Structural basis of homodimerization of the JNK scaffold protein JIP2 and its heterodimerization with JIP1.

The scaffold proteins JIP1 and JIP2 intervene in the c-Jun N-terminal kinase (JNK) pathway to mediate signaling specificity by coordinating the simultaneous assembly of multiple kinases. Using NMR, we demonstrate that JIP1 and JIP2 heterodimerize via their SH3 domains with the affinity of heterodimerization being comparable to homodimerization. We present the high-resolution crystal structure of the JIP2-SH3 homodimer and the JIP1-JIP2-SH3 heterodimeric complex. The JIP2-SH3 structure reveals how charge differences in residues at its dimer interface lead to formation of compensatory hydrogen bonds and salt bridges, distinguishing it from JIP1-SH3. In the JIP1-JIP2-SH3 complex, structural features of each homodimer are employed to stabilize the heterodimer. Building on these insights, we identify key residues crucial for stabilizing the dimer of both JIP1 and JIP2. Through targeted mutations in cellulo, we demonstrate a functional role for the dimerization of the JIP1 and JIP2 scaffold proteins in activation of the JNK signaling pathway.

Outcomes of carotid revascularization stratified by procedure in patients with an estimated glomerular filtration rate of <30 and dialysis patients.

OBJECTIVE: Renal failure is a predictor of adverse outcomes in carotid revascularization. There has been debate regarding the benefit of revascularization in patients with severe chronic kidney disease or on dialysis. METHODS: Patients in the Vascular Quality Initiative undergoing transcarotid artery revascularization (TCAR), transfemoral carotid artery stenting (tfCAS), or CEA between 2016 and 2023 with an estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m2 or on dialysis were included. Patients were divided into cohorts based on procedure. Additional analyses were performed for patients on dialysis only and by symptomatology. Primary outcomes were perioperative stroke/death/myocardial infarction (MI) (SDM). Secondary outcomes included perioperative death, stroke, MI, cranial nerve injury, and stroke/death. Inverse probability of treatment weighting was performed based on treatment assignment to TCAR, tfCAS, and CEA patients and adjusted for demographics, comorbidities, and preoperative symptoms. The χ2 test and multivariable logistic regression analysis were used to evaluate the association of procedure with perioperative outcomes in the weighted cohort. Five-year survival was evaluated using Kaplan-Meier and weighted Cox regression. RESULTS: In the weighted cohort, 13,851 patients with an eGFR of <30 (2506 on dialysis) underwent TCAR (3639; 704 on dialysis), tfCAS (1975; 393 on dialysis), or CEA (8237; 1409 on dialysis) during the study period. Compared with TCAR, CEA had higher odds of SDM (2.8% vs 3.6%; adjusted odds ratio [aOR], 1.27; 95% confidence interval [CI], 1.00-1.61; P = .049), and MI (0.7% vs 1.5%; aOR, 2.00; 95% CI, 1.31-3.05; P = .001). Compared with TCAR, rates of SDM (2.8% vs 5.8%), stroke (1.2% vs 2.6%), and death (0.9% vs 2.4%) were all higher for tfCAS. In asymptomatic patients CEA patients had higher odds of MI (0.7% vs 1.3%; aOR, 1.85; 95% CI, 1.15-2.97; P = .011) and cranial nerve injury (0.3% vs 1.9%; aOR, 7.23; 95% CI, 3.28-15.9; P < .001). Like in the primary analysis, asymptomatic tfCAS patients demonstrated higher odds of death and stroke/death. Symptomatic CEA patients demonstrated no difference in stroke, death, or stroke/death. Although tfCAS patients demonstrated higher odds of death, stroke, MI, stroke/death, and SDM. In both groups, the 5-year survival was similar for TCAR and CEA (eGFR <30, 75.1% vs 74.2%; aHR, 1.06; P = .3) and lower for tfCAS (eGFR <30, 75.1% vs 70.4%; aHR, 1.44; P < .001). CONCLUSIONS: CEA and TCAR had similar odds of stroke and death and are both a reasonable choice in this population; however, TCAR may be better in patients with an increased risk of MI. Additionally, tfCAS patients were more likely to have worse outcomes after weighting for symptom status. Finally, although patients with a reduced eGFR have worse outcomes than their healthy peers, this analysis shows that the majority of patients survive long enough to benefit from the potential stroke risk reduction provided by all revascularization procedures.

Seven years of the transcarotid artery revascularization surveillance project, comparison to transfemoral stenting and endarterectomy.

OBJECTIVE: This study utilizes the latest data from the Vascular Quality Initiative (VQI), which now encompasses over 50,000 transcarotid artery revascularization (TCAR) procedures, to offer a sizeable dataset for comparing the effectiveness and safety of TCAR, transfemoral carotid artery stenting (tfCAS), and carotid endarterectomy (CEA). Given this substantial dataset, we are now able to compare outcomes overall and stratified by symptom status across revascularization techniques. METHODS: Utilizing VQI data from September 2016 to August 2023, we conducted a risk-adjusted analysis by applying inverse probability of treatment weighting to compare in-hospital outcomes between TCAR vs tfCAS, CEA vs tfCAS, and TCAR vs CEA. Our primary outcome measure was in-hospital stroke/death. Secondary outcomes included myocardial infarction and cranial nerve injury. RESULTS: A total of 50,068 patients underwent TCAR, 25,361 patients underwent tfCAS, and 122,737 patients underwent CEA. TCAR patients were older, more likely to have coronary artery disease, chronic kidney disease, and undergo coronary artery bypass grafting/percutaneous coronary intervention as well as prior contralateral CEA/CAS compared with both CEA and tfCAS. TfCAS had higher odds of stroke/death when compared with TCAR (2.9% vs 1.6%; adjusted odds ratio [aOR], 1.84; 95% confidence interval [CI], 1.65-2.06; P < .001) and CEA (2.9% vs 1.3%; aOR, 2.21; 95% CI, 2.01-2.43; P < .001). CEA had slightly lower odds of stroke/death compared with TCAR (1.3% vs 1.6%; aOR, 0.83; 95% CI, 0.76-0.91; P < .001). TfCAS had lower odds of cranial nerve injury compared with TCAR (0.0% vs 0.3%; aOR, 0.00; 95% CI, 0.00-0.00; P < .001) and CEA (0.0% vs 2.3%; aOR, 0.00; 95% CI, 0.0-0.0; P < .001) as well as lower odds of myocardial infarction compared with CEA (0.4% vs 0.6%; aOR, 0.67; 95% CI, 0.54-0.84; P < .001). CEA compared with TCAR had higher odds of myocardial infarction (0.6% vs 0.5%; aOR, 1.31; 95% CI, 1.13-1.54; P < .001) and cranial nerve injury (2.3% vs 0.3%; aOR, 9.42; 95% CI, 7.78-11.4; P < .001). CONCLUSIONS: Although tfCAS may be beneficial for select patients, the lower stroke/death rates associated with CEA and TCAR are preferred. When deciding between CEA and TCAR, it is important to weigh additional procedural factors and outcomes such as myocardial infarction and cranial nerve injury, particularly when stroke/death rates are similar. Additionally, evaluating subgroups that may benefit from one procedure over another is essential for informed decision-making and enhanced patient care in the treatment of carotid stenosis.

Learning curve of transfemoral carotid artery stenting in the Vascular Quality Initiative registry.

OBJECTIVE: With the recent expansion of the Centers for Medicare and Medicaid Services coverage, transfemoral carotid artery stenting (tfCAS) is expected to play a larger role in the management of carotid disease. Existing research on the tfCAS learning curve, primarily conducted over a decade ago, may not adequately describe the current effect of physician experience on outcomes. Because approximately 30% of perioperative strokes/deaths post-CAS occur after discharge, appropriate thresholds for in-hospital event rates have been suggested to be <4% for symptomatic and <2% for asymptomatic patients. This study evaluates the tfCAS learning curve using Vascular Quality Initiative (VQI) data. METHODS: We identified VQI patients who underwent tfCAS between 2005 and 2023. Each physician's procedures were chronologically grouped into 12 categories, from procedure counts 1-25 to 351+. The primary outcome was in-hospital stroke/death rate; secondary outcomes were in-hospital stroke/death/myocardial infarction (MI), 30-day mortality, in-hospital stroke/transient ischemic attack (stroke/TIA), and access site complications. The relationship between outcomes and procedure counts was analyzed using the Cochran-Armitage test and a generalized linear model with restricted cubic splines. Our results were then validated using a generalized estimating equations model to account for the variability between physicians. RESULTS: We analyzed 43,147 procedures by 2476 physicians. In symptomatic patients, there was a decrease in rates of in-hospital stroke/death (procedure counts 1-25 to 351+: 5.2%-1.7%), in-hospital stroke/death/MI (5.8%-1.7%), 30-day mortality (4.6%-2.8%), in-hospital stroke/TIA (5.0%-1.1%), and access site complications (4.1%-1.1%) as physician experience increased (all P values < .05). The in-hospital stroke/death rate remained above 4% until 235 procedures. Similarly, in asymptomatic patients, there was a decrease in rates of in-hospital stroke/death (2.1%-1.6%), in-hospital stroke/death/MI (2.6%-1.6%), 30-day mortality (1.7%-0.4%), and in-hospital stroke/TIA (2.8%-1.6%) with increasing physician experience (all P values <.05). The in-hospital stroke/death rate remained above 2% until 13 procedures. CONCLUSIONS: In-hospital stroke/death and 30-day mortality rates after tfCAS decreased with increasing physician experience, showing a lengthy learning curve consistent with previous reports. Given that physicians' early cases may not be included in the VQI, the learning curve was likely underestimated. Nevertheless, a substantially high rate of in-hospital stroke/death was found in physicians' first 25 procedures. With the recent Centers for Medicare and Medicaid Services coverage expansion for tfCAS, a significant number of physicians would enter the early stage of the learning curve, potentially leading to increased postoperative complications.

Limited English proficiency and reported receipt of colorectal cancer screening among adults 45-75 in 2019 and 2021.

Introduction: Substantial barriers to screening exist for medically underserved populations, especially adults with limited English proficiency (LEP). We examined the proportion of US adults aged 45-75 up-to-date with colorectal cancer (CRC) screening by LEP after 2018. The American Cancer Society began recommending CRC screening for adults 45-49 in 2018. Methods: We analyzed cross-sectional data of adults 45-75 years old participating in the 2019 or 2021 National Health Interview Survey (N = 25,611). Adults were considered up-to-date with screening if they reported any stool test within 1 year, stool-DNA testing within 3 years, or colonoscopy within 10 years. Adults who interviewed in a language other than English were considered to have LEP. Adults not up-to-date with screening were asked if a healthcare professional (HCP) recommended screening, and if so which test(s). Regression models conducted in 2022-2023 evaluated receipt of screening, adjusting for sociodemographics, year, and healthcare access. Results: Overall, 54.0 % (95 % CI 53.1-54.9 %) of participants were up-to-date with screening (9.4 % aged 45-49 vs 75.5 % aged 65-75); prevalence increased from 2019 (52.9 %) to 2021(55.2 %). Adults with LEP (vs English proficiency) were less likely to be up-to-date with screening (31.6 % vs. 56.8 %, [aPR 0.86 (0.77-0.96)]). Among adults not up-to-date, 15.0 % reported their HCP recommended screening (8.4 % among adults with LEP). Conclusions: Nearly half of US adults were not up-to-date with CRC screening in 2019 and 2021 and few reported being recommended screening. Adults with LEP and those 45-49 were least likely to be screened suggesting targeted interventions are needed for these populations.

An Analysis of Trainee Status of the Primary Care Physician and Ambulatory Care Outcomes.

PURPOSE: Prior studies report disparities in outcomes for patients cared for by trainees versus faculty physicians at academic medical centers. This study examined the effect of having a trainee as the primary care physician versus a faculty member on routine population health outcomes after adjusting for differences in social determinants of health and primary care retention. METHOD: This cohort study assessed 38,404 patients receiving primary care at an academic hospital-affiliated practice by 60 faculty and 110 internal medicine trainees during academic year 2019. The effect of primary care practitioner trainee status on routine ambulatory care metrics was modeled using log-binomial regression with generalized estimating equation methods to account for physician-level clustering. Risk estimates before and after adjusting for social determinants of health and loss to follow-up are presented. RESULTS: Trainee and faculty cohorts had similar distributions of acute illness burden; however, patients in the trainee cohort were significantly more likely to identify as a race other than White (2,476 [52.6%] vs 14,785 [38.5%], P < .001), live in a zip code associated with poverty (1,688 [35.9%] vs 9,122 [23.8%], P < .001), use public health insurance (1,021 [21.7%] vs 6,108 [15.9%], P < .001), and have limited English proficiency (1,415 [30.1%] vs 5,203 [13.6%], P < .001). In adjusted analyses, trainee status of primary care physician was not associated with lack of breast cancer screening but was associated with missed opportunities to screen for colorectal cancer (relative risk [RR], 0.77; 95% confidence interval [CI], 0.68-0.88), control type 2 diabetes mellitus (RR, 0.78; 95% CI, 0.64-0.94), and control hypertension (RR, 0.80; 95% CI, 0.69-0.94). CONCLUSIONS: Primary care physician trainee status was associated with poorer quality of care in the ambulatory setting after adjusting for differences in socioeconomic factors and loss to follow-up, highlighting a potential ambulatory training gap.

Efficacy of Botulinum A Injection to the Laryngeal Adductor Compartment for Treatment of Cough.

OBJECTIVES: Studies examining electromyography (EMG)-guided laryngeal onobotulinumtoxinA (BTxA) injection for chronic cough reveal promising efficacy, however, are limited by small cohorts and absent quantifiable outcomes. It further remains unclear if pulmonary disease limits efficacy, or if vagal motor neuropathy prognosticates response. We hypothesize BTxA injection results in qualitative improvement in cough, decrease in Cough Severity Index (CSI), no change in Voice Handicap Index-10 (VHI-10), and complication rates comparable to historical data. We also examine the correlation of pulmonary comorbidities and vocal fold hypomobility with treatment efficacy. STUDY DESIGN: Retrospective review. METHODS: Charts for patients receiving percutaneous adductor compartment BTxA injection for cough were reviewed for the binary outcome of patient-reported presence or absence of improvement. Generalized estimating equations regression models were used to analyze the change in CSI (ΔCSI) and the correlation of ΔCSI with qualitative outcomes. Multivariable analyses were used to examine correlation of vocal fold hypomobility and pulmonary disease with qualitative outcomes and ΔCSI. RESULTS: Forty-seven patients underwent 197 BTxA injections from June 2012 to June 2022. A statistical proportion of 0.698 (0.599-0.813, p < 0.0001) or 69.8% of injections resulted in subjective improvement. Mean ΔCSI was -2.12 (0.22-4.02, p < 0.05), indicating overall improvement. With and without subjective improvement, estimated ΔCSI was -4.43 and +2.68, respectively (p < 0.0001). VHI-10 did not change (0.69, p = 0.483). Neither pulmonary disease nor vocal fold hypomobility correlated with subjective improvement or ΔCSI. Dysphagia occurred following 15 (7.6%) injections with no aspiration pneumonia or hospitalization. CONCLUSIONS: BTxA injection to the laryngeal adductors may effectively treat cough with limited risk for serious complications. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1749-1756, 2024.

Impact of Physician Experience on Stroke or Death Rates in Transfemoral Carotid Artery Stenting: Insights from the Vascular Quality Initiative.

Objective: With the recent expansion of the Centers for Medicare and Medicaid Services (CMS) coverage, transfemoral carotid artery stenting (tfCAS) is expected to play a larger role in the management of carotid disease. Existing research on the tfCAS learning curve, primarily conducted over a decade ago, may not adequately describe the current effect of physician experience on outcomes. This study evaluates the tfCAS learning curve using VQI data. Methods: We analyzed tfCAS patient data from 2005-2023. Each physician's procedures were chronologically grouped into 12 categories, from procedure counts 1-25 to 351+. Primary outcome was in-hospital stroke/death rate; secondary outcomes were in-hospital stroke/death/MI, 30-day mortality, and in-hospital stroke/TIA. The relationship between outcomes and procedure counts was analyzed using Cochran Armitage test and a generalized linear model with restricted cubic splines, validated using generalized estimating equations. Results: We analyzed 43,147 procedures by 2,476 physicians. In symptomatic patients, there was a decrease in rates of in-hospital stroke/death (procedure counts 1-25 to 351+: 5.2% to 1.7%), in-hospital stroke/death/MI (5.8% to 1.7%), 30-day mortality (4.6% to 2.8%), in-hospital stroke/TIA (5.0% to 1.1%) (all p-values<0.05). The in-hospital stroke/death rate remained above 4% until 235 procedures. Similarly, in asymptomatic patients, there was a decrease in rates of in-hospital stroke/death (2.1% to 1.6%), in-hospital stroke/death/MI (2.6% to 1.6%), 30-day mortality (1.7% to 0.4%), and in-hospital stroke/TIA (2.8% to 1.6%) with increasing physician experience (all p-values<0.05). The in-hospital stroke/death rate remained above 2% until 13 procedures. Conclusions: In-hospital stroke/death and 30-day mortality rates post-tfCAS decreased with increasing physician experience, showing a lengthy learning curve consistent with previous reports. Given that physicians' early cases may not be included in the VQI, the learning curve was likely underestimated. With the recent CMS coverage expansion for tfCAS, a significant number of physicians would enter the early stage of the learning curve, potentially leading to increased post-operative complications.

JNKs protect from cholestatic liver disease progression by modulating Apelin signalling.

Background & Aims: Cholestatic liver injury is associated with c-Jun N-terminal kinases (JNK) activation in distinct cell types. Its hepatocyte-specific function during cholestasis, however, has not yet been established. Therefore, in our present study, we investigated the role of JNK1/2 during cholestasis and dissected its hepatocyte-specific function. Methods: A cohort of patients with primary biliary cholangitis (n = 29) and primary sclerosing cholangitis (n = 37) was examined. Wild-type, hepatocyte-specific knockout mice for Jnk2 (Jnk2Δhepa) or Jnk1 and Jnk2 (Jnk1Δhepa/2Δhepa) were generated. Mice were subjected to bile duct ligation (BDL) or carbon tetrachloride (CCl4) treatment. Finally, Apelin signalling was blocked using a specific inhibitor. As an interventional approach, Jnk1/2 were silenced in wild-type mice using lipid nanoparticles for small interfering RNA delivery. Results: JNK activation was increased in liver specimens from patients with chronic cholestasis (primary biliary cholangitis and primary sclerosing cholangitis) and in livers of Mdr2-/- and BDL-treated animals. In Jnk1Δhepa/2Δhepa animals, serum transaminases increased after BDL, and liver histology demonstrated enhanced cell death, compensatory proliferation, hepatic fibrogenesis, and inflammation. Furthermore, microarray analysis revealed that hepatocytic Jnk1/2 ablation induces JNK-target genes involved in oxidative stress and Apelin signalling after BDL. Consequently, blocking Apelin signalling attenuated BDL-induced liver injury and fibrosis in Jnk1Δhepa/2Δhepa mice. Finally, we established an interventional small interfering RNA approach of selective Jnk1/2 targeting in hepatocytes in vivo, further demonstrating the essential protective role of Jnk1/2 during cholestasis. Conclusions: Jnk1 and Jnk2 work together to protect hepatocytes from cholestatic liver disease by controlling Apelin signalling. Dual modification of JNK signalling in hepatocytes is feasible, and enhancing its expression might be an attractive therapeutic approach for cholestatic liver disease. Impact and Implications: The cell-specific function of Jnk genes during cholestasis has not been explicitly explored. In this study, we showed that combined Jnk1/2, but not Jnk2 deficiency, in hepatocytes exacerbates liver damage and fibrosis by enhancing Apelin signalling, which contributes to cholestasis progression. Combined cell-specific Jnk targeting may be a new molecular strategy for treating cholestatic liver disease.

Histochemical mapping of the duration of action of photobiomodulation on cytochrome c oxidase in the rat brain.

Introduction: This is the first study mapping the duration of action of in vivo photobiomodulation (PBM) on cytochrome-c-oxidase (CCO). In cellular bioenergetics, CCO is the terminal rate-limiting enzyme in the mitochondrial electron transport chain, which catalyzes oxygen utilization for aerobic energy production. PBM using transcranial infrared laser stimulation (TILS) is a promising intervention for non-invasively modulating CCO in the brain. TILS of the human prefrontal cortex directly causes CCO photo-oxidation, which is associated with increased cerebral oxygenation and improved cognition. Methods: This experiment aimed to map the duration of action of in vivo PBM on CCO activity in discrete neuroanatomic locations within rat brains up to 4 weeks after a single TILS session (50 s, 1064 nm CW, 250 mW/cm2). Control brains from rats treated with a sham session without TILS (laser off) were compared to brains from TILS-treated rats that were collected 1 day, 2 weeks, or 4 weeks post-TILS. Cryostat sections of the 36 collected brains were processed using quantitative enzyme histochemistry and digitally imaged. Densitometric readings of 28 regions of interest were recorded and converted to CCO activity units of oxygen utilization using calibration standards. Data analysis (ANCOVA) compared each laser-treated group to sham with whole-brain average as a covariate. Results: The prefrontal infralimbic cortex showed the earliest significant increase in CCO activity between 1-day post-TILS and sham groups, which continued elevated for 2-4 weeks post-TILS. Significant differences in CCO activity between 2-weeks and sham groups were also found in the lateral septum, accumbens core, CA3 of the hippocampus, and the molecular layer of the hippocampus. The medial amygdala showed a significant decrease in CCO activity between 4-weeks and sham. Further analyses showed significant inter-regional CCO activity correlations among the brain regions as the result of TILS, with the most pronounced changes at 4-weeks post-stimulation. Discussion: The time course of changes in CCO activity and network connectivity suggested that TILS caused different neuroplasticity types of bioenergetic changes at different time scales, depending on brain region and its depth from the cortex. In conclusion, this controlled CCO histochemical study demonstrated a long-lasting duration of action of PBM in the rat brain.

Discordant Breast and Axillary Pathologic Response to Neoadjuvant Chemotherapy.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) for breast cancer has the advantage of determining in vivo response to treatment, enabling more conservative surgery, and facilitating the understanding of tumor biology. Pathologic complete response (pCR) after NAC is a predictor of improved overall survival. However, some patients demonstrate a discordant response to NAC between the breast and axillary nodes. This study was designed to identify factors that correlate to achieving a breast pCR without an axillary node pCR following NAC and explore the potential clinical implications. METHODS: The National Cancer Database was used to identify patients diagnosed with clinical T1-4, N1-3 breast cancer between 2004 and 2017. Patients underwent NAC followed surgical resection of the breast cancer and axillary node surgery. Multivariable analyses were used to identify clinical and pathologic factors associated with discordant pathologic response. RESULTS: In total, 13,934 patients met the inclusion criteria. Of these, 4292 (30.8%) patients demonstrated a breast pCR without a corresponding axillary pCR on final pathology. After adjusting for covariates, factors associated with higher discordance between axillary response in our cohort of breast pCR patients included older age (≥ 54), treatment at a community facility, T1 tumors, HR-positive, HER2 negative, low-grade tumors, and cN2/3 disease. CONCLUSIONS: Discordance between breast and axillary pCR is not infrequent and may be related to a number of patient-related factors and tumor characteristics impacting nodal response to NAC. Further investigation into differing responses to NAC is warranted to better understand the mechanism of this phenomenon and to determine how these findings may influence treatment.

Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition.

Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.

Prevalence and Predictors of Inappropriate Antithrombotic Prescription in Patients Presenting With Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: A growing proportion of the US population is on antithrombotic therapy (AT), most significantly within the older subpopulation. Decision to use AT is a balance between the intended benefits and known bleeding risk, especially after traumatic brain injury (TBI). Preinjury inappropriate AT offers no benefit for the patient and also increases the risk of intracranial hemorrhage and worse outcome in the setting of TBI. Our objective was to examine the prevalence and predictors of inappropriate AT among patients presenting with TBI to a Level-1 Trauma Center. METHODS: A retrospective chart review was performed on all patients with TBI and preinjury AT who presented to our institution between January 2016 and September 2020. Demographic and clinical data were collected. Appropriateness of AT was determined through established clinical guidelines. Clinical predictors were determined by logistic regression. RESULTS: Of 141 included patients, 41.8% were female (n = 59) and the average age (mean ± SD) was 80.6 ± 9.9. The prescribed antithrombotic agents included aspirin (25.5%, n = 36), clopidogrel (22.7%, n = 32), warfarin (46.8%, n = 66), dabigatran (2.1%, n = 3), rivaroxaban (Janssen) (10.6%, n = 15), and apixaban (Bristol-Myers Squibb Co.) (18.4%, n = 26). The indications for AT were atrial fibrillation (66.7%, n = 94), venous thromboembolism (13.4%, n = 19), cardiac stent (8.5%, n = 12), and myocardial infarction/residual coronary disease (11.3%, n = 16). Inappropriate antithrombotic therapy use varied significantly by antithrombotic indication ( P < .001) with the highest rates seen with venous thromboembolism. Predictive factors also include age ( P = .005) with higher rates younger than 65 years and older than 85 years and female sex ( P = .049). Race and antithrombotic agent were not significant predictors. CONCLUSION: Overall, 1 in 10 patients presenting with TBI were found to be on inappropriate AT. Our study is the first to describe this problem and warrants investigation into possible workflow interventions to prevent post-TBI continuation of inappropriate AT.

Rationale and Design of the Groceries for Black Residents of Boston to Stop Hypertension Among Adults Without Treated Hypertension (GoFresh) Trial.

BACKGROUND: Poor diet quality significantly contributes to hypertension disparities affecting Black adults. While the Dietary Approaches to Stop Hypertension (DASH) eating pattern lowers blood pressure (BP), access to DASH-patterned groceries is a major barrier for residents of urban food deserts. METHODS: The Groceries for Black Residents of Boston to Stop Hypertension among Adults without Treated Hypertension (GoFresh) study is one of five projects in the RESTORE Network, an AHA-funded initiative focused on hypertension prevention. GoFresh is testing whether online, dietitian-assisted, home-delivered, DASH-patterned groceries lowers BP among Black adults with elevated BP. This individual-level, parallel-arm trial will enroll up to 176 Black adults with SBP (systolic blood pressure) between 120 and <150 mm Hg residing in Boston-area communities with reduced grocery store access. Following randomization, half of the participants will be assigned to weekly sessions with a dietitian who will assist participants in ordering DASH-patterned groceries online for home delivery; the remainder will receive a $500 monthly stipend. Both interventions will last 3 months, followed by a 9-month maintenance phase. RESULTS: The primary outcome is the difference in SBP after 3 months. Secondary outcomes include a change in 24-hour ambulatory BP, body mass index, 24-hour urine sodium and potassium, hemoglobin A1C, lipids, fruit and vegetable intake, and saturated fat intake. Qualitative interviews with 45 participants 6 months after baseline assessments will determine barriers and facilitators to long-term maintenance of DASH-patterned grocery shopping. DISCUSSION: Findings from this study will inform ongoing work on scalable interventions to prevent hypertension among Black adults with implications for public and healthcare-based food supplementation programs. TRIAL REGISTRATION: NCT05121337. Registered on 16 November 2021, at ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT05121337.

Joint 2022 European Society of Thoracic Surgeons and The American Association for Thoracic Surgery guidelines for the prevention of cancer-associated venous thromboembolism in thoracic surgery.

BACKGROUND: Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a potentially fatal but preventable postoperative complication. Thoracic oncology patients undergoing surgical resection, often after multimodality induction therapy, represent among the highest risk groups for postoperative VTE. Currently there are no VTE prophylaxis guidelines specific to these thoracic surgery patients. Evidenced-based recommendations will help clinicians manage and mitigate risk of VTE in the postoperative period and inform best practice. OBJECTIVE: These joint evidence-based guidelines from The American Association for Thoracic Surgery and the European Society of Thoracic Surgeons aim to inform clinicians and patients in decisions about prophylaxis to prevent VTE in patients undergoing surgical resection for lung or esophageal cancer. METHODS: The American Association for Thoracic Surgery and the European Society of Thoracic Surgeons formed a multidisciplinary guideline panel that included broad membership to minimize potential bias when formulating recommendations. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to public comment. RESULTS: The panel agreed on 24 recommendations focused on pharmacological and mechanical methods for prophylaxis in patients undergoing lobectomy and segmentectomy, pneumonectomy, and esophagectomy, as well as extended resections for lung cancer. CONCLUSIONS: The certainty of the supporting evidence for the majority of recommendations was judged as low or very low, largely due to a lack of direct evidence for thoracic surgery. The panel made conditional recommendations for use of parenteral anticoagulation for VTE prevention, in combination with mechanical methods, over no prophylaxis for cancer patients undergoing anatomic lung resection or esophagectomy. Other key recommendations include: conditional recommendations for using parenteral anticoagulants over direct oral anticoagulants, with use of direct oral anticoagulants suggested only in the context of clinical trials; conditional recommendation for using extended prophylaxis for 28 to 35 days over in-hospital prophylaxis only for patients at moderate or high risk of thrombosis; and conditional recommendations for VTE screening in patients undergoing pneumonectomy and esophagectomy. Future research priorities include the role of preoperative thromboprophylaxis and the role of risk stratification to guide use of extended prophylaxis.

HER2-driven breast cancer suppression by the JNK signaling pathway.

The HER2+ subtype of human breast cancer is associated with the malignant transformation of luminal ductal cells of the mammary epithelium. The sequence analysis of tumor DNA identifies loss of function mutations and deletions of the MAP2K4 and MAP2K7 genes that encode direct activators of the JUN NH2-terminal kinase (JNK). We report that in vitro studies of human mammary epithelial cells with CRISPR-induced mutations in the MAPK and MAP2K components of the JNK pathway caused no change in growth in 2D culture, but these mutations promoted epithelial cell proliferation in 3D culture. Analysis of gene expression signatures in 3D culture demonstrated similar changes caused by HER2 activation and JNK pathway loss. The mechanism of signal transduction cross-talk may be mediated, in part, by JNK-suppressed expression of integrin α6ß4 that binds HER2 and amplifies HER2 signaling. These data suggest that HER2 activation and JNK pathway loss may synergize to promote breast cancer. To test this hypothesis, we performed in vivo studies using a mouse model of HER2+ breast cancer with Cre/loxP-mediated ablation of genes encoding JNK (Mapk8 and Mapk9) and the MAP2K (Map2k4 and Map2k7) that activate JNK in mammary epithelial cells. Kaplan-Meier analysis of tumor development demonstrated that JNK pathway deficiency promotes HER2+-driven breast cancer. Collectively, these data identify JNK pathway genes as potential suppressors for HER2+ breast cancer.

Joint 2022 European Society of Thoracic Surgeons and The American Association for Thoracic Surgery guidelines for the prevention of cancer-associated venous thromboembolism in thoracic surgery.

BACKGROUND: Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a potentially fatal but preventable postoperative complication. Thoracic oncology patients undergoing surgical resection, often after multimodality induction therapy, represent among the highest risk groups for postoperative VTE. Currently there are no VTE prophylaxis guidelines specific to these thoracic surgery patients. Evidenced-based recommendations will help clinicians manage and mitigate risk of VTE in the postoperative period and inform best practice. OBJECTIVE: These joint evidence-based guidelines from The American Association for Thoracic Surgery and the European Society of Thoracic Surgeons aim to inform clinicians and patients in decisions about prophylaxis to prevent VTE in patients undergoing surgical resection for lung or esophageal cancer. METHODS: The American Association for Thoracic Surgery and the European Society of Thoracic Surgeons formed a multidisciplinary guideline panel that included broad membership to minimize potential bias when formulating recommendations. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to public comment. RESULTS: The panel agreed on 24 recommendations focused on pharmacological and mechanical methods for prophylaxis in patients undergoing lobectomy and segmentectomy, pneumonectomy, and esophagectomy, as well as extended resections for lung cancer. CONCLUSIONS: The certainty of the supporting evidence for the majority of recommendations was judged as low or very low, largely due to a lack of direct evidence for thoracic surgery. The panel made conditional recommendations for use of parenteral anticoagulation for VTE prevention, in combination with mechanical methods, over no prophylaxis for cancer patients undergoing anatomic lung resection or esophagectomy. Other key recommendations include: conditional recommendations for using parenteral anticoagulants over direct oral anticoagulants, with use of direct oral anticoagulants suggested only in the context of clinical trials; conditional recommendation for using extended prophylaxis for 28 to 35 days over in-hospital prophylaxis only for patients at moderate or high risk of thrombosis; and conditional recommendations for VTE screening in patients undergoing pneumonectomy and esophagectomy. Future research priorities include the role of preoperative thromboprophylaxis and the role of risk stratification to guide use of extended prophylaxis. (J Thorac Cardiovasc Surg 2022;▪:1-31).

Phosphorylation of RXRα mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome.

The cJun NH2-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating peroxisome proliferator-activated receptor α (PPARα)-dependent expression of the hepatokine fibroblast growth factor 21 (FGF21). Hepatocyte-specific gene ablation studies demonstrated that the Mapk9 gene (encoding JNK2) plays a key mechanistic role. Mutually exclusive inclusion of exons 7a and 7b yields expression of the isoforms JNK2α and JNK2ß. Here we demonstrate that Fgf21 gene expression and metabolic regulation are primarily regulated by the JNK2α isoform. To identify relevant substrates of JNK2α, we performed a quantitative phosphoproteomic study of livers isolated from control mice, mice with JNK deficiency in hepatocytes, and mice that express only JNK2α or JNK2ß in hepatocytes. We identified the JNK substrate retinoid X receptor α (RXRα) as a protein that exhibited JNK2α-promoted phosphorylation in vivo. RXRα functions as a heterodimeric partner of PPARα and may therefore mediate the effects of JNK2α signaling on Fgf21 expression. To test this hypothesis, we established mice with hepatocyte-specific expression of wild-type or mutated RXRα proteins. We found that the RXRα phosphorylation site Ser260 was required for suppression of Fgf21 gene expression. Collectively, these data establish a JNK-mediated signaling pathway that regulates hepatic Fgf21 expression.