Addressing System and Clinician Barriers to Emergency Department-initiated Buprenorphine: An Evaluation of Post-intervention Physician Outcomes.

Introduction: Emergency departments (ED) are in the unique position to initiate buprenorphine, an evidence-based treatment for opioid use disorder (OUD). However, barriers at the system and clinician level limit its use. We describe a series of interventions that address these barriers to ED-initiated buprenorphine in one urban ED. We compare post-intervention physician outcomes between the study site and two affiliated sites without the interventions. Methods: This was a cross-sectional study conducted at three affiliated urban EDs where the intervention site implemented OUD-related electronic note templates, clinical protocols, a peer navigation program, education, and reminders. Post-intervention, we administered an anonymous, online survey to physicians at all three sites. Survey domains included demographics, buprenorphine experience and knowledge, comfort with addressing OUD, and attitudes toward OUD treatment. Physician outcomes were compared between the intervention site and the control sites with bivariate tests. We used logistic regression controlling for significant demographic differences to compare physicians' buprenorphine experience. Results: Of 113 (51%) eligible physicians, 58 completed the survey: 27 from the intervention site, and 31 from the control sites. Physicians at the intervention site were more likely to spend <75% of their work week in clinical practice and to be in medical practice for <7 years. Buprenorphine knowledge (including status of buprenorphine prescribing waiver), comfort with addressing OUD, and attitudes toward OUD treatment did not differ significantly between the sites. Physicians were 4.5 times more likely to have administered buprenorphine at the intervention site (odds ratio [OR] 4.5, 95% confidence interval 1.4-14.4, P = 0.01), which remained significant after adjusting for clinical time and years in practice, (OR 3.5 and 4.6, respectively). Conclusion: Physicians exposed to interventions addressing system- and clinician-level implementation barriers were at least three times as likely to have administered buprenorphine in the ED. Physicians' buprenorphine knowledge, comfort with addressing and attitudes toward OUD treatment did not differ significantly between sites. Our findings suggest that ED-initiated buprenorphine can be facilitated by addressing implementation barriers, while physician knowledge, comfort, and attitudes may be harder to improve.

Hospital-based clinicians lack knowledge and comfort in initiating medications for opioid use disorder: opportunities for training innovation.

BACKGROUND: Hospital-based clinicians infrequently initiate medications for opioid use disorder (MOUD) for hospitalized patients. Our objective was to understand hospital-based clinicians' knowledge, comfort, attitudes, and motivations regarding MOUD initiation to target quality improvement initiatives. METHODS: General medicine attending physicians and physician assistants at an academic medical center completed questionnaires eliciting barriers to MOUD initiation, including knowledge, comfort, attitudes and motivations regarding MOUD. We explored whether clinicians who had initiated MOUD in the prior 12 months differed in knowledge, comfort, attitudes, and motivations from those who had not. RESULTS: One-hundred forty-three clinicians completed the survey with 55% reporting having initiated MOUD for a hospitalized patient during the prior 12 months. Common barriers to MOUD initiation were: (1) Not enough experience (86%); (2) Not enough training (82%); (3) Need for more addiction specialist support (76%). Overall, knowledge of and comfort with MOUD was low, but motivation to address OUD was high. Compared to MOUD non-initiators, a greater proportion of MOUD initiators answered knowledge questions correctly, agreed or strongly agreed that they wanted to treat OUD (86% vs. 68%, p = 0.009), and agreed or strongly agreed that treatment of OUD with medication was more effective than without medication (90% vs. 75%, p = 0.022). CONCLUSIONS: Hospital-based clinicians had favorable attitudes toward MOUD and are motivated to initiate MOUD, but they lacked knowledge of and comfort with MOUD initiation. To increase MOUD initiation for hospitalized patients, clinicians will need additional training and specialist support.

Addiction Consult Service and Inpatient Outcomes Among Patients with Alcohol Use Disorder.

BACKGROUND: Alcohol use disorder (AUD) is the most prevalent substance use disorder, but evidence-based medications to treat AUD (MAUD), including naltrexone and acamprosate, are substantially underutilized. Hospitalization provides an opportunity to start MAUD for patients who may not otherwise seek treatment. Addiction consultation services (ACSs) have been increasingly utilized to ensure appropriate treatment. There is little research examining the effect of an ACS on health outcomes among patients with AUD. OBJECTIVE: To determine the association between an ACS consultation and provision of MAUD during admission and MAUD at discharge among admissions with AUD. DESIGN: Retrospective study comparing admissions which received an ACS consult and propensity score-matched historical control admissions. Subjects A total of 215 admissions with a primary or secondary diagnosis of AUD who received an ACS consult and 215 matched historical control admissions. Intervention ACS consultation from a multidisciplinary team offering withdrawal management, substance use disorder treatment, patient-centered counseling, discharge planning, and linkage to outpatient care for patients with substance use disorders, including AUD. Main Measures Primary outcomes were initiation of new MAUD during admission and new MAUD at discharge. Secondary outcomes were patient-directed discharge, time to 7- and 30-day readmission, and time to 7- and 30-day post-discharge ER visit. Key Results Among 430 admissions with AUD, those that received an ACS consultation were significantly more likely to receive new inpatient MAUD (33.0% vs 0.9%; OR 52.5 [CI 12.6-218.6]) and significantly more likely to receive new MAUD at discharge (41.4% vs 1.9%; OR 37.3 [13.3-104.6]), compared with historical controls. ACS was not significantly associated with patient-directed discharge, time to readmission, or time to post-discharge ER visit. CONCLUSIONS: ACS was associated with a large increase in provision of new inpatient MAUD and new MAUD at discharge when compared to propensity-matched historical controls.

Evaluation of Online Critical Care Fellowship Programs.

Background The objective of this study was to assess the accessibility and content of the critical care fellowship websites provided on the Electronic Residency Application Services (ERAS) website. Methods Using the online information provided by ERAS, we compiled a list of Accreditation Council for Graduate Medical Education (ACGME)-accredited critical care fellowship programs. Each of the links provided by ERAS was evaluated by a standard search on Google as follows: the program name + "critical care fellowship". After assembling the working links, those websites were subsequently evaluated based on the program description, application process, and educational content. Results We reviewed 59 critical care fellowship programs that were obtained from ERAS. Of the 59 programs, one retracted its participation and was not included in the study, and six other programs were excluded due to repeated links on ERAS, nonworking links, and websites without any content. We analyzed the data collected from the remaining 52 programs. Our data shows a general lack of information being provided to prospective critical care candidates. Conclusions ERAS is a major source of information for prospective fellows looking for critical care fellowships in the current match. Unfortunately, the majority of the programs evaluated lack substantial information for prospective candidates. Despite many websites containing adequate information regarding program descriptions, there was a lack of information regarding the application process and educational activities.

Genome screening, reporting, and genetic counseling for healthy populations.

Rapid advancements of genome sequencing (GS) technologies have enhanced our understanding of the relationship between genes and human disease. To incorporate genomic information into the practice of medicine, new processes for the analysis, reporting, and communication of GS data are needed. Blood samples were collected from adults with a PCR-confirmed SARS-CoV-2 (COVID-19) diagnosis (target N = 1500). GS was performed. Data were filtered and analyzed using custom pipelines and gene panels. We developed unique patient-facing materials, including an online intake survey, group counseling presentation, and consultation letters in addition to a comprehensive GS report. The final report includes results generated from GS data: (1) monogenic disease risks; (2) carrier status; (3) pharmacogenomic variants; (4) polygenic risk scores for common conditions; (5) HLA genotype; (6) genetic ancestry; (7) blood group; and, (8) COVID-19 viral lineage. Participants complete pre-test genetic counseling and confirm preferences for secondary findings before receiving results. Counseling and referrals are initiated for clinically significant findings. We developed a genetic counseling, reporting, and return of results framework that integrates GS information across multiple areas of human health, presenting possibilities for the clinical application of comprehensive GS data in healthy individuals.

Thyrotoxic periodic paralysis-still a diagnostic challenge.

Thyrotoxic periodic paralysis is a life-threatening complication characterized by acute paralysis of proximal muscles with severe hypokalemia in patients with a known or undiagnosed history of thyrotoxicosis. A 24-year-old man was brought to the emergency room with 1 month of progressively worsening lower-extremity weakness followed by urinary retention. He demonstrated severe motor weakness in proximal muscles with absent reflexes. Laboratory testing showed a dangerously low potassium of 1.3 mmol/L. Further testing to establish an etiology revealed a new diagnosis of thyrotoxicosis, and the patient was also started on the antithyroid medication methimazole and propranolol. Immediate oral and intravenous potassium supplementation was initiated to normalize the serum potassium levels to 4.7 mmol/L; that was followed by the gradual recovery of his motor function. This case report highlights the need for early consideration of endocrine and metabolic causes of acute flaccid paralysis.

Brain Abscess Due to Lactobacillus Fermentum in an Uncontrolled Diabetic.

Brain abscesses are collections of infectious fluid within the brain parenchyma, with mortality ranging from 15% to 31%. They can result from direct inoculation or via hematogenous spread. Streptococcus and staphylococcus species and Gram-negative bacilli are common bacteria responsible for brain abscesses. In immunocompromised patients, such as those with organ transplants or HIV, brain abscesses can be caused by fungi, mycobacteria, or parasites. Lactobacillus is a very rare cause of brain abscess and has only been observed in a few case reports. We report a case of a woman with uncontrolled diabetes who presented with altered mental status and was found to have a brain abscess secondary to Lactobacillus fermentum.

How to wrinkle a cell: Emerging mechanisms of microridge morphogenesis.

Microridges are laterally elongated actin-based protrusions arranged in striking maze-like patterns on the apical surfaces of mucosal epithelial cells. Recent studies have begun to reveal the molecular and mechanical factors that regulate microridge morphogenesis and allow them to adopt their unique properties. Microridges form from the coalescence of short actin-filled precursor protrusions called pegs. Microridge morphogenesis requires the establishment of apicobasal polarity, cortical myosin contraction, and Arp2/3 activity. Mature microridges contain branched actin networks, keratin filaments, and plakin cytolinkers that likely connect the two cytoskeletal elements. Once formed, microridges rearrange by fission and fusion to form increasingly regular patterns. Their highly organized arrangement provides an exciting system in which to study the interplay between molecular signaling and physical forces in the formation of subcellular patterns.

Cascade of care for office-based buprenorphine treatment in Bronx community clinics.

INTRODUCTION: The cascade of care for opioid use disorder (OUD) has been described at the population level to inform health policy and in health care systems, programs, and communities to guide targeted interventions. Office-based buprenorphine treatment is essential for expanding access to OUD treatment; however, few studies examine the cascade of care specifically for office-based buprenorphine treatment. Our objective was to describe a cascade of care for patients referred for office-based buprenorphine treatment in the primary care setting. METHODS: We conducted a retrospective cohort study of patients with OUD who were referred for office-based buprenorphine treatment within a large, urban health care system between 2018 and 2019. Our primary outcomes included completion of each step of the buprenorphine treatment cascade of care: 1) referred for treatment, 2) scheduled initial visit, 3) completed initial visit, 4) initiated buprenorphine treatment, and 5) retained in treatment at 90 days. We constructed a cascade of care by calculating proportions of patients identified at every step, starting with the total number of patients referred for treatment as the first step. We extracted data from the program's referral database and electronic medical record system. We compared characteristics of patients referred who initiated buprenorphine to those referred who did not initiate buprenorphine treatment using chi-squared tests and t-tests. To account for the hierarchical nature of the data, we conducted a Generalized Estimating Equation (GEE) modeling to test the differences in attrition rates among the steps of the cascade of care. RESULTS: In the 24-month period between 2018 and 2019, 226 patients were referred for office-based buprenorphine treatment at Montefiore's Buprenorphine Treatment Network. Patients' mean age at referral was 47 years, and most were male (68.6%), Hispanic (49.6%), and publicly insured (75.7%). Among all patients, 182 (80.5%) were scheduled for an initial visit, 142 (62.8%) completed the initial visit, 134 (59.3%) initiated buprenorphine treatment, and 95 (42.0%) were retained in treatment at 90 days. 37.2% of all patients referred did not complete the initial visit. A GEE model showed that attrition is significantly steeper in the first two steps of the cascade of care, compared to the later three steps (AOR = 1.95, 95% CI = 1.31-2.91, p < 0.05). Compared to referred patients who did not initiate treatment, those referred who initiated treatment were more likely to be using non-prescribed buprenorphine at time of referral (19.4% vs. 5.4%, p < 0.05) and be self-referred (22.4% vs. 9.8%, p < 0.05). CONCLUSION: Our study is the first to describe a cascade of care for office-based buprenorphine treatment in a large health care system. The study observed the steepest attrition in the first two steps of the cascade of care, where more than a third of patients referred did not complete the initial visit. Patients who were self-referred, or using non-prescribed buprenorphine were more likely to initiate treatment. A cascade of care specific for office-based buprenorphine can inform future efforts to improve linkage to care.

Clinical Management of Opioid Withdrawal.

Appropriate clinical management of opioid withdrawal is a crucial bridge to long-term treatment for opioid use disorder (OUD), because it is a high-risk time for potential opioid overdose and relapse. We provide a narrative review of evidence-based opioid withdrawal management strategies applicable to a variety of treatment settings and geographies. The goals of opioid withdrawal management include relieving suffering associated with withdrawal, providing appropriate diagnosis and screening, engaging patients in initiation of OUD treatment, and using harm reduction strategies, all guided by a patient-centered approach to care. In addition, we discuss complex cases, relapse prevention strategies, and new developments in opioid withdrawal management.

A comparison of office-based buprenorphine treatment outcomes in Bronx community clinics before versus during the COVID-19 pandemic.

INTRODUCTION: In 2020, the US and New York City experienced unprecedented deaths due to the COVID-19 pandemic and drug overdoses. Policy changes reduced burdensome regulations for medication treatment for opioid use disorder (OUD). Despite these policy changes, few studies examined buprenorphine treatment outcomes during the pandemic. We compared treatment outcomes among Bronx patients referred to office-based buprenorphine treatment before versus during the pandemic. METHODS: In a retrospective cohort study, we compared patients referred to buprenorphine treatment in a Bronx community clinic before (March-August 2019) versus during (March-August 2020) the pandemic. We describe changes to buprenorphine treatment during the pandemic, including telehealth and prioritizing harm reduction. Using data from medical records and program logs, main outcomes included steps of the OUD treatment cascade of care-initial visit scheduled and completed, treatment initiated, and retained in treatment at 90 days. Using chi square and t-tests, we examined differences in patient characteristics and OUD treatment cascade steps before versus during the pandemic. RESULTS: Before and during the pandemic, 72 and 35 patients were referred to buprenorphine treatment, respectively. Patients' mean age was 46 years, most were male (67.3%) or Hispanic (52.3%), and few had private insurance (19.6%). Patients referred during (vs. before) the pandemic were more likely to have private insurance (31.4% vs. 13.9%, p < 0.05) and be referred from acute care settings (37.1% vs. 19.4%, p < 0.05). No significant differences in OUD cascade of care outcomes existed between those referred during versus before the pandemic. However, among patients who initiated buprenorphine treatment, those referred during (vs. before) the pandemic were more likely to be retained in treatment at 90 days (68.0% vs. 42.9%, p < 0.05). CONCLUSIONS: Despite the COVID-19 pandemic's unprecedented devastation to the Bronx, along with worsening drug overdose deaths, OUD cascade of care outcomes were similar among patients referred to buprenorphine treatment before versus during the pandemic. Among patients who initiated buprenorphine treatment, treatment retention was better during (versus before) the pandemic. During a public health emergency, incorporating telehealth and prioritizing harm reduction are key strategies to maintain optimal OUD treatment outcomes.

Pseudo Hyperaldosteronism Secondary to Herbal Medicine Use.

Glycyrrhizic acid, better known as licorice, is commonly found in various food and cosmetic products. Excessive consumption is known to cause a syndrome of apparent mineralocorticoid excess or pseudo hyperaldosteronism. Patients typically present with resistant hypertension and hypokalemia mimicking symptoms of primary hyperaldosteronism however laboratory workup will reveal low or normal levels of plasma renin and aldosterone in the serum. While diagnosis of licorice toxicity is relatively straight forward, the challenge lies in determining the culpable agent. We report the case of a Chinese man who initially presented with resistant hypertension and hypokalemia refractory to therapy and was later diagnosed with pseudo hyperaldosteronism secondary to licorice toxicity.

Same-day vs. delayed buprenorphine prescribing and patient retention in an office-based buprenorphine treatment program.

BACKGROUND: Buprenorphine is a safe and effective treatment for opioid use disorder (OUD), yet a small fraction of people with OUD receive it, and rates of retention in treatment are suboptimal. Dropout most commonly occurs within 30 days of treatment initiation. Therefore, research needs to investigate modifiable factors contributing to early dropout. Requiring multiple visits for evaluation prior to providing an initial buprenorphine prescription (delayed prescription) may lead to more early dropout when compared with prescribing at the first medical visit (same-day prescription). Our objective was to determine whether same-day (vs. delayed) buprenorphine prescription was associated with 30-day retention in treatment. METHODS: We conducted a retrospective cohort study of 237 patients who initiated buprenorphine treatment at an urban federally qualified community health center (FQHC) between June 1, 2015, and December 31, 2017. We measured prescription delays by determining the time between patients' first request for buprenorphine treatment (by calling, presenting to the FQHC in-person, or requesting treatment during a visit) and when providers wrote buprenorphine prescriptions. We included only patients with prescription delays less than or equal to 30 days in the analysis. We defined same-day prescription as the patient experiencing no delays in starting treatment and receiving a prescription during the first medical visit. We examined whether patients who received same-day prescriptions had different sociodemographic and clinical characteristics than patients who received delayed prescriptions. We also evaluated whether there was an association between the initial provider who made the decision about same-day vs. delayed buprenorphine prescribing and same-day prescription. We built a multivariable logistic regression model to evaluate the independent association between same-day vs. delayed prescription receipt and odds of 30-day retention in treatment. RESULTS: Of the 237 patients who initiated buprenorphine treatment from June 1, 2015, to December 31, 2017, 222 had delays less than or equal to 30 days and we included them in the analysis. Of the 222 patients, the mean age was 46 (SD 10.4), the majority were Hispanic (n = 160, 72%), male (n = 175, 79%), and publicly insured (n = 165, 74%). The majority of patients experienced delayed buprenorphine prescription receipt (n = 133, 60%). The median time to buprenorphine prescription was 5 days (IQR 0-11). Of those who experienced a delay (n = 133), the median delay time was 8 days (IQR 5-20). Compared to those with same-day prescription receipt, more patients with delayed prescription receipt were non-Hispanic white (11% vs. 2%, p = 0.01), had a history of alcohol use (43% vs. 21%, p < 0.01) or benzodiazepine use (22% vs. 9%, p = 0.01), and had the buprenorphine coordinator as their initial provider (57 vs. 13%, p < 0.01). Same-day prescription receipt was not significantly associated with 30-day treatment retention in the adjusted analysis (AOR 1.92, 95% CI 0.81-4.56). CONCLUSION: Patients who received buprenorphine prescriptions on the same day as their initial evaluation differed from those who received delayed prescriptions. After adjustment for these differences, same-day prescription was not significantly associated with higher 30-day treatment retention. Providers may be delaying treatment when there is concern about alcohol and/or benzodiazepine use; however, providers could institute enhanced monitoring based on clinical concern for sedation or overdose risk without delaying buprenorphine prescription. Prospective studies of same-day vs. delayed buprenorphine receipt would elucidate the association between delays and retention more definitively.

Ezetimibe: An Unusual Suspect in Angioedema.

We describe a case of new onset angioedema likely due to Ezetimibe therapy in an elderly patient with a prior history of drug-induced bradykinin reactions who had been on the medication for multiple years. This is the second reported incidence of Ezetimibe-associated angioedema in literature. A 90-year-old African American female presented with angioedema of the face and oral mucosa with associated difficulty speaking developing hours after taking Ezetimibe 10 mg PO. She denied adding any new or unusual foods to her diet. A thorough clinical history determined Ezetimibe was the likely culprit. Ezetimibe was immediately discontinued. The swelling subsided after administration of methylprednisolone 125 mg, epinephrine 1 mg/mL, injection 0.3 mL, diphenhydramine 25 mg, and famotidine 20 mg BID within 48 hours. The patient's C1 esterase inhibitor level was measured to be within normal limits. Food panel allergy testing showed very low or undetectable IgE levels in all categories. Based on the limited reports in literature and our current case, we conclude that there is a likely association of angioedema with Ezetimibe. The mechanism, however, is unknown since it is not related to bradykinin or mast cell-mediated activation. Clinicians should advise patients taking Ezetimibe to report any swelling of the lips, face, and tongue and to immediately discontinue its use if these signs are present.

A Versatile Approach to Noncanonical, Dynamic Covalent Single- and Multi-Loop Peptide Macrocycles for Enhancing Antimicrobial Activity.

Peptide oligomers offer versatile scaffolds for the formation of potent antimicrobial agents due to their high sequence versatility, inherent biocompatibility, and chemical tunability. Though many methods exist for the formation of peptide-based macrocycles (MCs), increasingly pervasive in commercial antimicrobial therapeutics, the introduction of multiple looped structures into a single peptide oligomer remains a significant challenge. Herein, we report the utilization of dynamic hydrazone condensation for the versatile formation of single-, double-, and triple-loop peptide MCs using simple dialdehyde or dihydrazide small-molecule cross-linkers, as confirmed by MALDI-TOF MS, HPLC, and SDS-PAGE. Furthermore, incorporation of aldehyde-containing side chains onto peptides synthesized from hydrazide C-terminal resins resulted in tunable peptide MC assemblies formed directly upon resin cleavage post solid-phase peptide synthesis. Both of these types of dynamic covalent assemblies produced significant enhancements to overall antimicrobial properties when introduced into a known antimicrobial peptide, buforin II, when compared to the original unassembled sequence.

Perceived Impact of a Land and Property Rights Program on Violence Against Women in Rural Kenya: A Qualitative Investigation.

The current study focuses on a community-led land and property rights program in two rural provinces in western Kenya. The program was designed to respond to women's property rights violations to reduce violence against women and HIV risks at the community level. Through in-depth interviews with 30 women, we examine the perceived impact that this community-level property rights program had on violence against women at the individual and community level. We also examine perceptions as to how reductions in violence were achieved. Finally, we consider how our findings may aid researchers in the design of structural violence-prevention strategies.

Pantheon 1.0, a manually verified dataset of globally famous biographies.

We present the Pantheon 1.0 dataset: a manually verified dataset of individuals that have transcended linguistic, temporal, and geographic boundaries. The Pantheon 1.0 dataset includes the 11,341 biographies present in more than 25 languages in Wikipedia and is enriched with: (i) manually verified demographic information (place and date of birth, gender) (ii) a taxonomy of occupations classifying each biography at three levels of aggregation and (iii) two measures of global popularity including the number of languages in which a biography is present in Wikipedia (L), and the Historical Popularity Index (HPI) a metric that combines information on L, time since birth, and page-views (2008-2013). We compare the Pantheon 1.0 dataset to data from the 2003 book, Human Accomplishments, and also to external measures of accomplishment in individual games and sports: Tennis, Swimming, Car Racing, and Chess. In all of these cases we find that measures of popularity (L and HPI) correlate highly with individual accomplishment, suggesting that measures of global popularity proxy the historical impact of individuals.

What community-level strategies are needed to secure women's property rights in Western Kenya? Laying the groundwork for a future structural HIV prevention intervention.

Despite the recognized need for structural-level HIV prevention interventions that focus on economic empowerment to reduce women's HIV risks, few science-based programs have focused on securing women's land ownership as a primary or secondary HIV risk reduction strategy. The current study focused on a community-led land and property rights model that was implemented in two rural areas of western Kenya where HIV prevalence was high (24-30%) and property rights violations were common. The program was designed to reduce women's HIV risk at the community level by protecting and enhancing women's access to and ownership of land. Through in-depth interviews with 50 program leaders and implementers of this program we sought to identify the strategies that were used to prevent, mediate, and resolve property rights violations. Results included four strategies: (1) rights-based education of both women and men individually and at the community level, (2) funeral committees that intervene to prevent property grabbing and disinheritance, (3) paralegal training of traditional leaders and community members and local adjudication of cases of property rights violations, and (4) referring property rights violations to the formal justice system when these are not resolved at the community level. Study participants underscored that local mediation of cases resulted in a higher success rate than women experienced in the formal court system, underscoring the importance of community-level solutions to property rights violations. The current study assists researchers in understanding the steps needed to prevent and resolve women's property rights violations so as to bolster the literature on potential structural HIV prevention interventions. Future research should rigorously test property rights programs as a structural HIV prevention intervention.

ICOS-expressing lymphocytes promote resolution of CD8-mediated lung injury in a mouse model of lung rejection.

Acute rejection, a common complication of lung transplantation, may promote obliterative bronchiolitis leading to graft failure in lung transplant recipients. During acute rejection episodes, CD8(+) T cells can contribute to lung epithelial injury but the mechanisms promoting and controlling CD8-mediated injury in the lung are not well understood. To study the mechanisms regulating CD8(+) T cell-mediated lung rejection, we used a transgenic model in which adoptively transferred ovalbumin (OVA)-specific cytotoxic T lymphocytes (CTL) induce lung injury in mice expressing an ovalbumin transgene in the small airway epithelium of the lungs (CC10-OVA mice). The lung pathology is similar to findings in humans with acute lung transplant. In the presence of an intact immune response the inflammation resolves by day 30. Using CC10-OVA.RAG(-/-) mice, we found that CD4(+) T cells and ICOS(+/+) T cells were required for protection against lethal lung injury, while neutrophil depletion was not protective. In addition, CD4(+)Foxp3 (+) ICOS(+) T cells were enriched in the lungs of animals surviving lung injury and ICOS(+/+) Tregs promoted survival in animals that received ICOS(-/-) T cells. Direct comparison of ICOS(-/-) Tregs to ICOS(+/+) Tregs found defects in vitro but no differences in the ability of ICOS(-/-) Tregs to protect from lethal lung injury. These data suggest that ICOS affects Treg development but is not necessarily required for Treg effector function.

IL-33-dependent induction of allergic lung inflammation by FcγRIII signaling.

Atopic asthma is a chronic inflammatory disease of the lungs generally marked by excessive Th2 inflammation. The role of allergen-specific IgG in asthma is still controversial; however, a receptor of IgG-immune complexes (IgG-ICs), FcγRIII, has been shown to promote Th2 responses through an unknown mechanism. Herein, we demonstrate that allergen-specific IgG-ICs, formed upon reexposure to allergen, promoted Th2 responses in two different models of IC-mediated inflammation that were independent of a preformed T cell memory response. Development of Th2-type airway inflammation was shown to be both FcγRIII and TLR4 dependent, and T cells were necessary and sufficient for this process to occur, even in the absence of type 2 innate lymphoid cells. We sought to identify downstream targets of FcγRIII signaling that could contribute to this process and demonstrated that bone marrow-derived DCs, alveolar macrophages, and respiratory DCs significantly upregulated IL-33 when activated through FcγRIII and TLR4. Importantly, IC-induced Th2 inflammation was dependent on the ST2/IL-33 pathway. Our results suggest that allergen-specific IgG can enhance secondary responses by ligating FcγRIII on antigen-presenting cells to augment development of Th2-mediated responses in the lungs via an IL-33-dependent mechanism.