Mapping the Dynamic Complexity of Sexual and Gender Minority Healthcare Disparities: A Systems Thinking Approach.

Sexual and gender minority (SGM) populations experience extensive health disparities compared to their straight and cisgender counterparts. The importance of addressing these disparities is paramount, as SGM groups often encounter significant barriers to accessing comprehensive healthcare, including societal stigma, provider bias, and financial constraints. This study utilizes a community-based system dynamics approach to understand and visualize the barriers to and facilitators of healthcare engagement for SGM groups across their life course. It aims to identify core constructs, relationships, and dynamic feedback mechanisms related to the experiences of connection/disconnection with physical, mental, and dental healthcare of SGM individuals. Barriers to access, such as discriminatory practices and the limited availability of SGM-informed healthcare professionals, exacerbate these disparities, underscoring the urgency of developing targeted interventions. System dynamics, a complex systems science (CSS) methodology, was used for this research. Group model building sessions were conducted with diverse SGM groups, including youth, older adults, and trans and gender-expansive community members. Causal loop diagrams were developed according to an iterative process, and a meta-model of their collective experiences was created. The study revealed extensive, dynamic, and shifting structural barriers for SGM community members accessing healthcare. Societal and structural stigma, provider bias, and pathologization were identified as significant barriers throughout their life course. Community-led interventions and SGM-focused holistic healthcare were identified as critical facilitators of SGM healthcare connection. The findings highlight the need for SGM-affirming and culturally responsive healthcare settings. This paper calls for a concerted effort from SGM health researchers to use CSS in developing interventions to reduce SGM health disparities.

Designing a Situational Judgment Test for Use in Medical School Admissions.

ABSTRACT: It has long been acknowledged that professional competencies are required for success in medical school, residency training, and medical practice. Over the last decade, medical schools have begun to introduce standardized assessments of professional competencies, but many still rely on interviews to assess these competencies, which occur after about half of the applicant pool has already been screened out. In this article, the authors discuss the development, evaluation, and launch of the Association of American Medical Colleges (AAMC) situational judgment test (SJT) for use in medical school admissions. The AAMC SJT is designed to assess an examinee's understanding of effective and ineffective behaviors related to the core competencies for entering medical students, including service orientation, social skills, cultural competence, teamwork, ethical responsibility to self and others, reliability and dependability, resilience and adaptability, and capacity for improvement. The authors evaluate the evidence for the need for SJTs in medical school admissions by exploring common derailers in medical school, gaps in the admissions process regarding information about professional competencies, and the challenge of conducting holistic review in a high-volume context. They summarize existing research from the employment, international medical education, and residency selection contexts suggesting that SJT scores are positively associated with subsequent performance and may add value to the admissions process. The authors discuss 5 goals that were the foundation for developing the AAMC SJT: (1) assess the professional competencies needed for success in medical school using a proven method, (2) enable holistic review in a high-volume admissions context, (3) create and share a program of research to support the appropriate use of SJT scores, (4) signal the need for preparation in professionalism to learners, and (5) balance the need for a new assessment with minimizing the burden and risk for applicants.

Fluorescence-guided photoimmunotherapy using targeted nanotechnology and ML7710 to manage peritoneal carcinomatosis.

Fluorescence-guided intervention can bolster standard therapies by detecting and treating microscopic tumors before lethal recurrence. Tremendous progress in photoimmunotherapy and nanotechnology has been made to treat metastasis. However, many are lost in translation due to heterogeneous treatment effects. Here, we integrate three technological advances in targeted photo-activable multi-agent liposome (TPMAL), fluorescence-guided intervention, and laser endoscopy (ML7710) to improve photoimmunotherapy. TPMAL consists of a nanoliposome chemotherapy labeled with fluorophores for tracking and photosensitizer immunoconjugates for photoimmunotherapy. ML7710 is connected to Modulight Cloud to capture and analyze multispectral emission from TPMAL for fluorescence-guided drug delivery (FGDD) and fluorescence-guided light dosimetry (FGLD) in peritoneal carcinomatosis mouse models. FGDD revealed that TPMAL enhances drug delivery to metastases by 14-fold. ML7710 captured interpatient variability in TPMAL uptake and prompted FGLD in >50% of animals. By combining TPMAL, ML7710, and fluorescence-guided intervention, variation in treatment response was substantially reduced and tumor control improved without side effects.

Efficacy of a music-based intervention in a preclinical model of traumatic brain injury: An initial foray into a novel and non-pharmacological rehabilitative therapy.

Traumatic brain injury (TBI) causes neurobehavioral and cognitive impairments that negatively impact life quality for millions of individuals. Because of its pernicious effects, numerous pharmacological interventions have been evaluated to attenuate the TBI-induced deficits or to reinstate function. While many such pharmacotherapies have conferred benefits in the laboratory, successful translation to the clinic has yet to be achieved. Given the individual, medical, and societal burden of TBI, there is an urgent need for alternative approaches to attenuate TBI sequelae and promote recovery. Music based interventions (MBIs) may hold untapped potential for improving neurobehavioral and cognitive recovery after TBI as data in normal, non-TBI, rats show plasticity and augmented cognition. Hence, the aim of this study was to test the hypothesis that providing a MBI to adult rats after TBI would improve cognition, neurobehavior, and histological endpoints. Adult male rats received a moderate-to-severe controlled cortical impact injury (2.8 mm impact at 4 m/s) or sham surgery (n = 10-12 per group) and 24 h later were randomized to classical Music or No Music (i.e., ambient room noise) for 3 h/day from 19:00 to 22:00 h for 30 days (last day of behavior). Motor (beam-walk), cognitive (acquisition of spatial learning and memory), anxiety-like behavior (open field), coping (shock probe defensive burying), as well as histopathology (lesion volume), neuroplasticity (BDNF), and neuroinflammation (Iba1, and CD163) were assessed. The data showed that the MBI improved motor, cognitive, and anxiety-like behavior vs. No Music (p's < 0.05). Music also reduced cortical lesion volume and activated microglia but increased resting microglia and hippocampal BDNF expression. These findings support the hypothesis and provide a compelling impetus for additional preclinical studies utilizing MBIs as a potential efficacious rehabilitative therapy for TBI.

Study protocol for the Mindful Moms Study: A randomized controlled trial evaluating a mindful movement intervention for marginalized pregnant people experiencing depression.

More than 1 in 5 pregnant people in the United States experience depressive symptoms. Although treatments exist, many people remain under- or un-treated due to concerns about stigma, side effects, and costs of medications or psychotherapy, particularly those who are marginalized (defined as those who are minoritized, low-income, or with low-educational attainment). Further, the standard depression treatments do not address social connectedness, which is a potentially modifiable factor involved in depressive symptom etiology. This protocol presents the rationale, design, and status of the two-arm longitudinal parallel group randomized controlled trial - the Mindful Moms Study - which aims to evaluate the effects and mechanisms of a group-based mindful physical activity (yoga) intervention in marginalized pregnant people with depressive symptoms (n = 200) compared to a prenatal education control group. The primary aim is to evaluate effects of group assignment on depressive symptom severity, anxiety, and perceived stress over time from baseline to six weeks postpartum. Secondary aims include understanding the role of social connectedness as a moderator of the effects and to identify genome-wide DNA methylation patterns associated with depressive symptoms and perceived social connectedness at postpartum. A focus on adequate symptom management through non-pharmacologic, accessible therapies that address social connectedness during pregnancy in marginalized women is an urgent clinical and research priority. The successful completion of this study will provide important insights into social connectedness as a mechanism to decrease depressive symptoms in a largely understudied population. Trial registration: NCT04886856.

Regulation of Expression of Extracellular Matrix Proteins by Differential Target Multiplexed Spinal Cord Stimulation (SCS) and Traditional Low-Rate SCS in a Rat Nerve Injury Model.

There is limited research on the association between the extracellular matrix (ECM) and chronic neuropathic pain. The objective of this study was twofold. Firstly, we aimed to assess changes in expression levels and the phosphorylation of ECM-related proteins due to the spared nerve injury (SNI) model of neuropathic pain. Secondly, two modalities of spinal cord stimulation (SCS) were compared for their ability to reverse the changes induced by the pain model back toward normal, non-injury levels. We identified 186 proteins as ECM-related and as having significant changes in protein expression among at least one of the four experimental groups. Of the two SCS treatments, the differential target multiplexed programming (DTMP) approach reversed expression levels of 83% of proteins affected by the pain model back to levels seen in uninjured animals, whereas a low-rate (LR-SCS) approach reversed 67%. There were 93 ECM-related proteins identified in the phosphoproteomic dataset, having a combined 883 phosphorylated isoforms. DTMP back-regulated 76% of phosphoproteins affected by the pain model back toward levels found in uninjured animals, whereas LR-SCS back-regulated 58%. This study expands our knowledge of ECM-related proteins responding to a neuropathic pain model as well as providing a better perspective on the mechanism of action of SCS therapy.

Comparison of short-term outcomes and survival between minimally invasive colectomy and open colectomy in patients 80 years of age and older.

We investigated the short- and long-term outcomes of patients 80 years of age and older with colon cancer who underwent robotic colectomy versus laparoscopic colectomy. Data for patients treated at a comprehensive cancer center between January 2006 and November 2018 were collected retrospectively. Outcomes from minimally invasive laparoscopic or robotic colectomy were compared. Survival was analyzed by the Kaplan-Meier method with significance evaluated by the log-rank test. The laparoscopic (n = 104) and the robotic (n = 75) colectomy groups did not differ across baseline characteristics. Patients who underwent a robotic colectomy had a shorter median length of hospital stay (5 versus 6 days; p < 0.001) and underwent fewer conversions to open surgery (3% versus 17%; p = 0.002) compared to the laparoscopic cohort. The groups did not differ in postoperative complication rates, overall survival or disease-free survival. Elderly patients undergoing robotic colectomy for colon cancer have a shorter hospital stay and lower rates of conversion without compromise to oncologic outcomes.

Management of Recurrent Well-Differentiated Thyroid Carcinoma in the Neck: A Comprehensive Review.

Surgery has been historically the preferred primary treatment for patients with well-differentiated thyroid carcinoma and for selected locoregional recurrences. Adjuvant therapy with radioactive iodine is typically recommended for patients with an intermediate to high risk of recurrence. Despite these treatments, locally advanced disease and locoregional relapses are not infrequent. These patients have a prolonged overall survival that may result in long periods of active disease and the possibility of requiring subsequent treatments. Recently, many new options have emerged as salvage therapies. This review offers a comprehensive discussion and considerations regarding surgery, active surveillance, radioactive iodine therapy, ultrasonography-guided percutaneous ablation, external beam radiotherapy, and systemic therapy for well-differentiated thyroid cancer based on relevant publications and current reference guidelines. We feel that the surgical member of the thyroid cancer management team is empowered by being aware and facile with all management options.

Odor imagery but not perception drives risk for food cue reactivity and increased adiposity.

Mental imagery has been proposed to play a critical role in the amplification of cravings. Here we tested whether olfactory imagery drives food cue reactivity strength to promote adiposity in 45 healthy individuals. We measured odor perception, odor imagery ability, and food cue reactivity using self-report, perceptual testing, and neuroimaging. Adiposity was assessed at baseline and one year later. Brain responses to real and imagined odors were analyzed with univariate and multivariate decoding methods to identify pattern-based olfactory codes. We found that the accuracy of decoding imagined, but not real, odor quality correlated with a perceptual measure of odor imagery ability and with greater adiposity changes. This latter relationship was mediated by cue-potentiated craving and intake. Collectively, these findings establish odor imagery ability as a risk factor for weight gain and more specifically as a mechanism by which exposure to food cues promotes craving and overeating.

High-efficiency novel extraction process of target polyphenols using enzymes in hydroalcoholic media.

Agro-industrial by-products are a sustainable source of natural additives that can replace the synthetic ones in the food industry. Grape pomace is an abundant by-product that contains about 70% of the grape's polyphenols. Polyphenols are natural antioxidants with multiple health-promoting properties. They are secondary plant metabolites with a wide range of solubilities. Here, a novel extraction process of these compounds was developed using enzymes that specifically liberates target polyphenols in the appropriate hydroalcoholic mixture. Tannase, cellulase, and pectinase retained 22, 60, and 52% of their activity, respectively, in ethanol 30% v/v. Therefore, extractions were tested in ethanol concentrations between 0 and 30% v/v. Some of these enzymes presented synergistic effects in the extraction of specific polyphenols. Maximum yield of gallic acid was obtained using tannase and pectinase enzymes in ethanol 10% v/v (49.56 ± 0.01 mg L-1 h-1); in the case of p-coumaric acid, by cellulase and pectinase treatment in ethanol 30% v/v (7.72 ± 0.26 mg L-1 h-1), and in the case of trans-resveratrol, by pectinase treatment in ethanol 30% v/v (0.98 ± 0.04 mg L-1 h-1). Also, the effect of enzymes and solvent polarity was analysed for the extraction of malvidin-3-O-glucoside, syringic acid, and quercetin. Previous studies were mainly focused on the maximization of total polyphenols extraction yields, being the polyphenolic profile the consequence but not the driving force of the optimization. In the present study, the basis of a platform for a precise extraction of the desire polyphenols is provided. KEY POINTS: • Enzymes can be used up to ethanol 30% v/v. • The specific enzymes' action determines the polyphenolic profile of the extracts. • The yields obtained of target polyphenols are competitive.

Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma.

PURPOSE: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma. PATIENTS AND METHODS: Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS). RESULTS: Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs. CONCLUSIONS: With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167.

Reflective Journaling as Preparation for Spiritual Care of Patients.

Death is a human experience; however, an understanding of dying, grief, and loss continues to elude many cultures, even more elusive is the understanding of complicated grief for families and burnout for providers caring for the dying patient and their families. To prepare students taking care of dying patients and their families, the Catalyzing Relationships at the End of Life program included addressing perceptions of one's own death through journal reflection. The Catalyzing Relationships at the End of Life program utilized journals to ascertain student understanding of issues surrounding family communication at the end of life. Journal reflections were embedded in an online learning management system and utilized structured prompts as the journaling method. These prompts addressed what students desire for their own family relationships during their own death. Results from the qualitative descriptive analysis included 4 themes: meaning, beliefs, connections, and good death. Reflections about their own death were a powerful experience for student participants. Although questions about spirituality were not specifically asked, themes relating to spirituality emerged from the data.

Antagonist Temperature Variation Affects the Photosynthetic Parameters and Secondary Metabolites of Ocimum basilicum L. and Salvia officinalis L.

Climate change is one of the main challenges for actual and future generations. Global warming affects plants and animals and is responsible for considerable crop loss. This study studied the influence of antagonist successive stresses, cold-heat and heat-cold, on two medicinal plants Ocimum basilicum L. and Salvia officinalis L. The photosynthetic parameters decreased for plants under the variation of subsequent stress. Net assimilation rates and stomatal conductance to water vapor are more affected in the case of plants under cold-heat consecutive stress than heat-cold successive stress. Emissions of volatile organic compounds have been enhanced for plants under successive stress when compared with control plants. Chlorophyll concentrations for plants under successive stress decreased for basil and sage plants. The total phenolic and flavonoid contents were not affected by the successive stresses when compared with the plants under only one type of treatment.

Phosphorylated Curdlan Gel/Polyvinyl Alcohol Electrospun Nanofibres Loaded with Clove Oil with Antibacterial Activity.

Fibrous membranes based on natural polymers obtained by the electrospinning technique are a great choice for wound dressings. In order to promote an efficient wound repair, and to avoid antibiotics, antibacterial plant extracts can be incorporated. In the present work, the new electrospun nanofibre membranes based on monobasic phosphate curdlan (PCurd) and polyvinyl alcohol (PVA) were obtained for the first time. To establish the adequate mixing ratio for electrospinning, the behaviour of the PCurd and PVA mixture was studied by viscometry and rheology. In order to confer antimicrobial activity with the nanofibre membrane, clove essential oil (CEO) was incorporated into the electrospun solution. Well-defined and drop-free nanofibres with a diameter between 157 nm and 110 nm were obtained. The presence of CEO in the obtained nanofibres was confirmed by ATR-FTIR spectroscopy, by the phenolic and flavonoid contents, and by the antioxidant activity of the membranes. In physiological conditions, CEO was released from the membrane after 24 h. The in vivo antimicrobial tests showed a good inhibitory activity against E. coli and higher activity against S. aureus. Furthermore, the viability cell test showed the lack of cytotoxicity of the nanofibre membrane with and without CEO, confirming its potential use in wound treatment.

Circulating CD8+ mucosal-associated invariant T cells correlate with improved treatment responses and overall survival in anti-PD-1-treated melanoma patients.

OBJECTIVES: While much of the research concerning factors associated with responses to immune checkpoint inhibitors (ICIs) has focussed on the contributions of conventional peptide-specific T cells, the role of unconventional T cells, such as mucosal-associated invariant T (MAIT) cells, in human melanoma remains largely unknown. MAIT cells are an abundant population of innate-like T cells expressing a semi-invariant T-cell receptor restricted to the MHC class I-like molecule, MR1, presenting vitamin B metabolites derived from bacteria. We sought to characterise MAIT cells in melanoma patients and determined their association with treatment responses and clinical outcomes. METHODS: In this prospective clinical study, we analysed the frequency and functional profile of circulating and tumor-infiltrating MAIT cells in human melanoma patients. Using flow cytometry, we compared these across metastatic sites and between ICI responders vs. non-responders as well as healthy donors. RESULTS: We identified tumor-infiltrating MAIT cells in melanomas across metastatic sites and found that the number of circulating MAIT cells is reduced in melanoma patients compared to healthy donors. However, circulating MAIT cell frequencies are restored by ICI treatment in responding patients, correlating with treatment responses, in which patients with high frequencies of MAIT cells exhibited significantly improved overall survival. CONCLUSION: Our results suggest that MAIT cells may be a potential predictive marker of responses to immunotherapies and provide rationale for testing MAIT cell-directed therapies in combination with current and next-generation ICIs.

Collagen and Vitamin C Supplementation Increases Lower Limb Rate of Force Development.

BACKGROUND: Exercise and vitamin C-enriched collagen supplementation increase collagen synthesis, potentially increasing matrix density, stiffness, and force transfer. PURPOSE: To determine whether vitamin C-enriched collagen (hydrolyzed collagen [HC] + C) supplementation improves rate of force development (RFD) alongside a strength training program. METHODS: Using a double-blinded parallel design, over 3 weeks, healthy male athletes (n = 50, 18-25 years) were randomly assigned to the intervention (HC + C; 20 g HC + 50 mg vitamin C) or placebo (20 g maltodextrin). Supplements were ingested daily 60 min prior to training. Athletes completed the same targeted maximal muscle power training program. Maximal isometric squats, countermovement jumps, and squat jumps were performed on a force plate at the same time each testing day (baseline, Tests 1, 2, and 3) to measure RFD and maximal force development. Mixed-model analysis of variance compared performance variables across the study timeline, whereas t tests were used to compare the change between baseline and Test 3. RESULTS: Over 3 weeks, maximal RFD in the HC + C group returned to baseline, whereas the placebo group remained depressed (p = .18). While both groups showed a decrease in RFD through Test 2, only the treatment group recovered RFD to baseline by Test 3 (p = .036). In the HC + C group, change in countermovement jumps eccentric deceleration impulse (p = .008) and eccentric deceleration RFD (p = .04) was improved. A strong trend was observed for lower limb stiffness assessed in the countermovement jumps (p = .08). No difference was observed in maximal force or squat jump parameters. CONCLUSION: The HC + C supplementation improved RFD in the squat and countermovement jump alongside training.

Patients' lived experiences and recommendations for enhanced awareness and use of integrative oncology services in cancer care.

BACKGROUND: Consuming educational content, adhering to treatment plans and managing symptoms and side-effects can be overwhelming to new oncology patients. OBJECTIVE: The purpose of this study is to engage patients in conceptualization of enhanced clinic processes and digital health tools to support awareness and use of integrative oncology services. PATIENT INVOLVEMENT: We engaged patients in participatory design to understand lived experiences surrounding use of integrative oncology services during and after conventional cancer treatment. METHODS: Ten participatory design sessions were held with individual participants. Sessions began with patient story telling regarding diagnosis and paths to awareness and use of integrative oncology services. We then reviewed prototype mobile app screens to solicit feedback regarding digital health functionality to support patient navigation of symptom-alleviating options. RESULTS: Oncology patients are active participants in the management of symptoms and side effects. Patients who utilize yoga, acupuncture, and massage report a need for earlier patient education about these services. Patients express interest in digital health tools to match symptoms to options for relief, provide access to searchable information, and facilitate streamlined access to in-person and remote services. DISCUSSION: Patients co-produce wellbeing by seeking solutions to daily challenges and consuming educational content. Clinics can collaborate with patients to identify high priority needs and challenges. PRACTICAL VALUE: Active collaboration with patients is needed to identify unmet needs and guide development of clinic processes and digital health tools to enhance awareness and use of IO services in conventional cancer care. FUNDING: The principal investigator was supported by the U.S. Agency for Healthcare Research and Quality (AHRQ K12HS026370). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of AHRQ. The sponsor had no role in the study design, data collection, analysis, report writing, or decision to submit for publication.

Resistance patterns and clinical outcomes of Klebsiella pneumoniae and invasive Klebsiella variicola in trauma patients.

Recent reclassification of the Klebsiella genus to include Klebsiella variicola, and its association with bacteremia and mortality, has raised concerns. We examined Klebsiella spp. infections among battlefield trauma patients, including occurrence of invasive K. variicola disease. Klebsiella isolates collected from 51 wounded military personnel (2009-2014) through the Trauma Infectious Disease Outcomes Study were examined using polymerase chain reaction (PCR) and pulsed-field gel electrophoresis. K. variicola isolates were evaluated for hypermucoviscosity phenotype by the string test. Patients were severely injured, largely from blast injuries, and all received antibiotics prior to Klebsiella isolation. Multidrug-resistant Klebsiella isolates were identified in 23 (45%) patients; however, there were no significant differences when patients with and without multidrug-resistant Klebsiella were compared. A total of 237 isolates initially identified as K. pneumoniae were analyzed, with 141 clinical isolates associated with infections (remaining were colonizing isolates collected through surveillance groin swabs). Using PCR sequencing, 221 (93%) isolates were confirmed as K. pneumoniae, 10 (4%) were K. variicola, and 6 (3%) were K. quasipneumoniae. Five K. variicola isolates were associated with infections. Compared to K. pneumoniae, infecting K. variicola isolates were more likely to be from blood (4/5 versus 24/134, p = 0.04), and less likely to be multidrug-resistant (0/5 versus 99/134, p<0.01). No K. variicola isolates demonstrated the hypermucoviscosity phenotype. Although K. variicola isolates were frequently isolated from bloodstream infections, they were less likely to be multidrug-resistant. Further work is needed to facilitate diagnosis of K. variicola and clarify its clinical significance in larger prospective studies.

Tangeretin boosts the anticancer activity of metformin in breast cancer cells via curbing the energy production.

BACKGROUND: Breast cancer is the first leading cause of women cancer-related deaths worldwide. While there are many proposed treatments for breast cancer, low efficacy, toxicity, and resistance are still major therapeutic obstacles. Thus, there is a need for safer and more effective therapeutic approaches. Because of the direct link between obesity and carcinogenesis, energy restriction mimetic agents (ERMAs) such as the antidiabetic agent, metformin was proposed as a novel antiproliferative agent. However, the anticancer dose of metformin alone is relatively high and impractical to be implemented safely in patients. The current work aimed to sensitize resistant breast cancer cells to metformin's antiproliferative effect using the natural potential anticancer agent, tangeretin. METHODS: The possible synergistic combination between metformin and tangeretin was initially evaluated using MTT cell viability assay in different breast cancer cell lines (MCF-7, MDA-MB-231, and their resistant phenotype). The possible mechanisms of synergy were investigated via Western blotting analysis, reactive oxygen species (ROS) measurement, annexin/PI assay, cell cycle analysis, and wound healing assay. RESULTS: The results indicated the ability of tangeretin to improve the anticancer activity of metformin. Interestingly, the improved activity was almost equally observed in both parental and resistant cancer cells, which underlines the importance of this combination in cases of the emergence of resistance. The synergy was mediated through the enhanced activation of AMPK and ROS generation in addition to the improved inhibition of cell migration, induction of cell cycle arrest, and apoptosis in cancer cells. CONCLUSION: The current work underscores the importance of metformin as an ERMA in tackling breast cancer and as a novel approach to boost its anticancer activity via a synergistic combination with tangeretin.

High performance in risk stratification of intraductal papillary mucinous neoplasms by confocal laser endomicroscopy image analysis with convolutional neural networks (with video).

BACKGROUND AND AIMS: EUS-guided needle-based confocal laser endomicroscopy (EUS-nCLE) can differentiate high-grade dysplasia/adenocarcinoma (HGD-Ca) in intraductal papillary mucinous neoplasms (IPMNs) but requires manual interpretation. We sought to derive predictive computer-aided diagnosis (CAD) and artificial intelligence (AI) algorithms to facilitate accurate diagnosis and risk stratification of IPMNs. METHODS: A post hoc analysis of a single-center prospective study evaluating EUS-nCLE (2015-2019; INDEX study) was conducted using 15,027 video frames from 35 consecutive patients with histopathologically proven IPMNs (18 with HGD-Ca). We designed 2 CAD-convolutional neural network (CNN) algorithms: (1) a guided segmentation-based model (SBM), where the CNN-AI system was trained to detect and measure papillary epithelial thickness and darkness (indicative of cellular and nuclear stratification), and (2) a reasonably agnostic holistic-based model (HBM) where the CNN-AI system automatically extracted nCLE features for risk stratification. For the detection of HGD-Ca in IPMNs, the diagnostic performance of the CNN-CAD algorithms was compared with that of the American Gastroenterological Association (AGA) and revised Fukuoka guidelines. RESULTS: Compared with the guidelines, both n-CLE-guided CNN-CAD algorithms yielded higher sensitivity (HBM, 83.3%; SBM, 83.3%; AGA, 55.6%; Fukuoka, 55.6%) and accuracy (SBM, 82.9%; HBM, 85.7%; AGA, 68.6%; Fukuoka, 74.3%) for diagnosing HGD-Ca, with comparable specificity (SBM, 82.4%; HBM, 88.2%; AGA, 82.4%; Fukuoka, 94.1%). Both CNN-CAD algorithms, the guided (SBM) and agnostic (HBM) models, were comparable in risk stratifying IPMNs. CONCLUSION: EUS-nCLE-based CNN-CAD algorithms can accurately risk stratify IPMNs. Future multicenter validation studies and AI model improvements could enhance the accuracy and fully automatize the process for real-time interpretation.