Impact of influenza related hospitalization in Spain: characteristics and risk factor of mortality during five influenza seasons (2016 to 2021).

Background: Estimating the global influenza burden in terms of hospitalization and death is important for optimizing prevention policies. Identifying risk factors for mortality allows for the design of strategies tailored to groups at the highest risk. This study aims to (a) describe the clinical characteristics of hospitalizations with a diagnosis of influenza over five flu seasons (2016-2017 to 2020-2021), (b) assess the associated morbidity (hospitalization rates and ICU admissions rate), mortality and cost of influenza hospitalizations in different age groups and (c) analyze the risk factors for mortality. Methods: This retrospective study included all hospital admissions with a diagnosis of influenza in Spain for five influenza seasons. Data were extracted from the Spanish National Surveillance System for Hospital Data from 1 July 2016 to 30 June 2021. We identified cases coded as having influenza as a primary or secondary diagnosis (International Classification of Diseases, 10th revision, J09-J11). The hospitalization rate was calculated relative to the general population. Independent predictors of mortality were identified using multivariable logistic regression. Results: Over the five seasons, there were 127,160 hospitalizations with a diagnosis of influenza. The mean influenza hospitalization rate varied from 5/100,000 in 2020-2021 (COVID-19 pandemic) to 92.9/100,000 in 2017-2018. The proportion of influenza hospitalizations with ICU admission was 7.4% and was highest in people aged 40-59 years (13.9%). The case fatality rate was 5.8% overall and 9.4% in those aged 80 years or older. Median length of stay was 5 days (and 6 days in the oldest age group). In the multivariable analysis, independent risk factors for mortality were male sex (odds ratio [OR] 1.14, 95% confidence interval [95% CI] 1.08-1.20), age (<5 years: OR 1; 5-19 years: OR 2.02, 95%CI 1.17-3.49; 20-39 years: OR 4.11, 95% CI 2.67-6.32; 40-59 years: OR 8.15, 95% CI 5.60-11.87; 60-79 years: OR 15.10, 95% CI 10.44-21.84; ≥80 years: OR 33.41, 95% CI 23.10-48.34), neurological disorder (OR 1.97, 95% CI 1.83-2.11), heart failure (OR 1.85, 95% CI 1.74-1.96), chronic kidney disease (OR 1.33, 95% CI 1.25-1.41), chronic liver disease (OR 2.95, 95% CI 2.68-3.27), cancer (OR 1.85, 95% CI 1.48-2.24), coinfection with SARS-CoV2 (OR 3.17, 95% CI 2.34-4.28), influenza pneumonia (OR 1.76, 95% CI 1.66-1.86) and admission to intensive care (OR 7.81, 95% CI 7.31-8.36). Conclusion: Influenza entails a major public health burden. People aged over 60-and especially those over 80-show the longest hospital stays. Age is also the most significant risk factor for mortality, along with certain associated comorbidities.

Efficacy and safety of a structured de-escalation from antipseudomonal ß-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial.

BACKGROUND: De-escalation from broad-spectrum to narrow-spectrum antibiotics is considered an important measure to reduce the selective pressure of antibiotics, but a scarcity of adequate evidence is a barrier to its implementation. We aimed to determine whether de-escalation from an antipseudomonal ß-lactam to a narrower-spectrum drug was non-inferior to continuing the antipseudomonal drug in patients with Enterobacterales bacteraemia. METHODS: An open-label, pragmatic, randomised trial was performed in 21 Spanish hospitals. Patients with bacteraemia caused by Enterobacterales susceptible to one of the de-escalation options and treated empirically with an antipseudomonal ß-lactam were eligible. Patients were randomly assigned (1:1; stratified by urinary source) to de-escalate to ampicillin, trimethoprim-sulfamethoxazole (urinary tract infections only), cefuroxime, cefotaxime or ceftriaxone, amoxicillin-clavulanic acid, ciprofloxacin, or ertapenem in that order according to susceptibility (de-escalation group), or to continue with the empiric antipseudomonal ß-lactam (control group). Oral switching was allowed in both groups. The primary outcome was clinical cure 3-5 days after end of treatment in the modified intention-to-treat (mITT) population, formed of patients who received at least one dose of study drug. Safety was assessed in all participants. Non-inferiority was declared when the lower bound of the 95% CI of the absolute difference in cure rate was above the -10% non-inferiority margin. This trial is registered with EudraCT (2015-004219-19) and ClinicalTrials.gov (NCT02795949) and is complete. FINDINGS: 2030 patients were screened between Oct 5, 2016, and Jan 23, 2020, of whom 171 were randomly assigned to the de-escalation group and 173 to the control group. 164 (50%) patients in the de-escalation group and 167 (50%) in the control group were included in the mITT population. 148 (90%) patients in the de-escalation group and 148 (89%) in the control group had clinical cure (risk difference 1·6 percentage points, 95% CI -5·0 to 8·2). The number of adverse events reported was 219 in the de-escalation group and 175 in the control group, of these, 53 (24%) in the de-escalation group and 56 (32%) in the control group were considered severe. Seven (5%) of 164 patients in the de-escalation group and nine (6%) of 167 patients in the control group died during the 60-day follow-up. There were no treatment-related deaths. INTERPRETATION: De-escalation from an antipseudomonal ß-lactam in Enterobacterales bacteraemia following a predefined rule was non-inferior to continuing the empiric antipseudomonal drug. These results support de-escalation in this setting. FUNDING: Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases; Spanish Clinical Research and Clinical Trials Platform, co-financed by the EU; European Development Regional Fund "A way to achieve Europe", Operative Program Intelligence Growth 2014-2020.

Role of Relebactam in the Antibiotic Resistance Acquisition in Pseudomonas aeruginosa: In Vitro Study.

BACKGROUND: Pseudomonas aeruginosa shows resistance to several antibiotics and often develops such resistance during patient treatment. OBJECTIVE: Develop an in vitro model, using clinical isolates of P. aeruginosa, to compare the ability of the imipenem and imipenem/relebactam to generate resistant mutants to imipenem and to other antibiotics. Perform a genotypic analysis to detect how the selective pressure changes their genomes. METHODS: The antibiotics resistance was studied by microdilution assays and e-test, and the genotypic study was performed by NGS. RESULTS: The isolates acquired resistance to imipenem in an average of 6 days, and to imipenem/relebactam in 12 days (p value = 0.004). After 30 days of exposure, 75% of the isolates reached a MIC > 64 mg/L for imipenem and 37.5% for imipenem/relebactam (p value = 0.077). The 37.5% and the 12.5% imipenem/relebactam mutants developed resistance to piperacillin/tazobactam and ceftazidime, respectively, while the 87.5% and 37.5% of the imipenem mutants showed resistance to these drugs (p value = 0.003, p value = 0.015). The main biological processes altered by the SNPs were the glycosylation pathway, transcriptional regulation, histidine kinase response, porins, and efflux pumps. DISCUSSION: The addition of relebactam delays the generation of resistance to imipenem and limits the cross-resistance to other beta-lactams. The clinical relevance of this phenomenon, which has the limitation that it has been performed in vitro, should be evaluated by stewardship programs in clinical practice, as it could be useful in controlling multi-drug resistance in P. aeruginosa.

A retrospective real-world study of early short-course remdesivir in non-hospitalized COVID-19 patients at high risk for progression: low rate of hospitalization or death, regardless of immunocompetence status.

Introduction: The evidence for remdesivir therapy in immunocompromised patients is scarce. To evaluate remdesivir (RDV) effectiveness and safety in COVID-19 outpatients at high risk for progression in a real-world setting, we compare the outcome in immunocompromised (IC) patients with that in non-immunocompromised patients. Methods: Two hospitals conducted a retrospective study of all adult patients with mild-to-moderate SARS-CoV-2 infection at high risk for disease progression who were treated as outpatients with a 3-day course of RDV (1st January-30th September 2022). The primary effectiveness endpoint was a composite of any cause of hospitalization or death by day 30. A multiple logistic regression model was built to explore the association between immune status and clinical outcome, estimating adjusted odds ratios [aORs (95% CI)]. Results: We have included 211 patients, of which 57% were males, with a median age of 65 years (IQR 53-77), 70.1% were vaccinated (three or four doses), and 61.1% were IC. The median duration of symptoms before RDV treatment was 3 days (IQR 2-5). During follow-up, 14 (6.6%) patients were hospitalized, of which 6 (2.8%) were hospitalized for COVID-19 progression. No patient required mechanical ventilation, and two patients died (non-COVID-19-related). After accounting for potential confounders, only anti-CD20 treatment was associated with the composed outcome [aOR 5.35 (1.02-27.5, 95% CI)], whereas the immunocompetence status was not [aOR 1.94 (0.49-7.81, 95% CI)]. Conclusion: Early COVID-19 outpatient treatment with a 3-day course of remdesivir in vaccinated patients at high risk for disease progression during the Omicron surge had a good safety profile. It was associated with a low rate of all-cause hospitalization or death, regardless of immunocompetence status.

Cyclin D1-Cdk4 regulates neuronal activity through phosphorylation of GABAA receptors.

Nuclear Cyclin D1 (Ccnd1) is a main regulator of cell cycle progression and cell proliferation. Interestingly, Ccnd1 moves to the cytoplasm at the onset of differentiation in neuronal precursors. However, cytoplasmic functions and targets of Ccnd1 in post-mitotic neurons are unknown. Here we identify the α4 subunit of gamma-aminobutyric acid (GABA) type A receptors (GABAARs) as an interactor and target of Ccnd1-Cdk4. Ccnd1 binds to an intracellular loop in α4 and, together with Cdk4, phosphorylates the α4 subunit at threonine 423 and serine 431. These modifications upregulate α4 surface levels, increasing the response of α4-containing GABAARs, measured in whole-cell patch-clamp recordings. In agreement with this role of Ccnd1-Cdk4 in neuronal signalling, inhibition of Cdk4 or expression of the non-phosphorylatable α4 decreases synaptic and extra-synaptic currents in the hippocampus of newborn rats. Moreover, according to α4 functions in synaptic pruning, CCND1 knockout mice display an altered pattern of dendritic spines that is rescued by the phosphomimetic α4. Overall, our findings molecularly link Ccnd1-Cdk4 to GABAARs activity in the central nervous system and highlight a novel role for this G1 cyclin in neuronal signalling.

Rationale for combined therapies in severe-to-critical COVID-19 patients.

An unprecedented global social and economic impact as well as a significant number of fatalities have been brought on by the coronavirus disease 2019 (COVID-19), produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute SARS-CoV-2 infection can, in certain situations, cause immunological abnormalities, leading to an anomalous innate and adaptive immune response. While most patients only experience mild symptoms and recover without the need for mechanical ventilation, a substantial percentage of those who are affected develop severe respiratory illness, which can be fatal. The absence of effective therapies when disease progresses to a very severe condition coupled with the incomplete understanding of COVID-19's pathogenesis triggers the need to develop innovative therapeutic approaches for patients at high risk of mortality. As a result, we investigate the potential contribution of promising combinatorial cell therapy to prevent death in critical patients.

Severe Spontaneous Hematomas in Patients Hospitalized with COVID-19.

Objective: To describe the epidemiological, clinical, laboratory, and radiological characteristics, medical treatment, and outcomes of a case series of severe spontaneous hematoma in COVID-19. Material and Methods. This retrospective study included patients hospitalized for COVID-19 who were diagnosed with severe spontaneous bleeding complications by following a standardized treatment protocol that included computed tomography angiography (CTA) from 1 March 2020 to 28 February 2022. The main outcomes were embolization and all-cause mortality. Baseline variables were analyzed for their association with mortality using bivariable logistic regression, and results were expressed as odds ratios (OR) and 95% confidence intervals (CI). Results: In total, 2450 adults were hospitalized for COVID-19 in our center during the study period. 20 patients presented severe and spontaneous intramuscular bleeding (8.1 per 1000 COVID-19 admission vs. 0.47 per 1000 non-COVID-19 admissions, p < 0.001); their median age was 68.5 years (interquartile range (IQR) 63, 80), they had high comorbidity (median Charlson comorbidity index 4.5), and 95% were receiving high doses of heparin. The median interval from COVID-19 symptoms to bleeding was 17 days (IQR 13, 24), and 70% reported cough as a previous symptom. Hypovolemic shock, hypotension, and abdominal pain were the most frequent symptoms of the hematoma. All presented decreased hemoglobin, and 95% required transfusion. Intramuscular hematoma occurred most frequently in the rectus sheath, iliopsoas compartment, and femoral-iliac compartment. All patients underwent embolization; mortality was 45%. We did not identify risk factors associated with an increased risk of death. Conclusion: Although severe bleeding is an uncommon complication of COVID-19, its prevalence is higher than in inpatients without COVID-19, it usually needs embolization, and it is associated with high mortality.

Mild SARS-CoV-2 infection in vulnerable patients: implementation of a clinical pathway for early treatment.

INTRODUCTION: The objective of this report is to describe the clinical pathway for early treatment of patients with acute SARS-CoV-2 infection and to evaluate the first results of its implementation. METHODS: This is a descriptive and retrospective study of the implementation of a clinical pathway of treatment in outpatients (January 1 to June 30 2022). Clinical pathway: detection and referral systems from Primary Care, Emergency services, hospital specialities and an automated detection system; clinical evaluation and treatment administration in the COVID-19 day-hospital and subsequent clinical follow-up. Explanatory variables: demographics, comorbidity, vaccination status, referral pathways and treatment administration. OUTCOME VARIABLES: hospitalization and death with 30 days, grade 2-3 toxicity related to treatment. RESULTS: Treatment was administered to 262 patients (53,4% women, median age 60 years). The treatment indication criteria were immunosupression (68,3%), and the combination of age, vaccination status and comorbidity in the rest 47,3% of the patients s received remdesivir, 35,9% nirmatrelvir/ritonavir, 13,4% sotrovimab and 2,4% combined treatment with a median of 4 days after symptom onset. Hospital admission was required for 6,1% of the patients, 3,8% related to progression COVID-19. No patient died. Toxicity grade 2-3 toxicity was reported in 18,7%, 89,8% dysgeusia and metallic tasted related nirmatrelvir/ritonavir. Seven patients discontinued treatment due to toxicity. CONCLUSION: The creation and implementation of a clinical pathway for non-hospitalized patients with SARS-CoV-2 infection is effective and it allows early accessibility and equity of currently available treatments.

Role of previous systemic antibiotic therapy on the probability of recurrence after an initial episode of Clostridioides difficile infection treated with vancomycin.

Objectives: To investigate the role of previous antibiotic therapy in the risk of recurrence after a Clostridioides difficile infection (CDI) treated with vancomycin. Methods: Multicentre observational study. Patients with a CDI episode achieving clinical cure with oral vancomycin and followed up 8 weeks were included. Previous antibiotic exposure up to 90 days was collected. Multivariate analysis of predictors of recurrence adjusted by the propensity score (PS) of being previously treated with each non-CDI antibiotic was performed. Results: Two hundred and forty-one patients were included; 216 (90%) had received systemic antibiotics. Fifty-three patients (22%) had a CDI recurrence. Rates of recurrence were lower in those treated with piperacillin/tazobactam in the last month when compared with those not receiving piperacillin/tazobactam [3 (7%) versus 50 (25%); P = 0.01], whereas higher rates were seen in those treated with cephalosporins in the last month [26/87 (30%) versus 27/154 (17%); P = 0.03]. In multivariate analysis controlled by the inverse probability of treatment weighting by PS, receiving ≥5 days of piperacillin/tazobactam in the last month as the last antibiotic regimen prior to CDI was independently associated with a lower risk of recurrence [adjusted OR (AOR) 0.13; 95% CI: 0.06-0.29; P < 0.0001] whereas exposure for ≥5 days to cephalosporins (versus piperacillin/tazobactam) was associated with an increased risk (AOR 10.9; 95% CI: 4.4-27.1; P < 0.0001). Conclusions: Recent use of piperacillin/tazobactam might be associated with a lower risk of CDI recurrence, while recent use of cephalosporins might promote an increased risk. These findings should be considered when treating hospitalized patients.

Transient Changes in the Plasma of Astrocytic and Neuronal Injury Biomarkers in COVID-19 Patients without Neurological Syndromes.

The levels of several glial and neuronal plasma biomarkers have been found to increase during the acute phase in COVID-19 patients with neurological symptoms. However, replications in patients with minor or non-neurological symptoms are needed to understand their potential as indicators of CNS injury or vulnerability. Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), and total Tau (T-tau) were determined by Single molecule array (Simoa) immunoassays in 45 samples from COVID-19 patients in the acute phase of infection [moderate (n = 35), or severe (n = 10)] with minor or non-neurological symptoms; in 26 samples from fully recovered patients after ~2 months of clinical follow-up [moderate (n = 23), or severe (n = 3)]; and in 14 non-infected controls. Plasma levels of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), were also determined by Western blot. Patients with COVID-19 without substantial neurological symptoms had significantly higher plasma concentrations of GFAP, a marker of astrocytic activation/injury, and of NfL and T-tau, markers of axonal damage and neuronal degeneration, compared with controls. All these biomarkers were correlated in COVID-19 patients at the acute phase. Plasma GFAP, NfL and T-tau levels were all normalized after recovery. Recovery was also observed in the return to normal values of the quotient between the ACE2 fragment and circulating full-length species, following the change noticed in the acute phase of infection. None of these biomarkers displayed differences in plasma samples at the acute phase or recovery when the COVID-19 subjects were sub-grouped according to occurrence of minor symptoms at re-evaluation 3 months after the acute episode (so called post-COVID or "long COVID"), such as asthenia, myalgia/arthralgia, anosmia/ageusia, vision impairment, headache or memory loss. Our study demonstrated altered plasma GFAP, NfL and T-tau levels in COVID-19 patients without substantial neurological manifestation at the acute phase of the disease, providing a suitable indication of CNS vulnerability; but these biomarkers fail to predict the occurrence of delayed minor neurological symptoms.

Association between Clinical Frailty Scale (CFS) and clinical presentation and outcomes in older inpatients with COVID-19.

BACKGROUND: Frailty is a physiological condition characterized by a decreased reserve to stressors. In patients with COVID-19, frailty is a risk factor for in-hospital mortality. The aim of this study was to assess the relationship between clinical presentation, analytical and radiological parameters at admission, and clinical outcomes according to frailty, as defined by the Clinical Frailty Scale (CFS), in old people hospitalized with COVID-19. MATERIALS AND METHODS: This retrospective cohort study included people aged 65 years and older and admitted with community-acquired COVID-19 from 3 March 2020 to 31 April 2021. Patients were categorized using the CFS. Primary outcomes were symptoms of COVID-19 prior to admission, mortality, readmission, admission in intensive care unit (ICU), and need for invasive mechanical ventilation. Analysis of clinical symptoms, clinical outcomes, and CFS was performed using multivariable logistic regression, and results were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Of the 785 included patients, 326 (41.5%, 95% CI 38.1%-45.0%) were defined as frail (CFS ≥ 5 points): 208 (26.5%, 95% CI 23.5%-29.7%) presented mild-moderate frailty (CFS 5-6 points) and 118 (15.0%, 95% CI 12.7%-17.7%), severe frailty (7-9 points). After adjusting for epidemiological variables (age, gender, residence in a nursing home, and Charlson comorbidity index), frail patients were significantly less likely to present dry cough (OR 0.58, 95% CI 0.40-0.83), myalgia-arthralgia (OR 0.46, 95% CI 0.29-0.75), and anosmia-dysgeusia (OR 0.46, 95% CI 0.23-0.94). Confusion was more common in severely frail patients (OR 3.14; 95% CI 1.64-5.97). After adjusting for epidemiological variables, the risk of in-hospital mortality was higher in frail patients (OR 2.79, 95% CI 1.79-4.25), including both those with mild-moderate frailty (OR 1.98, 95% CI 1.23-3.19) and severe frailty (OR 5.44, 95% CI 3.14-9.42). Readmission was higher in frail patients (OR 2.11, 95% CI 1.07-4.16), but only in mild-moderate frailty (OR 2.35, 95% CI 1.17-4.75).. CONCLUSION: Frail patients presented atypical symptoms (less dry cough, myalgia-arthralgia, and anosmia-dysgeusia, and more confusion). Frailty was an independent predictor for death, regardless of severity, and mild-moderate frailty was associated with readmission.

Perinatal exposure to pesticides alters synaptic plasticity signaling and induces behavioral deficits associated with neurodevelopmental disorders.

Increasing evidence from animal and epidemiological studies indicates that perinatal exposure to pesticides cause developmental neurotoxicity and may increase the risk for psychiatric disorders such as autism and intellectual disability. However, the underlying pathogenic mechanisms remain largely elusive. This work was aimed at testing the hypothesis that developmental exposure to different classes of pesticides hijacks intracellular neuronal signaling contributing to synaptic and behavioral alterations associated with neurodevelopmental disorders (NDD). Low concentrations of organochlorine (dieldrin, endosulfan, and chlordane) and organophosphate (chlorpyrifos and its oxon metabolite) pesticides were chronically dosed ex vivo (organotypic rat hippocampal slices) or in vivo (perinatal exposure in rats), and then biochemical, electrophysiological, behavioral, and proteomic studies were performed. All the pesticides tested caused prolonged activation of MAPK/ERK pathway in a concentration-dependent manner. Additionally, some of them impaired metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). In the case of the pesticide chlordane, the effect was attributed to chronic modulation of MAPK/ERK signaling. These synaptic alterations were reproduced following developmental in vivo exposure to chlordane and chlorpyrifos-oxon, and were also associated with prototypical behavioral phenotypes of NDD, including impaired motor development, increased anxiety, and social and memory deficits. Lastly, proteomic analysis revealed that these pesticides differentially regulate the expression of proteins in the hippocampus with pivotal roles in brain development and synaptic signaling, some of which are associated with NDD. Based on these results, we propose a novel mechanism of synaptic dysfunction, involving chronic overactivation of MAPK and impaired mGluR-LTD, shared by different pesticides which may have important implications for NDD.

Efficacy and safety of oral fosfomycin for asymptomatic bacteriuria in kidney transplant recipients: Results from a Spanish multicenter cohort.

Current guidelines recommend against systematic screening or treating asymptomatic bacteriuria (AB) among kidney transplant (KT) recipients, although the evidence regarding episodes occurring early after transplantation or in the presence of anatomical abnormalities is inconclusive. Oral fosfomycin may constitute a good option for the treatment of post-transplant AB, particularly due to the emergence of multidrug-resistant (MDR) uropathogens. Available clinical evidence supporting its use in this specific setting, however, remains scarce. We performed a retrospective study in 14 Spanish institutions from January 2005 to December 2017. Overall, 137 episodes of AB diagnosed in 133 KT recipients treated with oral fosfomycin (calcium and trometamol salts) with a test-of-cure urine culture within the first 30 days were included. Median time from transplantation to diagnosis was 3.1 months (interquartile range [IQR]: 1.1 - 10.5). Most episodes (96.4% [132/137]) were caused by gram-negative bacteria (GNB), and 56.9% (78/137) were categorized as MDR (extended-spectrum ß-lactamase-producing Enterobacterales [20.4%] and carbapenem-resistant GNB [2.9%]). Rate of microbiological failure at month 1 was 40.1% (95% confidence interval [95%CI]: 31.9 - 48.9) for the whole cohort and 42.3% (95%CI: 31.2 - 54.0) for episodes due to MDR pathogens. Previous urinary tract infection (odds ratio [OR]: 2.42; 95%CI: 1.11 - 5.29; P-value = 0.027) and use of fosfomycin as salvage therapy (OR: 8.31; 95%CI: 1.67 - 41.35; P-value = 0.010) were predictors of microbiological failure. No severe treatment-related adverse event were detected. Oral fosfomycin appears to be a suitable and safe alternative for the treatment (if indicated) of AB after KT, including those episodes due to MDR uropathogens.

Tenofovir Disoproxil Fumarate/Emtricitabine and Baricitinib for Patients at High Risk of Severe Coronavirus Disease 2019: The PANCOVID Randomized Clinical Trial.

BACKGROUND: This study was designed to evaluate if patients with high risk for severe coronavirus disease 2019 (COVID-19) would benefit from treatment with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) followed by baricitinib in case of hypoxemia and systemic inflammation. METHODS: PANCOVID is an open-label, double-randomized, phase 3 pragmatic clinical trial including adults with symptomatic COVID-19 with ≥2 comorbidities or aged ≥60 years and was conducted between 10 October 2020 and 23 September 2021. In the first randomization, patients received TDF/FTC or no TDF/FTC. In the second randomization, patients with room air oxygen saturation <95% and at least 1 increased inflammatory biomarker received baricitinib plus dexamethasone or dexamethasone alone. The primary endpoint was 28-day mortality. Main secondary endpoint was 28-day disease progression or critical care unit admission or mortality. The trial was stopped before reaching planned sample size due to the decrease in the number of cases and a mortality rate substantially lower than expected. RESULTS: Of the 355 included participants, 97% were hospitalized at baseline. Overall, 28-day mortality was 3.1%. The 28-day mortality relative risk (RR) for participants treated with TDF/FTC was 1.76 (95% confidence interval [CI], .52-5.91; P = .379); it was 0.42 (95% CI, .11-1.59; P = .201) for those treated with baricitinib. The 28-day RR for the main secondary combined endpoint for participants treated with TDF/FTC was 0.95 (95% CI, .66-1.40; P = .774); it was 0.90 (95% CI, .61-1.33; P = .687) for those treated with baricitinib. CONCLUSIONS: Our results do not suggest a beneficial effect of TDF/FTC; nevertheless, they are compatible with the beneficial effect of baricitinib already established by other clinical trials. CLINICAL TRIALS REGISTRATION: EudraCT: 2020-001156-18.

[Mild SARS-CoV-2 infection in vulnerable patients: implementation of a clinical pathway for early treatment]. / Infección leve por SARS-CoV-2 en pacientes vulnerables: implantación de una vía clínica de tratamiento precoz.

INTRODUCTION: The objective of this report is to describe the clinical pathway for early treatment of patients with acute SARS-CoV-2 infection and to evaluate the first results of its implementation. METHODS: This is a descriptive and retrospective study of the implementation of a clinical pathway of treatment in outpatients (January 1 to June 30 2022). Clinical pathway: detection and referral systems from Primary Care, Emergency services, hospital specialities and an automated detection system; clinical evaluation and treatment administration in the COVID-19 day-hospital and subsequent clinical follow-up. Explanatory variables: demographics, comorbidity, vaccination status, referral pathways and treatment administration. OUTCOME VARIABLES: hospitalization and death with 30 days, grade 2-3 toxicity related to treatment. RESULTS: Treatment was administered to 262 patients (53,4% women, median age 60 years). The treatment indication criteria were immunosupression (68,3%), and the combination of age, vaccination status and comorbidity in the rest47,3% of the patients s received remdesivir, 35,9% nirmatrelvir/ritonavir, 13,4% sotrovimab and 2,4% combined treatment with a median of 4 days after symptom onset. Hospital admission was required for 6,1% of the patients, 3,8% related to progression COVID-19. No patient died. Toxicity grade 2-3 toxicity was reported in 18,7%, 89,8% dysgeusia and metallic tasted related nirmatrelvir/ritonavir. Seven patients discontinued treatment due to toxicity. CONCLUSION: The creation and implementation of a clinical pathway for non-hospitalized patients with SARS-CoV-2 infection is effective and it allows early accessibility and equity of currently available treatments.

Early carbohydrate antigen 125 as a mortality predictor in hospitalized patients with coronavirus disease 2019.

Background: Carbohydrate antigen 125 (CA125) is an indicator of inflammation, immune response, and impaired cardiac function. The aim was to investigate whether CA125 behaves as a biomarker of severity and poor clinical outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19). Methods: Serum CA125 [Elecsys CA125 II assay-(Roche Diagnostics GmbH)] was measured in stored biobank samples from COVID-19 hospitalized patients between 01 March 2020 and 17 October 2021. Multiple logistic regression models were built to explore the association between CA125 and clinical outcomes [in-hospital all-cause mortality, need for invasive mechanical ventilation (IMV), or non-invasive respiratory support (non-IRS)], estimating odds ratios (ORs; 95% CI). The gradient of risk of CA125 was evaluated by fractional polynomials. Results: A total of 691 patients were included, median age of 63 years (50-76), men (57.2%), with high comorbidity. At admission, 85.8% had pneumonia. Median CA125 was 10.33 U/ml (7.48-15.50). The in-hospital mortality rate was 7.2%. After adjusting for confounding factors, CA125 ≥ 15.5 U/ml (75th percentile) showed an increased risk of death [OR 2.85(1.21-6.71)], as age ≥ 65 years, diabetes, and immunosuppression. Furthermore, CA125 as a continuous variable was positive and significantly associated with the risk of death after multivariate adjustment. The mean hospital stay of the patients with CA125 ≥ 15.5 U/ml was longer than the rest of the study population. Conclusion: CA125 in the first 72 h of hospital admission seems a useful biomarker of mortality in hospitalized patients with moderate-severe COVID-19. If our findings are confirmed, the wide availability of this biomarker would make easy its widespread implementation in clinical practice.

Treatment of Clostridioides difficile infection: from guidelines to clinical practice

The Clostridioides difficile Infection (CDI) treatment guidelines were published in 2021; however, the incorporation of these recommendations into clinical practice was rather irregular and inconsistent. The differences in the implementation of these new guidelines were due, in part, to the variety in the different professionals who provided patient care, as well as to the issues involved in either their accessibility or availability or both. The main requirements for implementation include appropriate reflection on patient stratification, drug positioning, accessibility to drugs, as well as the organization of structured clinical pathways that can facilitate the functionality and evaluation of the management of CDI. (AU)

Concordance of the filmarray blood culture identification panel 2 and classical microbiological methods in a bacteriemia diagnostic unit.

Our study evaluates the effectiveness of the FilmArray Blood Culture Identification Panel 2 in a rapid bacteremia diagnostic system, using bacteriological culture as a reference. A total of 2042 positive blood cultures were analyzed, the FilmArray was performed for 175. Concordance was higher in monomicrobial bacteremia (95%) than in polymicrobial bacteremia's (72.2%). For detecting bacterial resistance mechanisms, concordance was very high (100% for Gram-positive bacteria and 98.12% for Gram-negative). This methodology provides significant improvements in response time and is especially useful for the detection of monomicrobial bacteremia.

Pathological Findings Associated With SARS-CoV-2 on Postmortem Core Biopsies: Correlation With Clinical Presentation and Disease Course.

Background: Autopsies can shed light on the pathogenesis of new and emerging diseases. Aim: To describe needle core necropsy findings of the lung, heart, and liver in decedents with COVID-19. Material: Cross-sectional study of needle core necropsies in patients who died with virologically confirmed COVID-19. Histopathological analyses were performed, and clinical data and patient course evaluated. Results: Chest core necropsies were performed in 71 decedents with a median age of 81 years (range 52-97); 47 (65.3%) were men. The median interval from symptoms onset to death was 17.5 days (range 1-84). Samples of lung (n = 62, 87.3%), heart (n = 48, 67.6%) and liver (n = 39, 54.9%) were obtained. Fifty-one lung samples (82.3%) were abnormal: 19 (30.6%) showed proliferative diffuse alveolar damage (DAD), 12 (19.4%) presented exudative DAD, and 10 (16.1%) exhibited proliferative plus exudative DAD. Of the 46 lung samples tested for SARS-CoV-19 by RT-PCR, 39 (84.8%) were positive. DAD was associated with premortem values of lactate dehydrogenase of 400 U/L or higher [adjusted odds ratio (AOR) 21.73; 95% confidence interval (CI) 3.22-146] and treatment with tocilizumab (AOR 6.91; 95% CI 1.14-41.7). Proliferative DAD was associated with an onset-to-death interval of over 15 days (AOR 7.85, 95% CI 1.29-47.80). Twenty-three of the 48 (47.9%) heart samples were abnormal: all showed fiber hypertrophy, while 9 (18.8%) presented fibrosis. Of the liver samples, 29/39 (74.4%) were abnormal, due to steatosis (n = 12, 30.8%), cholestasis (n = 6, 15.4%) and lobular central necrosis (n = 5, 12.8%). Conclusion: Proliferative DAD was the main finding on lung core needle necropsy in people who died from COVID-19; this finding was related to a longer disease course. Changes in the liver and heart were common.