Effect of a relative pricing intervention and active merchandising on snack purchases: interrupted time series analysis of a hospital retailer-led strategy.

BACKGROUND: Pricing policies have been shown to be an effective lever for promoting healthier dietary choices in consumer food environments. It is not yet well understood how pricing can be used to encourage healthier substitute purchases. The aim of the study was to assess the effect of a retailer-led relative pricing intervention on weekly purchases of targeted snack foods and beverages. METHODS: This was an ecological analysis in a real-world large tertiary hospital consumer food environment setting in urban Canada, comprised of four retail outlets: two large cafeterias, one smaller cafeteria, and one grab-and-go café. An interrupted time series analysis was designed to evaluate the effect of Snacking Made Simple, a retailer-led relative pricing intervention applied to 10 popular snack foods and beverages (n = 87 weeks, 66 weeks baseline and 21 weeks intervention, April 2018 to December 2019), on weekly purchase differences between healthier and less healthy targeted items, adjusted for weekly sales volume. Five healthier items were price discounted, alongside a price increase for five less healthy items. The intervention was actively merchandised in keeping with behaviour change theory. RESULTS: Weekly purchases of targeted snacks became healthier during the intervention period (ß = 21.41, p = 0.0024). This followed a baseline period during which weekly purchases of less healthy targeted snacks had outpaced over time those of healthier targeted snacks (ß = -11.02, p = 3.68E-14). We estimated that, all else being equal, a hypothetical 9.43 additional weeks of the intervention would be required to transition to net-healthier targeted snack purchases in this environment. The effects of the intervention varied by retail outlet, and the outcome appears driven by specific food items; further, examining merchandising implementation, we posited whether direct versus indirect substitution may have affected purchasing outcomes. CONCLUSIONS: Relative pricing may be a promising way to incentivize healthier substitute purchasing in the consumer food environment. Added attention to merchandising strategy as well as value-add factors within food categories and their effects on price salience may be an important factor in effective intervention design.

Quantification of Human Epidermal Growth Factor Receptor 2 by Immunopeptide Enrichment and Targeted Mass Spectrometry in Formalin-Fixed Paraffin-Embedded and Frozen Breast Cancer Tissues.

BACKGROUND: Conventional HER2-targeting therapies improve outcomes for patients with HER2-positive breast cancer (BC), defined as tumors showing HER2 protein overexpression by immunohistochemistry and/or ERBB2 gene amplification determined by in situ hybridization (ISH). Emerging HER2-targeting compounds show benefit in some patients with neither HER2 protein overexpression nor ERBB2 gene amplification, creating a need for new assays to select HER2-low tumors for treatment with these compounds. We evaluated the analytical performance of a targeted mass spectrometry-based assay for quantifying HER2 protein in formalin-fixed paraffin-embedded (FFPE) and frozen BC biopsies. METHODS: We used immunoaffinity-enrichment coupled to multiple reaction monitoring-mass spectrometry (immuno-MRM-MS) to quantify HER2 protein (as peptide GLQSLPTHDPSPLQR) in 96 frozen and 119 FFPE BC biopsies. We characterized linearity, lower limit of quantification (LLOQ), and intra- and inter-day variation of the assay in frozen and FFPE tissue matrices. We determined concordance between HER2 immuno-MRM-MS and predicate immunohistochemistry and ISH assays and examined the benefit of multiplexing the assay to include proteins expressed in tumor subcompartments (e.g., stroma, adipose, lymphocytes, epithelium) to account for tissue heterogeneity. RESULTS: HER2 immuno-MRM-MS assay linearity was ≥103, assay coefficient of variation was 7.8% (FFPE) and 5.9% (frozen) for spiked-in analyte, and 7.7% (FFPE) and 7.9% (frozen) for endogenous measurements. Immuno-MRM-MS-based HER2 measurements strongly correlated with predicate assay HER2 determinations, and concordance was improved by normalizing to glyceraldehyde-3-phosphate dehydrogenase. HER2 was quantified above the LLOQ in all tumors. CONCLUSIONS: Immuno-MRM-MS can be used to quantify HER2 in FFPE and frozen BC biopsies, even at low HER2 expression levels.

Transcriptomic analysis of equine chorioallantois reveals immune networks and molecular mechanisms involved in nocardioform placentitis.

Nocardioform placentitis (NP) continues to result in episodic outbreaks of abortion and preterm birth in mares and remains a poorly understood disease. The objective of this study was to characterize the transcriptome of the chorioallantois (CA) of mares with NP. The CA were collected from mares with confirmed NP based upon histopathology, microbiological culture and PCR for Amycolatopsis spp. Samples were collected from the margin of the NP lesion (NPL, n = 4) and grossly normal region (NPN, n = 4). Additionally, CA samples were collected from normal postpartum mares (Control; CRL, n = 4). Transcriptome analysis identified 2892 differentially expressed genes (DEGs) in NPL vs. CRL and 2450 DEGs in NPL vs. NPN. Functional genomics analysis elucidated that inflammatory signaling, toll-like receptor signaling, inflammasome activation, chemotaxis, and apoptosis pathways are involved in NP. The increased leukocytic infiltration in NPL was associated with the upregulation of matrix metalloproteinase (MMP1, MMP3, and MMP8) and apoptosis-related genes, such as caspases (CASP3 and CASP7), which could explain placental separation associated with NP. Also, NP was associated with downregulation of several placenta-regulatory genes (ABCG2, GCM1, EPAS1, and NR3C1), angiogenesis-related genes (VEGFA, FLT1, KDR, and ANGPT2), and glucose transporter coding genes (GLUT1, GLUT10, and GLUT12), as well as upregulation of hypoxia-related genes (HIF1A and EGLN3), which could elucidate placental insufficiency accompanying NP. In conclusion, our findings revealed for the first time, the key regulators and mechanisms underlying placental inflammation, separation, and insufficiency during NP, which might lead to the development of efficacious therapies or diagnostic aids by targeting the key molecular pathways.

New targets in endocrine-resistant hormone receptor-positive breast cancer.

Endocrine-based treatments are the backbone of initial therapy for advanced hormone receptor-positive breast cancers. Developing new therapeutic strategies to address resistance to endocrine therapy is an area of active research. In this review, we discuss targeted therapies that are currently the standard of care, as well as agents that are at present under investigation as potential treatments for advanced hormone receptor-positive breast cancer.

Setting the standard for healthy eating: Continuous quality improvement for health promotion at Nova Scotia Health.

Healthcare organizations engage in continuous quality improvement to improve performance and value-for-performance, but the pathway to change is often rooted in challenging the way things are "normally" done. In an effort to propel system-wide change to support healthy eating, Nova Scotia Health developed and implemented a healthy eating policy as a benchmark to create a food environment supportive of health. This article describes the healthy eating policy and its role as a benchmark in the quality improvement process. The policy, rooted in health promotion, sets a standard for healthy eating and applies to stakeholders both inside and outside of health. We explain how the policy offers nutrition but also cultural benchmarks around healthy eating, bringing practitioners throughout Nova Scotia Health together and sustaining collaborative efforts to improve upon the status quo.

Preexisting Autoimmune Disease: Implications for Immune Checkpoint Inhibitor Therapy in Solid Tumors.

The use of immune checkpoint inhibitors (ICIs) is rapidly expanding to the treatment of many cancer types, both in the metastatic setting and as an adjuvant to other therapies. Clinical trials using ICIs have largely excluded patients with preexisting autoimmune diseases due to concerns for increased toxicity. However, emerging evidence shows that ICIs may be considered in some patients with autoimmunity. This review discusses the commonalities between clinical autoimmune diseases and ICI-induced immunotherapy-related adverse events, and summarizes the existing case series that describes patients with solid tumors who have a preexisting autoimmune disease. This review also discusses which patients with autoimmunity could be considered reasonable candidates for ICI therapy.

"Those Conversations in My Experience Don't Go Well": A Qualitative Study of Primary Care Provider Experiences Tapering Long-term Opioid Medications.

Objective: Given the risks of long-term opioid therapy, patients may benefit from tapering these medications. There is little evidence to guide providers' approach to this process. We explored primary care providers' experiences discussing and implementing opioid tapering with patients on long-term opioid therapy. Design: Qualitative study using six semistructured, in-person focus groups. Subject: Primary care providers (N = 40). Setting: Six academically affiliated primary care clinics in university, urban safety net, and Veterans Health Administration medical centers in Colorado. Methods: Focus groups were audio-recorded, transcribed, and analyzed using a mixed inductive-deductive approach in ATLAS.ti. Emergent themes were identified through an iterative, multidisciplinary team-based process. Results: We identified 1) strategies for identifying candidates for opioid tapering, 2) barriers to opioid tapering, and 3) facilitators of opioid tapering. Strategies for identifying candidates for opioid tapering included evidence of high-risk behavior, serious adverse events, opioid-related side effects, and patient preference. Barriers included the providers' emotional burden, inadequate resources, and a lack of trust between patient and provider. Facilitators of opioid tapering included empathizing with the patient's experience, preparing patients for opioid tapering, individualizing implementation of opioid tapering, and supportive guidelines and policies. Conclusions: While discussing and implementing opioid tapering present significant challenges, primary care providers described key facilitators. These findings suggest a need to develop and test the effectiveness of resources to support patient-centered opioid tapering and locally developed policies to support and standardize providers' approaches to opioid prescribing.

Cognitive Behavioral Therapy Compared with Non-specialized Therapy for Alleviating the Effect of Auditory Hallucinations in People with Reoccurring Schizophrenia: A Systematic Review and Meta-analysis.

Cognitive behavioral therapy (CBT) is recommended as a psychological intervention for those diagnosed with schizophrenia. The prevalence of auditory hallucinations is high among this group, many of whom are cared for by community mental health teams that may not have easy access to qualified CBT practitioners. This systematic review examined the evidence for the superiority of CBT compared to non-specialized therapy in alleviating auditory hallucinations in community patients with schizophrenia. Two RCTs met the inclusion criteria totaling 105 participants. The Positive and Negative Syndrome Scale (PANSS)-Positive Scale was the outcome measure examined. A meta-analysis revealed a pooled mean difference of -0.86 [95 % CI -2.38, 0.65] in favor of CBT, although this did not reach statistical significance. This systematic review concluded there is no clinically significant difference in the reduction of positive symptoms of schizophrenia when treated by CBT compared to a non-specialized therapy for adults experiencing auditory hallucinations.

The Journey of Engaging With Web-Based Self-Harm and Suicide Content: Longitudinal Qualitative Study.

BACKGROUND: Self-harm and suicide are major public health concerns worldwide, with attention focused on the web environment as a helpful or harmful influence. Longitudinal research on self-harm and suicide-related internet use is limited, highlighting a paucity of evidence on long-term patterns and effects of engaging with such content. OBJECTIVE: This study explores the experiences of people engaging with self-harm or suicide content over a 6-month period. METHODS: This study used qualitative and digital ethnographic methods longitudinally, including one-to-one interviews at 3 time points to explore individual narratives. A trajectory analysis approach involving 4 steps was used to interpret the data. RESULTS: The findings from 14 participants established the web-based journey of people who engage with self-harm or suicide content. In total, 5 themes were identified: initial interactions with self-harm or suicide content, changes in what self-harm or suicide content people engage with and where, changes in experiences of self-harm or suicide behaviors associated with web-based self-harm or suicide content engagement, the disengagement-reengagement cycle, and future perspectives on web-based self-harm or suicide content engagement. Initial engagements were driven by participants seeking help, often when offline support had been unavailable. Some participants' exposure to self-harm and suicide content led to their own self-harm and suicide behaviors, with varying patterns of change over time. Notably, disengagement from web-based self-harm and suicide spaces served as a protective measure for all participants, but the pull of familiar content resulted in only brief periods of disconnection. Participants also expressed future intentions to continue returning to these self-harm and suicide web-based spaces, acknowledging the nonlinear nature of their own recovery journey and aiming to support others in the community. Within the themes identified in this study, narratives revealed that participants' behavior was shaped by cognitive flexibility and rigidity, metacognitive abilities, and digital expertise. Opportunities for behavior change arose during periods of cognitive flexibility prompted by life events, stressors, and shifts in mental health. Participants sought diverse and potentially harmful content during challenging times but moved toward recovery-oriented engagements in positive circumstances. Metacognitive and digital efficacy skills also played a pivotal role in participants' control of web-based interactions, enabling more effective management of content or platforms or sites that posed potential harms. CONCLUSIONS: This study demonstrated the complexity of web-based interactions, with beneficial and harmful content intertwined. Participants who demonstrated metacognition and digital efficacy had better control over web-based engagements. Some attributed these skills to study processes, including taking part in reflective diaries, showing the potential of upskilling users. This study also highlighted how participants remained vulnerable by engaging with familiar web-based spaces, emphasizing the responsibility of web-based industry leaders to develop tools that empower users to enhance their web-based safety.

Associations of immune checkpoint predictive biomarkers MHC-I and MHC-II with clinical and molecular features in a diverse breast cancer cohort.

PURPOSE: Immunotherapy (IO) in triple negative breast cancer (TNBC) has improved survival outcomes, with promising improvements in pCR rates among early high-risk HR+/HER2- breast cancers. However, biomarkers are needed to select patients likely to benefit from IO. MHC-I and tumor-specific MHC-II (tsMHC-II) expression are candidate biomarkers for PD-(L)1 checkpoint inhibition, but existing data from clinical trials included limited racial/ethnic diversity. METHODS: We performed multiplexed immunofluorescence assays in the Carolina Breast Cancer Study (CBCS, n=1628, 48% Black, 52% non-Black). Intrinsic subtype and P53 mutant-like status were identified using RNA-based multigene assays. We ranked participants based on tumoral MHC-I intensity (top 33% categorized as "MHC-IHigh") and MHC-II+ (≥5% of tumor cells as tsMHC-II+). MHC-I/II were evaluated in association with clinicopathological features by race. RESULTS: Black participants had higher frequency of TNBC (25% vs. 12.5%, p = < 0.001) and Basal-like (30% vs. 14%, p = < 0.001) tumors overall, and higher frequency of Basal-like (11% vs. 5.5%, p = 0.002) and TP53 mutant tumors (26% vs. 17%, p = 0.002) among HR+/HER2-. The frequency of tsMHC-II+ was higher in HR+/HER2- Black participants (7.9% vs. 4.9%, p = 0.04). Black participants also had higher frequency of MHC-Ihigh (38.7% vs. 28.2%, p <0.001), which was significant among HR+/HER2- (28.2% vs. 22.1%, p = 0.02). CONCLUSIONS: In this diverse study population, MHC-I and MHC-II tumor cell expression were more highly expressed in HR+/HER2- tumors from Black women, underscoring the importance of diverse and equitable enrollment in future IO trials.

Associations of Multiparametric Breast MRI Features, Tumor-Infiltrating Lymphocytes, and Immune Gene Signature Scores Following a Single Dose of Trastuzumab in HER2-Positive Early-Stage Breast Cancer.

Dynamic biomarkers that permit the real-time monitoring of the tumor microenvironment response to therapy are an unmet need in breast cancer. Breast magnetic resonance imaging (MRI) has demonstrated value as a predictor of pathologic complete response and may reflect immune cell changes in the tumor microenvironment. The purpose of this pilot study was to investigate the value of breast MRI features as early markers of treatment-induced immune response. Fourteen patients with early HER2+ breast cancer were enrolled in a window-of-opportunity study where a single dose of trastuzumab was administered and both tissue and MRIs were obtained at the pre- and post-treatment stages. Functional diffusion-weighted and dynamic contrast-enhanced MRI tumor measures were compared with tumor-infiltrating lymphocytes (TILs) and RNA immune signature scores. Both the pre-treatment apparent diffusion coefficient (ADC) and the change in peak percent enhancement (DPE) were associated with increased tumor-infiltrating lymphocytes with trastuzumab therapy (r = -0.67 and -0.69, p < 0.01 and p < 0.01, respectively). Low pre-treatment ADC and a greater decrease in PE in response to treatment were also associated with immune-activated tumor microenvironments as defined by RNA immune signatures. Breast MRI features hold promise as biomarkers of early immune response to treatment in HER2+ breast cancer.

Kailo: a systemic approach to addressing the social determinants of young people's mental health and wellbeing at the local level.

The mental health and wellbeing of children and young people is deteriorating. It is increasingly recognised that mental health is a systemic issue, with a wide range of contributing and interacting factors. However, the vast majority of attention and resources are focused on the identification and treatment of mental health disorders, with relatively scant attention on the social determinants of mental health and wellbeing and investment in preventative approaches. Furthermore, there is little attention on how the social determinants manifest or may be influenced at the local level, impeding the design of contextually nuanced preventative approaches. This paper describes a major research and design initiative called Kailo that aims to support the design and implementation of local and contextually nuanced preventative strategies to improve children's and young people's mental health and wellbeing. The Kailo Framework involves structured engagement with a wide range of local partners and stakeholders - including young people, community partners, practitioners and local system leaders - to better understand local systemic influences and support programmes of youth-centred and evidence-informed co-design, prototyping and testing. It is hypothesised that integrating different sources of knowledge, experience, insight and evidence will result in better embedded, more sustainable and more impactful strategies that address the social determinants of young people's mental health and wellbeing at the local level.

'You drink at home so they can go to work safely': A case study exploring alcohol marketing during the COVID-19 pandemic.

Alcohol marketing is linked to heavy consumption. Researchers have begun to examine how the alcohol industry has adapted its marketing practices during the 2020 Global COVID-19 pandemic. In Canada, Nova Scotia's culture of heavy drinking has been identified as a cause for concern by community, health care and government. This case study examines how one alcohol company coopted the facilities, staff, logos and fundraising efforts of a local health charity to market the sale and home delivery of a 6% alcohol by volume product via social media. This case study details the marketing practices of the alcohol brand, suggests why the marketing practices are problematic and concludes with recommendations for health promotion practice as well as suggestions for future research.

Vaping control in Nova Scotia: using research to catalyze change.

The tobacco, and now vaping, industries are skilled at creating falsification campaigns that leave policymakers and the public confused and distracted. As Nova Scotia saw youth vaping rates rise, a non-profit conducted a youth and young adult survey to discover why, what, and how often youth and young adults vape. They discovered that almost 96% of youth prefer flavours, and 48% believed they would quit if flavours were removed. This research was pivotal in capturing the voices of youth, gathering stakeholders, and countering industry opposition. On April 1, 2020, the Nova Scotian government implemented Canada's first ban on flavoured vaping products. This was followed by a nicotine cap of 20 mg/ml and a revamped taxation structure. The survey allowed non-profits to band together and align messages. It also provided government with information to take actions that reduce the prevalence and potential harms of vaping among youth. This commentary describes the advocacy process and opposition faced when advocating for vaping control measures. This approach can serve as a guide for assisting other jurisdictions in advocating for policy changes.

RéSUMé: Les industries du tabac, et maintenant du vapotage, sont habiles à créer des campagnes de falsification qui embrouillent les responsables des politiques et le public et qui distraient leur attention. Avec la hausse des taux de vapotage chez les jeunes en Nouvelle-Écosse, un organisme sans but lucratif a mené une enquête auprès des jeunes et des jeunes adultes pour découvrir pourquoi ils vapotent, à quelle fréquence et avec quels produits. L'enquête a révélé que près de 96 % des jeunes préféraient les arômes, et que 48 % croyaient qu'ils cesseraient de vapoter si ces arômes étaient retirés. Cette étude a été déterminante pour capter les voix des jeunes, réunir les acteurs et contrer l'opposition de l'industrie. Le 1er avril 2020, le gouvernement néo-écossais a mis en œuvre la toute première interdiction des produits de vapotage aromatisés au Canada. Il a ensuite limité la nicotine à 20 mg/ml et repensé la structure fiscale. L'enquête a permis aux organismes sans but lucratif de se regrouper et d'harmoniser leurs messages. Elle a aussi procuré au gouvernement les informations nécessaires pour prendre des mesures qui réduisent la prévalence et les préjudices potentiels du vapotage chez les jeunes. Notre commentaire décrit le processus de plaidoyer et l'opposition rencontrée lorsque l'on défend des mesures de contrôle du vapotage. Cette approche peut servir de guide pour aider d'autres administrations à préconiser des changements de politiques.

Detection and residence time of bisphosphonates in bone of horses.

Bisphosphonates are potent anti-resorptive agents that have the potential to adversely affect bone healing in equine athletes, and normal bone adaption in young racehorses. A concern exists that bisphosphonate inhibition of normal bone metabolism could lead to increased bone fractures during high-intensity exercise. We found only a single report describing concentrations of tiludronate in the bone of horses, and no studies describing clodronate. Knowledge of the residence time in bone could allow for a better understanding of the long-term effects of these compounds. Our objectives were to develop a method for detection of bisphosphonates in bone and add to the limited information available regarding the disposition of these drugs in the bone of horses. Two horses received clodronate and 2 tiludronate disodium. Postmortem collection of bones and teeth occurred either 4 or 30 d post drug administration. Additionally, postmortem blood, synovial fluid, aqueous humor, and bone samples from racehorses with various histories of bisphosphonate administration were collected, and concentrations determined using the developed LC-MS/MS method. Bisphosphonates were detected in bones and teeth tested at 4 and 30 d. In a postmortem sample, clodronate was detected in bone from a horse with reported administration 18 mo prior; clodronate was not detected in other sample types collected from this horse. Bisphosphonates reside in bone for extended periods of time, which could lead to potential long-term effects, increasing the potential for bone fractures in young and/or athletic horses.

Liquid Biopsy Assessment of Circulating Tumor Cell PD-L1 and IRF-1 Expression in Patients with Advanced Solid Tumors Receiving Immune Checkpoint Inhibitor.

BACKGROUND: Reliable biomarkers that can be serially monitored to predict treatment response to immune checkpoint inhibitors (ICIs) are still an unmet need. Here, we present a multiplex immunofluorescence (IF) assay that simultaneously detects circulating tumor cells (CTCs) and assesses CTC expression of programmed death ligand-1 (PD-L1) and interferon regulatory factor 1 (IRF-1) as a candidate biomarker related to ICI use. OBJECTIVE: To assess the potential of CTC PD-L1 and IRF-1 expression as candidate biomarkers for patients with advanced epithelial solid tumors receiving ICIs. PATIENTS AND METHODS: We tested the IF CTC assay in a pilot study of 28 patients with advanced solid tumors who were starting ICI. Blood for CTC evaluation was obtained prior to starting ICI, after a single cycle of therapy, and at the time of radiographic assessment or treatment discontinuation. RESULTS: At baseline, patients with 0-1 CTCs had longer progression-free survival (PFS) compared to patients with ≥ 2 CTCs (4.3 vs 1.3 months, p = 0.01). The presence of any PD-L1+ CTCs after a single dose of ICI portended shorter PFS compared to patients with no CTCs or PD-L1- CTCs (1.2 vs 4.2 months, p = 0.02); the presence of any PD-L1+ or IRF-1+ CTCs at time of imaging assessment or treatment discontinuation also was associated with shorter PFS (1.9 vs 5.5 months, p < 0.01; 1.6 vs 4.7 months, p = 0.05). CTC PD-L1 and IRF-1 expression did not correlate with tumor tissue PD-L1 or IRF-1 expression. Strong IRF-1 expression in tumor tissue was associated with durable (≥ 1 year) radiographic response (p = 0.02). CONCLUSIONS: Based on these results, CTC PD-L1 and IRF-1 expression is of interest in identifying ICI resistance and warrants further study.

A new era for cancer treatment: gold-nanoparticle-mediated thermal therapies.

Nanotechnology-based cancer treatment approaches potentially provide localized, targeted therapies that aim to enhance efficacy, reduce side effects, and improve patient quality of life. Gold-nanoparticle-mediated hyperthermia shows particular promise in animal studies, and early clinical testing is currently underway. In this article, the rapidly evolving field of gold nanoparticle thermal therapy is reviewed, highlighting recent literature and describing current challenges to clinical translation of the technology.

Alterations of Circulating Biomarkers During Late Term Pregnancy Complications in the Horse Part II: Steroid Hormones and Alpha-Fetoprotein.

Preterm labor and/or abortion causes considerable economic impact on the equine industry. Unfortunately, few experimental models exist for the induction of various pregnancy-related complications, and therefore extrapolations are made from the experimental model for ascending placentits, although inferences may be minimal. Certain steroid hormones (progestogens, estrogens) and fetal proteins (alpha-fetoprotein; AFP) might improve the diagnostics for abnormal pregnancy, but the utility of these markers in the field is unknown. To assess this, thoroughbred mares (n = 702) were bled weekly beginning in December 2013 until parturition/abortion. Following parturition, fetal membranes were assessed histopathologically and classified as either ascending placentitis (n = 6), focal mucoid placentitis (n = 6), idiopathic abortion (n = 6) or no disease (n = 20). Weekly serum samples were analyzed for concentrations of progesterone, estradiol-17ß, and AFP. Samples were analyzed retrospectively from the week of parturition/abortion in addition to the preceding four weeks. For both ascending and focal mucoid placentitis, a significant increase in progesterone and AFP was noted, alongside a significant decrease in estradiol-17ß and the ratio of estradiol-17ß to progesterone in comparison to controls. In contrast, idiopathic abortions experienced a decrease in progesterone concentrations alongside an increase in AFP, and this was only noted in the week preceding parturition/abortion. In conclusion, spontaneous placental infection in the horse altered both endocrine and feto-secretory markers in maternal circulation, while minimal changes were noted preceding noninfectious idiopathic abortion. Additionally, this is the first study to report an alteration in steroid hormones and AFP during the disease process of focal mucoid placentitis, the etiology of which includes Nocardioform placentitis.

FAK is required for TGFbeta-induced JNK phosphorylation in fibroblasts: implications for acquisition of a matrix-remodeling phenotype.

Transforming growth factor beta (TGFbeta) plays a critical role in connective tissue remodeling by fibroblasts during development, tissue repair, and fibrosis. We investigated the molecular pathways in the transmission of TGFbeta signals that lead to features of connective tissue remodeling, namely formation of an alpha-smooth muscle actin (alpha-SMA) cytoskeleton, matrix contraction, and expression of profibrotic genes. TGFbeta causes the activation of focal adhesion kinase (FAK), leading to JNK phosphorylation. TGFbeta induces JNK-dependent actin stress fiber formation, matrix contraction, and expression of profibrotic genes in fak+/+, but not fak-/-, fibroblasts. Overexpression of MEKK1, a kinase acting upstream of JNK, rescues TGFbeta responsiveness of JNK-dependent transcripts and actin stress fiber formation in FAK-deficient fibroblasts. Thus we propose a FAK-MEKK1-JNK pathway in the transmission of TGFbeta signals leading to the control of alpha-SMA cytoskeleton reorganization, matrix contraction, and profibrotic gene expression and hence to the physiological and pathological effects of TGFbeta on connective tissue remodeling by fibroblasts.

Untangling the Multidisciplinary Care Web: Streamlining Care Through an Immune-Related Adverse Events (IRAE) Tumor Board.

Immune-related adverse events (IRAEs) are becoming increasingly common as the use of immune checkpoint inhibitors expands into more tumor types and treatment settings. Although the majority of IRAEs are mild and can be managed in the outpatient setting by the medical oncologist, severe IRAEs can be life threatening and often require complex care coordination among multiple providers. These providers include a variety of non-oncology specialists who have interest and expertise in managing IRAEs. Multiple systems-based solutions have been proposed in the literature, but these need to be tailored to the needs and resources of each practice setting. In this article, we highlight the challenges of IRAE care by presenting an illustrative case from our institution. We then describe the format and structure of the IRAE Tumor Board established at the University of Washington/Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center. Finally, we discuss how this tumor board attempts to address clinical issues related to complex IRAE presentations and provide IRAE education.