Citations

ABSTRACTAlthough current treatment strategies for nonmalignant airway stenosis may offer short‐term relief, their effectiveness is limited by high recurrence rates, often requiring additional procedures. While paclitaxel‐coated balloons (PCB) have demonstrated effectiveness in treating stenosis across various vascular and nonvascular conditions, their evidence in recurrent airway stenosis remains limited. Here, we present the case of a 35‐year‐old female with bronchial stenosis who underwent multiple bronchoscopic interventions, all of which were complicated by restenosis. Following the addition of a PCB to the therapeutic regimen, the patient achieved sustained airway patency.

OBJECTIVE In many individuals, type 2 diabetes (T2D) remains poorly controlled despite taking multiple glucose-lowering therapies. Several studies have demonstrated that endogenous hypercortisolism is prevalent among these individuals. We tested whether cortisol-directed therapy improves their glycemic control. RESEARCH DESIGN AND METHODS In this prospective, multicenter, double-blind study, 136 individuals with T2D (hemoglobin A1c [HbA1c] 7.5%–11.5% [58–102 mmol/mol] on multiple medications) and hypercortisolism (by dexamethasone suppression test) were randomized 2:1 to the glucocorticoid receptor antagonist mifepristone (300–900 mg once daily; n = 91) or placebo (n = 45) for 24 weeks, with stratification by presence/absence of an adrenal imaging abnormality. The primary end point was the change in HbA1c. Secondary end points included changes in glucose-lowering medications, weight, and waist circumference and safety. RESULTS Mean baseline HbA1c in the study cohort was 8.55% (69.9 mmol/mol). At 24 weeks, the least squares mean (LSM) difference from placebo in HbA1c was −1.32% (95% CI −1.81 to −0.83; P < 0.001). Participants receiving mifepristone experienced reductions in body weight and waist circumference (placebo-adjusted LSM differences of −5.12 kg [95% CI −8.20 to −2.03] and −5.1 cm [−8.23 to −1.99], respectively). Of participants on mifepristone, 46% discontinued therapy, compared with 18% on placebo. Adverse events with mifepristone (>10% of participants) included hypokalemia, fatigue, nausea, vomiting, headache, peripheral edema, diarrhea, and dizziness, consistent with mifepristone’s known tolerability profile. Increases in blood pressure also occurred. CONCLUSIONS In individuals with inadequately controlled T2D and hypercortisolism, cortisol-directed medical therapy with mifepristone reduced HbA1c, with a manageable tolerability profile.

Background: Periacetabular osteotomy (PAO) is a complex procedure historically requiring inpatient stay. However, there is increased emphasis for other complex orthopaedic procedures (eg, arthroplasty) to be performed on an outpatient basis by insurance companies. Increasing resistance to insurance approval of inpatient listing for PAO patients at the participating institution suggests that this changing tide is affecting PAO surgery. Purpose: To (1) investigate the proportion of PAOs various surgical listing classifications (outpatient, outpatient-overnight, inpatient, etc), (2) determine the incidence of subsequent denial/request for additional documentation for approval of inpatient stay after PAO, and (3) characterize the accuracy of preoperative patient listing classification as well as mean length of stay (LOS) and incidence of successful same-day discharge after PAO at a single institution. Study Design: Case series; Level of evidence, 3. Methods: A retrospective chart review was performed to identify all PAOs, performed by 4 participating surgeons, at a single academic institution over a 2-year period. The initial listing status as an outpatient-overnight or inpatient procedure was identified. Whether a preoperative peer review was required for approval of inpatient listings as well as if additional documentation was necessary to convert outpatient-overnight listings to inpatient stays were also recorded. Results: A total of 140 PAOs among 117 patients were performed with 25 (17.9%) initially listed as an inpatient stay and 115 (82.1%) listed as outpatient-overnight. Of the 25 PAOs listed as inpatient, 2 (8.0%) required a preoperative peer review process to justify or clarify listing status. The mean LOS was 1.9 ± 1.4 days with 55.7% (78/140) of PAOs staying ≥2 nights in the hospital. Only 6 PAOs (4.3%) went home the same day as surgery. Patients who underwent PAO with concomitant hip arthroscopy stayed on average 2.4 ± 1.2 days in comparison with 1.6 ± 1.4 days for those who underwent PAO alone ( P < .001). Of the 115 PAOs listed as an outpatient-overnight, 53 (46.1%) converted to an inpatient stay, all of which required service documentation to support conversion to inpatient status. Conclusion: Over half of PAOs performed resulted in an inpatient stay with patients spending ≥2 nights in the hospital. Additionally, all conversions from outpatient-overnight to inpatient required additional service documentation to support status conversion. Understanding trends in postoperative hospitalizations and LOS may allow for better informed partnerships between surgeons and insurance companies creating more efficient preauthorizations, billing practices, and expected patterns of patient care and discharge.

Klippel–Trenaunay (KT) syndrome and Cardiac Sarcoidosis (CS) are two distinct medical conditions that rarely coexist, each presenting unique challenges in diagnosis and management. Here, we present a rare case of a 30-year-old male with a history of KT syndrome complicated by recurrent deep vein thrombosis, who presented with symptoms of acute heart failure including shortness of breath, fatigue, dizziness, palpitations, and chest pain and was subsequently diagnosed with isolated CS. We discuss the importance of thorough clinical evaluation and multimodal diagnostic approaches in this complex scenario with overlapping symptoms and diagnostic dilemmas.

In the INTRIGUE phase III trial (ClinicalTrials.gov identifier: NCT03673501 ), adult patients with advanced gastrointestinal stromal tumor previously treated with imatinib were randomly assigned 1:1 to ripretinib 150 mg once daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off). In the primary analysis, overall survival (OS) was immature. In this study, we report the final planned analysis of OS (key secondary end point), progression-free survival (PFS) on third-line therapy (second PFS; prespecified exploratory end point), and long-term safety. Final OS analysis was prespecified to occur with approximately 200 and ≥145 events in the overall and KIT exon 11 intention-to-treat (ITT) populations, respectively. As of March 15, 2023, there were 211 and 151 OS events in the overall ITT and KIT exon 11 ITT populations, respectively. Median OS was similar between second-line ripretinib and sunitinib in both populations (overall, 35.5 v 31.5 months; KIT exon 11, 35.5 v 32.8 months). Median second PFS (on third-line therapy) for the overall ITT population was similar between the ripretinib and sunitinib arms (7.7 v 7.4 months). Safety was consistent with the primary analysis. OS from this analysis was similar between arms, and second PFS suggests that receiving ripretinib did not adversely affect the PFS of third-line therapy.

Objective: Four hypertension-mediated left ventricular hypertrophy (LVH) phenotypes have been reported using cardiac magnetic resonance (CMR): normal LV, LV remodelling, eccentric and concentric LVH, with varying prognostic implications. The electrocardiogram (ECG) is routinely used to detect LVH; however, its capacity to differentiate between LVH phenotypes is unknown. This study aimed to classify hypertension-mediated LVH from the ECG using machine learning and test for associations of ECG-predicted phenotypes with incident cardiovascular outcomes. Methods: ECG biomarkers were extracted from the 12-lead ECG of 20 439 hypertensive patients in UK Biobank (UKB). Classification models integrating ECG and clinical variables were built using logistic regression, support vector machine (SVM), and random forest. The models were trained in 80% of the participants, and the remaining 20% formed the test set. External validation was sought in 877 hypertensive participants from the Study of Health in Pomerania (SHIP). In the UKB test set, we tested for associations between ECG-predicted LVH phenotypes and incident major adverse cardiovascular events (MACE) and heart failure. Results: Among UKB participants 19 408 had normal LV, 758 LV remodelling, 181 eccentric and 92 concentric LVH. Classification performance of the three models was comparable in UKB. SVM (accuracy 0.79, sensitivity 0.59, specificity 0.87, AUC 0.69) was taken forward for external validation with similar results in SHIP. There was superior prediction of eccentric LVH in both cohorts. In the UKB test set, ECG-predicted eccentric LVH was associated with heart failure (hazard ratio 3.42, 95% CI 1.06–9.86). Conclusion: ECG-based ML classifiers represent a potentially accessible screening strategy for the early detection of hypertension-mediated LVH phenotypes.

Abstract Glioblastoma (GBM) remains the most common and lethal adult malignant primary brain cancer with few treatment options. A significant issue hindering GBM therapeutic development is intratumor heterogeneity. GBM tumors contain neoplastic cells within a spectrum of different transcriptional states. Identifying effective therapeutics requires a platform that predicts the differential sensitivity and resistance of these states to various treatments. Here, we developed a novel framework, ISOSCELES ( I nferred cell S ensitivity O perating on the integration of S ingle- C ell E xpression and L 1000 E xpression S ignatures), to quantify the cellular drug sensitivity and resistance landscape. Using single-cell RNA sequencing of newly diagnosed and recurrent GBM tumors, we identified compounds from the LINCS L1000 database with transcriptional response signatures selectively discordant with distinct GBM cell states. We validated the significance of these findings in vitro, ex vivo, and in vivo , and identified a novel combination of an OLIG2 inhibitor and Depatux-M for GBM. Our studies suggest that ISOSCELES identifies cell states sensitive and resistant to targeted therapies in GBM and that it can be applied to identify new synergistic combinations. Highlights Integration of GBM single-cell RNA sequencing data with L1000-derived drug response signatures facilitates clustering of tumor cells and small molecules on cell-drug connectivity. Cell-drug connectivity predicts the identities of drug-sensitive and resistant cell states. In silico perturbation analysis using cell-drug connectivity predicts drug-induced changes in the cell-drug connectivity landscape in vivo. In silico perturbation analysis to predict drug-induced changes in the tumor cell-drug connectivity landscape predicts drug combinations that synergize in vivo to extend survival.

Abstract Background: Expiratory central airway collapse (ECAC) is defined by excessive inward bulging of either posterior tracheobronchial membrane or anterolateral cartilage. ECAC commonly coexists with COPD, asthma, GERD, and obstructive sleep apnea. ECAC association with bronchiectasis is yet to be documented. Common conditions leading to bronchiectasis are obstructive lung diseases predisposing to recurrent infections, cystic fibrosis, COPD, or idiopathic. This study aims to evaluate the occurrence of bronchiectasis in patients with ECAC as the primary outcome and the correlation between the severity of bronchiectasis and the severity of ECAC as a secondary outcome. Methods: A retrospective single-center study evaluated patients diagnosed with ECAC using dynamic bronchoscopy in Mayo Clinic, Florida, from June 2019 to December 2020. Radiologists analyzed dynamic, or non-contrast chest computed tomography (CT) scans to evaluate the presence of bronchiectatic changes and the prevalence of bronchiectasis in this population. Bronchiectatic changes were documented using the Brody scoring system which recorded the bronchiectasis size, extent and tree in bud appearance in individual lobes. The final score had a range from 0 to 72. The bronchiectasis scores for individual lung lobes were analyzed to interpret distribution of bronchiectasis in ECAC population. The combined bronchiectasis scores of severe ECAC and non-severe ECAC cohorts were compared to assess if severe ECAC had higher bronchiectatic involvement. Results: Out of the 166 patients diagnosed with ECAC through dynamic bronchoscopy, 133 patients (80.1%) presented bronchiectatic changes in their CT scans. Of the 59 patients with severe ECAC, 51 patients (86.4%) were diagnosed with bronchiectasis. Of the 107 patients with non-severe ECAC, 82 (76.6 %) had bronchiectasis. The mean bronchiectasis scores are greater in right and left lower lobes, followed by middle lobes. The median values between severe and non-severe ECAC were 3 and 3 respectively with a p value of 0.34. The inter quartile range was 9 in severe ECAC group and 6 in non-severe ECAC (graph 1). Discussion: The outcomes of this study showed a significant presence of bronchiectatic changes in the ECAC population, implying the importance of evaluating for other pathologies. It can signify a pathological process similar to other pathologies which predispose to recurrent infections except for cystic fibrosis, which has an upper lobe involvement. The correlation of severity between ECAC and bronchiectasis requires more studies with a larger cohort for significant outcomes.

OBJECTIVE Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes and HbA1c 7.5%–11.5% (58–102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure–lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol &gt;1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure–lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure–lowering medications (1.390); older age (1.316); BMI &lt;30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P &lt; 0.03). CONCLUSIONS Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.