Adipocyte derived exosomes promote cell invasion and challenge paclitaxel efficacy in ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in promoting disease progression, metastasis and chemoresistance. The signalling mechanisms underpinning EOC omentum tropism have yet to be elucidated. METHODS: Three-dimensional co-culture models were used to explore adipocyte-EOC interactions. The impact of adipocytes on EOC proliferation, response to therapy and invasive capacity was assessed. Primary adipocytes and omental tissue were isolated from patients with ovarian malignancies and benign ovarian neoplasms. Exosomes were isolated from omentum tissue conditioned media and the effect of omentum-derived exosomes on EOC evaluated. Exosomal microRNA (miRNA) sequencing was used to identify miRNAs abundant in omental exosomes and EOC cells were transfected with highly abundant miRNAs miR-21, let-7b, miR-16 and miR-92a. RESULTS: We demonstrate the capacity of adipocytes to induce an invasive phenotype in EOC populations through driving epithelial-to-mesenchymal transition (EMT). Exosomes secreted by omental tissue of ovarian cancer patients, as well as patients without malignancies, induced proliferation, upregulated EMT markers and reduced response to paclitaxel therapy in EOC cell lines and HGSOC patient samples. Analysis of the omentum-derived exosomes from cancer patients revealed highly abundant miRNAs that included miR-21, let-7b, miR-16 and miR-92a that promoted cancer cell proliferation and protection from chemotherapy when transfected in ovarian cancer cells. CONCLUSIONS: These observations highlight the capacity of omental adipocytes to generate a pro-tumorigenic and chemoprotective microenvironment in ovarian cancer and other adipose-related malignancies.

Emergency department utilization among adults with epilepsy: A multi-state cross-sectional analysis, 2010-2019.

OBJECTIVE: We described patterns and trends in ED use among adults with epilepsy in the United States. METHODS: Utilizing inpatient and ED discharge data from seven states, we conducted a cross-sectional analysis to identify adult ED visits diagnosed with epilepsy or seizures from 2010 to 2019. Using ED visit counts and estimates of state-level epilepsy prevalence, we calculated ED visit rates overall and by payer, condition, and year. RESULTS: Our data captured 304,935 ED visits with epilepsy as a primary or secondary diagnosis in 2019. Across the seven states, visit rates ranged between 366 and 726 per 1000 and were higher than rates for adults without epilepsy in all states but one. ED visit rates were highest among Medicare and Medicaid beneficiaries (vs commercial or self-pay). Adults with epilepsy were more likely to be admitted as inpatients. Visits for nervous system disorders were 6.3-8.2 times higher among people with epilepsy, and visits for mental health conditions were 1.2-2.6 times higher. Increases in ED visit rates from 2010 to 2019 among people with epilepsy exceeded increases among adults without by 6.0-27.3 percentage points. CONCLUSION: Adults with epilepsy visit the ED frequently and visit rates have been increasing over time. These results underscore the importance of identifying factors contributing to ED use and designing tailored interventions to improve ambulatory care quality.

Medicare-mandated shared decision making for left atrial appendage closure in clinical practice.

INTRODUCTION: The Centers for Medicare & Medicaid Services (CMS) required a shared decision-making (SDM) interaction, with an "independent" physician, before left atrial appendage closure (LAAC). The purpose of this study is to better understand how this requirement is implemented in clinical practice. METHODS: We surveyed LAAC-performing centers. The characteristics of respondent and nonrespondent hospitals were compared using the CMS Provider of Services File for 2017. RESULTS: We received 86 responses out of 269 surveys mailed (32%). Respondent and nonrespondent hospital affiliations were similar: mean hospital size 525 beds, 15% for-profit, and 34% teaching hospitals. Thirty-four respondents (39.5%) stated that the implanting physician conducts some or all of the SDM interactions. The percentage of patients who decide not to undergo LAAC after the SDM interaction was estimated at 8.1%. Out of 72 responses to an open-ended question about the benefit of the SDM interaction, 44 (61%) described the requirement in negative terms, of which most felt the requirement was burdensome for patients and providers. Only 28 respondents (39%) described the requirement in positive or mixed terms. CONCLUSION: In violation of the letter of the CMS policy for LAAC, implanting physicians perform the SDM interaction at nearly 40% of responding hospitals. Most respondents felt the SDM requirement was burdensome for patients. More detailed guidance from CMS on how to comply with the policy may result in better alignment between the intent of the policy and how it is implemented.

Quantifying the relative importance of genetics and environment on the comorbidity between mental and cardiometabolic disorders using 17 million Scandinavians.

Mental disorders are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders. Reasons for this comorbidity are still poorly understood. We leverage nation-wide health records and near-complete genealogies of Denmark and Sweden (n = 17 million) to reveal the genetic and environmental contributions underlying the observed comorbidity between six mental disorders and 15 cardiometabolic disorders. Genetic factors contributed about 50% to the comorbidity of schizophrenia, affective disorders, and autism spectrum disorder with cardiometabolic disorders, whereas the comorbidity of attention-deficit/hyperactivity disorder and anorexia with cardiometabolic disorders was mainly or fully driven by environmental factors. In this work we provide causal insight to guide clinical and scientific initiatives directed at achieving mechanistic understanding as well as preventing and alleviating the consequences of these disorders.

Freeform generative design of complex functional structures.

Generative machine learning is poised to revolutionise a range of domains where rational design has long been the de facto approach: where design is practically a time consuming and frustrating process guided by heuristics and intuition. In this article we focus on the domain of flow chemistry, which is an ideal candidate for generative design approaches. We demonstrate a generative machine learning framework that optimises diverse, bespoke reactor elements for flow chemistry applications, combining evolutionary algorithms and a scalable fluid dynamics solver for in silico performance assessment. Experimental verification confirms the discovery of never-before-seen bespoke mixers whose performance exceeds the state of the art by 45%. These findings highlight the power of autonomous generative design to improve the operational performance of complex functional structures, with potential wide-ranging industrial applications.

Hysterectomy Techniques and Outcomes for Benign Large Uteri: A Systematic Review.

OBJECTIVE: To identify the optimal hysterectomy approach for large uteri in gynecologic surgery for benign indications from a perioperative morbidity standpoint. DATA SOURCES: PubMed and Embase databases were searched from inception through September 19, 2022. Meta-analyses were conducted as feasible. METHODS OF STUDY SELECTION: This review included studies that compared routes of hysterectomy with or without bilateral salpingo-oophorectomy for large uteri (12 weeks or more or 250 g or more) and excluded studies with any concurrent surgery for pelvic organ prolapse, incontinence, gynecologic malignancy, or any obstetric indication for hysterectomy. TABULATION, INTEGRATION, AND RESULTS: The review included 25 studies comprising nine randomized trials, two prospective, and 14 retrospective nonrandomized comparative studies. Studies were at high risk of bias. There was lower operative time for total vaginal hysterectomy compared with laparoscopically assisted vaginal hysterectomy (LAVH) (mean difference 39 minutes, 95% CI, 18-60) and total vaginal hysterectomy compared with total laparoscopic hysterectomy (mean difference 50 minutes, 95% CI, 29-70). Total laparoscopic hysterectomy was associated with much greater risk of ureteral injury compared with total vaginal hysterectomy (odds ratio 7.54, 95% CI, 2.52-22.58). There were no significant differences in bowel injury rates between groups. There were no differences in length of stay among the laparoscopic approaches. For LAVH compared with total vaginal hysterectomy, randomized controlled trials favored total vaginal hysterectomy for length of stay. When rates of blood transfusion were compared between these abdominal hysterectomy and robotic-assisted total hysterectomy routes, abdominal hysterectomy was associated with a sixfold greater risk of transfusion than robotic-assisted total hysterectomy (6.31, 95% CI, 1.07-37.32). Similarly, single studies comparing robotic-assisted total hysterectomy with LAVH, total laparoscopic hysterectomy, or total vaginal hysterectomy all favored robotic-assisted total hysterectomy for reduced blood loss. CONCLUSION: Minimally invasive routes are safe and effective and have few complications. Minimally invasive approach (vaginal, laparoscopic, or robotic) results in lower blood loss and shorter length of stay, whereas the abdominal route has a shorter operative time. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021233300.

An epidemiological study of season of birth, mental health, and neuroimaging in the UK Biobank.

Environmental exposures during the perinatal period are known to have a long-term effect on adult physical and mental health. One such influential environmental exposure is the time of year of birth which affects the amount of daylight, nutrients, and viral load that an individual is exposed to within this key developmental period. Here, we investigate associations between season of birth (seasonality), four mental health traits (n = 137,588) and multi-modal neuroimaging measures (n = 33,212) within the UK Biobank. Summer births were associated with probable recurrent Major Depressive Disorder (ß = 0.026, pcorr = 0.028) and greater mean cortical thickness in temporal and occipital lobes (ß = 0.013 to 0.014, pcorr<0.05). Winter births were associated with greater white matter integrity globally, in the association fibers, thalamic radiations, and six individual tracts (ß = -0.013 to -0.022, pcorr<0.05). Results of sensitivity analyses adjusting for birth weight were similar, with an additional association between winter birth and white matter microstructure in the forceps minor and between summer births, greater cingulate thickness and amygdala volume. Further analyses revealed associations between probable depressive phenotypes and a range of neuroimaging measures but a paucity of interactions with seasonality. Our results suggest that seasonality of birth may affect later-life brain structure and play a role in lifetime recurrent Major Depressive Disorder. Due to the small effect sizes observed, and the lack of associations with other mental health traits, further research is required to validate birth season effects in the context of different latitudes, and by co-examining genetic and epigenetic measures to reveal informative biological pathways.

Patterns of Care for Medicare Beneficiaries With Metastatic Prostate Cancer.

INTRODUCTION: Therapeutic options for men with metastatic prostate cancer have increased in the past decade. We studied recent treatment patterns for men with metastatic prostate cancer and how treatment patterns have changed over time. METHODS: Using the Surveillance, Epidemiology, and End Results‒Medicare database, we identified fee-for-service Medicare beneficiaries who either were diagnosed with metastatic prostate cancer or developed metastases following diagnosis, as indicated by the presence of claims with diagnoses codes for metastatic disease, between 2007 and 2017. We evaluated treatment patterns using claims. RESULTS: We identified 29,800 men with metastatic disease, of whom 4721 (18.8%) had metastatic disease at their initial diagnosis. The mean age was 77 years, and 77.9% of patients were non-Hispanic White. The proportion receiving antineoplastic agents within 3 years of the index date increased over time (from 9.7% in 2007 to 25.9% in 2017; P < .001). Opioid use within 3 years of prostate cancer diagnosis was stable during 2007 to 2013 (around 73%) but decreased through 2017 to 65.5% (P < .001). Patients diagnosed during 2015 to 2017 had longer median survival (32.6 months) compared to those diagnosed during 2007 to 2010 (26.6 months; P < .001). CONCLUSIONS: Most metastatic prostate cancer patients do not receive life-prolonging antineoplastic therapies. Improved adoption of effective cancer therapies when appropriate may increase length and quality of survival among metastatic prostate cancer patients.

Fin-Bayes: A Multi-Objective Bayesian Optimization Framework for Soft Robotic Fingers.

Computational design is a critical tool to realize the full potential of Soft Robotics, maximizing their inherent benefits of high performance, flexibility, robustness, and safe interaction. Practically, computational design entails a rapid iterative search process over a parameterized design space, with assessment using (frequently) computational modeling and (more rarely) physical experimentation. Bayesian approaches work well for these expensive-to-analyze systems and can lead to efficient exploration of design space than comparative algorithms. However, such computational design typically entails weaknesses related to a lack of fidelity in assessment, a lack of sufficient iterations, and/or optimizing to a singular objective function. Our work directly addresses these shortcomings. First, we harness a sophisticated nonlinear Finite Element Modeling suite that explicitly considers geometry, material, and contact nonlinearity to perform rapid accurate characterization. We validate this through extensive physical testing using an automated test rig and printed robotic fingers, providing far more experimental data than that reported in the literature. Second, we explore a significantly larger design space than comparative approaches, with more free variables and more opportunity to discover novel, high performance designs. Finally, we use a multiobjective Bayesian optimizer that allows for the identification of promising trade-offs between two critical objectives, compliance and contact force. We test our framework on optimizing Fin Ray grippers, which are ubiquitous throughout research and industry due to their passive compliance and durability. Results demonstrate the benefits of our approach, allowing for the optimization and identification of promising gripper designs within an extensive design space, which are then 3D printed and usable in reality.

Starting fresh: a mixed method study of follower job satisfaction, trust, and views of their leader's behavior.

Introduction: The leadership literature has been dominated by the study of broad styles rather than the identification of specific key behaviors. To address this deficiency, a mixed method approach was utilized to explore how follower behavioral descriptions of their leaders would relate to potential outcomes of trust in that leader and job satisfaction. Methods: Data were collected from 273 hospital direct reports of 44 managers. They were asked to first describe the leadership approach of their managers in their own words, and then complete quantitative measures of the two potential outcomes. Results: The qualitative responses were coded into nine leadership behavior themes listed here in order from most to least often mentioned: Kindness, Supportive, Open to Input, Allow Autonomy, Engage with Team, Transparency, Fairness, Professionalism, Hold Accountable. All behavior themes related significantly to trust of the leader, with three themes relating significantly to job satisfaction (Transparency, Fairness, and Professionalism). Discussion: These results provide a more specific view of leader behavior than does the typical style approach.

Quantifying the Relative Importance of Genetics and Environment on the Comorbidity between Mental- and Cardiometabolic Disorders: A Comprehensive Analysis of National Register Data from 17 million Scandinavians.

Mental disorders (MDs) are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders (CMDs). Reasons for this comorbidity are still poorly understood. We leverage nation-wide health records and complete genealogies of Denmark and Sweden (n=17 million) to reveal the genetic and environmental contributions underlying the observed comorbidity between six MDs and 14 CMDs. Genetic factors contributed about 50% to the comorbidity of schizophrenia, affective disorders, and autism spectrum disorder with CMDs, whereas the comorbidity of attention-deficit/hyperactivity disorder and anorexia with CMDs was mainly or fully driven by environmental factors. These findings provide causal insight to guide clinical and scientific initiatives directed at achieving mechanistic understanding as well as preventing and alleviating the consequences of these disorders.

Prospectively accelerated dynamic speech magnetic resonance imaging at 3 T using a self-navigated spiral-based manifold regularized scheme.

This work develops and evaluates a self-navigated variable density spiral (VDS)-based manifold regularization scheme to prospectively improve dynamic speech magnetic resonance imaging (MRI) at 3 T. Short readout duration spirals (1.3-ms long) were used to minimize sensitivity to off-resonance. A custom 16-channel speech coil was used for improved parallel imaging of vocal tract structures. The manifold model leveraged similarities between frames sharing similar vocal tract postures without explicit motion binning. The self-navigating capability of VDS was leveraged to learn the Laplacian structure of the manifold. Reconstruction was posed as a sensitivity-encoding-based nonlocal soft-weighted temporal regularization scheme. Our approach was compared with view-sharing, low-rank, temporal finite difference, extra dimension-based sparsity reconstruction constraints. Undersampling experiments were conducted on five volunteers performing repetitive and arbitrary speaking tasks at different speaking rates. Quantitative evaluation in terms of mean square error over moving edges was performed in a retrospective undersampling experiment on one volunteer. For prospective undersampling, blinded image quality evaluation in the categories of alias artifacts, spatial blurring, and temporal blurring was performed by three experts in voice research. Region of interest analysis at articulator boundaries was performed in both experiments to assess articulatory motion. Improved performance with manifold reconstruction constraints was observed over existing constraints. With prospective undersampling, a spatial resolution of 2.4 × 2.4 mm2/pixel and a temporal resolution of 17.4 ms/frame for single-slice imaging, and 52.2 ms/frame for concurrent three-slice imaging, were achieved. We demonstrated implicit motion binning by analyzing the mechanics of the Laplacian matrix. Manifold regularization demonstrated superior image quality scores in reducing spatial and temporal blurring compared with all other reconstruction constraints. While it exhibited faint (nonsignificant) alias artifacts that were similar to temporal finite difference, it provided statistically significant improvements compared with the other constraints. In conclusion, the self-navigated manifold regularized scheme enabled robust high spatiotemporal resolution dynamic speech MRI at 3 T.

Enabling Technologies for Gynecologic Vaginal Surgery: A Systematic Review.

OBJECTIVE: To systematically review the literature to evaluate clinical and surgical outcomes for technologies that facilitate vaginal surgical procedures. DATA SOURCES: We systematically searched MEDLINE, EMBASE, and ClinicalTrials.gov from January 1990 to May 2022. METHODS OF STUDY SELECTION: Comparative and single-arm studies with data on contemporary tools or technologies facilitating intraoperative performance of vaginal gynecologic surgical procedures for benign indications were included. Citations were independently double screened, and eligible full-text articles were extracted by two reviewers. Data collected included study characteristics, technology, patient demographics, and intraoperative and postoperative outcomes. Risk of bias for comparative studies was assessed using established methods, and restricted maximum likelihood model meta-analyses were conducted as indicated. TABULATION, INTEGRATION, AND RESULTS: The search yielded 8,658 abstracts, with 116 eligible studies that evaluated pedicle sealing devices (n=32), nonrobotic and robotic vaginal natural orifice transluminal endoscopic surgery (n=64), suture capture devices (n=17), loop ligatures (n=2), and table-mounted telescopic cameras (n=1). Based on 19 comparative studies, pedicle sealing devices lowered vaginal hysterectomy operative time by 15.9 minutes (95% CI, -23.3 to -85), blood loss by 36.9 mL (95% CI, -56.9 to -17.0), hospital stay by 0.2 days (95% CI, -0.4 to -0.1), and visual analog scale pain scores by 1.4 points on a subjective 10-point scale (95% CI, -1.7 to -1.1). Three nonrandomized comparative studies and 53 single-arm studies supported the feasibility of nonrobotic vaginal natural orifice transluminal endoscopic surgery for hysterectomy, adnexal surgery, pelvic reconstruction, and myomectomy. Data were limited for robotic vaginal natural orifice transluminal endoscopic surgery, suture capture devices, loop ligatures, and table-mounted cameras due to few studies or study heterogeneity. CONCLUSION: Pedicle sealing devices lower operative time and blood loss for vaginal hysterectomy, with modest reductions in hospital stay and pain scores. Although other technologies identified in the literature may have potential to facilitate vaginal surgical procedures and improve outcomes, additional comparative effectiveness research is needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022327490.

Representational level matters for tone-word recognition: Evidence from form priming.

In a form priming experiment with a lexical decision task, we investigated whether the representational structure of lexical tone in lexical memory impacts spoken-word recognition in Mandarin. Target monosyllabic words were preceded by five types of primes: (1) the same real words (/lun4/-/lun4/), (2) real words with only tone contrasts (/lun2/-/lun4/), (3) unrelated real words (/pie3/-/lun4/), (4) pseudowords with only tone contrasts (*/lun3/-/lun4/), and (5) unrelated pseudowords (*/tai3/-/lun4/). We found a facilitation effect in target words with pseudoword primes that share the segmental syllable but contrast in tones (*/lun3/-/lun4/). Moreover, no evident form priming effect was observed in target words primed by real words with only tone contrasts (/lun2/-/lun4/). These results suggest that the recognition of a tone word is influenced by the representational level of tone accessed by the prime word. The distinctive priming patterns between real-word and pseudoword primes are best explained by the connectionist models of tone-word recognition, which assume a hierarchical representation of lexical tone.