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Research purpose: The sinoatrial node (SN) is the main pacemaker site, and it is located in the junctional area of the superior vena cava within the right atrium (RA). The precise micro-anatomy of the SN in males and females in ageing and obesity remains unclear. Basic procedures: Human SN/RA specimens were dissected from 25 post-mortem hearts (preserved in 4 % formaldehyde solution), under Polish local ethical rules. The SN/RA tissue blocks were embedded in paraffin. Masson's Trichrome staining and immunohistochemistry for CD31 (a marker of endothelial cells) and CD68 (a marker of macrophages) were performed. Images at different magnifications were taken and analysed. 12-lead ECGs from 24 patients under Polish local ethical rules were obtained. Heart rate and P wave morphologies from lead II, lead III and lead aVF were analysed. Statistical analysis was performed with the unpaired t-test. Principal results: Heart weight to body weight ratio was significantly higher in aged obese males vs. their female counterparts. In the RA samples, there was an increase in connective tissue and decreased myocyte content from aged obese females compared to aged obese males. Aged non-obese males had significantly increased cellular hypertrophy than the aged non-obese females. Both the aged obese and aged non-obese females showed more CD3 but less CD68 expressing cells than males. In the SN samples, CD31 and CD68 expressing cells were higher in both aged non-obese and aged obese males than their female counterparts. Major conclusions: Ageing and/or obesity are more likely to impact these cardiac tissues through increased inflammation, increased immune response and hypertrophy.

The most commonly applied way of teaching students to convey the foundations of human anatomy and physiology involves textbooks and lectures. This way of transmitting knowledge causes difficulties for students, especially in the context of three-dimensional imaging of organ structures, and as a consequence translates into difficulties with imagining them. Even despite the rapid uptake of knowledge dissemination provided by online materials, including courses and webinars, there is a clear need for learning programs featuring first-hand immersive experiences tailored to suit individual study paces. In this paper, we present an approach to enhance a classical study program by combining multi-modality data and representing them in a Mixed Reality (MR)-based environment. The advantages of the proposed approach have been proven by the conducted investigation of the relationship between atrial anatomy, its electrophysiological characteristics, and resulting P wave morphology on the electrocardiogram (ECG). Another part of the paper focuses on the role of the sinoatrial node in ECG formation, while the MR-based visualization of combined micro-computed tomography (micro-CT) data with non-invasive CineECG imaging demonstrates the educational application of these advanced technologies for teaching cardiac anatomy and ECG correlations.

Abstract Background In pediatric rheumatic diseases (PRD), adalimumab is dosed using fixed weight-based bands irrespective of methotrexate co-treatment, disease activity (DA) or other factors that might influence adalimumab pharmacokinetics (PK). In rheumatoid arthritis (RA) adalimumab exposure between 2–8 mg/L is associated with clinical response. PRD data on adalimumab is scarce. Therefore, this study aimed to analyze adalimumab PK and its variability in PRD treated with/without methotrexate. Methods A two-center prospective study in PRD patients aged 2–18 years treated with adalimumab and methotrexate (GA-M) or adalimumab alone (GA) for ≥ 12 weeks was performed. Adalimumab concentrations were collected 1–9 (maximum concentration; Cmax), and 10–14 days (minimum concentration; Cmin) during ≥ 12 weeks following adalimumab start. Concentrations were analyzed with enzyme-linked immunosorbent assay (lower limit of quantification: 0.5 mg/L). Log-normalized Cmin were compared between GA-M and GA using a standard t-test. Results Twenty-eight patients (14 per group), diagnosed with juvenile idiopathic arthritis (71.4%), non-infectious uveitis (25%) or chronic recurrent multifocal osteomyelitis (3.6%) completed the study. GA-M included more females (71.4%; GA 35.7%, p = 0.13). At first study visit, children in GA-M had a slightly longer exposure to adalimumab (17.8 months [IQR 9.6, 21.6]) compared to GA (15.8 months [IQR 8.5, 30.8], p = 0.8). Adalimumab dosing was similar between both groups (median dose 40 mg every 14 days) and observed DA was low. Children in GA-M had a 27% higher median overall exposure compared to GA, although median Cmin adalimumab values were statistically not different (p = 0.3). Cmin values ≥ 8 mg/L (upper limit RA) were more frequently observed in GA-M versus GA (79% versus 64%). Overall, a wide range of Cmin values was observed in PRD (0.5 to 26 mg/L). Conclusion This study revealed a high heterogeneity in adalimumab exposure in PRD. Adalimumab exposure tended to be higher with methotrexate co-treatment compared to adalimumab monotherapy although differences were not statistically significant. Most children showed adalimumab exposure exceeding those reported for RA with clinical response, particularly with methotrexate co-treatment. This highlights the need of further investigations to establish model-based personalized treatment strategies in PRD to avoid under- and overexposure. Trial registration NCT04042792 , registered 02.08.2019.

Introduction Syndromic panel assays, that is, using one test to simultaneously target multiple pathogens with overlapping signs and symptoms, have been integrated into routine paediatric care over the past decade, mainly for more severely ill and hospitalised patients. Their wider availability and short turnaround times open the possibility to apply them to non-hospitalised patients as well. In this context, it is important to trial how clinicians make use of pathogen detection data and if their early availability influences management decisions, particularly antibiotic use and hospitalisation.Methods and analysis Advanced Diagnostics for Enhanced QUality of Antibiotic prescription in respiratory Tract infections in Emergency rooms is an individually randomised, controlled, open-label effectiveness trial comparing the impact of a respiratory pathogen panel assay (BIOFIRE Respiratory Panel 2.1plus) used as a rapid syndromic test on nasopharyngeal swabs in addition to the standard of care versus standard of care alone. The trial will 1:1 randomise 520 participants under the age of 18 at 7 paediatric emergency departments in 5 European countries. Inclusion criteria for the trial consist of two sets, with the first describing respiratory tract infections in paediatric patients and the second describing the situation of potential management uncertainty in which test results may immediately affect management decisions. Enrolment started in July 2021 and is expected to be completed in early 2024. We will perform a two-sample t-test assuming a pooled variance estimate to compare the log-transformed mean time on antibiotic treatment (in hours) and number of days alive out of the hospital within 14 days after study enrolment between the control and intervention arms.Ethics and dissemination The trial protocol and materials were approved by research ethics committees in all participating countries. The respiratory pathogen panel assay is CE marked (assessed to meet European regulations) and FDA (United States Food and Drug Administration) cleared for diagnostic use. Participants and caregivers provide informed consent prior to study procedures commencing. The trial results will be published in peer-reviewed journals and at national and international conferences. Key messages will also be disseminated via press and social media where appropriate.Trial registration number NCT04781530.

Objectives In trials of acute severe infections or inflammations frequent administration of non-randomised treatment (ie, intercurrent event) in response to clinical events is expected. These events may affect the interpretation of trial findings. Swissped-RECOVERY was set up as one of the first randomised controlled trials worldwide, investigating the comparative effectiveness of anti-inflammatory treatment with intravenous methylprednisolone or intravenous immunoglobulins in children and adolescents with Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS). We present one approach towards improving the interpretation of non-randomised treatment in a randomised controlled trial.Design This is a pre-planned ancillary analysis of the Swissped-RECOVERY trial, a randomised multicentre open-label two-arm trial.Setting 10 Swiss paediatric hospitals (secondary and tertiary care) participated.Participants Paediatric patients hospitalised with PIMS-TS.Interventions All patient-first intercurrent events, if applicable, were presented to an independent adjudication committee consisting of four international paediatric COVID-19 experts to provide independent clinical adjudication to a set of standardised questions relating to whether additional non-randomised treatments were clinically indicated and disease classification at the time of the intercurrent event.Results Of 41 treatments in 75 participants (24/41 (59%) and 17/41 (41%) in the intravenous methylprednisolone and immunoglobulin arms of the trial, respectively), two-thirds were considered indicated. The most common treatment (oral glucocorticoids, 14/41, 35%) was mostly considered not indicated (11/14, 79%), although in line with local guidelines. Intercurrent events among patients with Shock-like PIMS-TS at baseline were mostly considered indicated. A significant proportion of patients with undifferentiated PIMS-TS at baseline were not attributed to the same group at the time of the intercurrent event (6/12 unchanged, 4/12 Kawasaki disease-like, 2/12 Shock-like).Conclusion The masked adjudication of intercurrent events contributes to the interpretation of results in open-label trials and should be incorporated in the future.Trial registration numbers SNCTP000004720 and NCT 04826588.

Abstract Background In Switzerland, the national surgical site infection (SSI) surveillance program showed a modest decrease in SSI rates for different procedures over the last decade. The study aimed to determine whether a multimodal, targeted intervention program in addition to existing SSI surveillance is associated with decreased SSI rates in the participating hospitals. Methods Prospective multicenter pre- and postintervention study conducted in eight Swiss acute care hospitals between 2013 and 2020. All consecutive patients > 18 years undergoing cardiac, colon, or hip/knee replacement surgery were included. The follow-up period was 30 days and one year for implant-related surgery. Patients with at least one follow-up were included. The intervention was to optimize three elements of preoperative management: (i) hair removal; (ii) skin disinfection; and (iii) perioperative antimicrobial prophylaxis. We compared SSI incidence rates (main outcome measure) pre- and postintervention (three years each) adjusted for potential confounders. Poisson generalized linear mixed models fitted to quarter-yearly confirmed SSIs and adjusted for baseline differences between hospitals and procedures. Adherence was routinely monitored through on-site visits. Results A total of 10 151 patients were included, with a similar median age pre- and postintervention (69.6 and IQR 60.9, 76.8 years, vs 69.5 and IQR 60.4, 76.8 years, respectively; P = 0.55) and similar proportions of females (44.8% vs. 46.1%, respectively; P = 0.227). Preintervention, 309 SSIs occurred in 5 489 patients (5.6%), compared to 226 infections in 4 662 cases (4.8%, P = 0.09) postintervention. The adjusted incidence rate ratio (aIRR) for overall SSI after intervention implementation was 0.81 (95% CI, 0.68 to 0.96, P = 0.02). For cardiac surgery (n = 2 927), the aIRR of SSI was 0.48 (95% CI, 0.32 to 0.72, P

Abstract Objective We aimed to evaluate the association between post-appendectomy SSI rates and the two most commonly used regimens for perioperative antimicrobial prophylaxis in Swiss children. Methods We conducted a retrospective cohort study, analysing data from the Swiss national SSI surveillance database with a study period from 2014 to 2018. All hospitals undertaking paediatric appendectomies in Switzerland participate in the surveillance. We compared the cumulative incidence and odds of post-appendectomy SSI within 30 days of surgery in children ≤ 16 years of age undergoing appendectomy for uncomplicated appendicitis and receiving perioperative antimicrobial prophylaxis with cefuroxime plus metronidazole or with amoxicillin/clavulanic acid using multivariable adjusted logistic regression and propensity-score matching. Results A total of 6207 cases were recorded in the study time frame. Overall SSI cumulative incidence was 1.9% (n = 119). 4256 children (54.9% male, median (IQR) age 12 [10, 14] years) received either cefuroxime plus metronidazole (n = 2348, 53.8% male) or amoxicillin/clavulanic acid (n = 1491, 57.0% male). SSI cumulative incidence was 1.1% (25/2348) among children receiving cefuroxime plus metronidazole and 2.8% (42/1491, p

Abstract Objective To compare intravenous (IV) amoxicillin/clavulanic acid (A/CA) to IV cefuroxime plus metronidazole (C + M) for preventing surgical site infections (SSI) in colorectal surgery. Background Given their spectra that include most Enterobacterales and anaerobes, C + M is commonly recommended as prophylaxis of SSI in colorectal surgery. A/CA offers good coverage of Enterobacterales and anaerobes as well, but, in contrast to C + M, it also includes Enterococcus faecalis which is also isolated from patients with SSI and could trigger anastomotic leakage. Methods Data from a Swiss SSI surveillance program were used to compare SSI rates after class II (clean contaminated) colorectal surgery between patients who received C + M and those who received A/CA. We employed multivariable logistic regression to adjust for potential confounders, along with propensity score matching to adjust for group imbalance. Results From 2009 to 2018, 27,922 patients from 127 hospitals were included. SSI was diagnosed in 3132 (11.2%): 278/1835 (15.1%) in those who received A/CA and 2854/26,087 (10.9%) in those who received C + M (p 2, a longer duration of operation, and a reoperation for a non-infectious complication. Protective factors were female sex, older age, antibiotic prophylaxis received 60 to 30 min before surgery, elective operation, and endoscopic approach. Conclusions Despite its activity against enterococci, A/CA was less effective than C + M for preventing SSI, suggesting that it should not be a first choice antibiotic prophylaxis for colorectal surgery.

Summary: Background: Previous findings from the Swissped RECOVERY trial showed that patients with Pediatric Inflammatory Multisystem Syndrome–Temporally Associated with SARS-CoV-2 (PIMS-TS) who were randomly assigned to intravenous immunoglobulins or methylprednisolone have a comparable length of hospital stay. Here, we report the 6-month follow-up outcomes of cardiac pathologies and normalisation of clinical or laboratory signs of inflammation from this study population. Methods: This pre-planned follow-up of patients with PIMS-TS included the Swissped RECOVERY Trial reports on the 6-month outcomes of the cohort after randomisation, with a focus on cardiac, haematological, and biochemical findings. The trial was an investigator-initiated randomised multicentre open-label two-arm trial in children and adolescents hospitalised with PIMS-TS at ten hospitals in Switzerland. Cardiological assessments and laboratory analyses were prospectively collected in the intention-to-treat analysis on pre-defined intervals after hospital discharge. Differences between randomised arms were investigated using Chi-square test for categorical and Wilcoxon test for continuous variables. The trial is registered with the Swiss National Clinical Trials Portal (SNCTP000004720) and ClinicalTrials.gov (NCT04826588). Findings: Between May 21, 2021 and April 15, 2022, 75 patients with a median age of 9.1 years (IQR 6.2–12.2) were included in the intention-to-treat population (37 in the methylprednisolone group and 38 in the intravenous immunoglobulin group). During follow-up, the incidence of abnormal left ventricular systolic function, coronary artery aneurysms (CAA), and other signs of inflammation were comparable in both groups. However, we detected cardiac abnormalities with low incidence and a mild degree grade of pathology. CAAs were observed in 2/38 children (5.3%) in the IVIG group and 1/37 children (2.7%) in the methylprednisolone group at 6-month follow-up (difference proportion 0.75; 95% confidence interval (CI) −0.05 to 1.0; p = 0.39). Interpretation: Methylprednisolone alone may be an acceptable first-line treatment as left ventricular systolic dysfunction and clinical/laboratory evidence for inflammation quickly resolved in all children. However, our findings need further confirmation through larger studies as our sample size is likely to be of insufficient power to address rare clinically relevant adverse outcomes. Funding: NOMIS, Vontobel, and Gaydoul Foundation.

Abstract Missing data create challenges in clinical research because they lead to loss of statistical power and potentially to biased results. Missing covariate data must be handled with suitable approaches to prepare datasets for pharmacometric analyses, such as population pharmacokinetic and pharmacodynamic analyses. To this end, various statistical methods have been widely adopted. Here, we introduce two machine‐learning (ML) methods capable of imputing missing covariate data in a pharmacometric setting. Based on a previously published pharmacometric analysis, we simulated multiple missing data scenarios. We compared the performance of four established statistical methods, listwise deletion, mean imputation, standard multiple imputation (hereafter “Norm”), and predictive mean matching (PMM) and two ML based methods, random forest (RF) and artificial neural networks (ANNs), to handle missing covariate data in a statistically plausible manner. The investigated ML‐based methods can be used to impute missing covariate data in a pharmacometric setting. Both traditional imputation approaches and ML‐based methods perform well in the scenarios studied, with some restrictions for individual methods. The three methods exhibiting the best performance in terms of least bias for the investigated scenarios are the statistical method PMM and the two ML‐based methods RF and ANN. ML‐based approaches had comparable good results to the best performing established method PMM. Furthermore, ML methods provide added flexibility when encountering more complex nonlinear relationships, especially when associated parameters are suitably tuned to enhance predictive performance.

In light of rising antibiotic resistance, better methods for selection of empiric antibiotic treatment based on clinical and microbiological data are needed. Most guidelines target specific clinical infections, and variably adjust empiric antibiotic selection by certain patient characteristics. Coverage estimates reflect the probability that an antibiotic regimen will be active against the causative pathogen once confirmed and can provide an objective basis for empiric regimen selection. Coverage can be estimated for specific infections using a weighted incidence syndromic combination antibiograms (WISCAs) framework. However, no comprehensive data combining clinical and microbiological data for specific clinical syndromes are available in Switzerland. We therefore describe estimating coverage from semi-deterministically linked routine microbiological and cohort data of hospitalised children with sepsis. Coverage estimates were generated for each hospital and separately pooling data across ten contributing hospitals for five pre-defined patient risk groups. Data from 1,082 patients collected during the Swiss Paediatric Sepsis Study (SPSS) 2011–2015 were included. Preterm neonates were the most commonly represented group, and half of infants and children had a comorbidity. 67% of neonatal sepsis cases were hospital-acquired late-onset whereas in children 76% of infections were community-acquired. Escherichia coli, Coagulase-negative staphylococci (CoNS) and Staphylococcus aureus were the most common pathogens. At all hospitals, ceftazidime plus amikacin regimen had the lowest coverage, and coverage of amoxicillin plus gentamicin and meropenem were generally comparable. Coverage was improved when vancomycin was included in the regimen, reflecting uncertainty about the empirically targeted pathogen spectrum. Children with community-acquired infections had high coverage overall. It is feasible to estimate coverage of common empiric antibiotic regimens from linked data. Pooling data by patient risk groups with similar expected pathogen and susceptibility profiles may improve coverage estimate precision, supporting better differentiation of coverage between regimens. Identification of data sources, selection of regimens and consideration of pathogens to target for improved empiric coverage is important.

Objectives The aim of this study was to investigate the association between surgical site infections (SSIs), a major source of patient harm, and safety and teamwork climate. Prior research has been unclear regarding this relationship.Design Based on the Swiss national SSI surveillance and a survey study assessing (a) safety climate and (b) teamwork climate, associations were analysed for three kinds of surgical procedures.Setting and participants SSI surveillance data from 20 434 surgeries for hip and knee arthroplasty from 41 hospitals, 8321 for colorectal procedures from 28 hospitals and 4346 caesarean sections from 11 hospitals and survey responses from Swiss operating room personnel (N=2769) in 54 acute care hospitals.Primary and secondary outcomes The primary endpoint of the study was the 30-day (all types) or 1-year (knee/hip with implants) National Healthcare Safety Network-adjusted SSI rate. Its association with climate level and strength was investigated in regression analyses, accounting for respondents’ professional background, managerial role and hospital size as confounding factors.Results Plotting climate levels against infection rates revealed a general trend with SSI rate decreasing as the safety climate increased, but none of the associations were significant (5% level). Linear models for hip and knee arthroplasties showed a negative association between SSI rate and climate perception (p=0.02). For climate strength, there were no consistent patterns, indicating that alignment of perceptions was not associated with lower infection rates. Being in a managerial role and being a physician (vs a nurse) had a positive effect on climate levels regarding SSI in hip and knee arthroplasties, whereas larger hospital size had a negative effect.Conclusions This study suggests a possible negative correlation between climate level and SSI rate, while for climate strength, no associations were found. Future research should study safety climate more specifically related to infection prevention measures to establish clearer links.

Abstract Background Future prevalence of colonization with extended-spectrum betalactamase (ESBL-) producing K. pneumoniae in humans and the potential of public health interventions against the spread of these resistant bacteria remain uncertain. Methods Based on antimicrobial consumption and susceptibility data recorded during > 13 years in a Swiss region, we developed a mathematical model to assess the comparative effect of different interventions on the prevalence of colonization. Results Simulated prevalence stabilized in the near future when rates of antimicrobial consumption and in-hospital transmission were assumed to remain stable (2025 prevalence: 6.8% (95CI%:5.4–8.8%) in hospitals, 3.5% (2.5–5.0%) in the community versus 6.1% (5.0–7.5%) and 3.2% (2.3–4.2%) in 2019, respectively). When overall antimicrobial consumption was set to decrease by 50%, 2025 prevalence declined by 75% in hospitals and by 64% in the community. A 50% decline in in-hospital transmission rate led to a reduction in 2025 prevalence of 31% in hospitals and no reduction in the community. The best model fit estimated that 49% (6–100%) of observed colonizations could be attributable to sources other than human-to-human transmission within the geographical setting. Conclusions Projections suggests that overall antimicrobial consumption will be, by far, the most powerful driver of prevalence and that a large fraction of colonizations could be attributed to non-local transmissions.

Abstract Background The guideline-driven and widely implemented single room isolation strategy for respiratory viral infections (RVI) such as influenza or respiratory syncytial virus (RSV) can lead to a shortage of available hospital beds. We discuss our experience with the introduction of droplet precautions on-site (DroPS) as a possible alternative. Methods During the 2018/19 influenza season we introduced DroPS on several wards of a single tertiary care center, while other wards maintained the traditional single room isolation strategy. On a daily basis, we evaluated patients for the development of respiratory symptoms and screened those with a clinical diagnosis of hospital-acquired respiratory viral infection (HARVI) for influenza/RSV by molecular rapid test. If negative, it was followed by a multiplex respiratory virus PCR. We report the concept of DroPS, the feasibility of the strategy and the rate of microbiologically confirmed HARVI with influenza or RSV infection on the DroPS wards compared to wards using the traditional single room isolation strategy. Results We evaluated all hospitalised patients at risk for a HARVI, 741 (72%) on the DroPS wards and 293 (28%) on the regular wards. The hospital-acquired infection rate with influenza or RSV was 2/741 (0.3%; 1× influenza A, 1× RSV) on the DroPS wards and 2/293 (0.7%; 2× influenza A) on the regular wards. Conclusions Droplet precautions on-site (DroPS) may be a simple and potentially resource-saving alternative to the standard single room isolation strategy for respiratory viral infections. Further studies in a larger clinical context are needed to document its safety.

Abstract Objective: To evaluate the effects of handshake antimicrobial stewardship on medicine floors at a large tertiary care hospital. Design: Retrospective observational study. Setting: 1,278-bed academic hospital. Patients: Adults admitted to non-ICU medicine services. Interventions: A handshake stewardship team consisting of an infectious diseases (ID) physician and pharmacist reviewed charts of patients receiving antimicrobials on medicine floors without a formal ID consult. Recommendations were communicated in-person to providers and acceptance rates were examined with descriptive statistics. Additional data regarding program perception among providers were obtained via surveys. Antibiotic usage trends were extracted from National Healthcare Safety Network Antimicrobial Use option data and evaluated using an interrupted time-series analysis pre- and post-intervention. Results:The overall acceptance rate of interventions was 80%, the majority being recommendations either to discontinue (37%) or de-escalate therapy (28%). Medical residents and hospitalists rated the intervention favorably with 90% reporting recommendations were helpful all or most of the time. There was a statistically significant decrease in vancomycin (78 vs 70 DOT/1,000 d present (DP), p = 0.002) and meropenem (24 vs 17 DOT/1,000 DP, p = 0.007) usage and a statistically significant increase in amoxicillin-clavulanate usage (11 vs 15 DOT/1,000 DP, p < 0.001). Overall antibiotic usage remained unchanged by the intervention, though pre-intervention there was a nonsignificant overall increasing trend while post-intervention there was a nonsignificant decreasing trend in overall usage. There was no change in in-hospital mortality. Conclusion: The addition of handshake stewardship with adult medicine services was favorably viewed by participants and led to shifts in antibiotic usage.

Abstract Objective: To determine the relationship between severe acute respiratory syndrome coronavirus 2 infection, hospital-acquired infections (HAIs), and mortality. Design: Retrospective cohort. Setting: Three St. Louis, MO hospitals. Patients: Adults admitted ≥48 hours from January 1, 2017 to August 31, 2020. Methods: Hospital-acquired infections were defined as those occurring ≥48 hours after admission and were based on positive urine, respiratory, and blood cultures. Poisson interrupted time series compared mortality trajectory before (beginning January 1, 2017) and during the first 6 months of the pandemic. Multivariable logistic regression models were fitted to identify risk factors for mortality in patients with an HAI before and during the pandemic. A time-to-event analysis considered time to death and discharge by fitting Cox proportional hazards models. Results: Among 6,447 admissions with subsequent HAIs, patients were predominantly White (67.9%), with more females (50.9% vs 46.1%, P = .02), having slightly lower body mass index (28 vs 29, P = .001), and more having private insurance (50.6% vs 45.7%, P = .01) in the pre-pandemic period. In the pre-pandemic era, there were 1,000 (17.6%) patient deaths, whereas there were 160 deaths (21.3%, P = .01) during the pandemic. A total of 53 (42.1%) coronavirus disease 2019 (COVID-19) patients died having an HAI. Age and comorbidities increased the risk of death in patients with COVID-19 and an HAI. During the pandemic, Black patients with an HAI and COVID-19 were more likely to die than White patients with an HAI and COVID-19. Conclusions: In three Midwestern hospitals, patients with concurrent HAIs and COVID-19 were more likely to die if they were Black, elderly, and had certain chronic comorbidities.

Abstract Objective: To investigate clinically relevant microbiological characteristics of uropathogens and to compare patients with catheter-associated urinary tract infections (CAUTIs) to those with non-CAUTIs. Methods: All urine cultures from the calendar year 2019 of the Swiss Centre for Antibiotic Resistance database were analyzed. Group differences in the proportions of bacterial species and antibiotic-resistant isolates from CAUTI and non-CAUTI samples were investigated. Results: Data from 27,158 urine cultures met the inclusion criteria. Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis together represented 70% and 85% of pathogens identified in CAUTI and non-CAUTI samples, respectively. Pseudomonas aeruginosa was significantly more often detected in CAUTI samples. The overall resistance rate for the empirically often-prescribed antibiotics ciprofloxacin (CIP), norfloxacin (NOR), and trimethoprim-sulfamethoxazole (TMP-SMX) was between 13% and 31%. Except for nitrofurantoin, E. coli from CAUTI samples were more often resistant (P ≤ .048) to all classes of antibiotics analyzed, including third-generation cephalosporines used as surrogate for extended-spectrum β-lactamase (ESBL). Significanty higher resistance proportions in CAUTI samples versus non-CAUTI samples were observed for CIP (P = .001) and NOR (P = .033) in K. pneumoniae, for NOR (P = .011) in P. mirabilis, and for cefepime (P = .015), and piperacillin-tazobactam (P = .043) in P. aeruginosa. Conclusion: CAUTI pathogens were more often resistant to recommended empirical antibiotics than non-CAUTI pathogens. This finding emphasizes the need for urine sampling for culturing before initiating therapy for CAUTI and the importance of considering therapeutic alternatives.

Abstract Background Clinical risk scores and machine learning models based on routine laboratory values could assist in automated early identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients at risk for severe clinical outcomes. They can guide patient triage, inform allocation of health care resources, and contribute to the improvement of clinical outcomes. Methods In- and out-patients tested positive for SARS-CoV-2 at the Insel Hospital Group Bern, Switzerland, between February 1st and August 31st (‘first wave’, n = 198) and September 1st through November 16th 2020 (‘second wave’, n = 459) were used as training and prospective validation cohort, respectively. A clinical risk stratification score and machine learning (ML) models were developed using demographic data, medical history, and laboratory values taken up to 3 days before, or 1 day after, positive testing to predict severe outcomes of hospitalization (a composite endpoint of admission to intensive care, or death from any cause). Test accuracy was assessed using the area under the receiver operating characteristic curve (AUROC). Results Sex, C-reactive protein, sodium, hemoglobin, glomerular filtration rate, glucose, and leucocytes around the time of first positive testing (− 3 to + 1 days) were the most predictive parameters. AUROC of the risk stratification score on training data (AUROC = 0.94, positive predictive value (PPV) = 0.97, negative predictive value (NPV) = 0.80) were comparable to the prospective validation cohort (AUROC = 0.85, PPV = 0.91, NPV = 0.81). The most successful ML algorithm with respect to AUROC was support vector machines (median = 0.96, interquartile range = 0.85–0.99, PPV = 0.90, NPV = 0.58). Conclusion With a small set of easily obtainable parameters, both the clinical risk stratification score and the ML models were predictive for severe outcomes at our tertiary hospital center, and performed well in prospective validation.

Abstract Background The World Health Organization (WHO) recommends administration of surgical antimicrobial prophylaxis (SAP) in cesarean section prior to incision to prevent surgical site infections (SSI). This study aimed to determine whether SAP administration following cord clamping confers an increased SSI risk to the mother. Methods Study design: Cohort. Setting: 75 participating Swiss hospitals, from 2009 to 2018. Participants: A total of 55,901 patients were analyzed. Main outcome measures: We assessed the association between SAP administration relative to incision and clamping and the SSI rate, using generalized linear multilevel models, adjusted for patient characteristics, procedural variables, and health-care system factors. Results SAP was administered before incision in 26′405 patients (47.2%) and after clamping in 29,496 patients (52.8%). Overall 846 SSIs were documented, of which 379 (1.6% [95% CI, 1.4–1.8%]) occurred before incision and 449 (1.7% [1.5–1.9%]) after clamping (p = 0.759). The adjusted odds ratio for SAP administration after clamping was not significantly associated with an increased SSI rate (1.14, 95% CI 0.96–1.36; p = 0.144) when compared to before incision. Supplementary and subgroup analyses supported these main results. Conclusions This study did not confirm an increased SSI risk for the mother in cesarean section if SAP is given after umbilical cord clamping compared to before incision.

IntroductionIn 2020, a new disease entitled Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C), emerged, with thousands of children affected globally. There is no available evidence based on randomized controlled trials (RCT) to date on the two most commonly used immunomodulatory treatments, intravenous immunoglobulins (IVIG) and corticosteroids. Therefore, the Swissped RECOVERY trial was conducted to assess whether intravenous (IV) methylprednisolone shortens hospital length of stay compared with IVIG.Methods and AnalysisSwissped RECOVERY is an ongoing investigator-initiated, open-label, multicenter two-arm RCT in children and adolescents

Background: Many bacterial and viral infections may cause sepsis or/and systemic or local proinflammatory responses that lead to life-threatening cardiovascular system failure. Severe bradycardia and/or bradyarrhythmias frequently accompany systemic inflammation and contribute to hemodynamic insufficiency. Markers for immunocompetent cells have been shown to be present in the tissue of the primary heart pacemaker, the sinoatrial node (SAN). However, the role of the resident cardiac immune cells in inflammation-induced bradycardia and SAN automaticity have still not been elucidated. Materials and methods: Confocal and bright field microscopy were used to identify toluidine blue-positive cells (TPC) in the SAN. Standard microelectrode technique and optical mapping were used to record action potentials (AP) and analyze activation pattern in the SAN tissue preparation from rats in presence of secretagogue C48/80. Results: Numerous TPC, which exhibit toluidine-accumulating granules, typical for mast cells, are revealed in the SAN region of the right atrium. The activation and degranulation of the resident mast cells by C48/80 leads to biphasic changes of the pacemaker AP rate in the SAN – an initial acceleration is followed by rate reduction. The activation of the resident mast cells causes an increase of the primary activation area in the SAN that probably underlies the AP rate increase in response to C48/80. In addition, the application of C48/80 causes the primary/leading activation point migration in the SAN and AP rate decrease is probably mediated by the shift of the primary pacemaker site to the region surrounding the coronary sinus. Moreover, inexcitable zones and conduction blocks induced in the central SAN myocardium by C48/80 underlie the suppression of automaticity. Conclusion: The degranulation of resident mast cells affects the pacemaker cardiomyocytes’ ability to generate spontaneous AP in the SAN tissue and causes shift of the dominant pacemaker site. Therefore, the activation of the resident mast cells in the SAN can be considered as a new mechanism of inflammatory induced bradyarrhythmias.

Abstract Background Preoperative skin antisepsis is an essential component of safe surgery. However, it is unclear how many antiseptic paints are needed to eliminate bacteria prior to incision. This study compared microbial skin counts after two and three antiseptic paints. Methods We conducted a prospective cohort study in non-emergency patients receiving a cardiac/abdominal surgery with standardized, preoperative skin antisepsis consisting of an alcoholic compound and either povidone iodine (PI) or chlorhexidine (CHX). We obtained three skin swabs from the participant’s thorax/abdomen using a sterile template with a 25 cm2 window: After collection of the first swab prior to skin antisepsis, and once the second and third application of PI/CHX had dried out, we obtained a second and third swab, respectively. Our primary outcome was the reduction in microbial skin counts after two and three paints of PI/CHX. Results Among the 239 enrolled patients, there was no significant difference in the reduction of mean square root-transformed microbial skin counts with three versus two paints (P = 0.2). But distributions of colony forming units (CFUs) decreased from paint 2 to 3 in a predefined analysis (P = 0.002). There was strong evidence of an increased proportion of patients with zero CFU after paint 3 versus paint 2 (P = 0.003). We did not identify risk factors for insufficient reduction of microbial skin counts after two paints, defined as the detection of > 5 CFUs and/or ≥ 1 pathogens. Conclusions In non-emergency surgical patients, three antiseptic paints may be superior to two paints in reducing microbial skin colonization prior to surgery.

Abstract Background Catheter-related bloodstream infections (CRBSI) with coagulase-negative Staphylococci (CoNS) are a common source of hospital-acquired bloodstream infections. The main objective of this study was to elucidate the role of systemic antibiotic therapy in the setting of catheter removal in adult patients with CoNS-CRBSI. Methods We conducted a retrospective cohort study on patients with CoNS-CRBSI diagnosed between 2008 and 2016 with follow-up for up to 12 months. The main inclusion criterion was a removed intravascular catheter with quantitative catheter tip culture growing CoNS and the same CoNS identified in the blood culture of a given patient. Outcomes were non-resolved infection (i.e. either presence of prolonged bacteremia or symptoms attributed to CoNS-CRBSI > 2 days after catheter removal), recurrence, mortality and length of hospitalization after catheter removal. We compared outcomes between a group with antibiotic treatment prescribed according to current IDSA guidelines (≥5 days, “treatment” group) and a “no-treatment” group. Results Our study population comprised 184 CoNS-CRBSI episodes. Seventy-six percent received antibiotic treatment ≥5 days, while 17% did not receive therapy. Non-resolved infections were absent from the patients who did not receive antibiotics. Severe neutropenia, hematologic cancer and immunosuppression were significantly more frequent in the treatment group. The subgroup analysis with 32 matched pairs showed no significant difference in frequency of non-resolved infection (0% in the no-treatment vs 15.6% in the ≥5 days treatment group, p = 0.06). The remaining outcomes were similar in the two groups. Conclusions Our findings indicate that withholding antimicrobial therapy in CoNS-CRBSI is neither associated with short-term complications nor with long-term recurrences.

BackgroundThe sinoatrial/sinus node (SAN) is the primary pacemaker of the heart. In humans, SAN is surrounded by the paranodal area (PNA). Although the PNA function remains debated, it is thought to act as a subsidiary atrial pacemaker (SAP) tissue and become the dominant pacemaker in the setting of sinus node disease (SND). Large animal models of SND allow characterization of SAP, which might be a target for novel treatment strategies for SAN diseases.MethodsA goat model of SND was developed (n = 10) by epicardially ablating the SAN and validated by mapping of emergent SAP locations through an ablation catheter and surface electrocardiogram (ECG). Structural characterization of the goat SAN and SAP was assessed by histology and immunofluorescence techniques.ResultsWhen the SAN was ablated, SAPs featured a shortened atrioventricular conduction, consistent with the location in proximity of atrioventricular junction. SAP recovery time showed significant prolongation compared to the SAN recovery time, followed by a decrease over a follow-up of 4 weeks. Like the SAN tissue, the SAP expressed the main isoform of pacemaker hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) and Na+/Ca2+ exchanger 1 (NCX1) and no high conductance connexin 43 (Cx43). Structural characterization of the right atrium (RA) revealed that the SAN was located at the earliest activation [i.e., at the junction of the superior vena cava (SVC) with the RA] and was surrounded by the paranodal-like tissue, extending down to the inferior vena cava (IVC). Emerged SAPs were localized close to the IVC and within the thick band of the atrial muscle known as the crista terminalis (CT).ConclusionsSAN ablation resulted in the generation of chronic SAP activity in 60% of treated animals. SAP displayed development over time and was located within the previously discovered PNA in humans, suggesting its role as dominant pacemaker in SND. Therefore, SAP in goat constitutes a promising stable target for electrophysiological modification to construct a fully functioning pacemaker.

Low copeptin levels may indicate inadequate arginine-vasopressin release promoting arterial hypotension, whereas high copeptin concentrations may reflect disease severity. This single-center prospective non-randomized clinical trial analyzed the course of blood copeptin in critically ill normo- and hypotensive children and its association with disease severity. In 164 patients (median age 0.5 years (interquartile range 0.1, 2.9)), the mean copeptin concentration at baseline was 43.5 pmol/L. Though not significantly different after 61 h (primary outcome, mean individual change: −12%, p = 0.36, paired t-test), we detected 1.47-fold higher copeptin concentrations during arterial hypotension when compared to normotension (mixed-effect ANOVA, p = 0.01). In total, 8 out of 34 patients (23.5%) with low copeptin concentrations p = 0.002). Moreover, we found a significant association with vasopressor-inotrope treatment intensity, infancy (1–12 months) and cardiopulmonary bypass (all p ≤ 0.001). In conclusion, high copeptin values were associated with arterial hypotension and severity of disease in critically ill children. This study does not support the hypothesis that low copeptin values might be indicative of arginine-vasopressin deficiency.

Summary: Background: Over the past decades, the Burkholderia cepacia complex (BCC) has been linked to multiple healthcare-associated outbreaks. No systematic analysis of these outbreaks has been carried out to date. The aim of this study was to conduct a systematic review of reports on nosocomial BCC outbreaks. Methods: Published studies from 1971 until 9/12/2019 presenting nosocomial BCC outbreaks were identified using Embase, Pubmed and abstracts from professional meetings. Results: We identified a total of 111 outbreak reports. Thirty-two percent of the affected institutions were academic hospitals and 43.8% community hospitals. The average outbreak duration was 198.6 ± 604.4 days. A total of 240 deaths (10% of the 2390 case patients) were reported but only 28 (1.2% of the 2390 case patients and 11.7% of the 240 deaths) were directly attributable to BCC. The source could be identified in 73.9% of the outbreaks; 53.2% were caused by contaminated medical solutions and medications, 12% were due to a contaminated disinfectant. In 28.2% of the outbreaks intrinsic product contamination was reported. Multidrug resistance was noted in 26.1% of the BCC strains. PFGE was the most frequently used typing method (43.2%) in the context of outbreak work-up. Conclusion: Medical products are the most frequent source of BCC outbreaks, representing over half of the identified sources, with 12% of the outbreaks caused by disinfectant products. Intrinsic product contamination was detected frequently, suggesting a need for stricter regulation. While BCC-related mortality was low, our systematic review revealed significant heterogeneity in both investigations and reporting of BCC outbreaks.

Abstract Caffeine is widely used in preterm neonates suffering from apnea of prematurity (AOP), and it has become one of the most frequently prescribed medications in neonatal intensive care units. Goal of this study is to investigate how caffeine citrate treatment affects sleep‐wake behavior in preterm neonates. The observational study consists of 64 preterm neonates during their first 5 days of life with gestational age (GA)

Abstract Cardiac arrhythmias and conduction disturbances are accompanied by structural remodelling of the specialised cardiomyocytes known collectively as the cardiac conduction system. Here, using contrast enhanced micro-computed tomography, we present, in attitudinally appropriate fashion, the first 3-dimensional representations of the cardiac conduction system within the intact human heart. We show that cardiomyocyte orientation can be extracted from these datasets at spatial resolutions approaching the single cell. These data show that commonly accepted anatomical representations are oversimplified. We have incorporated the high-resolution anatomical data into mathematical simulations of cardiac electrical depolarisation. The data presented should have multidisciplinary impact. Since the rate of depolarisation is dictated by cardiac microstructure, and the precise orientation of the cardiomyocytes, our data should improve the fidelity of mathematical models. By showing the precise 3-dimensional relationships between the cardiac conduction system and surrounding structures, we provide new insights relevant to valvar replacement surgery and ablation therapies. We also offer a practical method for investigation of remodelling in disease, and thus, virtual pathology and archiving. Such data presented as 3D images or 3D printed models, will inform discussions between medical teams and their patients, and aid the education of medical and surgical trainees.

Abstract In this cross-sectional Society for Healthcare Epidemiology of America Research Network survey on knowledge sharing in infection prevention we identified a rudimentary understanding of how to communicate and share knowledge within healthcare institutions. Our data support the need of further research in this important field.

Abstract Subsequent bloodstream infections (sBSI) occur with a delay after removal of the intravascular catheter (IVC) whose tip revealed microbial growth. Here we describe the epidemiology of sBSI in the intensive care setting. Serratia marcescens, Staphylococcus aureus, Pseudomonas aeruginosa, and yeast were the pathogens most frequently associated with sBSI. In contrast, Enterococci were rarely found in sBSI.

BackgroundIn a previous report, a clinical ST131 Escherichia coli isolate (Ec-1),producing a plasmid-encoded AmpC β-lactamase CMY-2, evolved in vivo under cefepime (FEP) treatment to the FEP-resistant Ec-2 strain expressing an extended-spectrum β-lactamase CMY-33. To compare factors responsible for in vitro and in vivo FEP resistance, we reproduced in vitro FEP resistance evolution in Ec-1.MethodsFEP-resistant mutants were generated by subjecting Ec-1 (FEP MIC = 0.125 mg/L) to sub-inhibitory concentrations of FEP. MICs were obtained by broth microdilution or Etest. Strains were sequenced on an Illumina HiSeq platform. Transcriptional levels and plasmid copy numbers were determined by real-time PCR. Outer membrane proteins (OMPs) were extracted and separated by SDS-PAGE. Growth kinetics was evaluated by measuring OD450.ResultsThe CMY-2 expressed by Ec-1 evolved to a CMY-69 (strain EC-4) by an Ala294Pro substitution after 24 passages. After 30 passages, the FEP MIC increased to 256 mg/L (strain EC-32). SDS PAGE did not reveal any lack of OMPs in the mutant strains. However, blaCMY transcription levels were up to 14-times higher than in Ec-1, which was partially explained by mutations in the upstream region of repA resulting in a higher copy number of the blaCMY-harboring IncI1 plasmid. All mutants showed a slight growth defect but no significant difference in relative growth rates compared to Ec-1.ConclusionIn vitro sub-inhibitory concentrations of FEP resulted in the selection of resistance mutations altering the H-10 helix of the CMY-2 and increasing the plasmid copy number. Appropriate dosing strategies may help preventing resistance evolution during treatments.

Background: Previous studies have shown cutaneous small fiber pathology in patients with Parkinson's disease (PD). These studies have focused on nerve degeneration, but recent reports suggest that nerve regeneration may also be important in PD pathology.Objective: To establish the extent of intraepidermal nerve fiber (IENF) degeneration and regeneration and its relationship to clinical and neurological deficits in Parkinson's disease (PD).Methods: Twenty-three PD patients and 10 age-matched controls underwent skin biopsy and assessment of somatic and autonomic symptoms and deficits. We have assessed Intraepidermal Nerve Fiber Density (IENFD) using standard PGP9.5 staining and GAP-43 to assess Mean Axonal Length (MAL) and Intraepidermal Total Nerve Fiber Length (IETNFL).Results: IENFD (p < 0.0001), MAL (p < 0.0001), IETNFL/Area (p = 0.009), and IETNFL/Length (p = 0.04) were significantly reduced in patients with PD compared to controls. IENFD correlated significantly with disease duration (p = 0.03), cumulative levodopa dose (p = 0.02), Unified Parkinson's Disease Rating Scale, Part III (UPDRS-III) (p = 0.01), Schwab and England Activities of Daily Living (ADL) (p = 0.03), NSP (p = 0.03), and 30:15 ratio (p = 0.03). IETNFL/Area correlated with the Autonomic Scale for Outcomes in Parkinson's Disease (SCOPA-AUT) (p = 0.03) and Diabetic Neuropathy Symptom score (DNS) (p = 0.04) and IETNFL/Length correlated with DNS (p = 0.03). MAL correlated with SCOPA-AUT (p = 0.01), DNS (p = 0.02), and DB-HRV (p = 0.02).Conclusion: Increased IENF degeneration and impaired regeneration correlates with somatic and autonomic symptoms and deficits in patients with PD.

BACKGROUND The term “predisposition” is used as an indication of antimicrobial prophylaxis to prevent infective endocarditis and as a criterion for diagnosing infective endocarditis according to the modified Duke criteria. The criterion for diagnosing infective endocarditis in native valves is not well defined. OBJECTIVES To identify conditions that increase the risk for infective endocarditis in native valves, for the diagnosis of infective endocarditis according to the modified Duke criteria. In parallel, we compared the results with the year of patient inclusion for each study and echocardiographic techniques. RESULTS Our systematic review included 207 studies published from January 1970 to August 2015. Studies that focused on mitral valve prolapse (112 studies), prior infective endocarditis (96) and bicuspid aortic valve (78) provided the most data. However, only six (5.3%), three (3.1%) and one (1.3%) of these studies, respectively, used analytical statistical methods. Three (2.7%), two (2.1%) and one (1.3%), respectively, were graded as good quality studies. Odds ratios (ORs) for developing infective endocarditis were 3.5–8.2 for mitral valve prolapse, and 2.2 and 2.8 for prior infective endocarditis. The hazard ratio for developing infective endocarditis was 6.3 for bicuspid aortic valve. The mean prevalence proportion of infective endocarditis in patients with these three heart conditions were 8.5% (mitral valve prolapse), 8.3% (prior infective endocarditis) and 8.8% (bicuspid aortic valve). The proportions of publications prior to the publication of the modified Duke criteria were 81.8, 75.6 and 74%, respectively. Evolution of the imaging method and echocardiographic technique was estimated to be considerable for mitral valve prolapse. The literature review on aortic valve stenosis (46 studies), mitral valve insufficiency (41) and aortic valve insufficiency (39) provided two analytical studies for aortic stenosis. One study was graded as good quality and reported a hazard ratio 4.9. The mean prevalence of these heart conditions in patients with infective endocarditis were 7.3, 19.9 and 10.2%, respectively. The proportions of publications prior to the publication of the modified Duke criteria were 78, 75.6 and 79.5%, respectively. The evolution of both the echocardiographic technique and the categorisation of valve disease severity was considerable for all three entities. CONCLUSIONS The evidence for native valve heart conditions predisposing to infective endocarditis is mainly based on studies with only descriptive statistics published prior to the release of the modified Duke criteria. Mitral valve prolapse, prior infective endocarditis and bicuspid aortic valve are frequently cited as predisposing heart conditions for infective endocarditis. The evolution in echocardiographic techniques over the past decades and its influence on diagnosis was considerable for mitral valve prolapse, aortic stenosis, mitral insufficiency and aortic insufficiency.

Carboxymethyl cellulose (CMC) is used in winemaking to prevent potassium bitartrate or potassium hydrogen tartrate deposits from forming. These deposits are particularly detrimental when occurring in bottle-fermented sparkling wine ahead of disgorging or in the finished product as they can cause gushing of the wine when bottles are opened. Despite CMC being used by several sparkling winemaking producers both on the base wine and after disgorging, its effect on the behavior of foam, a key indicator of sparkling wine quality, has not been systematically tested. In this work the effect on wine composition and foam attributes of CMC additions to an English sparkling wine at the dosage stage was assessed. Results showed that CMC did not cause major changes on wine parameters, with the exception of wine viscosity, and did not result in major modification of the foamability of a wine, especially when analyzed in real serving conditions. These results suggest that, at least for the wine analyzed in this work, CMC could be added at the dosage stage without compromising its foam quality attributes.