever, 50% reported general malaise and 25% reported cough). At day 7, there was no difference in the proportion of PCR positive patients (RR 0·92, 95% CI: 0·77-1·09, p = 1·0). The ivermectin group had non-statistically significant lower viral loads at day 4 (p = 0·24 for gene E; p = 0·18 for gene N) and day 7 (p = 0·16 for gene E; p = 0·18 for gene N) post treatment as well as lower IgG titers at day 21 post treatment (p = 0·24). Patients in the ivermectin group recovered earlier from hyposmia/anosmia (76 vs 158 patient-days; p < 0.001). Interpretation Among patients with non-severe COVID-19 and no risk factors for severe disease receiving a single 400 mcg/kg dose of ivermectin within 72 h of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers which warrants assessment in larger trials. Funding ISGlobal, Barcelona Institute for Global Health and Clínica Universidad de Navarra.

Reliable serological tests are required to determine the prevalence of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to characterize immunity to the disease in order to address key knowledge gaps in the coronavirus disease 2019 (COVID-19) pandemic. Quantitative suspension array technology (qSAT) assays based on the xMAP Luminex platform overcome the limitations of rapid diagnostic tests and enzyme-linked immunosorbent assays (ELISAs) with their higher precision, dynamic range, throughput, miniaturization, cost-efficiency, and multiplexing capacity., Reliable serological tests are required to determine the prevalence of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to characterize immunity to the disease in order to address key knowledge gaps in the coronavirus disease 2019 (COVID-19) pandemic. Quantitative suspension array technology (qSAT) assays based on the xMAP Luminex platform overcome the limitations of rapid diagnostic tests and enzyme-linked immunosorbent assays (ELISAs) with their higher precision, dynamic range, throughput, miniaturization, cost-efficiency, and multiplexing capacity. We developed three qSAT assays for IgM, IgA, and IgG against a panel of eight SARS-CoV-2 antigens, including spike protein (S), nucleocapsid protein (N), and membrane protein (M) constructs. The assays were optimized to minimize the processing time and maximize the signal-to-noise ratio. We evaluated their performances using 128 prepandemic plasma samples (negative controls) and 104 plasma samples from individuals with SARS-CoV-2 diagnosis (positive controls), of whom 5 were asymptomatic, 51 had mild symptoms, and 48 were hospitalized. Preexisting IgG antibodies recognizing N, M, and S proteins were detected in negative controls, which is suggestive of cross-reactivity to common-cold coronaviruses. The best-performing antibody/antigen signatures had specificities of 100% and sensitivities of 95.78% at ≥14 days and 95.65% at ≥21 days since the onset of symptoms, with areas under the curve (AUCs) of 0.977 and 0.999, respectively. Combining multiple markers as assessed by qSAT assays has the highest efficiency, breadth, and versatility to accurately detect low-level antibody responses for obtaining reliable data on the prevalence of exposure to novel pathogens in a population. Our assays will allow gaining insights into antibody correlates of immunity and their kinetics, required for vaccine development to combat the COVID-19 pandemic.

Identification of relevant epitopes is crucial for the development of subunit peptide vaccines inducing neutralizing and cellular immunity against SARS-CoV-2. Our aim was the characterization of epitopes in the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein to generate a peptide vaccine. Epitope mapping using a panel of 10 amino acid overlapped 15-mer peptides covering region 401-515 from RBD did not identify linear epitopes when tested with sera from infected individuals or from RBD-immunized mice. However, immunization of mice with these 15-mer peptides identified four peptides located at region 446-480 that induced antibodies recognizing the peptides and RBD/S1 proteins. Immunization with peptide 446-480 from S protein formulated with Freund’s adjuvant or with CpG oligodeoxinucleotide/Alum induced polyepitopic antibody responses in BALB/c and C56BL/6J mice, recognizing RBD (titres of 3 × 104–3 × 105, depending on the adjuvant) and displaying neutralizing capacity (80–95% inhibition capacity; p < 0.05) against SARS-CoV-2. Murine CD4 and CD8T-cell epitopes were identified in region 446-480 and vaccination experiments using HLA transgenic mice suggested the presence of multiple human T-cell epitopes. Antibodies induced by peptide 446-480 showed broad recognition of S proteins and S-derived peptides belonging to SARS-CoV-2 variants of concern. Importantly, vaccination with peptide 446-480 or with a cyclic version of peptide 446-488 containing a disulphide bridge between cysteines 480 and 488, protected humanized K18-hACE2 mice from a lethal dose of SARS-CoV-2 (62.5 and 75% of protection; p < 0.01 and p < 0.001, respectively). This region could be the basis for a peptide vaccine or other vaccine platforms against Covid-19.

Background: Excessive inflammation is pathogenic in pneumonitis associated to severe COVID-19. Neutrophils are among the most abundantly present leukocytes in the inflammatory infiltrates and may form neutrophil extracellular traps (NETs) under the local influence of cytokines. NETs constitute a defence mechanism against bacteria but have also been shown to mediate tissue damage in a number of diseases. Methods: In this retrospective cohort study, sixteen immediate post-mortem lung biopsies were methodologically analysed as exploratory and validation cohorts. NETs were quantitatively analysed by multiplexed immunofluorescence and correlated with local levels of IL-8 mRNA expression and the density of CD8+ T-cell infiltration. SARS-CoV-2 presence in tissue was quantified by RT-PCR and immunohistochemistry. Findings: NETs were found in the lung interstitium and surrounding the bronchiolar epithelium with interindividual and spatial heterogeneity. NET density did not correlate with SARS-CoV-2 tissue viral load. NETs were associated with local IL-8 mRNA levels. NETs were also detected in pulmonary thrombi and in only one out of eight liver tissues in spatial fashion. NET focal presence negatively correlated with CD8+ T-cell infiltration in the lungs. Interpretation: Abundant neutrophils undergoing NETosis are found in the lungs of patients with fatal COVID-19, showing no correlation with viral loads. The strong association between NETs and IL-8 focal expression points to this chemokine as the potential causative factor. The function of cytotoxic T-lymphocytes in the immune responses against SARS-CoV-2 may be interfered by the presence of NETs. Funding Information: This study was supported by Banco Bilbao Vizcaya (BBVA) Foundation, “Ayudas a Equipos de Investigacion Cientifica SARS-CoV-2 y COVID-19”. Declaration of Interests: I.M. reports receiving commercial research grants from BMS, Bioncotech, Alligator, Pfizer, Leadartis and Roche; has received speakers bureau honoraria from MSD; and is a consultant or advisory board member for BMS, Roche, Genmab, F-Star, Bioncotech, Bayer, Numab, Pieris, Alligator, and Merck Serono. C.E.A reports research grants from AstraZeneca. All other authors declare no competing interests. Ethics Approval Statement: This study was approved by the ethics committee of the University of Navarra, Spain (Approval 2020.192). Tissue collections were obtained with consent from a first-degree relative, following a protocol approved by the ethics committee of the University of Navarra (Protocol 2020.192p).

COVID-19 patients elicit strong responses to the nucleocapsid (N) protein of SARS-CoV-2 but binding antibodies are also detected in prepandemic individuals, indicating potential crossreactivity with common cold human coronaviruses (HCoV) and questioning its utility in seroprevalence studies. We investigated the immunogenicity of the full-length and shorter fragments of the SARS-CoV-2 N protein, and the crossreactivity of antibodies with HCoV. We indentified a C-terminus region in SARS-CoV2 N of minimal sequence homology with HCoV that was more specific and highly immunogenic. IgGs to the full-length SARS-CoV-2 N also recognised N229E N, and IgGs to HKU1 N recognised SARS-CoV-2 N. Crossreactivity with SARS-CoV-2 was stronger for alpha-rather than beta-HCoV despite having less sequence identity, revealing the importance of conformational recognition. Higher preexisting IgG to OC43 N correlated with lower IgG to SARS-CoV-2 in rRT-PCR negative individuals, reflecting less exposure and indicating a potential protective association. Antibodies to SARS-CoV-2 N were higher in patients with more severe and longer symptoms and in females. IgGs remained stable for at least 3 months, while IgAs and IgMs declined faster. In conclusion, N is a primary target of SARS-CoV-2-specific and HCoV crossreactive antibodies, both of which may affect the acquisition of immunity to COVID-19.

Ivermectin inhibits the replication of SARS-CoV-2 in vitro at concentrations not readily achievable with currently approved doses. There is limited evidence to support its clinical use in COVID-19 patients. We conducted a Pilot, randomized, double-blind, placebo-controlled trial to determine the efficacy of a single dose of ivermectin to reduce the proportion of PCR positives, viral load at day 7 post treatment.Consecutive patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mild COVID-19 (no pneumonia) and no risk factors for complicated disease attending the emergency room of the Clínica Universidad de Navarra. Patients were randomized 1:1 to receive ivermectin, 400 mcg/kg, single dose (n = 12) or placebo (n = 12). The primary outcome measure was the proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day 7 post-treatment. The primary outcome was supported by determination of the viral load and infectivity of each sample. The differences between ivermectin and placebo were calculated using Fisher’s exact test and presented as a relative risk ratio.All patients recruited completed the trial (median age, 26 [range, 18-54] years; 12 [50%] women; 100% had symptoms at recruitment, 70% reported headache, 62% reported fever, 50% reported general malaise and 25% reported cough). At day 7, there was no difference in the proportion of PCR positive patients (RR 0.92, 95% CI: 0.77-1.09, p = 1.0). The ivermectin group had lower median viral loads at days 4 and 7 post treatment as well as lower median IgG titers at day 21 post treatment. Hyposmia/anosmia (76 vs 158 patient-days) and cough (68 vs 97 patient-days) were less frequent in the ivermectin group.Among patients with mild COVID-19 and no risk factors for severe disease receiving a single 400 mcg/kg dose of ivermectin within 48 hours of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers which warrants assessment in larger trials.Trial registration ClinicalTrials.gov Identifier: NCT04390022 https://clinicaltrials.gov/ct2/show/NCT04390022

Objectives The primary objective is to determine the efficacy of a single dose of ivermectin, administered to low risk, non-severe COVID-19 patients in the first 48 hours after symptom onset to reduce the proportion of patients with detectable SARS-CoV-2 RNA by Polymerase Chain Reaction (PCR) test from nasopharyngeal swab at day 7 post-treatment. The secondary objectives are: To assess the efficacy of ivermectin to reduce the SARS-CoV-2 viral load in the nasopharyngeal swab at day 7 post treatment.To assess the efficacy of ivermectin to improve symptom progression in treated patients.To assess the proportion of seroconversions in treated patients at day 21.To assess the safety of ivermectin at the proposed dose.To determine the magnitude of immune response against SARS-CoV-2.To assess the early kinetics of immunity against SARS-CoV-2. Trial design SAINT is a single centre, double-blind, randomized, placebo-controlled, superiority trial with two parallel arms. Participants will be randomized to receive a single dose of 400 μg/kg ivermectin or placebo, and the number of patients in the treatment and placebo groups will be the same (1:1 ratio). Participants The population for the study will be patients with a positive nasopharyngeal swab PCR test for SARS-CoV-2, with non-severe COVID-19 disease, and no risk factors for progression to severity. Vulnerable populations such as pregnant women, minors (i.e.; under 18 years old), and seniors (i.e.; over 60 years old) will be excluded. Inclusion criteria Patients diagnosed with COVID-19 in the emergency room of the Clínica Universidad de Navarra (CUN) with a positive SARS-CoV-2 PCR. Residents of the Pamplona basin (“Cuenca de Pamplona”). The patient must be between the ages of 18 and 60 years of age. Negative pregnancy test for women of child bearing age*. The patient or his/her representative, has given informed consent to participate in the study. The patient should, in the PI's opinion, be able to comply with all the requirements of the clinical trial (including home follow up during isolation). Exclusion criteria Known history of ivermectin allergy. Hypersensitivity to any component of ivermectin. COVID-19 pneumonia. Diagnosed by the attending physician.Identified in a chest X-ray. Fever or cough present for more than 48 hours. Positive IgG against SARS-CoV-2 by rapid diagnostic test. Age under 18 or over 60 years. The following co-morbidities (or any other disease that might interfere with the study in the eyes of the PI): Immunosuppression.Chronic Obstructive Pulmonary Disease.Diabetes.Hypertension.Obesity.Acute or chronic renal failure.History of coronary disease.History of cerebrovascular disease.Current neoplasm. Recent travel history to countries that are endemic for Loa loa (Angola, Cameroon, Central African Republic, Chad, Democratic Republic of Congo, Ethiopia, Equatorial, Guinea, Gabon, Republic of Congo, Nigeria and Sudan). Current use of CYP 3A4 or P-gp inhibitor drugs such as quinidine, amiodarone, diltiazem, spironolactone, verapamil, clarithromycin, erythromycin, itraconazole, ketoconazole, cyclosporine, tacrolimus, indinavir, ritonavir or cobicistat. Use of critical CYP3A4 substrate drugs such as warfarin. *Women of child bearing age may participate if they use a safe contraceptive method for the entire period of the study and at least one month afterwards. A woman is considered to not have childbearing capacity if she is post-menopausal (minimum of 2 years without menstruation) or has undergone surgical sterilization (at least one month before the study). The trial is currently planned at a single center, Clínica Universidad de Navarra, in Navarra (Spain), and the immunology samples will be analyzed at the Barcelona Institute for Global Health (ISGlobal), in Barcelona (Spain). Participants will be recruited by the investigators at the emergency room and/or COVID-19 area of the CUN. They will remain in the trial for a period of 28 days at their homes since they will be patients with mild disease. In the interest of public health and to contain transmission of infection, follow-up visits will be conducted in the participant's home by a clinical trial team comprising nursing and medical members. Home visits will assess clinical and laboratory parameters of the patients. Intervention and comparator Ivermectin will be administered to the treatment group at a 400μg/Kg dose (included in the EU approved label of Stromectol and Scabioral). The control group will receive placebo. There is no current data on the efficacy of ivermectin against the virus in vivo, therefore the use of placebo in the control group is ethically justified. Main outcomes Primary Proportion of patients with a positive SARS-CoV-2 PCR from a nasopharyngeal swab at day 7 post-treatment. Secondary Mean viral load as determined by PCR cycle threshold (Ct) at baseline and on days 4, 7, 14, and 21.Proportion of patients with fever and cough at days 4, 7, 14, and 21 as well as proportion of patients progressing to severe disease or death during the trial.Proportion of patients with seroconversion at day 21.Proportion of drug-related adverse events during the trial.Median levels of IgG, IgM, IgA measured by Luminex, frequencies of innate and SARS-CoV-2-specific T cells assessed by flow cytometry, median levels of inflammatory and activation markers measured by Luminex and transcriptomics.Median kinetics of IgG, IgM, IgA levels during the trial, until day 28. Randomisation Eligible patients will be allocated in a 1:1 ratio using a randomization list generated by the trial statistician using blocks of four to ensure balance between the groups. A study identification code with the format “SAINT-##” (##: from 01 to 24) will be generated using a sequence of random numbers so that the randomization number does not match the subject identifier. The sequence and code used will be kept in an encrypted file accessible only to the trial statistician. A physical copy will be kept in a locked cabinet at the CUN, accessible only to the person administering the drug who will not enrol or attend to patient care. A separate set of 24 envelopes for emergency unblinding will be kept in the study file. Blinding (masking) The clinical trial team and the patients will be blinded. The placebo will not be visibly identical, but it will be administered by staff not involved in the clinical care or participant follow up. Numbers to be randomised (sample size) The sample size is 24 patients: 12 participants will be randomised to the treatment group and 12 participants to the control group. Trial Status Current protocol version: 1.0 dated 16 of April 2020. Recruitment is envisioned to begin by May 14th and end by June 14th. Trial registration EudraCT number: 2020-001474-29, registered April 1st. Clinicaltrials.gov: submitted, pending number Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Background Febrile neutropenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal β-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimized administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematologic patients with FN.Methods A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 minutes) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK model of the BLA studied.Discussion Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematologic patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes.Trial registration: European Clinical Trials Database: EudraCT 2018-001476-37ClinicalTrials.gov Identifier: NCT04233996

Background Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal β-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN. Methods A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem-cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 min) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK model of the BLA studied. Discussion Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematological patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes. Trial registration European Clinical Trials Database: EudraCT 2018–001476-37. ClinicalTrials.gov, ID: NCT04233996.

espanolResumen La disponibilidad y el uso cada vez mas extendido de tratamientos antibioticos de amplio espectro ha propiciado la aparicion de efectos adversos relacionados con su uso, destacando entre ellos, por su elevada frecuencia, la aparicion de diarrea. La infeccion por Clostridium difficile representa la etiologia identificable y tratable mas comun, no debiendo olvidar la capacidad de otros patogenos entericos para causar una presentacion clinica similar. Esta forma de presentacion y la evolucion clinica de los pacientes afectos definira las opciones terapeuticas disponibles en base a las ultimas guias clinicas. EnglishThe availability and increasingly widespread use of broad-spectrum antibiotic treatments have led to the development of adverse events related to its use, highlighting due to its high frequency the occurrence of diarrhoea. Clostridium difficile infection represents the most common identifiable and treatable aetiology, not forgetting the ability of other pathogens to cause a similar clinical presentation. This form of presentation and the clinical evolution of the affected patients will define the therapeutic options available based on the latest clinical guidelines.

Resumen Introduccion. Las infecciones del tracto urinario representan una de las causas infecciosas mas frecuentes tanto a nivel comunitario como a nivel nosocomial y relacionado con la asistencia sanitaria. Habitualmente no son infecciones graves, pero si que condicionan un uso frecuente y muchas veces innecesario de antibioticos, con el riesgo de seleccion de mecanismos de resistencia, ademas de los posibles efectos secundarios de un tratamiento evitable. Bacteriuria asintomatica. Representa el aislamiento de un uropatogeno en recuento significativo en una muestra de orina en una persona asintomatica. Su diagnostico y tratamiento es de especial interes en la mujer gestante y previo a la realizacion de un procedimiento urologico de alto riesgo. Cistitis aguda/pielonefritis aguda. Son infecciones urinarias sintomaticas en las que es importante conocer la evidencia disponible de diagnostico y de tratamiento para disminuir el riesgo de recurrencias y el uso adecuado de antibioticos. Infecciones recurrentes. Situacion clinica definida por la presencia de al menos 2 episodios en los 6 ultimos meses o 3 o mas episodios en el ano previo. Representa un problema relativamente frecuente en el que las estrategias preventivas, adaptadas a cada situacion clinica, son muy importantes.

espanolResumen Introduccion. Las infecciones del tracto urinario (ITU) son una de las enfermedades infecciosas mas frecuentes tanto en el ambito ambulatorio como en el hospitalario, en este ultimo caso, principalmente relacionado con la presencia de cateteres urinarios. Patogenia y manifestaciones clinicas. Las infecciones urinarias se producen por via ascendente de un uropatogeno que coloniza la mucosa periuretral, habitualmente procedente del intestino. Principalmente se manifiestan con un sindrome miccional. La mayoria de las ITU son infecciones no complicadas que se presentan en mujeres jovenes, sexualmente activas. Las infecciones de via urinaria alta-parenquimatosas entre las que incluyen aquellas infecciones que afectan a parenquima-pelvis renal y/o prostata se pueden producir por via ascendente o por via hematogena y clinicamente suelen asociar un sindrome infeccioso. Diagnostico y tratamiento. El diagnostico se basa fundamentalmente en la clinica y el cultivo de orina. El hemocultivo solo se recomienda en determinadas situaciones y, en la mayoria de los casos, no se requieren pruebas diagnosticas complementarias. El tratamiento habitualmente se puede realizar de modo ambulatorio y se establece de forma empirica, de acuerdo con el patron local de sensibilidad de Escherichia coli, que es el agente causal de mas del 80% de estas infecciones. La bacteriuria asintomatica (BA) y las ITU complicadas son otras formas de presentacion de la ITU. EnglishIntroduction. Urinary tract infections (UTI) are the most common infectious diseases that present in outpatient and hospital settings; in the latter case they are principally associated with urinary catheters. Pathogenesis and clinical manifestations. Urinary tract infections are caused by uropathogens travelling upwards and colonising the periurethral mucosa, generally from the bowel. They principally present with voiding symptoms. Most UTI are uncomplicated infections that present in young, sexually active women. Upper urinary tract infections that include infections that affect the renal and/or prostatic parenchyma-pelvis can also spread upwards and, less often, haematogenously, and are usually clinically associated with an infectious syndrome. Diagnosis and treatment. Diagnosis is essentially based on clinical symptoms and urine culture. Haemoculture is only recommended in certain situations and in most cases no complementary diagnostic tests are required. Treatment can usually be given as an outpatient and is empirical according to the local sensitivity pattern of Escherichia coli, which is the causative agent of more than 80% of these infections. Asymptomatic bacteriuria (AB) and complicated UTI are other forms in which UTI present.

Resumen Staphylococcus aureus es uno de los microorganismos aislados con mas frecuencia tanto a nivel nosocomial como comunitario. Las infecciones por este microorganismo generan una importante morbimortalidad y un enorme coste medico asociado. De hecho, la mortalidad de la bacteriemia estafilococica puede llegar a ser de un 60%, dependiendo del perfil de resistencias y del tipo de paciente. La resistencia de S. aureus a penicilina es un hecho desde que se empezo a utilizar de forma masiva en los anos cuarenta. Poco despues aparecian las primeras cepas resistentes a meticilina (SARM), inicialmente en el ambito hospitalario. Hoy en dia, SARM comunitario ha cobrado una importancia mayor que el de origen nosocomial en algunos paises como EE. UU. Durante muchos anos, los glicopeptidos y en concreto vancomicina han sido los antimicrobianos de eleccion para tratar estas infecciones. Sin embargo, en los ultimos anos hemos asistido a un incremento progresivo de las concentraciones minimas inhibitorias (CMI) de vancomicina (creep de la CMI) que ha supuesto un nuevo contratiempo para el tratamiento. Linezolid, tigeciclina y daptomicina han sido alternativas validas a los glicopeptidos que se han utilizado en los ultimos 10 anos, sin embargo, han surgido tambien resistencias que han limitado su uso en algunas ocasiones. Despues de muchos anos sin poder contar con nuevos antimicrobianos, nuevas opciones como dalvabancina, ceftarolina o tedizolid estan disponibles en nuestros hospitales.

Treatment of an infected postpneumonectomy cavity is very difficult. We present a patient with an infection of a postpneumonectomy cavity by Staphylococcus epidermidis treated with local daptomycin for different dwell times, maintaining high antibiotic levels above the MIC. Clinical and microbiological cure were achieved successfully.

ObjectiveTo study the association between adherence to several a priori-defined healthy food patterns and the risk of hypertension.DesignProspective, multipurpose, dynamic cohort study (recruitment permanently open). We followed up 10 800 men and women (all of them university graduates), who were initially free of hypertension, for a variable period (range 2–6 years, median 4·6 years). During follow-up, 640 participants reported a new medical diagnosis of hypertension. Baseline diet was assessed using a validated 136-item FFQ. Validated information about non-dietary potential confounders was also gathered. We calculated adherence to fifteen different hypothesis-oriented food patterns and assessed the association between each of them and incident hypertension using multivariable Cox models.SettingThe SUN (Seguimiento Universidad de Navarra – University of Navarra Follow-up) Project, Spain.SubjectsParticipants recruited to the SUN cohort before October 2005 were eligible for inclusion; after excluding those with self-reported hypertension or CVD at baseline, or with extreme total energy intake, data of 10 800 were analysed.ResultsHigher adherence to the DASH (Dietary Approaches to Stop Hypertension) diet (range of the score: 0 to 5) was significantly associated with a lower risk for developing hypertension (P for trend = 0·02). The other food patterns showed no significant association with incident hypertension.ConclusionsOur results support a long-term protection of the DASH diet against the incidence of hypertension, but we found no evidence of a similar inverse association with hypertension for any other a priori-defined healthy food pattern.

The aim of this nonrandomized, open label, phase 1 clinical trial was to evaluate the safety and the feasibility of the treatment with autologous bone marrow–derived endothelial progenitor cells (EPC) in decompensated liver cirrhosis. In addition, the changes in liver function and hepatic venous pressure gradient (HVPG) and their relation with the characteristics of the cellular product were analyzed. Twelve patients with Child-Pugh ≥8 liver cirrhosis underwent bone marrow harvest for ex vivo differentiation of EPC. The final product was administered through the hepatic artery in a single administration. Patients underwent clinical and radiologic follow-up for 12 months. The phenotype and the ability to produce cytokines and growth factors of the final cellular suspension were analyzed. Eleven patients were treated (feasibility 91%). No treatment-related severe adverse events were observed as consequence of any study procedure or treatment. Model for end-stage liver disease score improved significantly ( P 0.042) in the first 90 days after cells administration and 5 of the 9 patients alive at 90 days showed a decreased of HVPG. There was a direct correlation between the expression of acetylated-low density lipoprotein and von Willebrand factor in the cellular product and the improvement in liver function and HVPG. The treatment with EPCs in patients with decompensated liver cirrhosis is safe and feasible and might have therapeutic potential. Patients receiving a higher amount of functionally active EPC showed an improvement of liver function and portal hypertension suggesting that the potential usefulness of these cells for the treatment of liver cirrhosis deserves further evaluation.

Background Intermediate Care Units (ImCU) have become an alternative scenario to perform Non-Invasive Ventilation (NIV). The limited number of prognostic studies in this population support the need of mortality prediction evaluation in this context. Objective The objective of this study is to analyze the performance of Simplified Acute Physiology Score (SAPS) II and 3 in patients undergoing NIV in an ImCU. Additionally, we searched for new variables that could be useful to customize these scores, in order to improve mortality prediction. Design Cohort study with prospectively collected data from all patients admitted to a single center ImCU who received NIV. The SAPS II and 3 scores with their respective predicted mortality rates were calculated. Discrimination and calibration were evaluated by calculating the area under the receiver operating characteristic curve (AUC) and with the Hosmer-Lemeshow goodness of fit test for the models, respectively. Binary logistic regression was used to identify new variables to customize the scores for mortality prediction in this setting. Patients The study included 241 patients consecutively admitted to an ImCU staffed by hospitalists from April 2006 to December 2013. Key Results The observed in-hospital mortality was 32.4% resulting in a Standardized Mortality Ratio (SMR) of 1.35 for SAPS II and 0.68 for SAPS 3. Mortality discrimination based on the AUC was 0.73 for SAPS II and 0.69 for SAPS 3. Customized models including immunosuppression, chronic obstructive pulmonary disease (COPD), acute pulmonary edema (APE), lactic acid, pCO2 and haemoglobin levels showed better discrimination than old scores with similar calibration power. Conclusions These results suggest that SAPS II and 3 should be customized with additional patient-risk factors to improve mortality prediction in patients undergoing NIV in intermediate care.

Purpose. Wine consumption has been related to a reduced cardiovascular risk. This effect has been attributed partly to the healthier diet of wine drinkers. We compared food habits according to alcoholic beverage preference in a Mediterranean population. Design. A cross-sectional study of a large sample of participants at high risk for cardiovascular disease. Setting. Primary care centers in a Mediterranean country, Spain. Participants. A total of 1675 men aged 55 to 80 years old and 2150 women aged 60 to 80 years old who had no documented cardiovascular disease but had either diabetes or at least three major cardiovascular risk factors. Measures. A food frequency questionnaire, alcoholic beverage consumption, adherence to Mediterranean diet, age, family history of cardiovascular disease, smoking, body mass index, diabetes, dyslipidemia, and educational level were measured. Analysis. We analyzed differences in food consumption according to the type of alcoholic beverage preferentially consumed and adjusted the estimates for age, body mass index, cholesterol level, and total energy intake. Results. We found no substantial differences in adherence to the Mediterranean diet according to the main type of alcoholic beverage consumed, and we found no evidence that Mediterranean wine drinkers at high cardiovascular risk have a healthier diet than other drinkers. However, a better dietary pattern was found among nondrinkers than among drinkers. Conclusion. This large, Mediterranean study does not support an association between wine consumption and healthier dietary habits.

To describe the association between alcohol beverage preference and dietary habits comparing wine drinkers with other alcoholic beverage drinkers and with nondrinkers in Spanish university graduates.A total of 10 526 men and women, who were recruited using mailed questionnaires, participated in this study.A semiquantitative food frequency questionnaire previously validated in Spain was used together with other questionnaires designed to collect lifestyle characteristics.Wine drinkers reported higher intake of fibre and olive oil, and lower consumption of fat (only men), dairy products, sugared soda drinks and fast food as compared with other alcoholic beverage groups and nondrinkers. Men nondrinkers were more likely to be physically active during their leisure time than wine drinkers. No relevant differences were found in adherence to the Mediterranean food pattern according to alcoholic beverage preference.This similarity in dietary patterns between wine drinkers and other groups suggests that the positive cardiovascular effects reported for wine should not be attributed to an overall healthier dietary pattern of wine drinkers. .