Showing papers by "University of Bern published in 2022"

The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms.

Abstract: High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 cancer-related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicate a high potential for better-personalized treatments.

Evaluating the 35°C wet-bulb temperature adaptability threshold for young, healthy subjects (PSU HEAT Project)

Abstract: This study is the first to use empirical physiological observations to examine the well-publicized theoretical 35°C wet-bulb temperature limit for human to extreme environments. We find that uncompensable heat stress in humid environments occurs in young, healthy adults at wet-bulb temperatures significantly lower than 35°C. In addition, uncompensable heat stress occurs at widely different wet-bulb temperatures as a function of ambient vapor pressure.

Sleep apnoea and ischaemic stroke: current knowledge and future directions

Abstract: Sleep apnoea, one of the most common chronic diseases, is a risk factor for ischaemic stroke, stroke recurrence, and poor functional recovery after stroke. More than half of stroke survivors present with sleep apnoea during the acute phase after stroke, with obstructive sleep apnoea being the most common subtype. Following a stroke, sleep apnoea frequency and severity might decrease over time, but moderate to severe sleep apnoea is nevertheless present in up to a third of patients in the chronic phase after an ischaemic stroke. Over the past few decades evidence suggests that treatment for sleep apnoea is feasible during the acute phase of stroke and might favourably affect recovery and long-term outcomes. Nevertheless, sleep apnoea still remains underdiagnosed and untreated in many cases, due to challenges in the detection and prediction of post-stroke sleep apnoea, uncertainty as to the optimal timing for its diagnosis, and a scarcity of clear treatment guidelines (ie, uncertainty on when to treat and the optimal treatment strategy). Moreover, the pathophysiology of sleep apnoea associated with stroke, the proportion of stroke survivors with obstructive and central sleep apnoea, and the temporal evolution of sleep apnoea subtypes following stroke remain to be clarified. To address these shortcomings, the management of sleep apnoea associated with stroke should be integrated into a multidisciplinary diagnostic, treatment, and follow-up strategy.

Muonic force behind flavor anomalies

Abstract: A bstract We develop an economical theoretical framework for combined explanations of the flavor physics anomalies involving muons: ( g − 2) μ , $$ {R}_{K^{\left(\ast \right)}} $$ R K ∗ , and b → sμ + μ − angular distributions and branching ratios, that was first initiated by some of us in ref. [1]. The Standard Model (SM) is supplemented with a lepton-flavored U(1) X gauge group. The U(1) X gauge boson with the mass of $$ \mathcal{O} $$ O (0 . 1) GeV resolves the ( g − 2) μ tension. A TeV-scale leptoquark, charged under the U(1) X , carries a muon number and mediates B -decays without prompting charged lepton flavor violation or inducing proton decay. We explore the theory space of the chiral, anomaly-free U(1) X gauge extensions featuring the above scenario, and identify many suitable charge assignments for the SM+3 ν R fermion content with the integer charges in the range $$ {X}_{F_i} $$ X F i ∈ [ − 10 , 10]. We then carry out a comprehensive phenomenological study of the muonic force in representative benchmark models. Interestingly, we found models which can resolve the tension without conflicting the complementary constraints, and all of the viable parameter space will be tested in future muonic resonance searches. Finally, the catalog of the anomaly-free lepton-non-universal charge assignments motivated us to explore different directions in model building. We present a model in which the muon mass and the ( g − 2) μ are generated radiatively from a common short-distance dynamics after the U(1) X breaking. We also show how to charge a vector leptoquark under U(1) μ−τ in a complete gauge model.

Reaction classification and yield prediction using the differential reaction fingerprint DRFP

Abstract: Predicting the nature and outcome of reactions using computational methods is a crucial tool to accelerate chemical research. The recent application of deep learning-based learned fingerprints to reaction classification and reaction yield prediction has shown an impressive increase in performance compared to previous methods such as DFT- and structure-based fingerprints. However, learned fingerprints require large training data sets, are inherently biased, and are based on complex deep learning architectures. Here we present the differential reaction fingerprint DRFP. The DRFP algorithm takes a reaction SMILES as an input and creates a binary fingerprint based on the symmetric difference of two sets containing the circular molecular n-grams generated from the molecules listed left and right from the reaction arrow, respectively, without the need for distinguishing between reactants and reagents. We show that DRFP performs better than DFT-based fingerprints in reaction yield prediction and other structure-based fingerprints in reaction classification, reaching the performance of state-of-the-art learned fingerprints in both tasks while being data-independent.

Results and interpretation of a fitting challenge for MR spectroscopy set up by the MRS study group of ISMRM

Abstract: PURPOSE Fitting of MRS data plays an important role in the quantification of metabolite concentrations. Many different spectral fitting packages are used by the MRS community. A fitting challenge was set up to allow comparison of fitting methods on the basis of performance and robustness. METHODS Synthetic data were generated for 28 datasets. Short-echo time PRESS spectra were simulated using ideal pulses for the common metabolites at mostly near-normal brain concentrations. Macromolecular contributions were also included. Modulations of signal-to-noise ratio (SNR); lineshape type and width; concentrations of γ-aminobutyric acid, glutathione, and macromolecules; and inclusion of artifacts and lipid signals to mimic tumor spectra were included as challenges to be coped with. RESULTS Twenty-six submissions were evaluated. Visually, most fit packages performed well with mostly noise-like residuals. However, striking differences in fit performance were found with bias problems also evident for well-known packages. In addition, often error bounds were not appropriately estimated and deduced confidence limits misleading. Soft constraints as used in LCModel were found to substantially influence the fitting results and their dependence on SNR. CONCLUSIONS Substantial differences were found for accuracy and precision of fit results obtained by the multiple fit packages.

Acceptance and Adherence to COVID-19 Preventive Measures are Shaped Predominantly by Conspiracy Beliefs, Mistrust in Science and Fear – A Comparison of More than 20 Psychological Variables

Abstract: The global coronavirus (COVID-19) pandemic sparked a great interest in psychological factors that determine or explain peoples' responses to the novel threatening situation and the preventive measures (e.g. wearing masks, social distancing). In this study, we focused on contaminated mindware (conspiracy and paranormal beliefs) and investigated its relationship with both acceptance of and adherence to COVID-19 preventive measures, along with other variables from the domains of emotion (trait anxiety, fear), traditional personality traits (Big 5, locus of control, optimism/pessimism) and motivation (self-control, dispositional regulatory focus). A total of 22 variables were measured in an online survey ( N = 374) that took place during the second wave of COVID-19 (Nov. 2020 – March 2021) in Switzerland. Of all variables, the endorsement of specific COVID-19 conspiracy beliefs was most strongly associated with lower acceptance and adherence to the preventive measures, together with mistrust in science and a more right-wing political orientation. In contrast, fear of COVID-19 and prevention regulatory focus were positively associated with acceptance and adherence. Our results therefore highlight the importance of fighting (conspiratorial) misinformation and of increasing the perceived credibility of science in reducing the spread of the coronavirus. Moreover, when acceptance was used as predictor for adherence, agreeableness and dispositional prevention regulatory focus still explained unique variance in adherence, suggesting that such personality and motivational variables play an important role in adhering and regulating preventive behaviour independent from the attitude towards the preventive measures themselves.

Reliability of common mouse behavioural tests of anxiety: A systematic review and meta-analysis on the effects of anxiolytics

Abstract: The validity of widely used rodent behavioural tests of anxiety has been questioned, as they often fail to produce consistent results across independent replicate studies. In this study, we assessed the sensitivity of common behavioural tests of anxiety in mice to detect anxiolytic effects of drugs prescribed to treat anxiety in humans. We conducted a pre-registered systematic review of 814 studies reporting effects of 25 anxiolytic compounds using common behavioural tests for anxiety. Meta-analyses of effect sizes of treatments showed that only two out of 17 commonly used test measures reliably detected effects of anxiolytic compounds. We report considerable between-study variation in size and even direction of effects of most anxiolytics on most outcome variables. Our findings indicate a general lack of sensitivity of those behavioural tests and cast serious doubt on both construct and predictive validity of most of these tests. In view of scientifically valid and ethically responsible research, we call for a revision of behavioural tests of anxiety in mice and the development of more predictive tests.

Modelling submerged biofouled microplastics and their vertical trajectories

Abstract: Abstract. The fate of (micro)plastic particles in the open ocean is controlled by biological and physical processes. Here, we model the effects of biofouling on the subsurface vertical distribution of spherical, virtual plastic particles with radii of 0.01–1 mm. The biological specifications include the attachment, growth and loss of algae on particles. The physical specifications include four vertical velocity terms: advection, wind-driven mixing, tidally induced mixing and the sinking velocity of the biofouled particle. We track 10 000 particles for 1 year in three different regions with distinct biological and physical properties: the low-productivity region of the North Pacific Subtropical Gyre, the high-productivity region of the equatorial Pacific and the high mixing region of the Southern Ocean. The growth of biofilm mass in the euphotic zone and loss of mass below the euphotic zone result in the oscillatory behaviour of particles, where the larger (0.1–1.0 mm) particles have much shorter average oscillation lengths (<10 d; 90th percentile) than the smaller (0.01–0.1 mm) particles (up to 130 d; 90th percentile). A subsurface maximum particle concentration occurs just below the mixed-layer depth (around 30 m) in the equatorial Pacific, which is most pronounced for larger particles (0.1–1.0 mm). This occurs because particles become neutrally buoyant when the processes affecting the settling velocity of a particle and the seawater's vertical movement are in equilibrium. Seasonal effects in the subtropical gyre result in particles sinking below the mixed-layer depth only during spring blooms but otherwise remaining within the mixed layer. The strong winds and deepest average mixed-layer depth in the Southern Ocean (400 m) result in the deepest redistribution of particles (>5000 m). Our results show that the vertical movement of particles is mainly affected by physical (wind-induced mixing) processes within the mixed-layer and biological (biofilm) dynamics below the mixed layer. Furthermore, positively buoyant particles with radii of 0.01–1.0 mm can sink far below the euphotic zone and mixed layer in regions with high near-surface mixing or high biological activity. This work can easily be coupled to other models to simulate open-ocean biofouling dynamics, in order to reach a better understanding of where ocean (micro)plastic ends up.

Magnetic resonance imaging of cerebrospinal fluid outflow after low-rate lateral ventricle infusion in mice

Abstract: The anatomical routes for the clearance of cerebrospinal fluid (CSF) remain incompletely understood. However, recent evidence has given strong support for routes leading to lymphatic vessels. A current debate centers upon the routes through which CSF can access lymphatics, with evidence emerging for either direct routes to meningeal lymphatics or along cranial nerves to reach lymphatics outside the skull. Here, a method was established to infuse contrast agent into the ventricles using indwelling cannulae during imaging of mice at 2 and 12 months of age by magnetic resonance imaging. As expected, a substantial decline in overall CSF turnover was found with aging. Quantifications demonstrated that the bulk of the contrast agent flowed from the ventricles to the subarachnoid space in the basal cisterns. Comparatively little contrast agent signal was found at the dorsal aspect of the skull. The imaging dynamics from the 2 cohorts revealed that the contrast agent was cleared from the cranium through the cribriform plate to the nasopharyngeal lymphatics. On decalcified sections, we confirmed that fluorescently labeled ovalbumin drained through the cribriform plate and could be found within lymphatics surrounding the nasopharynx. In conclusion, routes leading to nasopharyngeal lymphatics appear to be a major efflux pathway for cranial CSF.

Use and Perception of Telemedicine in People with Type 1 Diabetes During the COVID-19 Pandemic: A 1-Year Follow-Up

Abstract: Background: In the spring of 2020, our research group circulated a worldwide survey with the aim of gathering information on the use and perception of telemedicine in people living with type 1 diabetes at the start of the COVID-19 pandemic. The data suggested that a large number of respondents had rapidly adopted to telemedicine, as in-person visits were not possible, and that this was perceived positively by many. In this study, we conducted a 1-year follow-up to investigate changes in opinions and experiences to telemedicine over the past year of the pandemic. Methods: An anonymous questionnaire was distributed through social media (Twitter, Facebook, and Instagram) between May 9 and May 15, 2021, using an open-access web-based platform (SurveyMonkey.com). The survey was identical to that used in the original study, covering questions relating to the use and perception of telemedicine, diabetes treatment and control, and medical supplies during the COVID-19 pandemic. The questionnaire was available in English, Spanish, German, French, and Italian. We compared the results from the two surveys descriptively and statistically, results were stratified according to age, gender, and HbA1c. Results: There were 531 survey responses from 40 countries (Europe 54%, North America 36%, South America 2%, and Africa and Asia 2%). A large percentage of respondents (67%) reported meeting with their health care provider remotely since the beginning of the pandemic, a significant increase compared with the 28% in the 2020 survey (P < 0.001). Eighty-three percent of respondents found remote appointments to be somewhat-to-extremely useful, similar to the 86% satisfaction rate in the previous survey (P = 0.061). Remote appointments were most frequently undertaken through telephone (50%) and video call (45%), which are significant changes compared with those in 2020 (72% and 28%, respectively, P < 0.001). Forty-five percent of respondents in 2021 were likely to consider remote appointments instead of in-person appointments in the future-being significantly lower than the 75% in the initial survey (P < 0.001)-whereas 37% indicated they would not. The majority of respondents (84%) reported no issues in their access to diabetes supplies and medication over the past year. Conclusions: This study showed that the use of telemedicine in the form of remote appointments increased during the COVID-19 pandemic in people living with type 1 diabetes, with high levels of satisfaction. However, a remarkable decline took place in the past year in the proportion of patients stating a willingness to continue with remote appointments beyond the pandemic. It seems that a personalized approach is needed since a substantial proportion of respondents in this follow-up still indicated a preference for in-person diabetes care, hence the use of telemedicine should be considered on an individual basis.

Network Meta-Analysis.

Abstract: There are often multiple potential interventions to treat a disease; therefore, we need a method for simultaneously comparing and ranking all of these available interventions. In contrast to pairwise meta-analysis, which allows for the comparison of one intervention to another based on head-to-head data from randomized trials, network meta-analysis (NMA) facilitates simultaneous comparison of the efficacy or safety of multiple interventions that may not have been directly compared in a randomized trial. NMAs help researchers study important and previously unanswerable questions, which have contributed to a rapid rise in the number of NMA publications in the biomedical literature. However, the conduct and interpretation of NMAs are more complex than pairwise meta-analyses: there are additional NMA model assumptions (i.e., network connectivity, homogeneity, transitivity, and consistency) and outputs (e.g., network plots and surface under the cumulative ranking curves [SUCRAs]). In this chapter, we will: (1) explore similarities and differences between pairwise and network meta-analysis; (2) explain the differences between direct, indirect, and mixed treatment comparisons; (3) describe how treatment effects are derived from NMA models; (4) discuss key criteria predicating completion of NMA; (5) interpret NMA outputs; (6) discuss areas of ongoing methodological research in NMA; (7) outline an approach to conducting a systematic review and NMA; (8) describe common problems that researchers encounter when conducting NMAs and potential solutions; and (9) outline an approach to critically appraising a systematic review and NMA.

Computing the gauge-invariant bubble nucleation rate in finite temperature effective field theory

Abstract: A bstract A gauge-invariant framework for computing bubble nucleation rates at finite temperature in the presence of radiative barriers was presented and advocated for model-building and phenomenological studies in an accompanying article [1]. Here, we detail this computation using the Abelian Higgs Model as an illustrative example. Subsequently, we recast this approach in the dimensionally-reduced high-temperature effective field theory for nucleation. This allows for including several higher order thermal resummations and furthermore delineate clearly the approach’s limits of validity. This approach provides for robust perturbative treatments of bubble nucleation during possible first-order cosmic phase transitions, with implications for electroweak baryogenesis and production of a stochastic gravitational wave background. Furthermore, it yields a sound comparison between results of perturbative and non-perturbative computations.

Critical environmental limits for young, healthy adults (PSU HEAT Project)

Abstract: Critical environmental limits are those combinations of ambient temperature and humidity above which heat balance cannot be maintained for a given metabolic heat production, limiting exposure time, and placing individuals at increased risk of heat-related illness. The aim of this study was to establish those limits in young (18-34 yr) healthy adults during low-intensity activity approximating the metabolic demand of activities of daily living. Twenty-five (12 men/13 women) subjects were exposed to progressive heat stress in an environmental chamber at two rates of metabolic heat production chosen to represent minimal activity (MinAct) or light ambulation (LightAmb). Progressive heat stress was performed with either 1) constant dry-bulb temperature (Tdb) and increasing ambient water vapor pressure (Pa) (Pcrit trials; 36°C, 38°C, or 40°C) or 2) constant Pa and increasing Tdb (Tcrit trials; 12, 16, or 20 mmHg). Each subject was tested during MinAct and LightAmb in two to three experimental conditions in random order, for a total of four to six trials per participant. Higher metabolic heat production (P < 0.001) during LightAmb compared with MinAct trials resulted in significantly lower critical environmental limits across all Pcrit and Tcrit conditions (all P < 0.001). These data, presented graphically herein on a psychrometric chart, are the first to define critical environmental limits for young adults during activity resembling those of light household tasks or other activities of daily living and can be used to develop guidelines, policy decisions, and evidence-based alert communications to minimize the deleterious impacts of extreme heat events.NEW & NOTEWORTHY Critical environmental limits are those combinations of temperature and humidity above which heat balance cannot be maintained, placing individuals at increased risk of heat-related illness. Those limits have been investigated in young adults during exercise at 30% V̇o2max, but not during metabolic rates that approximate those of light activities of daily living. Herein, we establish critical environmental limits for young adults at two metabolic rates that reflect activities of daily living and leisurely walking.

Bedside formulation of a personalized multi-neoantigen vaccine against mammary carcinoma

Abstract: Harnessing the immune system to purposely recognize and destroy tumors represents a significant breakthrough in clinical oncology. Non-synonymous mutations (neoantigenic peptides) were identified as powerful cancer targets. This knowledge can be exploited for further improvements of active immunotherapies, including cancer vaccines, as T cells specific for neoantigens are not attenuated by immune tolerance mechanism and do not harm healthy tissues. The current study aimed at developing an optimized multitarget vaccine using short or long neoantigenic peptides utilizing virus-like particles (VLPs) as an efficient vaccine platform.Mutations of murine mammary carcinoma cells were identified by integrating mass spectrometry-based immunopeptidomics and whole exome sequencing. Neoantigenic peptides were synthesized and covalently linked to virus-like nanoparticles using a Cu-free click chemistry method for easy preparation of vaccines against mouse mammary carcinoma.As compared with short peptides, vaccination with long peptides was superior in the generation of neoantigen-specific CD4+ and CD8+ T cells, which readily produced interferon gamma (IFN-γ) and tumor-necrosis factor α (TNF-α). The resulting anti-tumor effect was associated with favorable immune re-polarization in the tumor microenvironment through reduction of myeloid-derived suppressor cells. Vaccination with long neoantigenic peptides also decreased post-surgical tumor recurrence and metastases, and prolonged mouse survival, despite the tumor's low mutational burden.Integrating mass spectrometry-based immunopeptidomics and whole exome sequencing is an efficient approach for identifying neoantigenic peptides. Our multitarget VLP-based vaccine shows a promising anti-tumor effect in an aggressive murine mammary carcinoma model. Future clinical application using this strategy is readily feasible and practical, as click chemistry coupling of personalized synthetic peptides to the nanoparticles can be done at the bedside directly before injection.