Clinical effect of obesity on N-terminal pro-B-type natriuretic peptide cut-off concentrations for the diagnosis of acute heart failure

AIMS Obese patients have lower natriuretic peptide concentrations. We hypothesized that adjusting the concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP) for obesity could further increase its clinical utility in the early diagnosis of acute heart failure (AHF). METHODS AND RESULTS This hypothesis was tested in a prospective diagnostic study enrolling unselected patients presenting to the emergency department with acute dyspnoea. Two independent cardiologists/internists centrally adjudicated the final diagnosis using all individual patient information including cardiac imaging. NT-proBNP plasma concentrations were applied: first, using currently recommended cut-offs; second, using cut-offs lowered by 33% with body mass index (BMI) of 30-34.9 kg/m$^{2}$ and by 50% with BMI ≥ 35 kg/m$^{2}$ . Among 2038 patients, 509 (25%) were obese, of which 271 (53%) had AHF. The diagnostic accuracy of NT-proBNP as quantified by the area under the receiver-operating characteristic curve was lower in obese versus non-obese patients (0.890 vs. 0.938). For rapid AHF rule-out in obese patients, the currently recommended cut-off of 300 pg/ml achieved a sensitivity of 96.7% (95% confidence interval [CI] 93.8-98.2%), ruling out 29% of patients and missing 9 AHF patients. For rapid AHF rule-in, the age-dependent cut-off concentrations (age 75 years: 1800 pg/ml) achieved a specificity of 84.9% (95% CI 79.8-88.9%). Proportionally lowering the currently recommended cut-offs by BMI increased sensitivity to 98.2% (95% CI 95.8-99.2%), missing 5 AHF patients; reduced the proportion of AHF patients remaining in the 'gray zone' (48% vs. 26%; p = 0.002), achieving a specificity of 76.5% (95% CI 70.7-81.4%). CONCLUSIONS Adjusting NT-proBNP concentrations for obesity seems to further increase its clinical utility in the early diagnosis of AHF

Improved upper limb function in non-ambulant children with SMA type 2 and 3 during nusinersen treatment: a prospective 3-years SMArtCARE registry study

Background The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months. Methods SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Results Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score. Conclusion Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity

Land system regime shifts and their impacts on human well-being in forest frontier landscapes of Madagascar and Myanmar

Landscapes on forest frontiers in the humid tropics provide powerful examples of the challenge to reconcile human development with increasingly evident planetary boundaries. These social-ecological systems (SES) not only have to meet the immediate livelihood needs and the broader development aspirations of their local populations. They are also expected to ensure the complex mix of ecosystem service (ES) flows that support human well-being locally and provide environmental benefits worldwide. Driven by demands for commercial agricultural production, carbon sequestration or biodiversity conservation among others, distant socio-economic and environmental influences are becoming increasingly entangled, triggering not only rapid land use change processes at the local scale, but also unchaining multi-directional spill-over and feedback effects affecting other SES. Land science experts refer to these socio-economic and environmental interactions between distant SES as "telecoupling". In such contexts, managing land use to ensure both desired ES flows and human well-being - i.e. sustainability transformation - is often seen as a "wicked problem" The forest frontier contexts of Madagascar and Myanmar illustrate the abovementioned sustainable development challenges. Both countries have experienced a transformation of their subsistence based small-holder shifting cultivation systems towards commercial agriculture. Spatially distant actors and their claims on land have contributed to highly dynamic local land use changes and overall land system regime shifts. To date, however, there is little understanding of their impacts on ES and human well-being in local SES. Yet this understanding is crucial to the negotiation of trade-offs between economic development and maintaining bundles of ES between actors at different scales.  We have therefore collected empirical data on the impact of land use changes on human well-being via a methodological approach including gender-separated focus group discussions and individual semi-structured interviews in the two countries. Here, we propose to present first results of a comparative analysis regarding 1) the most important aspects of human well-being in each context; 2) interviewees' capabilities to achieve different well-being aspects; 3) the contribution of ES to different well-being aspects; 4) and how the capabilities and contribution of ES have changed over the last 20 years. Although both countries have experienced similar land use change trajectories, the impacts on well-being differ, which highlights the importance of context specifity in well-being assessments.peerReviewe

Mid- to long-term cardiac magnetic resonance findings in elite athletes recovered from COVID-19 - results from one German Olympic medical center

Background There is a lack of cardiac magnetic resonance (CMR) data regarding mid- to long-term myocardial damage due to Covid-19 in elite athletes. Objective This study investigated mid-to long-term consequences of myocardial involvement after a Covid-19 infection in elite athletes. Methods Between January 2020 and October 2021, 27 athletes of the German Olympic centre Rhineland with confirmed Covid-19 infection were analyzed. 9 healthy non-athlete volunteers served as control. CMR was performed in mean 182 days (SD 99) after initial positive test result. Results CMR did not reveal any signs of acute myocarditis in regard to the current Lake Louise criteria or myocardial damage in any of the 26 elite athletes with previous Covid-19 infection. Nevertheless, 92 % of the athletes experienced a symptomatic course and 54 % reported lasting symptoms for more than 4 weeks. In one male athlete CMR revealed an arrhythmogenic right ventricular cardiomyopathy (ARVC) and this athlete was excluded from the study. Athletes had significantly enlarged left and right ventricle volumes and increased left ventricular myocardial mass in comparison to the healthy control group (LVEDVi 103.4 vs. 91.1 ml/m 2 p=0.031; RVEDVi 104.1 vs. 86.6 ml/m 2 p=0.007; and LVMi 59.0 vs. 46.2 g/m 2 p=0.002). Conclusion Our findings suggest that the risk for mid-to long-term myocardial damage seems to be very low to negligible in elite athletes. No conclusions can be drawn regarding myocardial injury in the acute phase of infection nor about possible long-term myocardial effects in the general population

Mid- to long-term cardiac magnetic resonance findings in elite athletes recovered from COVID-19: results from an ongoing observational COVID-19 study at a German Olympic medical centre

INTRODUCTION: The cardiac magnetic resonance (CMR) data on mid- to long-term myocardial damage due to COVID-19 infections in elite athletes are scarce. Therefore, this study investigated the mid -to long-term consequences of myocardial involvement after a COVID-19 infection in elite athletes. MATERIALS AND METHODS: This study included 27 athletes at the German Olympic Centre North Rhine-Westphalia (NRW)/Rhineland with a confirmed previous COVID-19 infection between January 2020 and October 2021. The athletes were part of an ongoing observational COVID-19 study at the Institute of Cardiology and Sports Medicine Cologne at the German Sport University (DSHS).Nine healthy non-athletes with no prior COVID-19 illness served as controls. CMR was performed within a mean of 182 days (standard deviation [SD] 99) of the initial positive test result. RESULTS: CMR did not reveal any signs of acute myocarditis (according to the current Lake Louise criteria) or myocardial damage in any of the 26 elite athletes with previous COVID-19 infection. Of these athletes, 92% experienced a symptomatic course, and 54% reported symptoms lasting for more than 4 weeks. One male athlete was excluded from the analysis because CMR revealed an arrhythmogenic right ventricular cardiomyopathy (ARVC). Athletes had significantly enlarged left and right ventricle volumes and increased left ventricular myocardial mass in comparison to the healthy control group (LVEDVi 103.4 vs 91.1 ml/m2, p = 0.031; RVEDVi 104.1 vs 86.6 ml/m2, p = 0.007; LVMi 59.0 vs 46.2 g/m2, p = 0.002). Only two cases of elevated high-sensitivity-Troponin were documented; in one, the participant had previously engaged in high-intensity training, and in the other, CMR revealed a diagnosis of an arrhythmogenic cardiomyopathy. CONCLUSION: Our findings suggest that the risk for mid- to long-term myocardial damage is very low to negligible in elite athletes. Our results do not allow conclusions to be drawn regarding myocardial injury in the acute phase of infection nor about possible long-term myocardial effects in the general population

Liver damage and senescence increases in patients developing hepatocellular carcinoma

Most patients with a hepatocellular carcinoma (HCC) have an underlying chronic liver inflammation, which causes a continuous damage leading to liver cirrhosis and eventually HCC. However, only a minority of cirrhotic patients develop HCC. To assess a possible differential impact of liver inflammation in patients developing HCC versus patients remaining tumor-free, we designed a longitudinal study and analysed liver tissue of the same patients (n = 33) at two points in time: once when no HCC was present and once several years later when an HCC was present. As a control group, we followed cirrhotic patients (n = 37) remaining tumor-free over a similar time frame.; We analysed cell damage and senescence of hepatocytes by measuring γ-H2AX positivity, p16INK4 and p21WAF/Cip1 expression, nuclear size, and telomere length.; γ-H2AX positivity, p16INK4 and p21WAF/Cip1 expression, in the first liver biopsy was similar in patients developing HCC later on and cirrhotic patients remaining tumor free. In contrast, γ-H2AX positivity, p16INK4 and p21WAF/Cip1 expression, was significantly higher in the second non-tumoral liver biopsy of HCC patients than in the control patients. Consequently, the individual increase in γ-H2AX positivity, p16INK4 and p21WAF/Cip1 expression, from the first biopsy to the second biopsy was significantly higher in patients developing HCC than in patients remaining tumor free. In addition, changes in nuclear size and telomere length revealed a more pronounced cell aging in patients developing HCC than in patients remaining tumor free.; Hepatocytes from patients developing HCC go through more pronounced cell damage and senescence in contrast to cirrhotic patients remaining tumor free

Mutation Profiling of Lung Cancers with Long-Term Response to Gefitinib Therapy

Background: The role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) and unknown EGFR mutation status has recently been questioned. Patients and Methods: We conducted a retrospective study of patients with unknown EGFR mutation status and long-term response (LTR) to gefitinib in the Swiss lressa expanded access program (EAP). We assessed patient characteristics, and performed Sanger sequencing and next generation sequencing on archived tumor tissue. We hypothesized that EGFR mutations are prevalent in patients with LTR. Results: Of 430 patients in the EAP, 18 (4%) fulfilled our definition of LTR, and 16 of them had archived tumor tissue. Patient characteristics were as expected for age, sex, and smoking history. Median duration of therapy was 38 months (range 24-142 months). Sanger sequencing revealed EGFR exon 18-21 mutations in 6 (38%) of the tumors. Next generation sequencing revealed no further EGFR-mutated cases, but reported in 15 (94%) of the tumors mutations in other genes (ALK, BRAF, DDR2, KEAP1, MET, PTEN, STK11) previously associated with NSCLC. Conclusion: Larger studies are needed to define the prognostic values of different driver mutations in patients with NSCLC. (C) 2015 S. Karger GmbH, Freibur

Prospective Evaluation of Residual Breast Tissue After Skin- or Nipple-Sparing Mastectomy: Results of the SKINI-Trial

OBJECTIVE This study was designed to investigate the presence of residual breast tissue (RBT) after skin-sparing mastectomy (SSM) and nipple-sparing mastectomy (NSM) and to analyse patient- and therapy-related factors associated with RBT. Skin-sparing mastectomy and NSM are increasingly used surgical procedures. Prospective data on the completeness of breast tissue resection is lacking. However, such data are crucial for assessing oncologic safety of risk-reducing and curative mastectomies. METHODS Between April 2016 and August 2017, 99 SSM and 61 NSM were performed according to the SKINI-trial protocol, under either curative (n = 109) or risk-reducing (n = 51) indication. After breast removal, biopsies from the skin envelope (10 biopsies per SSM, 14 biopsies per NSM) were taken in predefined radial localizations and assessed histologically for the presence of RBT and of residual disease. RESULTS Residual breast tissue was detected in 82 (51.3%) mastectomies. The median RBT percentage per breast was 7.1%. Of all factors considered, only type of surgery (40.4% for SSM vs. 68.9% for NSM; P < 0.001) and surgeon (P < 0.001) were significantly associated with RBT. None of the remaining factors, e.g., skin flap necrosis, was associated significantly with RBT. Residual disease was detected in three biopsies. CONCLUSIONS Residual breast tissue is commonly observed after SSM and NSM. In contrast, invasive or in situ carcinomas are rarely found in the skin envelope. Radicality of mastectomy in this trial is not associated with increased incidence of skin flap necrosis. ClinicalTrials.gov Identifier NCT03470909

Quantifying inflammation using Interleukin-6 for improved phenotyping and risk stratification in acute heart failure

AIMS Systemic inflammation may be central in the pathophysiology of acute heart failure (AHF). We aimed to assess the possible role of systemic inflammation in the pathophysiology, phenotyping, and risk stratification of patients with AHF. METHODS AND RESULTS Using a novel Interleukin-6 immunoassay with unprecedented sensitivity (limit of detection 0.01ng/L) we quantified systemic inflammation in unselected patients presenting with acute dyspnea to the emergency department in a multicenter study. 1-year mortality was the primary prognostic endpoint. Among 2042 patients, 1026 (50.2%) had an adjudicated diagnosis of AHF, 83.7% of whom had elevated Interleukin-6 concentrations (>4.45ng/L). Interleukin-6 was significantly higher in AHF patients compared to patients with other causes of dyspnea (11.2 [6.1-26.5] ng/L vs 9.0 [3.2-32.3] ng/L, p<0.0005). Elevated Interleukin-6 concentrations were independently predicted by increasing NT-proBNP and high-sensitivity cardiac troponin T, as well as the clinical diagnosis of infection. Among the different AHF phenotypes, Interleukin-6 concentrations were highest in patients with cardiogenic shock (25.7 [14.0-164.2] ng/L) and lowest in patients with hypertensive AHF (9.3 [4.8-21.6] ng/L, p=0.001). Inflammation as quantified by Interleukin-6 was a strong and independent predictor of 1-year mortality both in all AHF patients, as well as those without clinically overt infection at presentation [adjusted hazard ratio (95%CI): 1.45 (1.15-1.83) vs 1.48 (1.09-2.00), respectively]. The addition of Interleukin-6 significantly improved the discrimination of the BIOSTAT-CHF risk score. CONCLUSION An unexpectedly high percentage of patients with AHF have subclinical systemic inflammation as quantified by Interleukin-6, which seems to contribute to AHF phenotype and to the risk of death

Pathologist computer-aided diagnostic scoring of tumor cell fraction: A Swiss national study.

Tumor cell fraction (TCF) estimation is a common clinical task with well-established large inter-observer variability. It thus provides an ideal testbed to evaluate potential impacts of employing a computer-aided diagnostic (TCFCAD) tool to support pathologists' evaluation. During a National Slide Seminar event, pathologists (n=69) were asked to visually estimate TCF in 10 regions of interest (ROI) from hematoxylin and eosin (H&E) colorectal cancer images intentionally curated for diverse tissue compositions, cellularity, and stain intensities. Next, they re-evaluated the same ROIs while being provided a TCFCAD created overlay highlighting predicted tumor versus non-tumor cells, together with the corresponding TCF percentage. Participants also reported confidence levels in their assessments using a 5-tiers scale, indicating no confidence to high confidence, respectively. The TCF ground truth (GT) was defined by manual cell-counting by experts. When assisted, inter-observer variability significantly decreased, showing estimates converging to the GT. This improvement remained even when TCFCAD predictions deviated slightly from the GT. The standard-deviation of estimated TCF to the GT across ROIs was 9.9% vs 5.8% with TCFCAD, p < 0.0001. The intraclass correlation coefficient increased from 0.8 to 0.93 (CI95% [0.65, 0.93] vs [0.86, 0.98]) and pathologists stated feeling more confident when aided (3.67 ± 0.81 vs. 4.17 ± 0.82 with CAD). TCFCAD estimation support demonstrated improved scoring accuracy, inter-pathologist agreement and scoring confidence. Interestingly, pathologists also expressed more willingness to use such a CAD tool at the end of the survey, highlighting the importance of training/education to increase adoption of CAD systems