Citations

COMMD1 deficiency results in defective copper homeostasis, but the mechanism for this has remained elusive. Here we report that COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. This COMMD/CCDC22/CCDC93 (CCC) complex interacts with the multisubunit WASH complex, an evolutionarily conserved system, which is required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. Interactions between the WASH complex subunit FAM21, and the carboxyl-terminal ends of CCDC22 and CCDC93 are responsible for CCC complex recruitment to endosomes. We show that depletion of CCC complex components leads to lack of copper-dependent movement of the copper transporter ATP7A from endosomes, resulting in intracellular copper accumulation and modest alterations in copper homeostasis in humans with CCDC22 mutations. This work provides a mechanistic explanation for the role of COMMD1 in copper homeostasis and uncovers additional genes involved in the regulation of copper transporter recycling.

Abstract— We evaluated whether droxidopa, a prodrug converted to norepinephrine, is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension, which results from failure to generate an appropriate norepinephrine response to postural challenge. Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa titration (100–600 mg, 3× daily). Responders then received an additional 7-day open-label treatment at their individualized dose. Patients were subsequently randomized to continue with droxidopa or withdraw to placebo for 14 days. We then assessed patient-reported scores on the Orthostatic Hypotension Questionnaire and blood pressure measurements. Mean worsening of Orthostatic Hypotension Questionnaire dizziness/lightheadedness score from randomization to end of study (the primary outcome; N=101) was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa ( P =0.509). Four of the other 5 Orthostatic Hypotension Questionnaire symptom scores and all 4 symptom-impact scores favored droxidopa, with statistical significance for the patient’s self-reported ability to perform activities requiring standing a short time ( P =0.033) and standing a long time ( P =0.028). Furthermore, a post hoc analysis of a predefined composite score of all symptoms (Orthostatic Hypotension Questionnaire composite) demonstrated a significant benefit for droxidopa ( P =0.013). There was no significant difference between groups for standing systolic blood pressure ( P =0.680). Droxidopa was well tolerated. In summary, this randomized withdrawal droxidopa study failed to meet its primary efficacy end point. Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension, as suggested by the positive secondary outcomes of this trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00633880.

Because of the complexity of cervical cancer prevention guidelines, clinicians often fail to follow best-practice recommendations. Moreover, existing clinical decision support (CDS) systems generally recommend a cervical cytology every three years for all female patients, which is inappropriate for patients with abnormal findings that require surveillance at shorter intervals. To address this problem, we developed a decision tree-based CDS system that integrates national guidelines to provide comprehensive guidance to clinicians. Validation was performed in several iterations by comparing recommendations generated by the system with those of clinicians for 333 patients. The CDS system extracted relevant patient information from the electronic health record and applied the guideline model with an overall accuracy of 87%. Providers without CDS assistance needed an average of 1 minute 39 seconds to decide on recommendations for management of abnormal findings. Overall, our work demonstrates the feasibility and potential utility of automated recommendation system for cervical cancer screening and surveillance.

BackgroundPast research has explored patients' expectations about the informed consent process. However, it is currently unknown if the complexity of the surgical procedure influences the type of anesthesia‐related risks that patients wish disclosed. This study explored fears of anesthesia‐related complications and whether these changed based on severity of surgery classification.MethodsPatients presenting to our pre‐operative evaluation clinic from February 2013 to May 2013 were asked to participate in a survey‐based study meant to evaluate their perception of five possible anesthetic risks (peripheral nerve injury, death, nausea and vomiting, heart attack and stroke) when confronted with differing levels of surgical severity.ResultsOne thousand surveys were administered, and 894 were returned for an overall response rate of 89%. Fear of death was the greatest concern as compared to the other risk factors independent of the severity of surgery. The level of fear for all risk factors, with the exception of stroke and heart attack, were dependent on the severity of surgery. Fear of death decreased as the severity of surgery decreased (major 46%, moderate 38%, minor 25%). For major surgery, the fear of perioperative death differed significantly with age (P < 0.001); specifically, with increasing age came a lessened fear of death.ConclusionAwareness by anesthesia providers of those fears that patients report may allow for a more personalized approach to providing information that may better allay anxiety. Further, these results may better tailor the informed consent process to one that meets particular patient concerns.

Abstract BACKGROUND Anticoagulation protocols used during mechanical circulatory support call for titration of antiplatelet agents. We compared the precision and reliability of 5 platelet function tests in healthy volunteers and donors on daily antiplatelet therapy to distinguish their efficacy for titrating antiplatelet therapy. METHODS We assessed arachidonic acid–induced platelet function by light transmission aggregometry (LTA), Multiplate impedance aggregometry, VerifyNow, and platelet mapping by thromboelastography (TEG PM). We assessed ADP-induced platelet function by the same methods and flow cytometry. Forty healthy volunteers and 10–13 volunteers on daily aspirin and/or clopidogrel therapy were evaluated. We compared tests for intraassay precision, interassay precision (samples from 2 separate blood draws), and reliability coefficient. RESULTS For arachidonic acid–induced platelet aggregation in healthy volunteers, intra- and interassay CVs were ≤10% for all methods. Intra- and interassay precision among donors on daily aspirin was ≤30% for all methods except LTA (38% interassay CV) and TEG PM (95% intraassay and 104% interassay CV). For ADP-induced platelet function, intra- and interassay precision was ≤10% and ≤30% for all methods. Only Multiplate demonstrated moderate or greater (R &gt; 0.40) reliability coefficients for arachidonic acid–induced platelet function among all subjects. All methods of ADP-induced platelet function, except TEG PM, demonstrated substantial or greater (R &gt; 0.60) reliability among all subjects. CONCLUSIONS TEG PM is least suited to monitor effects of antiplatelet agents. Multiplate impedance aggregometry was the only method to demonstrate an acceptable reliability coefficient among healthy volunteers and donors on both aspirin and clopidogrel therapy.

Pancreatic cancer is a devastating condition that is most often characterized by a poor prognosis. Microarray technologies are promising screening methods for the identification of potential markers for early diagnosis and chemotherapeutic intervention. In this article, we review the current state of pancreatic cancer research as it relates to the measurement of gene transcript levels by DNA microarray analysis.

ABSTRACTBACKGROUND AND PURPOSERequests for after‐hours emergent spine MR imaging seem to be increasing. We sought to review the trend in after hours spine MRI utilization at our institution and to determine how these results impacted therapeutic intervention.METHODSFollowing Institutional Review Board approval, reports from 179 after hours spinal MRI's performed over the past 13 years were obtained and the relevant electronic medical records were reviewed.RESULTSEmergent after hours spine MRI utilization increased from 7 per year to 23 over 13 years. Fifty‐eight percent (104/179) had significant findings. Twenty‐nine percent (52/179) of all patients imaged underwent surgery to treat pathologies identified on MR. Surgery was performed in only 2% (4/179) of these patients within 3 hours and 6% (10/179) within 6 hours of MRI completion. Five percent (8/179) had findings that were treated with radiation therapy and in 78% of these it was performed within 6–12 hours. Of those in whom steroids or antibiotics were initiated, 41% and 50% were treated within 3 hours of MR scanning, respectively.DISCUSSIONClinical use of emergent after hours spine MRI is steadily increasing at our institution. While MR imaging often discerned significant pathologies, performing these emergent studies rarely resulted in immediate surgical or radiotherapeutic intervention.