Plastic bronchitis (PB) is a rare disease that often occurs in patients with congenital heart disease (CHD) who have undergone staged single ventricle palliation. It is characterized by the formation of rubbery “casts” in the airways. PB treatment frequently includes inhaled tPA. However, the efficacy of tPA to reduce cast burden is unknown. This is further complicated by our lack of knowledge of cast composition. We obtained spontaneously expectorated PB casts from children (n=4) with CHD and one adult patient with idiopathic PB. Pathological assessment was made from paraffin-preserved samples. Casts were treated with phosphate-buffered saline (PBS) or tPA. Cast response to tPA was assessed by changes in cast weight and the production of fibrin D-dimer. Independent of dose, tPA reduced cast weight compared with PBS-treatment (p=0.001) and increased D-dimer levels. Histological staining showed that PB casts from all patients were comprised of fibrin and contained notable numbers of lymphocytes. Cast composition did not change over time. Collectively, these data support that in our PB patients, casts are comprised of fibrin and are responsive to tPA treatment. This makes inhaled tPA a potentially viable option for symptomatic relief of PB while we work to unravel the complexity of PB pathogenesis.

Regulator of G protein signaling 2 (RGS2), a G q -specific GTPase-activating protein, is strongly implicated in cardiovascular function. RGS2(Ϫ/Ϫ) mice are hypertensive and prone to heart failure, and several rare human mutations that accelerate RGS2 degradation have been identified among patients with hypertension. Therefore, pharmacological up-regulation of RGS2 protein levels might be beneficial. We used a ␤-galactosidase complementation method to screen several thousand compounds with known pharmacological functions for those that increased RGS2 protein levels. Several cardiotonic steroids (CTSs), including ouabain and digoxin, increased RGS2 but not RGS4 protein levels. CTSs increased RGS2 protein levels through a post-transcriptional mechanism, by slowing protein degradation. RGS2 mRNA levels in primary vascular smooth muscle cells were unaffected by CTS treatment, whereas protein levels were increased 2-to 3-fold. Na ϩ /K ϩ -ATPase was required for the increase in RGS2 protein levels, because the effect was lost in Na ϩ /K ϩ -ATPase-knockdown cells. Furthermore, we demonstrated that CTS-induced increases in RGS2 levels were functional and reduced receptor-stimulated, G qdependent, extracellular signal-regulated kinase phosphorylation. Finally, we showed that in vivo treatment with digoxin led to increased RGS2 protein levels in heart and kidney. CTSinduced increases in RGS2 protein levels and function might modify several deleterious mechanisms in hypertension and heart failure. This novel CTS mechanism might contribute to the beneficial actions of low-dose digoxin treatment in heart failure. Our results support the concept of small-molecule modulation of RGS2 protein levels as a new strategy for cardiovascular therapy.

Guidelines recommend patient follow-up within 2 weeks of antidepressant initiation or uptitration to minimize treatment discontinuation and suicidal ideation risks; however, time constraints and lack of systematic processes remain barriers in primary care. A pharmacist-led multidisciplinary telemonitoring service aimed to address these barriers. This was a retrospective, observational study of adults with depression initiated or uptitrated on an antidepressant between May and October 2016. Outcomes included the proportion of eligible patients successfully contacted, adherence, adverse effects, suicidal ideations, and pharmacist interventions. Clinical pharmacists successfully reached 258 of 380 (68%) patients and provided follow-up in 298 calls. Patients endorsed antidepressant nonadherence during 56 (19%) calls, adverse effects in 81 (27%) calls, and suicidal ideations in 13 (4%) calls. Pharmacists provided 109 total interventions for 102 patients. The clinical pharmacist-led multidisciplinary antidepressant telemonitoring service is an alternative resource to monitor patients after antidepressant initiation or titration in primary care settings.

Newly initiated, potentially interacting medications are a major preventable driver of ACS use for lithium toxicity, whereas age, chronic disease, and total daily lithium dose are small but significant factors. Clinicians should use extra caution when initiating a potentially interacting medication.

Background Elective percutaneous coronary interventions (PCI) are difficult to discriminate from nonelective PCI in administrative data due to non-specific encounter codes, limiting the ability to track outcomes, ensure appropriate medical management, and/or perform research on patients who undergo elective PCI. The objective of this study was to assess the abilities of several algorithms to identify elective PCI procedures using administrative data containing diagnostic, utilization, and/or procedural codes. Methods and results For this retrospective study, administrative databases in an integrated healthcare delivery system were queried between 1/1/2015 and 6/31/2016 to identify patients who had an encounter for a PCI. Using clinical criteria, each encounter was classified via chart review as a valid PCI, then as elective or non-elective. Cases were tested against nine predetermined algorithms. Performance statistics (sensitivity, specificity, positive predictive value, and negative predictive value) and associated 95% confidence intervals (CI) were calculated. Of 521 PCI encounters reviewed, 497 were valid PCI, 93 of which were elective. An algorithm that excluded emergency room visit events had the highest sensitivity (97.9%, 95%CI 92.5%-99.7%) while an algorithm that included events occurring within 90 days of a cardiologist visit and coronary angiogram or stress test had the highest positive predictive value (62.2%, 95%CI 50.8%-72.7%). Conclusions Without an encounter code specific for elective PCI, an algorithm excluding procedures associated with an emergency room visit had the highest sensitivity to identify elective PCI. This offers a reasonable approach to identify elective PCI from administrative data.

Introduction Depression is one of the most common mental illnesses in the United States and is often treated in primary care settings. Despite its prevalence, depression remains underdiagnosed and undertreated for a variety of reasons, including stigma. This may result in suboptimal management of depression. Studies evaluating stigma in US primary care providers (PCP) are scarce. The main objective of this study was to describe stigma in a cohort of PCPs. Methods We utilized a validated questionnaire to measure stigma (score range 15 to 75 with lower scores indicating lower stigma levels). PCPs in 2 academic internal medicine clinics were sent an electronic questionnaire and received a small monetary incentive for responding. In addition to the stigma survey, we collected demographic data, including age, provider type, gender, and other data related to social proximity to mental illness. To describe stigma, differences in stigma between provider characteristics were evaluated using t tests and ANOVA tests as appropriate. Results Of 107 PCPs, 71 responded (66.4% response rate). Male responders displayed higher stigma scores than females (31.8 vs 27.4, P = .0021). Medical residents displayed higher stigma scores than nonresidents (31.3 vs 27.2, P = .0045). Providers with personal exposure to mental illness and those who reported they frequently treated depression had less stigma. Discussion Overall, a range of stigma was present among PCPs surveyed. Higher levels of stigma were found in men, medical residents, those without personal exposure to mental illness, younger PCPs, and those who reported treating depression less frequently. Future studies should utilize larger sample sizes and focus on the impact of stigma on quality of care.

Purpose To gain knowledge of lung clearance mechanisms of inhaled tissue plasminogen activator (tPA). Methods Using an in vivo mouse model and ex vivo murine whole organ cell suspensions, we examined the capability of the lungs to utilize LRP1 receptor-mediated endocytosis (RME) for the uptake of exogenous tPA with and without an LRP1 inhibitor, receptor associated protein (RAP), and quantitatively compared it to the liver. We also used a novel imaging technique to assess the amount LRP1 in sections of mouse liver and lung. Results Following intratracheal administration, tPA concentrations in the BALF declined over time following two-compartment pharmacokinetics suggestive of RME clearance mechanism. Ex vivo studies showed that lung and liver cells are similarly capable of tPA uptake via LRP1 RME which was reduced by ~50% by RAP. The comparable lung and liver uptake of tPA is likely due to equivalent amounts of LRP1 of which there was an abundance of LRP1 in alveolar epithelium. Conclusions Our findings indicate that LRP1 RME is a candidate clearance mechanism for inhaled tPA which has implications for the development of safe and effective dosing regimens of inhaled tPA for the treatment of plastic bronchitis and other fibrin-inflammatory airway diseases in which inhaled tPA may have utility.

Summary Struma ovarii is a rare, usually benign ovarian tumour with malignancy occurring in <5% of cases. Metastases, particularly seeding to bone, are extremely rare. Presentation is variable but often features local pain and/or ascites and hyperthyroidism may occur. It is not established how to best treat and follow patients with extensive disease. Case reports of radioiodine (I131) ablative therapy following thyroidectomy have shown reduced recurrence. We describe the case of a 33-year-old woman who presented with bone pain and was diagnosed with skeletal metastases with features of follicular thyroid carcinoma. However, thyroid pathology was benign. She recalled that 5 years prior, an ovarian teratoma was excised, classified at that time as a dermoid cyst. Retrospective review of this pathology confirmed struma ovarii without obvious malignant features. The patient was found to have widespread metastases to bone and viscera and her thyroglobulin was >3000 µg/L following recombinant TSH administration prior to her first dose of I131. At 25 months following radioiodine treatment, she is in remission with an undetectable thyroglobulin and clear I131 surveillance scans. This case demonstrates an unusual presentation of malignant struma ovarii together with challenges of predicting metastatic disease, and demonstrates a successful radioiodine regimen inducing remission. Learning points: Malignant transformation of struma ovarii (MSO) is extremely rare and even rarer are metastatic deposits in bone and viscera. MSO can be difficult to predict by initial ovarian pathology, analogous to the difficulty in some cases of differentiating between follicular thyroid adenoma and carcinoma. No consensus exists on the management for post operative treatment of MSO; however, in this case, three doses of 6Gbq radioiodine therapy over a short time period eliminated metastases to viscera and bone. Patients should continue to have TSH suppression for ~5 years. Monitoring thyroglobulin levels can predict recurrence.