Interferons and tuft cell numbers are bottlenecks for persistent murine norovirus infection.

Noroviruses (NoVs) are a leading cause of viral gastroenteritis. Despite global clinical relevance, our understanding of how host factors, such as antiviral cytokines interferons (IFNs), modulate NoV population dynamics is limited. Murine NoV (MNoV) is a tractable in vivo model for the study of host regulation of NoV. A persistent strain of MNoV, CR6, establishes a reservoir in intestinal tuft cells for chronic viral shedding in stool. However, the influence of host innate immunity and permissive cell numbers on viral population dynamics is an open question. We generated a pool of 20 different barcoded viruses (CR6BC) by inserting 6-nucleotide barcodes at the 3' position of the NS4 gene and used this pool as our viral inoculum for in vivo infections of different mouse lines. We found that over the course of persistent CR6 infection, shed virus was predominantly colon-derived, and viral barcode richness decreased over time irrespective of host immune status, suggesting that persistent infection involves a series of reinfection events. In mice lacking the IFN-λ receptor, intestinal barcode richness was enhanced, correlating with increased viral intestinal replication. IL-4 treatment, which increases tuft cell numbers, also increased barcode richness, indicating the abundance of permissive tuft cells to be a bottleneck during CR6 infection. In mice lacking type I IFN signaling (Ifnar1-/-) or all IFN signaling (Stat1-/-), barcode diversity at extraintestinal sites was dramatically increased, implicating different IFNs as critical bottlenecks at specific tissue sites. Of interest, extraintestinal barcodes were overlapping but distinct from intestinal barcodes, indicating that disseminated virus represents a distinct viral population than that replicating in the intestine. Barcoded viruses are a valuable tool to explore the influence of host factors on viral diversity in the context of establishment and maintenance of infection as well as dissemination and have provided important insights into how NoV infection proceeds in immunocompetent and immunocompromised hosts.

The impact of tightened prescribing restrictions for PBS-subsidised opioid medicines and the introduction of half-pack sizes, Australia, 2020-21: an interrupted time series analysis.

OBJECTIVES: To evaluate the impact of the tightened Pharmaceutical Benefits Scheme (PBS) prescribing rules for immediate release (IR) and controlled release (CR) opioid medicines (1 June 2020), which also eliminated repeat dispensing without authorisation for codeine/paracetamol and tramadol IR and introduced half-pack size item codes for IR formulations. DESIGN, SETTING: Population-based interrupted time series analysis of PBS dispensing data claims for a 10% sample of PBS-eligible residents and IQVIA national opioid medicine sales data (PBS-subsidised and private prescriptions), 28 May 2018 - 6 June 2021. MAIN OUTCOME MEASURES: Mean amount of PBS-subsidised opioid medicines dispensed per day and mean overall amount sold per day - each expressed as oral morphine equivalent milligrams (OME) - overall, by formulation type (IR, CR), and by specific formulation. RESULTS: During the twelve months following the PBS changes, daily PBS-subsidised opioid medicine dispensing was 81 565 OME lower (95% CI, -106 146 to -56 984 OME) than the mean daily level for 2018-20, a decline of 3.8% after adjusting for the pre-intervention trend; the relative reduction was greater for IR (8.4%) than CR formulations (2.6%). Total daily sales of all, IR formulation, and CR formulation opioid medicines did not change significantly after the PBS changes. Repeat dispensing of prescriptions comprised 7.4% of PBS-subsidised opioid dispensing before 1 June 2020, and 1.3% after the changes. Half-pack sizes comprised 8.4% of PBS-subsidised IR opioid medicine dispensing and 2.8% of all opioid medicines sold in the twelve months after the PBS changes. CONCLUSIONS: The introduction of new PBS rules for subsidised opioid medicines was followed by a decline in PBS-subsidised dispensing. Some people may have bypassed the new restrictions by switching to private prescriptions, but our findings suggest that opioid medicine use in Australia declined as a result of the new restrictions.

Changes in systemic cancer therapy in Australia during the Delta and Omicron waves of the COVID-19 pandemic (2021-2022): a controlled interrupted time series analysis.

OBJECTIVES: Australian lockdowns in response to the initial coronavirus disease 2019 (COVID-19) outbreak in 2020 were associated with small and transient changes in the use of systemic cancer therapy. We aimed to investigate the impacts of the longer and more restrictive lockdowns in the Australian states of New South Wales (NSW) and Victoria during both the Delta subvariant lockdowns in mid-2021 and the Omicron subvariant outbreak in late 2021/early 2022. STUDY TYPE: Population-based, controlled interrupted time series analysis. METHODS: We conducted a national observational study using de-identified records of government-subsidised cancer medicines dispensed to a random 10% sample of Australians between July 2018 and July 2022. We used controlled interrupted time series analysis to investigate changes in the dispensing, initiation and discontinuation of all cancer medicines dispensed to residents of NSW and Victoria, using the rest of Australia as a control series. We used quasi-Poisson regression to model weekly counts and estimate incidence rate ratios (IRRs) for the effect of (each) the Delta phase lockdown and the Omicron outbreak on our systemic cancer therapy outcomes. RESULTS: Between July 2018 and July 2022, cancer medicines were dispensed 592 141 times to 33 198 people in NSW and Victoria. Overall, there were no changes to the rates of dispensing, initiation or discontinuation of antineoplastics during the Delta phase lockdowns. In both states during the Omicron outbreak, there were significant decreases in the dispensing of antineoplastics (NSW IRR 0.89; 95% confidence interval [CI] 0.84, 0.93. Victoria IRR 0.92; 95% CI 0.88, 0.96) and in the initiation of endocrine therapy (NSW IRR 0.85; 95% CI 0.74, 0.99. Victoria IRR 0.78; 95% CI 0.65, 0.94), and no changes in the discontinuation of any systemic cancer therapy. CONCLUSIONS: The 2021 lockdowns and 2021/2022 Omicron outbreaks in NSW and Victoria had significant impacts on the dispensing, initiation and discontinuation of systemic cancer therapies, however, the overall effects were minimal. The impacts of lockdowns were less significant than the Omicron outbreaks, suggesting COVID-19 infection, health system capacity, and patient and community concerns were important factors for treatment changes.

BloodChIP Xtra: an expanded database of comparative genome-wide transcription factor binding and gene-expression profiles in healthy human stem/progenitor subsets and leukemic cells.

The BloodChIP Xtra database (http://bloodchipXtra.vafaeelab.com/) facilitates genome-wide exploration and visualization of transcription factor (TF) occupancy and chromatin configuration in rare primary human hematopoietic stem (HSC-MPP) and progenitor (CMP, GMP, MEP) cells and acute myeloid leukemia (AML) cell lines (KG-1, ME-1, Kasumi1, TSU-1621-MT), along with chromatin accessibility and gene expression data from these and primary patient AMLs. BloodChIP Xtra features significantly more datasets than our earlier database BloodChIP (two primary cell types and two cell lines). Improved methodologies for determining TF occupancy and chromatin accessibility have led to increased availability of data for rare primary cell types across the spectrum of healthy and AML hematopoiesis. However, there is a continuing need for these data to be integrated in an easily accessible manner for gene-based queries and use in downstream applications. Here, we provide a user-friendly database based around genome-wide binding profiles of key hematopoietic TFs and histone marks in healthy stem/progenitor cell types. These are compared with binding profiles and chromatin accessibility derived from primary and cell line AML and integrated with expression data from corresponding cell types. All queries can be exported to construct TF-gene and protein-protein networks and evaluate the association of genes with specific cellular processes.

Contributions of diverse models of the female reproductive tract to the study of Chlamydia trachomatis-host interactions.

Chlamydia trachomatis is a common cause of sexually transmitted infections in humans with devastating sequelae. Understanding of disease on all scales, from molecular details to the immunology underlying pathology, is essential for identifying new ways of preventing and treating chlamydia. Infection models of various complexity are essential to understand all aspects of chlamydia pathogenesis. Cell culture systems allow for research into molecular details of infection, including characterization of the unique biphasic Chlamydia developmental cycle and the role of type-III-secreted effectors in modifying the host environment to allow for infection. Multicell type and organoid culture provide means to investigate how cells other than the infected cells contribute to the control of infection. Emerging comprehensive three-dimensional biomimetic systems may fill an important gap in current models to provide information on complex phenotypes that cannot be modeled in simpler in vitro models.

Evidence of non-Maxwellian ion velocity distributions in spherical shock-driven implosions.

The ion velocity distribution functions of thermonuclear plasmas generated by spherical laser direct drive implosions are studied using deuterium-tritium (DT) and deuterium-deuterium (DD) fusion neutron energy spectrum measurements. A hydrodynamic Maxwellian plasma model accurately describes measurements made from lower temperature (<10 keV), hydrodynamiclike plasmas, but is insufficient to describe measurements made from higher temperature more kineticlike plasmas. The high temperature measurements are more consistent with Vlasov-Fokker-Planck (VFP) simulation results which predict the presence of a bimodal plasma ion velocity distribution near peak neutron production. These measurements provide direct experimental evidence of non-Maxwellian ion velocity distributions in spherical shock driven implosions and provide useful data for benchmarking kinetic VFP simulations.

Neutron time of flight (nToF) detectors for inertial fusion experiments.

Neutrons generated in Inertial Confinement Fusion (ICF) experiments provide valuable information to interpret the conditions reached in the plasma. The neutron time-of-flight (nToF) technique is well suited for measuring the neutron energy spectrum due to the short time (100 ps) over which neutrons are typically emitted in ICF experiments. By locating detectors 10s of meters from the source, the neutron energy spectrum can be measured to high precision. We present a contextual review of the current state of the art in nToF detectors at ICF facilities in the United States, outlining the physics that can be measured, the detector technologies currently deployed and analysis techniques used.

Effects of Laser Bandwidth in Direct-Drive High-Performance DT-Layered Implosions on the OMEGA Laser.

In direct-drive inertial confinement fusion, the laser bandwidth reduces the laser imprinting seed of hydrodynamic instabilities. The impact of varying bandwidth on the performance of direct-drive DT-layered implosions was studied in targets with different hydrodynamic stability properties. The stability was controlled by changing the shell adiabat from (α_{F}≃5) (more stable) to (α_{F}≃3.5) (less stable). These experiments show that the performance of lower adiabat implosions improves considerably as the bandwidth is raised indicating that further bandwidth increases, beyond the current capabilities of OMEGA, would be greatly beneficial. These results suggest that the future generation of ultra-broadband lasers could enable achieving high convergence and possibly high gains in direct drive ICF.

Genome-wide transcription factor-binding maps reveal cell-specific changes in the regulatory architecture of human HSPCs.

Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay among transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs (FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2) bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remains unknown. We mapped genome-wide chromatin contacts (HiC, H3K27ac, HiChIP), chromatin modifications (H3K4me3, H3K27ac, H3K27me3) and 10 TF binding profiles (heptad, PU.1, CTCF, STAG2) in HSPC subsets (stem/multipotent progenitors plus common myeloid, granulocyte macrophage, and megakaryocyte erythrocyte progenitors) and found TF occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. Furthermore, heptad-occupied regions in HSPCs were subsequently bound by lineage-defining TFs, including PU.1 and GATA1, suggesting that heptad factors may prime regulatory elements for use in mature cell types. We also found that enhancers with cell-type-specific heptad occupancy shared a common grammar with respect to TF binding motifs, suggesting that combinatorial binding of TF complexes was at least partially regulated by features encoded in DNA sequence motifs. Taken together, this study comprehensively characterizes the gene regulatory landscape in rare subpopulations of human HSPCs. The accompanying data sets should serve as a valuable resource for understanding adult hematopoiesis and a framework for analyzing aberrant regulatory networks in leukemic cells.

German translation of the PROMIS® pediatric anxiety, anger, depressive symptoms, fatigue, pain interference and peer relationships item banks.

BACKGROUND: The present study aimed at the translation and cross-cultural adaptation of six PROMIS® pediatric self- and proxy- item banks and short forms to universal German: anxiety (ANX), anger (ANG), depressive symptoms (DEP), Fatigue (FAT), pain interference (P) and peer relationships (PR). METHODS: Using standardized methodology approved by the PROMIS Statistical Center and in line with recommendations of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) PRO Translation Task Force, two translators for each German-speaking country (Germany, Austria, and Switzerland) commented on and rated the translation difficulty and provided forward translations, followed by a review and reconciliation phase. An independent translator performed back translations, which were reviewed and harmonized. The items were tested in cognitive interviews with 58 children and adolescents from Germany (16), Austria (22), and Switzerland (20) for the self-report and 42 parents and other caregivers (Germany (12), Austria (17), and Switzerland (13)) for the proxy-report. RESULTS: Translators rated the translation difficulty of most items (95%) as easy or feasible. Pretesting showed that items of the universal German version were understood as they were intended, as only 14 out of 82 items of the self-report and 15 out of 82 items of the proxy-report versions required minor rewording. However, on average German translators rated the items more difficult to translate (M = 1.5, SD = 0.20) than the Austrian (M = 1.3, SD = 0.16) and the Swiss translators (M = 1.2, SD = 0.14) on a three-point Likert scale. CONCLUSIONS: The translated German short forms are ready for use by researchers and clinicians ( https://www.healthmeasures.net/search-view-measures ).

A multitude of questionnaires exist, which are not comparable due to different questions or no available translations. PROMIS is an initiative, which was funded by the National Institute of Health in the US, to build better, i.e., more precise and efficient questionnaires, which can be used and compared worldwide. The PROMIS questionnaires include paper-and-pencil short forms and computerized adaptive tests. So far numerous PROMIS surveys have been created using advanced methodologies. They can be used by health care professionals to assess different aspects of health and compare the results internationally. To allow for international comparability of studies using those questionnaires, they need to be translated. This study reports the thorough translation process of the US-American PROMIS^® questionnaires measuring anxiety, anger, depressive symptoms, fatigue, pain interference, and peer relationships in children and adolescents into German. The translation included researchers, children, and parents from Germany, Austria, and Switzerland to ensure that the final German version is fully and equally well understood in all of those German-speaking countries. The article describes the translation process, so that the user can understand the translations and use them in an informed way. The translated German questionnaires are ready for use by researchers and clinicians. ( https://www.healthmeasures.net/search-view-measures ).

A Prospective Study to Examine Responsiveness and Minimally Important Differences (MIDs) for the CLEFT-Q Scales Following Three Cleft-Specific Operations.

The aim of this study was to examine internal responsiveness and estimate minimally important differences (MIDs) for CLEFT-Q scales.In this prospective cohort study, participants completed the CLEFT-Q appearance and health-related quality of life (HRQL) scales before and six months after cleft-related surgery.Seven cleft centres in Canada, USA and UK participated.Patients were ages 8-29 years with CL/P.Patients underwent rhinoplasty, orthognathic or cleft lip scar revision surgery.Internal responsiveness was examined using Cohen's d effect sizes (ESs) based on the following interpretation: 0.20-0.49 small, 0.50-0.79 moderate and ≥ 0.80 large. MIDs were estimated using two distribution-based approaches.Participants had a rhinoplasty (n = 31), orthognathic (n = 21) or cleft lip scar revision (n = 18) surgery. Most participants were males (56%) and aged 8-11 years (41%). Following rhinoplasty, ESs were larger for the nose (0.92, p = 0.001) and nostrils (0.94, p < 0.001) scales than for the face scale (0.51, p = 0.003). MIDs ranged between 6.2-10.4. For orthognathic surgery, larger ES was observed for the jaws scale (1.80, p < 0.001) compared with the teeth (1.16, p < 0.001), face (1.15, p = 0.001) and lips (0.94, p < 0.001) scales. MIDs ranged between 5.9-14.4. In the cleft lip scar revision sample, the largest ES was observed for the nose scale (0.76, p = 0.03), followed by lips (0.58, p = 0.009) and cleft lip scar (0.50, p = 0.043) scales. MIDs ranged between 6.4-12.3.CLEFT-Q detected change in key outcomes for three cleft-specific surgeries, providing evidence of its responsiveness. Estimated MIDs will aid in interpreting this PROM.

Computational capacity of LRC, memristive, and hybrid reservoirs.

Reservoir computing is a machine learning paradigm that uses a high-dimensional dynamical system, or reservoir, to approximate and predict time series data. The scale, speed, and power usage of reservoir computers could be enhanced by constructing reservoirs out of electronic circuits, and several experimental studies have demonstrated promise in this direction. However, designing quality reservoirs requires a precise understanding of how such circuits process and store information. We analyze the feasibility and optimal design of electronic reservoirs that include both linear elements (resistors, inductors, and capacitors) and nonlinear memory elements called memristors. We provide analytic results regarding the feasibility of these reservoirs and give a systematic characterization of their computational properties by examining the types of input-output relationships that they can approximate. This allows us to design reservoirs with optimal properties. By introducing measures of the total linear and nonlinear computational capacities of the reservoir, we are able to design electronic circuits whose total computational capacity scales extensively with the system size. Our electronic reservoirs can match or exceed the performance of conventional "echo state network" reservoirs in a form that may be directly implemented in hardware.

Measurements of low-mode asymmetries in the areal density of laser-direct-drive deuterium-tritium cryogenic implosions on OMEGA using neutron spectroscopy.

Areal density is one of the key parameters that determines the confinement time in inertial confinement fusion experiments, and low-mode asymmetries in the compressed fuel are detrimental to the implosion performance. The energy spectra from the scattering of the primary deuterium-tritium (DT) neutrons off the compressed cold fuel assembly are used to investigate low-mode nonuniformities in direct-drive cryogenic DT implosions at the Omega Laser Facility. For spherically symmetric implosions, the shape of the energy spectrum is primarily determined by the elastic and inelastic scattering cross sections for both neutron-deuterium and neutron-tritium kinematic interactions. Two highly collimated lines of sight, which are positioned at nearly orthogonal locations around the OMEGA target chamber, record the neutron time-of-flight signal in the current mode. An evolutionary algorithm is being used to extract a model-independent energy spectrum of the scattered neutrons from the experimental neutron time-of-flight data and is used to infer the modal spatial variations (l = 1) in the areal density. Experimental observations of the low-mode variations of the cold-fuel assembly (ρL0 + ρL1) show good agreement with a recently developed model, indicating a departure from the spherical symmetry of the compressed DT fuel assembly. Another key signature that has been observed in the presence of a low-mode variation is the broadening of the kinematic end-point due to the anisotropy of the dense fuel conditions.

A new neutron time-of-flight detector for yield and ion-temperature measurements at the OMEGA Laser Facility.

A new neutron time-of-flight (nTOF) detector for deuterium-deuterium (DD)-fusion yield and ion-temperature measurements was designed, installed, and calibrated for the OMEGA Laser Facility. This detector provides an additional line of sight for DD neutron yield and ion-temperature measurements for yields exceeding 1 × 1010 with higher precision than existing detectors. The nTOF detector consists of a 90-mm-diam, 20-mm-thick BC-422 scintillator and a gated Photek photomultiplier tube (PMT240). The PMT collects scintillating light through the 20-mm side of the scintillator without the use of a light guide. There is no lead shielding from hard x rays in order to allow the x-ray instrument response function of the detector to be measured easily. Instead, hard x-ray signals generated in implosion experiments are gated out by the PMT. The design provides a place for glass neutral-density filters between the scintillator and the PMT to avoid PMT saturation at high yields. The nTOF detector is installed in the OMEGA Target Bay along the P8A sub-port line of sight at a distance of 5.3 m from the target chamber center. In addition to DD measurements, the same detector can be used to measure the neutron yield and ion temperature from deuterium-tritium (DT) implosion targets in the 5 × 1010 to 2 × 1012 yield range. The design details and the calibration results of this nTOF detector for both D2 and DT implosions on OMEGA will be presented.

3D Simulations Capture the Persistent Low-Mode Asymmetries Evident in Laser-Direct-Drive Implosions on OMEGA.

Spherical implosions in inertial confinement fusion are inherently sensitive to perturbations that may arise from experimental constraints and errors. Control and mitigation of low-mode (long wavelength) perturbations is a key milestone to improving implosion performances. We present the first 3D radiation-hydrodynamic simulations of directly driven inertial confinement fusion implosions with an inline package for polarized crossed-beam energy transfer. Simulations match bang times, yields (separately accounting for laser-induced high modes and fuel age), hot spot flow velocities and direction, for which polarized crossed-beam energy transfer contributes to the systematic flow orientation evident in the OMEGA implosion database. Current levels of beam mispointing, imbalance, target offset, and asymmetry from polarized crossed-beam energy transfer degrade yields by more than 40%. The effectiveness of two mitigation strategies for low modes is explored.

dRNASb: a systems biology approach to decipher dynamics of host-pathogen interactions using temporal dual RNA-seq data.

Infection triggers a dynamic cascade of reciprocal events between host and pathogen wherein the host activates complex mechanisms to recognise and kill pathogens while the pathogen often adjusts its virulence and fitness to avoid eradication by the host. The interaction between the pathogen and the host results in large-scale changes in gene expression in both organisms. Dual RNA-seq, the simultaneous detection of host and pathogen transcripts, has become a leading approach to unravelling complex molecular interactions between the host and the pathogen and is particularly informative for intracellular organisms. The amount of in vitro and in vivo dual RNA-seq data is rapidly growing, which demands computational pipelines to effectively analyse such data. In particular, holistic, systems-level, and temporal analyses of dual RNA-seq data are essential to enable further insights into the host-pathogen transcriptional dynamics and potential interactions. Here, we developed an integrative network-driven bioinformatics pipeline, dRNASb, a systems biology-based computational pipeline to analyse temporal transcriptional clusters, incorporate molecular interaction networks (e.g. protein-protein interactions), identify topologically and functionally key transcripts in host and pathogen, and associate host and pathogen temporal transcriptome to decipher potential between-species interactions. The pipeline is applicable to various dual RNA-seq data from different species and experimental conditions. As a case study, we applied dRNASb to analyse temporal dual RNA-seq data of Salmonella-infected human cells, which enabled us to uncover genes contributing to the infection process and their potential functions and to identify putative associations between host and pathogen genes during infection. Overall, dRNASb has the potential to identify key genes involved in bacterial growth or host defence mechanisms for future uses as therapeutic targets.

Bound on hot-spot mix in high-velocity, high-adiabat direct-drive cryogenic implosions based on comparison of absolute x-ray and neutron yields.

In laser-driven implosions for laboratory fusion, the comparison of hot-spot x-ray yield to neutron production can serve to infer hot-spot mix. For high-performance direct-drive implosions, this ratio depends sensitively on the degree of equilibration between the ion and electron fluids. A scaling for x-ray yield as a function of neutron yield and characteristic ion and electron hot-spot temperatures is developed on the basis of simulations with varying degrees of equilibration. We apply this model to hot-spot x-ray measurements of direct-drive cryogenic implosions typical of the direct-drive designs with best ignition metrics. The comparison of the measured x-ray and neutron yields indicates that hot-spot mix, if present, is below a sensitivity estimated as ∼2% by-atom mix of ablator plastic into the hot spot.

Measurements of the temperature and velocity of the dense fuel layer in inertial confinement fusion experiments.

The apparent ion temperature and mean velocity of the dense deuterium tritium fuel layer of an inertial confinement fusion target near peak compression have been measured using backscatter neutron spectroscopy. The average isotropic residual kinetic energy of the dense deuterium tritium fuel is estimated using the mean velocity measurement to be ∼103 J across an ensemble of experiments. The apparent ion-temperature measurements from high-implosion velocity experiments are larger than expected from radiation-hydrodynamic simulations and are consistent with enhanced levels of shell decompression. These results suggest that high-mode instabilities may saturate the scaling of implosion performance with the implosion velocity for laser-direct-drive implosions.

Temporal Trends in Traumatic Brain Injury.

Aims Traumatic brain injury (TBI) is a leading cause of preventable mortality and morbidity. Our aim was to examine the demographics, injury characteristics and management of TBI patients treated in an intensive care unit (ICU) in an Irish tertiary-level hospital with a neurosurgical department. Methods A retrospective, longitudinal study of all TBI patients treated in ICU between 2013-2018. Results 77% (n=171) were male and median age was 46 (Q1-Q3: 28-62). The most common mechanism of injury was fall from less than two meters (<2m) followed by road traffic accident (RTA). The proportion of injuries due to RTA increased over the six-year period (p=0.006). 41.4% (n=92) of injuries had reported alcohol involvement. Patients with fall<2m had double the median age and double the rate of alcohol involvement compared to those suffering RTA (p<0.001, p<0.001). The neurosurgical intervention rate was 74% (n=165). The median duration of ICU admission and of intracranial-pressure monitoring, advanced ventilation and inotropic therapy increased over the six-year period (p=0.031, p=0.038, p=0.033, p<0.001). Discussion This study's findings could inform precise and impactful public prevention measures. The increasing duration of ICU admission and of other interventions should be examined further for their effect on patient outcome and resource consumption.

Disentangling single-cell omics representation with a power spectral density-based feature extraction.

Emerging single-cell technologies provide high-resolution measurements of distinct cellular modalities opening new avenues for generating detailed cellular atlases of many and diverse tissues. The high dimensionality, sparsity, and inaccuracy of single cell sequencing measurements, however, can obscure discriminatory information, mask cellular subtype variations and complicate downstream analyses which can limit our understanding of cell function and tissue heterogeneity. Here, we present a novel pre-processing method (scPSD) inspired by power spectral density analysis that enhances the accuracy for cell subtype separation from large-scale single-cell omics data. We comprehensively benchmarked our method on a wide range of single-cell RNA-sequencing datasets and showed that scPSD pre-processing, while being fast and scalable, significantly reduces data complexity, enhances cell-type separation, and enables rare cell identification. Additionally, we applied scPSD to transcriptomics and chromatin accessibility cell atlases and demonstrated its capacity to discriminate over 100 cell types across the whole organism and across different modalities of single-cell omics data.