Transition times across the HIV care continuum in Spain from 2005 to 2022: a longitudinal cohort study.

BACKGROUND: Ending AIDS by 2030 requires improvements across all stages of the HIV care continuum. We used a longitudinal approach to assess changes in the HIV care continuum in Spain and transition probabilities across different stages. METHODS: We used data from the prospective Cohort of the Spanish HIV/AIDS Research Network to analyse the time from diagnosis to linkage to care, linkage to care to antiretroviral therapy (ART), and ART to viral suppression in five calendar periods defined by milestones in ART, from 2005 to 2022. We used the Kaplan-Meier method and Cox proportional hazard models to estimate cumulative probabilities of stage transition within 1, 3, 6, and 12 months of stage eligibility, by period. FINDINGS: We included 18 529 participants. Comparing the initial (2005-09) and final (2020-22) periods, time to linkage to care decreased from a median of 6·0 weeks to 1·3 weeks, time to ART initiation from 15·9 weeks to 0·4 weeks, and time to viral suppression from 13·3 weeks to 7·1 weeks. Adjusted hazard ratios for the comparison between the last period and the initial period were 3·1 (95% CI 2·8-3·4) for linkage to care within 1 month, 11·4 (10·1-12·3) for ART initiation within 1 month, and 2·2 (1·2-2·4) for viral suppression within 3 months. The aggregate proportion of late diagnoses was 38·6%, increasing after 2012 to 46·4% in the 2020-22 period. Same-day ART initiation increased from 18% to 39% from 2005 to 2022. The overall incidence rate of virological failure was 1·05 failures per 1000 person-years and showed a non-significant decline throughout the study. INTERPRETATION: The great improvement in transition times through the HIV care cascade might put Spain on the verge of achieving the UNAIDS targets for HIV elimination. However, late diagnosis remains a challenge that should be addressed. FUNDING: Instituto de Salud Carlos III and Spanish AIDS Research Network.

Association between COVID-19 and outstanding academic performance at a Spanish university.

BACKGROUND: SARS-CoV-2 is the causative agent of COVID-19 identified in December 2019, an acute infectious respiratory disease that can cause persistent neurological and musculoskeletal symptoms such as headache, fatigue, myalgias difficulty concentrating, among others including acute cerebrovascular disease with a prevalence of 1-35%. The aim of this study is to evaluate the impact of COVID-19 in undergraduate students on their academic performance as an indicator of their intellectual ability and performance in a university that maintained 100% face-to-face teaching during the 2020-2021 academic year. METHODS: A total of 7,039 undergraduate students were analyzed in a prospective cohort study at the University of Navarra. A questionnaire including sociodemographic and behavioral questions was sent. PCRs were performed throughout the academic year for the diagnosis of SARS-CoV-2 infection and students' academic results were provided by the academic center, adjusted descriptive and multivariate models were performed to assess the association. RESULTS: A total of 658 (9.3%) participants were diagnosed with COVID-19, almost 4.0% of them achieved outstanding academic results, while uninfected students did so in 7.3%. SARS-CoV-2 infection was associated with a significant decrease in having outstanding academic results (OR = 0.57; 95% CI: 0.38-0.86). CONCLUSION: Having COVID-19 disease, decreased academic performance in undergraduate students. Therefore, it is necessary to prevent infection even in the youngest sections of the population.

Performance evaluation of human cough annotators: optimal metrics and sex differences.

INTRODUCTION: Despite its high prevalence and significance, there is still no widely available method to quantify cough. In order to demonstrate agreement with the current gold standard of human annotation, emerging automated techniques require a robust, reproducible approach to annotation. We describe the extent to which a human annotator of cough sounds (a) agrees with herself (intralabeller or intrarater agreement) and (b) agrees with other independent labellers (interlabeller or inter-rater agreement); we go on to describe significant sex differences in cough sound length and epochs size. MATERIALS AND METHODS: 24 participants wore an audiorecording smartwatch to capture 6-24 hours of continuous audio. A randomly selected sample of the whole audio was labelled twice by an expert annotator and a third time by six trained annotators. We collected 400 hours of audio and analysed 40 hours. The cough counts as well as cough seconds (any 1 s of time containing at least one cough) from different annotators were compared and summary statistics from linear and Bland-Altman analyses were used to quantify intraobserver and interobserver agreement. RESULTS: There was excellent intralabeller (less than two disagreements per hour monitored, Pearson's correlation 0.98) and interlabeller agreement (Pearson's correlation 0.96), using cough seconds as the unit of analysis decreased annotator discrepancies by 50% in comparison to coughs. Within this data set, it was observed that the length of cough sounds and epoch size (number of coughs per bout or attach) differed between women and men. CONCLUSION: Given the decreased interobserver variability in annotation when using cough seconds (vs just coughs) we propose their use for manually annotating cough when assessing of the performance of automatic cough monitoring systems. The differences in cough sound length and epochs size may have important implications for equality in the development of cough monitoring tools. TRIAL REGISTRATION NUMBER: NCT05042063.

Behavioral and Personal Characteristics Associated With Risk of SARS-CoV-2 Infection in a Spanish University Cohort.

The aim of this study was to analyze the life habits and personal factors associated with increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) risk in a university environment with in-person lectures during the coronavirus disease 2019 (COVID-19) pandemic. To our knowledge, there are no previous longitudinal studies that have analyzed associations of behavioral and personal factors with the risk of SARS-CoV-2 infection on an entire university population. A cohort study was conducted in the 3 campuses of the University of Navarra between August 24, 2020, and May 30, 2021, including 14,496 students and employees; the final sample included 10,959. Descriptive and multivariate-adjusted models were fitted using Cox regression. A total of 1,032 (9.4%) participants were diagnosed with COVID-19 (879 students and 153 employees), almost 50% living with their families. COVID-19 was associated with living in college or residence (hazard ratio (HR) = 1.96, 95% CI: 1.45, 2.64), motor transportation (HR = 1.35, 95% CI: 1.14, 1.61), South American origin (HR = 1.43, 95% CI: 1.20, 1.72), and belonging to Madrid's campus (HR = 3.11, 95% CI: 2.47, 3.92). 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.

Breast Implant Capsule: A Murine Model Comparing Capsular Contracture Susceptibility Among Six Breast Implants Available in the Market.

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 .

Infection-specific PET imaging with 18F-fluorodeoxysorbitol and 2-[18F]F-ρ-aminobenzoic acid: An extended diagnostic tool for bacterial and fungal diseases.

Introduction: Suspected infectious diseases located in difficult-to-access sites can be challenging due to the need for invasive procedures to isolate the etiological agent. Positron emission tomography (PET) is a non-invasive imaging technology that can help locate the infection site. The most widely used radiotracer for PET imaging (2-deoxy-2[18F] fluoro-D-glucose: [18F]FDG) shows uptake in both infected and sterile inflammation. Therefore, there is a need to develop new radiotracers able to specifically detect microorganisms. Methods: We tested two specific radiotracers: 2-deoxy-2-[18F]-fluoro-D-sorbitol ([18F]FDS) and 2-[18F]F-ρ-aminobenzoic acid ([18F]FPABA), and also developed a simplified alternative of the latter for automated synthesis. Clinical and reference isolates of bacterial and yeast species (19 different strains in all) were tested in vitro and in an experimental mouse model of myositis infection. Results and discussion: Non-lactose fermenters (Pseudomonas aeruginosa and Stenotrophomonas maltophilia) were unable to take up [18F]FDG in vitro. [18F]FDS PET was able to visualize Enterobacterales myositis infection (i.e., Escherichia coli) and to differentiate between yeasts with differential assimilation of sorbitol (i.e., Candida albicans vs. Candida glabrata). All bacteria and yeasts tested were detected in vitro by [18F]FPABA. Furthermore, [18F]FPABA was able to distinguish between inflammation and infection in the myositis mouse model (E. coli and Staphylococcus aureus) and could be used as a probe for a wide variety of bacterial and fungal species.

Photodynamic nasal SARS-CoV-2 decolonization shortens infectivity and influences specific T-Cell responses.

Background: The main objective was to evaluate the efficacy of intranasal photodynamic therapy (PDT) in SARS-CoV-2 mildly symptomatic carriers on decreasing the infectivity period. SARS-CoV-2-specific immune-stimulating effects and safety were also analysed. Methods: We performed a randomized, placebo-controlled, clinical trial in a tertiary hospital (NCT05184205). Patients with a positive SARS-CoV-2 PCR in the last 48 hours were recruited and aleatorily assigned to PDT or placebo. Patients with pneumonia were excluded. Participants and investigators were masked to group assignment. The primary outcome was the reduction in in vitro infectivity of nasopharyngeal samples at days 3 and 7. Additional outcomes included safety assessment and quantification of humoral and T-cell immune-responses. Findings: Patients were recruited between December 2021 and February 2022. Most were previously healthy adults vaccinated against COVID-19 and most carried Omicron variant. 38 patients were assigned to placebo and 37 to PDT. Intranasal PDT reduced infectivity at day 3 post-treatment when compared to placebo with a ß-coefficient of -812.2 (CI95%= -478660 - -1.3, p<0.05) infectivity arbitrary units. The probability of becoming PCR negative (ct>34) at day 7 was higher on the PDT-group, with an OR of 0.15 (CI95%=0.04-0.58). There was a decay in anti-Spike titre and specific SARS-CoV-2 T cell immunity in the placebo group 10 and 20 weeks after infection, but not in the PDT-group. No serious adverse events were reported. Interpretation: Intranasal-PDT is safe in pauci-symptomatic COVID-19 patients, it reduces SARS-CoV-2 infectivity and decelerates the decline SARS-CoV-2 specific immune-responses.

In Vivo Effectiveness of Several Antimicrobial Locks To Eradicate Intravascular Catheter Coagulase-Negative Staphylococci Biofilms.

Tunneled central venous catheter (TCVC) related infection remains a challenge in the care of hemodialysis patients. We aimed to determine the best antimicrobial lock therapy (ALT) to eradicate coagulase-negative staphylococci (CoNS) biofilms. We studied the colonization status of the catheter every 30 days by quantitative blood cultures (QBC) drawn through all catheter lumens. Those patients with a significant culture (i.e.,100 to 1,000 CFU/mL) of a CoNS were classified as patients with a high risk of developing catheter-related bloodstream infections (CRBSI). They were assigned to receive daptomycin, vancomycin, teicoplanin lock solution, or the standard of care (SoC) (i.e., heparin lock). The primary endpoint was to compare eradication ability (i.e., negative QBC for 30 days after ending ALT) rates between different locks and the SoC. A second objective was to analyze the correlation between ALT exposure and isolation of CoNS with antimicrobial resistance. Daptomycin lock was associated with a significant higher eradication success than with the SoC: 85% versus 30% (relative risk [RR] = 14, 95% confidence interval [CI] = 2.4 - 82.7); followed by teicoplanin locks with a 83.3% success (RR = 11.7; 95% CI = 2 - 70.2). We observed CoNs isolates with a higher teicoplanin MIC in patients with repeated teicoplanin locks exposure (coefficient = 0.3; 95% CI = 0.11 - 0.47). However, teicoplanin MICs decreased in patients treated with vancomycin locks (coefficient = -0.56; 95% CI = -0.85 - -0.02). Methicillin-resistance decreased with accumulative ALT (RR = 0.82; 95% CI = 0.69 - 0.98). In this study, daptomycin locks achieve the highest eradication rate of CoNS from hemodialysis catheters in vivo.

Pre-Emptive Antimicrobial Locks Decrease Long-Term Catheter-Related Bloodstream Infections in Hemodialysis Patients.

This study aimed to prove that pre-emptive antimicrobial locks in patients at risk of bacteremia decrease infection. We performed a non-randomized prospective pilot study of hemodialysis patients with tunneled central venous catheters. We drew quantitative blood cultures monthly to detect colonization. Patients with a critical catheter colonization by coagulase-negative staphylococci (defined as counts of 100−999 CFU/mL) were at high risk of developing a catheter-related bloodstream infection. We recommended antimicrobial lock for this set of patients. The nephrologist in charge of the patient decided whether to follow the recommendation or not (i.e., standard of care). We compared bloodstream infection rates between patients treated with antimicrobial lock therapy versus patients treated with the standard of care (i.e., heparin). We enrolled 149 patients and diagnosed 86 episodes of critical catheter colonization by coagulase-negative staphylococci. Patients treated with antimicrobial lock had a relative risk of bloodstream infection of 0.19 when compared with heparin lock (CI 95%, 0.11−0.33, p < 0.001) within three months of treatment. We avoided one catheter-related bloodstream infection for every ten catheter-critical colonizations treated with antimicrobial lock [number needed to treat 10, 95% CI, 5.26−100, p = 0.046]. In conclusion, pre-emptive antimicrobial locks decrease bloodstream infection rates in hemodialysis patients with critical catheter colonization.

Humoral and cellular immune response over 9 months of mRNA-1273, BNT162b2 and ChAdOx1 vaccination in a University Hospital in Spain.

Scarce data have been reported about cellular immunity and longevity for different COVID-19 vaccination schedules. We carried out a prospective study enrolling 709 healthcare workers receiving two doses of mRNA-1273, BNT162b2, ChAdOx1, ChAdOx1/BNT162b2 or ChAdOx1 single dose to compare humoral and cellular immunogenicity across 9 months. Higher SARS-CoV-2 spike antibody levels were observed among individuals with hybrid immunity with one dose of any vaccine in comparison to uninfected individuals receiving two doses (mRNA-1273: 20,145 vs 4295 U/mL; BNT162b2: 15,659 vs 1959 U/mL; ChAdOx1: 5344 vs 2230 U/mL), except for ChAdOx1/BNT162b2 heterologous schedule (12,380 U/mL). Naturally infected individuals did not increase substantially the titers after the second dose and showed higher levels throughout the 9 months follow-up. The mean elimination half-life of antibodies among COVID-19 naïve participants was 98, 111, 60 and 36 days, for mRNA-1273, BNT162b2, ChAdOx1/ChAdOx1 and ChAdOx1/BNT162b2, respectively. Cellular immunity was preserved in 96%, 98%, 88% and 92% of uninfected individuals who received mRNA-1273, BNT162b2, ChAdOx1/ChAdOx1 and ChAdOx1/BNT162b2 after 6/9 months. Individuals with specific T cells showed robust long lasting protection, especially when m-RNA based vaccines are inoculated. These data may influence the validity of the vaccination passport and the need for booster vaccinations.

An Experimental Murine Model to Assess Biofilm Persistence on Commercial Breast Implant Surfaces.

Capsular contracture is the most frequently associated complication following breast implant placement. Biofilm formation on the surface of such implants could significantly influence the pathogenesis of this complication. The objective of this study was to design an experimental model of breast implant infection that allowed us to compare the in vivo S. epidermidis ability to form and perpetuate biofilms on commonly used types of breast implants (i.e., macrotexturized, microtexturized, and smooth). A biofilm forming S. epidermidis strain (ATCC 35984) was used for all experiments. Three different implant surface types were tested: McGhan BIOCELL® (i.e., macrotexturized); Mentor Siltex® (i.e., microtexturized); and Allergan Natrelle Smooth® (i.e., smooth). Two different infection scenarios were simulated. The ability to form biofilm on capsules and implants over time was evaluated by quantitative post-sonication culture of implants and capsules biopsies. This experimental model allows the generation of a subclinical staphylococcal infection associated with a breast implant placed in the subcutaneous tissue of Wistar rats. The probability of generating an infection was different according to the type of implant studied and to the time from implantation to implant removal. Infection was achieved in 88.9% of macrotextured implants (i.e., McGhan), 37.0% of microtexturized implants (i.e., Mentor), and 18.5% of smooth implants (i.e., Allergan Smooth) in the short-term (p < 0.001). Infection was achieved in 47.2% of macrotextured implants, 2.8% of microtexturized implants, and 2.8% of smooth implants (i.e., Allergan Smooth) in the long-term (p < 0.001). There was a clear positive correlation between biofilm formation on any type of implant and capsule colonization/infection. Uniformly, the capsules formed around the macro- or microtexturized implants were consistently macroscopically thicker than those formed around the smooth implants regardless of the time at which they were removed (i.e., 1−2 weeks or 3−5 weeks). We have shown that there is a difference in the ability of S epidermidis to develop in vivo biofilms on macrotextured, microtextured, and smooth implants. Smooth implants clearly thwart bacterial adherence and, consequently, biofilm formation and persistence are hindered.

Neutrophil Extracellular Traps, Local IL-8 Expression, and Cytotoxic T-Lymphocyte Response in the Lungs of Patients With Fatal COVID-19.

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.

Dysautonomia in COVID-19 Patients: A Narrative Review on Clinical Course, Diagnostic and Therapeutic Strategies.

Introduction: On March 11, 2020, the World Health Organization sounded the COVID-19 pandemic alarm. While efforts in the first few months focused on reducing the mortality of infected patients, there is increasing data on the effects of long-term infection (Post-COVID-19 condition). Among the different symptoms described after acute infection, those derived from autonomic dysfunction are especially frequent and limiting. Objective: To conduct a narrative review synthesizing current evidence of the signs and symptoms of dysautonomia in patients diagnosed with COVID-19, together with a compilation of available treatment guidelines. Results: Autonomic dysfunction associated with SARS-CoV-2 infection occurs at different temporal stages. Some of the proposed pathophysiological mechanisms include direct tissue damage, immune dysregulation, hormonal disturbances, elevated cytokine levels, and persistent low-grade infection. Acute autonomic dysfunction has a direct impact on the mortality risk, given its repercussions on the respiratory, cardiovascular, and neurological systems. Iatrogenic autonomic dysfunction is a side effect caused by the drugs used and/or admission to the intensive care unit. Finally, late dysautonomia occurs in 2.5% of patients with Post-COVID-19 condition. While orthostatic hypotension and neurally-mediated syncope should be considered, postural orthostatic tachycardia syndrome (POTS) appears to be the most common autonomic phenotype among these patients. A review of diagnostic and treatment guidelines focused on each type of dysautonomic condition was done. Conclusion: Symptoms deriving from autonomic dysfunction involvement are common in those affected by COVID-19. These symptoms have a great impact on the quality of life both in the short and medium to long term. A better understanding of the pathophysiological mechanisms of Post-COVID manifestations that affect the autonomic nervous system, and targeted therapeutic management could help reduce the sequelae of COVID-19, especially if we act in the earliest phases of the disease.

Real-Life Use of Ceftolozane/Tazobactam for the Treatment of Bloodstream Infection Due to Pseudomonas aeruginosa in Neutropenic Hematologic Patients: a Matched Control Study (ZENITH Study).

We sought to assess the characteristics and outcomes of neutropenic hematologic patients with Pseudomonas aeruginosa (PA) bloodstream infection (BSI) treated with ceftolozane-tazobactam (C/T). We conducted a multicenter, international, matched-cohort study of PA BSI episodes in neutropenic hematologic patients who received C/T. Controls were patients with PA BSI treated with other antibiotics. Risk factors for overall 7-day and 30-day case fatality rates were analyzed. We compared 44 cases with 88 controls. Overall, 91% of episodes were caused by multidrug-resistant (MDR) strains. An endogenous source was the most frequent BSI origin (35.6%), followed by pneumonia (25.8%). There were no significant differences in patient characteristics between groups. C/T was given empirically in 11 patients and as definitive therapy in 41 patients. Treatment with C/T was associated with less need for mechanical ventilation (13.6% versus 33.3%; P = 0.021) and reduced 7-day (6.8% versus 34.1%; P = 0.001) and 30-day (22.7% versus 48.9%; P = 0.005) mortality. In the multivariate analysis, pneumonia, profound neutropenia, and persistent BSI were independent risk factors for 30-day mortality, whereas lower mortality was found among patients treated with C/T (adjusted OR [aOR] of 0.19; confidence interval [CI] 95% of 0.07 to 0.55; P = 0.002). Therapy with C/T was associated with less need for mechanical ventilation and reduced 7-day and 30-day case fatality rates compared to alternative agents in neutropenic hematologic patients with PA BSI. IMPORTANCE Ceftolozane-tazobactam (C/T) has been shown to be a safe and effective alternative for the treatment of difficult to treat infections due to Pseudomonas aeruginosa (PA) in the general nonimmunocompromised population. However, the experience of this agent in immunosuppressed neutropenic patients is very limited. Our study is unique because it is focused on extremely immunosuppressed hematological patients with neutropenia and bloodstream infection (BSI) due to PA (mainly multidrug resistant [MDR]), a scenario which is often associated with very high mortality rates. In our study, we found that the use of C/T for the treatment of MDR PA BSI in hematological neutropenic patients was significantly associated with improved outcomes, and, in addition, it was found to be an independent risk factor associated with increased survival. To date, this is the largest series involving neutropenic hematologic patients with PA BSI treated with C/T.

Risk Factors of DAIR Failure and Validation of the KLIC Score: A Multicenter Study of Four Hundred Fifty-Five Patients.

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.

Therapeutic versus Prophylactic Bemiparin in Hospitalized Patients with Nonsevere COVID-19 Pneumonia (BEMICOP Study): An Open-Label, Multicenter, Randomized, Controlled Trial.

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.

Persistence of High Levels of Serum Complement C5a in Severe COVID-19 Cases After Hospital Discharge.

Evidence supports a role of complement anaphylatoxin C5a in the pathophysiology of COVID-19. However, information about the evolution and impact of C5a levels after hospital discharge is lacking. We analyzed the association between circulating C5a levels and the clinical evolution of hospitalized patients infected with SARS-CoV-2. Serum C5a levels were determined in 32 hospitalized and 17 non-hospitalized patients from Clinica Universidad de Navarra. One hundred and eighty eight serial samples were collected during the hospitalization stay and up to three months during the follow-up. Median C5a levels were 27.71 ng/ml (25th to 75th percentile: 19.35-34.96) for samples collected during hospitalization, versus 16.76 ng/ml (12.90-25.08) for samples collected during the follow-up (p<0.001). There was a negative correlation between serum C5a levels and the number of days from symptom onset (p<0.001). C5a levels also correlated with a previously validated clinical risk score (p<0.001), and was associated with the severity of the disease (p<0.001). An overall reduction of C5a levels was observed after hospital discharge. However, elevated C5a levels persisted in those patients with high COVID-19 severity (i.e. those with a longest stay in the hospital), even after months from hospital discharge (p=0.020). Moreover, high C5a levels appeared to be associated with the presence of long-term respiratory symptoms (p=0.004). In conclusion, serum C5a levels remain high in severe cases of COVID-19, and are associated with the presence of respiratory symptoms after hospital discharge. These results may suggest a role for C5a in the long-term effects of COVID-19 infection.

Preclinical evaluation of a synthetic peptide vaccine against SARS-CoV-2 inducing multiepitopic and cross-reactive humoral neutralizing and cellular CD4 and CD8 responses.

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.

Immunological Biomarkers of Fatal COVID-19: A Study of 868 Patients.

Information on the immunopathobiology of coronavirus disease 2019 (COVID-19) is rapidly increasing; however, there remains a need to identify immune features predictive of fatal outcome. This large-scale study characterized immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection using multidimensional flow cytometry, with the aim of identifying high-risk immune biomarkers. Holistic and unbiased analyses of 17 immune cell-types were conducted on 1,075 peripheral blood samples obtained from 868 COVID-19 patients and on samples from 24 patients presenting with non-SARS-CoV-2 infections and 36 healthy donors. Immune profiles of COVID-19 patients were significantly different from those of age-matched healthy donors but generally similar to those of patients with non-SARS-CoV-2 infections. Unsupervised clustering analysis revealed three immunotypes during SARS-CoV-2 infection; immunotype 1 (14% of patients) was characterized by significantly lower percentages of all immune cell-types except neutrophils and circulating plasma cells, and was significantly associated with severe disease. Reduced B-cell percentage was most strongly associated with risk of death. On multivariate analysis incorporating age and comorbidities, B-cell and non-classical monocyte percentages were independent prognostic factors for survival in training (n=513) and validation (n=355) cohorts. Therefore, reduced percentages of B-cells and non-classical monocytes are high-risk immune biomarkers for risk-stratification of COVID-19 patients.

Immunogenicity and crossreactivity of antibodies to the nucleocapsid protein of SARS-CoV-2: utility and limitations in seroprevalence and immunity studies.

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.