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Objectives The purpose of this study was to evaluate prevalence, progression, treatment, and outcome of silent coronary artery disease (CAD) in asymptomatic patients with diabetes (DM) at high coronary risk. Background Despite the close association of diabetes and CAD, general CAD screening in asymptomatic patients with DM is discouraged even though outcome data in patients at high coronary risk are lacking. Methods Prospective multicenter outcome study—with a pilot randomized treatment substudy. The study comprised 400 asymptomatic patients with DM (type 2) without history or symptoms of CAD at high CAD risk. They underwent clinical evaluation and myocardial perfusion single-photon emission computed tomography (MPS) at baseline and after 2 years. Patients with normal MPS received usual care; those with abnormal MPS received medical or combined invasive and medical management. Results An abnormal MPS was found in 87 of 400 patients (22%). In patients with normal MPS, MACE occurred in 2.9% and ischemia or new scar in 3.2%. Patients with abnormal MPS had more MACE (9.8%; hazard ratio: 3.44; 95% confidence interval [CI]: 1.32 to 8.95; p = 0.011) and ischemia or new scar (34.2%; odds ratio: 15.91; 95% CI: 7.24 to 38.03; p < 0.001) despite therapy, resulting in “overt or silent CAD progression” of 35.6% versus 4.6% (odds ratio: 11.53; 95% CI: 5.63 to 24.70; p < 0.001). Patients with abnormal MPS randomized to medical versus invasive-medical strategies had similar event rates (p = 0.215), but more ischemic or new scar findings (54.3% vs. 15.8%; p < 0.001). Conclusions High-risk asymptomatic patients with DM and normal MPS (78%) have a low rate of first manifestations of CAD. Patients with abnormal MPS at baseline (22%) have a 7-fold higher rate of progression to “overt or silent CAD,” despite therapy. Randomized patients’ outcomes suggest that a combined invasive and medical strategy for silent CAD may reduce scintigraphic but not symptomatic CAD progression versus medical therapy alone. (Trial of Invasive versus Medical therapy of Early coronary artery disease in Diabetes Mellitus ISRCTN87953632 ). [ABSTRACT FROM AUTHOR]

Abstract: Background: In multiple sclerosis (MS), periaqueductal lesions (PAL) have been described histopathologically. Objectives: We sought to investigate the frequency and characteristics of PAL on magnetic resonance images (MRIs) in patients with MS or clinically isolated syndrome (CIS). Methods: We analyzed proton density (PD)-weighted MRIs of 247 MS and 10 CIS patients. PAL were identified based on their abnormal hyperintensity and lesion shape on at least two consecutive slices. Patients with and without PAL were compared for clinical characteristics in a propensity score weighted analysis. Results: We identified PAL in 48/257 patients (18.7%), 34 of which had CIS or relapsing-remitting MS and 14 a progressive disease course. The shape of PAL was often circular (65%), or/and wedge-like (42%). Multi-planar image analysis in a subgroup of patients with double inversion recovery sequences revealed that 36% of PAL were periventricular lesions of the third ventricle extending towards the aqueduct. We found an association of PAL and brainstem functional system. Conclusions: Although PAL may be underreported in MS, they are relatively frequent and found at all clinical stages and in CIS. They could be considered as a variant of periventricular lesions in the supratentorial midbrain and thus be useful in the diagnosis of MS. [Copyright &y& Elsevier]

Non-ventilator-associated hospital-acquired pneumonia (nvHAP) is a frequent, but under-researched infection. We aimed to simultaneously test an nvHAP prevention intervention and a multifaceted implementation strategy. In this single-centre, type 2 hybrid effectiveness–implementation study, all patients of nine surgical and medical departments at the University Hospital Zurich, Switzerland, were included and surveyed over three study periods: baseline (14–33 months, depending on department), implementation (2 months), and intervention (3–22 months, depending on department). The five-measure nvHAP prevention bundle consisted of oral care, dysphagia screening and management, mobilisation, discontinuation of non-indicated proton-pump inhibitors, and respiratory therapy. The implementation strategy comprised department-level implementation teams who conducted and locally adapted the core strategies of education, training, and changing infrastructure. Intervention effectiveness on the primary outcome measure of nvHAP incidence rate was quantified using a generalised estimating equation method in a Poisson regression model, with hospital departments as clusters. Implementation success scores and determinants were derived longitudinally through semistructured interviews with health-care workers. This trial is registered with ClinicalTrials.gov (NCT03361085). Between Jan 1, 2017, and Feb 29, 2020, 451 nvHAP cases occurred during 361 947 patient-days. nvHAP incidence rate was 1·42 (95% CI 1·27–1·58) per 1000 patient-days in the baseline period and 0·90 (95% CI 0·73–1·10) cases per 1000 patient-days in the intervention period. The intervention-to-baseline nvHAP incidence rate ratio, adjusted for department and seasonality, was 0·69 (95% CI 0·52–0·91; p=0·0084). Implementation success scores correlated with lower nvHAP rate ratios (Pearson correlation –0·71, p=0·034). Determinants of implementation success were positive core business alignment, high perceived nvHAP risk, architectural characteristics promoting physical proximity of health-care staff, and favourable key individual traits. The prevention bundle led to a reduction of nvHAP. Knowledge of the determinants of implementation success might help in upscaling nvHAP prevention. Swiss Federal Office of Public Health. [ABSTRACT FROM AUTHOR]

During the first 3 months of the coronavirus disease 2019 (COVID-19) pandemic, our hospital's quality management team determined a decline in the rate of cesarean deliveries (CD). Thus, in this study we examined both the factors associated with this decrease as well as neonatal outcomes. This was a retrospective observational cohort study comparing deliveries (n=597) between March and May 2020 (first nationwide "lockdown" in Switzerland) with those during the same period in 2018 and 2019 (n=1,063). A multivariable logistic regression analysis was used to examine the association between CD and the pandemic, adjusting for relevant risk factors for CD. The overall rate of CD during the pandemic period was lower (30.0%), than during the pre-pandemic period (38.7%, unadjusted odds ratio 0.68, 95% confidence interval [95%CI]: 0.55 to 0.84, p=0.0004) a result that was supported by the adjusted odds ratio (0.73, 95%CI: 0.54 to 0.99, p=0.04). The results of this study confirmed a significant reduction in the rate of CD in early 2020, during the first lockdown period due to COVID-19, but without major differences in maternal and infant health indicators or in obstetric risk factors than before the pandemic. These results may have been due to a difference in the composition of the obstetric team as well as the behavior of the obstetrics team and in the patients during the pandemic, given the burden it placed on healthcare systems. However, this hypothesis remains to be tested in further research. [ABSTRACT FROM AUTHOR]

Recent biodiversity-ecosystem functioning experiments in temperate grasslands have shown that productivity positively correlates with plant species richness. Resource partitioning (in particular, nitrogen [N] partitioning) has been proposed as one possible mechanism to explain this pattern. There is evidence for interspecific differences in chemical form, soil depth, and timing of N uptake. However, it has rarely been tested whether such differences result in increased N exploitation at the plant community level. Using l5N-labeled litter that was mixed into different soil layers, we tested whether eight common grasses and forbs grown in communities of one, two, or four species differ with respect to the proportions of N taken up from different soil depths (N niche), and how this affects the total N uptake of plant communities. We calculated proportional similarity between species (niche overlap) with regard to N uptake from the labeled soil layers; we further calculated an a priori measure of community N uptake based on species N uptake in monoculture (community niche). Interestingly, however, plant community N uptake was not affected by species richness, possibly because community-level N uptake was determined by (diversity-independent) soil N mineralization rates. We nevertheless observed a positive effect of species richness on productivity due to increased aboveground biomass :N ratios. This may indicate increased competition for light, resulting in increased amounts of comparably N-poor stem tissue. However, community N content and biomass were positively correlated with the community niche, a measure which is strongly linked to species composition. Thus, our results suggest that the studied species are generalists rather than specialists regarding N uptake depth, and that species composition was more important than species richness in determining community N uptake. Overall, N partitioning may be a less important driver of positive biodiversity-productivity effects in temperate grasslands than previously assumed. [ABSTRACT FROM AUTHOR]

Alpine snowbeds are habitats where the major limiting factors for plant growth are herbivory and a small time window for growth due to late snowmelt. Despite these limitations, snowbed vegetation usually forms a dense carpet of palatable plants due to favourable abiotic conditions for plant growth within the short growing season. These environmental characteristics make snowbeds particularly interesting to study the interplay of facilitation and competition. We hypothesised an interplay between resource competition and facilitation against herbivory. Further, we investigated whether these predicted neighbour effects were species-specific and/or dependent on ontogeny, and whether the balance of positive and negative plant-plant interactions shifted along a snowmelt gradient. We determined the neighbour effects by means of neighbour removal experiments along the snowmelt gradient, and linear mixed model analyses. The results showed that the effects of neighbour removal were weak but generally consistent among species and snowmelt dates, and depended on whether biomass production or survival was considered. Higher total biomass and increased fruiting in removal plots indicated that plants competed for nutrients, water, and light, thereby supporting the hypothesis of prevailing competition for resources in snowbeds. However, the presence of neighbours reduced herbivory and thereby also facilitated survival. For plant growth the facilitative effects against herbivores in snowbeds counterbalanced competition for resources, leading to a weak negative net effect. Overall the neighbour effects were not species-specific and did not change with snowmelt date. Our finding of counterbalancing effects of competition and facilitation within a plant community is of special theoretical value for species distribution models and can explain the success of models that give primary importance to abiotic factors and tend to overlook interrelations between biotic and abiotic effects on plants. [ABSTRACT FROM AUTHOR]

1. Factorial analysis of variance (anova) with unbalanced (non-orthogonal) data is a commonplace but controversial and poorly understood topic in applied statistics. 2. We explain thatanova calculates the sum of squares for each term in the model formula sequentially (type I sums of squares) and show howanova tables of adjusted sums of squares are composite tables assembled from multiple sequential analyses. A differentanova is performed for each explanatory variable or interaction so that each term is placed last in the model formula in turn and adjusted for the others. 3. The sum of squares for each term in the analysis can be calculated after adjusting only for the main effects of other explanatory variables (type II sums of squares) or, controversially, for both main effects and interactions (type III sums of squares). 4. We summarize the main recent developments and emphasize the shift away from the search for the ‘right’anova table in favour of presenting one or more models that best suit the objectives of the analysis. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. [ABSTRACT FROM AUTHOR]

Background The tradeoff between stent thrombosis (ST) and major bleeding (MB) of 12- versus 6-month dual antiplatelet therapy (DAPT) after coronary stent implantation has not been clearly defined. Methods Definite/probable ST and MB (TIMI major and Bleeding Academic Research Consortium (BARC) ≥3) were compared in 2 subsequent trials with similar inclusion criteria but different DAPT duration, that is, BASKET (6 months; n = 557) and BASKET-PROVE (12 months; n = 2,314), between months 0 to 6 (DAPT in both trials), 7 to 12 (DAPT in BASKET-PROVE only), and 13 to 24 (aspirin in both trials) using propensity score-adjusted, time-stratified Cox proportional hazard models. Results Overall, event rates were low with fewer ST but similar MB in prolonged DAPT. Analysis of the 3 periods showed a uniform pattern for ST (interaction DAPT/period; P = .145) but an inconsistent pattern for MB (interaction DAPT/period; P < .001 for TIMI major and P = .046 for BARC ≥3), with more MB occurring during months 7 to 12 with prolonged DAPT. Considering observed case fatality rates of 31% with ST and 11% with MB, the extrapolated prevention of 27 ST deaths and the excess of 5 MB deaths resulted in an expected benefit of 22 survivors/10,000 patients treated over 2 years with prolonged DAPT. Conclusion Despite overall low event rates, prolonged DAPT was associated with more MB during months 7 to 12 according to the interaction DAPT/period. Given the higher observed case fatality rates of ST versus MB, 12- versus 6-month DAPT was associated with an extrapolated reduction in mortality. Effective treatment periods and case fatality rates seem important in the analysis of different DAPT durations, specifically with regard to ongoing trials. [ABSTRACT FROM AUTHOR]

Machine perfusion is a novel method intended to optimize livers before transplantation. However, its effect on morbidity within a 1-year period after transplantation has remained unclear. In this multicenter controlled trial, we randomly assigned livers donated after brain death (DBD) for liver transplantation (LT). Livers were either conventionally cold stored (control group), or cold stored and subsequently treated by 1-2 h hypothermic oxygenated perfusion (HOPE) before implantation (HOPE group). The primary endpoint was the occurrence of at least one post-transplant complication per patient, graded by the Clavien score of ≥III, within 1-year after LT. The comprehensive complication index (CCI), laboratory parameters, as well as duration of hospital and intensive care unit stay, graft survival, patient survival, and biliary complications served as secondary endpoints. Between April 2015 and August 2019, we randomized 177 livers, resulting in 170 liver transplantations (85 in the HOPE group and 85 in the control group). The number of patients with at least one Clavien ≥III complication was 46/85 (54.1%) in the control group and 44/85 (51.8%) in the HOPE group (odds ratio 0.91; 95% CI 0.50-1.66; p = 0.76). Secondary endpoints were also not significantly different between groups. A post hoc analysis revealed that liver-related Clavien ≥IIIb complications occurred less frequently in the HOPE group compared to the control group (risk ratio 0.26; 95% CI 0.07-0.77; p = 0.027). Likewise, graft failure due to liver-related complications did not occur in the HOPE group, but occurred in 7% (6 of 85) of the control group (log-rank test, p = 0.004, Gray test, p = 0.015). HOPE after cold storage of DBD livers resulted in similar proportions of patients with at least one Clavien ≥III complication compared to controls. Exploratory findings suggest that HOPE decreases the risk of severe liver graft-related events. This randomized controlled phase III trial is the first to investigate the impact of hypothermic oxygenated perfusion (HOPE) on cumulative complications within a 12-month period after liver transplantation. Compared to conventional cold storage, HOPE did not have a significant effect on the number of patients with at least one Clavien ≥III complication. However, we believe that HOPE may have a beneficial effect on the quantity of complications per patient, based on its application leading to fewer severe liver graft-related complications, and to a lower risk of liver-related graft loss. The HOPE approach can be applied easily after organ transport during recipient hepatectomy. This appears fundamental for wide acceptance since concurring perfusion technologies need either perfusion at donor sites or continuous perfusion during organ transport, which are much costlier and more laborious. We conclude therefore that the post hoc findings of this trial should be further validated in future studies. [Display omitted] • The number of patients with at least one Clavien ≥III complication was not significantly different between groups. • Severe post-transplant complications (Clavien grade IIIb or more), occurred less frequently in the HOPE-group. • This was caused by a 3.7-fold lower number of liver-related Clavien ≥IIIb complications per patient in the HOPE-group. • Graft failure due to liver-related complications did not occur in the HOPE-group but occurred in 7% in the control-group. [ABSTRACT FROM AUTHOR]

Background: The number of children and adolescents living with life-limiting conditions and potentially in need for specialised paediatric palliative care (SPPC) is rising. Ideally, a specialised multiprofessional team responds to the complex healthcare needs of children and their families. The questions of, how SPPC is beneficial, for whom, and under what circumstances, remain largely unanswered in the current literature. This study's overall target is to evaluate the effectiveness of a SPPC programme in Switzerland with respect to its potential to improve patient-, family-, health professional-, and healthcare-related outcomes. Methods: This comparative effectiveness study applies a quasi-experimental design exploring the effectiveness of SPPC as a complex intervention at one treatment site in comparison with routine care provided in a generalised PPC environment at three comparison sites. As the key goal of palliative care, quality of life - assessed at the level of the patient-, the family- and the healthcare professional - will be the main outcome of this comparative effectiveness research. Other clinical, service, and economic outcomes will include patient symptom severity and distress, parental grief processes, healthcare resource utilisation and costs, direct and indirect health-related expenditure, place of death, and introduction of SPPC. Data will be mainly collected through questionnaire surveys and chart analysis. Discussion: The need for SPPC has been demonstrated through numerous epidemiological and observational studies. However, in a healthcare environment focused on curative treatment and struggling with limited resources, the lack of evidence contributes to a lack of acceptance and financing of SPPC which is a major barrier against its sustainability. This study will contribute to current knowledge by reporting individual and child level outcomes at the family level and by collecting detailed contextual information on healthcare provision. We hope that the results of this study can help guiding the expansion and sustainability of SPPC and improve the quality of care for children with life-limiting conditions and their families internationally. Trial registration: Registered prospectively on ClinicalTrials.gov on January 22, 2020. NCT04236180 Protocol version: Amendment 2, March 01, 2021. [ABSTRACT FROM AUTHOR]

Background: Family members of critically ill patients face considerable uncertainty and distress during their close others' intensive care unit (ICU) stay. About 20–60% of family members experience adverse mental health outcomes post-ICU, such as symptoms of anxiety, depression, and posttraumatic stress. Guidelines recommend structured family inclusion, communication, and support, but the existing evidence base around protocolized family support interventions is modest and requires substantiation. Methods: To test the clinical effectiveness and explore the implementation of a multicomponent, nurse-led family support intervention in ICUs, we will undertake a parallel, cluster-randomized, controlled, multicenter superiority hybrid-type 1 trial. It will include eight clusters (ICUs) per study arm, with a projected total sample size of 896 family members of adult, critically ill patients treated in the German-speaking part of Switzerland. The trial targets family members of critically ill patients with an expected ICU stay of 48 h or longer. Families in the intervention arm will receive a family support intervention in addition to usual care. The intervention consists of specialist nurse support that is mapped to the patient pathway with follow-up care and includes psycho-educational and relationship-focused family interventions, and structured, interprofessional communication, and shared decision-making with families. Families in the control arm will receive usual care. The primary study endpoint is quality of family care, operationalized as family members' satisfaction with ICU care at discharge. Secondary endpoints include quality of communication and nurse support, family management of critical illness (functioning, resilience), and family members' mental health (well-being, psychological distress) measured at admission, discharge, and after 3, 6, and 12 months. Data of all participants, regardless of protocol adherence, will be analyzed using linear mixed-effects models, with the individual participant as the unit of inference. Discussion: This trial will examine the effectiveness of the family support intervention and generate knowledge of its implementability. Both types of evidence are necessary to determine whether the intervention works as intended in clinical practice and could be scaled up to other ICUs. The study findings will make a significant contribution to the current body of knowledge on effective ICU care that promotes family participation and well-being. Trial registration: ClinicalTrials.gov NCT05280691. Prospectively registered on 20 February 2022. [ABSTRACT FROM AUTHOR]

Background Although radiofrequency (RF) and cryoballoon (CB) based technologies for pulmonary vein isolation (PVI) have both individually been demonstrated to be effective and safe for the treatment of paroxysmal AF, head-to-head comparisons are lacking. The purpose of this study was to compare the outcome of cryoballoon versus radiofrequency ablation in patients with paroxysmal atrial fibrillation undergoing pulmonary vein isolation. Methods Out of a prospective registry of 327 patients undergoing PVI, 208 patients (age 58 ± 11 years, ejection fraction 59 ± 6%, left atrial size 39 ± 6 mm) with paroxysmal AF were identified. The presented dataset was obtained by 1:1 propensity score matching and contained 142 patients undergoing CB-PVI or RF-PVI in conjunction with a 3D mapping system, respectively. We compared single procedure efficacy of the two methods using a Cox proportional hazards model. Results After a mean follow-up of 28 months and a single procedure, AF recurred in 37 of 71 (52%) in the CB-PVI group and in 31 of 71 patients (44%) in the RF-PVI group (HR [95% CI] = 1.19 [0.74, 1.92], p = 0.48). Recurrence of AF for PVI using solely the CB was observed in 23 of 51 (45%) patients and in 23 of 51 (45%) patients in the corresponding RF-PVI group (HR [95% CI] = 0.93 [0.52, 1.66], p = 0.81). Complication rate was not different between the groups. Conclusion A propensity score matched comparison between CB-PVI and RF-PVI using a 3D-mapping system for AF ablation showed similar long-term success rates. [ABSTRACT FROM AUTHOR]

Simple Summary: Most patients with skull base tumors require radiation therapy as part of their overall treatment, preferably with protons. However, vital and healthy organs, such as the cochlea, are often located in the immediate anatomical vicinity of the tumor. Despite the high precision of the proton beam, irradiating the cochlea is often unavoidable, resulting in an increased risk of hearing loss. To assess the frequency and severity of changes in hearing after proton therapy, we performed a retrospective study in a cohort of 51 patients undergoing proton therapy for skull base tumors. We observed that a hearing threshold shift correlates to the applied radiation dose intensity to the cochlea. In addition, advancing age, hearing sensitivity before proton therapy, and the time elapsed after the end of proton therapy are independently associated with the deterioration of the hearing threshold after proton therapy. These results are essential to adequately inform patients about the treatment's impact and side effects. To assess the incidence and severity of changes in hearing threshold in patients undergoing high-dose pencil-beam-scanning proton therapy (PBS-PT). This retrospective cohort study included fifty-one patients (median 50 years (range, 13–68)) treated with PBS-PT for skull base tumors. No chemotherapy was delivered. Pure tone averages (PTAs)were determined before (baseline) and after PBS-PT as the average hearing thresholds at frequencies of 0.5, 1, 2, and 4 kHz. Hearing changes were calculated as PTA differences between pre-and post-PBS-PT. A linear mixed-effects model was used to assess the relationship between the PTA at the follow-up and the baseline, the cochlea radiation dose intensity, the increased age, and the years after PBS-PT. Included patients were treated for chordoma (n = 24), chondrosarcoma (n = 9), head and neck tumors (n = 9), or meningioma (n = 3), with a mean tumor dose of 71.1 Gy (RBE) (range, 52.0–77.8), and a mean dose of 37 Gy (RBE) (range, 0.0–72.7) was delivered to the cochleas. The median time to the first follow-up was 11 months (IQR, 5.5–33.7). The PTA increased from a median of 15 dB (IQR 10.0–25) at the baseline to 23.8 (IQR 11.3–46.3) at the first follow-up. In the linear mixed-effect model, the baseline PTA (estimate 0.80, 95%CI 0.64 to 0.96, p ≤ 0.001), patient's age (0.30, 0.03 to 0.57, p = 0.029), follow-up time (2.07, 0.92 to 3.23, p ≤ 0.001), and mean cochlear dose in Gy (RBE) (0.34, 0.21 to 0.46, p ≤ 0.001) were all significantly associated with an increase in PTA at follow-up. The applied cochlear dose and baseline PTA, age, and time after treatment were significantly associated with hearing loss after proton therapy. [ABSTRACT FROM AUTHOR]

Background: Measures of the sonorheometry based Quantra® viscoelastic hemostatic analyzer (HemoSonics, LCC, Charlottesville, VA, USA) were compared with corresponding results of the ROTEM® sigma device (Instrumentation Laboratory, Bedford, MA, USA). Methods: In thirty-eight patients scheduled for elective cardiac surgery between December 2018 and October 2019, blood samples were taken after induction of anesthesia (sample 1) and after heparin neutralization (sample 2) and measured on Quantra (QPlus® Cartridge) and ROTEM sigma (ROTEM® sigma complete + hep Cartridge). Clot times and clot stiffness values were recorded. Clot stiffness values of ROTEM amplitudes (A in mm) were converted to shear modulus (G) in hectoPascal (hPa): G (hPa) = (5 x A)/(100-A). Additionally, time-to-results was recorded. Spearman rank test correlation and Bland Altman analysis were performed. Results: Clot stiffness parameters of the Quantra correlated strongly with corresponding measurements of the ROTEM with r = 0.93 and 0.94 for EXTEM A10 vs CS and r = 0.94 and 0.96 for FIBTEM A10 vs FCS for sample 1 and 2, respectively. Quantra clot time correlated strongly with ROTEM INTEM CT with r = 0.71 for sample 1 and r = 0.75 for sample 2. However, Bland Altman analysis showed no agreement in all compared assays of both methods. The median time to delivery of first and complete results was significantly shorter for Quantra (412 and 658 s) compared to ROTEM sigma (839 and 1290 s). Conclusions: The Quantra showed a strong correlation with the ROTEM sigma for determining clot times and clot stiffness and the parameters assess similar aspects of clot development. However, these parameters are not directly interchangeable and implicate that separate cut-off values need to be established for users of the Quantra device. Word count: 278. Trial registration: The study was retrospectively registered with ClinicalTrials.gov (ID: NCT04210830) at December 20th 2019. [ABSTRACT FROM AUTHOR]

Background: Klebsiella spp. are opportunistic pathogens which can cause severe infections, are often multi-drug resistant and are a common cause of hospital-acquired infections. Multiple new Klebsiella species have recently been described, yet their clinical impact and antibiotic resistance profiles are largely unknown. We aimed to explore Klebsiella group- and species-specific clinical impact, antimicrobial resistance (AMR) and virulence. Methods: We analysed whole-genome sequence data of a diverse selection of Klebsiella spp. isolates and identified resistance and virulence factors. Using the genomes of 3594 Klebsiella isolates, we predicted the masses of 56 ribosomal subunit proteins and identified species-specific marker masses. We then re-analysed over 22,000 Matrix-Assisted Laser Desorption Ionization - Time Of Flight (MALDI-TOF) mass spectra routinely acquired at eight healthcare institutions in four countries looking for these species-specific markers. Analyses of clinical and microbiological endpoints from a subset of 957 patients with infections from Klebsiella species were performed using generalized linear mixed-effects models. Results: Our comparative genomic analysis shows group- and species-specific trends in accessory genome composition. With the identified species-specific marker masses, eight Klebsiella species can be distinguished using MALDI-TOF MS. We identified K. pneumoniae (71.2%; n = 12,523), K. quasipneumoniae (3.3%; n = 575), K. variicola (9.8%; n = 1717), "K. quasivariicola" (0.3%; n = 52), K. oxytoca (8.2%; n = 1445), K. michiganensis (4.8%; n = 836), K. grimontii (2.4%; n = 425) and K. huaxensis (0.1%; n = 12). Isolates belonging to the K. oxytoca group, which includes the species K. oxytoca, K. michiganensis and K. grimontii, were less often resistant to 4th-generation cephalosporins than isolates of the K. pneumoniae group, which includes the species K. pneumoniae, K. quasipneumoniae, K. variicola and "K. quasivariicola" (odds ratio = 0.17, p < 0.001, 95% confidence interval [0.09,0.28]). Within the K. pneumoniae group, isolates identified as K. pneumoniae were more often resistant to 4th-generation cephalosporins than K. variicola isolates (odds ratio = 2.61, p = 0.003, 95% confidence interval [1.38,5.06]). K. oxytoca group isolates were found to be more likely associated with invasive infection to primary sterile sites than K. pneumoniae group isolates (odds ratio = 2.39, p = 0.0044, 95% confidence interval [1.05,5.53]). Conclusions: Currently misdiagnosed Klebsiella spp. can be distinguished using a ribosomal marker-based approach for MALDI-TOF MS. Klebsiella groups and species differed in AMR profiles, and in their association with invasive infection, highlighting the importance for species identification to enable effective treatment options. [ABSTRACT FROM AUTHOR]

Aggressive behavior and violence in psychiatric patients have often been quoted to justify more restrictive settings in psychiatric facilities. However, the effects of open vs. locked door policies on aggressive incidents remain unclear. This study had a naturalistic observational design and analyzed the occurrence of aggressive behavior as well as the use of seclusion or restraint in 21 German hospitals. The analysis included data from 1998 to 2012 and contained a total of n = 314,330 cases, either treated in one of 17 hospitals with (n = 68,135) or in one of 4 hospitals without an open door policy (n = 246,195). We also analyzed the data according to participants' stay on open, partially open, or locked wards. To compare hospital and ward types, we used generalized linear mixed-effects models on a propensity score matched subset (n = 126,268) and on the total dataset. The effect of open vs. locked door policy was non-significant in all analyses of aggressive behavior during treatment. Restraint or seclusion during treatment was less likely in hospitals with an open door policy. On open wards, any aggressive behavior and restraint or seclusion were less likely, whereas bodily harm was more likely than on closed wards. Hospitals with open door policies did not differ from hospitals with locked wards regarding different forms of aggression. Other restrictive interventions used to control aggression were significantly reduced in open settings. Open wards seem to have a positive effect on reducing aggression. Future research should focus on mental health care policies targeted at empowering treatment approaches, respecting the patient's autonomy and promoting reductions of institutional coercion. [ABSTRACT FROM AUTHOR]

Purpose: Postpartum haemorrhage (PPH) represents a leading cause of maternal morbidity and mortality. Giving oxytocin after birth reduces the risk for PPH. It has never been tested whether different methods of oxytocin administration affect the maternal outcome. This study aims to compare the infusion versus the bolus application of oxytocin after singleton vaginal delivery.Methods: This retrospective monocentre study compares the incidence of clinically relevant postpartum complications in women receiving 5 IE of oxytocin as a bolus or as a 100 ml-infusion over 5 min, given immediately after birth. Included were women delivering singletons vaginally at term. We used propensity score weighting to compare outcomes between women receiving bolus and infusion and to minimize the selection bias in this retrospective cohort.Results: 1765 patients were included. Patient characteristics were balanced. We found no significant differences for the combined overall postpartum adverse outcome (the incidence of PPH, manual removal of the placenta and/or curettage). For the single outcomes, we observed a significantly higher frequency of manual removal of the placenta (Odds ratio 1.47, 95 % CI 1.02-2.13) and a slightly higher but clinically not relevant estimated blood loss (Relative effect 1.05, 95 % CI 1.01-1.10) in the infusion group.Conclusion: The data show a tendency towards more complications in the infusion group. It is related to a more frequent need for manual removal of the placenta. [ABSTRACT FROM AUTHOR]

Purpose: To explore the use of different, zonal-specific PSA density (PSAD) variants in combination with the Prostate Signal Intensity Homogeneity Score (PSHS) to improve the detection of clinically significant prostate cancer (csPCa) and thus potentially help in risk stratification and adequate patient selection for prostate biopsy., Methods: This retrospective, single-center study included patients with available PSA values who were suspected of having prostate cancer and underwent multiparametric MRI (mpMRI) in combination with a subsequent prostate biopsy. Histopathologic biopsy results served as reference standard. Whole-gland (PSAD-T), peripheral zone (PSAD-PZ), and transition zone (PSAD-TZ) PSA densities were computed based on MRI-derived volume assessment. The diagnostic performance of these PSAD variants in predicting csPCa was assessed using ROC analysis. Conditional inference trees were used to examine the value of combining PI-RADS, PSAD-TZ and PSHS., Results: Among the 297 patients included, 126 (42.4 %) were diagnosed with csPCa based on histopathologic biopsy results. PSAD-TZ demonstrated superior diagnostic performance (AUC 0.78) for csPCa prediction compared to PSAD-T (AUC 0.75) and PSAD-PZ (AUC 0.63). Conditional inference tree analysis revealed that patients with negative or indeterminate mpMRI (PI-RADS ≤ 3) and an elevated PSAD-TZ in combination with low PSHS scores (≤3), which indicate increased background signal intensity changes of the peripheral zone, were at an elevated risk for a missed csPCa., Conclusions: Integrating PI-RADS, PSAD-TZ, and PSHS may enhance risk stratification for csPCa at biopsy, enabling more precise identification of patients at an elevated risk who may require further evaluation. This approach may consequently reduce false-negative MRI results and facilitate more precise decision-making regarding biopsy indications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Lyme disease (LD) is caused by Borrelia burgdorferi and is the most common tickborne disease in the northern hemisphere. Although classical characteristics of LD are well-known, the diagnosis and treatment are often delayed. Laboratory diagnosis by serological testing is recommended for most LD manifestations. The objective of this study was to describe clinical characteristics and associated serological profiles in children with LD., Methods: This retrospective cohort study included children aged 0-18 years, diagnosed with LD according to current guidelines at University Children's Hospital Zurich between January 1, 2006 and December 31, 2020. Two-tier serological testing with the recom Well enzyme-linked immunosorbent assay and recom Line Western blot (MIKROGEN Diagnostik, MIKROGEN GmbH, Neuried, Germany) was performed at the Institute of Medical Microbiology, University of Zurich., Findings: In total, 469 children diagnosed with LD were included (median age, 7.9 years); 190 patients (40.5%) with Lyme neuroborreliosis (LNB), 171 (36.5%) patients with skin manifestations (erythema migrans, n  = 121; multiple erythema migrans, n  = 11; borrelial lymphocytoma, n  = 37; and acrodermatitis chronica atrophicans, n  = 2), and 108 (23.0%) patients with Lyme arthritis. We observed seasonal variations for patients with skin manifestations and LNB, with high prevalence in May-October, but not for patients with Lyme arthritis. Significant differences between LD manifestation groups were found for age, inflammatory parameters, and specificity and concentration of B. burgdorferi -specific serum antibody responses. We observed distinct patterns of pronounced serum antibody responses against B. burgdorferi antigens in LNB (IgM against VlsE, p41, and OspC) and Lyme arthritis (IgG against p100, VlsE, p58, p41, p39, and p18)., Interpretation: Our study is one of the largest and most detailed for children with LD. We present unique findings regarding the differences in clinical characteristics and immune responses between various manifestations of LD in children., Funding: No specific funding to disclose for this study., Competing Interests: In the past 36 months, P.M.M.S. has served on advisory boards (Roche, Sanofi, AstraZeneca) and given presentations (Fomf, FPH Forum, ZAIM MediDays, Insight Paediatrics) with payments to the institution (University Children's Hospital Zurich). A.E. has received consultancy fees from Sefunda and Phast (advisory role to start-up companies), honoraria for presentations at various conferences at industry sponsored symposia (lllumina, Copan, Bruker), and support from the Laboratory Medicine Society of Korea for attendance at and travel to the annual meeting of the Laboratory Medicine Society of Korea in the past 36 months. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© 2024 The Author(s).)

Aims: To describe the point prevalence, risk factors and possible outcomes of delirium in inpatients., Design: A cross-sectional point prevalence study., Background: Delirium is an acute brain syndrome that negatively affects patients, healthcare professionals and institutions alike; it is common in inpatient settings and is preventable in about one third of cases. Although guidelines recommend systematic screening and assessment, delirium is often unrecognised, undiagnosed and uncoded. There is a lack of valid data on this patient safety indicator in German-speaking countries., Methods: The study was conducted in a tertiary care hospital in Switzerland on 5 July 2022. Specially trained registered nurses collected data from all patients meeting the inclusion criteria using CAM, ICDSC or mCAM-ED. Data were analysed descriptively with stratification by delirium status, setting and surgery., Results: The point prevalence across all settings was 6.9% (27/390), with large variation between settings: ICU 28.6% (4/14), IMC 28.0% (7/25), wards 4.6% (15/326) and ED 4% (1/25). Surgical patients were almost twice as likely to be affected as medical patients (8.9% vs. 4.8%). Patients with delirium differed most clearly from those without by having a larger number of ICD-10 F-diagnoses, a larger number of medications and higher age, which are known risk factors. Moreover, those with delirium had more missed diagnoses, increased mortality, more adverse events and higher costs., Conclusions: A significant number of patients experienced delirium and adverse clinical outcomes. Missed delirium diagnoses may further jeopardise patient safety and result in lost revenue. It remains unclear to what extent the risk factors and effects of delirium are causal and what determinants underlie missed diagnoses., Relevance to Clinical Practice: Consistent identification of high-risk patients and treatment settings with elevated risk, accompanied by the implementation of effective preventive and management strategies, is critical to addressing delirium., (© 2024 The Authors. Journal of Clinical Nursing published by John Wiley & Sons Ltd.)

Background: Mycoplasma pneumoniae is a major cause of community-acquired pneumonia (CAP) in school-aged children. Macrolides are the first-line treatment for this infection. However, it is unclear whether macrolides are effective in treating M. pneumoniae CAP, mainly due to limitations in microbiological diagnosis of previous studies. The extensive global use of macrolides has led to increasing antimicrobial resistance. The overall objective of this trial is to produce efficacy data for macrolide treatment in children with M. pneumoniae CAP., Methods: The MYTHIC Study is a randomized, double-blind, placebo-controlled, multicenter, non-inferiority trial in 13 Swiss pediatric centers. Previously healthy ambulatory and hospitalized children aged 3-17 years with clinically diagnosed CAP will be screened with a sensitive and commercially available M. pneumoniae-specific IgM lateral flow assay from capillary blood. Mycoplasma pneumoniae infection in screened patients will be verified retrospectively by respiratory PCR (reference test) and IgM antibody-secreting cell enzyme-linked immunospot (ELISpot) assay (confirmatory test for distinguishing between carriage and infection). Patients will be randomized 1:1 to receive a 5-day treatment of macrolides (azithromycin) or placebo. The co-primary endpoints are (1) time to normalization of all vital signs, including body temperature, respiratory rate, heart rate, and saturation of peripheral oxygen (efficacy), and (2) CAP-related change in patient care status (i.e., admission, re-admission, or intensive care unit transfer) within 28 days (safety). Secondary outcomes include adverse events (AEs), as well as antimicrobial and anti-inflammatory effects. For both co-primary endpoints, we aim to show non-inferiority of placebo compared to macrolide treatment. We expect no macrolide effect (hazard ratio of 1, absolute risk difference of 0) and set the corresponding non-inferiority margins to 0.7 and -7.5%. The "at least one" success criterion is used to handle multiplicity with the two co-primary endpoints. With a power of 80% to reject at least one null hypothesis at a one-sided significance level of 1.25%, 376 patients will be required., Discussion: This trial will produce efficacy data for macrolide treatment in children with M. pneumoniae CAP that might help to reduce the prescription of antibiotics and therefore contribute to the global efforts toward reducing antimicrobial resistance., Trial Registration: ClinicalTrials.gov, NCT06325293. Registered on 24 April 2024., (© 2024. The Author(s).)

The FICUS trial is a cluster-randomized superiority trial to determine the effectiveness of a nurse-led, interprofessional family support intervention (FSI) on the quality of care, family management and individual mental health of family members of critically ill patients, compared to usual care. This paper describes the statistical analysis plan of the FICUS trial. The primary outcome is quality of family care, assessed by the Family Satisfaction in ICU Questionnaire (FS-ICU-24R) at patient discharge from the ICU. Several secondary outcomes are additionally assessed 3, 6, and 12 months thereafter. Sixteen clusters (ICUs) were randomly assigned 1:1 to FSI or usual care using minimization (8 per treatment). The target sample size is 56 patients per cluster (896 in total). Recruitment has been completed in January 2024. The follow-up of the last participant will be completed in early 2025. The primary and secondary outcomes will be analyzed by linear mixed-effects models (LMM). The main model for the primary outcome will include a random intercept per cluster with treatment (FSI vs. usual care) as the only explanatory variable due to the relatively small number of clusters. In addition, covariate-adjusted analyses will be conducted, including two cluster-level characteristics used in the minimization as well as participant-level characteristics. Moreover, a number of subgroup analyses by cluster- and participant-level characteristics are pre-specified.Trial registration ClinicalTrials.gov NCT05280691 . Registered on February 20, 2022., (© 2024. The Author(s).)

Introduction and Objectives: Our aim was to assess the impact of prosthetic pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot (rTOF) on changes in biventricular volumes and function and on adverse cardiac events., Methods: Adults with rTOF were identified from the SACHER-registry. Data from serial cardiac magnetic resonance imaging, echocardiography, exercise capacity and n-terminal pro b-type natriuretic peptide (NT-proBNP) were collected. The primary endpoint was right ventricular ejection fraction (RVEF) as measured by cardiac magnetic resonance. Secondary endpoints were biventricular volumes, left ventricular ejection fraction, exercise capacity and NT-proBNP levels, and time to adverse cardiac outcomes (atrial and ventricular arrhythmia, endocarditis). Associations between previous PVR and longitudinal changes in functional outcomes and time to adverse cardiac outcomes were analyzed using linear mixed-effects models and Cox proportional hazards models, respectively., Results: A total of 308 patients (153 with and 155 without PVR) with 887 study visits were analyzed. Previous PVR was not significantly associated with changes in RVEF (CE, -1.33; 95%CI, -5.87 to 3.21; P=.566). Previous PVR was associated with lower right ventricular end-diastolic volume but had no significant effect on left ventricular ejection fraction, exercise capacity, or NT-proBNP-levels. Previous PVR was associated with an increased hazard of atrial arrhythmias (HR, 2.09; 95%CI, 1.17-3.72; P=.012) and infective endocarditis (HR, 12.72; 95%CI, 4.69-34.49; P<.0001) but not with an increased hazard of sustained ventricular arrhythmias (HR, 0.64; 95%CI, 0.18-2.27; P=.490)., Conclusions: Previous PVR was not significantly associated with changes in RVEF but was associated with an increased risk of atrial arrhythmias and infective endocarditis., (Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)