Inhibitors of the small membrane (M) protein viroporin prevent Zika virus infection.

Flaviviruses, including Zika virus (ZIKV), are a significant global health concern, yet no licensed antivirals exist to treat disease. The small Membrane (M) protein plays well-defined roles during viral egress and remains within virion membranes following release and maturation. However, it is unclear whether M plays a functional role in this setting. Here, we show that M forms oligomeric membrane-permeabilising channels in vitro, with increased activity at acidic pH and sensitivity to the prototypic channel-blocker, rimantadine. Accordingly, rimantadine blocked an early stage of ZIKV cell culture infection. Structure-based channel models, comprising hexameric arrangements of two trans-membrane domain protomers were shown to comprise more stable assemblages than other oligomers using molecular dynamics (MD) simulations. Models contained a predicted lumenal rimantadine binding site, as well as a second druggable target region on the membrane-exposed periphery. In silico screening enriched for repurposed drugs/compounds predicted to bind to either one site or the other. Hits displayed superior potency in vitro and in cell culture compared with rimantadine, with efficacy demonstrably linked to virion-resident channels. Finally, rimantadine effectively blocked ZIKV viraemia in preclinical models, supporting that M constitutes a physiologically relevant target. This could be explored by repurposing rimantadine, or development of new M-targeted-therapies.

Fluoroscopic-guided hysteroscopic tubal cannulation results in high technical success and pregnancy rates comparable with the more traditional laparoscopically guided hysteroscopic tubal cannulation.

Objective: To compare women with proximal tubal obstruction (PTO) undergoing hysteroscopic tubal cannulation with fluoroscopic guidance vs. laparoscopic guidance. Design: Retrospective cohort study. Setting: All fluoroscopically-guided hysteroscopic tubal cannulations were performed in an ambulatory suite. All laparoscopically-guided hysteroscopic tubal cannulations were performed in a hospital operating room. Patients: Infertile women with unilateral or bilateral PTO on hysterosalpingography who failed selective salpingography in the radiology suite and had a planned laparoscopy or hysteroscopy in the operating room for defects seen on sonohysterography were studied. Intervention: All women had a Novy catheter system positioned hysteroscopically to cannulate the occluded fallopian tube(s). Women undergoing fluoroscopically guided hysteroscopic tubal cannulation (FHTC), which used contrast and C-arm pelvic imaging at an ambulatory center, were compared with those undergoing hospital-based laparoscopically guided hysteroscopic tubal cannulation (LHTC) with laparoscopic visualization. Main Outcome Measurements: Tubal cannulation success; bilateral cannulation success; tubal perforations; post-FHTC non-in vitro fertilization (non-IVF) intrauterine pregnancies; days from procedure to pregnancy for non-IVF intrauterine pregnancies; and time to non-IVF pregnancy hazards ratio. Results: A total of 76 infertile women undergoing either FHTC (34 women) or LHTC (42 women) between 2015 and 2019 were included. Demographic variables were similar among the 2 groups. A total of 31 (92%) of 34 of patients undergoing FHTC and 36 (86%) of 42 of patients undergoing LHTC had at least one tube successfully cannulated. In total, 30 (78%) of 34 of patients undergoing FHTC and 32 (79%) of 42 patients undergoing LHTC had all occluded tubes successfully cannulated. Tubal perforation occurred in 1 (3%) of 34 FHTC cases and 3 (7%) of 42 LHTC cases. A similar percentage of non-IVF treatment-induced intrauterine pregnancies were achieved in the FHTC and LHTC groups (10/34 [29%] vs. 12/42 [29%]). Among patients who conceived without IVF, time from procedure to pregnancy was lower in the FHTC group (101 ± 124.6 days) compared with the LHTC group (228 ± 216 days). There was a significant difference in time to pregnancy when only those who conceived were considered (hazard ratio, 9.39; 95% confidence interval, 2.42-36.51); however, there was no significant difference when all subjects regardless of pregnancy outcome were analyzed (hazard ratio, 1.48; 95% confidence interval, 0.64-3.446). Conclusion: Fluoroscopically guided hysteroscopic tubal cannulation is a safe, effective, incision free procedure that results in comparable rates of tubal patency and intrauterine pregnancies as LHTC. This technique should be considered in women undergoing treatment of PTO when operative laparoscopy is not otherwise indicated.

Dog owners' perceptions and veterinary-related decisions pertaining to changes in their dog's behavior that could indicate pain.

OBJECTIVE: Assess dog owners' concern levels and veterinary care decisions pertaining to behaviors that might signify pain before and after receiving brief pain-related educational information. Additionally, evaluate dog owners' perceptions of a modified version of the Colorado State University Canine Acute Pain Scale to identify their dog's pain level, determine whether they should take their dog to the veterinarian, and describe their dog's pain to their veterinarian. SAMPLE: 367 survey respondents who resided in the US and were the primary caretaker of at least 1 dog. METHODS: An electronic survey was created in Qualtrics and distributed via Prolific. Data were analyzed. RESULTS: When assessing differences between participants' concern levels before and after educational pain-related information, significant differences were found for 2 of the 3 scenarios. Significant differences were also found between participants' veterinary-related behaviors before and after educational pain-related information for all 3 scenarios. The most common reasons for not seeking immediate veterinary care included elements related to cost, convenience, and dog-related stress during veterinary visits. Most participants reported finding the Canine Acute Pain Scale useful for identifying their dog's pain level (89%), determining whether they should take their dog to the veterinarian (84%), and describing their dog's pain to their veterinarian (89%). CLINICAL RELEVANCE: Owners' interpretations of and subsequent actions (or inactions) to behaviors that might suggest pain carry great implications for companion animals' overall well-being. Following exposure to brief educational material about signs and symptoms of canine pain, owners in our study reported significant increases in stated concern related to their dog's change in behavior and intention to seek veterinary care. These findings suggest that even very brief pain-related educational material can have a positive impact on owners' perceptions of canine behavioral changes and increase the possibility that they will seek veterinary care.

Megalin Knockout Reduces SGLT2 Expression and Sensitizes to Western Diet-induced Kidney Injury.

Megalin (Lrp2) is a multiligand receptor that drives endocytic flux in the kidney proximal tubule (PT) and is necessary for the recovery of albumin and other filtered proteins that escape the glomerular filtration barrier. Studies in our lab have shown that knockout (KO) of Lrp2 in opossum PT cells leads to a dramatic reduction in sodium-glucose co-transporter 2 (SGLT2) transcript and protein levels, as well as differential expression of genes involved in mitochondrial and metabolic function. SGLT2 transcript levels are reduced more modestly in Lrp2 KO mice. Here, we investigated the effects of Lrp2 KO on kidney function and health in mice fed regular chow (RC) or a Western-style diet (WD) high in fat and refined sugar. Despite a modest reduction in SGLT2 expression, Lrp2 KO mice on either diet showed increased glucose tolerance compared to control mice. Moreover, Lrp2 KO mice were protected against WD-induced fat gain. Surprisingly, renal function in male Lrp2 KO mice on WD was compromised, and the mice exhibited significant kidney injury compared with control mice on WD. Female Lrp2 KO mice were less susceptible to WD-induced kidney injury than male Lrp2 KO. Together, our findings reveal both positive and negative contributions of megalin expression to metabolic health, and highlight a megalin-mediated sex-dependent response to injury following WD.

PD-L1 has a heterogeneous and dynamic expression in gastric cancer with implications for immunoPET.

Introduction: This study aimed to investigate the dynamics of programmed death-ligand 1 (PD-L1) expression, spatial heterogeneity, and binding affinity of FDA-approved anti-PD-L1 antibodies (avelumab and atezolizumab) in gastric cancer. Additionally, we determined how PD-L1 glycosylation impacts antibody accumulation in gastric cancer cells. Methods: Dynamic PD-L1 expression was examined in NCIN87 gastric cancer cells. Comparative binding studies of avelumab and atezolizumab were conducted in gastric cancer models, both in vitro and in vivo. Antibody uptake in tumors was visualized through positron emission tomography (PET) imaging. PD-L1 glycosylation status was determined via Western blot analyses before and after PNGase F treatment. Results: Consistent findings revealed time-dependent PD-L1 induction in NCIN87 gastric cancer cells and spatial heterogeneity in tumors, as shown by PET imaging and immunofluorescence. Avelumab displayed superior binding affinity to NCIN87 cells compared to atezolizumab, confirmed by in vivo PET imaging and ex vivo biodistribution analyses. Notably, PD-L1 glycosylation at approximately 50 kDa was observed, with PNGase F treatment inducing a shift to 35 kDa in molecular weight. Tissue samples from patient-derived xenografts (PDXs) validated the presence of both glycosylated and deglycosylated PD-L1 (degPD-L1) forms in gastric cancer. Immunofluorescence microscopy and binding assays demonstrated enhanced avelumab binding post-deglycosylation. Discussion: This study provides an understanding of dynamic and spatially heterogeneous PD-L1 expression in gastric cancer. Anti-PD-L1 immunoPET was able to visualize gastric tumors, and PD-L1 glycosylation has significant implications for antibody recognition. These insights contribute to demonstrating the complexities of PD-L1 in gastric cancer, holding relevance for refining PD-L1 imaging-based approaches.

Unsupervised Segmentation of 3D Microvascular Photoacoustic Images Using Deep Generative Learning.

Mesoscopic photoacoustic imaging (PAI) enables label-free visualization of vascular networks in tissues with high contrast and resolution. Segmenting these networks from 3D PAI data and interpreting their physiological and pathological significance is crucial yet challenging due to the time-consuming and error-prone nature of current methods. Deep learning offers a potential solution; however, supervised analysis frameworks typically require human-annotated ground-truth labels. To address this, an unsupervised image-to-image translation deep learning model is introduced, the Vessel Segmentation Generative Adversarial Network (VAN-GAN). VAN-GAN integrates synthetic blood vessel networks that closely resemble real-life anatomy into its training process and learns to replicate the underlying physics of the PAI system in order to learn how to segment vasculature from 3D photoacoustic images. Applied to a diverse range of in silico, in vitro, and in vivo data, including patient-derived breast cancer xenograft models and 3D clinical angiograms, VAN-GAN demonstrates its capability to facilitate accurate and unbiased segmentation of 3D vascular networks. By leveraging synthetic data, VAN-GAN reduces the reliance on manual labeling, thus lowering the barrier to entry for high-quality blood vessel segmentation (F1 score: VAN-GAN vs. U-Net = 0.84 vs. 0.87) and enhancing preclinical and clinical research into vascular structure and function.

Life-long music and dance relationships inform impressions of music- and dance-based movement therapies in individuals with and without mild cognitive impairment.

Background: No effective therapies exist to prevent degeneration from Mild Cognitive Impairment (MCI) to Alzheimer's disease. Therapies integrating music and/or dance are promising as effective, non-pharmacological options to mitigate cognitive decline. Objective: To deepen our understanding of individuals' relationships (i.e., histories, experiences and attitudes) with music and dance that are not often incorporated into music- and dance-based therapeutic design, yet may affect therapeutic outcomes. Methods: Eleven older adults with MCI and five of their care partners/ spouses participated (4M/12F; Black: n=4, White: n=10, Hispanic/ Latino: n=2; Age: 71.4±9.6). We conducted focus groups and administered questionnaires that captured aspects of participants' music and dance relationships. We extracted emergent themes from four major topics, including: (1) experience and history, (2) enjoyment and preferences, (3) confidence and barriers, and (4) impressions of music and dance as therapeutic tools. Results: Thematic analysis revealed participants' positive impressions of music and dance as potential therapeutic tools, citing perceived neuropsychological, emotional, and physical benefits. Participants viewed music and dance as integral to their lives, histories, and identities within a culture, family, and/ or community. Participants also identified lifelong engagement barriers that, in conjunction with negative feedback, instilled persistent low self-efficacy regarding dancing and active music engagement. Questionnaires verified individuals' moderately-strong music and dance relationships, strongest in passive forms of music engagement (e.g., listening). Conclusions: Our findings support that individuals' music and dance relationships and the associated perceptions toward music and dance therapy may be valuable considerations in enhancing therapy efficacy, participant engagement and satisfaction for individuals with MCI.

Less is more: Smaller hippocampal subfield volumes predict greater improvements in posttraumatic stress disorder symptoms over 2 years.

Posttraumatic stress disorder (PTSD) is a heterogeneous disorder, and symptom severity varies over time. Neurobiological factors that predict PTSD symptoms and their chronicity remain unclear. This study investigated whether the volume of the hippocampus and its subfields, particularly cornu ammonis (CA) 1, CA3, and dentate gyrus, are associated with current PTSD symptoms and whether they predict PTSD symptom changes over 2 years. We examined clinical and structural magnetic resonance imaging measures from 252 trauma-exposed post-9/11 veterans (159 with Time 1 PTSD diagnosis) during assessments approximately 2 years apart. Automated hippocampal subfield segmentation was performed with FreeSurfer Version 7.1, producing 19 bilateral subfields. PTSD symptoms were measured at each assessment using the Clinician-Administered PTSD Scale-IV (CAPS). All models included total intracranial volume as a covariate. First, similar to previous reports, we showed that smaller overall hippocampal volume was associated with greater PTSD symptom severity at Time 1. Notably, when examining regions of interest (CA1, CA3, dentate gyrus), we found that smaller Time 1 hippocampal volumes in the bilateral CA1-body and CA2/3-body predicted decreased PTSD symptom severity at Time 2. These findings were not accounted for by combat exposure or treatment history. Additionally, both Time 1 CA1-body and CA2/3-body volume showed unique associations with changes in avoidance/numbing, but not with changes in reexperiencing or hyperarousal symptoms. This supports a more complex and nuanced relationship between hippocampal structure and PTSD symptoms, where during the posttrauma years bigger may not always mean better, and suggests that the CA1-body and CA2/3-body are important factors in the maintenance of PTSD symptoms. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

An Indocyanine Green-Based Nanoprobe for In Vivo Detection of Cellular Senescence.

There is an urgent need to improve conventional cancer-treatments by preventing detrimental side effects, cancer recurrence and metastases. Recent studies have shown that presence of senescent cells in tissues treated with chemo- or radiotherapy can be used to predict the effectiveness of cancer treatment. However, although the accumulation of senescent cells is one of the hallmarks of cancer, surprisingly little progress has been made in development of strategies for their detection in vivo. To address a lack of detection tools, we developed a biocompatible, injectable organic nanoprobe (NanoJagg), which is selectively taken up by senescent cells and accumulates in the lysosomes. The NanoJagg probe is obtained by self-assembly of indocyanine green (ICG) dimers using a scalable manufacturing process and characterized by a unique spectral signature suitable for both photoacoustic tomography (PAT) and fluorescence imaging. In vitro, ex vivo and in vivo studies all indicate that NanoJaggs are a clinically translatable probe for detection of senescence and their PAT signal makes them suitable for longitudinal monitoring of the senescence burden in solid tumors after chemotherapy or radiotherapy.

Perceptions of gender equity in emergency medicine in Canada.

INTRODUCTION: Women-identifying emergency physicians face gender-based discrimination throughout their careers. The purpose of this study was to explore emergency physician's perceptions and experiences of gender equity in emergency medicine. METHODS: We conducted a secondary analysis of data from a previously conducted survey of Canadian emergency physicians on barriers to gender equity in emergency medicine. Survey responses were analyzed using logistic regression to determine the impact that gender, practice setting, years since graduation, race, equity-seeking status, and parental status had on agreement about gender equity in emergency medicine and five of the problem statements. RESULTS: A total of 710 participants completed the survey. Most identified as women (58.8%), white (77.4%), graduated between 2010 and 2019 (40%), had CCFP (Emergency Medicine) designation (47.9%), an urban practice (84.4%), were parents (62.4%) and did not identify as equity-seeking (79.9%). Women-identifying physicians were less likely to perceive gender equity in emergency medicine, OR 0.52, CI [0.38, 0.73]. Women-identifying physicians were more likely to agree with statements about microaggressions, OR 4.39, CI [2.66, 7.23]; barriers to leadership, OR 3.51, CI [2.25, 5.50]; gender wage gap, OR 13.46, CI [8.27, 21.91]; lack of support for parental leave, OR 2.85, CI [1.82, 4.44]; and education on allyship, OR 2.23 CI [1.44, 3.45] than men-identifying physicians. CONCLUSION: In this study, women-identifying physicians were less likely to perceive that there was gender equity in emergency medicine than men-identifying physicians. Women-identifying physicians agreed that there are greater barriers for career advancement including fewer opportunities for leadership, a gender wage gap, a lack of parental leave policies to support a return to work and a lack of education for men to become allies. Men-identifying physicians were less aware of these inequities. Health systems must work to improve gender equity in emergency medicine and this will require education and allyship from men-identifying physicians.

RéSUMé: INTRODUCTION: Les femmes médecins urgentistes sont confrontées à une discrimination fondée sur le sexe tout au long de leur carrière. L'objectif de cette étude était d'explorer les perceptions et les expériences des médecins urgentistes en matière d'équité entre les sexes en médecine d'urgence. MéTHODES: Nous avons procédé à une analyse secondaire des données d'une enquête menée précédemment auprès des médecins urgentistes canadiens sur les obstacles à l'équité entre les sexes en médecine d'urgence. Les réponses au sondage ont été analysées à l'aide d'une régression logistique pour déterminer l'incidence que le sexe, le milieu de pratique, les années écoulées depuis l'obtention du diplôme, la race, le statut de demandeur d'équité et le statut parental avaient sur l'accord sur l'équité entre les sexes en médecine d'urgence et cinq des énoncés de problème. RéSULTATS: Au total, 710 participants ont répondu à l'enquête. La plupart d'entre eux sont des femmes (58.8 %), de race blanche (77.4 %), ont obtenu leur diplôme entre 2010 et 2019 (40 %), ont le titre de CCMF (médecine d'urgence) (47.9 %), exercent en milieu urbain (84.4 %), sont parents (62.4 %) et ne se déclarent pas en quête d'équité (79.9 %). Les médecins s'identifiant à des femmes étaient moins susceptibles de percevoir l'équité entre les sexes en médecine d'urgence, OR 0.52, IC [0.38,0.73]. Les médecins s'identifiant comme femmes étaient plus susceptibles d'être d'accord avec les déclarations sur les microagressions, OR 4.39, IC [2.66, 7.23] ; obstacles au leadership, OR 3.51, IC [2.25, 5.50] ; écart salarial entre les hommes et les femmes, OR 13.46, IC [8.27, 21.91] ; le manque de soutien pour le congé parental, OR 2.85, IC [1.82, 4.44]; et l'éducation sur l'alliance, OR 2.23 IC [1.44, 3.45] que les médecins s'identifiant comme hommes. CONCLUSION: Dans cette étude, les médecins s'identifiant à des femmes étaient moins susceptibles de percevoir qu'il y avait une équité entre les sexes en médecine d'urgence que les médecins s'identifiant à des hommes. Les femmes médecins s'accordent à dire qu'il existe davantage d'obstacles à l'avancement professionnel, notamment moins d'opportunités de leadership, un écart salarial entre les hommes et les femmes, un manque de politiques de congé parental pour favoriser le retour au travail et un manque d'éducation des hommes pour qu'ils deviennent des alliés. Les médecins s'identifiant à des hommes étaient moins conscients de ces inégalités. Les systèmes de santé doivent s'efforcer d'améliorer l'équité entre les sexes dans la médecine d'urgence, ce qui nécessitera une formation et un allié de la part des médecins qui s'identifient aux hommes.

Inferring transmission routes for foot-and-mouth disease virus within a cattle herd using approximate Bayesian computation.

To control an outbreak of an infectious disease it is essential to understand the different routes of transmission and how they contribute to the overall spread of the pathogen. With this information, policy makers can choose the most efficient methods of detection and control during an outbreak. Here we assess the contributions of direct contact and environmental contamination to the transmission of foot-and-mouth disease virus (FMDV) in a cattle herd using an individual-based model that includes both routes. Model parameters are inferred using approximate Bayesian computation with sequential Monte Carlo sampling (ABC-SMC) applied to data from transmission experiments and the 2007 epidemic in Great Britain. This demonstrates that the parameters derived from transmission experiments are applicable to outbreaks in the field, at least for closely related strains. Under the assumptions made in the model we show that environmental transmission likely contributes a majority of infections within a herd during an outbreak, although there is a lot of variation between simulated outbreaks. The accumulation of environmental contamination not only causes infections within a farm, but also has the potential to spread between farms via fomites. We also demonstrate the importance and effectiveness of rapid detection of infected farms in reducing transmission between farms, whether via direct contact or the environment.

Importance of validity testing in psychiatric assessment: evidence from a sample of multimorbid post-9/11 veterans.

OBJECTIVE: Performance validity (PVTs) and symptom validity tests (SVTs) are necessary components of neuropsychological testing to identify suboptimal performances and response bias that may impact diagnosis and treatment. The current study examined the clinical and functional characteristics of veterans who failed PVTs and the relationship between PVT and SVT failures. METHOD: Five hundred and sixteen post-9/11 veterans participated in clinical interviews, neuropsychological testing, and several validity measures. RESULTS: Veterans who failed 2+ PVTs performed significantly worse than veterans who failed one PVT in verbal memory (Cohen's d = .60-.69), processing speed (Cohen's d = .68), working memory (Cohen's d = .98), and visual memory (Cohen's d = .88-1.10). Individuals with 2+ PVT failures had greater posttraumatic stress (PTS; ß = 0.16; p = .0002), and worse self-reported depression (ß = 0.17; p = .0001), anxiety (ß = 0.15; p = .0007), sleep (ß = 0.10; p = .0233), and functional outcomes (ß = 0.15; p = .0009) compared to veterans who passed PVTs. 7.8% veterans failed the SVT (Validity-10; ≥19 cutoff); Multiple PVT failures were significantly associated with Validity-10 failure at the ≥19 and ≥23 cutoffs (p's < .0012). The Validity-10 had moderate correspondence in predicting 2+ PVTs failures (AUC = 0.83; 95% CI = 0.76, 0.91). CONCLUSION: PVT failures are associated with psychiatric factors, but not traumatic brain injury (TBI). PVT failures predict SVT failure and vice versa. Standard care should include SVTs and PVTs in all clinical assessments, not just neuropsychological assessments, particularly in clinically complex populations.

Routine, molecular point-of-care testing for SARS-CoV-2 and other respiratory viruses within an acute oncology service improves patient care.

OBJECTIVES: COVID-19 has caused significant challenges for infection prevention measures and patient flow in hospital admission pathways. We aimed to assess the impact of replacing laboratory PCR with molecular point-of-care testing (mPOCT) for respiratory viruses including SARS-CoV-2, within an Acute Oncology Service (AOS). METHODS: This pre- and post-implementation study took place in the AOS of a large teaching hospital, in Southampton, UK. We collected data from two periods: November 25th, 2019 to November 24th, 2020, when respiratory virus testing utilised laboratory PCR, and December 1st, 2020 to May 31st, 2021 following the introduction of mPOCT. The primary outcome was the time to results. RESULTS: 2189 patients were tested in the pre-implementation period and 1540 in the post implementation period. Median (IQR) time to results was 5.8 h (4.2-10.6) pre-implementation and 1.9 h (1.5-3.0) post-implementation (difference -3.6 h [95%CI to -3.8 to -3.5]; p < 0.0001). Median time spent in assessment areas was 6.0 h (4.1-7.9) pre-implementation and 5.5 h (3.8-7.4) post-implementation (p < 0.0001). 20 (0.9%) patients admitted via AOS assessment unit developed hospital-acquired respiratory virus infection pre-implementation versus 0 (0%) post-implementation (p = 0.031). CONCLUSIONS: Routine mPOCT for respiratory viruses, including SARS-CoV-2, was associated with a reduced time to results, reduced time in assessment areas, and a reduction in the rates of hospital-acquired respiratory virus infection in an acute oncology assessment unit.

Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial.

BACKGROUND: PROpel met its primary endpoint showing statistically significant improvement in radiographic progression-free survival with olaparib plus abiraterone versus placebo plus abiraterone in patients with first-line metastatic castration-resistant prostate cancer (mCRPC) unselected by homologous recombination repair mutation (HRRm) status, with benefit observed in all prespecified subgroups. Here we report the final prespecified overall survival analysis. METHODS: This was a randomised, double-blind, phase 3 trial done at 126 centres in 17 countries worldwide. Patients with mCRPC aged at least 18 years, Eastern Cooperative Oncology Group performance status 0-1, a life expectancy of at least 6 months, with no previous systemic treatment for mCRPC and unselected by HRRm status were randomly assigned (1:1) centrally by means of an interactive voice response system-interactive web response system to abiraterone acetate (orally, 1000 mg once daily) plus prednisone or prednisolone with either olaparib (orally, 300 mg twice daily) or placebo. The patients, the investigator, and study centre staff were masked to drug allocation. Stratification factors were site of metastases and previous docetaxel at metastatic hormone-sensitive cancer stage. Radiographic progression-free survival was the primary endpoint and overall survival was a key secondary endpoint with alpha-control (alpha-threshold at prespecified final analysis: 0·0377 [two-sided]), evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03732820, and is completed and no longer recruiting. FINDINGS: Between Oct 31, 2018 and March 11, 2020, 1103 patients were screened, of whom 399 were randomly assigned to olaparib plus abiraterone and 397 to placebo plus abiraterone. Median follow-up for overall survival in patients with censored data was 36·6 months (IQR 34·1-40·3) for olaparib plus abiraterone and 36·5 months (33·8-40·3) for placebo plus abiraterone. Median overall survival was 42·1 months (95% CI 38·4-not reached) with olaparib plus abiraterone and 34·7 months (31·0-39·3) with placebo plus abiraterone (hazard ratio 0·81, 95% CI 0·67-1·00; p=0·054). The most common grade 3-4 adverse event was anaemia reported in 64 (16%) of 398 patients in the olaparib plus abiraterone and 13 (3%) of 396 patients in the placebo plus abiraterone group. Serious adverse events were reported in 161 (40%) in the olaparib plus abiraterone group and 126 (32%) in the placebo plus abiraterone group. One death in the placebo plus abiraterone group, from interstitial lung disease, was considered treatment related. INTERPRETATION: Overall survival was not significantly different between treatment groups at this final prespecified analysis. FUNDING: Supported by AstraZeneca and Merck Sharp & Dohme.

Risks & Protective Factors for Depression & Suicide Among Hawai'i Agricultural Producers.

Studies have consistently shown that agricultural producers in the continental United States have disproportionately high rates of depression and suicide as compared to other occupations. It is not known whether this is true in Hawai'i, which is both geographically distinct and ethnically diverse. To examine rates of depression and suicide as well as potential risk and protective factors, a state-wide mental health needs assessment was conducted from November 2021 to September 2022. We conducted a survey with a nonprobability-based convenience sample targeting agricultural producers across Hawai'i, and performed descriptive statistics and logistic regression analyses. In a sample of 408 respondents, 35% (n = 143) had clinical depression symptomatology, and 8% (n = 33) had suicidal ideation based on the Patient Health Questionnaire-9. Older age was slightly protective in that every year of increase in age was associated with 0.98 times (95% CI: 0.96, 0.99) reduced odds of depression symptomatology, and 0.96 times (95% CI:0.94, 0.98) reduced odds of suicidal ideation. Identifying as East Asian had 2.04 times (95% CI: 1.16, 3.61) higher odds of depression symptomatology, and Southeast Asian had 3.04 times odds (95% CI:1.15, 8.00) of suicidal ideation. However, in the presence of stress and coping variables, the demographic factors became statistically non-significant. Instead, feeling stressed, uncertainty as the stressor, and media-focused coping were significant risk factors in increasing two to eight times the odds of depressive symptoms. For suicidal ideation, depression symptomatology increased odds by 31.95 (95% CI: 5.60-182.32), using media-focused coping increased 5.20 odds (95% CI: 1.66, 16.27), but problem-focused coping decreased 0.32 times odds (0.10, 0.99). Culturally specific prevention and intervention measures should be tailored for Hawai'i agricultural producers with an emphasis toward younger, East, and Southeast Asian producers and attention toward providing skillful coping strategies for effective stress regulation and management.

Immuno-PET Detects Antibody-Drug Potency on Coadministration with Statins.

The human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are antibody-drug conjugates (ADC) clinically used to treat HER2-positive breast cancer, with the latter receiving clinical approval in 2021 for HER2-positive gastric cancer. Lovastatin, a cholesterol-lowering drug, temporally elevates cell-surface HER2 in ways that enhance HER2-ADC binding and internalization. Methods: In an NCIN87 gastric xenograft model and a gastric patient-derived xenograft model, we used the 89Zr-labeled or 64Cu-labeled anti-HER2 antibody trastuzumab to investigate the dosing regimen of ADC therapy with and without coadministration of lovastatin. We compared the ADC efficacy of a multiple-dose ADC regime, which replicates the clinical dose regimen standard, with a single-dose regime. Results: T-DM1/lovastatin treatment inhibited tumor growth, regardless of multiple- or single-dose T-DM1 administration. Coadministration of lovastatin with T-DM1 or T-DXd as a single dose enhanced tumor growth inhibition, which was accompanied by a decrease in signal on HER2-targeted immuno-PET and a decrease in HER2-mediated signaling at the cellular level. DNA damage signaling was increased on ADC treatment in vitro. Conclusion: Our data from a gastric cancer xenograft show the utility of HER2-targeted immuno-PET to inform the tumor response to ADC therapies in combination with modulators of cell-surface target availability. Our studies also demonstrate that statins enhance ADC efficacy in both a cell-line and a patient-derived xenograft model in ways that enable a single-dose administration of the ADC.

Metformin-Induced Receptor Turnover Alters Antibody Accumulation in HER-Expressing Tumors.

Metformin has effects beyond its antihyperglycemic properties, including altering the localization of membrane receptors in cancer cells. Metformin decreases human epidermal growth factor receptor (HER) membrane density. Depletion of cell-surface HER decreases antibody-tumor binding for imaging and therapeutic approaches. Here, we used HER-targeted PET to annotate antibody-tumor binding in mice treated with metformin. Methods: Small-animal PET annotated antibody binding in HER-expressing xenografts on administration of an acute versus a daily dose schedule of metformin. Analyses at the protein level in the total, membrane, and internalized cell extracts were performed to determine receptor endocytosis, HER surface and internalized protein levels, and HER phosphorylation. Results: At 24 h after injection of radiolabeled anti-HER antibodies, control tumors had higher antibody accumulation than tumors treated with an acute dose of metformin. These differences were temporal, and by 72 h, tumor uptake in acute cohorts was similar to uptake in control. Additional PET imaging revealed a sustained decrease in tumor uptake on daily metformin treatment compared with control and acute metformin cohorts. The effects of metformin on membrane HER were reversible, and after its removal, antibody-tumor binding was restored. The time- and dose-dependent effects of metformin-induced HER depletion observed preclinically were validated with immunofluorescence, fractionation, and protein analysis cell assays. Conclusion: The findings that metformin decreases cell-surface HER receptors and reduces antibody-tumor binding may have significant implications for the use of antibodies targeting these receptors in cancer treatment and molecular imaging.

Performance evaluation of mesoscopic photoacoustic imaging.

Photoacoustic mesoscopy visualises vascular architecture at high-resolution up to ~3 mm depth. Despite promise in preclinical and clinical imaging studies, with applications in oncology and dermatology, the accuracy and precision of photoacoustic mesoscopy is not well established. Here, we evaluate a commercial photoacoustic mesoscopy system for imaging vascular structures. Typical artefact types are first highlighted and limitations due to non-isotropic illumination and detection are evaluated with respect to rotation, angularity, and depth of the target. Then, using tailored phantoms and mouse models, we investigate system precision, showing coefficients of variation (COV) between repeated scans [short term (1 h): COV= 1.2%; long term (25 days): COV= 9.6%], from target repositioning (without: COV=1.2%, with: COV=4.1%), or from varying in vivo user experience (experienced: COV=15.9%, unexperienced: COV=20.2%). Our findings show robustness of the technique, but also underscore general challenges of limited-view photoacoustic systems in accurately imaging vessel-like structures, thereby guiding users when interpreting biologically-relevant information.