Enhancing Diagnostic Follow-up and Care Coordination for Children with Autism in a Busy Resident Continuity Clinic: Leveraging the Electronic Health Record.

PURPOSE: A high-quality primary care clinic should provide clear action points and important care coordination for a child receiving a new diagnosis of autism spectrum disorder (ASD). Unfortunately, a substantial proportion of caregivers report little-to-no post-diagnosis support from their home clinics and primary care providers often report lack of training and resources in providing these supports. METHODS: We implemented an intervention package to investigate the impact on the frequency and quality of follow-up care for children with ASD in a busy, high-volume resident continuity clinic. The package consisted of a care coordination scheduling pathway and a standardized clinical template-embedded in the electronic health record (EHR)-that guided providers through best-practice recommendations and patient resources. RESULTS: As a result of these interventions, 74% of patients had ASD-specific follow-up, a more than threefold increase from baseline with a majority of providers using the EHR-embedded template to guide their visit. Providers also indicated a high degree of usability for the system and that it aided them in following best-practice guidelines for ASD care. CONCLUSION: Through explicit scheduling pathways and a novel EHR template, we saw a significant increase in ASD-specific follow-up visits and implementation of best practices for ASD care, demonstrating a new process for training and engaging primary care providers in clear action steps for post-diagnostic care without having to rely on tertiary referrals.

Echocardiographic caudal vena cava measurements in healthy cats and in cats with congestive heart failure and non-cardiac causes of cavitary effusions.

BACKGROUND: Echocardiographic indices of the inferior vena cava have been associated with elevated right atrial pressures in humans. HYPOTHESIS/OBJECTIVES: Describe caudal vena caval (CVC) sonographic dimensions in healthy cats compared to cats with cardiogenic cavitary effusion (CCE), cardiogenic pulmonary edema (CPE), or non-cardiac causes of cavitary effusion (NCE). ANIMALS: 30 healthy control cats and 52 client-owned cats with CCE, CPE, or NCE examined at two university hospitals. METHODS: Sagittal 2-dimensional (2D) and M-mode CVC dimensions were acquired from the subxiphoid view. Caudal vena cava collapsibility index (CVC-CI) was calculated. Variables were compared between study groups using Kruskal-Wallis and Dunn's Bonferroni testing. Receiver operating characteristic curves were used to assess sensitivity and specificity for diagnostic categories. RESULTS: Healthy cats had sagittal 2D and M-mode (median, interquartile range) CVC maximal dimensions of 2.4 mm (1.3-4.0) and 3.4 mm (1.5-4.9) and CVC-CI of 52% (45.2-61.8) and 55% (47.8-61.3), respectively. The CVC maximal dimensions in healthy controls were smaller than in cats with cavitary effusions or pulmonary edema (all P<0.05). CVC-CI was different between CCE and NCE (P<0.0001) with cutoffs of CVC-CI ≤38% (2D) or ≤29% (M-mode) being 90.5% and 85.7% sensitive, and 94.4% and 100% specific for diagnosis of CCE, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Caudal vena cava measurements are larger in cats with cavitary effusions and cats with CPE than healthy cats. In cats with cavitary effusion, decreased CVC-CI, ≤38% (2D) or ≤29% (M-mode), was helpful in distinguishing between cardiogenic and noncardiogenic etiology.

Using AI-generated suggestions from ChatGPT to optimize clinical decision support.

OBJECTIVE: To determine if ChatGPT can generate useful suggestions for improving clinical decision support (CDS) logic and to assess noninferiority compared to human-generated suggestions. METHODS: We supplied summaries of CDS logic to ChatGPT, an artificial intelligence (AI) tool for question answering that uses a large language model, and asked it to generate suggestions. We asked human clinician reviewers to review the AI-generated suggestions as well as human-generated suggestions for improving the same CDS alerts, and rate the suggestions for their usefulness, acceptance, relevance, understanding, workflow, bias, inversion, and redundancy. RESULTS: Five clinicians analyzed 36 AI-generated suggestions and 29 human-generated suggestions for 7 alerts. Of the 20 suggestions that scored highest in the survey, 9 were generated by ChatGPT. The suggestions generated by AI were found to offer unique perspectives and were evaluated as highly understandable and relevant, with moderate usefulness, low acceptance, bias, inversion, redundancy. CONCLUSION: AI-generated suggestions could be an important complementary part of optimizing CDS alerts, can identify potential improvements to alert logic and support their implementation, and may even be able to assist experts in formulating their own suggestions for CDS improvement. ChatGPT shows great potential for using large language models and reinforcement learning from human feedback to improve CDS alert logic and potentially other medical areas involving complex, clinical logic, a key step in the development of an advanced learning health system.

Assessing the Value of ChatGPT for Clinical Decision Support Optimization.

Objective: To determine if ChatGPT can generate useful suggestions for improving clinical decision support (CDS) logic and to assess noninferiority compared to human-generated suggestions. Methods: We supplied summaries of CDS logic to ChatGPT, an artificial intelligence (AI) tool for question answering that uses a large language model, and asked it to generate suggestions. We asked human clinician reviewers to review the AI-generated suggestions as well as human-generated suggestions for improving the same CDS alerts, and rate the suggestions for their usefulness, acceptance, relevance, understanding, workflow, bias, inversion, and redundancy. Results: Five clinicians analyzed 36 AI-generated suggestions and 29 human-generated suggestions for 7 alerts. Of the 20 suggestions that scored highest in the survey, 9 were generated by ChatGPT. The suggestions generated by AI were found to offer unique perspectives and were evaluated as highly understandable and relevant, with moderate usefulness, low acceptance, bias, inversion, redundancy. Conclusion: AI-generated suggestions could be an important complementary part of optimizing CDS alerts, can identify potential improvements to alert logic and support their implementation, and may even be able to assist experts in formulating their own suggestions for CDS improvement. ChatGPT shows great potential for using large language models and reinforcement learning from human feedback to improve CDS alert logic and potentially other medical areas involving complex, clinical logic, a key step in the development of an advanced learning health system.

Improving Adherence to AAP Acute Otitis Media Guidelines in an Academic Pediatrics Practice through a Quality Improvement Project.

Introduction: Acute otitis media (AOM) is the most common reason for antibiotic use in children. The American Academy of Pediatrics (AAP) published its latest AOM guidelines in 2013. A safety-net antibiotic prescription (SNAP) is recommended for some patients based on age, severity, and duration of symptoms. At baseline, 78% of patients diagnosed with AOM in our general pediatrics practice met AAP guidelines, and 20% of eligible patients received a SNAP according to guidelines. We aimed to increase adherence to AAP AOM guidelines in an academic general pediatrics clinic from 78% to 90% by January 2020. Methods: A quality improvement team determined key drivers and developed interventions. Patients included were 6 months to 12 years old with AOM. Encounters were reviewed for adherence to AAP AOM guidelines. During the project, interventions included an ear pain note template, which generated guideline-based recommendations, note template education in clinic orientation sessions, a didactic session on AOM management, and reminders on workstations. Data were analyzed using P-charts. Results: Percent of AOM encounters (n = 1266) adhering to AAP AOM guidelines increased from 78% to 92%. We also reviewed two process measures. First, the use of the ear pain note template increased from 0% to 44%. Second, the percent of AOM encounters where an eligible patient received a SNAP increased from 21% to 78% (encounters n = 421). Conclusion: We demonstrate increased adherence to AAP AOM guidelines, including improved use of SNAPs after introducing a note template with clinical decision support and provider educational sessions.

Clinician collaboration to improve clinical decision support: the Clickbusters initiative.

OBJECTIVE: We describe the Clickbusters initiative implemented at Vanderbilt University Medical Center (VUMC), which was designed to improve safety and quality and reduce burnout through the optimization of clinical decision support (CDS) alerts. MATERIALS AND METHODS: We developed a 10-step Clickbusting process and implemented a program that included a curriculum, CDS alert inventory, oversight process, and gamification. We carried out two 3-month rounds of the Clickbusters program at VUMC. We completed descriptive analyses of the changes made to alerts during the process, and of alert firing rates before and after the program. RESULTS: Prior to Clickbusters, VUMC had 419 CDS alerts in production, with 488 425 firings (42 982 interruptive) each week. After 2 rounds, the Clickbusters program resulted in detailed, comprehensive reviews of 84 CDS alerts and reduced the number of weekly alert firings by more than 70 000 (15.43%). In addition to the direct improvements in CDS, the initiative also increased user engagement and involvement in CDS. CONCLUSIONS: At VUMC, the Clickbusters program was successful in optimizing CDS alerts by reducing alert firings and resulting clicks. The program also involved more users in the process of evaluating and improving CDS and helped build a culture of continuous evaluation and improvement of clinical content in the electronic health record.

Association of diet with clinical outcomes in dogs with dilated cardiomyopathy and congestive heart failure.

INTRODUCTION: Dilated cardiomyopathy (DCM) in dogs has been associated with feeding of grain-free (GF), legume-rich diets. Some dogs with presumed diet-associated DCM have shown improved myocardial function and clinical outcomes following a change in diet and standard medical therapy. HYPOTHESIS: Prior GF (pGF) diet influences reverse cardiac remodeling and clinical outcomes in dogs with DCM and congestive heart failure (CHF). ANIMALS AND METHODS: A retrospective study was performed with 67 dogs with DCM and CHF for which diet history was known. Dogs were grouped by diet into pGF and grain-inclusive (GI) groups. Dogs in the pGF group were included if diet change was a component of therapy. Survival was analyzed using Kaplan-Meier curves and the Cox proportional-hazards model. RESULTS: The median survival time was 344 days for pGF dogs vs. 253 days for GI dogs (P = 0.074). Statistically significant differences in median survival were identified when the analysis was limited to dogs surviving longer than one week (P = 0.033). Prior GF dogs had a significantly worse outcome the longer a GF diet was fed prior to diagnosis (P = 0.004) or if they were diagnosed at a younger age (P = 0.017). Prior GF dogs showed significantly greater improvement in normalized left ventricular internal diastolic diameter (P = 0.038) and E-point septal separation (P = 0.031) measurements and significant decreases in their furosemide (P = 0.009) and pimobendan (P < 0.005) dosages over time compared to GI dogs. CONCLUSIONS: Prior GF dogs that survived at least one week after diagnosis of DCM, treatment of CHF, and diet change had better clinical outcomes and showed reverse ventricular remodeling compared to GI dogs.

H2A.Z overexpression suppresses senescence and chemosensitivity in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable and devastating malignant tumors. Epigenetic modifications such as DNA methylation and histone modification regulate tumor initiation and progression. However, the contribution of histone variants in PDAC is unknown. Here, we demonstrated that the histone variant H2A.Z is highly expressed in PDAC cell lines and PDAC patients and that its overexpression correlates with poor prognosis. Moreover, all three H2A.Z isoforms (H2A.Z.1, H2A.Z.2.1, and H2A.Z.2.2) are highly expressed in PDAC cell lines and PDAC patients. Knockdown of these H2A.Z isoforms in PDAC cell lines induces a senescent phenotype, cell cycle arrest in phase G2/M, increased expression of cyclin-dependent kinase inhibitor CDKN2A/p16, SA-ß-galactosidase activity and interleukin 8 production. Transcriptome analysis of H2A.Z-depleted PDAC cells showed altered gene expression in fatty acid biosynthesis pathways and those that regulate cell cycle and DNA damage repair. Importantly, depletion of H2A.Z isoforms reduces the tumor size in a mouse xenograft model in vivo and sensitizes PDAC cells to gemcitabine. Overexpression of H2A.Z.1 and H2A.Z.2.1 more than H2A.Z.2.2 partially restores the oncogenic phenotype. Therefore, our data suggest that overexpression of H2A.Z isoforms enables cells to overcome the oncoprotective barrier associated with senescence, favoring PDAC tumor grow and chemoresistance. These results make H2A.Z a potential candidate as a diagnostic biomarker and therapeutic target for PDAC.

Using Quality Improvement Methodology to Implement Survivorship Care Plans.

PURPOSE: Accreditation requirements for cancer centers by the American College of Surgeons' Commission on Cancer have included provision of survivorship care plans (SCPs) to patients treated with curative intent soon after completion of therapy. These were traditionally provided in a dedicated survivorship clinic for our pediatric oncology patients later in the survivorship time period. Our goal was to increase timely provision of SCPs to eligible patients in our acute care pediatric oncology clinic and to have this serve as a bridge to longer-term survivorship care. METHODS: Our pediatric oncology clinic used quality improvement methodology to implement a process for creation of SCPs. We defined eligible patients on the basis of curative intent. Cancer registry data were queried to find eligible patients, and chart reviews were done weekly. A P chart and run chart were used to monitor our process for creation of plans and overall completion rate, respectively. RESULTS: During the intervention period, we increased the percentage of eligible patients with an SCP from 28% on June 30, 2017, to 53% by December 31, 2017. Since that time, we have continued to increase the percentage of patients with SCPs, reaching 69% by June 30, 2019. CONCLUSION: By using quality improvement methodology, our pediatric oncology clinic was able to change its clinical practice and implement a sustainable process for provision of SCPs and survivorship planning earlier in the post-treatment course, and meet the Commission on Cancer accreditation standard.

Impact of coblation versus electrocautery on acute post-operative outcomes in pediatric tonsillectomy.

OBJECTIVE: Based on previous studies in the pediatric population, it remains unclear whether there is a difference in postoperative pain between two widely used tonsillectomy techniques: coblation and bovie electrocautery. This large prospective study investigates whether postoperative pain scores differ between these two surgical techniques for tonsillectomy. METHODS: Prospective, non-randomized study of children aged 2-8 enrolled in a randomized controlled trial of single-dose intravenous acetaminophen for pain associated with adenotonsillectomy. Included procedures occurred between October 2012 and June 2015 at a tertiary referral center. Only patients whose operations exclusively used coblation or electrocautery and who required postoperative admission for extended observation were included. Follow-up period was the length of inpatient stay. Patients and nurses who recorded the pain scores were blinded to the tonsillectomy technique. RESULTS: A total of 183 patients were included: 117 coblation cases and 66 electrocautery cases. Pain scores in the surgical recovery unit and pain scores after admission to the floor unit were not significantly different between coblation and electrocautery, either before or after adjustment for patient age, body mass index, intravenous acetaminophen use, and surgeon. There was also no difference in length of stay, readmission rate, or post-tonsillectomy hemorrhage. CONCLUSIONS: Coblation and electrocautery tonsillectomy are associated with similar post-operative pain scores in the recovery and inpatient units in the pediatric population. As coblation is costlier, the results of this study may affect which tool is used by otolaryngologists from a cost-benefit perspective. LEVEL OF EVIDENCE: III.

The Role of Flaviviral Proteins in the Induction of Innate Immunity.

Flaviviruses are positive, single-stranded, enveloped cytoplasmic sense RNA viruses that cause a variety of important diseases worldwide. Among them, Zika virus, West Nile virus, Japanese encephalitis virus, and Dengue virus have the potential to cause severe disease. Extensive studies have been performed to elucidate the structure and replication strategies of flaviviruses, and current studies are aiming to unravel the complex molecular interactions between the virus and host during the very early stages of infection. The outcomes of viral infection and rapid establishment of the antiviral state, depends on viral detection by pathogen recognition receptors and rapid initiation of signalling cascades to induce an effective innate immune response. Extracellular and intracellular pathogen recognition receptors play a crucial role in detecting flavivirus infection and inducing a robust antiviral response. One of the main hallmarks of flaviviral nonstructural proteins is their multiple strategies to antagonise the interferon system. In this chapter, we summarize the molecular characteristics of flaviviral proteins and discuss how viral proteins target different components of the interferon signalling pathway by blocking phosphorylation, enhancing degradation, and downregulating the expression of major components of the Janus kinase/signal transducer and activator of transcription pathway. We also discuss how the interactions of viral proteins with host proteins facilitate viral pathogenesis. Due to the lack of antivirals or prophylactic treatments for many flaviviral infections, it is necessary to fully elucidate how these viruses disrupt cellular processes to influence pathogenesis and disease outcomes.

Embedding Autism Spectrum Disorder Diagnosis Within the Medical Home: Decreasing Wait Times Through Streamlined Assessment.

Long waits for diagnostic assessment prevent early identification of children suspected of having autism spectrum disorder. We evaluated the benefit of embedded diagnostic consultation within primary care clinics. Using a streamlined diagnostic model, 119 children with concerns for autism spectrum disorder were seen over 14 months. Diagnostic clarity was determined through streamlined assessment for 59% of the children, while others required follow-up. Latency from first concern to diagnosis was 55 days and median age at diagnosis was 32 months: considerably lower than national averages or comparable tertiary clinics. Findings support that embedded processes for effective triage and diagnosis within the medical home is a viable mechanism for efficient access to diagnostic services and assists in bypassing a common barrier to specialized services.

Fatty acids, vitamins and cholesterol content, and sensory properties of cheese made with milk from sheep fed rapeseed oilcake.

The aim of the present study was to evaluate the influence of rapeseed oilcake used for feeding sheep on the content of fatty acids (FA), tocopherols, retinoids, and cholesterol of milk and cheese, and on the sensory properties of cheese. Indoor animal feeding (in winter) is the highest cost of production for cheesemakers, and the inclusion of locally produced rapeseed oilcake in the concentrate feed formulation can reduce the cost of cheese production, as long as the quality of the cheese is not altered. The experiment was carried out in March (mid lactation) with 72 Latxa sheep from an experimental farm located in the Basque Country (northern Spain). Two homogeneous groups of animals (n = 36) were set to receive each a different diet based on commercial or rapeseed concentrate, respectively, and forage (Festuca hay). Animal production parameters were individually recorded for each feeding group, whereas bulk milk from each group was used for cheesemaking trials. The rapeseed concentrate had higher amounts of unsaturated FA (mainly C18:1 cis isomers, C18:2 cis-9,cis-12 and C18:3 cis-9,cis-12,cis-15) and tocopherols than the commercial concentrate. The inclusion of rapeseed oilcake in the diet of dairy sheep did not compromise animal production parameters or milk gross composition. Bulk milk and cheese from sheep fed rapeseed concentrate showed higher content of unsaturated FA and tocopherols than those from sheep fed commercial concentrate. No differences were observed in the content of retinoid in milk and cheese between feeding groups, whereas the cholesterol content was slightly lower in cheese made with milk from sheep fed rapeseed concentrate. Thus, milk and cheese from sheep fed rapeseed concentrate had a healthier lipid profile. In addition, the inclusion of rapeseed oilcake in the diet of sheep did not change the typical sensory attributes of Protected Denomination of Origin Idiazabal cheese. Therefore, rapeseed concentrate could be a good local resource for feeding sheep to improve the nutritional quality of dairy products and to provide higher returns to farms.

Risk Factors for Outpatient Use of Antibiotics in Children with Acute Respiratory Illnesses.

OBJECTIVES: Antibiotics for acute respiratory illness (ARI) constitute most pediatric medication use and contribute to the emergence of antimicrobial resistance. We investigated antibiotic prescription risk factors for ARI in pediatric clinics and clinical follow-up in individuals prescribed and not prescribed antibiotics. METHODS: In this observational study, we enrolled children ages 2 to 17 years old presenting with ARI with fever to two academic pediatric primary care outpatient clinics during influenza season 2013-2014. We collected information on demographics, initial symptoms, medical conditions, laboratory tests, discharge diagnoses, treatments, and 30 days of follow-up medical encounters. Factors associated with antibiotic prescription receipt were evaluated using logistic regression. RESULTS: Of 206 consented and enrolled children, 59 (29%) were prescribed antibiotics, 51 of 59 (86%) for indicated diagnoses: 34 for streptococcal pharyngitis, 15 for acute otitis media (AOM), and 2 for pneumonia. Discharge diagnoses were the only factors independently associated with an antibiotic prescription. Of children prescribed/not prescribed an antibiotic, 17%/17% received follow-up telephone calls and 27%/17% had follow-up visits related to ARI within 30 days. Two children with AOM were prescribed a second antibiotic during follow-up, and one developed Clostridium difficile colitis. Eighteen of 206 (9%) additional children were prescribed antibiotics within 30 days for ARI symptoms, 17 for streptococcal pharyngitis, AOM, pneumonia, or sinusitis; one was prescribed antibiotics for influenza-like illness. CONCLUSIONS: Among study children 2 to 17 years old with outpatient ARI, 29% were prescribed antibiotics at the initial visit and another 9% were prescribed antibiotics during the 30-day follow-up (most were for appropriate indications). Further decreasing antibiotic use in similar settings will likely require wider implementation of watchful waiting for AOM, a change in guidelines for pharyngitis management, and/or reductions in these diseases.

Evaluation of the safety and adjuvant effect of a detoxified listeriolysin O mutant on the humoral response to dengue virus antigens.

Listeriolysin O (LLO) has been proposed as a potential carrier or adjuvant molecule in the vaccination field. However, the cytotoxic and pro-apoptotic effects of LLO are the major limitations for this purpose. Here, we have performed a preclinical safety evaluation and characterized a new potential adjuvant application for a non-cytolytic LLO mutant (dtLLO) to enhance and modulate the immune response against the envelope (E) protein from dengue virus. In addition, we have studied the adjuvant effects of dtLLO on human immune cells and the role of membrane cholesterol for the binding and proinflammatory property of the toxoid. Our in-vivo results in the murine model confirmed that dtLLO is a safer molecule than wild-type LLO (wtLLO), with a significantly increased survival rate for mice challenged with dtLLO compared with mice challenged with wtLLO (P < 0·001). Histopathological analysis showed non-toxic effects in key target organs such as brain, heart, liver, spleen, kidney and lung after challenge with dtLLO. In vitro, dtLLO retained the capacity of binding to plasma membrane cholesterol on the surface of murine and human immune cells. Immunization of 6-8-week-old female BALB/c mice with a combination of dtLLO mixed with E protein elicited a robust specific humoral response with isotype diversification of immunoglobulin (Ig)G antibodies (IgG1 and IgG2a). Finally, we demonstrated that cholesterol and lipid raft integrity are required to induce a proinflammatory response by human cells. Taken together, these findings support a potential use of the dtLLO mutant as a safe and effective adjuvant molecule in vaccination.

Non-Conjugated Chitosan-Based Nanoparticles to Proteic Antigens Elicit Similar Humoral Immune Responses to Those Obtained with Alum.

Biodegradables Chitosan-based Nanoparticles (CS NPs) have been extensively studied as delivery system for therapeutic molecules and as efficient carriers or adjuvants in experimental vaccination. Physicochemical association between CS NPs and antigens is a key step for the biological function as carrier devices. However, for the adjuvant CS NPs property, it is not well known if coupling with vaccine antigens is required or not to potentiate the immune response. To address this issue, in this work, we evaluated the potential adjuvant effect of CS NPs by simply mixing with two different antigens such as Bovine Serum Albumin (BSA) or E protein from Dengue Virus serotype 2 (E protein DENV2). Thus the CS NPs were prepared by ionic gelation with sodium tripolyphosphate, resulting particles among 68 and 188 nm of size. Immunization of 6­8 week old female BALB/c mice, were carried out by intraperitoneal route with a simple combination of CS NPs either with BSA (CS NPs-BSA) at 10 µg or with E protein DENV2 (CS NPs-Protein E) at 5 µg. Combinations with the above antigens with CS NPs elicited robust specific primary and secondary humoral responses comparable to alum, a well-known adjuvant. BSA-specific IgG titers were detectable by day 14 after priming with the CS NPs-BSA formulation, with titers that ranged from 102 to 103 EU ml-. After a second immunization, the anti-BSA titers ranged around 104 EU ml-. In contrast, in the group of mice immunized with the protein alone, BSA-specific serum IgG titers were undetectable at day 14 and 28. For the immunizations with the CS NPs-E protein formulation, we observed also a remarkable specific-antibody production in the primary response, with titers reaching 103 EU ml-. After the booster immunization the anti-E protein DENV2 antibodies titers reached peak values around 104 EU ml-. Interestingly, for both antigens, the combination with CS NPs polarized the immune response to a Th2-like profile, which is characterized mainly by the production of the IgG1 Isotype, confirming that CS NPs can enhance and modulate the humoral immune responses against different antigens independently of physicochemical conjugation. This could represent a simplification in the use of CS NPs as adjuvants in vaccination.

Case study of a commercial sheep flock under extensive mountain grazing: Pasture derived lipid compounds in milk and cheese.

Terpenoid, fat-soluble antioxidant and fatty acid (FA) composition of pasture as well as those of milk and cheese from a commercial sheep flock managed under extensive mountain grazing in the east region of the Cantabrian mountain (Northern Spain) was investigated. The grazing period lasted for 2 months and ewes were at late lactation stage. Plants, feces, bulk milk and cheese samples were collected on two sampling dates. The abundance of the dominating botanical families in the mountain pasture prevailed in the sheep diet of the commercial flock. Major terpenoids and tocols in the pasture appeared as major ones in milk and cheese, whereas C18 unsaturated FAs in milk and cheese were derived from the intake of C18 polyunsaturated FAs which were prevalent in the pasture. No carotene was detected in the dairy samples but retinol (free or esterified), derived from the intake of ß-carotene present in pasture plants, was found in milk and cheese.

Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis.

The roles of macrophages in type 2-driven inflammation and fibrosis remain unclear. Here, using CD11b-diphtheria toxin receptor (DTR) transgenic mice and three models of interleukin 13 (IL-13)-dependent inflammation, fibrosis, and immunity, we show that CD11b(+) F4/80(+) Ly6C(+) macrophages are required for the maintenance of type 2 immunity within affected tissues but not secondary lymphoid organs. Direct depletion of macrophages during the maintenance or resolution phases of secondary Schistosoma mansoni egg-induced granuloma formation caused a profound decrease in inflammation, fibrosis, and type 2 gene expression. Additional studies with CD11c-DTR and CD11b/CD11c-DTR double-transgenic mice suggested that macrophages but not dendritic cells were critical. Mechanistically, macrophage depletion impaired effector CD4(+) T helper type 2 (Th2) cell homing and activation within the inflamed lung. Depletion of CD11b(+) F4/80(+) Ly6C(+) macrophages similarly reduced house dust mite-induced allergic lung inflammation and suppressed IL-13-dependent immunity to the nematode parasite Nippostrongylus brasiliensis. Consequently, therapeutic strategies targeting macrophages offer a novel approach to ameliorate established type 2 inflammatory diseases.