ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma.

Here, we evaluated in vivo antitumor activity, target engagement, selectivity, and tumor specificity of ADT-1004, an orally bioavailable prodrug of ADT-007 having highly potent and selective pan-RAS inhibitory activity. ADT-1004 strongly blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity. As evidence of target engagement and tumor specificity, ADT-1004 inhibited activated RAS and ERK phosphorylation in PDAC tumors at dosages approximately 10-fold below the maximum tolerated dose and without discernable toxicity. ADT-1004 inhibited ERK phosphorylation in PDAC tumors. In addition, ADT-1004 blocked tumor growth and ERK phosphorylation in PDX PDAC models with KRAS G12D , KRAS G12V , KRAS G12C , or KRAS G13Q mutations. ADT-1004 treatment increased CD4 + and CD8 + T cells in the TME consistent with exhaustion and increased MHCII + M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRAS G12C inhibitors. As evidence of selectivity for tumors from PDAC cells with mutant KRAS, ADT-1004 did not impact the growth of tumors from RAS WT PDAC cells. Displaying broad antitumor activity in multiple mouse models of PDAC, along with target engagement and selectivity at dosages that were well tolerated, ADT-1004 warrants further development. Significance: ADT-1004 displayed robust antitumor activity in aggressive and clinically relevant PDAC models with unique tumor specificity to block RAS activation and MAPK signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors by averting resistance. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.

The Relationship Between Glabellar Contraction Patterns and Glabellar Muscle Anatomy: A Magnetic Resonance Imaging-based Study.

BACKGROUND: Glabellar contraction patterns were introduced to the scientific literature to help guide glabellar neuromodulator injection algorithms. However, the relationship between the underlying musculature and its influence on these glabellar contraction patterns is unclear. OBJECTIVES: The aim of this study was to identify via Magnetic Resonance Imaging (MRI) glabellar muscle parameters that display an influence on the distribution of individual glabellar contraction patterns. METHODS: Thirty-four healthy young individuals of Caucasian Polish descent were investigated (17 women, 17 men) with a mean age of 23.6 years and a mean BMI of 22.8 kg/m2. MRI-based measurements of length, thickness, width and surface area of procerus, corrugator supercilii, orbicularis oculi and frontalis muscles were conducted. RESULTS: Unadjusted models revealed that there was no statistically significant difference between the five glabellar contraction types and the investigated muscle parameters indicating that independent of the skin rhytid pattern, the underlying musculature was not different between the investigated groups in this sample with all p ≥ 0.102. Adjusted models revealed that sex was the most influential factor due to males displayed in general higher values for the investigated parameters when compared to females. CONCLUSIONS: The results of this study reveal that based on the MRI parameters investigated and based on the investigated cohort, there does not appear to be a strong relationship between glabellar contraction patterns and underlying glabella muscle anatomy. Utilizing glabellar contraction patterns to design neuromodulator treatment algorithms may be of variable clinical merit.

Transgender and Non-Binary Surgery Registry: Building a Patient-Focused Registry for Genital Gender Affirming Surgery.

Purpose: High quality data regarding long-term clinical and patient-reported outcomes (PROs) of genital gender-affirming surgery (GGAS) are lacking, and transgender and non-binary (TGNB) community voices have not historically been included in research development. These factors limit the utility of current research for guiding patients, clinicians, payers, and other GGAS stakeholders in decision-making. The Transgender and Non-Binary Surgery (TRANS) Registry has been developed to meet the needs of GGAS stakeholders and address limitations of traditional GGAS research. Methods: Development of the TRANS Registry occurred over several developmental phases beginning in May 2019 to present. Stakeholder engagement was performed throughout these phases, including: determination of key clinical outcomes and PROs, creation and implementation of data collection tools within the electronic health record (EHR), and development of centralized registry infrastructure. Results: The TRANS Registry is a prospective observational registry of individuals seeking vaginoplasty and vulvoplasty. The EHR-enabled infrastructure allows patients and clinicians to contribute longitudinal outcomes data to the TRANS Registry. We describe our community engaged approach to designing the TRANS Registry, including lessons learned, challenges, and future directions. Conclusions: The TRANS Registry is the first multicenter initiative to prospectively track the health of individuals seeking vaginoplasty and vulvoplasty using EHR-enabled methods, engaging TGNB community members and clinicians as partners in the process. This process may be used as a model for registry development in other emerging fields where high-quality longitudinal outcomes data are needed.

External validation of the MiGUTS nomogram for the prediction of bleeding control intervention after renal trauma.

INTRODUCTION: The American Association for the Surgery of Trauma (AAST) renal trauma grading leads to a variable management of patients with high-grade renal injuries. For a better prediction of the risk for bleeding interventions, Keihani et al. introduced the multi-institutional genito-urinary trauma study (MiGUTS) renal trauma nomogram in 2019. The aim of this study was to conduct an external validation and generalization for all kidney trauma cases of the nomogram with a European cohort of a Swiss level 1 trauma center. METHODS: We collected data from the clinical information system of the Kantonsspital Graubünden, Chur, Switzerland. All patients ≥ 18 years of age from 01.01.2008 to 01.12.2020 with a renal trauma who underwent computed tomography imaging of the abdomen were included. The descriptive analysis was performed by a t-test/Wilcoxon signed-rank test and a Chi-square test. The predictions of the nomogram were analysed by the Pearson correlation coefficient. The threshold of prediction of a bleeding intervention was optimized by a ROC analysis. RESULTS: Overall, 166 patients were included. Most patients were male (80.7%) with a median age of 44 years. Using the prediction from the MiGUTS nomogram developed by Keihani et al. we were able to identify a threshold with a sensitivity of 1.00, specificity of 0.87, positive predictive value of 0.44, negative predictive value of 1.00 and accuracy of 0.88. CONCLUSION: The MiGUTS nomogram by Keihani et al. demonstrated to be reliable in the prediction of an intervention for bleeding control in our validation study in a European cohort.

Low incidence of microplastics in coral reefs of Kane'ohe Bay, Hawai'i, USA.

This study investigated microplastic and other micro-debris pollution in sediment, seawater, sea cucumbers, and corals from fringing and patch reefs in Kane'ohe Bay, O'ahu, Hawai'i, USA. Microplastic pollution in Kane'ohe Bay Bay was low compared to other tropical coral reefs. Microplastics were detected in sediments (29 %), sea cucumbers (9 %), and coral (0-2 %) samples but were not quantifiable. Seawater had quantifiable microplastic (< 0.5 mm) and macroplastic (> 0.5 mm) pollution, with mean concentrations ranging from 0.0061 to 0.081 particles m-3. Most particles detected in seawater samples were larger, floating plastic debris consisting mostly of polyethylene, polypropylene fragments, and fibers. Across the other matrices, the most detected particles were polyester, polypropylene, and cotton fibers. These results provide baseline data for this important coral reef ecosystem, and further monitoring is recommended to understand the seasonal and long-term trends in microplastic pollution and its potential future impacts.

Myofiber-specific FoxP1 knockout protects against pancreatic cancer-induced muscle wasting in male but not female mice.

Cancer cachexia affects up to 80% of cancer patients and results in reduced quality of life and survival. We previously demonstrated that the transcriptional repressor Forkhead box P1 (FoxP1) is upregulated in skeletal muscle of cachectic mice and people with cancer, and when overexpressed in skeletal muscle is sufficient to induce pathological features characteristic of cachexia. However, the role of myofiber-derived FoxP1 in both normal muscle physiology and cancer-induced muscle wasting remains largely unexplored. To address this gap, we generated a conditional mouse line with myofiber-specific ablation of FoxP1 (FoxP1SkmKO) and found that in cancer-free mice, deletion of FoxP1 in skeletal myofibers resulted in increased myofiber size in both males and females, with a significant increase in muscle mass in males. In response to murine KPC pancreatic tumor burden, we found that myofiber-derived FoxP1 is required for cancer-induced muscle wasting and diaphragm muscle weakness in male mice. In summary, our findings identify myofiber-specific FoxP1 as a negative regulator of skeletal muscle with sex-specific differences in the context of cancer.

The Impact of Social Deprivation on Anterior Urethral Stricture Recurrence After Urethroplasty - A Trauma and Urologic Reconstructive Network of Surgeons (TURNS) Analysis.

INTRODUCTION AND OBJECTIVES: Several factors influence recurrence after urethral stricture repair. The impact of socioeconomic factors on stricture recurrence after urethroplasty is poorly understood. This study aims to assess the impact that social deprivation, an area-level measure of disadvantage, has on urethral stricture recurrence after urethroplasty. METHODS: We performed a retrospective review of patients undergoing urethral reconstruction by surgeons participating in a collaborative research group. Home zip code was used to calculate Social Deprivation Indices (SDI; 0-100), which quantifies the level of disadvantage across several sociodemographic domains collected in the American Community Survey. Patients without zip code data were excluded from the analysis. The Cox Proportional Hazards model was used to study the association between SDI and the hazard of functional recurrence, adjusting for stricture characteristics as well as age and body mass index. RESULTS: Median age was 46.0 years with a median follow up of 367 days for the 1452 men included in the study. Patients in the fourth SDI quartile (worst social deprivation) were more likely to be active smokers with traumatic and infectious strictures compared to the first SDI quartile. Patients in the fourth SDI quartile had 1.64 times the unadjusted hazard of functional stricture recurrence vs patients in the first SDI quartile (95% CI 1.04-2.59). Compared to anastomotic ± excision, substitution only repair had 1.90 times the unadjusted hazard of recurrence. The adjusted hazard of recurrence was 1.08 per 10-point increase in SDI (95% CI 1.01-1.15, P = .027). CONCLUSIONS: Patient social deprivation identifies those at higher risk for functional recurrence after anterior urethral stricture repair, offering an opportunity for preoperative counseling and postoperative surveillance. Addressing these social determinants of health can potentially improve outcomes in reconstructive surgery.

Clinical Benefits of DaxibotulinumtoxinA for Injection: Beyond Glabellar Line Effacement?

BACKGROUND: Botulinum toxin type A (BoNTA) is standard of care for glabellar lines ameliorization. DaxibotulinumtoxinA for Injection (DAXI) is a new BoNTA with a unique formulation representing the latest advancement in BoNTA technology. There is an unmet need for patients to understand the full potential of BoNTA treatment and new technologies. OBJECTIVE: To update clinical data supporting the use of DAXI for glabellar lines within the context of clinical experience. MATERIALS AND METHODS: A narrative review of the literature and summary of clinical experience with DAXI. RESULTS: The DAXI clinical trial program reflects clinical experience post-FDA approval, with DAXI demonstrating rapid onset, high patient response rates, and extended treatment duration versus conventional BoNTAs. Clinical observations suggest that DAXI has limited diffusion from the injection site, enabling more localized control of muscle activity and greater improvements in wrinkle severity. DAXI enables practitioners to exert greater finesse in their injections and in predicting changes to eyebrow shape and position and achieve improvement in skin quality. CONCLUSION: Advances in BoNTA technology can provide patients with greater options for treatment outcomes. The potential for enhanced localized effects with DAXI may contribute to more precise and targeted effects on muscle activity and additional aesthetic benefits to patients.

Safe and Effective Restoration of Jawline Definition With Hyaluronic Acid Injectable Gel VYC-25L: Results From a Randomized Controlled Study.

BACKGROUND: A well-defined jawline improves overall facial aesthetics, thus motivating patients to seek jawline augmentation. OBJECTIVES: This study will evaluate the safety and effectiveness of the hyaluronic acid injectable gel VYC-25L for restoring jawline definition. METHODS: A US multicenter, evaluator-blinded study randomized adults with grade 2 (moderate) or 3 (severe) Allergan Loss of Jawline Definition Scale (ALJDS) scores. Participants were randomized to VYC-25L treatment group or control group at study onset, with 12 months follow-up. The control group had the option to receive treatment after 6 months (primary endpoint completion). Effectiveness measures included month 6 ALJDS responders rate (proportion of participants with ≥1-grade improvement from baseline on both sides), FACE-Q Satisfaction With Lower Face and Jawline scores, and Global Aesthetic Improvement Scale (GAIS) responders (improved/much improved) as assessed by the investigator and participants. Injection site responses (ISRs) and adverse events (AEs) were monitored. RESULTS: At month 6, ALJDS responder rates were 69.0% versus 38.0% in the VYC-25L treatment (n = 157) and control (n = 49) groups, respectively (p = .0001). In the VYC-25L treatment group, FACE-Q scores improved by a mean of 45.9 points versus baseline at month 6 (p < .0001). Furthermore, 88.4% and 89.0% of participants in the VYC-25L treatment group were GAIS responders on month 6 by participant- and investigator-assessment, respectively. Most ISRs were mild or moderate and resolved within 2 weeks. Most treatment-related AEs were mild and resolved within a week. CONCLUSIONS: VYC-25L safely and effectively restores jawline definition through 1 year.

AL amyloidosis manifesting as a vertebral amyloidoma secondary to an unrecognized plasmacytoma expressing cyclin D1 case report.

INTRODUCTION: Immunoglobin-related (AL) amyloidosis is the production of amyloidogenic immunoglobulin light chains from clonal plasma cells or, rarely, B-cell lymphomas with plasmacytic differentiation. Amyloid deposition causes progressive end organ destruction with profound morbidity. PRESENTATION OF CASE: We present a rare case of a lambda light chain AL amyloidoma localized to a thoracic vertebra of an 87-year-old woman who had a remote history of an unspecified non-Hodgkin B-cell lymphoma (NHL). Our patient presented with upper extremity neuropathy and was found by MRI to have a malignant-appearing lesion throughout the T1 vertebra. Initial biopsy showed amyloid deposition and staging evaluation found localized disease. Prior to planned surgery and radiation the following year, she had worsening neuropathy including multiple falls. Repeat MRI confirmed lesion progression with concern for cord compression. Urgent surgical resection was performed. Histology showed numerous plasma cells with abundant amyloid deposition that was found by amyloid typing to be lambda light chain. An incidental B-cell rich lymphoid aggregate was also seen in a bone marrow fragment that required additional immunohistochemical evaluation, showing the aggregate to be benign while revealing the plasma cells to be positive for cyclin D1. She received localized radiation and has been asymptomatic. DISCUSSION: Amyloidosis and plasma cell neoplasms require appropriate staging evaluation. The cyclin D1-positive plasma cells raises the possibility of the t(11;14)/IGH::CCND1 translocation that portends better prognosis and therapeutic response with venetoclax. CONCLUSION: Amyloidomas are uncommon and may present in nearly any site, requiring a high index of clinical suspicion for proper diagnosis.

FERONIA orchestrates P2K1-driven purinergic signaling in plant roots.

Extracellular ATP (eATP) orchestrates vital processes in plants, akin to its role in animals. P2K1 is a crucial receptor mediating eATP effects. Immunoprecipitation tandem mass spectrometry data highlighted FERONIA's significant interaction with P2K1, driving us to explore its role in eATP signaling. Here, we investigated putative P2K1-interactor, FERONIA, which is a versatile receptor kinase pivotal in growth and stress responses. We employed a FERONIA loss-of-function mutant, fer-4, to dissect its effects on eATP signaling. Interestingly, fer-4 showed distinct calcium responses compared to wild type, while eATP-responsive genes were constitutively upregulated in fer-4. Additionally, fer-4 displayed insensitivity to eATP-regulated root growth and reduced cell wall accumulation. Together, these results uncover a role for FERONIA in regulating eATP signaling. Overall, our study deepens our understanding of eATP signaling, revealing the intricate interplay between P2K1 and FERONIA impacting the interface between growth and defense.

Exploring Decisional Conflict Experienced by Individuals Considering Metoidioplasty and Phalloplasty Gender-affirming Surgery.

Background: Metoidioplasty and phalloplasty gender-affirming surgery (MaPGAS) is increasingly performed and requires patients to make complex decisions that may lead to decisional uncertainty. This study aimed to evaluate decisional conflict in individuals considering MaPGAS. Methods: We administered a cross-sectional survey to adult participants assigned female sex at birth and considering MaPGAS, recruited via social media platforms and community health centers. We collected data on demographics, medical and surgical history, MaPGAS type considered, and the Decisional Conflict Scale (DCS). DCS scores range from 0 to 100 (>37.5 indicates greater decisional conflict). Demographic characteristics and DCS scores were compared between subgroups, using descriptive and chi-square statistics. Participants commented on MaPGAS uncertainty, and their comments were evaluated and thematically analyzed. Results: Responses from 264 participants were analyzed: mean age 29 years; 64% (n = 168) trans men, 80% (n = 210) White, 78% (n = 206) nonrural, 45% (n = 120) privately insured, 56% (n = 148) had 4 or more years of college, 23% (n = 84) considering metoidioplasty, 24% (n = 87) considering phalloplasty, and 26% (n = 93) considering metoidioplasty and phalloplasty. DCS total scores were significantly higher (39.8; P < 0.001) among those considering both MaPGAS options, as were mean ratings on the Uncertainty subscale [64.1 (SD 25.5; P < 0.001)]. Concerns surrounding complications were the top factor contributing to uncertainty and decisional conflict. Conclusions: In a cross-sectional national sample of individuals seeking MaPGAS, decisional uncertainty was the highest for those considering both MaPGAS options compared with metoidioplasty or phalloplasty alone. This suggests this cohort would benefit from focused decision support.

Unpacking overuse of androgen deprivation therapy for prostate cancer to inform de-implementation strategies.

BACKGROUND: Many men with prostate cancer will be exposed to androgen deprivation therapy (ADT). While evidence-based ADT use is common, ADT is also used in cases with no or limited evidence resulting in more harm than benefit, i.e., overuse. Since there are risks of ADT (e.g., diabetes, osteoporosis), it is important to understand the behaviors facilitating overuse to inform de-implementation strategies. For these reasons, we conducted a theory-informed survey study, including a discrete choice experiment (DCE), to better understand ADT overuse and provider preferences for mitigating overuse. METHODS: Our survey used the Action, Actor, Context, Target, Time (AACTT) framework, the Theoretical Domains Framework (TDF), the Capability, Opportunity, Motivation-Behavior (COM-B) Model, and a DCE to elicit provider de-implementation strategy preferences. We surveyed the Society of Government Service Urologists listserv in December 2020. We stratified respondents based on the likelihood of stopping overuse as ADT monotherapy for localized prostate cancer ("yes"/"probably yes," "probably no"/"no"), and characterized corresponding Likert scale responses to seven COM-B statements. We used multivariable regression to identify associations between stopping ADT overuse and COM-B responses. RESULTS: Our survey was completed by 84 respondents (13% response rate), with 27% indicating "probably no"/"no" to stopping ADT overuse. We found differences across respondents who said they would and would not stop ADT overuse in demographics and COM-B statements. Our model identified 2 COM-B domains (Opportunity-Social, Motivation-Reflective) significantly associated with a lower likelihood of stopping ADT overuse. Our DCE demonstrated in-person communication, multidisciplinary review, and medical record documentation may be effective in reducing ADT overuse. CONCLUSIONS: Our study used a behavioral theory-informed survey, including a DCE, to identify behaviors and context underpinning ADT overuse. Specifying behaviors supporting and gathering provider preferences in addressing ADT overuse requires a stepwise, stakeholder-engaged approach to support evidence-based cancer care. From this work, we are pursuing targeted improvement strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03579680.

Perioperative management of a double valve replacement and coronary artery bypass graft in a patient with carcinoid syndrome; a case report and literature review.

INTRODUCTION: Carcinoid tumors are rare neuroendocrine tumors; about 5% of patients develop the carcinoid syndrome. We present the case of a patient with carcinoid syndrome undergoing cardiac surgery. CASE REPORT: A 74-year-old patient with carcinoid heart disease and hepatic metastases underwent double valve replacement and CABG. The patient was on octreotide therapy and antihypertensive medication. An octreotide infusion was commenced perioperatively. Pharmaceutical agents that could potentially precipitate histamine release or exacerbate catecholamine secretion and carcinoid crises were avoided. Postoperatively, recovery was complicated by atrial fibrillation, chest infection, pleural effusions, acute kidney injury and delirium. DISCUSSION: Hepatic metastases cause systemic hormones' secretion, which cause a carcinoid crisis. Perioperative administration of octreotide is used, while vigilance is required to differentiate between hemodynamic effects related to the operation or disease specific factors. CONCLUSION: No carcinoid crisis was evident perioperatively. High vigilance with appropriate monitoring, aggressive management combined with meticulous choice of pharmaceutical agents led to this outcome.

Deep Phenotyping the Anterior Urethral Stricture: Characterizing the Relationship Between Inflammation, Fibrosis, Patient History, and Disease Pathophysiology.

PURPOSE: Anterior urethral stricture disease (aUSD) is a complex, heterogeneous condition that is idiopathic in origin for most men. This gap in knowledge rarely affects the current management strategy for aUSD, as urethroplasty does not generally consider etiology. However, as we transition towards personalized, minimally invasive treatments for aUSD and begin to consider aUSD prevention strategies, disease pathophysiology will become increasingly important. The purpose of this study was to perform a deep phenotype of men undergoing anterior urethroplasty for aUSD. We hypothesized that unique biologic signatures and potential targets for intervention would emerge based on stricture presence/absence, stricture etiology, and the presence/absence of stricture inflammation. MATERIALS AND METHODS: Men with aUSD undergoing urethroplasty were recruited from one of 5 participating centers. Enrollees provided urethral stricture tissue and blood/serum on the day of surgery and completed patient-reported outcome measure questionnaires both pre- and postoperatively. The initial study had 3 aims: (1) to determine pediatric and adult subacute and repeated perineal trauma (SRPT) exposures using a study-specific SRPT questionnaire, (2) to determine the degree of inflammation and fibrosis in aUSD and peri-aUSD (normal urethra) tissue, and (3) to determine levels of systemic inflammatory and fibrotic cytokines. Two controls groups provided serum (normal vasectomy patients) and urethral tissue (autopsy patients). Cohorts were based on the presence/absence of stricture, by presumed stricture etiology (idiopathic, traumatic/iatrogenic, lichen sclerosus [LS]), and by the presence/absence of stricture inflammation. RESULTS: Of 138 enrolled men (120 tissue/serum; 18 stricture tissue only), 78 had idiopathic strictures, 33 had trauma-related strictures, and 27 had LS-related strictures. BMI, stricture length, and stricture location significantly differed between cohorts (P < .001 for each). The highest BMIs and the longest strictures were observed in the LS cohort. SRPT exposures did not significantly differ between etiology cohorts, with > 60% of each reporting low/mild risk. Stricture inflammation significantly differed between cohorts, with mild to severe inflammation present in 27% of trauma-related strictures, 54% of idiopathic strictures, and 48% of LS strictures (P = .036). Stricture fibrosis did not significantly differ between cohorts (P = .7). Three serum cytokines were significantly higher in patients with strictures compared to stricture-free controls: interleukin-9 (IL-9; P = .001), platelet-derived growth factor-BB (P = .004), and CCL5 (P = .01). No differences were observed in the levels of these cytokines based on stricture etiology. However, IL-9 levels were significantly higher in patients with inflamed strictures than in patients with strictures lacking inflammation (P = .019). Degree of stricture inflammation positively correlated with serum levels of IL-9 (Spearman's rho 0.224, P = .014). CONCLUSIONS: The most common aUSD etiology is idiopathic. Though convention has implicated SRPT as causative for idiopathic strictures, here we found that patients with idiopathic strictures had low SRPT rates that were similar to rates in patients with a known stricture etiology. Stricture and stricture-adjacent inflammation in idiopathic stricture were similar to LS strictures, suggesting shared pathophysiologic mechanisms. IL-9, platelet-derived growth factor-BB, and CCL5, which were elevated in patients with strictures, have been implicated in fibrotic conditions elsewhere in the body. Further work will be required to determine if this shared biologic signature represents a potential mechanism for an aUSD predisposition.

A Multicenter, Randomized, Evaluator-Blinded Study to Examine the Safety and Effectiveness of Hyaluronic Acid Filler in the Correction of Infraorbital Hollows.

BACKGROUND: Hyaluronic acid injections are increasingly administered for correction of infraorbital hollows (IOHs). OBJECTIVES: The objective of this study was to examine the effectiveness (IOH correction) and safety of Restylane Eyelight hyaluronic acid (HAEYE) injections. METHODS: Patients with moderate/severe IOHs, assessed with the Galderma infraorbital hollows scale (GIHS), were randomized to HAEYE injections (by needle/cannula) (Day 1 + optional Month 1 touch-up) or no-treatment control. The primary endpoint was blinded evaluator-reported Month 3 response, defined as ≥1-point GIHS improvement from baseline (both sides, concurrently). Other endpoints examined investigator-reported aesthetic improvement on the Global Aesthetic Improvement Scale (GAIS), patient-reported satisfaction (FACE-Q satisfaction with outcome; satisfaction questionnaire), and adverse events. RESULTS: Overall, 333 patients were randomized. Month 3 GIHS responder rate was significantly higher for HA-EYE (87.4%) vs control (17.7%; P < .001), and comparable between HA-EYE-needle and HA-EYE-cannula groups (P = .967). HAEYE GAIS responder rate was 87.5-97.7% (Months 3-12). Mean FACE-Q Rasch-transformed scores were 64.3-73.5 (HAEYE) vs 14.1-16.2 (control) through Month 12. Patients reported looking younger (≥71%) and less tired (≥79%) with reduced undereye shadows (≥76%) and recovered within 3-5 hours posttreatment. Efficacy was maintained through Month 12 (63.5% GIHS responders) and through Month 18, after Month 12 retreatment (80.3% GIHS responders; 99.4% GAIS responders; FACE-Q scores 72.5-72.8). Forty patients (12.7%) reported typically mild adverse events (4.9% HAEYE-needle; 20.9% HAEYE-cannula). CONCLUSIONS: HAEYE treatment was effective in correcting moderate/severe IOHs at the primary endpoint (Month 3). Efficacy was sustained through Month 12 after first treatment for 63.5% and through Month 18 for 80.3% (after 1 retreatment) with needle or cannula administration. Safety outcomes were reassuring.

Neighborhood Deprivation, Race and Ethnicity, and Prostate Cancer Outcomes Across California Health Care Systems.

Importance: Non-Hispanic Black (hereafter, Black) individuals experience worse prostate cancer outcomes due to socioeconomic and racial inequities of access to care. Few studies have empirically evaluated these disparities across different health care systems. Objective: To describe the racial and ethnic and neighborhood socioeconomic status (nSES) disparities among residents of the same communities who receive prostate cancer care in the US Department of Veterans Affairs (VA) health care system vs other settings. Design, Setting, and Participants: This cohort study obtained data from the VA Central Cancer Registry for veterans with prostate cancer who received care within the VA Greater Los Angeles Healthcare System (VA cohort) and from the California Cancer Registry (CCR) for nonveterans who received care outside the VA setting (CCR cohort). The cohorts consisted of all males with incident prostate cancer who were living within the same US Census tracts. These individuals received care between 2000 and 2018 and were followed up until death from any cause or censoring on December 31, 2018. Data analyses were conducted between September 2022 and December 2023. Exposures: Health care setting, self-identified race and ethnicity (SIRE), and nSES. Main Outcomes and Measures: The primary outcome was all-cause mortality (ACM). Cox proportional hazards regression models were used to estimate hazard ratios for associations of SIRE and nSES with prostate cancer outcomes in the VA and CCR cohorts. Results: Included in the analysis were 49 461 males with prostate cancer. Of these, 1881 males were in the VA cohort (mean [SD] age, 65.3 [7.7] years; 833 Black individuals [44.3%], 694 non-Hispanic White [hereafter, White] individuals [36.9%], and 354 individuals [18.8%] of other or unknown race). A total of 47 580 individuals were in the CCR cohort (mean [SD] age, 67.0 [9.6] years; 8183 Black individuals [17.2%], 26 206 White individuals [55.1%], and 13 191 individuals [27.8%] of other or unknown race). In the VA cohort, there were no racial disparities observed for metastasis, ACM, or prostate cancer-specific mortality (PCSM). However, in the CCR cohort, the racial disparities were observed for metastasis (adjusted odds ratio [AOR], 1.36; 95% CI, 1.22-1.52), ACM (adjusted hazard ratio [AHR], 1.13; 95% CI, 1.04-1.24), and PCSM (AHR, 1.15; 95% CI, 1.05-1.25). Heterogeneity was observed for the racial disparity in ACM in the VA vs CCR cohorts (AHR, 0.90 [95% CI, 0.76-1.06] vs 1.13 [95% CI, 1.04-1.24]; P = .01). No evidence of nSES disparities was observed for any prostate cancer outcomes in the VA cohort. However, in the CCR cohort, heterogeneity was observed for nSES disparities with ACM (AHR, 0.82; 95% CI, 0.80-0.84; P = .002) and PCSM (AHR, 0.86; 95% CI, 0.82-0.89; P = .007). Conclusions and Relevance: Results of this study suggest that racial and nSES disparities were wider among patients seeking care outside of the VA health care system. Health systems-related interventions that address access barriers may mitigate racial and socioeconomic disparities in prostate cancer.

Increasing Precision When Targeting the Depressor Anguli Oris Muscle With Neuromodulators: An Ultrasound-Based Investigation.

BACKGROUND: Neuromodulator treatments of the perioral region are increasingly popular and aim to modulate the position of the modiolus. The predominantly targeted muscle is the depressor anguli oris (DAO) which allows for the modiolus to reposition cranially once temporarily relaxed. OBJECTIVES: The aim of this study was to identify the precise anatomic position of the DAO in relation to the marionette line, thereby increasing precision and reducing adverse events during neuromodulator treatments. METHODS: A total of n = 80 DAO muscles were investigated in n = 40 healthy, toxin-naïve volunteers (11 males, 29 females) with a mean [standard deviation] age of 48.15 [15] years and a mean BMI of 24.07 [3.7] kg/m2. The location of the DAO in relation to the labiomandibular sulcus, and its depth, extent, and thickness were investigated with high-frequency ultrasound imaging. RESULTS: The skin surface projection of the labiomandibular sulcus separates the DAO into medial and lateral portions. The distance between skin surface and muscle surface was on average 4.4 mm, with males having a greater distance (P < .001) and higher BMI being an important influencing factor for a greater distance (P < .001). The thickness of the DAO was on average 3.5 mm, with a range of 2.8 to 4.8 mm and with females having thinner muscles compared with males (P < .001). The most favorable injection depth was calculated to be 6.1 mm for intramuscular product placement. CONCLUSIONS: Understanding the perioral anatomy and the influence of age, sex, and BMI will potentially allow injectors to increase the efficacy and duration of neuromodulator treatments while expertly managing adverse events.

CPK28 is a modulator of purinergic signaling in plant growth and defense.

Extracellular ATP (eATP) is a key signaling molecule that plays a pivotal role in plant growth and defense responses. The receptor P2K1 is responsible for perceiving eATP and initiating its signaling cascade. However, the signal transduction mechanisms downstream of P2K1 activation remain incompletely understood. We conducted a comprehensive analysis of the P2K1 interactome using co-immunoprecipitation-coupled tandem mass spectrometry, leading to the identification of 121 candidate proteins interacting with P2K1. In silico analysis narrowed down the candidates to 47 proteins, including Ca2+-binding proteins, ion transport-related proteins, and receptor kinases. To investigate their involvement in eATP signaling, we employed a screening strategy based on changes in gene expression in response to eATP in mutants of the identified interactors. This screening revealed several Ca2+-dependent protein kinases (CPKs) that significantly affected the expression of eATP-responsive genes, suggesting their potential roles in eATP signaling. Notably, CPK28 and CPK6 showed physical interactions with P2K1 both in yeast and plant systems. Calcium influx and gene expression studies demonstrated that CPK28 perturbed eATP-induced Ca2+ mobilization and some early transcriptional responses. Overexpression of CPK28 resulted in an antagonistic physiological response to P2K1-mediated eATP signaling during both plant growth and defense responses to the necrotrophic pathogen Botrytis cinerea. Our findings highlight CPK28, among other CPKs, as a modulator of P2K1-mediated eATP signaling, providing valuable insights into the coordination of eATP signaling in plant growth and immunity.