Testis specific protein, Y-encoded-like 2 activates JAK2/STAT3 pathway in hypothalamic paraventricular nucleus to sustain hypertension.

BACKGROUND: In the hypothalamic paraventricular nucleus (PVN) of spontaneously hypertensive rats (SHRs), the expression of Testis specific protein, Y-encoded-like 2 (TSPYL2) and the phosphorylation level of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) are higher comparing with the normotensive Wistar-Kyoto rats (WKY). But how they are involved in hypertension remains unclear. TSPYL2 may interact with JAK2/STAT3 in PVN to sustain the high blood pressure during hypertension. METHODS: Knockdown of TSPYL2 via adeno-associated virus (AAV) carrying shRNA was conducted through bilateral micro-injection into the PVN of SHR and WKY rats. JAK2/STAT3 inhibition was achieved by intraperitoneally or PVN injection of AG490 into the SHRs. Blood pressure (BP), plasma norepinephrine (NE), PVN inflammatory response, and PVN oxidative stress were measured. RESULTS: TSPYL2 knock-down in the PVN of SHRs but not WKYs led to reduced BP and plasma NE, and deactivation of JAK2/STAT3, decreased expression of pro-inflammatory cytokine IL-1ß, and increased expression of anti-inflammatory cytokine IL-10 in the PVN. Meanwhile, AG490 administrated in both ways reduced the blood pressure in the SHRs and deactivated JAK2/STAT3 but failed to change the expression of TSPYL2 in PVN. AG490 also downregulated expression of IL-1ß and upregulated expression of IL-10. Both knockdown of TSPYL2 and inhibition of JAK2/STAT3 can reduce the oxidative stress in the PVN of SHRs. CONCLUSION: JAK2/STAT3 is regulated by TSPYL2 in the PVN of SHRs, and PVN TSPYL2/JAK2/STAT3 is essential for maintaining high blood pressure in the hypertensive rats, making it a potential therapeutic target for hypertension.

Low-Income Participants' Preference Between Financial Incentives for Behavioral Goals vs Weight Loss Targets and Associations With Behavioral Goal Adherence.

PURPOSE: Examine associations between whether participants' were matched to their preferred financial incentive design and behavioral goal adherence in a weight management intervention. DESIGN: Secondary quantitative analysis incorporating qualitative survey data. SETTING: Primary care clinics in socioeconomically disadvantaged communities in New York City and Los Angeles. SUBJECTS: 668 participants (mean age 46.9 years, 81.0% female, 97.7% Hispanic) with obesity were enrolled in the Financial Incentives foR Weight Reduction (FIReWoRk) intervention. MEASURES: We explored qualitatively participant's reasons for hypothetically choosing a behavioral goal-directed vs a weight loss outcome-based financial incentive program. Additionally, behavioral adherence to different goals was collected at the 6-month timepoint, categorized by match to preferred financial incentive design. ANALYSIS: Logistic regression was used to examine if participants with certain demographic and higher psychosocial factors were more likely to choose goal-directed over outcome-based incentives. Additionally, logistic regression was used to test for associations between preference and behavioral adherence, using incentive type as an interaction term. RESULTS: 60.1% of participants preferred the goal-directed incentive, with the majority stating that it was more structured. Married participants were more likely to prefer goal-directed incentives (OR = 1.57, CI = 1.06-2.33, P = .025). Moderation analysis revealed that participants who preferred goal-directed and were matched to goal-directed had greater rates of behavioral adherence for program attendance and self-weighing, but not dietary tracking and physical activity tracking, compared to those who preferred outcome-based and were matched to outcome-based. CONCLUSION: Receiving one's preferred incentive design may not play a strong role in behavioral goal adherence during financially incentivized weight loss interventions.

Self-regulating CAR-T cells modulate cytokine release syndrome in adoptive T-cell therapy.

Cytokine release syndrome (CRS) is a frequently observed side effect of chimeric antigen receptor (CAR)-T cell therapy. Here, we report self-regulating T cells that reduce CRS severity by secreting inhibitors of cytokines associated with CRS. With a humanized NSG-SGM3 mouse model, we show reduced CRS-related toxicity in mice treated with CAR-T cells secreting tocilizumab-derived single-chain variable fragment (Toci), yielding a safety profile superior to that of single-dose systemic tocilizumab administration. Unexpectedly, Toci-secreting CD19 CAR-T cells exhibit superior in vivo antitumor efficacy compared with conventional CD19 CAR-T cells. scRNA-seq analysis of immune cells recovered from tumor-bearing humanized mice revealed treatment with Toci-secreting CD19 CAR-T cells enriches for cytotoxic T cells while retaining memory T-cell phenotype, suggesting Toci secretion not only reduces toxicity but also significantly alters the overall T-cell composition. This approach of engineering T cells to self-regulate inflammatory cytokine production is a clinically compatible strategy with the potential to simultaneously enhance safety and efficacy of CAR-T cell therapy for cancer.

Text vs Patient Portal Messaging to Improve Influenza Vaccination Coverage: A Health System-Wide Randomized Clinical Trial.

Importance: Increasing influenza vaccination rates is a public health priority. One method recommended by the US Centers for Disease Control and Prevention and others is for health systems to send reminders nudging patients to be vaccinated. Objective: To evaluate and compare the effect of electronic health record (EHR)-based patient portal reminders vs text message reminders on influenza vaccination rates across a health system. Design, Setting, and Participants: This 3-arm randomized clinical trial was conducted from September 7, 2022, to April 30, 2023, among primary care patients within the University of California, Los Angeles (UCLA) health system. Interventions: Arm 1 received standard of care. The health system sent monthly reminder messages to patients due for an influenza vaccine by portal (arm 2) or text (arm 3). Arm 2 had a 2 × 2 nested design, with fixed vs responsive monthly reminders and preappointment vs no preappointment reminders. Arm 3 had 1 × 2 design, with preappointment vs no preappointment reminders. Preappointment reminders for eligible patients were sent 24 and 48 hours before scheduled primary care visits. Fixed reminders (in October, November, and December) involved identical messages via portal or text. Responsive portal reminders involved a September message asking patients about their plans for vaccination, with a follow-up reminder if the response was affirmative but the patient was not yet vaccinated. Main Outcomes and Measures: The primary outcome was influenza vaccination by April 30, 2023, obtained from the UCLA EHR, including vaccination from pharmacies and other sources. Results: A total of 262 085 patients (mean [SD] age, 45.1 [20.7] years; 237 404 [90.6%] adults; 24 681 [9.4%] children; 149 349 [57.0%] women) in 79 primary care practices were included (87 257 in arm 1, 87 478 in arm 2, and 87 350 in arm 3). At the entire primary care population level, none of the interventions improved influenza vaccination rates. All groups had rates of approximately 47%. There was no statistical or clinically significant improvement following portal vs text, preappointment reminders vs no preappointment reminders (portal and text reminders combined), or responsive vs fixed monthly portal reminders. Conclusions and Relevance: At the population level, neither portal nor text reminders for influenza vaccination were effective. Given that vaccine hesitancy may be a major reason for the lack of impact of portal or text reminders, more intensive interventions by health systems are needed to raise influenza vaccination coverage levels. Trial Registration: ClinicalTrials.gov Identifier: NCT05525494.

Addressing Barriers to Chronic Obstructive Pulmonary Disease (COPD) Care: Three Innovative Evidence-Based Approaches: A Review.

Chronic obstructive pulmonary disease (COPD) is a preventable yet widespread and profoundly debilitating respiratory condition, exerting substantial personal and global health ramifications alongside significant economic implications. The first objective of this literature review was to identify reviews the barriers to optimal COPD care, categorizing them into personal patient factors, professional awareness and knowledge, patient-professional relationships, and healthcare service models, including access to care that significantly impacts the quality of COPD management. The second objective was to introduce three approaches for enhancing COPD care outcomes: Self-Management Educational Programs, Health Qigong, and Telehealth service provision, each demonstrating positive effects on COPD patients' health status. These evidence-based interventions offer promising avenues for enhancing COPD care and patient outcomes. Integrating these approaches into comprehensive COPD management strategies holds potential for improving the well-being and quality of life of individuals living with this chronic condition.

N-Containing Na2 VTi(PO4 )3 /C for Aqueous Sodium-Ion Batteries.

Phosphates featuring a 3D framework offer a promising alternative to aqueous sodium-ion batteries, known for their safety, cost-effectiveness, scalability, high power density, and tolerance to mishandling. Nevertheless, they often suffer from poor reversible capacity stemming from limited redox couples. Herein, N-containing Na2 VTi(PO4 )3 is synthesized for aqueous sodium-ion storage through multi-electron redox reactions. It demonstrates a capacity of 155.2 mAh g-1 at 1 A g-1 (≈ 5.3 C) and delivers an ultrahigh specific energy of 55.9 Wh kg-1 in a symmetric aqueous sodium-ion battery. The results from in situ X-ray diffraction analysis, ex situ X-ray photoelectron spectroscopy analysis, and first-principle calculations provide insights into the local chemical environment of sodium ions, the mechanisms underlying capacity decay during cycling, and the dynamics of ion and electron transfer at various states of charge. This understanding will contribute to the advancement of electrode materials for aqueous sodium-ion batteries.

Extent of Surgery for Medullary Thyroid Cancer and Prevalence of Occult Contralateral Foci.

Importance: Standard treatment for patients with medullary thyroid cancer (MTC) consists of total thyroidectomy with central neck dissection, but the rationale for bilateral surgery in patients with unilateral disease on ultrasonography remains unclear. Objective: To determine the presence of occult contralateral disease (lesions not seen on preoperative ultrasonography) in patients with MTC as a rationale for total thyroidectomy. Design, Setting, and Participants: This multi-institutional, retrospective cohort study was conducted from September 1998 to April 2022 in academic medical centers and included patients with MTC who underwent thyroidectomy with preoperative imaging. Main Outcomes and Measures: The primary end point was the prevalence of sonographically occult foci of MTC in the contralateral lobe among patients with sporadic MTC. Results: The cohort comprised 176 patients with a median age at diagnosis of 55 years (range, 2-87 years), 69 (57.6%) of whom were female. Genetic testing was performed in 109 patients (61.9%), 48 (27.5%) of whom carried germline RET variants. Initial surgical management consisted of total thyroidectomy (161 [91.0%]), lobectomy followed by completion thyroidectomy (7 [4.0%]), and lobectomy alone (8 [4.5%]). Central and lateral neck dissections were performed as part of initial therapy for 146 patients (83.1%). In the entire cohort of 176 patients, 46 (26.0%) had contralateral foci disease and 9 (5.1%) had occult contralateral foci that were not identified on preoperative ultrasonography. Among 109 patients who underwent genetic testing, 38 (34.9%) had contralateral disease, 8 (7.3%) of whom had occult contralateral disease not seen on preoperative ultrasonography. Patients with sporadic MTC experienced a 95.7% reduction in the odds of having a focus of MTC in the contralateral lobe compared with patients with a germline RET variant (odds ratio, 0.043; 95% CI, 0.013-0.123). When adjusting for age, sex, tumor size, and lymph node involvement, the odds ratio of having contralateral MTC in patients with sporadic disease was 0.034 (95% CI, 0.007-0.116). Among patients who underwent lobectomy alone with postoperative calcitonin levels, 5 of 12 (41.7%) achieved undetectable calcitonin levels (<2.0 pg/mL; to convert to pmol/L, multiply by 0.292). Conclusions and Relevance: The results of this cohort study suggest that a staged approach involving initial thyroid lobectomy could be considered in patients with sporadic MTC and no contralateral ultrasonography findings, with no further surgery if calcitonin levels became undetectable. Further work using prospective randomized clinical trials to evaluate lobectomy as a biochemical cure in patients presenting with unilateral disease is warranted.

Post-translational Modification of PD-1: Potential Targets for Cancer Immunotherapy.

Activation of effector T cells leads to upregulation of PD-1, which can inhibit T-cell activity following engagement with its ligand PD-L1. Post-translational modifications (PTM), including glycosylation, phosphorylation, ubiquitination, and palmitoylation, play a significant role in regulating PD-1 protein stability, localization, and interprotein interactions. Targeting PTM of PD-1 in T cells has emerged as a potential strategy to overcome PD-1-mediated immunosuppression in cancer and enhances antitumor immunity. The regulatory signaling pathways that induce PTM of PD-1 can be suppressed with small-molecule inhibitors, and mAbs can directly target PD-1 PTMs. Preliminary outcomes from exploratory studies suggest that focusing on the PTM of PD-1 has strong therapeutic potential and can enhance the response to anti-PD-1.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Hepatitis B virus clinical and virologic characteristics in an HIV perinatal transmission study in sub-Saharan Africa.

OBJECTIVES: To describe the clinical and virologic characteristics of HIV-HBV coinfection, including the predictors of high maternal HBV viral load in pregnant women with HIV in sub-Saharan Africa (SSA). METHODS: HPTN 046 was a HIV perinatal transmission clinical trial evaluating infant nevirapine vs. placebo. Women-infant pairs ( n  = 2016) were enrolled in SSA from 2007 to 2010; 1579 (78%) received antiretrovirals (ARV). Maternal delivery samples were retrospectively tested for hepatitis B surface antigen (HBsAg), and if positive, were tested for hepatitis B e antigen (HBeAg) and HBV viral load (VL). High HBV VL was defined as ≥10 6  IU/ml. RESULTS: Overall, 4.4% (88/2016) had HBV co-infection, with geographic variability ranging from 2.4% to 8.7% ( P  < 0.0001); 25% (22/88) were HBeAg positive with prevalence in countries ranging from 10.5% to 39%. Fifty-two percentage (40/77) of those with HBV received ARV, the majority (97%) received 3TC as the only HBV active agent. HBeAg positivity was associated with high maternal HBV VL, odds ratio (OR) 37.0, 95% confidence interval (CI) 5.4-252.4. Of those with high HBV VL, 40% (4/10) were receiving HBV active drugs (HBV-ARV). HBV drug resistance occurred in 7.5% (3/40) receiving HBV-ARV. CONCLUSIONS: In SSA, HBV co-infection is common in pregnant women with HIV. HBsAg and HBeAg prevalence vary widely by country in this clinical trial cohort. HBeAg is a surrogate for high HBV viral load. HBV drug resistance occurred in 7.5% receiving HBV-ARV with lamivudine as the only HBV active agent. These findings reinforce the importance of HBsAg screening and early treatment with two active agents for HBV.

Cost-effectiveness of goal-directed and outcome-based financial incentives for weight loss in low-income populations: the FIReWoRk randomized clinical trial.

BACKGROUND: The Financial Incentives for Weight Reduction (FIReWoRk) clinical trial showed that financial incentive weight-loss strategies designed using behavioral economics were more effective than provision of weight-management resources only. We now evaluate cost-effectiveness. METHODS: Cost-effectiveness analysis of a multisite randomized trial enrolling 668 participants with obesity living in low-income neighborhoods. Participants were randomized to (1) goal-directed incentives (targeting behavioral goals), (2) outcome-based incentives (targeting weight-loss), and (3) resources only, which were provided to all participants and included a 1-year commercial weight-loss program membership, wearable activity monitor, food journal, and digital scale. We assessed program costs, time costs, quality of life, weight, and incremental cost-effectiveness in dollars-per-kilogram lost. RESULTS: Mean program costs at 12 months, based on weight loss program attendance, physical activity participation, food diary use, self-monitoring of weight, and incentive payments was $1271 in the goal-directed group, $1194 in the outcome-based group, and $834 in the resources-only group (difference, $437 [95% CI, 398 to 462] and $360 [95% CI, 341-363] for goal-directed or outcome-based vs resources-only, respectively; difference, $77 [95% CI, 58-130] for goal-directed vs outcome-based group). Quality of life did not differ significantly between the groups, but weight loss was substantially greater in the incentive groups (difference, 2.34 kg [95% CI, 0.53-4.14] and 1.79 kg [95% CI, -0.14 to 3.72] for goal-directed or outcome-based vs resources only, respectively; difference, 0.54 kg [95% CI, -1.29 to 2.38] for goal-directed vs outcome-based). Cost-effectiveness of incentive strategies based on program costs was $189/kg lost in the goal-directed group (95% CI, $124/kg to $383/kg) and $186/kg lost in the outcome-based group (95% CI, $113/kg to $530/kg). CONCLUSIONS: Goal-directed and outcome-based financial incentives were cost-effective strategies for helping low-income individuals with obesity lose weight. Their incremental cost per kilogram lost were comparable to other weight loss interventions.

Rural-Urban Disparities in the Continuum of Thyroid Cancer Care: Analysis of 92,794 Cases.

Objective: Rurality is associated with higher incidence and higher disease-specific mortality for most cancers. Outcomes for rural and ultrarural ("frontier") patients with thyroid cancer are poorly understood. This study aimed to identify actionable deficits in thyroid cancer outcomes for rural patients. Methods: We queried linked California Cancer Registry and California Office of Statewide Health Planning and Development databases for patients diagnosed with thyroid cancer (1999-2017). We analyzed time from disease stage at diagnosis, time from diagnosis to surgery, receipt of appropriate radioactive iodine ablation, surveillance status, and overall and disease-specific mortality for urban, rural, and frontier patients. Cox and logistic regression models controlled for clinical and demographic covariates a stepwise manner. All incidence figures are expressed as a proportion of newly diagnosed cases. Results: Our cohort comprised 92,794 subjects: (65,475 women [70.6%]; mean age 50.0 years). Compared to urban patients, rural and frontier patients were more likely to be American Indian, White, uninsured, and from lower quintiles of socioeconomic status (p < 0.01). Distant disease at diagnosis was more common in rural (56.0 vs. 50.4 cases per 1000 new cases, p < 0.01) and frontier patients (80.9 vs. 50.4 per 1000, p < 0.01) compared to urban patients. The incidence of medullary thyroid cancer was greater in rural patients (17.9 vs. 13.6 cases per 1000, p < 0.01) and frontier patients (31.0 vs. 13.6 per 1000, p < 0.01) compared to urban patients. The incidence of anaplastic thyroid cancer was higher in frontier versus urban patients (15.5 vs. 7.1 per 1000, p < 0.01). When compared to urban patients, rural and frontier patients were more often lost to follow-up (odds ratio [OR] 1.69 [confidence interval, CI 1.54-1.85], and OR 3.03 [CI 1.89-5.26], respectively) and had higher disease-specific mortality (OR 1.18 [CI 1.07-1.30], and OR 1.92 [CI 1.22-2.77], respectively). Rural and frontier residence was independently associated with being lost to follow-up, suggesting that it is a key driver of disparities. Conclusion: Compared to their urban counterparts, rural and frontier patients with thyroid cancer present with later-stage disease and experience higher disease-specific mortality. They also are more often lost to follow-up, which presents an opportunity for targeted outreach to reduce the observed disparities in outcomes.

Diagnostic performance of molecular testing in indeterminate (Bethesda III and IV) thyroid nodules with Hürthle cell cytology.

BACKGROUND: Indeterminate thyroid nodules with Hürthle cell cytology remain a diagnostic challenge. The low benign call rate and positive predictive value of first-generation molecular tests precluded their use to rule out malignancy. We examined the diagnostic performance of current tests. METHOD: This subset analysis of our prospective randomized trial compared the benign call rate and positive predictive value of Afirma Gene Sequencing Classifier and Thyroseq v3 in Bethesda III and IV nodules with Hürthle cell cytology. Molecular test samples were obtained at initial fine-needle aspiration (8/2017-7/2022) and reflexively sent for processing. RESULTS: Molecular testing was performed on 140 Hürthle cell nodules. Of 79 nodules tested with the Afirma Gene Sequencing Classifier, the benign call rate was 84% (66/79). Nine of 66 nodules with benign results were resected, with no malignancies. Twelve of 13 nodules with suspicious results were resected, revealing 3 malignancies-2 papillary thyroid carcinomas and one Hürthle cell carcinoma (positive predictive value 25%). Of 61 nodules tested with Thyroseq v3, the benign call rate was 56% (34/61; (P < .01 versus Afirma Gene Sequencing Classifier). Five of 34 nodules with negative results were resected, with no malignancies. Nineteen of 27 nodules with positive results were resected, revealing 3 malignancies-2 papillary thyroid carcinomas and 1 Hürthle cell carcinoma (positive predictive value 16%). CONCLUSION: The high benign call rate of current molecular tests in Hürthle cell nodules strengthens their value in enabling patients to avoid surgery.

Developing an electronic health record measure of low-value esophagogastroduodenoscopy for GERD at a large academic health system.

OBJECTIVES: Low-value esophagogastroduodenoscopies (EGDs) for uncomplicated gastro-oesophageal reflux disease (GERD) can harm patients and raise patient and payer costs. We developed an electronic health record (EHR) 'eMeasure' to detect low-value EGDs. DESIGN: Retrospective cohort of 518 adult patients diagnosed with GERD who underwent initial EGD between 1 January 2019 and 31 December 2019. SETTING: Outpatient primary care and gastroenterology clinics at a large, urban, academic health centre. PARTICIPANTS: Adult primary care patients at the University of California Los Angeles who underwent initial EGD for GERD in 2019. MAIN OUTCOME MEASURES: EGD appropriateness criteria were based on the American College of Gastroenterology 2012 guidelines. An initial EGD was considered low-value if it lacked a documented guideline-based indication, including alarm symptoms (eg, iron-deficiency anaemia); failure of an 8-week proton pump inhibitor trial or elevated Barrett's oesophagus risk. We performed manual chart review on a random sample of 204 patients as a gold standard of the eMeasure's validity. We estimated EGD costs using Medicare physician and facility fee rates. RESULTS: Among 518 initial EGDs performed (mean age 53 years; 54% female), the eMeasure identified 81 (16%) as low-value. The eMeasure's sensitivity was 42% (95% CI 22 to 61) and specificity was 93% (95% CI 89 to 96). Stratifying across clinics, 62 (74.6%) low-value EGDs originated from 2 (12.5%) out of 16 clinics. Total cost for 81 low-value EGDs was approximately US$75 573, including US$14 985 in patients' out-of-pocket costs. CONCLUSIONS: We developed a highly specific eMeasure that showed that low-value EGDs occurred frequently in our healthcare system and were concentrated in a minority of clinics. These results can inform future QI efforts at our institution, such as best practice alerts for the ordering physician. Moreover, this open-source eMeasure has a much broader potential impact, as it can be integrated into any EHR and improve medical decision-making at the point of care.

GMI, a Ganoderma microsporum protein, abolishes focal adhesion network to reduce cell migration and metastasis of lung cancer.

BACKGROUND: Cancer metastasis is a major cause of cancer-related deaths, emphasizing the urgent need for effective therapies. Although it has been shown that GMI, a fungal protein from Ganoderma microsporum, could suppress primary tumor growth in a wide spectrum of cancer types, it is still unclear whether GMI exhibits anti-metastasis properties, particularly in lung cancers. Further investigation is needed. AIMS AND OBJECTIVES: The objective of this study is to investigate the potential inhibitory effects of GMI on lung cancer metastasis in vivo. Utilizing systematic and comprehensive approaches, our research aims to elucidate the underlying molecular mechanisms responsible for the anti-metastatic effects. MATERIALS AND METHODS: In vitro migration and cell adhesion assays addressed the epithelial-to-mesenchymal transition (EMT)-related phenotype. Proteomic and bioinformatic analyses identified the GMI-regulated proteins and cellular responses. GMI-treated LLC1-bearing mice were analyzed using IVIS Spectrum to assess the anti-metastatic effect. KEY FINDINGS: GMI inhibits EMT as well as cell migration. GMI disrupts cell adhesion and downregulates integrin, resulting in inhibition of phosphorylated FAK. GMI induces macropinocytosis and lysosome-mediated degradation of integrin αv, α5, α6 and ß1. GMI downregulates Slug via inhibition of FAK activity, which in turn enhances expressions of epithelial-related markers and decreases cell mobility. Mechanistically, GMI-induced FAK inhibition engenders MDM2 expression and enhances MDM2/p21/Slug complex formation, leading to Slug degradation. GMI treatment reduces the metastatic pulmonary lesion and prolongs the survival of LLC1-bearing mice. SIGNIFICANCE: Our findings highlight GMI as a promising therapeutic candidate for metastatic lung cancers, offering potential avenues for further research and drug development.

Influence of depression on racial and ethnic disparities in diabetes control.

INTRODUCTION: We tested the hypotheses that depression diagnoses influence racial and ethnic disparities in diabetes control and that mental health treatment moderates that relationship. RESEARCH DESIGN AND METHODS: We created a national cohort of Veterans Health Administration (VHA) patients with diabetes using administrative data (n=815 067). Cross-sectional linear mixed effects regression models tested the hypothesized indirect effect of depression on poor diabetes control (glycosylated hemoglobin >9%) and tested whether mental health treatment (visits or antidepressant prescriptions) moderated the effect of depression (α=0.05). Results represent the percentage point difference in probability of poor diabetes control. Covariates included primary care visits, sex, age, and VHA facility. RESULTS: Overall, 20% of the cohort had poor diabetes control and 22% had depression. Depression was more common among racial and ethnic minoritized groups. The probability of poor diabetes control was higher for most minoritized groups compared with White patients (largest difference: American Indian or Alaska Native patients, 5.2% (95% CI 4.3%, 6.0%)). The absolute value of the proportion of racial and ethnic disparities accounted for by depression ranged from 0.2% (for Hispanic patients) to 2.0% (for Asian patients), with similar effects when accounting for the moderating effect of mental health treatment. Patients with depression and 5+ mental health visits had a lower probability of poor diabetes control compared with those with fewer visits, regardless of antidepressant prescription status. CONCLUSIONS: The influence of depression on disparities in diabetes control was small. High rates of depression among people with diabetes, especially among those from racial and ethnic minoritized groups, highlight a need to ensure equitable and coordinated care for both conditions, as the effects of mental health treatment may extend to the control of physical health conditions.

Goal-directed versus outcome-based financial incentives for smoking cessation among low-income, hospitalised patients: rationale and design of the Financial Incentives for Smoking Treatment II (FIESTA II) randomised controlled trial.

INTRODUCTION: Smoking remains the leading preventable cause of death in the USA. Low utilisation of treatments for smoking cessation remains a major barrier for reducing smoking rates. Financial incentives represent an innovative approach to increasing use of therapies for smoking cessation. This paper will describe the rationale and design of the Financial Incentives for Smoking Treatment II (FIESTA II) study, a randomised controlled trial to evaluate the effectiveness and feasibility of goal-directed and outcome-based financial incentives to promote smoking cessation among hospitalised smokers. METHODS AND ANALYSIS: We are recruiting adult participants who smoked tobacco in the 30 days prior to initial interview and are contemplating quitting smoking. These participants will come from two hospitals in underserved communities in New York City and Los Angeles. They will be randomised into one of three arms. The first arm consists of goal-directed financial incentives plus enhanced usual care, which includes hospital-directed information about quitting smoking, nicotine replacement therapy and referral to a Quitline. The second arm involves outcome-based financial incentives plus enhanced usual care. The third arm consists of enhanced usual care alone. Multiple phone interviews with the participants will be completed after randomisation to assess smoking cessation. Participants will earn $20 for each follow-up interview completed and $30 for each smoking cessation test completed. Those who are randomised to the financial incentive groups can earn an additional $700. The participants in the outcome-based group will receive payments solely for exhibiting cessation, whereas the participants in the goal-based group are also eligible for receiving payments after meeting milestones such as speaking with a helpline coach. ETHICS: Human research protection committees at New York University School of Medicine and the University of California Los Angeles (UCLA) David Geffen School of Medicine granted ethics approval.Protocol number: IRB#19-000 084. TRIAL REGISTRATION NUMBER: NCT03979885.

Pharmacist-Led Diabetes Control Intervention and Health Outcomes in Hispanic Patients With Diabetes.

Importance: Among patients with type 2 diabetes (T2D), Hispanic individuals are more likely than non-Hispanic White individuals to develop diabetes-related complications. Objective: To examine the association of a pharmacist-led intervention (UCMyRx) with hemoglobin A1c (HbA1c) and systolic blood pressure (SBP) among Hispanic patients with T2D. Design, Setting, and Participants: This quality improvement study used electronic health record data and a difference-in-differences study design to evaluate the association of UCMyRx exposure with changes in HbA1c concentration and SBP among Hispanic patients with T2D, relative to usual care, at University of California, Los Angeles primary care clinics between February and April of 2023. The study population included patients with an International Classification of Diseases, Ninth Revision/International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis of T2D, self-reporting Hispanic ethnicity, age 18 years or older, with 1 or more visits with a UCMyRx pharmacist (treatment) or 2 or more visits, 2 or more years apart, during the study window (comparison). Additionally, patients had to have the following observations during the study window (March 2, 2013-December 31, 2018): (1) a HbA1c 8% or higher, anywhere between 365 days before and 14 days after the index date (date of the first UCMyRx visit or a randomly generated index date) and a follow-up HbA1c measure within 120 to 365 days after the index date (n = 396) and/or (2) a SBP 140 mm Hg or higher between 365 days before and 14 days after the index date, and a follow-up SBP measure within 120 to 450 days after the index date (n = 795). Exposure: Pharmacists review laboratory results/vital signs, perform medication reconciliation, and develop personally tailored interventions to address adherence barriers and increase guideline-concordant care. Main Outcomes and Measures: Pre- to post-index date changes in HbA1c and SBP. Results: Of the 931 unique patients with T2D analyzed, the mean (SD) age was 64 (14.1) years, and 552 (59.3%) were female. In adjusted analyses, having 1 or more UCMyRx visits was associated with a reduction in HbA1c concentration (ß = -0.46%; 95% CI, -0.84% to -0.07%) but no change in SBP (ß = -1.71 mm Hg; 95% CI, -4.00 to 0.58 mm Hg). Conclusions and Relevance: In this quality improvement study of UCMyRx among Hispanic patients with T2D, a negative association was observed between UCMyRx exposure and HbA1c concentration but not SBP. Pharmacist-led intervention may be a strategy for improving outcomes among Hispanic patients with T2D.

The Effectiveness of Shared Decision-making for Diabetes Prevention: 24- and 36-Month Results From the Prediabetes Informed Decision and Education (PRIDE) Trial.

OBJECTIVE: We conducted a cluster-randomized, shared decision-making (SDM) trial offering lifestyle change, metformin, or both options, to adults at risk for diabetes in a primary care network (n = 20 practices). RESEARCH DESIGN AND METHODS: We used propensity score matching to identify control patients and used electronic health record data to compare weight loss at 24 and 36 months of follow-up and diabetes incidence at 36 months of follow-up. RESULTS: In adjusted post hoc analyses, SDM participants (n = 489) maintained modestly greater 24-month weight loss of -3.1 lb and 36-month weight loss of -2.7 lb versus controls (n = 1,430, both comparisons P < 0.001). SDM participants who chose both lifestyle change and metformin sustained weight loss at 36 months of -4.1 lb (P < 0.001 vs. controls). We found no differences in incident diabetes (15% of SDM participants, 14% of control participants; P = 0.64). CONCLUSIONS: This is one of the first studies to demonstrate weight loss maintenance up to 36 months after diabetes prevention SDM.

DoSurvive: A webtool for investigating the prognostic power of a single or combined cancer biomarker.

We present DoSurvive, a user-friendly survival analysis web tool and a cancer prognostic biomarker centered database. DoSurvive is the first database that allows users to perform multivariant survival analysis for cancers with customized gene/patient list. DoSurvive offers three survival analysis methods, Log rank test, Cox regression and accelerated failure time model (AFT), for users to analyze five types of quantitative features (mRNA, miRNA, lncRNA, protein and methylation of CpG islands) with four survival types, i.e. overall survival, disease-specific survival, disease-free interval, and progression-free interval, in 33 cancer types. Notably, the implemented AFT model provides an alternative method for genes/features which failed the proportional hazard assumption in Cox regression. With the unprecedented number of survival models implemented and high flexibility in analysis, DoSurvive is a unique platform for the identification of clinically relevant targets for cancer researcher and practitioners. DoSurvive is freely available at http://dosurvive.lab.nycu.edu.tw/.