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Abstract Background Dual-energy CT (DECT) can acknowledge differences in tissue compositions and can colour-code tissues with specific features including monosodium urate (MSU) crystals. However, when evaluating gout patients, DECT frequently colour-codes material not truly representing MSU crystals and this might lead to misinterpretations. The characteristics of and variations in properties of colour-coded DECT lesions in gout patients have not yet been systematically investigated. The objective of this study was to evaluate the properties and locations of colour-coded DECT lesions in gout patients. Methods DECT of the hands, knees and feet were performed in patients with suspected gout using factory default gout settings, and colour-coded DECT lesions were registered. For each lesion, properties [mean density (mean of Hounsfield Units (HU) at 80 kV and Sn150kV), mean DECT ratio and size] and location were determined. Subgroup analysis was performed post hoc evaluating differences in locations of lesions when divided into definite MSU depositions and possibly other lesions. Results In total, 4033 lesions were registered in 27 patients (23 gout patients, 3918 lesions; 4 non-gout patients, 115 lesions). In gout patients, lesions had a median density of 160.6 HU and median size of 6 voxels, and DECT ratios showed an approximated normal distribution (mean 1.06, SD 0.10), but with a right heavy tail consistent with the presence of smaller amounts of high effective atomic number lesions (e.g. calcium-containing lesions). The most common locations of lesions were 1st metatarsophalangeal (MTP1), knee and midtarsal joints along with quadriceps and patella tendons. Subgroup analyses showed that definite MSU depositions (large volume, low DECT ratio, high density) had a similar distribution pattern, whereas possible calcium-containing material (high DECT ratio) and non-gout MSU-imitating lesions (properties as definite MSU depositions in non-gout patients) were primarily found in some larger joints (knee, midtarsal and talocrural) and tendons (Achilles and quadriceps). MTP1 joints and patella tendons showed only definite MSU depositions. Conclusion Colour-coded DECT lesions in gout patients showed heterogeneity in properties and distribution. MTP1 joints and patella tendons exclusively showed definite MSU depositions. Hence, a sole focus on these regions in the evaluation of gout patients may improve the specificity of DECT scans.

Surfactant protein B (SP-B) deficiency is a genetic lung disease that results in lethal respiratory distress within months of birth. Here, the authors describe a gene therapy strategy using a rationally designed AAV6 capsid that restores surfactant homeostasis, prevents lung injury, and improves survival in a mouse model of SP-B deficiency.

Abstract Neurodegenerative diseases are a growing burden, and there is an urgent need for better biomarkers for diagnosis, prognosis, and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF). Alzheimer's disease (AD) patients have higher CSF levels of tau, but we lack knowledge of systems‐wide changes of CSF protein levels that accompany AD. Here, we present a highly reproducible mass spectrometry (MS)‐based proteomics workflow for the in‐depth analysis of CSF from minimal sample amounts. From three independent studies (197 individuals), we characterize differences in proteins by AD status (> 1,000 proteins, CV

Abstract Background Phosphoinositide lipids provide spatial landmarks during polarized cell growth and migration. Yet how phosphoinositide gradients are oriented in response to extracellular cues and environmental conditions is not well understood. Here, we elucidate an unexpected mode of phosphatidylinositol 4-phosphate (PI4P) regulation in the control of polarized secretion. Results We show that PI4P is highly enriched at the plasma membrane of growing daughter cells in budding yeast where polarized secretion occurs. However, upon heat stress conditions that redirect secretory traffic, PI4P rapidly increases at the plasma membrane in mother cells resulting in a more uniform PI4P distribution. Precise control of PI4P distribution is mediated through the Osh (oxysterol-binding protein homology) proteins that bind and present PI4P to a phosphoinositide phosphatase. Interestingly, Osh3 undergoes a phase transition upon heat stress conditions, resulting in intracellular aggregates and reduced cortical localization. Both the Osh3 GOLD and ORD domains are sufficient to form heat stress-induced aggregates, indicating that Osh3 is highly tuned to heat stress conditions. Upon loss of Osh3 function, the polarized distribution of both PI4P and the exocyst component Exo70 are impaired. Thus, an intrinsically heat stress-sensitive PI4P regulatory protein controls the spatial distribution of phosphoinositide lipid metabolism to direct secretory trafficking as needed. Conclusions Our results suggest that control of PI4P metabolism by Osh proteins is a key determinant in the control of polarized growth and secretion.

Abstract Background Bevacizumab, a monoclonal antibody against soluble VEGFA, is an approved and commonly administered anti-angiogenic drug in patients with metastasized colorectal cancer (mCRC). The survival benefit of anti-VEGF therapy in mCRC patients is limited to a few months, and acquired resistance mechanisms are largely unknown. Here, we employed whole-genome sequencing of plasma DNA to evaluate the tumor genome of patients undergoing treatment with bevacizumab to determine novel aberrations associated with resistance. Methods Using longitudinal plasma analyses, we studied the evolution of tumor genomes in a mCRC cohort (n = 150) and conducted analyses of CRC cases from The Cancer Genome Atlas (TCGA) database (n = 619) to identify associations between genomic aberrations and clinical features. We employed whole-genome sequencing to identify the most frequently occurring focal somatic copy number alterations (SCNAs). Using the TCGA data as a comparative and supporting dataset, we defined the minimally amplified overlapping region and studied the mechanistic consequences of copy number gain of the involved genes in this segment. In addition, we established an in vitro cell model and conducted downstream gene expression and cell viability assays to confirm our findings from the patient dataset. Results We observed a recurrent focal amplification (8.7% of cases) on chromosome 13q12.2. Analysis of CRC cases from the TCGA database suggested that this amplicon is associated with more advanced stages. We confirmed that this 13q12.2 amplicon frequently emerges later during the clinical course of disease. After defining the minimally amplified region, we observed that the amplification and expression of one gene, POLR1D, impacted cell proliferation and resulted in upregulation of VEGFA, an important regulator of angiogenesis which has been implicated in the resistance to bevacizumab treatment. In fact, in several patients, we observed the emergence of this 13q12.2 amplicon under bevacizumab treatment, which was invariably associated with therapy resistance. Conclusions Non-invasive analyses of cell-free DNA from patients undergoing treatment with bevacizumab enabled the tracking of evolving tumor genomes and helped identify a recurrent focal SCNA of clinical relevance. Here, we describe a novel resistance mechanism against a widely applied treatment in patients with mCRC which will impact the clinical management of patients.

Purpose: The frequency of medication prescribing and polypharmacy has increased in recent years in different settings, including Swiss general practice. We aimed to describe patient age- and sex-specific rates of polypharmacy and of prescriptions of the most frequent medication classes, and to explore practitioner variability in prescribing.Methods: Retrospective cross-sectional study based on anonymized electronic medical records data of 111 811 adult patients presenting to 116 Swiss general practitioners in 2019. We used mixed-effects regression analyses to assess the association of patient age and sex with polypharmacy (≥5 medications) and with the prescription of specific medication classes (second level of the Anatomical Therapeutic Chemical Classification System). Practitioner variability was quantified in terms of the random effects distributions.Results: The prevalence of polypharmacy increased with age from 6.4% among patients aged 18–40 years to 19.7% (41–64 years), 45.3% (65–80 years), and 64.6% (81–92 years), and was higher in women than in men, particularly at younger ages. The most frequently prescribed medication classes were antiinflammatory and antirheumatic products (21.6% of patients), agents acting on the renin-angiotensin system (19.9%), analgesics (18.7%), and drugs for acid related disorders (18.3%). Men were more often prescribed agents targeting the cardiovascular system, whereas most other medications were more often prescribed to women. The highest practitioner variabilities were observed for vitamins, for antiinflammatory and antirheumatic products, and for mineral supplements.Conclusion: Based on practitioner variability, prevalence, and risk potential, antiinflammatory drugs and polypharmacy in older patients appear to be the most pressing issues in current drug prescribing routines.

JWST has revolutionized the field of extragalactic astronomy with its sensitive and high-resolution infrared view of the distant Universe. Adding to the new legacy of JWST observations, we present the first NIRCam imaging data release from the JWST Advanced Deep Extragalactic Survey (JADES), providing nine filters of infrared imaging of ∼25 arcmin ^2 covering the Hubble Ultra Deep Field and portions of Great Observatories Origins Deep Survey South. Utilizing 87 on-sky dual-filter hours of exposure time, these images reveal the deepest ever near-infrared view of this iconic field. We supply carefully constructed nine-band mosaics of the JADES bands, as well as matching reductions of five additional bands from the JWST Extragalactic Medium-band Survey. Combining with existing Hubble Space Telescope imaging, we provide 23-band space-based photometric catalogs and photometric redshifts for ≈47,500 sources. To promote broad engagement with JADES, we have created an interactive FitsMap website to provide an interface for professional researchers and the public to experience these JWST data sets. Combined with the first JADES NIRSpec data release, these public JADES imaging and spectroscopic data sets provide a new foundation for discoveries of the infrared Universe by the worldwide scientific community.

We present JWST Extragalactic Medium-band Survey, the first public medium-band imaging survey carried out using JWST/NIRCam and NIRISS. These observations use ∼2 and ∼4 μ m medium-band filters (NIRCam F182M, F210M, F430M, F460M, F480M; and NIRISS F430M and F480M in parallel) over 15.6 arcmin ^2 in the Hubble Ultra Deep Field (UDF), thereby building on the deepest multiwavelength public data sets available anywhere on the sky. We describe our science goals, survey design, NIRCam and NIRISS image reduction methods, and describe our first data release of the science-ready mosaics, which reach 5 σ point-source limits (AB mag) of ∼29.3–29.4 in 2 μ m filters and ∼28.2–28.7 at 4 μ m. Our chosen filters create a JWST imaging survey in the UDF that enables novel analysis of a range of spectral features potentially across the redshift range of 0.3 < z < 20, including Paschen- α , H α +[N ii ], and [O iii ]+H β emission at high spatial resolution. We find that our JWST medium-band imaging efficiently identifies strong line emitters (medium-band colors >1 mag) across redshifts 1.5 < z < 9.3, most prominently H α +[N ii ] and [O iii ]+H β . We present our first data release including science-ready mosaics of each medium-band image available to the community, adding to the legacy value of past and future surveys in the UDF. This survey demonstrates the power of medium-band imaging with JWST, informing future extragalactic survey strategies using JWST observations.

We present JWST NIRCam nine-band near-infrared imaging of the luminous z = 10.6 galaxy GN-z11 from the JWST Advanced Deep Extragalactic Survey of the GOODS-N field. We find a spectral energy distribution (SED) entirely consistent with the expected form of a high-redshift galaxy: a clear blue continuum from 1.5 to 4 μ m with a complete dropout in F115W. The core of GN-z11 is extremely compact in JWST imaging. We analyze the image with a two-component model, using a point source and a Sérsic profile that fits to a half-light radius of 200 pc and an index n = 0.9. We find a low-surface-brightness haze about 0.″4 to the northeast of the galaxy, which is most likely a foreground object but might be a more extended component of GN-z11. At a spectroscopic redshift of 10.60 (Bunker et al. 2023 ), the comparison of the NIRCam F410M and F444W images spans the Balmer jump. From population-synthesis modeling, here assuming no light from an active galactic nucleus, we reproduce the SED of GN-z11, finding a stellar mass of ∼10 ^9 M _⊙ , a star formation rate of ∼20 M _⊙ yr ^−1 , and a young stellar age of ∼20 Myr. Since massive galaxies at high redshift are likely to be highly clustered, we search for faint neighbors of GN-z11, finding nine galaxies out to ∼5 comoving Mpc transverse with photometric redshifts consistent with z = 10.6, and a tenth more tentative dropout only 3″ away. This is consistent with GN-z11 being hosted by a massive dark-matter halo (≈8 × 10 ^10 M _⊙ ), though lower halo masses cannot be ruled out.

Hyperpolarization of nuclear spins enhances nuclear magnetic resonance signals, which play a key role for imaging and spectroscopy in the natural and life sciences. This signal amplification unlocks previously inaccessible techniques, such as metabolic imaging of cancer cells. In this paper, electron spins from the photoexcited triplet state of pentacene-doped naphthalene crystals are used to polarize surrounding protons. As existing strategies are rendered less effective by experimental constraints, they are replaced with optimal control pulses designed with redcrab. In contrast to previous optimal control approaches, which consider one or two effective nuclei, this closed-loop optimization is macroscopic. A 26% improvement in signal and 15% faster polarization rate are observed. Additionally, a strategy called autonomously optimized repeated linear sweep (ARISE) is introduced to efficiently tailor existing hyperpolarization sequences in the presence of experimental uncertainty to enhance their performance. ARISE is expected to be broadly applicable in many experimental settings.

Background: The level of evidence for palliative second-line therapy in advanced esophageal squamous cell carcinoma (aESCC) is limited. This is the first study that reports efficacy data comparing second-line therapy + active symptom control (ASC) versus ASC alone in aESCC. Methods: We conducted a tri-center retrospective cohort study ( n = 166) including patients with aESCC who had experienced disease progression on palliative first-line therapy. A propensity score model using inverse probability of treatment weighting (IPTW) was implemented for comparative efficacy analysis of overall survival (OS) in patients with second-line + ASC ( n = 92, 55%) versus ASC alone ( n = 74, 45%). Results: The most frequent second-line regimens used were docetaxel (36%) and paclitaxel (18%). In unadjusted primary endpoint analysis, second-line + ASC was associated with significantly longer OS compared with ASC alone [hazard ratio (HR) = 0.49, 95% confidence interval (CI): 0.35–0.69, p

Two-component systems, consisting of a histidine kinase and a response regulator, serve signal transduction in bacteria, often regulating transcription in response to environmental stimuli. Here, we identify a tandem serine histidine kinase function for KdpD, previously described as a histidine kinase of the KdpDE two-component system, which controls production of the potassium pump KdpFABC. We show that KdpD additionally mediates an inhibitory serine phosphorylation of KdpFABC at high potassium levels, using not its C-terminal histidine kinase domain but an N-terminal atypical serine kinase domain. Sequence analysis of KdpDs from different species highlights that some KdpDs are much shorter than others. We show that, while Escherichia coli KdpD's atypical serine kinase domain responds directly to potassium levels, a shorter version from Deinococcus geothermalis is controlled by second messenger cyclic di-AMP. Our findings add to the growing functional diversity of sensor kinases while simultaneously expanding the framework for regulatory mechanisms in bacterial potassium homeostasis. KdpD is known as the sensory histidine kinase of two-component system KdpDE that controls the transcription of the kdpFABC genes. Here, the authors show that KdpD acts as atypical serine kinase, which post-translationally regulates KdpFABC. [ABSTRACT FROM AUTHOR]

Abstract Plasma and serum are rich sources of information regarding an individual's health state, and protein tests inform medical decision making. Despite major investments, few new biomarkers have reached the clinic. Mass spectrometry (MS)‐based proteomics now allows highly specific and quantitative readout of the plasma proteome. Here, we employ Plasma Proteome Profiling to define quality marker panels to assess plasma samples and the likelihood that suggested biomarkers are instead artifacts related to sample handling and processing. We acquire deep reference proteomes of erythrocytes, platelets, plasma, and whole blood of 20 individuals (> 6,000 proteins), and compare serum and plasma proteomes. Based on spike‐in experiments, we determine sample quality‐associated proteins, many of which have been reported as biomarker candidates as revealed by a comprehensive literature survey. We provide sample preparation guidelines and an online resource ( www.plasmaproteomeprofiling.org ) to assess overall sample‐related bias in clinical studies and to prevent costly miss‐assignment of biomarker candidates.

Jana S Jensen,1,* Stella Reiter-Theil,2,* Diana A Celio,3 Marcel Jakob,1 Werner Vach,1 Franziska J Saxer1 1Department of Orthopaedic and Trauma Surgery, University Hospital Basel, Basel 4031, Switzerland; 2Department of Clinical Ethics, University Hospital Basel/Psychiatric Hospitals of the University Basel, Basel 4012, Switzerland; 3Department for Visceral, Thoracic and Vascular Surgery, Triemli Hospital, Zürich 8063, Switzerland *These authors contributed equally to this work Background: Despite the aging of numerous societies and future health care challenges, clinical research in the elderly is underrepresented. The aim of this review was to analyze the current practice exemplary in gerontotraumatology and to discuss potential improvements. Materials and methods: A literature review was performed in 2016 based on a PubMed search for gerontotraumatologic studies published between 2005 and 2015. Trials were evaluated for methodology and ethical and age-related aspects. Results: The search revealed 649 articles, 183 of which met the inclusion criteria. The age range for inclusion was heterogeneous; one-third of trials included patients Conclusion: Many trials in gerontotraumatology exclude relevant subgroups of patients, and thus risk presenting biased estimates of the relevant treatment effects. Exclusion based on age, cognitive impairment, or other exhaustive exclusion criteria impedes specific scientific progress in the treatment of elderly patients. Meaningful trials could profit from a staged, transparent approach that fosters shared decision making. Rethinking current policies is indispensable to improve treatment and care of elderly trauma patients and to protect study participants and researchers alike. Keywords: systematic review, orthogeriatric, gerontotraumatology, informed consent, clinical research ethics, decisional capacity

Over the past years, NGS has become a crucial workhorse for open-view pathogen diagnostics. Yet, long turnaround times result from using massively parallel high-throughput technologies as the analysis can only be performed after sequencing has finished. The interpretation of results can further be challenged by contaminations, clinically irrelevant sequences, and the sheer amount and complexity of the data. We implemented PathoLive, a real-time diagnostics pipeline for the detection of pathogens from clinical samples hours before sequencing has finished. Based on real-time alignment with HiLive2, mappings are scored with respect to common contaminations, low-entropy areas, and sequences of widespread, non-pathogenic organisms. The results are visualized using an interactive taxonomic tree that provides an easily interpretable overview of the relevance of hits. For a human plasma sample that was spiked in vitro with six pathogenic viruses, all agents were clearly detected after only 40 of 200 sequencing cycles. For a real-world sample from Sudan, the results correctly indicated the presence of Crimean-Congo hemorrhagic fever virus. In a second real-world dataset from the 2019 SARS-CoV-2 outbreak in Wuhan, we found the presence of a SARS coronavirus as the most relevant hit without the novel virus reference genome being included in the database. For all samples, clinically irrelevant hits were correctly de-emphasized. Our approach is valuable to obtain fast and accurate NGS-based pathogen identifications and correctly prioritize and visualize them based on their clinical significance: PathoLive is open source and available on GitLab and BioConda.

Abstract Tracer methods are widespread in computational geodynamics for modeling the advection of chemical data. However, they present certain numerical challenges, especially when used over long periods of simulation time. We address two of these in this work: the necessity for mass conservation of chemical composition fields and the need for the velocity field to be pointwise divergence free to avoid gaps in tracer coverage. We do this by implementing the hybrid discontinuous Galerkin (HDG) finite element (FE) method combined with a mass conserving constrained projection of the tracer data. To demonstrate the efficacy of this system, we compare it to other common FE formulations of the Stokes system and projections of the chemical composition. We provide a reference of the numerical properties and error convergence rates which should be observed by using these various discretization schemes. This serves as a tool for verification of existing or new implementations. We summarize these data in a reproduction of a published Rayleigh‐Taylor instability benchmark, demonstrating the importance of careful choices of appropriate and compatible discretization methods for all aspects of geodynamics simulations.

Background: Molecular profiling (MP) represents an opportunity to match patients to a targeted therapy and when tumor tissue is unavailable, circulating tumor deoxyribonucleic acid (ctDNA) can be harnessed as a non-invasive analyte for this purpose. We evaluated the success of a targeted therapy selected by profiling of ctDNA and tissue in patients with advanced and refractory carcinoma. Patients and methods: A blood draw as well as an optional tissue biopsy were obtained for MP. Whole-genome sequencing and a cancer hotspot panel were performed, and publicly available databases were used to match the molecular profile to targeted treatments. The primary endpoint was the progression-free survival (PFS) ratio (PFS on MP-guided therapy/PFS on the last evidence-based therapy), whereas the success of the targeted therapy was defined as a PFS ratio ⩾1.2. To test the impact of molecular profile-treatment matching strategies, we retrospectively analyzed selected cases via the CureMatch PreciGENE™ decision support algorithm. Results: Interim analysis of 24 patients yielded informative results from 20 patients (83%). A potential tumor-specific drug could be matched in 11 patients (46%) and eight (33%) received a matched treatment. Median PFS in the matched treatment group was 61.5 days [interquartile range (IQR) 49.8–71.0] compared with 81.5 days (IQR 68.5–117.8) for the last evidence-based treatment, resulting in a median PFS ratio of 0.7 (IQR 0.6–0.9). Hence, as no patient experienced a PFS ratio ⩾1.2, the study was terminated. Except for one case, the CureMatch analysis identified either a two-drug or three-drug combination option. Conclusions: Our study employed a histotype–agnostic approach to harness molecular profiling data from both ctDNA and metastatic tumor tissue. The outcome results indicate that more innovative approaches to study design and matching algorithms are necessary to achieve improved patient outcomes. EU Clinical Trials Registry ( https://www.clinicaltrialsregister.eu ): EudraCT: 2014-005341-44