Rate of cardiovascular events up to 8 years after uncomplicated myocarditis: a nationwide cohort study.

AIMS: While prognosis of acute myocarditis with uncomplicated presentation is perceived as benign, data on long-term outcomes are scarce. We evaluated rates of myocarditis-associated cardiovascular events after a first-time hospitalization with uncomplicated acute myocarditis in patients without known heart disease. METHODS AND RESULTS: In this retrospective nationwide population-based cohort study from 2013 to 2020, hospitalized patients with uncomplicated acute myocarditis but without known heart disease were 1:1 propensity score-matched with surgical controls hospitalized for laparoscopic appendectomy. As assessed in time-to-event analyses, the primary outcome was a composite of rehospitalization for myocarditis, pericardial disease, heart failure and its complications, arrhythmias, implantation of cardiac devices, and heart transplant. After matching, we identified 1439 patients with uncomplicated acute myocarditis (median age of 35 years, 74.0% male) and 1439 surgical controls (median age of 36 years, 74.4% male). Over a median follow-up of 39 months, compared with surgical controls, the hazard ratio for the primary composite outcome was 42.3 [95% confidence interval (CI) 17.4-102.8], corresponding to an incidence rate of 43.7 vs. 0.9 per 1000 patient-years (py) and an incidence rate difference of 42.7 (95% CI 36.7-48.8) per 1000 py. CONCLUSION: Patients hospitalized with uncomplicated acute myocarditis and no known prior heart disease were associated with substantial risk for cardiovascular events over a follow-up of up to 8 years. This calls for a more efficient therapeutic management of this population of patients.

Trends and outcomes of children, adolescents, and adults hospitalized with inherited metabolic disorders: A population-based cohort study.

Inherited metabolic disorders (IMDs) comprise a heterogeneous class of genetic disorders characterized by impaired biochemical functions in metabolism. However, incidences and outcomes of patients hospitalized with IMDs are largely unknown. We conducted a population-based cohort study using nationwide in-hospital claims data in Switzerland from 2012 to 2020. We assessed incidence rates of hospitalizations and hospital-associated outcomes, stratified in five age groups (0-9, 10-19, 20-39, 40-59, and 60-90 years) and three types of IMDs (peptide, amine and amino acid metabolism disorders [AD], carbohydrate metabolism disorders [CD], fatty acid, and ketone body metabolism disorders [FD]). A total of 7293 hospitalizations with IMD were identified, of which 3638 had AD, 3153 CD, and 502 FD. Incidence rates for hospitalizations per 100 000 person-years were highest under the age of 10 years across all types of IMDs (8.69 for AD, 5.73 for CD, 3.71 for FD) and decreased thereafter. In patients with AD and CD, hospitalization rates increased again in adults aged 60-90 years (7.28 for AD, 7.25 for CD), while they remained low in patients with FD (0.31). Compared to inpatients without IMD, adult IMD patients had a higher burden of hospital-associated adverse outcomes including an increased risk of in-hospital mortality, intensive care unit admission, mechanical ventilation, and longer length of hospital or intensive care unit stay. Incremental risk of 30-day, 1-year, and 2-year hospital readmission was highest among children and adolescents with IMD.

Association of Different Malnutrition Parameters and Clinical Outcomes among COVID-19 Patients: An Observational Study.

Background: Malnutrition is highly prevalent in medical inpatients and may also negatively influence clinical outcomes of patients hospitalized with COVID-19. We analyzed the prognostic implication of different malnutrition parameters with respect to adverse clinical outcomes in patients hospitalized with COVID-19. Methods: In this observational study, consecutively hospitalized adult patients with confirmed COVID-19 at the Cantonal Hospital Aarau (Switzerland) were included between February and December 2020. The association between Nutritional Risk Screening 2002 (NRS 2002) on admission, body mass index, and admission albumin levels with in-hospital mortality and secondary endpoints was studied by using multivariable regression analyses. Results: Our analysis included 305 patients (median age of 66 years, 66.6% male) with a median NRS 2002-score of 2.0 (IQR 1.0, 3.0) points. Overall, 44 patients (14.4%) died during hospitalization. A step-wise increase in mortality risk with a higher nutritional risk was observed. When compared to patients with no risk for malnutrition (NRS 2002 < 3 points), patients with a moderate (NRS 2002 3−4 points) or high risk for malnutrition (NRS 2002 ≥ 5 points) had a two-fold and five-fold increase in risk, respectively (10.5% vs. 22.7% vs. 50.0%, p < 0.001). The increased risk for mortality was also confirmed in a regression analysis adjusted for gender, age, and comorbidities (odds ratio for high risk for malnutrition 4.68, 95% CI 1.18 to 18.64, p = 0.029 compared to patients with no risk for malnutrition). Conclusions: In patients with COVID-19, the risk for malnutrition was a risk factor for in-hospital mortality. Future studies should investigate the role of nutritional treatment in this patient population.

Combination of the National Early Warning Score (NEWS) and inflammatory biomarkers for early risk stratification in emergency department patients: results of a multinational, observational study.

OBJECTIVES: The National Early Warning Score (NEWS) helps to estimate mortality risk in emergency department (ED) patients. This study aimed to investigate whether the prognostic value of the NEWS at ED admission could be further improved by adding inflammatory blood markers (ie, white cell count (WCC), procalcitonin (PCT) and midregional-proadrenomedullin (MR-proADM). DESIGN: Secondary analysis of a multinational, observational study (TRIAGE study, March 2013-October 2014). SETTING: Three tertiary care centres in France, Switzerland and the USA. PARTICIPANTS: A total of 1303 adult medical patients with complete NEWS data seeking ED care were included in the final analysis. NEWS was calculated retrospectively based on admission data. MAIN OUTCOME MEASURES: The primary outcome was all-cause 30-day mortality. Secondary outcome was intensive care unit (ICU) admission. We used multivariate regression analyses to investigate associations of NEWS and blood markers with outcomes and area under the receiver operating curve (AUC) as a measure of discrimination. RESULTS: Of the 1303 included patients, 54 (4.1%) died within 30 days. The NEWS alone showed fair prognostic accuracy for all-cause 30-day mortality (AUC 0.73), with a multivariate adjusted OR of 1.26 (95% CI 1.13 to 1.40, p<0.001). The AUCs for the prediction of mortality using the inflammatory markers WCC, PCT and MR-proADM were 0.64, 0.71 and 0.78, respectively. Combining NEWS with all three blood markers or only with MR-proADM clearly improved discrimination with an AUC of 0.82 (p=0.002). Combining the three inflammatory markers with NEWS improved prediction of ICU admission (AUC 0.70vs0.65 when using NEWS alone, p=0.006). CONCLUSION: NEWS is helpful in risk stratification of ED patients and can be further improved by the addition of inflammatory blood markers. Future studies should investigate whether risk stratification by NEWS in addition to biomarkers improve site-of-care decision in this patient population. TRIAL REGISTRATION NUMBER: NCT01768494; Post-results.

Validation of the hospital frailty risk score in a tertiary care hospital in Switzerland: results of a prospective, observational study.

OBJECTIVES: Recently, the Hospital Frailty Risk Score based on a derivation and validation study in the UK has been proposed as a low-cost, systematic screening tool to identify older, frail patients who are at a greater risk of adverse outcomes and for whom a frailty-attuned approach might be useful. We aimed to validate this Score in an independent cohort in Switzerland. DESIGN: Secondary analysis of a prospective, observational study (TRIAGE study). SETTING: One 600-bed tertiary care hospital in Aarau, Switzerland. PARTICIPANTS: Consecutive medical inpatients aged ≥75 years that presented to the emergency department or were electively admitted between October 2015 and April 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was all-cause 30-day mortality. Secondary endpoints were length of hospital stay, hospital readmission, functional impairment and quality of life measures. We used multivariate regression analyses. RESULTS: Of 4957 included patients, 3150 (63.5%) were classified as low risk, 1663 (33.5%) intermediate risk, and 144 (2.9%) high risk for frailty. Compared with the low-risk group, patients in the moderate risk and high-risk groups had increased risk for 30-day mortality (OR (OR) 2.53, 95% CI 2.09 to 3.06, p<0.001 and OR 4.40, 95% CI 2.94 to 6.57, p<0.001) with overall moderate discrimination (area under the ROC curve 0.66). The results remained robust after adjustment for important confounders. Similarly, we found longer length of hospital stay, more severe functional impairment and a lower quality of life in higher risk group patients. CONCLUSION: Our data confirm the prognostic value of the Hospital Frailty Risk Score to identify older, frail people at risk for mortality and adverse outcomes in an independent patient population. TRIAL REGISTRATION NUMBER: NCT01768494; Post-results.

[Childhood temperament and maternal affectivity]. / Kindliches Temperament und müterliche Affektivität.

This study examines the question whether early childhood temperaments of children of mothers suffering from postnatal depression differs from children of non-depressed mothers. Children of clinically depressed mothers were assessed with regard to their temperament on two different dimensions and compared to a control group. The level of cortisol concentration in the children's saliva was the first variable. Saliva samples were gathered on three consecutive days to obtain a baseline, and before and after a mother-children interaction, which was interrupted by a still-face phase. As second variable the early childhood temperament was assessed with the Infant Behavior Questionnaire (IBQ). After the mother-children interaction the cortisol concentration levels of children of mothers suffering from postnatal depression were significantly lower. In the IBQ-Scales the children of depressed mothers showed significantly higher values on the scales Distress to Limitations and Activity. The significantly lower cortisol concentration in the saliva of children of mothers suffering from postpartum depression could be an indication that these children are already used to the fact that their mothers are not paying attention to them during the still-face phase. Overall, the results give rise to the assumption that postpartum depression does have an adverse impact on the development of affected children and that early intervention would be expedient to prevent the occurrence of pathological behavior characteristics and difficult mother-child relationships.

Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10.

In many different tumor entities, increased expression of tissue inhibitor of metalloproteinases-1 (Timp-1) is associated with poor prognosis. We previously reported in mouse models that elevated systemic levels of Timp-1 induce a gene expression signature in the liver microenvironment increasing the susceptibility of this organ to tumor cells. This host effect was dependent on increased activity of the hepatocyte growth factor (Hgf)/hepatocyte growth factor receptor (Met) signaling pathway. In a recent study we showed that Met signaling is regulated by Timp-1 as it inhibits the Met sheddase A disintegrin and metalloproteinase-10 (Adam-10). The aim of the present study was to elucidate whether the metastatic potential of tumor cells benefits from autocrine Timp-1 as well and involves Adam-10 and Met signaling. In a syngeneic murine model of experimental liver metastasis Timp-1 expression and Met signaling were localized within metastatic colonies and expressed by tumor cells. Knock down of tumor cell Timp-1 suppressed Met signaling in metastases and inhibited metastasis formation and tumor cell-scattering in the liver. In vitro, knock down of tumor cell Timp-1 prevented Hgf-induced Met phosphorylation. Consequently, knock down of Met sheddase Adam-10 triggered auto-phosphorylation and responsiveness to Hgf. Accordingly, Adam-10 knock down increased Met phosphorylation in metastatic foci and induced tumor cell scattering into the surrounding liver parenchyma. In conclusion, these findings show that tumor cell-derived Timp-1 acts as a positive regulator of the metastatic potential and support the concept that proteases and their natural inhibitors, as members of the protease web, are major players of signaling during normal homeostasis and disease.

Full-length L1CAM and not its Δ2Δ27 splice variant promotes metastasis through induction of gelatinase expression.

Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression.

Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling.

Balanced expression of proteases and their inhibitors is one prerequisite of tissue homeostasis. Metastatic spread of tumor cells through the organism depends on proteolytic activity and is the death determinant for cancer patients. Paradoxically, increased expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural inhibitor of several endometalloproteinases, including matrix metalloproteinases and a disintegrin and metalloproteinase-10 (ADAM-10), in cancer patients is negatively correlated with their survival, although TIMP-1 itself inhibits invasion of some tumor cells. Here, we show that elevated stromal expression of TIMP-1 promotes liver metastasis in two independent tumor models by inducing the hepatocyte growth factor (HGF) signaling pathway and expression of several metastasis-associated genes, including HGF and HGF-activating proteases, in the liver. We also found in an in vitro assay that suppression of ADAM-10 is in principle able to prevent shedding of cMet, which may be one explanation for the increase of cell-associated HGF receptor cMet in livers with elevated TIMP-1. Similar TIMP-1-associated changes in gene expression were detected in livers of patients with metastatic colorectal cancer. The newly identified role of TIMP-1 to create a prometastatic niche may also explain the TIMP-1 paradoxon.

pH-Activated fusogenic transmembrane LV-peptides.

LV-peptides mimic the in vitro fusogenicity of synthetic fusion protein transmembrane domains. The original versions of these peptides consist of a variable hydrophobic core (containing leucine and/or valine residues (LV)) that is flanked by invariant lysine triplets at both termini. Previously, peptide fusogenicity was correlated with the structural plasticity of their hydrophobic cores. Here, we examined the functional importance of positively charged flanking residues. To this end, we determined the fusogenicities of peptide variants that contain terminal His and/or Lys triplets. Interestingly, liposome fusion by peptides with His triplets was triggered by acidic pH. The pH dependence of fusion is reflected by a sigmoidal titration curve whose midpoint is close to the pKa value of histidine. Thus, only peptides with positively charged residues at both termini are fusogenic. The previously established dependence of fusogenicity on the sequence of the hydrophobic peptide core of Lys-flanked LV-peptides was preserved with the His-flanked versions at low pH. We propose that the structural flexibility of the core region as well as positive terminal charges are required for LV-peptide function in lipid mixing. In a potential practical application, the pH-dependent LV-peptides might prove to be useful in the lipofection of eukaryotic cells.