Sensitivity of magnetic resonance elastography to extracellular matrix and cell motility in human prostate cancer cell line-derived xenograft models.

Prostate cancer (PCa) is a significant health problem in the male population of the Western world. Magnetic resonance elastography (MRE), an emerging medical imaging technique sensitive to mechanical properties of biological tissues, detects PCa based on abnormally high stiffness and viscosity values. Yet, the origin of these changes in tissue properties and how they correlate with histopathological markers and tumor aggressiveness are largely unknown, hindering the use of tumor biomechanical properties for establishing a noninvasive PCa staging system. To infer the contributions of extracellular matrix (ECM) components and cell motility, we investigated fresh tissue specimens from two PCa xenograft mouse models, PC3 and LNCaP, using magnetic resonance elastography (MRE), diffusion-weighted imaging (DWI), quantitative histology, and nuclear shape analysis. Increased tumor stiffness and impaired water diffusion were observed to be associated with collagen and elastin accumulation and decreased cell motility. Overall, LNCaP, while more representative of clinical PCa than PC3, accumulated fewer ECM components, induced less restriction of water diffusion, and exhibited increased cell motility, resulting in overall softer and less viscous properties. Taken together, our results suggest that prostate tumor stiffness increases with ECM accumulation and cell adhesion - characteristics that influence critical biological processes of cancer development. MRE paired with DWI provides a powerful set of imaging markers that can potentially predict prostate tumor development from benign masses to aggressive malignancies in patients. STATEMENT OF SIGNIFICANCE: Xenograft models of human prostate tumor cell lines, allowing correlation of microstructure-sensitive biophysical imaging parameters with quantitative histological methods, can be investigated to identify hallmarks of cancer.

BRWD1 establishes epigenetic states for germinal center initiation, maintenance, and function.

Germinal center (GC) B cells segregate into three subsets that compartmentalize the antagonistic molecular programs of selection, proliferation, and somatic hypermutation. In bone marrow, the epigenetic reader BRWD1 orchestrates and insulates the sequential stages of cell proliferation and Igk recombination. We hypothesized BRWD1 might play similar insulative roles in the periphery. In Brwd1 -/- follicular B cells, GC initiation and class switch recombination following immunization were inhibited. In contrast, in Brwd1 -/- GC B cells there was admixing of chromatin accessibility across GC subsets and transcriptional dysregulation including induction of inflammatory pathways. This global molecular GC dysregulation was associated with specific defects in proliferation, affinity maturation, and tolerance. These data suggest that GC subset identity is required for some but not all GC-attributed functions. Furthermore, these data demonstrate a central role for BRWD1 in orchestrating epigenetic transitions at multiple steps along B cell developmental and activation pathways.

Partial Fourier in the presence of respiratory motion in prostate diffusion-weighted echo planar imaging.

PURPOSE: To investigate the effect of respiratory motion in terms of signal loss in prostate diffusion-weighted imaging (DWI), and to evaluate the usage of partial Fourier in a free-breathing protocol in a clinically relevant b-value range using both single-shot and multi-shot acquisitions. METHODS: A controlled breathing DWI acquisition was first employed at 3 T to measure signal loss from deep breathing patterns. Single-shot and multi-shot (2-shot) acquisitions without partial Fourier (no pF) and with partial Fourier (pF) factors of 0.75 and 0.65 were employed in a free-breathing protocol. The apparent SNR and ADC values were evaluated in 10 healthy subjects to measure if low pF factors caused low apparent SNR or overestimated ADC. RESULTS: Controlled breathing experiments showed a difference in signal coefficient of variation between shallow and deep breathing. In free-breathing single-shot acquisitions, the pF 0.65 scan showed a significantly (p < 0.05) higher apparent SNR than pF 0.75 and no pF in the peripheral zone (PZ) of the prostate. In the multi-shot acquisitions in the PZ, pF 0.75 had a significantly higher apparent SNR than 0.65 pF and no pF. The single-shot pF 0.65 scan had a significantly lower ADC than single-shot no pF. CONCLUSION: Deep breathing patterns can cause intravoxel dephasing in prostate DWI. For single-shot acquisitions at a b-value of 800 s/mm2, any potential risks of motion-related artefacts at low pF factors (pF 0.65) were outweighed by the increase in signal from a lower TE, as shown by the increase in apparent SNR. In multi-shot acquisitions however, the minimum pF factor should be larger, as shown by the lower apparent SNR at low pF factors.

Characterization of arsenic species by liquid sampling-atmospheric pressure glow discharge ionization mass spectrometry.

A liquid sampling-atmospheric pressure glow discharge (LS-APGD) ionization source operating at a nominal power of 30 W and solution flow rate of 30 µL min-1 and supported in a He sheath gas flow rate of 500 mL min-1 was interfaced to an Orbitrap mass spectrometer and assessed for use in rapid identification of inorganic and organic arsenic species, including As(III), As(V), monomethylarsonic acid, dimethylarsinic acid, and arsenobetaine in a 2% (v/v) nitric acid medium. Mass spectral acquisition in low-resolution mode, using only the ion trap analyzer, provided detection of protonated molecular ions for AsBet (m/z 179), DMA (m/z 139), MMA (m/z 141), and As(V) (m/z 143). As(III) is oxidized to As(V), likely due to in-source processes. Typical fragmentation of these compounds resulted in the loss of either water or methyl groups, as appropriate, i.e., introducing DMA also generated ions corresponding to MMA and As(V) as dissociation products. Structure assignments were also confirmed by high-resolution Orbitrap measurements. Spectral fingerprint assignments were based on the introduction of solutions containing 5 µg mL-1 of each arsenic compound.

Interventions for smoking cessation in hospitalised patients.

BACKGROUND: In 2020, 32.6% of the world's population used tobacco. Smoking contributes to many illnesses that require hospitalisation. A hospital admission may prompt a quit attempt. Initiating smoking cessation treatment, such as pharmacotherapy and/or counselling, in hospitals may be an effective preventive health strategy. Pharmacotherapies work to reduce withdrawal/craving and counselling provides behavioural skills for quitting smoking. This review updates the evidence on interventions for smoking cessation in hospitalised patients, to understand the most effective smoking cessation treatment methods for hospitalised smokers. OBJECTIVES: To assess the effects of any type of smoking cessation programme for patients admitted to an acute care hospital. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 7 September 2022. SELECTION CRITERIA: We included randomised and quasi-randomised studies of behavioural, pharmacological or multicomponent interventions to help patients admitted to hospital quit. Interventions had to start in the hospital (including at discharge), and people had to have smoked within the last month. We excluded studies in psychiatric, substance and rehabilitation centres, as well as studies that did not measure abstinence at six months or longer. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was abstinence from smoking assessed at least six months after discharge or the start of the intervention. We used the most rigorous definition of abstinence, preferring biochemically-validated rates where reported. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included 82 studies (74 RCTs) that included 42,273 participants in the review (71 studies, 37,237 participants included in the meta-analyses); 36 studies are new to this update. We rated 10 studies as being at low risk of bias overall (low risk in all domains assessed), 48 at high risk of bias overall (high risk in at least one domain), and the remaining 24 at unclear risk. Cessation counselling versus no counselling, grouped by intensity of intervention Hospitalised patients who received smoking cessation counselling that began in the hospital and continued for more than a month after discharge had higher quit rates than patients who received no counselling in the hospital or following hospitalisation (risk ratio (RR) 1.36, 95% confidence interval (CI) 1.24 to 1.49; 28 studies, 8234 participants; high-certainty evidence). In absolute terms, this might account for an additional 76 quitters in every 1000 participants (95% CI 51 to 103). The evidence was uncertain (very low-certainty) about the effects of counselling interventions of less intensity or shorter duration (in-hospital only counselling ≤ 15 minutes: RR 1.52, 95% CI 0.80 to 2.89; 2 studies, 1417 participants; and in-hospital contact plus follow-up counselling support for ≤ 1 month: RR 1.04, 95% CI 0.90 to 1.20; 7 studies, 4627 participants) versus no counselling. There was moderate-certainty evidence, limited by imprecision, that smoking cessation counselling for at least 15 minutes in the hospital without post-discharge support led to higher quit rates than no counselling in the hospital (RR 1.27, 95% CI 1.02 to 1.58; 12 studies, 4432 participants). Pharmacotherapy versus placebo or no pharmacotherapy Nicotine replacement therapy helped more patients to quit than placebo or no pharmacotherapy (RR 1.33, 95% CI 1.05 to 1.67; 8 studies, 3838 participants; high-certainty evidence). In absolute terms, this might equate to an additional 62 quitters per 1000 participants (95% CI 9 to 126). There was moderate-certainty evidence, limited by imprecision (as CI encompassed the possibility of no difference), that varenicline helped more hospitalised patients to quit than placebo or no pharmacotherapy (RR 1.29, 95% CI 0.96 to 1.75; 4 studies, 829 participants). Evidence for bupropion was low-certainty; the point estimate indicated a modest benefit at best, but CIs were wide and incorporated clinically significant harm and clinically significant benefit (RR 1.11, 95% CI 0.86 to 1.43, 4 studies, 872 participants). Hospital-only intervention versus intervention that continues after hospital discharge Patients offered both smoking cessation counselling and pharmacotherapy after discharge had higher quit rates than patients offered counselling in hospital but not offered post-discharge support (RR 1.23, 95% CI 1.09 to 1.38; 7 studies, 5610 participants; high-certainty evidence). In absolute terms, this might equate to an additional 34 quitters per 1000 participants (95% CI 13 to 55). Post-discharge interventions offering real-time counselling without pharmacotherapy (RR 1.23, 95% CI 0.95 to 1.60, 8 studies, 2299 participants; low certainty-evidence) and those offering unscheduled counselling without pharmacotherapy (RR 0.97, 95% CI 0.83 to 1.14; 2 studies, 1598 participants; very low-certainty evidence) may have little to no effect on quit rates compared to control. Telephone quitlines versus control To provide post-discharge support, hospitals may refer patients to community-based telephone quitlines. Both comparisons relating to these interventions had wide CIs encompassing both possible harm and possible benefit, and were judged to be of very low certainty due to imprecision, inconsistency, and risk of bias (post-discharge telephone counselling versus quitline referral: RR 1.23, 95% CI 1.00 to 1.51; 3 studies, 3260 participants; quitline referral versus control: RR 1.17, 95% CI 0.70 to 1.96; 2 studies, 1870 participants). AUTHORS' CONCLUSIONS: Offering hospitalised patients smoking cessation counselling beginning in hospital and continuing for over one month after discharge increases quit rates, compared to no hospital intervention. Counselling provided only in hospital, without post-discharge support, may have a modest impact on quit rates, but evidence is less certain. When all patients receive counselling in the hospital, high-certainty evidence indicates that providing both counselling and pharmacotherapy after discharge increases quit rates compared to no post-discharge intervention. Starting nicotine replacement or varenicline in hospitalised patients helps more patients to quit smoking than a placebo or no medication, though evidence for varenicline is only moderate-certainty due to imprecision. There is less evidence of benefit for bupropion in this setting. Some of our evidence was limited by imprecision (bupropion versus placebo and varenicline versus placebo), risk of bias, and inconsistency related to heterogeneity. Future research is needed to identify effective strategies to implement, disseminate, and sustain interventions, and to ensure cessation counselling and pharmacotherapy initiated in the hospital is sustained after discharge.

Exploring the opinions and potential impact of unflavoured e-liquid on smoking cessation among people who smoke and smoking relapse among people who previously smoked and now use e-cigarettes: findings from a UK-based mixed methods study.

BACKGROUND: Although electronic cigarettes (e-cigarettes) appear to be effective in helping people who smoke to stop smoking, concerns about use of e-cigarettes among young people have led to restrictions on non-tobacco flavoured e-liquids in some countries and some US states. These restrictions could reduce the appeal of these products to non-smoking youth but could have negative consequences for people who smoke or use e-cigarettes. METHODS: In this mixed methods study, we recruited UK adults who smoked or used to smoke and subsequently vaped to explore their opinions of unflavoured e-liquids and their beliefs about how they would be impacted by hypothetical e-liquid flavour restrictions. Participants trialled an unflavoured e-liquid instead of their usual nicotine product for four hours and completed a survey and an online interview. RESULTS: Using Interpretive Phenomenological Analysis and graphically presented data, we found differences in participants' opinions of unflavoured e-liquid. If only unflavoured, tobacco flavoured, and menthol flavoured e-liquids remained on the UK market, some people who smoke or vape may be unaffected, but some may relapse to smoking or continue smoking. Despite most wanting to prevent young people from initiating vaping, participants had varying opinions on whether flavour restrictions would be an effective method. CONCLUSIONS: The findings highlight that people who smoke and vape could be impacted by flavour restrictions in a range of ways, some of which could have a potential adverse impact on harm reduction efforts in the UK (e.g., by making smoking more appealing than vaping).

Integrating Text and Image Analysis: Exploring GPT-4V's Capabilities in Advanced Radiological Applications Across Subspecialties.

This study demonstrates that GPT-4V outperforms GPT-4 across radiology subspecialties in analyzing 207 cases with 1312 images from the Radiological Society of North America Case Collection.

In-line coupling of capillary-channeled polymer fiber columns with optical absorbance and multi-angle light scattering detection for the isolation and characterization of exosomes.

Extracellular vesicles (EVs) have garnered much interest due to their fundamental role in intracellular communication and their potential utility in clinical diagnostics and as biotherapeutic vectors. Of particular relevance is the subset of EVs referred to as exosomes, ranging in size from 30 to 150 nm, which contain incredible amounts of information about their cell of origin, which can be used to track the progress of disease. As a complementary action, exosomes can be engineered with therapeutic cargo to selectively target diseases. At present, the lack of highly efficient methods of isolation/purification of exosomes from diverse biofluids, plants, and cell cultures is a major bottleneck in the fundamental biochemistry, clinical analysis, and therapeutic applications. Equally impactful, the lack of effective in-line means of detection/characterization of isolate populations, including concentration and sizing, is limiting in the applications. The method presented here couples hydrophobic interaction chromatography (HIC) performed on polyester capillary-channeled polymer (C-CP) fiber columns followed by in-line optical absorbance and multi-angle light scattering (MALS) detection for the isolation and characterization of EVs, in this case present in the supernatant of Chinese hamster ovary (CHO) cell cultures. Excellent correlation was observed between the determined particle concentrations for the two detection methods. C-CP fiber columns provide a low-cost platform (< $5 per column) for the isolation of exosomes in a 15-min workflow, with complementary absorbance and MALS detection providing very high-quality particle concentration and sizing information.

IntEgrating Smoking Cessation treAtment into usual online Psychological care for people with common mEntal illness: Protocol for an online randomised feasibility and pilot study (ESCAPE digital).

BACKGROUND: In the UK, smoking prevalence in people with depression (34%) and anxiety (29%) is more than double that of the general population (13%). People who stop smoking improve their mental health with comparable effect sizes found for antidepressants. In England, online psychological therapy is a standard treatment for depression and anxiety. Online therapy is an acceptable setting for smoking cessation support; however, integrated smoking and mental health support is not available. This novel study aims to assess the acceptability and feasibility of an online smoking cessation intervention, and trial procedures, offered alongside online mental health treatment as it offers increased reach to people with common mental health difficulties who smoke. METHODS: A two-armed; Intervention (Integrated SilverCloud smoking cessation support) and control group (SilverCloud usual care), pragmatic, randomised controlled feasibility trial. We aim to recruit 500 adult smokers eligible for online mental health treatment. Follow-up will be conducted at 3-months and 6-months. We will assess the acceptability and feasibility of the trial procedures (i.e., recruitment, data completeness, self-reported acceptability and satisfaction) and the intervention (i.e., self-reported quit attempt, engagement with the smoking cessation and mental health programs, smoking cessation medicine and e-cigarette use, self-reported acceptability and satisfaction) and pilot clinical outcomes (i.e., biologically validated smoking abstinence, anxiety, depression, quality of health). CONCLUSION: If the Trial is successful, a randomised controlled effectiveness trial will follow to examine whether integrated smoking cessation and mental health treatment increases smoking abstinence and improves depression and anxiety compared to usual care. TRIAL REGISTRATION: ISRCTN10612149 (https://doi.org/10.1186/ISRCTN10612149), 02/02/2023.

Urocortin 3 contributes to paracrine inhibition of islet alpha cells in mice.

Pancreatic alpha cell activity and glucagon secretion lower as glucose levels increase. While part of the decrease is regulated by glucose itself, paracrine signaling by their neighboring beta and delta cells also plays an important role. Somatostatin from delta cells is an important local inhibitor of alpha cells at high glucose. Additionally, urocortin 3 (UCN3) is a hormone that is co-released from beta cells with insulin and acts locally to potentiate somatostatin secretion from delta cells. UCN3 thus inhibits insulin secretion via a negative feedback loop with delta cells, but its role with respect to alpha cells and glucagon secretion is not understood. We hypothesize that the somatostatin-driven glucagon inhibition at high glucose is regulated in part by UCN3 from beta cells. Here, we use a combination of live functional Ca2+ and cAMP imaging as well as direct glucagon secretion measurement, all from alpha cells in intact mouse islets, to determine the contributions of UCN3 to alpha cell behavior. Exogenous UCN3 treatment decreased alpha cell Ca2+ and cAMP levels and inhibited glucagon release. Blocking endogenous UCN3 signaling increased alpha cell Ca2+ by 26.8 ± 7.6%, but this did not result in increased glucagon release at high glucose. Furthermore, constitutive deletion of Ucn3 did not increase Ca2+ activity or glucagon secretion relative to controls. UCN3 is thus capable of inhibiting mouse alpha cells, but, given the subtle effects of endogenous UCN3 signaling on alpha cells, we propose that UCN3-driven somatostatin may serve to regulate local paracrine glucagon levels in the islet instead of inhibiting gross systemic glucagon release.

Results of an interlaboratory study on the working curve in vat photopolymerization.

The working curve informs resin properties and print parameters for stereolithography, digital light processing, and other photopolymer additive manufacturing (PAM) technologies. First demonstrated in 1992, the working curve measurement of cure depth vs radiant exposure of light is now a foundational measurement in the field of PAM. Despite its widespread use in industry and academia, there is no formal method or procedure for performing the working curve measurement, raising questions about the utility of reported working curve parameters. Here, an interlaboratory study (ILS) is described in which 24 individual laboratories performed a working curve measurement on an aliquot from a single batch of PAM resin. The ILS reveals that there is enormous scatter in the working curve data and the key fit parameters derived from it. The measured depth of light penetration Dp varied by as much as 7x between participants, while the critical radiant exposure for gelation Ec varied by as much as 70x. This significant scatter is attributed to a lack of common procedure, variation in light engines, epistemic uncertainties from the Jacobs equation, and the use of measurement tools with insufficient precision. The ILS findings highlight an urgent need for procedural standardization and better hardware characterization in this rapidly growing field.

Synchrotron-source micro-x-ray computed tomography for examining butterfly eyes.

Comparative anatomy is an important tool for investigating evolutionary relationships among species, but the lack of scalable imaging tools and stains for rapidly mapping the microscale anatomies of related species poses a major impediment to using comparative anatomy approaches for identifying evolutionary adaptations. We describe a method using synchrotron source micro-x-ray computed tomography (syn-µXCT) combined with machine learning algorithms for high-throughput imaging of Lepidoptera (i.e., butterfly and moth) eyes. Our pipeline allows for imaging at rates of ~15 min/mm3 at 600 nm3 resolution. Image contrast is generated using standard electron microscopy labeling approaches (e.g., osmium tetroxide) that unbiasedly labels all cellular membranes in a species-independent manner thus removing any barrier to imaging any species of interest. To demonstrate the power of the method, we analyzed the 3D morphologies of butterfly crystalline cones, a part of the visual system associated with acuity and sensitivity and found significant variation within six butterfly individuals. Despite this variation, a classic measure of optimization, the ratio of interommatidial angle to resolving power of ommatidia, largely agrees with early work on eye geometry across species. We show that this method can successfully be used to determine compound eye organization and crystalline cone morphology. Our novel pipeline provides for fast, scalable visualization and analysis of eye anatomies that can be applied to any arthropod species, enabling new questions about evolutionary adaptations of compound eyes and beyond.

Multimaterial decomposition in dual-energy CT for characterization of clots from acute ischemic stroke patients.

BACKGROUND: Nowadays, there is no method to quantitatively characterize the material composition of acute ischemic stroke thrombi prior to intervention, but dual-energy CT (DE-CT) offers imaging-based multimaterial decomposition. We retrospectively investigated the material composition of thrombi ex vivo using DE-CT with histological analysis as a reference. METHODS: Clots of 70 patients with acute ischemic stroke were extracted by mechanical thrombectomy and scanned ex vivo in formalin-filled tubes with DE-CT. Multimaterial decomposition in the three components, i.e., red blood cells (RBC), white blood cells (WBC), and fibrin/platelets (F/P), was performed and compared to histology (hematoxylin/eosin staining) as reference. Attenuation and effective Z values were assessed, and histological composition was compared to stroke etiology according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. RESULTS: Histological and imaging analysis showed the following correlation coefficients for RBC (r = 0.527, p < 0.001), WBC (r = 0.305, p = 0.020), and F/P (r = 0.525, p < 0.001). RBC-rich thrombi presented higher clot attenuation in Hounsfield units than F/P-rich thrombi (51 HU versus 42 HU, p < 0.01). In histological analysis, cardioembolic clots showed less RBC (40% versus 56%, p = 0.053) and more F/P (53% versus 36%, p = 0.024), similar to cryptogenic clots containing less RBC (34% versus 56%, p = 0.006) and more F/P (58% versus 36%, p = 0.003) than non-cardioembolic strokes. No difference was assessed for the mean WBC portions in all TOAST groups. CONCLUSIONS: DE-CT has the potential to quantitatively characterize the material composition of ischemic stroke thrombi. RELEVANCE STATEMENT: Using DE-CT, the composition of ischemic stroke thrombi can be determined. Knowledge of histological composition prior to intervention offers the opportunity to define personalized treatment strategies for each patient to accomplish faster recanalization and better clinical outcomes. KEY POINTS: • Acute ischemic stroke clots present different recanalization success according to histological composition. • Currently, no method can determine clot composition prior to intervention. • DE-CT allows quantitative material decomposition of thrombi ex vivo in red blood cells, white blood cells, and fibrin/platelets. • Histological clot composition differs between stroke etiology. • Insights into the histological composition in situ offer personalized treatment strategies.

Motion-induced phase-corrected homodyne reconstruction for partial Fourier single-shot diffusion-weighted echo planar imaging of the liver.

Partial Fourier encoding is popular in single-shot (ss) diffusion-weighted (DW) echo planar imaging (EPI) because it enables a shorter echo time (TE) and, hence, improves the signal-to-noise-ratio. Motion during diffusion encoding causes k-space shifting and dispersion, which compromises the quality of the homodyne reconstruction. This work provides a comprehensive understanding of the artifacts in homodyne reconstruction of partial Fourier ss-DW-EPI data in the presence of motion-induced phase and proposes the motion-induced phase-corrected homodyne (mpc-hdyne) reconstruction method to ameliorate these artifacts. Simulations with different types of motion-induced phase were performed to provide an understanding of the potential artifacts that occur in the homodyne reconstruction of partial Fourier ss-DW-EPI data. To correct for the artifacts, the mpc-hdyne reconstruction is proposed. The algorithm recenters k-space, updates the partial Fourier factor according to detected global k-space shifts, and removes low-resolution nonlinear phase before the conventional homodyne reconstruction. The mpc-hdyne reconstruction is tested on both simulation and in vivo data. Motion-induced phase can cause signal overestimation, worm artifacts, and signal loss in partial Fourier ss-DW-EPI data with the conventional homodyne reconstruction. Simulation and in vivo data showed that the proposed mpc-hdyne reconstruction ameliorated artifacts, yielding higher quality DW images compared with conventional homodyne reconstruction. Based on the understanding of the artifacts in homodyne reconstruction of partial Fourier ss-DW-EPI data, the mpc-hdyne reconstruction was proposed and showed superior performance compared with the conventional homodyne reconstruction on both simulation and in vivo data.

The impact of introducing alcohol-free beer options in bars and public houses on alcohol sales and revenue: A randomised crossover field trial.

AIMS: The study aimed to estimate the impact of introducing a draught alcohol-free beer, thereby increasing the relative availability of these products, on alcohol sales and monetary takings in bars and pubs in England. DESIGN: Randomised crossover field trial. SETTING: England. PARTICIPANTS: Fourteen venues that did not previously sell draught alcohol-free beer. INTERVENTION AND COMPARATOR: Venues completed two intervention periods and two control periods in a randomised order over 8 weeks. Intervention periods involved replacing one draught alcoholic beer with an alcohol-free beer. Control periods operated business as usual. MEASUREMENTS: The primary outcome was mean weekly volume (in litres) of draught alcoholic beer sold. The secondary outcome was mean weekly revenue [in GBP (£)] from all drinks. Analyses adjusted for randomised order, special events, season and busyness. FINDINGS: The adjusted mean difference in weekly sales of draught alcoholic beer was -20 L [95% confidence interval (CI) = -41 to +0.4], equivalent to a 4% reduction (95% CI = 8% reduction to 0.1% increase) in the volume of alcoholic draught beer sold when draught alcohol-free beer was available. Excluding venues that failed at least one fidelity check resulted in an adjusted mean difference of -29 L per week (95% CI = -53 to -5), equivalent to a 5% reduction (95% CI = 8% reduction to 0.8% reduction). The adjusted mean difference in weekly revenue was +61 GBP per week (95% CI = -328 to +450), equivalent to a 1% increase (95% CI = 5% decrease to 7% increase) when draught alcohol-free beer was available. CONCLUSIONS: Introducing a draught alcohol-free beer in bars and pubs in England reduced the volume of draught alcoholic beer sold by 4% to 5%, with no evidence of the intervention impacting net revenue.

Deep Learning to Differentiate Benign and Malignant Vertebral Fractures at Multidetector CT.

Background Differentiating between benign and malignant vertebral fractures poses diagnostic challenges. Purpose To investigate the reliability of CT-based deep learning models to differentiate between benign and malignant vertebral fractures. Materials and Methods CT scans acquired in patients with benign or malignant vertebral fractures from June 2005 to December 2022 at two university hospitals were retrospectively identified based on a composite reference standard that included histopathologic and radiologic information. An internal test set was randomly selected, and an external test set was obtained from an additional hospital. Models used a three-dimensional U-Net encoder-classifier architecture and applied data augmentation during training. Performance was evaluated using the area under the receiver operating characteristic curve (AUC) and compared with that of two residents and one fellowship-trained radiologist using the DeLong test. Results The training set included 381 patients (mean age, 69.9 years ± 11.4 [SD]; 193 male) with 1307 vertebrae (378 benign fractures, 447 malignant fractures, 482 malignant lesions). Internal and external test sets included 86 (mean age, 66.9 years ± 12; 45 male) and 65 (mean age, 68.8 years ± 12.5; 39 female) patients, respectively. The better-performing model of two training approaches achieved AUCs of 0.85 (95% CI: 0.77, 0.92) in the internal and 0.75 (95% CI: 0.64, 0.85) in the external test sets. Including an uncertainty category further improved performance to AUCs of 0.91 (95% CI: 0.83, 0.97) in the internal test set and 0.76 (95% CI: 0.64, 0.88) in the external test set. The AUC values of residents were lower than that of the best-performing model in the internal test set (AUC, 0.69 [95% CI: 0.59, 0.78] and 0.71 [95% CI: 0.61, 0.80]) and external test set (AUC, 0.70 [95% CI: 0.58, 0.80] and 0.71 [95% CI: 0.60, 0.82]), with significant differences only for the internal test set (P < .001). The AUCs of the fellowship-trained radiologist were similar to those of the best-performing model (internal test set, 0.86 [95% CI: 0.78, 0.93; P = .39]; external test set, 0.71 [95% CI: 0.60, 0.82; P = .46]). Conclusion Developed models showed a high discriminatory power to differentiate between benign and malignant vertebral fractures, surpassing or matching the performance of radiology residents and matching that of a fellowship-trained radiologist. © RSNA, 2024 See also the editorial by Booz and D'Angelo in this issue.

A deep learning model of tumor cell architecture elucidates response and resistance to CDK4/6 inhibitors.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have revolutionized breast cancer therapy. However, <50% of patients have an objective response, and nearly all patients develop resistance during therapy. To elucidate the underlying mechanisms, we constructed an interpretable deep learning model of the response to palbociclib, a CDK4/6i, based on a reference map of multiprotein assemblies in cancer. The model identifies eight core assemblies that integrate rare and common alterations across 90 genes to stratify palbociclib-sensitive versus palbociclib-resistant cell lines. Predictions translate to patients and patient-derived xenografts, whereas single-gene biomarkers do not. Most predictive assemblies can be shown by CRISPR-Cas9 genetic disruption to regulate the CDK4/6i response. Validated assemblies relate to cell-cycle control, growth factor signaling and a histone regulatory complex that we show promotes S-phase entry through the activation of the histone modifiers KAT6A and TBL1XR1 and the transcription factor RUNX1. This study enables an integrated assessment of how a tumor's genetic profile modulates CDK4/6i resistance.