Corrination mitigates peptide aggregation as exemplified for Glucagon.

Pharmaceutical development of glucagon for use in acute hypoglycemia has proved challenging, due in large part to poor solubility, poor stability and aggregate formation. Herein, we describe highly soluble, low aggregating, glucagon conjugates generated through use of the commercially available vitamin B12 precursor dicyanocobinamide ('corrination'), which retain full stimulatory action at the human glucagon receptor. The modified glucagon analogs were tested in a chemical stability assay in 50 mM phosphate buffer and the percentage of original concentration retained was determined after two weeks of incubation at 37° C. Aggregate formation assays were also performed after 48 h of agitation at 37°C using a thioflavin (ThT) fluorescence-based assay. All corrinated compounds retained original concentration to a higher degree than glucagon controls and showed markedly decreased aggregation compared to their respective noncorrinated analogues. Based on the statistically significant increase in chemical stability coupled with the notably decreased tendency to form aggregates, analogues 2 and its corrinated conjugate 5 were used for a functional assay study performed after agitation at 37°C for 24-hr after which agonism was measured at the human glucagon receptor using a cAMP FRET assay. Corrinated 5 exhibited a 6.6-fold increased potency relative to glucagon, which was shown to have a 165-fold reduction in potency. The relative potency of 5 was also improved compared to that of 2 with EC50 values of 5.5 nM and 9.6 nM for 5 and 2, respectively. In conclusion, corrination of peptides mitigates aggregation, presenting a compound with prolonged stability and agonism as demonstrated for glucagon.

Intercostal Artery Laceration after Adrenal Mass Cryoablation.

We present a case of a 69-year-old male with profound Cushing's syndrome and hypercortisolemia secondary to a cortisol-secreting adrenocortical carcinoma. Patient was not a surgical candidate and subsequently underwent a successful posterior approach tumor cryoablation. The procedure was complicated by a T11 intercostal artery injury and hemothorax. The detection of the culprit injury was almost immediate and the quick response time, and treatment of the injury via an intercostal artery embolization was critical to limiting the patient's morbidity and mortality. This case discusses the technical challenges of a posterior-approach ablation, the pitfalls to avoid, and the importance of attaining rapid hemostasis.

Prediction of in-hospital deterioration in normotensive pulmonary embolism remains elusive: external validation of the calgary acute pulmonary embolism score.

Acute pulmonary embolism (PE) is a frequently diagnosed condition. Prediction of in-hospital deterioration is challenging with current risk models. The Calgary Acute Pulmonary Embolism (CAPE) score was recently derived to predict in-hospital adverse PE outcomes but has not yet been externally validated. Retrospective cohort study of normotensive acute pulmonary embolism cases diagnosed in our emergency department between 2017 and 2019. An external validation of the CAPE score was performed in this population for prediction of in-hospital adverse outcomes and a secondary outcome of 30-day all-cause mortality. Performance of the simplified Pulmonary Embolism Severity Index (sPESI) and Bova score was also evaluated. 712 patients met inclusion and exclusion criteria, with 536 patients having a sPESI score of 1 or more. Among this population, the CAPE score had a weak discriminative power to predict in-hospital adverse outcomes, with a calculated c-statistic of 0.57. In this study population, an external validation study found weak discriminative power of the CAPE score to predict in-hospital adverse outcomes among normotensive PE patients. Further efforts are needed to define risk assessment models that can identify normotensive PE patients at risk for in hospital deterioration. Identification of such patients will better guide intensive care utilization and invasive procedural management of PE.

Adverse Clinical Outcomes Among Patients With Acute Low-risk Pulmonary Embolism and Concerning Computed Tomography Imaging Findings.

Importance: Most patients presenting to US emergency departments (EDs) with acute pulmonary embolism (PE) are hospitalized, despite evidence from multiple society-based guidelines recommending consideration of outpatient treatment for those with low risk stratification scores. One barrier to outpatient treatment may be clinician concern regarding findings on PE-protocol computed tomography (CTPE), which are perceived as high risk but not incorporated into commonly used risk stratification tools. Objective: To evaluate the association of concerning CTPE findings with outcomes and treatment of patients in the ED with acute, low-risk PE. Design, Setting, and Participants: This cohort study used a registry of all acute PEs diagnosed in the adult ED of an academic medical center from October 10, 2016, to December 31, 2019. Acute PE cases were divided into high- and low-risk groups based on PE Severity Index (PESI) class alone or using a combination of PESI class and biomarker results. The low-risk group was further divided based on the presence of concerning CTPE findings: (1) bilateral central embolus, (2) right ventricle-to-left ventricle ratio greater than 1.0, (3) right ventricle enlargement, (4) septal abnormality, or (5) pulmonary infarction. Data analysis was conducted from June to October 2022. Main Outcomes and measures: The primary outcome was all-cause mortality at 7 and 30 days. Secondary outcomes included hospitalization, length of stay, need for intensive care, use of echocardiography and/or bedside ultrasonography, and activation of the PE response team (PERT) . Results: Of 817 patients (median [IQR] age, 58 [47-71] years; 417 (51.0%) female patients; 129 [15.8%] Black and 645 [78.9%] White patients) with acute PEs, 331 (40.5%) were low risk and 486 (59.5%) were high risk by PESI score. Clinical outcomes were similar for all low-risk patients, with no 30-day deaths in the low-risk group with concerning CTPE findings (0 of 151 patients) vs 4 of 180 (2.2%) in the low-risk group without concerning CTPE findings and 88 (18.1%) in the high-risk group (P < .001). Low-risk patients with concerning CTPE findings were less frequently discharged from the ED than those without concerning CTPE findings (3 [2.0%] vs 14 [7.8%]; P = .01) and had more frequent echocardiography (87 [57.6%] vs 49 [27.2%]; P < .001) and PERT activation for consideration of advanced therapies (34 [22.5%] vs 11 [6.1%]; P < .001). Conclusions and Relevance: In this single-center study, CTPE findings widely believed to confer high risk were associated with increased hospitalization and resource utilization in patients with low-risk PE but not short-term adverse clinical outcomes.

Peripherally restricted oxytocin is sufficient to reduce food intake and motivation, while CNS entry is required for locomotor and taste avoidance effects.

OBJECTIVES: Oxytocin (OT) has a well-established role in reproductive behaviours; however, it recently emerged as an important regulator of energy homeostasis. In addition to central nervous system (CNS), OT is found in the plasma and OT receptors (OT-R) are found in peripheral tissues relevant to energy balance regulation. Here, we aim to determine whether peripheral OT-R activation is sufficient to alter energy intake and expenditure. METHODS AND RESULTS: We first show that systemic OT potently reduced food intake and food-motivated behaviour for a high-fat reward in male and female rats. As it is plausible that peripherally, intraperitoneally (IP) injected OT crosses the blood-brain barrier (BBB) to produce some of the metabolic effects within the CNS, we screened, with a novel fluorescently labelled-OT (fAF546-OT, Roxy), for the presence of IP-injected Roxy in CNS tissue relevant to feeding control and compared such with BBB-impermeable fluorescent OT-B12 (fCy5-OT-B12; BRoxy). While Roxy did penetrate the CNS, BRoxy did not. To evaluate the behavioural and thermoregulatory impact of exclusive activation of peripheral OT-R, we generated a novel BBB-impermeable OT (OT-B12 ), with equipotent binding at OT-R in vitro. In vivo, IP-injected OT and OT-B12 were equipotent at food intake suppression in rats of both sexes, suggesting that peripheral OT acts on peripheral OT-R to reduce feeding behaviour. Importantly, OT induced a potent conditioned taste avoidance, indistinguishable from that induced by LiCl, when applied peripherally. Remarkably, and in contrast to OT, OT-B12 did not induce any conditioned taste avoidance. Limiting the CNS entry of OT also resulted in a dose-dependent reduction of emesis in male shrews. While both OT and OT-B12 proved to have similar effects on body temperature, only OT resulted in home-cage locomotor depression. CONCLUSIONS: Together our data indicate that limiting systemic OT CNS penetrance preserves the anorexic effects of the peptide and reduces the clinically undesired side effects of OT: emesis, taste avoidance and locomotor depression. Thus, therapeutic targeting of peripheral OT-R may be a viable strategy to achieve appetite suppression with better patient outcomes.

Iliocaval Reconstruction: Review of Technique, Challenges, and Outcomes.

Iliocaval thrombosis is a major source of morbidity for patients, with a range of clinical presentations, including recurrent lower extremity deep venous thrombosis and postthrombotic syndrome. Endovascular reconstruction of chronic iliocaval occlusion has been demonstrated to be a technically feasible procedure that provides long-lasting symptom relief in combination with antithrombotic therapy and close clinical monitoring. Herein, we describe the etiologies of iliocaval thrombosis, patient assessment, patient management prior to and after intervention, procedural techniques, and patient outcomes.

Common Causes of Outpatient CT and MRI Callback Examinations: Opportunities for Improvement.

OBJECTIVE. The purposes of this study were to investigate factors driving callback MRI and CT examinations and to discern opportunities for optimizing the patient experience by reducing future callbacks. MATERIALS AND METHODS. All consecutive outpatient CT and MRI callback examinations from October 2015 to October 2017 in four radiology subspecialties (cardiothoracic imaging, abdominal imaging, neuroradiology, musculoskeletal imaging) were reviewed at an academic quaternary care center. Callback details (modality, subspecialty, protocoling radiologist, protocol assigned, protocol performed, interpreting radiologist, and reason for callback) were recorded, and reason for callback was categorized. Callback rates were calculated and compared across subspecialties and modalities. RESULTS. There were 194 callbacks among 147,068 MRI and 195,578 CT examinations. The callback rate for MRI was approximately nine times that of CT (MRI, 0.114% [n = 168]; CT, 0.013% [n = 26]). The callback rate was highest for musculoskeletal radiology (CT, 0.090% [7/7802]; MRI, 0.265% [73/27501]; p < 0.0001). Of 65 subspecialty radiologists, nine initiated 52% (101/194) of all callback examinations, and 20 initiated 80% (155/194). One musculoskeletal radiologist was responsible for 11.8% (23/194) of all callbacks. The most common reasons for callbacks were protocol error (28% [55/194]), inadequate anatomic coverage (21% [40/194]), incomplete examination (13% [25/194]), and perceived suboptimal image quality (11% [22/194]). The three most common causes of callbacks (62% [120/194] of all callbacks) were largely preventable. CONCLUSION. Outpatient callback examinations are uncommon, occur more often for MRI than CT, and are often preventable. Callback proclivities likely vary between attending radiologists. Targeted improvement efforts may mitigate callbacks.

Advanced Quality Training in Radiology: Inaugural Report of a 2-Year Program.

OBJECTIVE. The purpose of this study is to describe and analyze the outcomes of a 2-year advanced quality training program for radiology residents. MATERIALS AND METHODS. In 2016, the radiology quality committee of a quaternary health system created a hands-on 2-year advanced quality training curriculum for diagnostic and interventional radiology residents. Internal candidates with the following prerequisites submitted competitive applications: registration for a 2-day lean health care management course, completion of four or more Radiological Society of North America (RSNA) quality essentials certificates, identification of faculty mentor(s), selection of one quality improvement project to champion, and completion of a two-page essay summarizing interest in quality improvement, the proposed project, and its potential impact. Residents were required to attend monthly quality meetings, pursue their project and its derivatives, submit completed work for consideration to a national meeting and for publication, and present at departmental grand rounds. Outcomes were summarized using descriptive statistics. RESULTS. Five residents submitted four projects for consideration, and all five were selected. In addition to the four submitted projects, seven additional projects were pursued. Participants worked on nine local and three multicenter process improvements, gave one to two grand rounds each, presented three oral and five poster presentations, generated eight publications, received three awards, formed 14 mentor-mentee relationships, and influenced local and multisite practice patterns. Participants reported gaining firsthand experience in quality improvement principles and developing real-world leadership skills. CONCLUSION. A targeted 2-year curriculum emphasizing hands-on quality improvement experience with rich mentor-mentee relationships can produce meaningful results.

Diversity and severity of adverse reactions to quinine: A systematic review.

Quinine is a common cause of drug-induced thrombocytopenia and the most common cause of drug-induced thrombotic microangiopathy. Other quinine-induced systemic disorders have been described. To understand the complete clinical spectrum of adverse reactions to quinine we searched 11 databases for articles that provided sufficient data to allow evaluation of levels of evidence supporting a causal association with quinine. Three reviewers independently determined the levels of evidence, including both immune-mediated and toxic adverse reactions. The principal focus of this review was on acute, immune-mediated reactions. The source of quinine exposure, the involved organ systems, the severity of the adverse reactions, and patient outcomes were documented. One hundred-fourteen articles described 142 patients with definite or probable evidence for a causal association of quinine with acute, immune-mediated reactions. These reactions included chills, fever, hypotension, painful acral cyanosis, disseminated intravascular coagulation, hemolytic anemia, thrombocytopenia, neutropenia, acute kidney injury, rhabdomyolysis, liver toxicity, cardiac ischemia, respiratory failure, hypoglycemia, blindness, and toxic epidermal necrolysis. One hundred-two (72%) reactions were caused by quinine pills; 28 (20%) by quinine-containing beverages; 12 (8%) by five other types of exposures. Excluding 41 patients who had only dermatologic reactions, 92 (91%) of 101 patients had required hospitalization for severe illness; 30 required renal replacement therapy; three died. Quinine, even with only minute exposure from common beverages, can cause severe adverse reactions involving multiple organ systems. In patients with acute, multi-system disorders of unknown origin, an adverse reaction to quinine should be considered.