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In situ and simultaneous measurement of the three most abundant isotopologues of methane using mid-infrared laser absorption spectroscopy is demonstrated. A field-deployable, autonomous platform is realized by coupling a compact quantum cascade laser absorption spectrometer (QCLAS) to a preconcentration unit, called trace gas extractor (TREX). This unit enhances CH4 mole fractions by a factor of up to 500 above ambient levels and quantitatively separates interfering trace gases such as N2O and CO2. The analytical precision of the QCLAS isotope measurement on the preconcentrated (750 ppm, parts-per-million, µmole mole-1) methane is 0.1 and 0.5‰ for δ 13C- and δDCH4 at 10min averaging time. Based on repeated measurements of compressed air during a 2-week intercomparison campaign, the repeatability of the TREX--QCLAS was determined to be 0.19 and 1.9‰ for δ13C and ΔD-CH4, respectively. In this intercomparison campaign the new in situ technique is compared to isotoperatio mass spectrometry (IRMS) based on glass flask and bag sampling and real time CH4 isotope analysis by two commercially available laser spectrometers. Both laser-based analyzers were limited to methane mole fraction and δ13C-CH4 analysis, and only one of them, a cavity ring down spectrometer, was capable to deliver meaningful data for the isotopic composition. After correcting for scale offsets, the average difference between TREX--QCLAS data and bag/flask sampling--IRMS values are within the extended WMO com patibility goals of 0.2 and 5‰ for δ13C- and δD-CH4, respectively. This also displays the potential to improve the interlaboratory compatibility based on the analysis of a reference air sample with accurately determined isotopic composition. [ABSTRACT FROM AUTHOR]

In situ and simultaneous measurement of the three most abundant isotopologues of methane using mid-infrared laser absorption spectroscopy is demonstrated. A fielddeployable, autonomous platform is realized by coupling a compact quantum cascade laser absorption spectrometer (QCLAS) to a preconcentration unit, called TRace gas EXtractor (TREX). This unit enhances CH4 mole fractions by a factor of up to 500 above ambient levels and quantitatively separates interfering trace gases such as N2O and CO2. The analytical precision of the QCLAS isotope measurement on the preconcentrated (750 ppm, parts-per-million, μmole/mole) methane is 0.1 and 0.5‰for δ13C and δD-CH4 at 10min averaging time. Based on replicate measurements of compressed air during a two-week intercomparison campaign, the repeatability of the TREX-QCLAS was determined to be 0.19 and 1.9‰ for δ13C and δD-CH4, respectively. In this intercomparison campaign the new in situ technique is compared to isotope-ratio mass-spectrometry (IRMS) based on glass flask and bag sampling and real time CH4 isotope analysis by two commercially available laser spectrometers. Both laser-based analyzers were limited to methane mole fraction and δ13C-CH4 analysis, and only one of them, a cavity ring down spectrometer, was capable to deliver meaningful data for the isotopic composition. After correcting for scale offsets, the average difference between TREX-QCLAS data and bag/flask sampling-IRMS values are within the extended WMO compatibility goals of 0.2 and 5‰ for δ13C- and δD-CH4, respectively. Thus, the intercomparison also reveals the need for reference air samples with accurately determined isotopic composition of CH4 to further improve the interlaboratory compatibility. [ABSTRACT FROM AUTHOR]

Traditional techniques for measuring the mole fractions of greenhouse gases in the well-mixed atmosphere have required dry sample gas streams (dew point <-25 °C) to achieve the inter-laboratory compatibility goals set forth by the Global Atmosphere Watch programme of the World Meteorological Organisation (WMO/GAW) for carbon dioxide (±0.1 ppm in the Northern Hemisphere and ±0.05 ppm in the Southern Hemisphere) and methane (±2 ppb). Drying the sample gas to low levels of water vapour can be expensive, time-consuming, and/or problematic, especially at remote sites where access is difficult. Recent advances in optical measurement techniques, in particular cavity ring down spectroscopy, have led to the development of greenhouse gas analysers capable of simultaneous measurements of carbon dioxide, methane and water vapour. Unlike many older technologies, which can suffer from significant uncorrected interference from water vapour, these instruments permit accurate and precise greenhouse gas measurements that can meet the WMO/GAW inter-laboratory compatibility goals (WMO, 2011a) without drying the sample gas. In this paper, we present laboratory methodology for empirically deriving the water vapour correction factors, and we summarise a series of in-situ validation experiments comparing the measurements in humid gas streams to well-characterised dry-gas measurements. By using the manufacturer-supplied correction factors, the dry-mole fraction measurements have been demonstrated to be well within the GAWcompatibility goals up to a water vapour concentration of at least 1 %. By determining the correction factors for individual instruments once at the start of life, this water vapour concentration range can be extended to at least 2% over the life of the instrument, and if the correction factors are determined periodically over time, the evidence suggests that this range can be extended up to and even above 4% water vapour concentrations. [ABSTRACT FROM AUTHOR]

The article presents a study which compares new laser spectometer techniques in measuring in situ-carbon monoxide. It states that the instruments were evaluated based on temperature dependence, reproducibility, and water vapour interference. Results show that new techniques perform better compared to previous techniques.

The article presents a study which compares three lase spectrometer for measuring carbon monoxide (CO). The three instruments in the study were vacuum ultraviolet (UV) resonance fluorescence (VURF), cavity ring down spectroscopy (CRDS), and integrated cavity output spectroscopy (ICOS) Quantum Cascade Laser (QCL) (ICOS-QCL). Results show that these techniques offer better measurement performances.

The article discusses the measurement of dry mole fractions of greenhouse gases in humid air particularly carbon dioxide and methane. It says that greenhouse gas analyzers have been developed to provide high accuracy measurement of carbon dioxide, methane, and water vapor to meet the Global Atmospheric Watch program of the World Meteorological Organization (WMO/GAW) inter-laboratory compatibility goals. It adds that the dry-mole fraction measurements have met the compatibility goals of GAW.

OBJECTIVE: The early diagnosis of acute myocardial infarction (AMI) can be particularly challenging in patients with known coronary artery disease (CAD) due to pre-existing ECG changes and chronic increases in cardiac troponin (cTn) levels. DESIGN: Of 1170 consecutive patients presenting with symptoms suggestive of AMI, 433 (37%) with pre-existing CAD were analysed in a prospective multicentre study and the diagnostic and prognostic impact of copeptin in combination with either fourth generation cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT) was evaluated. RESULTS: AMI was the final diagnosis in 78 patients with pre-existing CAD (18%). Copeptin was significantly higher in patients with AMI than in those without (26 pmol/l (IQR 9-71) vs 7 pmol/l (IQR 4-16), p<0.001). The diagnostic accuracy for AMI as quantified by the area under the receiver operating characteristic curve (AUC) was significantly higher for the combination of copeptin and cTnT than for cTnT alone (0.94 vs 0.86, p<0.001). The combination of copeptin and hs-cTnT (0.94) was trending to superiority compared with hs-cTnT alone (0.92, p=0.11). The combination of copeptin and the cTn assays was able to improve the negative predictive value up to 99.5% to rule out AMI. Copeptin was a strong and independent predictor of 1-year mortality (HR 4.18-4.63). Irrespective of cTn levels, patients with low levels of copeptin had an excellent prognosis compared with patients with raised levels of both copeptin and cTn (360-day mortality 2.8-3.6% vs 23.1-33.8%, p<0.001). CONCLUSION: In patients with pre-existing CAD, copeptin significantly improves the diagnostic accuracy if used in addition to cTnT, but only trended to superiority compared with hs-cTnT alone. Copeptin provides independent prognostic information, largely by overcoming the challenging interpretation of mild increases in hs-cTnT. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials Gov number NCT00470587. [ABSTRACT FROM AUTHOR]

The article presents a study which explores the concept of flux correction for closed-path laser spectrometers. The study uses a Fast Greenhouse Gas Analyzer in an effort to look into water's (H2O) phase shift and damping with respect of methane (CH4) signal. It discovers that the measurement of trace gas flux is directly affected by the damping of the water vapor signal and cross-sensitivity effects to water.

Quasicontinuous measurements of carbon monoxide (CO) recorded over three years at Mount Waliguan (WLG), a global baseline station in remote western China, were examined using back trajectory analysis. The data include a revision to correct the working reference scale to the WMO2000 scale and corrections for drift in the reference gases. Between July 2004 and June 2007, CO exhibited large fluctuations and the 5%, 50% and 95%-percentiles of relevant CO mixing ratios were 102 ppb, 126 ppb and 194 ppb. Approximately 50% of all observed data were selected as CO background data using a mathematical procedure of robust local regression, with the remainder affected by regional-scale pollution. The monthly mean background CO mixing ratios showed a minimum in summer and a maximum in late winter, although all seasons were affected by short-term enhancements that exceeded background levels. The CO data were compared to values observed at the high alpine research station at Jungfraujoch, Switzerland. Smaller seasonal amplitudes were observed at WLG compared to the Jungfraujoch due to lower winter and spring CO levels, however, episodic enhancements of polluted air were greater at WLG. The air parcels arriving at WLG came predominately from the west, except in summer when advection from the east and southeast prevailed. Transport from the east or southeast typically brought polluted air to the site, having passed over populated urban areas upwind. A large number of elevated CO mixing ratios could also be associated with advection from the northwest of WLG via the central Xinjiang Uygur Autonomous Region (XUAR) and the Ge'ermu urban area where growing industrial activities as well as crops residue burning provide sources of CO. Air masses passing over northwestern Gansu were associated with relatively high CO values suggesting an anthropogenic influence, which was likely due to anthropogenic emissions from northwestern China (based on back-trajectory and potential source contribution analysis and on the INTEX-B: intercontinental Chemical Transport Experiment-Phase B). Background conditions were observed most frequently in air parcels from remote Tibet west of WLG. The probability that air parcels pass over regions of clean or polluted regions was further identified using potential source contribution function (PSCF) analysis. [ABSTRACT FROM AUTHOR]

High frequency measurements of carbon monoxide (CO) recorded over three years at Mount Waliguan (WLG), a global background station in remote western China, were examined using back trajectory analysis. Corrections for the drift in reference gases were also included in the data revision. Between July 2004 and June 2007, a time series of CO exhibited large fluctuations and the 5%, 50% and 95%-percentiles of relevant CO mixing ratios were 102 ppb, 126 ppb and 194 ppb. Approximately 50% of all observed data have been selected as CO background data using a mathematical procedure of robust local regression with the remainder affected by regional-scale pollution. The monthly mean background CO mixing ratios showed a minimum in summer and a maximum in late winter, although all seasons were effected by short-term enhancements that exceeded background levels two or more times. The CO data were compared to the values observed at the high alpine research station Jungfraujoch, Switzerland. Smaller seasonal amplitudes were observed at WLG compared to the Jungfraujoch due to lower winter and spring CO levels, however, episodic enhancements of polluted air were much greater at the site in China. The air parcels arriving at WLG came predominately from the West, except in summer when advection from the East and Southeast prevailed. Transport from the East typically brought polluted air to the site, having passed over populated urban areas upwind. A large number of elevated CO mixing ratios could also be associated with advection from the Northwest of WLG via the central Xinjiang Uygur Autonomous Region (XUAR) and the Ge'ermu urban area where growing industrial activities as well as crops residue burning provide large sources of CO. These background conditions were observed most frequently when air masses originated from remote Tibet west of WLG. The probability that air parcels pass over regions of clean or polluted regions was further identified using potential source contribution function (PSCF) analysis. [ABSTRACT FROM AUTHOR]

Despite the importance of carbon monoxide (CO) for the overall oxidative capacity of the atmosphere, there is still considerable uncertainty in ambient measurements of CO. To address this issue, an inter-comparison between four different measurement techniques was made over a period of two months at the high-alpine site Jungfraujoch (JFJ), Switzerland. The measurement techniques were Nondispersive Infrared Absorption (NDIR), Vacuum UV Resonance Fluorescence (VURF), gas chromatographic separation with a mercuric oxide reduction detector (GC/HgO), and gas chromatographic separation followed by reduction on a nickel catalyst and analysis by a flame ionization detector (GC/FID). The agreement among all techniques was better than 2% for one-hourly averages, which confirmed the suitability of the NDIR method for CO measurements even at remote sites. The inter-comparison added to the validation of the 12-year record (1996-2007) of continuous CO measurements at JFJ. To date this is one of the longest time series of continuous CO measurements in the free troposphere over Central Europe. This data record was further investigated with a focus on trend analysis. A significant negative trend was observed at JFJ showing a decrease of 21.4±0.3% over the investigated period, or an average annual decrease of 1.78%/yr (2.65±0.04 ppb/yr). These results were compared with emission inventory data reported to the Longrange Transboundary Air Pollution (LRTAP) Convention. It could be shown that long range transport significantly influences the CO levels observed at JFJ, with air masses of non-European origin contributing at least one third of the observed mole fractions. [ABSTRACT FROM AUTHOR]

In this study we present the seasonal variability of ozone production efficiencies (EN), defined as the net number of ozone molecules produced per molecule of nitrogen oxides (nitrogen oxide (NO) + nitrogen dioxide (NO2)=NOx) oxidized to NOz (total reactive nitrogen (NOy)-NOx) determined from field measurements of seven-year period (1998-2004) at the Swiss high-alpine research station Jungfraujoch (JFJ), 3580 ma.s.l. This dataset is a unique long-term data series of nitrogen levels in the free troposphere over Central Europe and hence it offers an excellent opportunity to perform such an analysis and provide further evidence to the photochemical origin of the ozone spring maximum at locations of the northern hemisphere distant from nearby pollution sources. Experimentally derived daily EN values have been selected for 571 days out of the 2557 days from 1998 to 2004, from which an average ozone production efficiency of 18.8±1.3 molecules of O3 produced per molecule of NOx oxidized was calculated. This value indicates the great potential and importance of photochemical ozone production in the free troposphere. The monthly means of experimentally derived daily EN values show a seasonal variation with lower values from May to August, which can be probably attributed to more efficient vertical transport of polluted air masses from the atmospheric boundary layer up to JFJ. In agreement, theoretically derived monthly EN values show similar seasonal variation. The ratio NOy/CO, a parameter to assess the aging process that has occurred in an air parcel, was used as a criterion to disaggregate the 571 selected days between undisturbed and disturbed free tropospheric (FT). The monthly means of experimentally derived EN values for the undisturbed FT conditions show a distinct seasonal cycle with higher values in the cold season from November to April. The EN values for undisturbed FT conditions are particularly higher than the respective monthly EN values for disturbed FT conditions from February to October. It should be noted that the monthly EN values of March (EN=35.8) and April (EN=34.9) are among the highest values throughout the year for undisturbed FT conditions at JFJ. These results highlight the key and possibly the dominant role for photochemistry in the observed build-up of tropospheric ozone in the winter-spring transition period. [ABSTRACT FROM AUTHOR]

An automated, ground-based instrument was used to measure gas-phase hydroperoxides at the Jungfraujoch High Altitude Research Station as part of the Free Tropospheric EXperiment (FREETEX) during February/March 2003. A nebulising reflux concentrator sampled ambient air twice hourly, prior to on-site analysis by HPLC speciation, coupled with post-column peroxidase derivatisation and fluorescence detection. Hydrogen peroxide (H2O2) concentrations reached up to 1330 pptv over the 13-day period with a mean of 183±233 pptv (± one standard deviation). Methyl hydroperoxide (CH3OOH) reached up to 379 pptv with a mean of 51±55 pptv. No other organic hydroperoxides were detected. The lack of an explicit diurnal cycle suggests that hydroperoxide concentrations are chiefly influenced by transport processes rather than local photochemistry at this mountainous site. There was some evidence that elevated concentrations of H2O2 existed in air-masses originating from the south-west, suggesting higher concentrations of HOx due to more active photochemistry. Air which had been recently polluted exhibited low H2O2 concentration due to a combination of suppression of HO2 by NOx and deposition. The concentrations of H2O2 sampled here are consistent with previous box modelling studies of hydroperoxides, except in periods influenced by the boundary layer, where agreement required a depositional sink. [ABSTRACT FROM AUTHOR]

The first continuous-wave InGaN multiple quantum well laser diodes grown by molecular beam epitaxy are reported. Ridge waveguide lasers are fabricated on free-standing GaN substrates and operated at room temperature under continuous-wave current injection. For 2.2 × 1000 μm lasers with highly reflective facet coatings a continuous-wave threshold current of 125 mA is obtained, corresponding to a threshold current density of 5.7 kA cm-2. The lasers have a thresh- old voltage of 8.6 V and lase at a wavelength of ∼ 405 nm for >3 min at 20° C. [ABSTRACT FROM AUTHOR]

The highest power InGaN light emitting diodes produced by molecular beam epitaxy are reported. When operated in continuous-wave mode at room temperature, the optical output power of the devices was 3.75 mW at a forward injection current of 20 mA, and the maximum output power was 14.3 mW. The electroluminescence had a peak at 405 nm and a full width half maximum of 15 nm. The electrical characteristics showed a voltage of 4.8 V and a resistance of 31 O at a forward injection current of 20 mA. [ABSTRACT FROM AUTHOR]

Abstract: The latest results from MBE-grown InGaN multiple quantum well laser diodes and light emitting diodes are presented. The laser diodes were grown on free-standing n-type GaN substrates and fabricated into index guided structures with a ridge width of 3.6 and 1000μm cavity length. Laser operation occurred at room temperature under pulsed current injection up to a 10% duty cycle. A typical best threshold current density of 7kAcm−2 and as operating voltage of 10V was achieved. Light emitting diodes were grown on silicon-doped GaN template substrates and fabricated into 1mm2 header mounted, non-encapsulated chips. At 20mA dc current operation, an output power of 3mW was measured. A peak power of 10mW was achieved at 90mA before thermal rollover occurred. The lasers and light emitting diodes emitted in the wavelength range 390–410nm. [Copyright &y& Elsevier]

Metastatic uveal melanoma (mUM) is a rare type of melanoma with poor outcomes. The first systemic treatment to significantly prolong overall survival (OS) in patients with mUM was tebentafusp, a bispecific protein that can redirect T-cells to gp-100 positive cells. However, the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the clinical impact of tebentafusp. As metabolic response assessed by PET Response Criteria in Solid Tumors (PERCIST) has been reported to better correlate with clinical outcome, we here compared the patterns of radiological and morphological responses in HLA-A*02:01-positive patients with mUM treated with tebentafusp. In the 19 enrolled patients, RECIST showed an overall response rate (ORR) of 10%, median progression-free survival of 2.8 months (95% CI 2.5-8.4), and median OS (mOS) of 18.8 months. In 10 patients, where both RECIST and PERCIST evaluation was available, the ORR was 10% for both; however, the PFS was longer for PERCIST compared to RECIST, 3.1 and 2.4 months, respectively. A poor agreement between the criteria was observed at all assessments (Cohen's kappa ≤0), yet they differed significantly only at the first on-treatment imaging ( P  = 0.037). Elevated baseline LDH and age were associated with an increased risk for RECIST progression, while lymphocyte decrease after the first infusions correlated to reduced risk of RECIST progression. Detectable ctDNA at baseline did not correlate with progression. Early response to tebentafusp may be incompletely captured by conventional imaging, leading to a need to consider both tumor morphology and metabolism., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Targeted therapy (TT) of BRAF V600 mutated unresectable melanoma with inhibitors of the MAPK pathway achieves response rates of up to 76%, but most patients develop secondary resistance. Albeit TT is strikingly efficacious during the first days of treatment, even in advanced cases, long-term survival is highly unlikely, especially in patients with unfavorable baseline characteristics like elevated lactate dehydrogenase (LDH). In patients treated with anti-PD-1 immune checkpoint inhibitors, elevated baseline metastatic growth rate (MGR) was the most important prognostic factor. Here, we aimed at investigating the prognostic impact of MGR in patients with unresectable melanoma receiving TT., Methods: Clinical records of 242 patients with at least one measurable target lesion (TL) receiving TT at seven skin cancer centers were reviewed. Baseline MGR was determined measuring the largest TL at baseline and at one earlier timepoint., Results: Overall survival (OS) and progression-free survival (PFS) were significantly impaired in patients with an MGR > 3.9 mm/month (median OS: 11.4 vs. 35.5 months, P < 0.0001; median PFS: 4.8 vs. 9.2 months, P < 0.0001). Multivariable analysis of OS and PFS revealed that the prognostic impact of elevated MGR was independent of LDH, presence of brain and liver metastases, tumor burden, and line of treatment. The prognostic significance of elevated MGR was highest in patients with normal LDH., Conclusions: Baseline MGR is an important independent prognostic marker for OS and PFS in melanoma patients treated with TT. Its implementation in clinical routine is easy and could facilitate the prognostic stratification., Competing Interests: Declaration of Competing Interest N.B.W. has participated in advisory board meetings for Novartis, Pierre Fabre, and Sanofi, and received speaker fees from Sanofi, outside the submitted work. A.Oe. has received consultant fees from MSD and Bristol-Myers Squibb; has participated in advisory board meetings for MSD and Bristol-Myers Squibb. T.A. received institutional grants from SkylineDx, Neracare, Novartis, Sanofi, and consulting fees from Novartis, Neracare, BMS, CeCaVa and Chemosat, outside the submitted work. A.F. served as a consultant to Novartis, MSD, BMS, Pierre-Fabre and Immunocore; received travel support from Novartis, BMS, Pierre-Fabre, and received speaker fees from Novartis, BMS and MSD and reports institutional research grants from BMS Stiftung Immunonkologie, outside the submitted work. U.L. has received consultancy fees from MSD, Novartis, and Roche; has participated in advisory board meetings for MSD, Novartis, and Roche; has received honoraria from MSD, Novartis, and Roche. P.T. has received honoraria and/or consultancy fees from Bristol-Myers Squibb, Curevac, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi; has received travel support from Bristol-Myers Squibb and Pierre-Fabre. J.M. has received consultancy fees from Merck/Pfizer, MSD, Amgen, Novartis, Bristol-Myers Squibb, and Pierre Fabre; has participated in advisory board meetings for Merck/Pfizer, MSD, Amgen, Novartis, Bristol-Myers Squibb, and Pierre Fabre; has received travel support from Ultrasun, L′Oreal, MSD, Bristol-Myers Squibb, and Pierre Fabre. C.L. has received consultancy fees from, has participated in advisory board meetings for, has received speaker’s fees, and/or has received travel reimbursements from Roche, Pierre Fabre, Novartis, Bristol-Myers Squibb, Merck, MSD, Biontech, Almiral Hermal, Kyowa Kirin, Sun Pharma and Sanofi. C.G. has received personal fees from CeCaVa, MSD, NeraCare and Philogen. F.M. has received speaker’s fees from, has received travel support from, and has participated in advisory board meeting for Novartis, Roche, Bristol-Myers Squibb, MSD and Pierre Fabre; has received research funding from Novartis and Roche. T.K.E. has received consultancy fees from Philogen, Bristol-Myers Squibb, Novartis, Roche, Merck, and Sanofi; has participated in advisory board meetings for CureVac, Philogen, Bristol-Myers Squibb, Novartis, Roche, and Sanofi. L.F. has received grant funding from the Swiss National Science Foundation, Swiss Cancer League, Hookipa Pharma and Novartis Foundation; has participated in advisory board meetings for Novartis and Bristol-Myers Squibb. M.M.L., K.K., L.R., M.F., N.R., R.S., C.Z., C.E., S.K., B.K., W.H., and A.C. have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Ltd.)

This pilot study conducted in Switzerland aims to assess the implementation, execution, and performance of low-dose CT lung cancer screening (LDCT-LCS). With lung cancer being the leading cause of cancer-related deaths in Switzerland, the study seeks to explore the potential impact of screening on reducing mortality rates. However, initiating a lung cancer screening program poses challenges and depends on country-specific factors. This prospective study, initiated in October 2018, enrolled participants meeting the National Lung Cancer Study criteria or a lung cancer risk above 1.5% according to the PLCOm2012 lung cancer risk-model. LDCT scans were assessed using Lung-RADS. Enrollment and follow-up are ongoing. To date, we included 112 participants, with a median age of 62 years (IQR 57-67); 42% were female. The median number of packs smoked each year was 45 (IQR 38-57), and 24% had stopped smoking before enrollment. The mean PLCOm2012 was 3.7% (±2.5%). We diagnosed lung cancer in 3.6% of participants (95%, CI:1.0-12.1%), with various stages, all treated with curative intent. The recall rate for intermediate results (Lung-RADS 3,4a) was 15%. LDCT-LCS in Switzerland, using modified inclusion criteria, is feasible. Further analysis will inform the potential implementation of a comprehensive lung cancer screening program in Switzerland.

Objective: To investigate aspects of image quality, feasibility and patient comfort in dedicated spiral breast computed tomography (B-CT) in a large patient cohort., Methods: This retrospective study was approved by the institutional review board. 2418 B-CT scans from 1222 women examined between 04/16/2019 and 04/13/2022 were analyzed. Patients evaluated their comfort during the examination, radiographers carrying out the scans evaluated the patient's mobility and usability of the B-CT device, whereas radiologists assessed lesion contrast, detectability of calcifications, breast coverage and overall image quality. For semi-quantitative assessment, a Likert-Scale was used and statistical significance and correlations were calculated using ANOVAs and Spearman tests., Results: Comfort, mobility and usability of the B-CT were rated each with either "no" or "negligible" complaints in >99%. Image quality was rated with "no" or "negligible complaints" in 96.7%. Lesion contrast and detectability of calcifications were rated either "optimal" or "good" in 92.6% and 98.4%. "Complete" and "almost complete" breast coverage were reported in 41.9%, while the pectoral muscle was found not to be covered in 56.0%. Major parts of the breast were not covered in 2.1%. Some variables were significantly correlated, such as age with comfort (ρ = -0.168, p < .001) and mobility (ρ = -0.172, p < .001) as well as patient weight with lesion contrast (ρ = 0.172, p < .001) and breast coverage (ρ = -0.109, p < .001)., Conclusions: B-CT provides high image quality and contrast of soft tissue lesions as well as calcifications, while covering the pre-pectoral areas of the breast remains challenging. B-CT is easy to operate for the radiographer and comfortable for the majority of women., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to evaluate the diagnostic performance of the maximum intensity projection (MIP) reformations of breast computed tomography (B-CT) images as a stand-alone method for the detection and characterization of breast imaging findings., Materials and Methods: A total of 160 women undergoing B-CT between August 2018 and December 2020 were retrospectively included; 80 patients with known breast imaging findings were matched with 80 patients without imaging findings according to age and amount of fibroglandular tissue (FGT). A total of 71 benign and 9 malignant lesions were included. Images were evaluated using 15-mm MIP in 3 planes by 2 radiologists with experience in B-CT. The presence of lesions and FGT were evaluated, using the BI-RADS classification. Interreader agreement and descriptive statistics were calculated., Results: The interreader agreement of the 2 readers for finding a lesion (benign or malignant) was 0.86 and for rating according to BI-RADS classification was 0.82. One of 9 cancers (11.1%) was missed by both readers due to dense breast tissue. BI-RADS 1 was correctly applied to 73 of 80 patients (91.3%) by reader 1 and to 74 of 80 patients (92.5%) by reader 2 without recognizable lesions. BI-RADS 2 or higher with a lesion in at least one of the breasts was correctly applied in 69 of 80 patients (86.3%) by both readers. For finding a malignant lesion, sensitivity was 88.9% (95% confidence interval [CI], 51.75%-99.72%) for both readers, and specificity was 99.3% (95% CI, 96.4%-100%) for reader 1 and 100% (95% CI, 97.20%-100.00%) for reader 2., Conclusions: Evaluation of B-CT images using the MIP reformations may help to reduce the reading time with high diagnostic performance and confidence., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Checkpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies., Methods: MGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB-IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR., Results: Pretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, p<0.0001), in the confirmation cohort (HR 3.62, 95% CI 2.19 to 5.98, p<0.0001) and in the independent validation cohort (HR 2.57, 95% CI 1.56 to 4.25, p=0.00023). Prior lines of systemic treatment did not influence the significance of MGR. Importantly, the prognostic impact of MGR was independent of total tumor burden, diameter of the largest metastasis, number of prior lines of systemic treatment, LDH, as well as liver and brain metastasis (discovery and confirmation cohorts: both p<0.0001). Superiority of MGR compared with these variables was confirmed in the independent multicenter validation cohort (HR 2.92, 95% CI 1.62 to 5.26, p=0.00036)., Conclusions: High pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens., Competing Interests: Competing interests: NBW reports a consulting/advisory role for Sanofi and has received travel support from AbbVie and Amgen outside the submitted work. RL has received research funding from Bristol-Myers Squibb, Pierre Fabre and Roche, honoraria and travel support from Merck Sharp & Dohme and travel support from Amgen. AO is a consultant/advisory board member for MSD and Bristol-Myers Squibb. AF has received speaker’s honoraria from Bristol-Myers Squibb, MSD, Roche, and Novartis, is advisory board member for Roche and Novartis and received travel support from Roche, Novartis, and Bristol-Myers Squibb. UL is a consultant/advisory board member for and has received honoraria from MSD, Novartis, and Roche. MG is an advisory board member of Novartis and has received grants from Novartis outside the submitted work. CB has received speaker's honoraria and consultancy fees from Amgen, Bristol-Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Regeneron, Roche, and Sanofi-Aventis outside the submitted work, and has received travel support from Bristol-Myers Squibb. ER has received honoraria from and has a consultancy or advisory role for Amgen, Bayer, Bristol-Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche and Sanofi, reports speakers' bureau for Amgen, Bristol-Myers Squibb, MSD, Merck, Novartis, Pierre Fabre and Sanofi, received research funding (at the institution) from Amgen, Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre and Roche, is a member of the research funding steering committee of Novartis, and received travel accommodations and/or expenses from Amgen, Bristol-Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche and Sanofi. JM has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol-Myers Squibb and Pierre Fabre, and has received travel support from Ultrasun, L’Oreal, Merck Sharp & Dohme, Bristol-Myers Squibb and Pierre Fabre outside of the submitted work. PT has received honoraria and/or consultancy fees from Bristol-Myers Squibb, Curevac, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi outside the submitted work, and has received travel support from Bristol-Myers Squibb and Pierre-Fabre. CL is a consultant/advisory board member for and has received advisory board fees, speaker's fees and/or travel reimbursements from Roche, Pierre Fabre, Novartis, Bristol-Myers Squibb, Merck, MSD, Biontech, Almiral Hermal, Kyowa Kirin, Sun Pharma and Sanofi. VAN has received speaker’s honoraria and consultancy fees from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche, and Takeda outside of the submitted work. CGe has received personal speaker/advisory board fees from Amgen, Beiersdorf, BMS, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma and Sanofi Genzyme. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre, and research funding from Novartis and Roche. SD has received travel support from MSD. AC has received consultancy fees from AbbVie, BMS, Almirall, Amgen, Eli Lilly, Galderma, Janssen, Kyowa Kirin, Leo, Novartis, and Sanofi. LF reports grants from the Swiss National Science Foundation, Swiss Cancer League, Hookipa Pharma and Novartis Foundation as well as an advisory role for Novartis and Bristol-Myers Squibb. CGa has received grants and personal fees from Bristol-Myers Squibb, Roche, Novartis and personal fees from Amgen, MSD and Philogen outside the submitted work. TE is a consultant/advisory board member for Philogen, Bristol-Myers Squibb, Novartis, Roche and Sanofi. No other disclosures were reported., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Brown adipose tissue (BAT) is a specialized form of adipose tissue, able to increase energy expenditure by heat generation in response to various stimuli. Recently, its pathological activation has been implicated in the pathogenesis of cancer cachexia. To establish a causal relationship, we retrospectively investigated the longitudinal changes in BAT and cancer in a large FDG-PET/CT cohort., Methods: We retrospectively analyzed 13 461 FDG-PET/CT examinations of n = 8 409 patients at our institution from the winter months of 2007-2015. We graded the activation strength of BAT based on the anatomical location of the most caudally activated BAT depot into three tiers, and the stage of the cancer into five general grades. We validated the cancer grading by an interreader analysis and correlation with histopathological stage. Ambient temperature data (seven-day average before the examination) was obtained from a meteorological station close to the hospital. Changes of BAT, cancer, body mass index (BMI) and temperature between the different examinations were examined with Spearman's test and a mixed linear model for correlation, and with a causal inference algorithm for causality., Results: We found n = 283 patients with at least two examinations and active BAT in at least one of them. There was no significant interaction between the changes in BAT activation, cancer burden or BMI. Temperature changes exhibited a strong negative correlation with BAT activity (ϱ = -0.57, p<0.00001). These results were confirmed with the mixed linear model. Causal inference revealed a link of Temperature ➜ BAT in all subjects and also of BMI ➜ BAT in subjects who had lost weight and increased cancer burden, but no role of cancer and no causal links of BAT ➜ BMI., Conclusions: Our data did not confirm the hypothesis that BAT plays a major role in cancer-mediated weight loss. Temperature changes are the main driver of incidental BAT activity on FDG-PET scans., Competing Interests: The authors have declared that no competing interests exist.

Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell-autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.

Purpose: To evaluate the interreader agreement of a three-tier craniocaudal grading system for brown fat activation and investigate the accuracy of the distinction between the three grades., Materials and Methods: After IRB approval, 340 cases were retrospectively selected from patients undergoing (18)FDG-PET/CT between 2007 and 2015 at our institution, with 85 cases in each grade and 85 controls with no active brown fat. Three readers evaluated all cases independently. Furthermore standardized uptake values (SUV) measurements were performed by two readers in a subset of 53 cases. Agreement between the readers was assessed with Cohen's Kappa (k), the concordance correlation coefficient (CCC) and the intraclass correlation coefficient (ICC). Accuracy was assessed with Bland-Altman and receiver operating characteristics (ROC) analysis. A Bonferroni-corrected two-tailed p<0.016 was considered statistically significant., Results: Agreement for BAT grade was excellent by all three metrics with k=0.83-0.89, CCC=0.83-0.89 and ICC=0.91-0.94. Bland-Altman analysis revealed only slight average over- or underestimation (-0.01-0.14) with the majority of disagreements within one grade. ROC analysis yielded slightly less accurate classification between higher vs. lower grades (Area under the ROC curves 0.78-0.84 vs. 0.88-0.92) but no significant differences between readers. Agreement was also excellent for the maximum SUV and the total brown fat volume (k=0.90 and 0.94, CCC=0.93 and 0.99, ICC=0.96 and 0.99), but Bland-Altman plots revealed a tendency to underestimate activity by one of the readers., Conclusion: Grading the activation of brown fat by assessment of the most caudally activated depots results in excellent interreader agreement, comparable to SUV measurements., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: We explored whether hemodynamic cardiac stress leads to a differential release of cardiomyocyte injury biomarkers, used in the diagnosis of acute myocardial infarction (AMI)., Methods: In an observational international multicenter study, we enrolled 831 unselected patients presenting with symptoms suggestive of AMI to the emergency department. The final diagnosis was adjudicated by two independent cardiologists. Hemodynamic cardiac stress was quantified by levels of B-type natriuretic peptide (BNP). Spearman's rho correlation was used to analyze the correlations between BNP and high-sensitivity cardiac troponin T (hs-cTnT), Siemens cTnI-Ultra (cTnI-ultra), CK-MB and Myoglobin. Patients were categorized according to the extent of hemodynamic cardiac stress as quantified by BNP tertiles., Results: Among all patients, the positive pair-wise correlation with BNP was strongest with hs-cTnT and cTnI-ultra (r=0.58 and 0.50, respectively), moderate for Myoglobin (r=0.43), and weakest with CK-MB (r=0.25; p<0.001 for each). Similar pattern of correlations was also observed among AMI patients. Among patients diagnosed with non-cardiac cause of chest pain (n=385, 46%) and cardiac but non-coronary (n=109, 13%), BNP had significant positive correlations with hs-cTnT, cTnI-ultra and Myoglobin (p<0.05), but not with CK-MB (p=NS). A similar pattern of stronger correlation between BNP and hs-cTnT, cTnI-ultra and Myoglobin as compared to that with CK-MB was also observed within the higher BNP tertile range. There was no correlation between BNP and other biomarkers within the 1st BNP tertile group., Conclusion: Hemodynamic cardiac stress, as quantified by BNP, as a likely cause of cardiomyocyte injury, is more closely reflected by concentrations of hs-cTnT, cTnI-ultra and Myoglobin than CK-MB., (Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: High-sensitivity cardiac troponin (hs-cTn) may allow an earlier diagnosis of acute myocardial infarction (AMI)., Methods: We prospectively enrolled 1148 (derivation cohort) and 517 (external validation cohort) unselected patients presenting with suspected AMI to the emergency department. Final diagnosis was adjudicated by 2 independent cardiologists. Hs-cTnT was measured at presentation and after 2 hours. A diagnostic algorithm incorporating hs-cTnT values at presentation and absolute changes within the first 2 hours was derived., Results: AMI was the final diagnosis in 16% of patients in the derivation and 9.1% in the validation cohort. The 2-hour algorithm developed in the derivation cohort classified 60% of patients as "rule-out," 16% as "rule-in," and 24% in the "observational-zone." Resulting sensitivity and negative predictive value (NPV) were 99.5% and 99.9%, respectively, for rule-out, and specificity and positive predictive value (PPV) were 96% and 78%, respectively, for rule-in. Applying the 2-hour triage algorithm in the external validation cohort, 78% of patients could be classified as "rule-out," 8% as "rule-in," and 14% in the "observational-zone." Resulting sensitivity and NPV were 96% and 99.5%, respectively, for rule-out, and specificity and PPV were 99% and 85%, respectively, for rule-in. Cumulative 30-day survival rates were 100%, 98.9%, and 95.2% (P < .001), and 100%, 100%, and 95% (P < .001) in patients classified as "rule-out," "observational-zone," and "rule-in" in the 2 cohorts, respectively., Conclusions: A simple algorithm incorporating hs-cTnT baseline values and absolute changes over 2 hours allowed a triage toward safe rule-out, or accurate rule-in, of AMI in the vast majority of patients, with only 20% requiring more prolonged monitoring and serial blood sampling., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The incremental value of copeptin, a novel marker of endogenous stress, for rapid rule-out of non-ST-elevation myocardial infarction (NSTEMI) is unclear when sensitive or even high-sensitivity cardiac troponin cTn (hs-cTn) assays are used., Methods: In an international multicenter study we evaluated 1929 consecutive patients with symptoms suggestive of acute myocardial infarction (AMI). Measurements of copeptin, three sensitive and three hs-cTn assays were performed at presentation in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists using all clinical information including coronary angiography and levels of hs-cTnT. The incremental value in the diagnosis of NSTEMI was quantified using four outcome measures: area under the receiver-operating characteristic curve (AUC), integrated discrimination improvement (IDI), sensitivity and negative predictive value (NPV). Early presenters (< 4h since chest pain onset) were a pre-defined subgroup., Results: NSTEMI was the adjudicated final diagnosis in 358 (18.6%) patients. As compared to the use of cTn alone, copeptin significantly increased AUC for two (33%) and IDI (between 0.010 and 0.041 (all p < 0.01)), sensitivity and NPV for all six cTn assays (100%); NPV to 96-99% when the 99 th percentile of the respective cTnI assay was combined with a copeptin level of 9 pmol/l (all p < 0.01). The incremental value in early presenters was similar to that of the overall cohort., Conclusion: When used for rapid rule-out of NSTEM in combination with sensitive or hs-cTnI assays, copeptin provides a numerically small, but statistically and likely also clinically significant incremental value., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)