Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.

Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic ß-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-ß1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis.

Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis1,2. Here we interrogated functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts3, during hepatocarcinogenesis. Genetic depletion, activation or inhibition of HSCs in mouse models of HCC revealed their overall tumour-promoting role. HSCs were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analyses of mouse and human HSC subpopulations by single-cell RNA sequencing together with genetic ablation of subpopulation-enriched mediators revealed dual functions of HSCs in hepatocarcinogenesis. Hepatocyte growth factor, enriched in quiescent and cytokine-producing HSCs, protected against hepatocyte death and HCC development. By contrast, type I collagen, enriched in activated myofibroblastic HSCs, promoted proliferation and tumour development through increased stiffness and TAZ activation in pretumoural hepatocytes and through activation of discoidin domain receptor 1 in established tumours. An increased HSC imbalance between cytokine-producing HSCs and myofibroblastic HSCs during liver disease progression was associated with increased HCC risk in patients. In summary, the dynamic shift in HSC subpopulations and their mediators during chronic liver disease is associated with a switch from HCC protection to HCC promotion.

Lipid droplets are intracellular mechanical stressors that impair hepatocyte function.

Matrix stiffening and external mechanical stress have been linked to disease and cancer development in multiple tissues, including the liver, where cirrhosis (which increases stiffness markedly) is the major risk factor for hepatocellular carcinoma. Patients with nonalcoholic fatty liver disease and lipid droplet-filled hepatocytes, however, can develop cancer in noncirrhotic, relatively soft tissue. Here, by treating primary human hepatocytes with the monounsaturated fatty acid oleate, we show that lipid droplets are intracellular mechanical stressors with similar effects to tissue stiffening, including nuclear deformation, chromatin condensation, and impaired hepatocyte function. Mathematical modeling of lipid droplets as inclusions that have only mechanical interactions with other cellular components generated results consistent with our experiments. These data show that lipid droplets are intracellular sources of mechanical stress and suggest that nuclear membrane tension integrates cell responses to combined internal and external stresses.

Glycosaminoglycans modulate long-range mechanical communication between cells in collagen networks.

Cells can sense and respond to mechanical forces in fibrous extracellular matrices (ECMs) over distances much greater than their size. This phenomenon, termed long-range force transmission, is enabled by the realignment (buckling) of collagen fibers along directions where the forces are tensile (compressive). However, whether other key structural components of the ECM, in particular glycosaminoglycans (GAGs), can affect the efficiency of cellular force transmission remains unclear. Here we developed a theoretical model of force transmission in collagen networks with interpenetrating GAGs, capturing the competition between tension-driven collagen fiber alignment and the swelling pressure induced by GAGs. Using this model, we show that the swelling pressure provided by GAGs increases the stiffness of the collagen network by stretching the fibers in an isotropic manner. We found that the GAG-induced swelling pressure can help collagen fibers resist buckling as the cells exert contractile forces. This mechanism impedes the alignment of collagen fibers and decreases long-range cellular mechanical communication. We experimentally validated the theoretical predictions by comparing the intensity of collagen fiber alignment between cellular spheroids cultured on collagen gels versus collagen­GAG cogels. We found significantly lower intensities of aligned collagen in collagen­GAG cogels, consistent with the prediction that GAGs can prevent collagen fiber alignment. The role of GAGs in modulating force transmission uncovered in this work can be extended to understand pathological processes such as the formation of fibrotic scars and cancer metastasis, where cells communicate in the presence of abnormally high concentrations of GAGs.

Understanding the use of media analysis in public health research through food tax debates (HEALTHEI Project): a scoping review.

BACKGROUND: Poor diet is a major public health concern. In 2021, 63·8% of adults and 22·2% of reception-age children were either overweight or obese in England. Fiscal interventions have become a popular policy measure to reduce obesity and encourage healthy eating. Such measures are highly controversial, leading to media debate promoting pro-tax and anti-tax arguments. To better understand food tax debates and the use of media analysis in public health research, we conducted a scoping review of media analyses using food taxes as a case study. METHODS: In this scoping review, we searched SCOPUS, PubMed, and EBSCOhost databases on Feb 14-22, 2023, using keyword variations for "food", "tax", and "media analysis". Results were restricted to English-only, peer-reviewed journal articles. The initial results were manually screened through an iterative process to exclude articles that did not analyse a food tax, were non-English language, were not peer-reviewed, or did not use media analysis as the primary method. Modelled on Arksey and O'Malley's (2005) five-stage review protocol, two researchers used a coding framework to independently code all articles and checked result quality through regular discussion. Extracted data included article title, author, year, country, tax type, media sources used, identified media frames, and research aims, methods, results, and conclusions. Results are reported according to PRISMA guidelines and data files submitted to FigShare Repository (non-accessible). FINDINGS: Of 1087 articles reviewed, 19 were eligible to be included in the study. Articles were published between 2013 and 2023, with 2021 having the highest concentration of studies carried out mainly in UK and USA. Despite search terms encompassing a range of food products, the retrieved media analyses focused on three types of food product taxes: sugar-sweetened beverages, meat, and groceries. Most articles explored arguments for and against policy implementation, with some investigating stakeholder representation. Results demonstrate that stakeholders' arguments, both positive and negative, are consistent across countries and food products. INTERPRETATION: The consistency of how both pro-tax and anti-tax arguments are presented in the media demonstrates the importance of coordination between stakeholder groups to influence policy adoption. To our knowledge, this is the first study to investigate media analysis across a diverse range of food products. FUNDING: National Institute for Health and Care Research (NIHR).

Usual Source of Care and Contraceptive Use.

BACKGROUND: A high proportion of people in the United States at risk of unintended pregnancy also have limited primary care access. STUDY DESIGN: We pooled data for analyses from separate 2015-2017 and 2017-2019 waves of the National Survey of Family Growth. Multivariable logistic regression was used to estimate associations between the usual source of health care and self-reported use of a comprehensive range of contraceptive options, as well as alignment between patient preference and the current method. RESULTS: Compared with having a private doctor or Health Maintenance Organization, not having a usual source of care was associated with lower odds of using short-term hormonal methods (OR=0.54, 95% CI: 0.40-0.73, for an 11 percentage point lower rate); higher odds of using time-based methods (OR=1.47, 95% CI: 1.10-1.97, for a 6 percentage point higher rate); and higher odds of preferring a contraceptive method other than the one most recently used (OR=1.39, 95% CI: 1.01-1.90, for a 6 percentage point higher probability). Reliance on an emergency department as a usual source of care was not associated with contraceptive use or satisfaction with the method used. Reliance on urgent care was associated only with higher odds of using time-based methods (OR=1.60, 95% CI: 1.03-2.50, for a 7 percentage point higher rate). Clinic-based usual care was not associated with any differences in contraceptive use but was associated with preferring a contraceptive method other than the one most recently used (OR=1.65, 95% CI: 1.21-2.25, for an 8 percentage point higher probability). CONCLUSIONS: All sources of usual care can improve contraceptive access.

Biliary atresia: insights into mechanisms using a toxic model of the disease including Wnt and Hippo signaling pathways and microtubules.

BACKGROUND: Mechanisms underlying bile duct injury in biliary atresia (BA) remain unclear and mechanisms of bile duct repair are unknown. This study aimed to explore the roles of microtubule instability and Wnt and Hippo signaling pathways in a biliatresone-induced BA model. METHODS: Using primary murine neonatal cholangiocytes in both 2D and 3D cultures, and ex-vivo extra hepatic bile ducts (EHBD) which also has peri-cholangiocyte area, we analyzed injury and recovery processes. Injury was induced by the toxin biliatresone and recovery was induced by toxin wash-out. RESULTS: Microtubule stabilizer paclitaxel prevented biliatresone-induced injury, both to cholangiocytes as well as reduced periductal αSMA stain, this process is mediated by decreased glutathione levels. RhoU and Wnt11 (Wnt signaling) and Pard6g and Amotl1 (Hippo signaling) are involved in both injury and recovery processes, with the latter acting upstream to Wnt signaling. CONCLUSIONS: Early stages of biliatresone-induced EHBD injury in cholangiocytes and periductal structures are reversible. Wnt and Hippo signaling pathways play crucial roles in injury and recovery, providing insights into BA injury mechanisms and potential recovery avenues. IMPACT: Microtubule stabilization prevents cholangiocyte injury and lumen obstruction in a toxic model of biliary atresia (biliatresone induced). Early stages of biliatresone-induced injury, affecting both cholangiocytes and periductal structures, are reversible. Both Wnt and Hippo signaling pathways play a crucial role in bile duct injury and recovery, with a noted interplay between the two. Understanding mechanisms of cholangiocyte recovery is imperative to unveil potential therapeutic avenues.

In Utero Extrahepatic Bile Duct Damage and Repair: Implications for Biliary Atresia.

Biliary atresia (BA) is a cholangiopathy affecting the extrahepatic bile duct (EHBD) of newborns. The etiology and pathophysiology of BA are not fully understood; however, multiple causes of damage and obstruction of the neonatal EHBD have been identified. Initial damage to the EHBD likely occurs before birth. We discuss how different developmental stages in utero and birth itself could influence the susceptibility of the fetal EHBD to damage and a damaging wound-healing response. We propose that a damage-repair response of the fetal and neonatal EHBD involving redox stress and a program of fetal wound healing could-regardless of the cause of the initial damage-lead to either obstruction and BA or repair of the duct and recovery. This overarching concept should guide future research targeted toward identification of factors that contribute to recovery as opposed to progression of injury and fibrosis. Viewing BA through the lens of an in utero damage-repair response could open up new avenues for research and suggests exciting new therapeutic targets.

Scaling concepts in 'omics: Nuclear lamin-B scales with tumor growth and often predicts poor prognosis, unlike fibrosis.

Physicochemical principles such as stoichiometry and fractal assembly can give rise to characteristic scaling between components that potentially include coexpressed transcripts. For key structural factors within the nucleus and extracellular matrix, we discover specific gene-gene scaling exponents across many of the 32 tumor types in The Cancer Genome Atlas, and we demonstrate utility in predicting patient survival as well as scaling-informed machine learning (SIML). All tumors with adjacent tissue data show cancer-elevated proliferation genes, with some genes scaling with the nuclear filament LMNB1, including the transcription factor FOXM1 that we show directly regulates LMNB1 SIML shows that such regulated cancers cluster together with longer overall survival than dysregulated cancers, but high LMNB1 and FOXM1 in half of regulated cancers surprisingly predict poor survival, including for liver cancer. COL1A1 is also studied because it too increases in tumors, and a pan-cancer set of fibrosis genes shows substoichiometric scaling with COL1A1 but predicts patient outcome only for liver cancer-unexpectedly being prosurvival. Single-cell RNA-seq data show nontrivial scaling consistent with power laws from bulk RNA and protein analyses, and SIML segregates synthetic from contractile cancer fibroblasts. Our scaling approach thus yields fundamentals-based power laws relatable to survival, gene function, and experiments.

A fetal wound healing program after intrauterine bile duct injury may contribute to biliary atresia.

BACKGROUND & AIMS: Biliary atresia (BA) is an obstructive cholangiopathy that initially affects the extrahepatic bile ducts (EHBDs) of neonates. The etiology is uncertain, but evidence points to a prenatal cause. Fetal tissues have increased levels of hyaluronic acid (HA), which plays an integral role in fetal wound healing. The objective of this study was to determine whether a program of fetal wound healing is part of the response to fetal EHBD injury. METHODS: Mouse, rat, sheep, and human EHBD samples were studied at different developmental time points. Models included a fetal sheep model of prenatal hypoxia, human BA EHBD remnants and liver samples taken at the time of the Kasai procedure, EHBDs isolated from neonatal rats and mice, and spheroids and other models generated from primary neonatal mouse cholangiocytes. RESULTS: A wide layer of high molecular weight HA encircling the lumen was characteristic of the normal perinatal but not adult EHBD. This layer, which was surrounded by collagen, expanded in injured ducts in parallel with extensive peribiliary gland hyperplasia, increased mucus production and elevated serum bilirubin levels. BA EHBD remnants similarly showed increased HA centered around ductular structures compared with age-appropriate controls. High molecular weight HA typical of the fetal/neonatal ducts caused increased cholangiocyte spheroid growth, whereas low molecular weight HA induced abnormal epithelial morphology; low molecular weight HA caused matrix swelling in a bile duct-on-a-chip device. CONCLUSION: The fetal/neonatal EHBD, including in human EHBD remnants from Kasai surgeries, demonstrated an injury response with prolonged high levels of HA typical of fetal wound healing. The expanded peri-luminal HA layer may swell and lead to elevated bilirubin levels and obstruction of the EHBD. IMPACT AND IMPLICATIONS: Biliary atresia is a pediatric cholangiopathy associated with high morbidity and mortality rates; although multiple etiologies have been proposed, the fetal response to bile duct damage is largely unknown. This study explores the fetal pathogenesis after extrahepatic bile duct damage, thereby opening a completely new avenue to study therapeutic targets in the context of biliary atresia.

Mechanisms of mindfulness in patients with migraine: Results of a qualitative study.

OBJECTIVE: To understand the mechanisms of mindfulness' impact on migraine. BACKGROUND: Promising mindfulness research demonstrates potential benefit in migraine, but no data-driven model exists from the lived experiences of patients that explains the mechanisms of mindfulness in migraine. METHODS: Semi-structured qualitative interviews were conducted with adults with migraine who participated in two mindfulness-based stress reduction (MBSR) clinical trials (n = 43). Interviews were audio-recorded, transcribed, and summarized into a framework matrix with development of a master codebook. Constructivist grounded theory approach was used to identify themes/subthemes. RESULTS: Participants who learned mindfulness techniques through MBSR experienced altered pain perception, altered response to migraine attacks and disease, increased awareness of external and internal experiences, improved overall well-being, and group benefits. Mindfulness resulted in earlier stress-body awareness and increased interoceptive awareness resulting in earlier attack recognition, leading to earlier and more effective management. Interictal factors of self-blame, guilt, and stigma decreased while migraine acceptance, hope, empowerment, self-efficacy, and self-compassion increased. Improved emotion regulation resulted in decreased fear of migraine, pain catastrophizing, anticipatory anxiety, and pain reactivity. Although taught as prevention, mindfulness was used both acutely and prophylactically. We created a conceptual model hypothesizing that MBSR skills led to an infusion of mindfulness in daily life, resulting in altered pain perception and experience, ultimately leading to improvement in overall well-being, which may positively feed back to the infusion of mindfulness in daily life. The therapeutic benefit of learning mindfulness in a group setting may moderate these effects. CONCLUSIONS: This study identified several new potential mechanisms of mindfulness' effect on migraine. After learning MBSR skills, participants reported altered pain and migraine perception and experiences. Increased stress-body and interoceptive awareness resulted in earlier migraine awareness and treatment. Mindfulness may target important interictal factors that affect disease burden such as fear of migraine, pain catastrophizing, and anticipatory anxiety. This is the first data-driven study to help elucidate the mechanisms of mindfulness on migraine from patient voices and can help direct future research endeavors.

Black with 'Baby Blues': A Systematic Scoping Review of Programs to Address Postpartum Depression in African American Women.

OBJECTIVE:  The literature review reports on programs and interventions that address postpartum depression (PPD) in African American women. African American women are at a higher risk of developing PPD compared to white women. The review will highlight and recommend approaches that may render positive outcomes in the future for this population. METHODS:  A systematic scoping literature review was conducted using Academic Search Complete, CINAHL, APA PsycArticles, APA PsychInfo, PubMed, Social Services Abstracts, and Social Work Abstracts. Keywords used in the search included "postpartum depression," "African American," and "interventions OR programs OR therapy OR treatment." Fourteen studies were selected, analyzed, and included in the review. RESULTS: Group psychosocial, individual psychosocial, internet-based, and integrated care interventions were included. While many articles noted within group changes in depression symptoms, fewer studies documented between group differences. Studies that investigated subsamples of "high risk" participants or those that used "culturally tailored" approaches showed promise. CONCLUSION: The literature review yielded some examples of programs/interventions that target postpartum depression in African American women; however, results were mixed. More research is needed to confirm the most effective interventions to address postpartum depression in African American women.

The data shows a limited number of public health interventions tailored to address and reduce postpartum depression in this marginalized population. The recommendations included in the review highlight the need for public health professionals to develop programs to support African American women during the postpartum period.

Cues Disseminated by Professional Associations That Represent 5 Health Care Professions Across 5 Nations: Lexical Analysis of Tweets.

BACKGROUND: Collaboration across health care professions is critical in efficiently and effectively managing complex and chronic health conditions, yet interprofessional care does not happen automatically. Professional associations have a key role in setting a profession's agenda, maintaining professional identity, and establishing priorities. The associations' external communication is commonly undertaken through social media platforms, such as Twitter. Despite the valuable insights potentially available into professional associations through such communication, to date, their messaging has not been examined. OBJECTIVE: This study aimed to identify the cues disseminated by professional associations that represent 5 health care professions spanning 5 nations. METHODS: Using a back-iterative application programming interface methodology, public tweets were sourced from professional associations that represent 5 health care professions that have key roles in community-based health care: general practice, nursing, pharmacy, physiotherapy, and social work. Furthermore, the professional associations spanned Australia, Canada, New Zealand, the United Kingdom, and the United States. A lexical analysis was conducted of the tweets using Leximancer (Leximancer Pty Ltd) to clarify relationships within the discourse. RESULTS: After completing a lexical analysis of 50,638 tweets, 7 key findings were identified. First, the discourse was largely devoid of references to interprofessional care. Second, there was no explicit discourse pertaining to physiotherapists. Third, although all the professions represented in this study support patients, discourse pertaining to general practitioners was most likely to be connected with that pertaining to patients. Fourth, tweets pertaining to pharmacists were most likely to be connected with discourse pertaining to latest and research. Fifth, tweets about social workers were unlikely to be connected with discourse pertaining to health or care. Sixth, notwithstanding a few exceptions, the findings across the different nations were generally similar, suggesting their generality. Seventh and last, tweets pertaining to physiotherapists were most likely to refer to discourse pertaining to profession. CONCLUSIONS: The findings indicate that health care professional associations do not use Twitter to disseminate cues that reinforce the importance of interprofessional care. Instead, they largely use this platform to emphasize what they individually deem to be important and advance the interests of their respective professions. Therefore, there is considerable opportunity for professional associations to assert how the profession they represent complements other health care professions and how the professionals they represent can enact interprofessional care for the benefit of patients and carers.

Conjugated hyperbilirubinemia is associated with increased morbidity and mortality after neonatal heart surgery.

BACKGROUND: Cholestasis characterised by conjugated hyperbilirubinemia is a marker of hepatobiliary dysfunction following neonatal cardiac surgery. We aimed to characterise the incidence of conjugated hyperbilirubinemia following neonatal heart surgery and examine the effect of conjugated hyperbilirubinemia on post-operative morbidity and mortality. METHODS: This was a retrospective study of all neonates who underwent surgery for congenital heart disease (CHD) at our institution between 1/1/2010 and 12/31/2020. Patient- and surgery-specific data were abstracted from local registry data and review of the medical record. Conjugated hyperbilirubinemia was defined as perioperative maximum conjugated bilirubin level > 1 mg/dL. The primary outcome was in-hospital mortality. Survival analysis was conducted using the Kaplan-Meier survival function. RESULTS: Conjugated hyperbilirubinemia occurred in 8.5% of patients during the study period. Neonates with conjugated hyperbilirubinemia were more likely to be of younger gestational age, lower birth weight, and non-Caucasian race (all p < 0.001). Patients with conjugated hyperbilirubinemia were more likely to have chromosomal and non-cardiac anomalies and require ECMO pre-operatively. In-hospital mortality among patients with conjugated hyperbilirubinemia was increased compared to those without (odds ratio 5.4). Post-operative complications including mechanical circulatory support, reoperation, prolonged ventilator dependence, and multi-system organ failure were more common with conjugated hyperbilirubinemia (all p < 0.04). Patients with higher levels of conjugated bilirubin had worst intermediate-term survival, with patients in the highest conjugated bilirubin group (>10 mg/dL) having a 1-year survival of only 6%. CONCLUSIONS: Conjugated hyperbilirubinemia is associated with post-operative complications and worse survival following neonatal heart surgery. Cholestasis is more common in patients with chromosomal abnormalities and non-cardiac anomalies, but the underlying mechanisms have not been delineated.

What's old is new again: The anatomical studies of Franklin P. Mall and the fascial-interstitial spaces.

Franklin Mall was one of the foremost scientists of the turn of the 19th century, an exemplary mentor as well as researcher, and his revolutionary contributions are still relevant today. Mall's early training in Leipzig with Wilhelm His and Carl Ludwig provided him with an unusual perspective on the integration of anatomy and physiology, and his interest in the links between structure and function guided the work he carried out after joining the faculty of the new Johns Hopkins University School of Medicine. Mall carried out innovative studies on the one hand using dye injection to trace blood and lymphatic supplies to different organs and on the other hand using "putrefaction" to digest tissues and study the organization of the reticular space, demonstrating that it was the underlying source of support for all the organs. These two studies of Mall's, carried out independently, provide the basis for modern studies integrating the understanding of fascia and interstitial spaces.

Digital headache self-management interventions for patients with a primary headache disorder: A systematic review of randomized controlled trials.

OBJECTIVE: This article systematically reviews the empirical literature examining the efficacy of digital headache management interventions for patients with a primary headache disorder. BACKGROUND: Digital headache management interventions provide opportunities to improve access to behavioral headache interventions to underserved groups. METHODS: A systematic search of PubMed, Scopus, and EBSCO (PsycInfo, Education Research Complete, ERIC, Health Source: Nursing/Academic Edition, Psychology and Behavioral Sciences Collection) and reference review was conducted. Included studies had to recruit a sample with a primary headache diagnosis, be a randomized controlled trial including a digital component, assess a headache outcome (i.e., frequency, duration, severity, intensity, disability) or quality of life, and be published in English. Two authors independently extracted data for included studies. The methodological quality of studies was assessed using the revised Cochrane risk-of-bias tool. RESULTS: Thirteen studies with unique interventions met inclusion criteria. More than half of the studies were pilots; however, nearly 70% (9/13) demonstrated significant between-group or within-group improvements on one or more headache-related outcomes. All interventions included some form of relaxation training and the majority were delivered via interactive website. While fewer than half the studies report participant race and/or ethnicity, of those that do, 83% (5/6) reported a predominately White/Caucasian sample. CONCLUSIONS: Efficacy testing of digital headache interventions is in its infancy with the majority of these studies relying on pilot studies with small samples comprised of homogenous patient populations. Interactive websites were the most common digital medium to deliver digital headache management interventions and have demonstrated promising results. Further testing using large-scale randomized controlled trials and exploration of other digital tools is warranted. Future studies with more diverse samples are needed to inform health equity of digital headache interventions.

Insights from the national maternal and Child Health Workforce Development Center on Title V Teams' collaborative readiness and goal accomplishment.

PURPOSE: State Title V programs collaborate with diverse partners to improve maternal and child health. Since 2014, the National Maternal and Child Health Workforce Development Center has trained Title V leaders in facilitating system change. This article describes aspects of initial collaborative readiness differentiating state and jurisdiction teams that later reported meeting their goals to greater or lesser degrees. DESCRIPTION: We used quantitative data from initial team leader reports to characterize readiness to collaborate with external partners, and their responses twelve months later to a prompt about how fully they had accomplished their goals. In addition, we coded excerpts from team leader accounts six and twelve months into their work with the Center, and retrospective coach perspectives, to identify collaborative readiness patterns. ASSESSMENT: Teams whose leaders reported higher goal accomplishment twelve months after beginning work with the Center had initially reported higher levels of collaboration with key partners. Our analyses suggest that such teams were also better able to use their cohort experience with the Center to improve collaboration, including information sharing with external stakeholders. Challenges working with Medicaid were reported both by teams with more and less goal accomplishment. CONCLUSIONS: Title V teams with lower levels of initial collaborative readiness may benefit from additional support in skill development, connections to key partners, and convening power. Given the crucial and increasing role of Medicaid in maternal and child health systems, more attention may be warranted to supporting all Title V programs in partnering with this funder.

Framing of policy responses to migrant horticultural labour shortages during Covid-19 in the Italian print media.

The Covid-19 pandemic led to a global food crisis. Like previous food crises how the debate is framed by food policy actors can have a bearing on policy outcomes. This study researches how the policy responses to migrant horticultural labour shortages, due to the pandemic, were framed in the Italian print media and how this relates to longer-term food policy making. Data were gathered from the six highest-circulation Italian daily newspapers. The coverage was dominated by left-leaning outlets and peaked in relation to Covid-19 recovery policies and political processes. Farmer industry bodies were the most quoted group, and the legalisation of undocumented migrant workers was the most frequently discussed policy response. A frames analysis was conducted and identified three principal frames: food security, worker exploitation and immigration. The worker exploitation and immigration frames were most frequently used by left-leaning newspapers, while centre-right papers used the food security frame the most often. The results suggest that media framing could contribute to both policy change, helping to open policy windows, as well as policy lock-ins, side-lining certain debates, actors and policy solutions. The research aims to contribute to growing empirical work which seeks to understand the impact of Covid-19 on migrant agricultural workers and food policy.

A Bile Duct-on-a-Chip With Organ-Level Functions.

BACKGROUND AND AIMS: Chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are frequently associated with damage to the barrier function of the biliary epithelium. Here, we report on a bile duct-on-a-chip that phenocopies not only the tubular architecture of the bile duct in three dimensions, but also its barrier functions. APPROACH AND RESULTS: We showed that mouse cholangiocytes in the channel of the device became polarized and formed mature tight junctions, that the permeability of the cholangiocyte monolayer was comparable to ex vivo measurements, and that cholangiocytes in the device were mechanosensitive (as demonstrated by changes in calcium flux under applied luminal flow). Permeability decreased significantly when cells formed a compact monolayer with cell densities comparable to those observed in vivo. This device enabled independent access to the apical and basolateral surfaces of the cholangiocyte channel, allowing proof-of-concept toxicity studies with the biliary toxin, biliatresone, and the bile acid, glycochenodeoxycholic acid. The cholangiocyte basolateral side was more vulnerable than the apical side to treatment with either agent, suggesting a protective adaptation of the apical surface that is normally exposed to bile. Further studies revealed a protective role of the cholangiocyte apical glycocalyx, wherein disruption of the glycocalyx with neuraminidase increased the permeability of the cholangiocyte monolayer after treatment with glycochenodeoxycholic acid. CONCLUSIONS: This bile duct-on-a-chip captured essential features of a simplified bile duct in structure and organ-level functions and represents an in vitro platform to study the pathophysiology of the bile duct using cholangiocytes from a variety of sources.

The Role of Expectations and Endogenous Opioids in Mindfulness-Based Relief of Experimentally Induced Acute Pain.

OBJECTIVE: Expectations contribute to cognitive pain modulation through opioidergically mediated descending inhibition. Mindfulness meditation reduces pain independent of endogenous opioids, engaging unique corticothalamocortical mechanisms. However, it remains unknown whether expectations for pain relief predict mindfulness-induced analgesia and if these expectations are modified by endogenous opioids. METHODS: In this secondary analysis of previously published work, 78 pain-free participants (mean age, 27 ± 7 years; 50% women) were randomized to a four-session mindfulness meditation or book listening regimen. Expectations for intervention-induced pain relief were assessed before and after each intervention. Pain ratings were examined after meditation or rest (control group) during noxious heat (49°C) and intravenous administration of saline placebo or the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg kg-1 h-1 infusion. RESULTS: Mindfulness significantly lowered pain during saline and naloxone infusion. Higher expected pain relief from mindfulness predicted lower pain intensity (r(40) = -0.41, p = .009). The relationship between meditation-related expectations and pain intensity reductions was exhibited during naloxone (r(20) = -0.76, p < .001) but not saline (r(20) = -0.22, p = .36). Expectations for book listening-based analgesia did not significantly predict pain changes during saline (r(20) = -0.37, p = .11) or naloxone (r(18) = 0.26, p = .30) in the control group. CONCLUSIONS: These novel findings demonstrate a significant role for expectations in mindfulness-based pain relief. However, this role was minimal during saline and stronger during opioid blockade, despite similar pain reductions. This supports growing evidence that mindfulness engages multiple mechanisms to reduce pain, suggesting that mindfulness might be an effective pain-reducing technique even for individuals with low expectations for pain relief.