Cardiovascular risk in patients with acromegaly vs. non-functioning pituitary adenoma following pituitary surgery: an active-comparator cohort study.

PURPOSE: Given the increased cardio-metabolic risk in patients with acromegaly, this study compared cardiovascular outcomes, mortality, and in-hospital outcomes between patients with acromegaly and non-functioning pituitary adenoma (NFPA) following pituitary surgery. METHODS: This was a nationwide cohort study using data from hospitalized patients with acromegaly or NFPA undergoing pituitary surgery in Switzerland between January 2012 and December 2021. Using 1:3 propensity score matching, eligible acromegaly patients were paired with NFPA patients who underwent pituitary surgery, respectively. The primary outcome comprised a composite of cardiovascular events (myocardial infarction, cardiac arrest, ischemic stroke, hospitalization for heart failure, unstable angina pectoris, cardiac arrhythmias, intracranial hemorrhage, hospitalization for hypertensive crisis) and all-cause mortality. Secondary outcomes included individual components of the primary outcome, surgical re-operation, and various hospital-associated outcomes. RESULTS: Among 231 propensity score-matched patients with acromegaly and 491 with NFPA, the incidence rate of the primary outcome was 8.18 versus 12.73 per 1,000 person-years (hazard ratio [HR], 0.64; [95% confidence interval [CI], 0.31-1.32]). Mortality rates were numerically lower in acromegaly patients (2.43 vs. 7.05 deaths per 1,000 person-years; HR, 0.34; [95% CI, 0.10-1.17]). Individual components of the primary outcome and in-hospital outcomes showed no significant differences between the groups. CONCLUSION: This cohort study did not find an increased risk of cardiovascular outcomes and mortality in patients with acromegaly undergoing pituitary surgery compared to surgically treated NFPA patients. These findings suggest that there is no legacy effect regarding higher cardio-metabolic risk in individuals with acromegaly once they receive surgical treatment.

Finerenone in chronic kidney disease and type 2 diabetes: the known and the unknown.

The novel nonsteroidal mineralocorticoid receptor antagonist finerenone has been shown to reduce the risk of kidney and cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease. In this issue of Kidney International, Bakris et al. present new data on the kidney efficacy of finerenone across subgroups of estimated glomerular filtration rate and urinary albumin-to-creatinine ratio, as well as safety data. We attempt to place these results in context by discussing the benefits and risks of finerenone, as well as the generalizability of the study findings to routine care settings.

Prevalence of markers of beta cell autoimmunity and thyroid disease in children with coeliac disease.

BACKGROUND: Over the last decades, the prevalence of coeliac disease (CD), an autoimmune disorder, rose to 1-2%. Whether patients with CD have higher risk of developing other autoimmune disorders such as type 1 diabetes, Hashimoto thyroiditis, or Graves` disease remains unclear. AIM: The aim of this study was to determine the prevalence of biomarkers of beta cell and thyroid autoimmunity in children with CD. METHODS: Retrospective cross-sectional cohort study comparing pediatric patients suffering from CD with age and sex-matched healthy controls (HC). Participant`s serum was tested by immunoassay for following autoantibodies (aAb): TSH-receptor antibodies (TRAb), anti-thyroglobulin (anti-Tg), anti-thyroid peroxidase (anti-TPO), anti-glutamic acid decarboxylase (anti-GAD), anti-zinc transporter 8 (anti-ZnT8), anti-islet antigen 2 (anti-IA2) and anti-insulin. RESULTS: A total of 95 patients with CD (mean age 8.9 years; 63% female) and 199 matched healthy controls (mean age 9.2 years; 59.8% female) were included in the study. For patients with CD, a seroprevalence of 2.1% (vs. 1.5% in HC) was calculated for anti-GAD, 1.1% for anti-IA2 (vs. 1.5% in HC), 3.2% for anti-ZnT8 (vs. 4.2% in HC), and 1.1% (vs. 1% in HC) for anti-insulin. For thyroid disease, a seroprevalence of 2.2% for TRAb (vs. 1% in HC), 0% for anti-TPO (vs. 2.5% in HC) and 4.3% for anti-Tg (vs. 3.5% in HC) was found for patients with CD. CONCLUSION: This study suggests a higher prevalence of autoimmune antibodies againstthyroid in children with CD compared to HC, whilst it is similar for pancreatic antibodies. Prospective cohort studies are needed to first evaluate the occurrence of autoimmune antibodies against beta cells and thyroid over a longer follow-up time and second to explore their clinical relevance.

Call, chosen, HA2T2, ANDC: validation of four severity scores in COVID-19 patients.

PURPOSE: To externally validate four previously developed severity scores (i.e., CALL, CHOSEN, HA2T2 and ANDC) in patients with COVID-19 hospitalised in a tertiary care centre in Switzerland. METHODS: This observational analysis included adult patients with a real-time reverse-transcription polymerase chain reaction or rapid-antigen test confirmed severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection hospitalised consecutively at the Cantonal Hospital Aarau from February to December 2020. The primary endpoint was all-cause in-hospital mortality. The secondary endpoint was disease progression, defined as needing invasive ventilation, ICU admission or death. RESULTS: From 399 patients (mean age 66.6 years ± 13.4 SD, 68% males), we had complete data for calculating the CALL, CHOSEN, HA2T2 and ANDC scores in 297, 380, 151 and 124 cases, respectively. Odds ratios for all four scores showed significant associations with mortality. The discriminative power of the HA2T2 score was higher compared to CALL, CHOSEN and ANDC scores [area under the curve (AUC) 0.78 vs. 0.65, 0.69 and 0.66, respectively]. Negative predictive values (NPV) for mortality were high, particularly for the CALL score (≥ 6 points: 100%, ≥ 9 points: 95%). For disease progression, discriminative power was lower, with the CHOSEN score showing the best performance (AUC 0.66). CONCLUSION: In this external validation study, the four analysed scores had a lower performance compared to the original cohorts regarding prediction of mortality and disease progression. However, all scores were significantly associated with mortality and the NPV of the CALL and CHOSEN scores in particular allowed reliable identification of patients at low risk, making them suitable for outpatient management.

Association of endothelial activation assessed through endothelin-I precursor peptide measurement with mortality in COVID-19 patients: an observational analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has been linked to thrombotic complications and endothelial dysfunction. We assessed the prognostic implications of endothelial activation through measurement of endothelin-I precursor peptide (proET-1), the stable precursor protein of Endothelin-1, in a well-defined cohort of patients hospitalized with COVID-19. METHODS: We measured proET-1 in 74 consecutively admitted adult patients with confirmed COVID-19 and compared its prognostic accuracy to that of patients with community-acquired pneumonia (n = 876) and viral bronchitis (n = 371) from a previous study by means of logistic regression analysis. The primary endpoint was all-cause 30-day mortality. RESULTS: Overall, median admission proET-1 levels were lower in COVID-19 patients compared to those with pneumonia and exacerbated bronchitis, respectively (57.0 pmol/l vs. 113.0 pmol/l vs. 96.0 pmol/l, p < 0.01). Although COVID-19 non-survivors had 1.5-fold higher admission proET-1 levels compared to survivors (81.8 pmol/l [IQR: 76 to 118] vs. 53.6 [IQR: 37 to 69]), no significant association of proET-1 levels and mortality was found in a regression model adjusted for age, gender, creatinine level, diastolic blood pressure as well as cancer and coronary artery disease (adjusted OR 0.1, 95% CI 0.0009 to 14.7). In patients with pneumonia (adjusted OR 25.4, 95% CI 5.1 to 127.4) and exacerbated bronchitis (adjusted OR 120.1, 95% CI 1.9 to 7499) we found significant associations of proET-1 and mortality. CONCLUSIONS: Compared to other types of pulmonary infection, COVID-19 shows only a mild activation of the endothelium as assessed through measurement of proET-1. Therefore, the high mortality associated with COVID-19 may not be attributed to endothelial dysfunction by the surrogate marker proET-1.

Does mid-regional pro-adrenomedullin (MR-proADM) improve the sequential organ failure assessment-score (SOFA score) for mortality-prediction in patients with acute infections? Results of a prospective observational study.

OBJECTIVES: Risk stratification in patients with infection is usually based on the Sequential Organ Failure Assessment-Score (SOFA score). Our aim was to investigate whether the vasoactive peptide mid-regional pro-adrenomedullin (MR-proADM) improves the predictive value of the SOFA score for 30-day mortality in patients with acute infection presenting to the emergency department (ED). METHODS: This secondary analysis of the prospective observational TRIAGE study included 657 patients with infection. The SOFA score, MR-proADM, and traditional inflammation markers were all measured at time of admission. Associations of admission parameters and 30-day mortality were investigated by measures of logistic regression, discrimination analyses, net reclassification index (NRI), and integrated discrimination index (IDI). RESULTS: MR-proADM values were higher in non-survivors compared with survivors (4.5±3.5 nmol/L vs. 1.7 ± 1.8 nmol/L) with an adjusted odds ratio of 26.6 (95% CI 3.92 to 180.61, p=0.001) per 1 nmol/L increase in admission MR-proADM levels and an area under the receiver operator curve (AUC) of 0.86. While the SOFA score alone revealed an AUC of 0.81, adding MR-proADM further improved discrimination (AUC 0.87) and classification within predefined risk categories (NRI 0.075, p-value <0.05). An admission MR-proADM threshold of 1.75 nmol/L provided the best prognostic accuracy for 30-day mortality; with a sensitivity of 81% and a specificity of 75%, and a negative predictive value of 98%. CONCLUSIONS: MR-proADM improved the mortality risk stratification in patients with infection presenting to the ED beyond SOFA score alone and may further improve initial therapeutic site-of-care decisions. TRIAL REGISTRATION: ClinicalTrials.gov NCT01768494. Registered January 15, 2013.

The vasoactive peptide MR-pro-adrenomedullin in COVID-19 patients: an observational study.

OBJECTIVES: Midregional pro-adrenomedullin (MR-proADM) is a vasoactive peptide with key roles in reducing vascular hyperpermeability and thereby improving endothelial stability during infection. While MR-proADM is useful for risk stratification in patients with sepsis, clinical data about prediction accuracy in patients with severe acute respiratory syndrome coronavirus 2 disease (COVID-19) is currently missing. METHODS: We included consecutively adult patients hospitalized for confirmed COVID-19 at a tertiary care center in Switzerland between February and April 2020. We investigated the association of MR-proADM levels with in-hospital mortality in logistic regression and discrimination analyses. RESULTS: Of 89 included COVID-19 patients, 19% (n=17) died while in the hospital. Median admission MR-proADM levels (nmol/L) were increased almost 1.5-fold increased in non-survivors compared to survivors (1.3 [interquartile range IQR 1.1-2.3]) vs. 0.8 [IQR 0.7-1.1]) and showed good discrimination (area under the curve 0.78). An increase of 1 nmol/L of admission MR-proADM was independently associated with a more than fivefold increase in in-hospital mortality (adjusted odds ratio of 5.5, 95% confidence interval 1.4-21.4, p=0.015). An admission MR-proADM threshold of 0.93 nmol/L showed the best prognostic accuracy for in-hospital mortality with a sensitivity of 93%, a specificity of 60% and a negative predictive value of 97%. Kinetics of follow-up MR-proADM provided further prognostic information for in-hospital treatment. CONCLUSIONS: Increased levels of MR-proADM on admission and during hospital stay were independently associated with in-hospital mortality and may allow a better risk stratification, and particularly rule-out of fatal outcome, in COVID-19 patients.

A Randomized Trial of Empagliflozin to Increase Plasma Sodium Levels in Patients with the Syndrome of Inappropriate Antidiuresis.

BACKGROUND: Treatment options to address the hyponatremia induced by the syndrome of inappropriate antidiuresis (SIAD) are inadequate. The sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin promotes osmotic diuresis via urinary glucose excretion and therefore, might offer a novel treatment option for SIAD. METHODS: In this double-blind, randomized trial, we recruited 88 hospitalized patients with SIAD-induced hyponatremia <130 mmol/L at the University Hospital Basel from September 2016 until January 2019 and assigned patients to receive, in addition to standard fluid restriction of <1000 ml/24 h, a once-daily dose of oral empagliflozin or placebo for 4 days. The primary end point was the absolute change in plasma sodium concentration after 4 days of treatment. Secondary end points included predisposing factors for treatment response and safety of the intervention. RESULTS: Of the 87 patients who completed the trial, 43 (49%) received treatment with empagliflozin, and 44 (51%) received placebo. Baseline plasma sodium concentrations were similar for the two groups (median 125.5 mmol/L for the empaflozin group and median 126 mmol/L for the placebo group). Patients treated with empagliflozin had a significantly higher increase of median plasma sodium concentration compared with those receiving placebo (10 versus 7 mmol/L, respectively; P=0.04). Profound hyponatremia (<125 mmol/L) and lower baseline osmolality levels increased the likelihood of response to treatment with empagliflozin. Treatment was well tolerated, and no events of hypoglycemia or hypotension occurred among those receiving empagliflozin. CONCLUSIONS: Among hospitalized patients with SIAD treated with fluid restriction, those who received empagliflozin had a larger increase in plasma sodium levels compared with those who received placebo. This finding indicates that empagliflozin warrants further study as a treatment for the disorder.

Individualised nutritional support in medical inpatients at nutritional risk: a randomised clinical trial.

BACKGROUND: Guidelines recommend the use of nutritional support during hospital stays for medical patients (patients not critically ill and not undergoing surgical procedures) at risk of malnutrition. However, the supporting evidence for this recommendation is insufficient, and there is growing concern about the possible negative effects of nutritional therapy during acute illness on recovery and clinical outcomes. Our aim was thus to test the hypothesis that protocol-guided individualised nutritional support to reach protein and caloric goals reduces the risk of adverse clinical outcomes in medical inpatients at nutritional risk. METHODS: The Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT) is a pragmatic, investigator-initiated, open-label, multicentre study. We recruited medical patients at nutritional risk (nutritional risk screening 2002 [NRS 2002] score ≥3 points) and with an expected length of hospital stay of more than 4 days from eight Swiss hospitals. These participants were randomly assigned (1:1) to receive either protocol-guided individualised nutritional support to reach protein and caloric goals (intervention group) or standard hospital food (control group). Randomisation was done with variable block sizes and stratification according to study site and severity of malnutrition using an interactive web-response system. In the intervention group, individualised nutritional support goals were defined by specialist dietitians and nutritional support was initiated no later than 48 h after admission. Patients in the control group received no dietary consultation. The composite primary endpoint was any adverse clinical outcome defined as all-cause mortality, admission to intensive care, non-elective hospital readmission, major complications, and decline in functional status at 30 days, and it was measured in all randomised patients who completed the trial. This trial is registered with ClinicalTrials.gov, number NCT02517476. FINDINGS: 5015 patients were screened, and 2088 were recruited and monitored between April 1, 2014, and Feb 28, 2018. 1050 patients were assigned to the intervention group and 1038 to the control group. 60 patients withdrew consent during the course of the trial (35 in the intervention group and 25 in the control group). During the hospital stay, caloric goals were reached in 800 (79%) and protein goals in 770 (76%) of 1015 patients in the intervention group. By 30 days, 232 (23%) patients in the intervention group experienced an adverse clinical outcome, compared with 272 (27%) of 1013 patients in the control group (adjusted odds ratio [OR] 0·79 [95% CI 0·64-0·97], p=0·023). By day 30, 73 [7%] patients had died in the intervention group compared with 100 [10%] patients in the control group (adjusted OR 0·65 [0·47-0·91], p=0·011). There was no difference in the proportion of patients who experienced side-effects from nutritional support between the intervention and the control group (162 [16%] vs 145 [14%], adjusted OR 1·16 [0·90-1·51], p=0·26). INTERPRETATION: In medical inpatients at nutritional risk, the use of individualised nutritional support during the hospital stay improved important clinical outcomes, including survival, compared with standard hospital food. These findings strongly support the concept of systematically screening medical inpatients on hospital admission regarding nutritional risk, independent of their medical condition, followed by a nutritional assessment and introduction of individualised nutritional support in patients at risk. FUNDING: The Swiss National Science Foundation and the Research Council of the Kantonsspital Aarau, Switzerland.

What Are They Worth? Six 30-Day Readmission Risk Scores for Medical Inpatients Externally Validated in a Swiss Cohort.

BACKGROUND: Several clinical risk scores for unplanned 30-day readmission have been published, but there is a lack of external validation and head-to-head comparison. OBJECTIVE: Retrospective replication of six clinical risk scores (LACE, HOSPITAL, SEMI, RRS, PARA, Tsui et al.)f DESIGN: Models were fitted with the original intercept and beta coefficients as reported. Otherwise, a logistic model was refitted (SEMI and Tsui et al). We performed subgroup analyses on main admission specialty. This report adheres to the TRIPOD statement for reporting of prediction models. PARTICIPANTS: We used our prospective cohort of 15,639 medical patients from a Swiss tertiary care institution from 2016 through 2018. MAIN MEASURES: Thirty-day readmission rate and area under the curve (AUC < 0.50 worse than chance, > 0.70 acceptable, > 0.80 excellent) CONCLUSIONS: Among several readmission risk scores, HOSPITAL, PARA, and the score from Tsui et al. showed the best predictive abilities and have high potential to improve patient care. Interventional research is now needed to understand the effects of these scores when used in clinical routine. KEY RESULTS: Among the six risk scores externally validated, calibration of the models was overall poor with overprediction of events, except for the HOSPITAL and the PARA scores. Discriminative abilities (AUC) were as follows: LACE 0.53 (95% CI 0.50-0.56), HOSPITAL 0.73 (95% CI 0.72-0.74), SEMI 0.47 (95% CI 0.46-0.49), RRS 0.64 (95% CI 0.62-0.66), PARA 0.72 (95% CI 0.72-0.74), and the score from Tsui et al. 0.73 (95% CI 0.72-0.75). Performance in subgroups did not differ from the overall performance, except for oncology patients in the PARA score (0.57, 95% CI 0.54-0.60), and nephrology patients in the SEMI index (0.25, 95% CI 0.18-0.31), respectively.

The relevance, feasibility and benchmarking of nursing quality indicators: A Delphi study.

AIMS: To identify indicators of nursing care performance by identifying structures, processes, and outcomes that are relevant, feasible and have the potential for benchmarking in Swiss acute hospitals. DESIGN: A modified Delphi-Consensus Technique. METHODS: We examined 19 indicators based on the current evidence and that were pre-selected by nursing scientists. Between August-October 2019, a consortium of experts (representatives of different cantons, hospitals, and healthcare roles in Switzerland) determined the relevance, feasibility, and suitability for benchmarking these indicators in two-round modus of digital survey. Consensus was defined a priori by at least 75% agreement on the highest level of a 3-point Likert-type scale. RESULTS: The response rate was 70.4% in the first and 68.4% in the second round. In round one consensus was reached for three indicators on relevance but for none of the indicators regarding feasibility or potential for benchmarking. For round two, the experts suggested two additional indicators (new total of 21 indicators). Of 21 indicators, consensus was reached on twelve regarding relevance, seven regarding feasibility, and two regarding the potential for benchmarking. CONCLUSION: A national expert consortium defined 12 of 21 nursing care indicators as relevant. Feasibility, however, was estimated only among seven indicators and a consensus on suitability for benchmarking was reached for two nursing-sensitive indicators. IMPACT: The results show how the indicators to evaluate nursing care performance, which have been identified as priority by Canadian nursing scientists, are assessed in a different setting. There are many overlaps, but also some differences in the assessment of the indicators between the different settings. Different health systems prioritize the indicators to evaluate nursing care performance differently, which is why national surveys are important for the compilation of their own (priority) indicator sets.

Association of functional status and hospital-acquired functional decline with 30-day outcomes in medical inpatients: A prospective cohort study.

BACKGROUND: There is growing evidence that patients with functional decline are at increased risk of readmission, mortality and institutionalization. Instruments to measure the status of self-care could provide important information for efficient care planning. The widely used Self Care Index serves as an indicator for the severity of nursing dependency. To date, no evidence is available on the association of the instrument with rehospitalization, mortality and institutionalization. OBJECTIVES: To examine the association of functional status measures (Self Care Index on admission, at discharge and functional decline) with 30-day mortality, readmission and institutionalization in hospitalized non-surgical patients. DESIGN: Prospective cohort study. PARTICIPANTS: We included 4540 emergency medical patients at a single hospital in Switzerland. METHODS: Primary outcome was 30-day mortality rate; secondary outcomes were 30-day readmission and institutionalization. We analyzed the association of the functional status with the binary endpoints using logistic regression models and C-statistics for discrimination. RESULTS: All of the examined measures were significant predictors of overall 30-day mortality; Self Care Index on admission: adj. OR: 0.90 (95% CI: 0.87-0.92); Self Care Index at discharge: adj. OR: 0.86 (95% CI: 0.83-0.88); functional decline: adj. OR: 1.22 (95% CI: 1.14-1.31) and all Self Care Index single items. A combined model (functional status on admission and functional decline during hospitalization) showed a good accuracy with regard to the AUC: adj. AUC: 0.80 (95% CI: 0.74-0.86). CONCLUSIONS: Several functional measures were associated with 30-day mortality. Self Care Index total score, five single items and a combined model showed the best performance.

Metabolomics and Their Ability to Distinguish Thyroid Disorders: A Retrospective Pilot Study.

Early diagnosis of thyroid disorders is key to further treatment. We assessed the ability of a high-throughput proton NMR metabolomic profile to distinguish disease type amongst of Graves' disease (n=87), Hashimoto's thyroiditis (n=17), toxic goiter (n=11), and autoimmune thyroiditis [i. e., subacute thyroiditis (n=4), postpartum thyroiditis (n=1)]. This observational study was conducted investigating patients presenting with a thyroid disorder at a Swiss hospital endocrine referral center and an associated endocrine outpatient clinic. The main outcome was diagnosis of thyroid disorder based on classical parameters. Blood draws took place as close as possible to treatment initiation. We performed one-way ANOVA and partial least squares discriminant analysis (PLS-DA) as multivariate classification and feature ranking method. One-way ANOVA analysis yielded following significantly different metabolites, triglycerides in small VLDL, triglycerides in very small VLDL, and triglycerides in large LDL (FDR=0.04). There was no distinct separation of any of the 4 diagnoses by PLS-DA. We did not find a metabolomic biomarker combination capable of predicting diagnosis. Preanalytical issues might have influenced our results. We strongly suggest replicating our work in another cohort.

Diagnostic and prognostic value of the D-dimer test in emergency department patients: secondary analysis of an observational study.

Background D-dimer measurement improves the rule-out of thromboembolic disease. However, little is known about the risk of false positive results for the diagnosis of thromboembolic disease and its prognostic value. Herein, we investigated factors influencing the accuracy of D-dimer and its prognostic value in a large cohort of emergency department (ED) patients. Methods This is a secondary analysis of a prospective observational single center, cohort study. Consecutive patients, for whom a D-dimer test was requested by the treating physician, were included. Associations of clinical parameters on admission with false positive D-dimer results for the diagnosis of thromboembolic disease were investigated with logistic regression analysis. Results A total of 3301 patients were included, of which 203 (6.1%) had confirmed thromboembolic disease. The negative and positive predictive values of the D-dimer test at the 0.5 mg/L cut-off were 99.9% and 11.4%, respectively. Several factors were associated with positive D-dimer results potentially falsely indicating thromboembolic disease in multivariate analysis including advanced age (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.04-1.05, p < 0.001), congestive heart failure (CHF) (OR 2.79, 95% CI 1.77-4.4, p < 0.01), renal failure (OR 2.00, 95% CI 1.23-3.24, p = 0.005), history of malignancy (OR 2.6, 95% CI 1.57-4.31, p < 0.001), C-reactive protein (CRP) (OR 1.02, 95% CI 1.01-1.02, p < 0.001) and glomerular filtration rate (GFR) (OR 0.99, 95% CI 0.99-1.00, p = 0.003). Regarding its prognostic value, D-dimer was associated with a 30-day mortality (adjusted OR 1.05, 95% CI 1.02-1.09, p = 0.003) with an area under the curve (AUC) of 0.79. Conclusions While D-dimer allows an accurate rule-out of thromboembolic disease, its positive predictive value in routine ED patients is limited and largely influenced by age, comorbidities and acute disease factors. The strong prognostic value of D-dimer in this population warrants further investigation.

Correction to: The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study.

In the publication of this article [1], there are two errors in contributing author affiliations. This has now been included in this correction article.

The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study.

BACKGROUND: There is a lack of validated tools to assess potential disease progression and hospitalisation decisions in patients presenting to the emergency department (ED) with a suspected infection. This study aimed to identify suitable blood biomarkers (MR-proADM, PCT, lactate and CRP) or clinical scores (SIRS, SOFA, qSOFA, NEWS and CRB-65) to fulfil this unmet clinical need. METHODS: An observational derivation patient cohort validated by an independent secondary analysis across nine EDs. Logistic and Cox regression, area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves were used to assess performance. Disease progression was identified using a composite endpoint of 28-day mortality, ICU admission and hospitalisation > 10 days. RESULTS: One thousand one hundred seventy-five derivation and 896 validation patients were analysed with respective 28-day mortality rates of 7.1% and 5.0%, and hospitalisation rates of 77.9% and 76.2%. MR-proADM showed greatest accuracy in predicting 28-day mortality and hospitalisation requirement across both cohorts. Patient subgroups with high MR-proADM concentrations (≥ 1.54 nmol/L) and low biomarker (PCT < 0.25 ng/mL, lactate < 2.0 mmol/L or CRP < 67 mg/L) or clinical score (SOFA < 2 points, qSOFA < 2 points, NEWS < 4 points or CRB-65 < 2 points) values were characterised by a significantly longer length of hospitalisation (p < 0.001), rate of ICU admission (p < 0.001), elevated mortality risk (e.g. SOFA, qSOFA and NEWS HR [95%CI], 45.5 [10.0-207.6], 23.4 [11.1-49.3] and 32.6 [9.4-113.6], respectively) and a greater number of disease progression events (p < 0.001), compared to similar subgroups with low MR-proADM concentrations (< 1.54 nmol/L). Increased out-patient treatment across both cohorts could be facilitated using a derivation-derived MR-proADM cut-off of < 0.87 nmol/L (15.0% and 16.6%), with decreased readmission rates and no mortalities. CONCLUSIONS: In patients presenting to the ED with a suspected infection, the blood biomarker MR-proADM could most accurately identify the likelihood of further disease progression. Incorporation into an early sepsis management protocol may therefore aid rapid decision-making in order to either initiate, escalate or intensify early treatment strategies, or identify patients suitable for safe out-patient treatment.

Comparison of Five TSH-Receptor Antibody Assays in Graves' disease: results from an observational pilot study.

BACKGROUND: Early diagnosis and relapse prediction in Graves' disease influences treatment. We assessed the abilities of four TSH-receptor antibody tests [TRAb] and one cyclic adenosine monophosphate bioassay to predict relapse of Graves' disease. METHODS: Observational study investigating patients presenting with Graves' disease at a Swiss hospital endocrine referral center or an endocrine outpatient clinic. Main outcomes were diagnosis and relapse of Graves' disease after stop of anti-thyroid drugs. We used Cox regression to study associations of TRAb levels with relapse risk and calculated c-statistics [AUC] to assess discrimination. Blood draws took place as close as possible to treatment initiation. RESULTS: AUCs ranged from 0.90 (TSAb Biossay by RSR) to 0.97 (IMMULITE TSI by Siemens). Highest sensitivity (94.0%) was observed for IMMULITE TSI and RSR TRAb Fast, while the greatest specificity (97.9%) was found with the EliA anti-TSH-R (by Thermo Fisher). In Cox regression analysis comparing the highest versus the lower quartiles, the highest hazard ratio [HR] for relapse was found for BRAHMS TRAK (by Thermo Fisher) (2.98, 95% CI 1.13-7.84), IMMULITE TSI (2.40, 95% CI 0.91-6.35), EliA anti-TSH-R (2.05, 95% CI 0.82-5.10), RSR Fast TRAb (1.80, 95% CI 0.73-4.43), followed by RSR STIMULATION (1.18, 95% CI 0.46-2.99). Discrimination analyses showed respective AUCs of 0.68, 0.65, 0.64, 0.64, and 0.59. CONCLUSION: The assays tested had good diagnostic power and relapse risk prediction with few differences among the new assays. Due to the small sample size and retrospective design with possible selection bias, our data need prospective validation.

Integrative hospital treatment in older patients to benchmark and improve outcome and length of stay - the In-HospiTOOL study.

BACKGROUND: A comprehensive in-hospital patient management with reasonable and economic resource allocation is arguably the major challenge of health-care systems worldwide, especially in elderly, frail, and polymorbid patients. The need for patient management tools to improve the transition process and allocation of health care resources in routine clinical care particularly for the inpatient setting is obvious. To address these issues, a large prospective trial is warranted. METHODS: The "Integrative Hospital Treatment in Older patients to benchmark and improve Outcome and Length of stay" (In-HospiTOOL) study is an investigator-initiated, multicenter effectiveness trial to compare the effects of a novel in-hospital management tool on length of hospital stay, readmission rate, quality of care, and other clinical outcomes using a time-series model. The study aims to include approximately 35`000 polymorbid medical patients over an 18-month period, divided in an observation, implementation, and intervention phase. Detailed data on treatment and outcome of polymorbid medical patients during the in-hospital stay and after 30 days will be gathered to investigate differences in resource use, inter-professional collaborations and to establish representative benchmarking data to promote measurement and display of quality of care data across seven Swiss hospitals. The trial will inform whether the "In-HospiTOOL" optimizes inter-professional collaboration and thereby reduces length of hospital stay without harming subjective and objective patient-oriented outcome markers. DISCUSSION: Many of the current quality-mirroring tools do not reflect the real need and use of resources, especially in polymorbid and elderly patients. In addition, a validated tool for optimization of patient transition and discharge processes is still missing. The proposed multicenter effectiveness trial has potential to improve interprofessional collaboration and optimizes resource allocation from hospital admission to discharge. The results will enable inter-hospital comparison of transition processes and accomplish a benchmarking for inpatient care quality.

Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial.

Neutrophil extracellular traps (NETs) are a hallmark of the immune response in inflammatory diseases. However, the role of NETs in community-acquired pneumonia (CAP) is unknown. This study aims to characterise the impact of NETs on clinical outcomes in pneumonia.This is a secondary analysis of a randomised controlled, multicentre trial. Patients with CAP were randomly assigned to either 50 mg prednisone or placebo for 7 days. The primary end-point was time to clinical stability; main secondary end-points were length of hospital stay and mortality.In total, 310 patients were included in the analysis. Levels of cell-free nucleosomes as surrogate markers of NETosis were significantly increased at admission and declined over 7 days. NETs were significantly associated with reduced hazards of clinical stability and hospital discharge in multivariate adjusted analyses. Moreover, NETs were associated with a 3.8-fold increased adjusted odds ratio of 30-day mortality. Prednisone treatment modified circulatory NET levels and was associated with beneficial outcome.CAP is accompanied by pronounced NET formation. Patients with elevated serum NET markers were at higher risk for clinical instability, prolonged length of hospital stay and 30-day all-cause mortality. NETs represent a novel marker for outcome and a possible target for adjunct treatments of pneumonia.

Dihydrotestosterone is a predictor for mortality in males with community-acquired pneumonia: results of a 6-year follow-up study.

BACKGROUND: Adrenal hormone metabolite levels are altered in acute illnesses such as community-acquired pneumonia (CAP). Our aim was to investigate associations of sex and mineralocorticoid hormone metabolites with short- and long-term mortality and severity of CAP in male and female patients. METHODS: We prospectively followed 285 patients (60.4% male, mean age 71 years) with CAP from a previous multicenter trial. At baseline, levels of different metabolites of sex hormones and mineralocorticoids were measured by liquid chromatography coupled to tandem mass spectrometry. We calculated Cox regression models adjusted for age and comorbidities. RESULTS: All-cause mortality was 5.3% after 30 days and increased to 47.4% after 6 years. In males, high levels of dihydrotestosterone were associated with higher 6-year mortality (adjusted HR 2.84, 95%CI 1.15-6.99, p = 0.023), whereas high levels of 17-OH-progesterone were associated with lower 6-year mortality (adjusted HR 0.72, 95%CI 0.54-0.97, p = 0.029). Testosterone levels in males correlated inversely with inflammatory markers (CRP rho = - 0.39, p < 0.001; PCT rho = - 0.34, p < 0.001) and disease severity as assessed by the Pneumonia severity index (PSI) (rho = - 0.23, p = 0.003). No similar association was found for female patients. CONCLUSION: Whereas in males with CAP, sex and mineralocorticoid hormone metabolite levels correlated with inflammation, disease severity and long-term survival, no similar association was found for females. Further study of sex and mineralocorticoid hormones in acute illness could generate predictive signatures with implementation in clinical practice.