Atomic diffusion in liquid gallium and gallium-nickel alloys probed by quasielastic neutron scattering and molecular dynamic simulations.

The atomic mobility in liquid pure gallium and a gallium-nickel alloy with 2 at% of nickel is studied experimentally by incoherent quasielastic neutron scattering. The integral diffusion coefficients for all-atom diffusion are derived from the experimental data at different temperatures. DFT-basedab-initiomolecular dynamics (MD) is used to find numerically the diffusion coefficient of liquid gallium at different temperatures, and numerical theory results well agree with the experimental findings at temperatures below 500 K. Machine learning force fields derived fromab-initiomolecular dynamics (AIMD) overestimate within a small 6% error the diffusion coefficient of pure gallium within the genuine AIMD. However, they better agree with experiment for pure gallium and enable the numerical finding of the diffusion coefficient of nickel in the considered melted alloy along with the diffusion coefficient of gallium and integral diffusion coefficient, that agrees with the corresponding experimental values within the error bars. The temperature dependence of the gallium diffusion coefficientDGa(T)follows the Arrhenius law experimentally for all studied temperatures and below 500 K also in the numerical simulations. However,DGa(T)can be well described alternatively by an Einstein-Stokes dependence with the metallic liquid viscosity following the Arrhenius law, especially for the MD simulation results at all studied temperatures. Moreover, a novel variant of the excess entropy scaling theory rationalized our findings for gallium diffusion. Obtained values of the Arrhenius activation energies are profoundly different in the competing theoretical descriptions, which is explained by different temperature-dependent prefactors in the corresponding theories. The diffusion coefficient of gallium is significantly reduced (at the same temperature) in a melted alloy with natural nickel, even at a tiny 2 at% concentration of nickel, as compared with its pure gallium value. This highly surprising behavior contradicts the existing excess entropy scaling theories and opens a venue for further research.

Direct to Operating Room for Decompressive Craniotomy/Craniectomy in Patients With Traumatic Brain Injury.

BACKGROUND: Emergent decompressive craniotomy/craniectomy can be a lifesaving surgical intervention for select patients with traumatic brain injury. Prompt management is critical as early decompression can impact traumatic brain injury outcomes. OBJECTIVE: This study aims to describe the feasibility and clinical impact of a new pathway for transporting patients with severe traumatic brain injury directly to the operating room from the trauma bay for decompressive craniotomy/craniectomy. METHODS: This is a retrospective cohort preintervention and postintervention study of severe traumatic brain injury patients undergoing decompressive craniectomy/craniotomy at a Midwestern U.S. Level I trauma center between 2016 and 2022. In the new pathway, the in-house trauma surgeon takes the patient directly to the operating room with the neurosurgery advanced practice provider to drape and prepare the patient for surgery while the neurosurgeon is en route to the hospital. RESULTS: A total of 44 patients were studied, five (5/44, 11.4%) of which were in the preintervention group and 39 (39/44, 88.6%) in the postintervention group. The median arrival-to-operating room time was shorter in the postintervention cohort (1.4 hr) than in the preintervention cohort (1.5 hr). In examining night shifts only, the preintervention cohort had shorter arrival-to-operating room times (1.2 hr) than the postintervention cohort (1.5 hr). CONCLUSION: The study demonstrated that the new pathway is feasible and expedites patient transport to the operating room while awaiting the arrival of the on-call neurosurgeon.

Near index matching enables solid diffractive optical element fabrication via additive manufacturing.

Diffractive optical elements (DOEs) have a wide range of applications in optics and photonics, thanks to their capability to perform complex wavefront shaping in a compact form. However, widespread applicability of DOEs is still limited, because existing fabrication methods are cumbersome and expensive. Here, we present a simple and cost-effective fabrication approach for solid, high-performance DOEs. The method is based on conjugating two nearly refractive index-matched solidifiable transparent materials. The index matching allows for extreme scaling up of the elements in the axial dimension, which enables simple fabrication of a template using commercially available 3D printing at tens-of-micrometer resolution. We demonstrated the approach by fabricating and using DOEs serving as microlens arrays, vortex plates, including for highly sensitive applications such as vector beam generation and super-resolution microscopy using MINSTED, and phase-masks for three-dimensional single-molecule localization microscopy. Beyond the advantage of making DOEs widely accessible by drastically simplifying their production, the method also overcomes difficulties faced by existing methods in fabricating highly complex elements, such as high-order vortex plates, and spectrum-encoding phase masks for microscopy.

Spatial Omics Imaging of Fresh-Frozen Tissue and Routine FFPE Histopathology of a Single Cancer Needle Core Biopsy: A Freezing Device and Multimodal Workflow.

The complex molecular alterations that underlie cancer pathophysiology are studied in depth with omics methods using bulk tissue extracts. For spatially resolved tissue diagnostics using needle biopsy cores, however, histopathological analysis using stained FFPE tissue and the immunohistochemistry (IHC) of a few marker proteins is currently the main clinical focus. Today, spatial omics imaging using MSI or IRI is an emerging diagnostic technology for the identification and classification of various cancer types. However, to conserve tissue-specific metabolomic states, fast, reliable, and precise methods for the preparation of fresh-frozen (FF) tissue sections are crucial. Such methods are often incompatible with clinical practice, since spatial metabolomics and the routine histopathology of needle biopsies currently require two biopsies for FF and FFPE sampling, respectively. Therefore, we developed a device and corresponding laboratory and computational workflows for the multimodal spatial omics analysis of fresh-frozen, longitudinally sectioned needle biopsies to accompany standard FFPE histopathology of the same biopsy core. As a proof-of-concept, we analyzed surgical human liver cancer specimens using IRI and MSI with precise co-registration and, following FFPE processing, by sequential clinical pathology analysis of the same biopsy core. This workflow allowed for a spatial comparison between different spectral profiles and alterations in tissue histology, as well as a direct comparison for histological diagnosis without the need for an extra biopsy.

Automated high-throughput image processing as part of the screening platform for personalized oncology.

Cancer is a devastating disease and the second leading cause of death worldwide. However, the development of resistance to current therapies is making cancer treatment more difficult. Combining the multi-omics data of individual tumors with information on their in-vitro Drug Sensitivity and Resistance Test (DSRT) can help to determine the appropriate therapy for each patient. Miniaturized high-throughput technologies, such as the droplet microarray, enable personalized oncology. We are developing a platform that incorporates DSRT profiling workflows from minute amounts of cellular material and reagents. Experimental results often rely on image-based readout techniques, where images are often constructed in grid-like structures with heterogeneous image processing targets. However, manual image analysis is time-consuming, not reproducible, and impossible for high-throughput experiments due to the amount of data generated. Therefore, automated image processing solutions are an essential component of a screening platform for personalized oncology. We present our comprehensive concept that considers assisted image annotation, algorithms for image processing of grid-like high-throughput experiments, and enhanced learning processes. In addition, the concept includes the deployment of processing pipelines. Details of the computation and implementation are presented. In particular, we outline solutions for linking automated image processing for personalized oncology with high-performance computing. Finally, we demonstrate the advantages of our proposal, using image data from heterogeneous practical experiments and challenges.

Survivorship and functional outcome of a cemented acetabular component with bulk roof autograft for severe acetabular dysplasia: 12- to 23-year follow-up.

AIMS: Primary aim was to determine survival of a cemented acetabular component with bulk roof autograft with a minimum of 12 years follow-up. The secondary aim was to determine the clinical outcome. METHODS: A cohort of 62 consecutive patients (74 hips) undergoing cemented total hip arthroplasty with acetabular bulk roof autograft for acetabular dysplasia were retrospectively identified. The group consisted of 57 female patients (67 hips) and 5 male patients (7 hips) with a mean age at operation of 45 years. No patient was lost to follow-up, however 9 patients died had during the study period. The Oxford Hip Score (OHS), Forgotten Joint Score (FJS), EuroQol 5-Dimensional Score (EQ-5D), Short Form (SF-12) physical score and patient satisfaction were used to assess clinical outcome for patients with a surviving prosthesis. RESULTS: The median follow-up was 16.6 (13.4-19.1) years. 6 revisions were performed during the follow-up period, all of which were due to aseptic loosening of the acetabular component. The all-cause Kaplan Meier survival rate for the acetabular component was 99% at 10 years, 95% at 15 years and 83% at 20 years. Neither age, gender, femoral osteotomy or polyethylene (UHMW vs. cross-linked) were significant predictors of aseptic revision of the acetabular component. There were no case of graft resorption and all grafts were radiologically incorporated. 45 patients were available for functional assessment at a mean follow-up of 18.2 years. The mean OHS was 37.8, FJS was 55.7, EQ5D was 0.73, and SF-12 physical component was 43.2. No patient was dissatisfied, with 2 patients reporting a neutral satisfaction, 7 stating they were satisfied and the remaining 36 were very satisfied. CONCLUSIONS: A cemented acetabular component with bulk roof autograft for dysplasia offers excellent survival with good to excellent functional outcome with high patient satisfaction in the medium- to long-term.

DNA-PAINT MINFLUX nanoscopy.

MINimal fluorescence photon FLUXes (MINFLUX) nanoscopy, providing photon-efficient fluorophore localizations, has brought about three-dimensional resolution at nanometer scales. However, by using an intrinsic on-off switching process for single fluorophore separation, initial MINFLUX implementations have been limited to two color channels. Here we show that MINFLUX can be effectively combined with sequentially multiplexed DNA-based labeling (DNA-PAINT), expanding MINFLUX nanoscopy to multiple molecular targets. Our method is exemplified with three-color recordings of mitochondria in human cells.

Impact of COVID-19 on surgical specialist training as quantified by trainee complication rates for cataract surgery.

BACKGROUND: Reduction in elective surgeries during the COVID-19 pandemic has negatively impacted surgical specialist training. Posterior capsule rupture rate (PCR), a complication of cataract surgery, is an objective measure of the quality of ophthalmic surgery. This study aimed to compare PCR pre- and post-COVID-19 in trainees and consultants. METHODS: A single-centre consecutive cases series of cataract surgeries performed at Groote Schuur Hospital, between 1 February 2017 and 31 May 2021 were analysed. Our main outcome measure was the effect of the volume of cataract surgeries on PCRs between ophthalmology trainees and consultants before and after the COVID-19 reduction in elective surgeries on 23 March 2020. RESULTS: During the study period, 4 157 cataract surgeries were performed (3 493 in the 38 months pre-COVID-19 and 664 in the 14 months post-COVID-19). Fourteen ophthalmology trainees and six consultants performed 2 919 and 1 238 cataract surgeries, respectively. In the trainees the PCR was 4.4% pre-COVID-19 and 10.0% post-COVID-19 (odds ratio [OR] 2.44; p < 0.001; CI 1.71-3.47; relative risk [RR] 2.29). The PCR of consultants remained unchanged with a PCR of 3.4% pre- and post-COVID-19 (OR 1.02; p = 0.97; CI 0.42-2.46; RR 1.02). CONCLUSION: COVID-19 has caused a marked reduction in the volume of cataract surgery which has resulted in a deterioration in the performance of trainees, but not consultants, and quantifies the negative impact of the pandemic on surgical training in ophthalmology. This highlights the need to develop plans to improve surgical training during the COVID-19 recovery period.

Designing chromatic optical retarder stacks for segmented next-generation easySTED phase plates.

Fluorescence nanoscopy methods based on the RESOLFT principle, such as beam-scanning STED nanoscopy, require the co-alignment of optical beams for molecular state (on/off) switching and fluorescence excitation. The complexity and stability of the beam alignment can be drastically simplified and improved by using a single-mode fibre as the sole light source for all required laser beams. This in turn then requires a chromatic optical element for shaping the off-switching beam into a focal-plane donut while simultaneously leaving the focal intensity distributions at other wavelengths shaped as regular focal spots. Here we describe novel designs of such so-called 'easySTED phase plates' and provide a rationale how to find the desired spectral signature for combinations of multiple wavelengths.

Enhanced incorporation of subnanometer tags into cellular proteins for fluorescence nanoscopy via optimized genetic code expansion.

With few-nanometer resolution recently achieved by a new generation of fluorescence nanoscopes (MINFLUX and MINSTED), the size of the tags used to label proteins will increasingly limit the ability to dissect nanoscopic biological structures. Bioorthogonal (click) chemical groups are powerful tools for the specific detection of biomolecules. Through the introduction of an engineered aminoacyl-tRNA synthetase/tRNA pair (tRNA: transfer ribonucleic acid), genetic code expansion allows for the site-specific introduction of amino acids with "clickable" side chains into proteins of interest. Well-defined label positions and the subnanometer scale of the protein modification provide unique advantages over other labeling approaches for imaging at molecular-scale resolution. We report that, by pairing a new N-terminally optimized pyrrolysyl-tRNA synthetase (chPylRS2020) with a previously engineered orthogonal tRNA, clickable amino acids are incorporated with improved efficiency into bacteria and into mammalian cells. The resulting enhanced genetic code expansion machinery was used to label ß-actin in U2OS cell filopodia for MINFLUX imaging with minimal separation of fluorophores from the protein backbone. Selected data were found to be consistent with previously reported high-resolution information from cryoelectron tomography about the cross-sectional filament bundling architecture. Our study underscores the need for further improvements to the degree of labeling with minimal-offset methods in order to fully exploit molecular-scale optical three-dimensional resolution.

HIOPP-6 - a pilot study on the evaluation of an electronic tool to assess and reduce the complexity of drug treatment considering patients' views.

BACKGROUND: A complex drug treatment might pose a barrier to safe and reliable drug administration for patients. Therefore, a novel tool automatically analyzes structured medication data for factors possibly contributing to complexity and subsequently personalizes the results by evaluating the relevance of each identified factor for the patient by means of key questions. Hence, tailor-made optimization measures can be proposed. METHODS: In this controlled, prospective, exploratory trial the tool was evaluated with nine general practitioners (GP) in three study groups: In the two intervention groups the tool was applied in a version with (GI_with) and a version without (GI_without) integrated key questions for the personalization of the analysis, while the control group (GC) did not use any tools (routine care). Four to eight weeks after application of the tool, the benefits of the optimization measures to reduce or mitigate complexity of drug treatment were evaluated from the patient perspective. RESULTS: A total of 126 patients regularly using more than five drugs could be included for analysis. GP suggested 117 optimization measures in GI_with, 83 in GI_without, and 2 in GC. Patients in GI_with were more likely to rate an optimization measure as helpful than patients in GI_without (IRR: 3.5; 95% CI: 1.2-10.3). Thereby, the number of optimization measures recommended by the GP had no significant influence (P = 0.167). CONCLUSIONS: The study suggests that an automated analysis considering patient perspectives results in more helpful optimization measures than an automated analysis alone - a result which should be further assessed in confirmatory studies. TRIAL REGISTRATION: The trial was registered retrospectively at the German Clinical Trials register under DRKS-ID DRKS00025257 (17/05/2021).

Optimal precision and accuracy in 4Pi-STORM using dynamic spline PSF models.

Coherent fluorescence imaging with two objective lenses (4Pi detection) enables single-molecule localization microscopy with sub-10 nm spatial resolution in three dimensions. Despite its outstanding sensitivity, wider application of this technique has been hindered by complex instrumentation and the challenging nature of the data analysis. Here we report the development of a 4Pi-STORM microscope, which obtains optimal resolution and accuracy by modeling the 4Pi point spread function (PSF) dynamically while also using a simpler optical design. Dynamic spline PSF models incorporate fluctuations in the modulation phase of the experimentally determined PSF, capturing the temporal evolution of the optical system. Our method reaches the theoretical limits for precision and minimizes phase-wrapping artifacts by making full use of the information content of the data. 4Pi-STORM achieves a near-isotropic three-dimensional localization precision of 2-3 nm, and we demonstrate its capabilities by investigating protein and nucleic acid organization in primary neurons and mammalian mitochondria.

Prevalence and patient-rated relevance of complexity factors in medication regimens of community-dwelling patients with polypharmacy.

PURPOSE: To describe the prevalence of complexity factors in the medication regimens of community-dwelling patients with more than five drugs and to evaluate the relevance of these factors for individual patients. METHODS: Data were derived from the HIOPP-6 trial, a controlled study conducted in 9 general practices which evaluated an electronic tool to detect and reduce complexity of drug treatment. The prevalence of complexity factors was based on the results of the automated analysis of 139 patients' medication data. The relevance assessment was based on the patients' rating of each factor in an interview (48 patients included for analysis). RESULTS: A median of 5 (range 0-21) complexity factors per medication regimen were detected and at least one factor was observed in 131 of 139 patients. Almost half of these patients found no complexity factor in their medication regimen relevant. CONCLUSION: In most medication regimens, complexity factors could be identified automatically, yet less than 15% of factors were indeed relevant for patients as judged by themselves. When assessing complexity of medication regimens, one should especially consider factors that are both particularly frequent and often challenging for patients, such as use of inhalers or tablet splitting. TRIAL REGISTRATION: The HIOPP-6 trial was registered retrospectively on May 17, 2021, in the German Clinical Trials register under DRKS-ID DRKS00025257.

Prostatic Artery Embolization for Treatment of Lower Urinary Tract Symptoms: A Markov Model-Based Cost-Effectiveness Analysis.

PURPOSE: The aim of this study was to investigate whether prostatic artery embolization (PAE) can be considered a long-term cost-effective treatment option in patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia in comparison to transurethral resection of the prostate (TURP). METHODS: The in-hospital costs of PAE and TURP in the United States were obtained from a recent cost analysis. Clinical outcomes including nature and rate of adverse events for TURP and PAE along with rates of retreatment because of complications or clinical failure were obtained from peer-reviewed literature. A decision tree-based Markov model was created, analyzing long-term cost-effectiveness for TURP and PAE from a US health care sector perspective. Cost-effectiveness over a time frame of 5 years was estimated while assuming a willingness to pay of $50,000 per quality-adjusted life-year (QALY). The primary outcome was incremental cost-effectiveness ratio. RESULTS: PAE resulted in overall cost of $6,464.92 and an expected outcome of 4.566 QALYs. In comparison, TURP cost $9,221.09 and resulted in expected outcome of 4.577 QALYs per treatment. The incremental cost-effectiveness ratio for TURP was $247,732.65 per QALY. On the basis of the willingness-to-pay threshold, PAE is cost effective compared with TURP. CONCLUSIONS: On the basis of our model, PAE in comparison with TURP can be regarded as a cost-effective treatment option for patients with lower urinary tract symptoms within the US health care system.

[Modern tomography imaging techniques in urological diseases]. / Moderne Schnittbildgebung für urologische Erkrankungen.

BACKGROUND: Radiologic imaging is important for the detection, staging and follow-up of urological tumors. Basic therapy decisions for both oncological (surgical vs. systemic therapy, e.g. in testicular cancer) and non-oncological pathologies (interventional vs. conservative therapy, e.g. for ureteral stones) depend largely on the tomographic imaging performed. Due to its almost ubiquitous availability, speed and cost-effectiveness, computed tomography (CT) plays an important role not only in the clarification of abdominal trauma and non-traumatic emergencies, but also in staging and follow-up of oncological patients. However, the level of radiation exposure, impaired renal function and allergies to iodinated contrast media limit the use of CT. Magnetic resonance imaging (MRI) can be a good alternative for many areas of application in oncological and non-oncological imaging due to its high soft tissue differentiation and functional-specific protocols but without the use of ionizing radiation. AIM: In the following, the main indications of abdominal and pelvic CT and MRI in urology and their limitations are summarized. RESULTS: The areas of application between CT and MRI are increasingly overlapping, since the latest developments in CT continue to further reduce radiation exposure and increase contrast information, while the speed and robustness of MRI are significantly improving at the same time.

Wnt signaling is boosted during intestinal regeneration by a CD44-positive feedback loop.

Enhancement of Wnt signaling is fundamental for stem cell function during intestinal regeneration. Molecular modules control Wnt activity by regulating signal transduction. CD44 is such a positive regulator and a Wnt target gene. While highly expressed in intestinal crypts and used as a stem cell marker, its role during intestinal homeostasis and regeneration remains unknown. Here we propose a CD44 positive-feedback loop that boosts Wnt signal transduction, thus impacting intestinal regeneration. Excision of Cd44 in Cd44fl/fl;VillinCreERT2 mice reduced Wnt target gene expression in intestinal crypts and affected stem cell functionality in organoids. Although the integrity of the intestinal epithelium was conserved in mice lacking CD44, they were hypersensitive to dextran sulfate sodium, and showed more severe inflammation and delayed regeneration. We localized the molecular function of CD44 at the Wnt signalosome, and identified novel DVL/CD44 and AXIN/CD44 complexes. CD44 thus promotes optimal Wnt signaling during intestinal regeneration.

Hotter Than It Looks: A Retrospective Review of Patients With Cholecystitis and With Negative Imaging.

INTRODUCTION: Ultrasound is the gold standard for workup of cholecystitis in the emergency department, and findings heavily influence clinical decision-making. Patients with negative imaging for acute cholecystitis may be inappropriately sent home. The purpose of our study was to review the pathology and outcomes of patients presenting with biliary pain and negative ultrasound findings of acute cholecystitis. MATERIALS AND METHODS: Emergency department patients who underwent laparoscopic cholecystectomy between January 2015 and February 2019 were reviewed retrospectively. Only patients with negative or equivocal imaging were included. The primary outcome was the incidence of cholecystitis on final pathology. RESULTS: Two hundred fifty-seven patients underwent laparoscopic cholecystectomy. Pathology demonstrated cholecystitis in 84% of patients. Only 15% of patients had cholelithiasis without cholecystitis on pathology. The incidence of cholecystitis was similar in negative and equivocal imaging groups (84% versus 83%; P = 0.960). The median time from admission to the operating room was 12.1 h (interquartile range 7.1-18.3 h), and hospital length of stay was 1.2 d (interquartile range 0.8-1.7 d). CONCLUSIONS: This study found that patients with negative or equivocal imaging had cholecystitis on pathology. On review of patient outcomes, those patients who underwent surgical intervention had a low rate of complications and short hospital stay.

Robotic Assistance System for Cone-Beam Computed Tomography-Guided Percutaneous Needle Placement.

PURPOSE: The study aimed to evaluate a new robotic assistance system (RAS) for needle placement in combination with a multi-axis C-arm angiography system for cone-beam computed tomography (CBCT) in a phantom setting. MATERIALS AND METHODS: The RAS consisted of a tool holder, dedicated planning software, and a mobile platform with a lightweight robotic arm to enable image-guided needle placement in conjunction with CBCT imaging. A CBCT scan of the phantom was performed to calibrate the robotic arm in the scan volume and to plan the different needle trajectories. The trajectory data were sent to the robot, which then positioned the tool holder along the trajectory. A 19G needle was then manually inserted into the phantom. During the control CBCT scan, the exact needle position was evaluated and any possible deviation from the target lesion measured. RESULTS: In total, 16 needle insertions targeting eight in- and out-of-plane sites were performed. Mean angular deviation from planned trajectory to actual needle trajectory was 1.12°. Mean deviation from target point and actual needle tip position was 2.74 mm, and mean deviation depth from the target lesion to the actual needle tip position was 2.14 mm. Mean time for needle placement was 361 s. Only differences in time required for needle placement between in- and out-of-plane trajectories (337 s vs. 380 s) were statistically significant (p = 0.0214). CONCLUSION: Using this RAS for image-guided percutaneous needle placement with CBCT was precise and efficient in the phantom setting.