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Posttraumatic venous thromboembolism (VTE) remains prevalent in severely injured patients despite chemoprophylaxis. Importantly, although platelets are central to thrombosis, they are not routinely targeted in prevention of posttraumatic VTE. Furthermore, platelets from injured patients show ex vivo evidence of increased activation yet impaired aggregation, consistent with functional exhaustion. However, the relationship of this platelet functional phenotype with development of posttraumatic VTE is unknown. We hypothesized that, following injury, impaired ex vivo platelet aggregation (PA) is associated with the development of posttraumatic VTE.We performed a secondary analysis of 133 severely injured patients from a prospective observational study investigating coagulation and inflammation (2011-2019). Platelet aggregation in response to stimulation with adenosine diphosphate (ADP), collagen, and thrombin was measured at presentation (preresuscitation) and 24 hours (postresuscitation). Viscoelastic clot strength and lysis were measured in parallel by thromboelastography. Multivariable regression examined relationships between PA at presentation, 24 hours, and the change (δ) in PA between presentation and 24 hours with development of VTE.The 133 patients were severely injured (median Injury Severity Score, 25), and 14% developed VTE (all48 hours after admission). At presentation, platelet count and PA were not significantly different between those with and without incident VTE. However, at 24 hours, those who subsequently developed VTE had significantly lower platelet counts (126 × 10 9 /L vs. 164 × 10 9 /L, p = 0.01) and lower PA in response to ADP ( p0.05), collagen ( p0.05), and thrombin ( p = 0.06). Importantly, the magnitude of decrease in PA (δ) from presentation to 24 hours was independently associated with development of VTE (adjusted odds ratios per 10 aggregation unit decrease: δ-ADP, 1.31 [ p = 0.03]; δ-collagen, 1.36 [ p = 0.01]; δ-thrombin, 1.41 [ p0.01]).Severely injured patients with decreasing ex vivo measures of PA despite resuscitation have an increased risk of developing VTE. This may have implications for predicting development of VTE and for studying platelet targeted chemoprophylaxis regimens.Prognostic/Epidemiological; Level III.

Background Chemotoxicity risk scores were developed to predict grade 3-5 chemotherapy toxicity in older women with early breast cancer. However, whether these toxicity risk scores are associated with clinically meaningful decline in patient health remains unknown. Methods In a prospective study of women aged 65 years and older with stage I-III breast cancer treated with chemotherapy, we assessed chemotoxicity risk using the Cancer and Aging Research Group-Breast Cancer (CARG-BC) score (categorized as low, intermediate, and high). We measured patient health status before (T1) and after (T2) chemotherapy using a clinical frailty index (Deficit Accumulation Index, categorized as robust, prefrail, and frail). The population of interest was robust women at T1. The primary outcome was decline in health status after chemotherapy, defined as a decline in Deficit Accumulation Index from robust at T1 to prefrail or frail at T2. Multivariable logistic regression was used to examine the association between T1 CARG-BC score and decline in health status, adjusted for sociodemographic and clinical characteristics. Results Of the 348 robust women at T1, 83 (24%) experienced declining health status after chemotherapy, of whom 63% had intermediate or high CARG-BC scores. After adjusting for sociodemographic and clinical characteristics, women with intermediate (odds ratio = 3.14, 95% confidence interval = 1.60 to 6.14, P Conclusions In this cohort of older women with early breast cancer, higher CARG-BC scores before chemotherapy were associated with decline in health status after chemotherapy independent of sociodemographic and clinical risk factors.

Semaphorin 3A (sema3A) is an osteoprotective factor that enhances bone formation while inhibiting osteoclast bone resorption. It is produced by rat calvarial osteoblasts cultured on grit-blasted/acid-etched microtextured (SLA) titanium surfaces at higher levels than on tissue culture polystyrene, suggesting that it may improve performance of titanium implants in vivo, particularly in conditions characterized by compromised bone quality. To test this, we established a clinically relevant type 2 diabetes mellitus (T2DM) rat model and used a non-toxic click hydrogel that rapidly polymerizes in situ (GEL) to provide localized controlled delivery of sema3A. In vitro studies confirmed that sema3A released from GEL was biologically active, increasing osteoblast differentiation of a pre-osteoblast cell-line. Whereas increased sema3A production was not observed in T2DM calvarial osteoblasts cultured on SLA, exogenous sema3A enhanced surface-induced osteoblast differentiation, indicating that it would be a viable candidate for in vivo use. Delivery of sema3A either by GEL or by local injection to bone defects enhanced osseointegration of SLA implants in the T2DM rats. Trabecular bone mass and bone-to-implant contact were decreased in T2DM rats compared to normal rats; sema3A delivered locally improved both parameters. These findings suggest that reduced trabecular bone contributes to poor osseointegration in T2DM patients and support GEL as a promising treatment option for sustained release of therapeutic doses of sema3A. Moreover, using this clinically translatable T2DM model and developing a biocompatible, Cu-free click chemistry hydrogel platform for the non-invasive delivery of therapeutics has major implications for regenerative medicine as a whole. STATEMENT OF SIGNIFICANCE: Osseointegration is compromised in patients with poor bone quality due to conditions like type 2 diabetes mellitus (T2DM). Previously, we showed that semaphorin 3A (sema3A) production is increased when human bone marrow stromal cells are cultured on titanium substrates that support osseointegration in vivo, suggesting it may enhance peri-implant osteogenesis in diabetes. Here we established a spontaneously developing T2DM rat model with clinical translatability and used it to assess sema3A effectiveness. Sema3A was delivered to the implant site via a novel copper-free click hydrogel, which has minimal swelling behavior and superior rheological properties. Osseointegration was successfully restored, and enhanced compared to burst release through injections. This study provides scientific evidence for using sema3A to treat impaired osseointegration in T2DM patients.

Retrospective vote choice is a critical question asked in political science surveys. Yet, this question suffers from persistently high item nonresponse rates, which can bias estimates and limit scholars’ ability to make sound inferences. In this paper, we develop a sensitive survey technique to decrease nonresponse to the vote-choice question in a representative, face-to-face survey in Mexico City and Mexico State in 2018–2019. Respondents received different iterations of three treatments: an anonymity guarantee, a confidentiality reminder, and audio-assisted interviewing technology. The use of audio technology combined with a credible anonymity guarantee significantly improved item response. Both anonymity and confidentiality assurances improved the accuracy of response, which more closely resembled official results in the treatment conditions. We then evaluate two non-rival mechanisms that might drive our findings: beliefs about response anonymity and re-engagement with the survey. We find that increased perceptions of response anonymity are associated with improved item response.

PURPOSE To examine longitudinal relationships between levels of C-reactive protein (CRP) and cognition in older breast cancer survivors and noncancer controls. METHODS English-speaking women age ≥ 60 years, newly diagnosed with primary breast cancer (stage 0-III), and frequency-matched controls were enrolled from September 2010 to March 2020; women with dementia, neurologic disorders, and other cancers were excluded. Assessments occurred presystemic therapy/enrollment and at annual visits up to 60 months. Cognition was measured using the Functional Assessment of Cancer Therapy-Cognitive Function and neuropsychological testing. Mixed linear effect models tested for survivor-control differences in natural log (ln)-transformed CRP at each visit. Random effect–lagged fluctuation models tested directional effects of ln-CRP on subsequent cognition. All models controlled for age, race, study site, cognitive reserve, obesity, and comorbidities; secondary analyses evaluated if depression or anxiety affected results. RESULTS There were 400 survivors and 329 controls with CRP specimens and follow-up data (average age of 67.7 years; range, 60-90 years). The majority of survivors had stage I (60.9%), estrogen receptor–positive (87.6%) tumors. Survivors had significantly higher adjusted mean ln-CRP than controls at baseline and 12-, 24-, and 60-month visits (all P < .05). Higher adjusted ln-CRP predicted lower participant-reported cognition on subsequent visits among survivors, but not controls ( P interaction = .008); effects were unchanged by depression or anxiety. Overall, survivors had adjusted Functional Assessment of Cancer Therapy-Cognitive Function scores that were 9.5 and 14.2 points lower than controls at CRP levels of 3.0 and 10.0 mg/L. Survivors had poorer neuropsychological test performance ( v controls), with significant interactions with CRP only for the Trails B test. CONCLUSION Longitudinal relationships between CRP and cognition in older breast cancer survivors suggest that chronic inflammation may play a role in development of cognitive problems. CRP testing could be clinically useful in survivorship care.

Guidelines for managing and preventing chronic disease tend to be well-known. Yet, translation of this evidence into practice is inconsistent. We identify a combination of factors that are connected to guideline concordant delivery of evidence-informed chronic disease care in primary care.Cross-sectional observational study; purposively selected 22 practices to vary on size, ownership and geographic location, using National Quality Forum metrics to ensure practices had a ≥ 70% quality level for at least 2 of the following: aspirin use in high-risk individuals, blood pressure control, cholesterol and diabetes management. Interviewed 2 professionals (eg, medical director, practice manager) per practice (n = 44) to understand staffing and clinical operations. Analyzed data using an iterative and inductive approach.Community Health Centers (CHCs) employed interdisciplinary clinical teams that included a variety of professionals as compared with hospital-health systems (HHS) and clinician-owned practices. Despite this difference, practice members consistently reported a number of functions that may be connected to clinical chronic care quality, including: having engaged leadership; a culture of teamwork; engaging in team-based care; using data to inform quality improvement; empaneling patients; and managing the care of patient panels, with a focus on continuity and comprehensiveness, as well as having a commitment to the community.There are mutable organizational attributes connected-guideline concordant chronic disease care in primary care. Research and policy reform are needed to promote and study how to achieve widespread adoption of these functions and organizational attributes that may be central to achieving equity and improving chronic disease prevention.

To review all studies providing evidence of the correlation between folinic acid (FA) rescue inadequacy and long-term cognitive damage in neuropsychological studies of children with acute lymphoblastic leukemia or osteogenic sarcoma treated under protocols using high-dose methotrexate and FA rescue.A comprehensive literature search was performed of all databases of the Web of Science Citation Index, during 1990-2020, for the terms: neuropsychological, neurocognitive, and cognitive, together with acute lymphoblastic (and lymphocytic) leukemia and osteogenic sarcoma. English-language peer-reviewed articles on neuropsychological assessments of children who had been treated with high-dose methotrexate without irradiation, and which included details of methotrexate and FA schedules, were selected. In addition, a personal database of over 500 reprints of articles from over 130 journals was reviewed on the subjects of methotrexate and FA and their side effects.Three groups of studies were found and analyzed, with (1) no evidence of cognitive deterioration, (2) evidence of cognitive deterioration, and (3) more than 1 protocol grouped together, preventing separate analysis of any protocols, Protocols without cognitive deterioration reported adequate FA rescue, and those with cognitive deterioration reported inadequate FA rescue.Neuropsychological evaluation supported inadequate FA being the cause of neurocognitive damage after high-dose methotrexate and that adequate FA rescue prevents this complication.

Here, we present a strong test of the hypothesis that sacrificial moral dilemmas are solved using the same value-based decision mechanism that operates on decisions concerning economic goods. To test this hypothesis, we developed Psychological Value Theory. Psychological Value Theory is an expansion and generalization of Cohen and Ahn's (2016) Theory of Subjective Utilitarianism. Psychological Value Theory defines a new theoretical construct termed Psychological Value, measures Psychological Value using a traditional psychophysics paradigm, and predicts preferential choice from those measurements using a value-based computational model. We evaluate the validity of Psychological Value Theory across six experiments. In Experiment 1, we use Psychological Value Theory to estimate the perceived Psychological Value of human lives and economic goods. The data reveal that perceived Psychological Value of lives is highly influenced by individual differences of people but minimally influenced by the number of people in a group. In Experiments 2-5, we demonstrate that when used as input in a value-based computational model, perceived Psychological Values of human lives accurately predict participants' RT and response choices to sacrificial moral dilemmas. In Experiment 6, we replicate these findings for decisions involving economic goods. We cross-validate our results with multiple data sets using multiple methods. We conclude that the same value-based processes underlying economic decisions also underlie choices involving human lives. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Surgical aortic valve replacement can be performed through a minimally invasive (MI) or full sternotomy (FS) approach. The present study compared outcomes of MI vs FS for isolated surgery among patients enrolled in the Placement of Aortic Transcatheter Valves (PARTNER) 3 low-risk trial.Patients with severe, symptomatic aortic stenosis at low surgical risk with anatomy suitable for transfemoral access were eligible for PARTNER 3 enrollment. The primary outcome was the composite end point of death, stroke, or rehospitalization (valve-, procedure-, or heart failure-related) at 1 year. Secondary outcomes included the individual components of the primary end point as well as patient-reported health status at 30 days and 1 year.In the PARTNER 3 study, 358 patients underwent isolated valve replacement at 68 centers through an MI (n = 107) or FS (n = 251) approach (8 patients were converted from MI to FS). Mean age and Society of Thoracic Surgeons score were similar between groups. The Kaplan-Meier estimate of the primary outcome was similar in the MI vs FS groups (16.9% vs 14.9%; hazard ratio, 1.15; 95% CI, 0.66-2.03; P = .618). There were no significant differences in the 1-year rates of all-cause death (2.8% vs 2.8%), all stroke (1.9% vs 3.6%), or rehospitalization (13.3% vs 10.6%, P.05 for all). Quality of life, as assessed by the Kansas City Cardiomyopathy Questionnaire score at 30 days or 1 year, was comparable in both groups.For patients at low risk for isolated surgery, MI and FS approaches were associated with similar in-hospital and 1-year outcomes.

Wild-caught fish provide an irreplaceable source of essential nutrients in food-insecure places. Fishers catch thousands of species, yet the diversity of aquatic foods is often categorized homogeneously as ‘fish’, obscuring an understanding of which species supply affordable, nutritious and abundant food. Here, we use catch, economic and nutrient data on 2,348 species to identify the most affordable and nutritious fish in 39 low- and middle-income countries. We find that a 100 g portion of fish cost between 10 and 30% of the cheapest daily diet, with small pelagic fish (herring, sardine, anchovy) being the cheapest nutritious fish in 72% of countries. In sub-Saharan Africa, where nutrient deficiencies are rising

To describe rates of urology consultation following renal trauma and assess subsequent impact on imaging and intervention. Renal trauma may be initially managed by either trauma or urologic surgeons alone or collaboratively. Differences in management between the specialties are not well studied.We conducted an IRB-approved retrospective review of patients at a Level I trauma center sustaining renal trauma between 2014 and 2021. Demographic, injury, radiologic, and intervention variables were extracted. Frequencies and medians were compared using chi-squared and Fischer's exact tests or Mann-Whitney U tests, respectively. Analyses were performed using STATA with P.05 considered significant.From 2014 to 2021, 118 patients with median age 29 (IQR 22-41) sustained renal trauma. Urology was consulted in 18 (15.3%) cases. Demographic and injury characteristics were similar between the 2 groups. AAST renal injury grade was transcribed in the initial radiologic reports for 49 (41.5%) of patients. Those in the urology consult group were more likely to receive delayed contrast imaging during their admission (50.0% vs 17.0%, P.01). Among those with high-grade injuries, those with urology consult were less likely to undergo nephrectomy (36.4% vs 78.8%, P = .02).We observed differences in imaging patterns between renal trauma patients who are managed primarily by trauma surgery versus urology. However, the impact of these differences in imaging remains to be elucidated. Among patients with high-grade renal trauma, urology consult was associated with decreased rate of nephrectomy, emphasizing the feasibility of renal salvage in a multidisciplinary trauma setting.

Duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) influences ischemic and bleeding events. Platelet expression of constant fragment of immunoglobulin, low affinity IIa, receptor (FcγRIIa) independently predicts risk of ischemic complications and is proposed as a tool to guide individualized care.We used a Markov model to predict lifetime ischemic and bleeding events and healthcare costs in acute myocardial infarction (MI) patients treated with PCI and DAPT and to project cost-effectiveness of platelet FcγRIIa-assay-guided care (30:3 months DAPT for patients at high: low ischemic risk) versus current standard care (12 months DAPT) from the perspective of the US healthcare system. Model inputs included assay sensitivity and specificity, ischemic and bleeding event rates, and impacts on quality of life, mortality, and costs. Assay cost was $90. Sensitivity analyses were conducted over a range of plausible clinical and cost assumptions.Under base case assumptions, platelet FcγRIIa-assay-guided DAPT duration was projected to increase lifetime costs by $19 versus standard care, with an associated incremental cost-effectiveness ratio (ICER) of $436 per quality-adjusted life-year (QALY) gained. Assay-guided DAPT duration was consistent with high-value care (ICER$50 000/QALY gained) over a broad range of alternative assumptions.Based on a decision-analytic model, for patients with MI treated with PCI, the additional costs of the platelet FcγRIIa assay for guiding DAPT duration would be largely offset by reductions in downstream event-related costs, and assay-guided care would be highly cost-effective by current standards. These findings require confirmation in prospective studies and in a randomized clinical trial of assay-guided versus nonassay-guided DAPT duration.

Severe injury can provoke systemic processes that lead to organ dysfunction, and hemolysis of both native and transfused red blood cells (RBC's) may contribute. Hemolysis can release erythrocyte proteins, such as hemoglobin and arginase-1, the latter with the potential to disrupt arginine metabolism and limit physiologic nitric oxide (NO) production. We aimed to quantify hemolysis and arginine metabolism in trauma patients and measure association with injury severity, transfusions, and outcomes.Blood was collected from injured patients at a Level I Trauma Center enrolled in the COMBAT trial. Proteomics and metabolomics were performed on plasma fractions through liquid chromatography coupled with mass spectrometry. Abundances of erythrocyte proteins comprising a hemolytic profile as well as haptoglobin, L-arginine, ornithine, and L-citrulline (NO surrogate marker) were analyzed at different timepoints and correlated with transfusions and adverse outcomes.More critically injured patients, non-survivors, and those with longer ventilator requirement had higher levels of hemolysis markers with reduced L-arginine and L-citrulline. In logistic regression, elevated hemolysis markers, reduced L-arginine, and reduced L-citrulline were significantly associated with these adverse outcomes. An increased number of blood transfusions was significantly associated with elevated hemolysis markers and reduced L-arginine and L-citrulline independently of new injury severity score and arterial base excess.Severe injury induces intravascular hemolysis, which may mediate post-injury organ dysfunction. In addition to native RBC's, transfused RBC's can lyse and may exacerbate trauma-induced hemolysis. Arginase-1 released from RBC's may contribute to the depletion of L-arginine and the subsequent reduction in the NO necessary to maintain organ perfusion.

BackgroundKetamine infusions are frequently employed for refractory complex regional pain syndrome (CRPS), but there are limited data on factors associated with treatment response. Sympathetic blocks are also commonly employed in CRPS for diagnostic and therapeutic purposes and generally precede ketamine infusions.ObjectivesWe sought to determine whether demographic and clinical factors, and technical and psychophysical characteristics of sympathetic blocks are associated with response to ketamine infusion.MethodsIn this multi-center retrospective study, 71 patients who underwent sympathetic blocks followed by ketamine infusions at 4 hospitals were evaluated. Sympathetically maintained pain (SMP) was defined as ≥ 50% immediate pain relief after sympathetic block and a positive response to ketamine was defined as ≥ 30% pain relief lasting over 3 weeks.ResultsFactors associated with a positive response to ketamine in univariable analysis were the presence of SMP (61.0% success rate vs 26.7% in those with sympathetically independent pain; P = .009) and post-block temperature increase (5.66 ± 4.20 in ketamine responders vs 3.68 ± 3.85 in non-responders; P = .043). No psychiatric factor was associated with ketamine response. In multivariable analysis, SMP (OR 6.54 [95% CI 1.83, 23.44]) and obesity (OR 8.75 [95% 1.45, 52.73]) were associated with a positive ketamine infusion outcome.ConclusionsThe response to sympathetic blocks may predict response to ketamine infusion in CRPS patients, with alleviation of the affective component of pain and predilection to a positive placebo effect being possible explanations.

Introduction: Severely injured patients develop a dysregulated inflammatory state characterized by vascular endothelial permeability, which contributes to multiple organ failure. To date, however, the mediators of and mechanisms for this permeability are not well established. Endothelial permeability in other inflammatory states such as sepsis is driven primarily by overactivation of the RhoA GTPase. We hypothesized that tissue injury and shock drive endothelial permeability after trauma by increased RhoA activation leading to break down of endothelial tight and adherens junctions. Methods: Human umbilical vein endothelial cells (HUVECs) were grown to confluence, whereas continuous resistance was measured using electrical cell-substrate impedance sensing (ECIS) Z-Theta technology, 10% ex vivo plasma from severely injured trauma patients was added, and resistance measurements continued for 2 hours. Areas under the curve (AUCs) were calculated from resistance curves. For GTPase activity analysis, HUVECs were grown to confluence and incubated with 10% trauma plasma for 5 minutes before harvesting of cell lysates. Rho and Rac activity were determined using a G-LISA assay. Significance was determined using Mann-Whitney tests or Kruskal-Wallis test, and Spearman ρ was calculated for correlations. Results: Plasma from severely injured patients induces endothelial permeability with plasma from patients with both severe injury and shock contributing most to this increased permeability. Surprisingly, Injury Severity Score (ISS) does not correlate with in vitro trauma-induced permeability (-0.05, P0.05), whereas base excess (BE) does correlate with permeability (-0.47, P = 0.0001). The combined impact of shock and injury resulted in a significantly smaller AUC in the injury + shock group (ISS15, BE-9) compared with the injury only (ISS15, BE-9; P = 0.04) or minimally injured (ISS15, BE-9; P = 0.005) groups. In addition, incubation with injury + shock plasma resulted in higher RhoA activation ( P = 0.002) and a trend toward decreased Rac1 activation ( P = 0.07) compared with minimally injured control. Conclusions: Over the past decade, improved early survival in patients with severe trauma and hemorrhagic shock has led to a renewed focus on the endotheliopathy of trauma. This study presents the largest study to date measuring endothelial permeability in vitro using plasma collected from patients after traumatic injury. Here, we demonstrate that plasma from patients who develop shock after severe traumatic injury induces endothelial permeability and increased RhoA activation in vitro . Our ECIS model of trauma-induced permeability using ex vivo plasma has potential as a high throughput screening tool to phenotype endothelial dysfunction, study mediators of trauma-induced permeability, and screen potential interventions.

Background: Blood type O is the most common blood type and has lower von Willebrand factor (vWF) levels (25%-35% lower than non-O blood types). von Willebrand factor is important for initiating platelet attachment and binding factor VIII. We hypothesized that patients with type O blood are at an increased risk of trauma-induced coagulopathy and bleeding post injury. Study Design: Adult trauma activations with known blood type at a level I trauma center with field systolic blood pressure90 mm Hg were studied retrospectively. The relationships of blood group O versus non-O to coagulation assays, massive transfusion (MT), ventilator-free days, and mortality were adjusted for confounders. Hyperfibrinolysis (HF) was defined as thromboelastogram of percent lysis in 30 min3%, and fibrinolysis shutdown was defined as percent lysis in 30 min0.9%. von Willebrand factor activity was quantified on 212 injured patients using a STAGO apparatus. Results: Overall, 268 patients met criteria. Type O patients were more likely to develop HF than non-type O blood patients (43% vs. 29%, P = 0.06) and had significantly lower vWF activity (222% vs. 249%, P = 0.01). After adjustment for New Injury Severity Score and blunt mechanism, type O had higher odds of HF (odds ratio, 1.94, 95% confidence interval, 1.09-3.47) and increased odds of MT (odds ratio, 3.02; 95% confidence interval, 1.22-7.49). Other outcomes were not significantly affected. Conclusion: Type O patients with hypotension had increased HF and MT post injury, and these were associated with lower vWF activity. These findings have implications for the monitoring of HF in patients receiving type O whole-blood transfusions post injury.

Injustices are prevalent in food systems, where the accumulation of vast wealth is possible for a few, yet one in ten people remain hungry. Here, for 194 countries we combine aquatic food production, distribution and consumption data with corresponding national policy documents and, drawing on theories of social justice, explore whether barriers to participation explain unequal distributions of benefits. Using Bayesian models, we find economic and political barriers are associated with lower wealth-based benefits; countries produce and consume less when wealth, formal education and voice and accountability are lacking. In contrast, social barriers are associated with lower welfare-based benefits; aquatic foods are less affordable where gender inequality is greater. Our analyses of policy documents reveal a frequent failure to address political and gender-based barriers. However, policies linked to more just food system outcomes centre principles of human rights, specify inclusive decision-making processes and identify and challenge drivers of injustice.

Purpose: Multi-tyrosine kinase inhibitors (TKI) have shown clinical activity in patients with metastatic colorectal cancer. Cabozantinib, a multi-TKI, exhibited potent antitumor activity superior to regorafenib in preclinical colorectal cancer patient-derived tumor xenograft models. This phase II study aimed to investigate cabozantinib, a multi-TKI, in patients with refractory, metastatic colorectal cancer (mCRC). Experimental Design: A nonrandomized, two-stage, phase II clinical trial evaluating 12-week progression-free survival (PFS) was conducted in eight cancer centers across the United States between May 2018 and July 2020. Results: A total of 44 patients were enrolled between May 2018 and May 2019, 40 of which were response evaluable. Of the total 769 reported adverse events (AE), 93 (12%) were ≥ grade 3. Five grade 5 AEs were reported of which four were unrelated to study drug and one was reported as possibly related due to bowel perforation. Eighteen patients (45%) achieved 12-week PFS with stable disease or better (confidence interval, 0.29–0.62; P < 0.001). One patient (3%) had a partial response, and 27 other patients achieved stable disease as best response per RECISTv1.1. Median PFS was 3.0 months, and median overall survival was 8.3 months. Of the 18 patients who achieved 12-week PFS, 12 had left-sided primary tumors, 11 were RAS wild type, 11 were PIK3CA wild type, and 6 had previous regorafenib therapy. The 12-week PFS rate was higher in RAS wild-type tumors compared with RAS mutant tumors (0.61 vs. 0.32; P = 0.11). Conclusions: This phase II study demonstrated clinical activity of cabozantinib in heavily pretreated, patients with refractory mCRC, and supports further investigation. Significance: Targeting angiogenesis through VEGF axis blockade provides incremental survival benefit in patients with mCRC. The hepatocyte growth factor/MET signal transduction pathway has been observed as a mechanism for acquired resistance. Dual inhibition of VEGF plus MET is an attractive therapeutic strategy. This phase II trial demonstrated clinical activity with cabozantinib, a multi-TKI targeting VEGFR2 and MET, in patients with refractory, mCRC.

In a 1983 article, Legal Negotiation: A Study of Strategies in Search of a Theory, Carrie Menkel-Meadow took stock of what was motivating a diverse range of scholars to want to reimagine negotiation theory. She described these negotiation scholars as shaped by the exigencies of their own political moments. Some were lawyers concerned about too much litigation of an unsatisfying quality. Many, however, were concerned more broadly about “the general level of hostility in the world,” even haunted by the possibility that nuclear weapons could destroy all of humanity. Negotiation scholars included “[e]conomists and game theorists . . . concerned that the earth’s limited resources be allocated efficiently and productively,” as well as “[e]thicists . . . concerned that those resources be divided fairly.” Carrie’s own pioneering work would soon establish that a few of these scholars—including those who cared about ethics—approached negotiation through feminist theory. In 1984, in a pathbreaking and widely celebrated article, Toward Another View of Legal Negotiation, Carrie introduced what she called a problem-solving model of negotiation. She included a footnote with an argument she foreshadowed in Legal Negotiation and that she would develop in subsequent years. Her position was that problem-solving negotiation should enact a feminist ethic of care. From this perspective, negotiation is not only a set of professional tools but a deeply ethical practice—a means of cultivating self and social relations differently. In this celebration of Carrie’s contributions to feminist theory, I suggest that Carrie’s early work in negotiation created an opening for a radically caring and democratic practice of negotiation—one whose underlying feminist values of interdependence and connectedness implicitly and explicitly challenge capitalist logics of competition and accumulation. Speaking broadly, she told her readers that “[t]he goal, rooted in experience, [is] achieving a world without domination.” Echoing the feminist turn in critical legal studies, of which she was an important part, Carrie called for a world without patriarchal domination but also without domination produced through socioeconomic relations. Contextualizing this project, I will also suggest that negotiation theory, as it mainstreamed in legal and popular practice and notwithstanding Carrie’s inspiration, has not yet embraced the radicalism she envisioned, but rather, in notable ways, has turned away from it. And yet the legacy of Carrie’s visionary work as a set of possible prescriptions remains. As offering and as inspiration, Carrie’s work awaits interpretations and reimaginings by people shaped by the exigencies of their own political moments. In the spirit of such reimaginings, undertaken in the present tense and as its own way of honoring her work, I read Carrie’s scholarship together with the work of J.K. Gibson-Graham, the pen name of feminist Marxist economic geographers Katherine Gibson and Julie Graham, and their collaborators. By means of this reading, I endeavor to show how Carrie’s work holds space today for a feminist praxis of negotiation—a praxis organized around the “ethical question of our interdependence with others and its implications” rather than the coordinates of “growth” and distribution” more familiar within the field of negotiation Carrie so vitally helped seek to change.

There is a critical need to better understand psychological treatments from a culturally sensitive lens. Using a process-oriented model, we examined treatment satisfaction among perinatal patients who received behavioral activation (BA) within a large psychotherapy trial for perinatal depression and anxiety, and explored how to optimize culturally sensitive delivery through a multistakeholder perspective.In this mixed methods study, we estimated treatment satisfaction through mean client satisfaction scores (Client Satisfaction Questionnaire [CSQ]-8) among perinatal participants (CSQ-8 scores were similar across ethnic groups,BA offers one psychotherapeutic model that uses an idiosyncratic and process-oriented approach that fosters intersectional humility and benefits from cultural humility, comfort, and opportunities. We identify key recommendations to inform culturally sensitive, evidence-based psychological treatments that include explicitly acknowledging and eliciting topics of race, ethnicity, and culture during sessions and supervision and ongoing training and supervision. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

ImportanceIn patients with multivessel coronary artery disease (CAD) presenting with ST-segment elevation myocardial infarction (STEMI), complete revascularization reduces major cardiovascular events compared with culprit lesion–only percutaneous coronary intervention (PCI). Whether complete revascularization also improves angina-related health status is unknown.ObjectiveTo determine whether complete revascularization improves angina status in patients with STEMI and multivessel CAD.Design, Setting, and ParticipantsThis secondary analysis of a randomized, multinational, open label trial of patient-reported outcomes took place in 140 primary PCI centers in 31 countries. Patients presenting with STEMI and multivessel CAD were randomized between February 1, 2013, and March 6, 2017. Analysis took place between July 2021 and December 2021.InterventionsFollowing PCI of the culprit lesion, patients with STEMI and multivessel CAD were randomized to receive either complete revascularization with additional PCI of angiographically significant nonculprit lesions or to no further revascularization.Main Outcomes and MeasuresSeattle Angina Questionnaire Angina Frequency (SAQ-AF) score (range, 0 [daily angina] to 100 [no angina]) and the proportion of angina-free individuals by study end.ResultsOf 4041 patients, 2016 were randomized to complete revascularization and 2025 to culprit lesion–only PCI. The mean (SD) age of patients was 62 (10.7) years, and 3225 (80%) were male. The mean (SD) SAQ-AF score increased from 87.1 (17.8) points at baseline to 97.1 (9.7) points at a median follow-up of 3 years in the complete revascularization group (score change, 9.9 [95% CI, 9.0-10.8]; P P P = .006). Overall, 1457 patients (87.5%) were free of angina (SAQ-AF score, 100) in the complete revascularization group compared with 1376 patients (84.3%) in the culprit lesion–only group (absolute difference, 3.2% [95% CI, 0.7%-5.7%]; P = .01). This benefit was observed mainly in patients with nonculprit lesion stenosis severity of 80% or more (absolute difference, 4.7%; interaction P = .02).Conclusions and RelevanceIn patients with STEMI and multivessel CAD, complete revascularization resulted in a slightly greater proportion of patients being angina-free compared with a culprit lesion–only strategy. This modest incremental improvement in health status is in addition to the established benefit of complete revascularization in reducing cardiovascular events.

In the setting of uncertain efficacy and additional, unreimbursed cost, use of an embolic protection device (EPD) during transcatheter aortic valve replacement (TAVR) has had variable uptake. The Centers for MedicareMedicaid Services (CMS) instituted a new technology add-on payment to cover EPD use in October 2018.To evaluate the association between CMS TAVR reimbursement rates and EPD use.This cohort study used the Society for Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy registry to identify patients who underwent TAVR between January 2018 and September 2019. Analysis took place between July 2020 and February 2022.The association between EPD use and CMS reimbursement was assessed using multivariable logistic regression models adjusted for patient characteristics (model 1) and patient/hospital (annualized TAVR volume and teaching status) characteristics (model 2).Among 511 institutions, CMS reimbursement for TAVR ranged from $28 062 to $111 280 with a median (IQR) of $45 884 ($40 331-$53 627). Among 84 353 patients (median [IQR] age, 81.0 [75.0-86.0] years; 46 247 male individuals [54.8%]; 3958 [4.7%] of Hispanic or Latino ethnicity; 78 170 White individuals [92.7%]) treated at the sites, 6012 (7.1%) underwent TAVR with EPD. Patient characteristics associated with EPD use included prior stroke (adjusted odds ratio [aOR], 1.13 [95% CI, 1.00-1.27]; P = .048), female sex (aOR, 0.85 [95% CI, 0.78-0.93]; P .001), hemodialysis (aOR, 0.52 [95% CI, 0.40-0.68]; P .001), and shock (aOR, 0.62 [95% CI, 0.41-0.94]; P = .03). Higher CMS reimbursement up to $50 000 per TAVR was associated with greater likelihood of EPD use in model 1 (per $1000; aOR, 1.08 [95% CI, 1.01-1.16]; P = .02). However, this association was no longer apparent after adjusting for site characteristics (model 2; aOR, 1.03 [95% CI, 0.96-1.11]; P = .38). Higher TAVR volume was associated with increased EPD use (per 25 TAVRs; aOR, 1.15 [95% CI, 1.09-1.21]; P .001). There was no significant change in the odds of EPD uptake before vs after institution of the CMS new technology add-on payment across tertiles of CMS TAVR reimbursement (Wald χ2 = 3.59; P = .17).EPD use during TAVR remains infrequent and is associated with multiple patient and site characteristics. While CMS reimbursement varies significantly across institutions, TAVR case volume, rather than CMS TAVR reimbursement or the CMS new technology add-on payment, appears to be the predominant factor associated with EPD use. Ongoing work is needed to understand the economic drivers that contribute to the association between procedural volume and EPD use.

In patients with severe aortic stenosis and left ventricular ejection fraction (LVEF) less than 50%, early LVEF improvement after transcatheter aortic valve replacement (TAVR) is associated with improved 1-year mortality; however, its association with long-term clinical outcomes is not known.To examine the association between early LVEF improvement after TAVR and 5-year outcomes.This cohort study analyzed patients enrolled in the Placement of Aortic Transcatheter Valves (PARTNER) 1, 2, and S3 trials and registries between July 2007 and April 2015. High- and intermediate-risk patients with baseline LVEF less than 50% who underwent transfemoral TAVR were included in the current study. Data were analyzed from August 2020 to May 2021.Early LVEF improvement, defined as increase of 10 percentage points or more at 30 days and also as a continuous variable (ΔLVEF between baseline and 30 days).All-cause death at 5 years.Among 659 included patients with LVEF less than 50%, 468 (71.0%) were male, and the mean (SD) age was 82.4 (7.7) years. LVEF improvement within 30 days following transfemoral TAVR occurred in 216 patients (32.8%) (mean [SD] ΔLVEF, 16.4 [5.7%]). Prior myocardial infarction, diabetes, cancer, higher baseline LVEF, larger left ventricular end-diastolic diameter, and larger aortic valve area were independently associated with lower likelihood of LVEF improvement. Patients with vs without early LVEF improvement after TAVR had lower 5-year all-cause death (102 [50.0%; 95% CI, 43.3-57.1] vs 246 [58.4%; 95% CI, 53.6-63.2]; P = .04) and cardiac death (52 [29.5%; 95% CI, 23.2-37.1] vs 135 [38.1%; 95% CI, 33.1-43.6]; P = .05). In multivariable analyses, early improvement in LVEF (modeled as a continuous variable) was associated with lower 5-year all-cause death (adjusted hazard ratio per 5% increase in LVEF, 0.94 [95% CI, 0.88-1.00]; P = .04) and cardiac death (adjusted hazard ratio per 5% increase in LVEF, 0.90 [95% CI, 0.82-0.98]; P = .02) after TAVR. Restricted cubic spline analysis demonstrated a visual inflection point at ΔLVEF of 10% beyond which there was a steep decline in all-cause mortality with increasing degree of LVEF improvement. There were no statistically significant differences in rehospitalization, New York Heart Association functional class, or Kansas City Cardiomyopathy Questionnaire Overall Summary score at 5 years in patients with vs without early LVEF improvement. In subgroup analysis, the association between early LVEF improvement and 5-year all-cause death was consistent regardless of the presence or absence of coronary artery disease or prior myocardial infarction.In patients with severe aortic stenosis and LVEF less than 50%, 1 in 3 experience LVEF improvement within 1 month after TAVR. Early LVEF improvement is associated with lower 5-year all-cause and cardiac death.

Patients with epidermolysis bullosa (EB) are susceptible to development of squamous cell carcinomas (SCC) at sites of chronic inflammation and fibrosis. While triterpenoids such as RTA 408 (Omaveloxolone) have been shown to reduce inflammation and inhibit tumour growth in various cancer models, the utility of this class of drugs in the treatment of SCC has not been investigated. Given the dual anti-inflammatory and anti-neoplastic properties of triterpenoids, we hypothesized RTA 408 would be an effective treatment for SCCs that arise in the chronic inflammatory setting in EB. We tested the effects of topical RTA 408 on a mouse model of non-Herlitz, junctional EB. RTA 408 significantly reduced phenotypic severity in the affected ears of Lamc2jeb mice. In cultures, RTA 408 reduced cell viability in EB-associated SCC cell lines and normal human epidermal keratinocytes. When administered in vivo, RTA 408 inhibited SCC tumour growth in mice without cutaneous or systemic toxicity. These results suggest that RTA 408 can be a promising new therapy to reduce inflammation and inhibit SCC growth in patients with EB.

Marginalized communities have been disproportionally impacted by SARS-CoV-2. How the associations between social determinants of health and the risk of SARS-CoV-2 infection shifted across time is unknown. In this evaluation, we examine individual-level social determinants of health as social risk factors for SARS-CoV-2 infection across the first 12 months of the pandemic among US Veterans.We conducted a retrospective cohort analysis of 946,358 Veterans who sought testing or treatment for SARS-CoV-2 infection in U.S. Department of Veterans Affairs medical facilities. We estimated risk ratios for testing positive by social risk factors, adjusting for demographics, comorbidities, and time. Adjusted models were stratified by pandemic phase to assess temporal fluctuations in social risks.Approximately 19% of Veterans tested positive for SARS-CoV-2. Larger household size was a persistent risk factor and this association increased over time. Early in the pandemic, lower county-level population density was associated with lower SARS-CoV-2 infection risk, but between June 1 and August 31, 2020, this trend reversed.Temporal fluctuations in social risks associated with Veterans' SARS-CoV-2 infection suggest the need for ongoing, real-time tracking as the social and medical environment continues to evolve.