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.

Ten Issues to Update in Nosocomial or Hospital-Acquired Pneumonia: An Expert Review.

Nosocomial pneumonia, or hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) are important health problems worldwide, with both being associated with substantial morbidity and mortality. HAP is currently the main cause of death from nosocomial infection in critically ill patients. Although guidelines for the approach to this infection model are widely implemented in international health systems and clinical teams, information continually emerges that generates debate or requires updating in its management. This scientific manuscript, written by a multidisciplinary team of specialists, reviews the most important issues in the approach to this important infectious respiratory syndrome, and it updates various topics, such as a renewed etiological perspective for updating the use of new molecular platforms or imaging techniques, including the microbiological diagnostic stewardship in different clinical settings and using appropriate rapid techniques on invasive respiratory specimens. It also reviews both Intensive Care Unit admission criteria and those of clinical stability to discharge, as well as those of therapeutic failure and rescue treatment options. An update on antibiotic therapy in the context of bacterial multiresistance, in aerosol inhaled treatment options, oxygen therapy, or ventilatory support, is presented. It also analyzes the out-of-hospital management of nosocomial pneumonia requiring complete antibiotic therapy externally on an outpatient basis, as well as the main factors for readmission and an approach to management in the emergency department. Finally, the main strategies for prevention and prophylactic measures, many of them still controversial, on fragile and vulnerable hosts are reviewed.

Significant increase of CTX-M-15-ST131 and emergence of CTX-M-27-ST131 Escherichia coli high-risk clones causing healthcare-associated bacteraemia of urinary origin in Spain (ITUBRAS-2 project).

OBJECTIVES: To assess the microbiological characteristics of Escherichia coli causing healthcare-associated bacteraemia of urinary origin (HCA-BUO) in Spain (ITUBRAS-2 project), with particular focus on ESBL producers and isolates belonging to ST131 high-risk clone (HiRC). Clinical characteristics and outcomes associated with ST131 infection were investigated. METHODS: A total of 222 E. coli blood isolates were prospectively collected from patients with HCA-BUO from 12 tertiary-care hospitals in Spain (2017-19). Antimicrobial susceptibility and ESBL/carbapenemase production were determined. ST131 subtyping was performed. A subset of 115 isolates were selected for WGS to determine population structure, resistome and virulome. Clinical charts were reviewed. RESULTS: ESBL-producing E. coli prevalence was 30.6% (68/222). ST131 represented 29.7% (66/222) of E. coli isolates and accounted for the majority of ESBL producers (46/68, 67.6%). The C2/H30-Rx subclone accounted for most ST131 isolates (44/66) and was associated with CTX-M-15 (37/44) and OXA-1 enzymes (27/44). Cluster C1-M27 was identified in 4/10 isolates belonging to subclade C1/H30-R1 and associated with CTX-M-27. Additionally, ST131 isolates showed a high content of other acquired resistance genes, and clade C/ST131 isolates carried characteristic QRDR mutations. They were categorized as uropathogenic E. coli and had higher aggregate virulence scores. ST131 infection was associated with more complex patients, prior use of cephalosporins and inadequate empirical treatment but was not associated with worse clinical outcomes. CONCLUSIONS: ST131 HiRC is the main driver of ESBL-producing E. coli causing HCA-BUO in Spain, mainly associated with the expansion of subclade CTX-M-15-C2/H30-Rx and the emergence of CTX-M-27-C1/H30-R1 (Cluster C1-M27).

Prediction of effective humoral response to SARS-CoV-2 vaccines in healthy subjects by cortical thickness of post-vaccination reactive lymphadenopathy.

PURPOSE: To study the association between ultrasound cortical thickness in reactive post-vaccination lymph nodes and the elicited humoral response and to evaluate the performance of cortical thickness as a predictor of vaccine effectiveness in patients with and without a previous history of COVID-19 infection. METHODS: A total of 156 healthy volunteers were recruited and followed prospectively after receiving two COVID-19 vaccination doses using different protocols. Within a week after receiving the second dose, an axillary ultrasound of the ipsilateral vaccinated arm was performed, and serial post-vaccination serologic tests (PVST) were collected. Maximum cortical thickness was chosen as a nodal feature to analyze association with humoral immunity. Total antibodies quantified during consecutive PVST in previously-infected patients and in coronavirus-naïve volunteers were compared (Mann-Whitney U test). The association between hyperplastic-reactive lymph nodes and effective humoral response was studied (odds ratio). The performance of cortical thickness in detecting vaccination effectiveness was evaluated (area under the ROC curve). RESULTS: Significantly higher values for total antibodies were observed in volunteers with a previous history of COVID-19 infection (p < 0.001). The odds ratio associating immunized coronavirus-naïve volunteers after 90 and 180 days of the second dose with a cortical thickness ≥ 3 mm was statistically significant (95% CI 1.52-6.97 and 95% CI 1.47-7.29, respectively). The best AUC result was obtained comparing antibody secretion of coronavirus-naïve volunteers at 180 days (0.738). CONCLUSIONS: Ultrasound cortical thickness of reactive lymph nodes in coronavirus-naïve patients may reflect antibody production and a long-term effective humoral response elicited by vaccination. CLINICAL RELEVANCE STATEMENT: In coronavirus-naïve patients, ultrasound cortical thickness of post-vaccination reactive lymphadenopathy shows a positive association with protective antibody titers against SARS-CoV-2, especially in the long term, providing new insights into previous publications. KEY POINTS: • Hyperplastic lymphadenopathy was frequently observed after COVID-19 vaccination. • Ultrasound cortical thickness of reactive post-vaccine lymph nodes may reflect a long-term effective humoral response in coronavirus-naïve patients.

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.

Pseudomonas aeruginosa Bloodstream Infections in Patients with Cancer: Differences between Patients with Hematological Malignancies and Solid Tumors.

Objectives: To assess the clinical features and outcomes of Pseudomonas aeruginosa bloodstream infection (PA BSI) in neutropenic patients with hematological malignancies (HM) and with solid tumors (ST), and identify the risk factors for 30-day mortality. Methods: We performed a large multicenter, retrospective cohort study including onco-hematological neutropenic patients with PA BSI conducted across 34 centers in 12 countries (January 2006−May 2018). Episodes occurring in hematologic patients were compared to those developing in patients with ST. Risk factors associated with 30-day mortality were investigated in both groups. Results: Of 1217 episodes of PA BSI, 917 occurred in patients with HM and 300 in patients with ST. Hematological patients had more commonly profound neutropenia (0.1 × 109 cells/mm) (67% vs. 44.6%; p < 0.001), and a high risk Multinational Association for Supportive Care in Cancer (MASCC) index score (32.2% vs. 26.7%; p = 0.05). Catheter-infection (10.7% vs. 4.7%; p = 0.001), mucositis (2.4% vs. 0.7%; p = 0.042), and perianal infection (3.6% vs. 0.3%; p = 0.001) predominated as BSI sources in the hematological patients, whereas pneumonia (22.9% vs. 33.7%; p < 0.001) and other abdominal sites (2.8% vs. 6.3%; p = 0.006) were more common in patients with ST. Hematological patients had more frequent BSI due to multidrug-resistant P. aeruginosa (MDRPA) (23.2% vs. 7.7%; p < 0.001), and were more likely to receive inadequate initial antibiotic therapy (IEAT) (20.1% vs. 12%; p < 0.001). Patients with ST presented more frequently with septic shock (45.8% vs. 30%; p < 0.001), and presented worse outcomes, with increased 7-day (38% vs. 24.2%; p < 0.001) and 30-day (49% vs. 37.3%; p < 0.001) case-fatality rates. Risk factors for 30-day mortality in hematologic patients were high risk MASCC index score, IEAT, pneumonia, infection due to MDRPA, and septic shock. Risk factors for 30-day mortality in patients with ST were high risk MASCC index score, IEAT, persistent BSI, and septic shock. Therapy with granulocyte colony-stimulating factor was associated with survival in both groups. Conclusions: The clinical features and outcomes of PA BSI in neutropenic cancer patients showed some differences depending on the underlying malignancy. Considering these differences and the risk factors for mortality may be useful to optimize their therapeutic management. Among the risk factors associated with overall mortality, IEAT and the administration of granulocyte colony-stimulating factor were the only modifiable variables.

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.

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.