CBCT-based synthetic CT image generation using a diffusion model for CBCT-guided lung radiotherapy.

BACKGROUND: Although cone beam computed tomography (CBCT) has lower resolution compared to planning CTs (pCT), its lower dose, higher high-contrast resolution, and shorter scanning time support its widespread use in clinical applications, especially in ensuring accurate patient positioning during the image-guided radiation therapy (IGRT) process. PURPOSE: While CBCT is critical to IGRT, CBCT image quality can be compromised by severe stripe and scattering artifacts. Tumor movement secondary to respiratory motion also decreases CBCT resolution. In order to improve the image quality of CBCT, we propose a Lung Diffusion Model (L-DM) framework. METHODS: Our proposed algorithm is based on a conditional diffusion model trained on pCT and deformed CBCT (dCBCT) image pairs to synthesize lung CT images from dCBCT images and benefit CBCT-based radiotherapy. dCBCT images were used as the constraint for the L-DM. The image quality and Hounsfield unit (HU) values of the synthetic CTs (sCT) images generated by the proposed L-DM were compared to three selected mainstream generation models. RESULTS: We verified our model in both an institutional lung cancer dataset and a selected public dataset. Our L-DM showed significant improvement in the four metrics of mean absolute error (MAE), peak signal-to-noise ratio (PSNR), normalized cross-correlation (NCC), and structural similarity index measure (SSIM). In our institutional dataset, our proposed L-DM decreased the MAE from 101.47 to 37.87 HU and increased the PSNR from 24.97 to 29.89 dB, the NCC from 0.81 to 0.97, and the SSIM from 0.80 to 0.93. In the public dataset, our proposed L-DM decreased the MAE from 173.65 to 58.95 HU, while increasing the PSNR, NCC, and SSIM from 13.07 to 24.05 dB, 0.68 to 0.94, and 0.41 to 0.88, respectively. CONCLUSIONS: The proposed L-DM significantly improved sCT image quality compared to the pre-correction CBCT and three mainstream generative models. Our model can benefit CBCT-based IGRT and other potential clinical applications as it increases the HU accuracy and decreases the artifacts from input CBCT images.

Pros and Cons of APOE4 Homozygosity and Effects on Neuroplasticity, Malnutrition, and Infections in Early Life Adversity, Alzheimer's Disease, and Alzheimer's Prevention.

Fortea et al.'s. (2024) recent data analysis elegantly calls attention to familial late-onset Alzheimer's disease (AD) with APOE4 homozygosity. The article by Grant (2024) reviews the factors associated with AD, particularly the APOE genotype and lifestyle, and the broad implications for prevention, both for individuals with the lifestyles associated with living in resource-rich countries and for those enduring environmental adversity in poverty settings, including high exposure to enteric pathogens and precarious access to healthcare. Grant discusses the issue of APOE genotype and its implications for the benefits of lifestyle modifications. This review highlights that bearing APOE4 could constitute an evolutionary benefit in coping with heavy enteric infections and malnutrition early in life in the critical formative first two years of brain development. However, the critical issue may be that this genotype could be a health concern under shifts in lifestyle and unhealthy diets during aging, leading to severe cognitive impairments and increased risk of AD. This commentary supports the discussions of Grant and the benefits of improving lifestyle for decreasing the risks for AD while providing further understanding and modelling of the early life benefits of APOE4 amidst adversity. This attention to the pathophysiology of AD should help further elucidate these critical, newly appreciated pathogenic pathways for developing approaches to the prevention and management in the context of the APOE genetic variations associated with AD.

Evaluating the Importance of Mentoring in Undergraduate Research Education Programs.

The National Institute of Health R25 Research Education Program was evaluated in the second year of implementation. Twelve mentors and 20 underrepresented minority students (URMs) scholars from partnerships and collaborations among five colleges and universities were added to the program to provide a more diverse research experience. Findings reveal that 100% of research mentors agree that the approachableness and accessibility of the program coordinator were beneficial in achieving mentorship goals and objectives. In addition, 85% of the students strongly agreed that the presentation of their research findings and the weekly reflection on goals, identification of accomplishments, and obstacles through the individual development plan were very effective. Of the 23 successfully tracked students for 2 years, six URMs (26.09%) obtained a bachelor's degree and were admitted into a graduate program; two were directly admitted to a PhD program in biomedical sciences.

Inflammatory Profile of Chronic Rhinosinusitis With Nasal Polyp Patients in Brazil: Multicenter Study.

OBJECTIVES: To determine the inflammatory profile of CRSwNP in Brazil and characterize the subgroups of CRSwNP patients in this population through cluster analysis. STUDY DESIGN: Multicenter cross-sectional study involving 15 centers representing different regions of Brazil. SUBJECTS AND METHODS: Clinical data of 166 patients and 80 controls, aged 18 to 70 years old, number of surgeries for CRS, history of asthma and aspirin sensitivity, and Lund-Mackay scores on CT scans. During nasal endoscopy, we obtained the Lund-Kennedy scores and collected 2 samples of nasal polyps: one for eosinophil and neutrophil tissue counts and one to quantify different cytokines. RESULTS: 79.6% of our patients had 10 or more eosinophils/HPF. CRSwNP groups exhibited significantly lower concentrations of TNF-alpha and significantly higher concentrations of IFN-gamma, CCL11/Eotaxin, CCL24/Eotaxin-2/MPIF-2, and CCL26/Eotaxin-3 versus the control group (Kruskal-Wallis test). Comparison between CRSwNP groups (≥10 vs <10 eosinophils/HPF) showed no difference in cytokine concentration (Mann-Whitney test). Hierarchical clustering and PCA according to cytokine concentrations revealed 2 main Clusters, with a significantly higher concentration of all cytokines in Cluster 1 (n = 35) than in Cluster 2 (n = 121), except IL-6 and IL-33 (Mann-Whitney test). According to ROC curve analysis the best cut-off to differentiate the 2 clusters was 43 eosinophils/HPF. The group with ≥43 presented a higher prevalence of men and a higher Lund-Mackay score (Mann-Whitney test). CONCLUSIONS: CRSwNP patients in Brazil present mixed inflammation, with 2 distinct groups (high and low inflammatory pattern) that can be distinguished by tissue eosinophilia of ≥43 eosinophils/HPF cut-off in nasal polyps.

Rehabilitation after musculoskeletal injury: European perspective.

Trauma is one of the main causes of death in younger people and ongoing disability worldwide. In Europe, while there is generally good organization of trauma reception and acute treatment, rehabilitation from major musculoskeletal injuries is less well defined and provided. This article documents the diverse approaches to rehabilitation after major injury in 6 European nations. The recognition of need is universal, but achieving a robust rehabilitation strategy is more elusive across the varying health care systems. Switzerland has the most robust service in the insured population. In the other countries, particularly where there is a reliance on public institutes, this provision is at best patchy. In the Netherlands, innovative patient-empowering strategies have gained traction with notable success, and in the United Kingdom, a recent randomized trial also showed this approach to be reproducible and robust. Overall, there is a clear need for learning across the national systems and implementation of a minimum set of standards.

Validation of AI-assisted ThinPrep® Pap test screening using the GeniusTM Digital Diagnostics System.

Advances in whole-slide imaging and artificial intelligence present opportunities for improvement in Pap test screening. To date, there have been limited studies published regarding how best to validate newer AI-based digital systems for screening Pap tests in clinical practice. In this study, we validated the Genius™ Digital Diagnostics System (Hologic) by comparing the performance to traditional manual light microscopic diagnosis of ThinPrep® Pap test slides. A total of 319 ThinPrep® Pap test cases were prospectively assessed by six cytologists and three cytopathologists by light microscopy and digital evaluation and the results compared to the original ground truth Pap test diagnosis. Concordance with the original diagnosis was significantly different by digital and manual light microscopy review when comparing across: (i) exact Bethesda System diagnostic categories (62.1% vs 55.8%, respectively, p = 0.014), (ii) condensed diagnostic categories (76.8% vs 71.5%, respectively, p = 0.027), and (iii) condensed diagnoses based on clinical management (71.5% vs 65.2%, respectively, p = 0.017). Time to evaluate cases was shorter for digital (M = 3.2 min, SD = 2.2) compared to manual (M = 5.9 min, SD = 3.1) review (t(352) = 19.44, p < 0.001, Cohen's d = 1.035, 95% CI [0.905, 1.164]). Not only did our validation study demonstrate that AI-based digital Pap test evaluation had improved diagnostic accuracy and reduced screening time compared to light microscopy, but that participants reported a positive experience using this system.

Ethical choice reversals.

Understanding the systematic ways that human decision making departs from normative principles has been important in the development of cognitive theory across multiple decision domains. We focus here on whether such seemingly "irrational" decisions occur in ethical decisions that impose difficult tradeoffs between the welfare and interests of different individuals or groups. Across three sets of experiments and in multiple decision scenarios, we provide clear evidence that contextual choice reversals arise in multiples types of ethical choice settings, in just the way that they do in other domains ranging from economic gambles to perceptual judgments (Trueblood et al., 2013; Wedell, 1991). Specifically, we find within-participant evidence for attraction effects in which choices between two options systematically vary as a function of features of a third dominated and unchosen option-a prima facie violation of rational choice axioms that demand consistency. Unlike economic gambles and most domains in which such effects have been studied, many of our ethical scenarios involve features that are not presented numerically, and features for which there is no clear majority-endorsed ranking. We provide empirical evidence and a novel modeling analysis based on individual differences of feature rankings within attributes to show that such individual variations partly explains observed variation in the attraction effects. We conclude by discussing how recent computational analyses of attraction effects may provide a basis for understanding how the observed patterns of choices reflect boundedly rational decision processes.

Partial asynchrony of coniferous forest carbon sources and sinks at the intra-annual time scale.

As major terrestrial carbon sinks, forests play an important role in mitigating climate change. The relationship between the seasonal uptake of carbon and its allocation to woody biomass remains poorly understood, leaving a significant gap in our capacity to predict carbon sequestration by forests. Here, we compare the intra-annual dynamics of carbon fluxes and wood formation across the Northern hemisphere, from carbon assimilation and the formation of non-structural carbon compounds to their incorporation in woody tissues. We show temporally coupled seasonal peaks of carbon assimilation (GPP) and wood cell differentiation, while the two processes are substantially decoupled during off-peak periods. Peaks of cambial activity occur substantially earlier compared to GPP, suggesting the buffer role of non-structural carbohydrates between the processes of carbon assimilation and allocation to wood. Our findings suggest that high-resolution seasonal data of ecosystem carbon fluxes, wood formation and the associated physiological processes may reduce uncertainties in carbon source-sink relationships at different spatial scales, from stand to ecosystem levels.

The Central Roles of Keratinocytes in Coordinating Skin Immunity.

The function of keratinocytes (KCs) to form a barrier and produce cytokines is well-known, but recent progress has revealed many different roles for KCs in regulation of skin immunity. In this review, we provide an update on the current understanding of how KCs communicate with microbes, immunocytes, neurons, and other cells to form an effective immune barrier. We catalog the large list of genes and metabolites of KCs that participate in host defense and discuss the mechanisms of immune crosstalk, addressing how KCs simultaneously form a physical barrier, communicate with fibroblasts, and control immune signals. Overall, the signals sent and received by KCs are an exciting group of therapeutic targets to explore in the treatment of dermatologic disorders.

Workplace support for physicians during the COVID-19 Pandemic: Did it affect burnout?

BACKGROUND: A concern before 2020, physician burnout worsened during the COVID-19 pandemic. Little empirical data are available on pandemic workplace support interventions or their influence on burnout. We surveyed a national sample of frontline physicians on burnout and workplace support during the pandemic. METHODS: We surveyed a stratified random sample of 12,833 US physicians most likely to care for adult COVID-19 patients from the comprehensive AMA Physician Professional Data ™ file. The sample included 6722 primary care physicians (3331 family physicians, 3391 internists), 880 hospitalists, 1783 critical care physicians (894 critical care physicians, 889 pulmonary intensivists), 2548 emergency medicine physicians, and 900 infectious disease physicians. The emailed survey elicited physicians' perceptions of organizational interventions to provide workplace support and/or to address burnout. Burnout was assessed with the Professional Fulfillment Index Burnout Composite scale (PFI-BC). Proportional specialty representation and response bias were addressed by survey weighting. Logistic regression assessed the association of physician characteristics and workplace interventions with burnout. RESULTS: After weighting, respondents were representative of the total sample. Overall physician burnout was 45.4%, significantly higher than in our previous survey. Open-ended responses mentioned that staffing shortages (physician, nursing, and other staff) combined with the increased volume, complexity, and acuity of patients during the pandemic increased job demands. The most frequent workplace support interventions were direct pandemic control measures (increased access to personal protective equipment, 70.0%); improved telehealth functionality (43.4%); and individual resiliency tools (yoga, meditation, 30.7%). Respondents placed highest priority on workplace interventions to increase financial support and increase nursing and clinician staffing. Factors significantly associated with lower odds of burnout were practicing critical care (compared with emergency medicine) OR 0.33 (95% CI 0.12 - 0.93), improved telehealth functionality OR 0.47 (95% CI 0.23 - 0.97) and being in practice for 11 years or longer OR 0.44 (95% CI 0.19-0.99). CONCLUSIONS: Burnout across frontline specialties increased during the pandemic. Physician respondents focused on inadequate staffing in the context of caring for more and sicker patients, combined with the lack of administrative efforts to mitigate problems. Burnout mitigation requires system-level interventions beyond individual-focused stress reduction programs to improve staffing, increase compensation, and build effective teams.

Zonation, ligand and dose dependence of S1PR1 signalling in blood and lymphatic vasculature.

AIMS: Circulating levels of sphingosine 1-phosphate (S1P), an HDL-associated ligand for endothelial cell (EC) protective S1P receptor-1 (S1PR1), are reduced in disease states associated with endothelial dysfunction. Yet as S1PR1 has high affinity for S1P and can be activated by ligand-independent mechanisms and EC-autonomous S1P production, it is unclear if relative reductions in circulating S1P impact endothelial function. It is also unclear how EC S1PR1 insufficiency, whether induced by ligand deficiency or by S1PR1-directed immunosuppressive therapy, affects different vascular subsets. METHODS AND RESULTS: We here fine-map the zonation of S1PR1 signalling in the murine blood and lymphatic vasculature, superimpose cell type-specific and relative deficiencies in S1P production to define ligand source- and dose-dependence, and correlate receptor engagement to essential functions. In naïve blood vessels, despite broad expression, EC S1PR1 engagement was restricted to resistance-size arteries, lung capillaries and high-endothelial venules (HEV). Similar zonation was observed for albumin extravasation in EC S1PR1 deficient mice, and brain extravasation was reproduced with arterial EC-selective S1pr1 deletion. In lymphatic EC, S1PR1 engagement was high in collecting vessels and lymph nodes and low in terminal capillaries that drain tissue fluids. While EC S1P production sustained S1PR1 signaling in lymphatics and HEV, hematopoietic cells provided ∼90% of plasma S1P and sustained signaling in resistance arteries and lung capillaries. S1PR1 signaling and endothelial function were both surprisingly sensitive to reductions in plasma S1P with apparent saturation around 50% of normal levels. S1PR1 engagement did not depend on sex or age, but modestly increased in arteries in hypertension and diabetes. Sphingosine kinase (Sphk)-2 deficiency also increased S1PR1 engagement selectively in arteries, which could be attributed to Sphk1-dependent S1P release from perivascular macrophages. CONCLUSIONS: This study highlights vessel subtype-specific S1PR1 functions and mechanisms of engagement and supports the relevance of S1P as circulating biomarker for endothelial function.

Development of 3D-iNET ORION: a novel, pre-clinical, three-dimensional in vitro cell model for modeling human metastatic neuroendocrine tumor of the pancreas.

Neuroendocrine tumors (NETs) of the pancreas are rare neoplasms that present complex challenges to diagnosis and treatment due to their indolent course. The incidence of pancreatic neuroendocrine tumors has increased significantly over the past two decades. A limited number of pancreatic neuroendocrine cell lines are currently available for the research. Here, we present 3D-iNET ORION, a novel 3-dimensional (spheroid) cell line, isolated from human pancreatic neuroendocrine tumor liver metastasis. Three-dimensionally grown (3D) cancer cell lines have gained interest over the past years as 3D cancer cell lines better recapitulate the in vivo structure of tumors, and are more suitable for in vitro and in vivo experiments. 3D-iNET ORION cancer cell line showed high potential to form tumorspheres when embedded in Matrigel matrix and expresses synaptophysin and EpCAM. Electron microscopy analysis of cancer cell line proved the presence of dense neurosecretory granules. When xenografted into athymic mice, 3D-iNET ORION cells produce slow-growing tumors, positive for chromogranin and synaptophysin. Human Core Exome Panel Analysis has shown that 3DiNET ORION cell line retains the genetic aberration profile detected in the original tumor. In conclusion, our newly developed neuroendocrine cancer cell line can be considered as a new research tool for in vitro and in vivo experiments.

A System for Teaching Advanced Colonoscopic Skills and Endoscopic Submucosal Dissection Based on Nonclinical Models.

Endoscopic submucosal dissection (ESD) requires skills that the vast majority of endoscopists do not possess. ESD be broken down into component skills and at least three of the necessary skill sets can be taught separately. In the United States most trainees initially participate in half- or full-day courses that utilize ex vivo and in vivo animal models and the great majority learn these advanced skills in the clinical setting. We describe a comprehensive training over a well-defined period using ex vivo porcine or bovine large bowel models. There are five components or modules that make up the training program: (1) bowel wall injections in ex vivo tissue, (2) inanimate figure tracing model to teach scope control, (3) ESD in plastic tube with window cutout over which square of ex vivo tissue is placed, (4) ESD in ex vivo porcine or bovine large bowel, and (5) mucosal wound closure. The authors are in the midst of training a group of residents, fellows, and young attendings using this approach. This approach has not been vetted yet; however, the preliminary results are promising.

Diversity, Equity, and Inclusion in US Anesthesiology Residency Matching.

BACKGROUND: Patient outcomes are improved with physician-patient gender, racial, and ethnic concordance. However, female, Black, Hispanic or Latino, Native Hawaiian-Pacific Islander (NH-PI), and American Indian-Native Alaskan (AI-AN) physicians are underrepresented in anesthesiology. The American Association of Medical Colleges 2018 Diversity in Medicine Report revealed that women comprise only 35% of anesthesiologists yet nearly half of medical school graduates are women. More than 77% of anesthesiologists are White or Asian. Anesthesiology applicant and match trends may provide insights needed to address underrepresentation within anesthesiology. We hypothesized that proportionally fewer women and racially and ethnically minoritized applicants apply and match into anesthesiology. METHODS: This retrospective observational study identified 47,117 anesthesiology applicants among the 546,298 residency applicants in the Electronic Residency Application Service (ERAS) system between 2011 and 2022 and stratified applicants by self-reported gender, race, and ethnicity. The demographics of anesthesiology trainees reported in the 2014 to 2015, 2018 to 2019, and 2022 to 2023 Accreditation Counsel of Graduate Medical Education (ACGME) Data Resource Books were used as surrogates for matched applicants as demographics are not reported by the National Residency Match Program. To facilitate comparisons, ERAS applicants were grouped into 4-year epochs to align with consolidated ACGME reports corresponding to the application years. Odds ratios (OR); 95% confidence interval of applying to and matching into anesthesiology were analyzed. RESULTS: Women had lower odds of applying to anesthesiology compared to men overall (OR, 0.55; 95% CI, 0.54-0.56, P < .0001) and maintained significantly lowered odds of applying within each epoch. Women had similar odds of matching into anesthesiology residency compared to men (OR, 1.10; 95% CI, 1.06-1.14, P < .0001). Black, Hispanic or Latino, Asian and NH-PI, and AI-AN applicants had similar odds to White applicants of applying to anesthesiology but odds of matching were significantly lower overall (P < .0001) for Asian and NH-PI (OR, 0.66; 95% CI, 0.63-0.70), Black (OR, 0.49; 95% CI, 0.45-0.53), Hispanic or Latino (OR, 0.50; 95% CI, 0.46-0.54), and AI-AN (OR, 0.20; 95% CI, 0.15-0.28) applicants. The odds of matching among some minoritized applicants increased in the ACGME 2022 to 2023 report year. CONCLUSIONS: From 2011 to 2022, women had lower odds of applying to anesthesiology residency than men yet had similar odds of matching. Racial and ethnic minoritized groups had significantly lower odds of matching compared to White applicants despite similar odds of applying. These findings highlight disparities in the anesthesiology match and may help identify opportunities to promote workforce diversity within the field. More detailed reporting of gender, race, and ethnicity in annual match data may better define barriers to entry and identify opportunities for improvement.

Forest defoliation by an invasive outbreak insect: Catastrophic consequences for a charismatic mega moth.

Earth is now experiencing declines in insect abundance and diversity unparalleled in human history. The drivers underlying those declines are many, complex, and incompletely known. Here, using a natural experiment, we report the first test of the hypothesis that forest defoliation by an invasive outbreak insect compromises the fitness of a native insect via damage-induced increases in toxicity of the forest canopy. We demonstrate that defoliation by the invasive spongy moth (Lymantria dispar) elicits an average 8.4-fold increase in foliar defense expression among aspen (Populus tremuloides) genotypes. In turn, elevated defense dramatically reduces survivorship, feeding, and growth of a charismatic mega moth (Anthereae polyphemus). This work suggests that changes to the phytochemical landscape of forests, mediated by invasive outbreak insects, are likely to negatively impact native insects, with potential repercussions for community diversity and ecosystem function across expansive scales.

Plasticity of the heart in response to changes in physical activity.

The human heart is very adaptable, with chamber size, wall thickness and ventricular stiffness all modified by periods of inactivity or exercise training. Herein, we summarize the cardiac adaptations induced by changes in physical activity, ranging from bed rest and spaceflight to endurance exercise training, while also highlighting how the ageing process (a long-term model of inactivity) affects cardiac plasticity. Severe inactivity during bed rest or spaceflight leads to cardiac atrophy and ventriculo-vascular stiffening. Conversely, endurance training induces eccentric hypertrophy and enhances ventricular compliance, and can be used as an effective countermeasure to prevent adverse cardiac changes during prolonged periods of bed rest or spaceflight. With sedentary ageing, the heart undergoes concentric remodelling and irreversibly stiffens at advanced age. Specifically, older adults who initiate endurance training later in life are unable to improve ventricular compliance and diastolic function, suggesting reduced cardiac plasticity with advanced age; however, lifelong exercise training prevents age-associated cardiac remodelling and maintains cardiac compliance of older adults at a level similar to those of younger healthy individuals. Nevertheless, there are still many knowledge gaps related to cardiac remodelling and changes in cardiac function induced by bed rest, exercise training and spaceflight, as well as how these different stimuli may interact with advancing age. Future studies should focus on understanding what factors (sex, age, heritability, etc.) may influence the heart's responsiveness to training or deconditioning, as well as understanding the long-term cardiac consequences of spaceflight beyond low-Earth orbit with the added stimulus of galactic cosmic radiation.

Changing trends in anabolic-androgenic steroid use within Scottish prisons: Detection, prevalence, and quantitation.

Anabolic-androgenic steroids (AASs) are a subclassification of image performance enhancing drugs (IPEDs). While AAS use is most prevalent among people in athletics, there is also high lifetime prevalence of AAS use among prisoners. This study reports the qualitative detection of AASs in seized samples from the Scottish prisons from 2019-2023. Additionally, methods were developed for the quantitative analysis of AASs using gas chromatography-mass spectrometry (GC-MS) and applied to 61 samples of tablets or powders seized from Scottish prisons between July 2022 and July 2023. Since 2022, there has been an increase in AAS detections in the Scottish prisons. Oxymetholone was the most prevalent AAS, followed by metandienone (methandrostenolone, methandienone), methyltestosterone, oxandrolone, mestanolone (methylandrostanolone), stanozolol, and androstenedione. Multiple AASs were found in 21 samples and 10 samples contained other drugs, including amitriptyline, sertraline, zopiclone, mirtazapine, sildenafil, etizolam, Δ9-tetrahydrocannabinol, and the synthetic cannabinoid MDMB-INACA. Most AAS samples were tablets (77.0%), although they were also detected in powders, herbal material, e-cigarettes, and a fragmented soap bar-type sample. There was a large variation in the concentration of AASs in the tablets and powders seized from the Scottish prisons, demonstrating AASs are another highly variable component of the polydrug use situation in prisons, the effects of which need to be examined further.

Incorporating Individual-Level Treatment Effects and Outcome Preferences Into Personalized Blood Pressure Target Recommendations.

BACKGROUND: There are no shared decision-making frameworks for selecting blood pressure (BP) targets for individuals with hypertension. This study addressed whether results from the SPRINT (Systolic Blood Pressure Intervention Trial) could be tailored to individuals using predicted risks and simulated preferences. METHODS AND RESULTS: Among 8202 SPRINT participants, Cox models were developed and internally validated to predict each individual's absolute difference in risk from intensive versus standard BP lowering for cardiovascular events, cognitive impairment, death, and serious adverse events (AEs). Individual treatment effects were combined using simulated preference weights into a net benefit, which represents a weighted sum of risk differences across outcomes. Net benefits were compared among those above versus below the median AE risk. In simulations for which cardiovascular, cognitive, and death events had much greater weight than the AEs of BP lowering, the median net benefit was 3.3 percentage points (interquartile range [IQR], 2.0-5.7), and 100% of participants had a net benefit favoring intensive BP lowering. When simulating benefits and harms to have similar weights, the median net benefit was 0.8 percentage points (IQR, 0.2-2.2), and 87% had a positive net benefit. Compared with participants at lower risk of AEs from BP lowering, those at higher risk had a greater net benefit from intensive BP lowering despite experiencing more AEs (P<0.001 in both simulations). CONCLUSIONS: Most SPRINT participants had a predicted net benefit that favored intensive BP lowering, but the degree of net benefit varied considerably. Tailoring BP targets using each patient's risks and preferences may provide more refined BP target recommendations.

Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) experience in patients with recurrent low grade serous ovarian carcinoma (LGSOC): sub-cohort report of phase 1 clinical trial.

Introduction: Low grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer (OC) that is challenging to treat due to its relative chemoresistance. Given that LGSOC patients often recur in the peritoneal cavity, novel intraperitoneal (IP) chemotherapy should be explored. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a method that has demonstrated peritoneal disease control in cancers with peritoneal metastases. Methods: NCT04329494 is a US multicenter phase 1 trial evaluating the safety of PIPAC in recurrent ovarian, uterine, and GI cancers with peritoneal metastases. This analysis describes the outcomes of a sub-cohort of four LGSOC patients treated with IP cisplatin 10.5 mg/m2, doxorubicin 2.1 mg/m2 PIPAC q4-6 weeks. Primary endpoints included dose-limiting toxicities (DLT) and incidence of adverse events (AE). Secondary endpoints were progression free survival (PFS) and treatment response based on radiographic, intraoperative, and pathological findings. Results: Four patients with LGSOC were enrolled of which three were heavily pretreated. Median prior lines of therapy was 5 (range 2-10). Three patients had extraperitoneal metastases, and two patients had baseline partial small bowel obstructive (SBO) symptoms. Median age of patients was 58 (38-68). PIPAC completion rate (≥2 PIPACs) was 75%. No DLTs or Clavien-Dindo surgical complications occurred. No G4/G5 AEs were observed, and one G3 abdominal pain was reported. One patient had a partial response after 3 cycles of PIPAC and completed an additional 3 cycles with compassionate use amendment. Two patients came off study after 2 cycles due to extraperitoneal progressive disease. One patient came off study after 1 cycle due to toxicity. Median decrease in peritoneal carcinomatosis index between cycles 1 and 2 was 5.0%. Ascites decreased in 2 out of 3 patients who had ≥2 PIPACs. Median PFS was 4.3 months (1.7-21.6), median overall survival was 11.6 months (5.4-30.1), and objective response rate was 25%. Conclusion: PIPAC with cisplatin/doxorubicin is well tolerated in LGSOC patients without baseline SBO symptoms. IP response was seen in 2 out of 3 patients that completed ≥2 PIPAC cycles. Further study of PIPAC for patients with recurrent disease limited to the IP cavity and with no partial SBO symptoms should be considered.