Citations

Dihydropyrimidine dehydrogenase (DPD; DPYD gene) variants have emerged as reliable predictors of adverse toxicity to the chemotherapy agent 5‐fluorouracil (5‐FU). The intronic DPYD variant rs75017182 has been recently suggested to promote alternative splicing of DPYD. However, both the extent of alternative splicing and the true contribution of rs75017182 to DPD function remain unclear. In the present study we quantified alternative splicing and DPD enzyme activity in rs75017182 carriers utilizing healthy volunteer specimens from the Mayo Clinic Biobank. Although the alternatively spliced transcript was uniquely detected in rs75017182 carriers, canonically spliced DPYD levels were only reduced by 30% (P = 2.8 × 10‐6) relative to controls. Similarly, DPD enzyme function was reduced by 35% (P = 0.025). Carriers of the well‐studied toxicity‐associated variant rs67376798 displayed similar reductions in DPD activity (31% reduction). The modest effects on splicing and function suggest that rs75017182 may have clinical utility as a predictor of 5‐FU toxicity similar to rs67376798.

AbstractBackgroundFactor XI (FXI) deficiency (hemophilia C [HEM‐C]) is a bleeding disorder with unpredictable severity that correlates poorly with FXI coagulation activity (FXI:C). It poses a perioperative hemostatic management challenge. For US patients with severe disease, fresh frozen plasma (FFP) or, in current use, thawed plasma is the most readily available option but comes with risk of volume overload. We report our experience of using therapeutic plasma exchange (TPE) as an alternative perioperative management strategy.MethodsA retrospective review of all HEM‐C patients who underwent surgical procedures. Data were collected, including demographics, bleeding history, surgical site, perioperative hemostatic intervention, and outcome.ResultsBetween July 1997 and September 2014, 28 HEM‐C patients (12 men) were identified, 4 with severe disease (FXI:C <2% or excessive bleeding). Nineteen patients underwent 91 invasive procedures. For nearly 60% of the procedures, no periprocedural hemostatic intervention was provided; before 4 procedures (3 patients), 1 plasma volume TPE preoperatively with FFP was administered. Patient 1, a 28‐year‐old woman (FXI:C, 35%) with a history of excessive surgical bleeding, underwent 2 TPE procedures before laparoscopic pelvic biopsy and subsequent abdominal hysterectomy with salpingo‐oophorectomy that increased her FXI:C to 48%. Patient 2, a 79‐year‐old man (FXI:C, <2%), had TPE before total hip arthroplasty, increasing his FXI:C to 24%. Patient 3, a 59‐year‐old man (FXI:C, <2%), had TPE before prostate laser enucleation, increasing his FXI:C to 46%. Patients 1 and 3 had mild reactions during TPE; no patient had evidence of volume overload. All patients had adequate intraoperative surgical hemostatic outcomes.ConclusionTPE is an effective alternative presurgical hemostatic intervention in HEM‐C with potentially lower risk of circulatory volume overload.

Background: The spasticity and increased muscle tone observed in patients with cerebral palsy can lead to hip degeneration, subluxation, and pain. Currently, there is hesitation to perform total hip arthroplasty in patients with cerebral palsy because of fears of early wear and dislocation. The purpose of this study was to review the outcomes of total hip arthroplasty in patients with cerebral palsy and to compare outcomes with those of matched patients with a diagnosis of osteoarthritis. Methods: Over a 24-year period, 39 patients undergoing a total hip arthroplasty with a diagnosis of cerebral palsy were identified. The cohort included 26 male patients (67%), and the mean patient age was 49 years. The mean follow-up was 7 years. Patients with cerebral palsy were matched 1:2 with a group of patients undergoing total hip arthroplasty for osteoarthritis. Results: There was no difference in the rate of reoperation, implant survival, or complications, specifically dislocation. Prior to the surgical procedure, all patients had severe or moderate pain, and postoperatively no patient had moderate or severe pain. Twenty-three patients had an improvement in their ability to independently walk, and all preoperative hip flexion contractures were corrected (n = 9). There was also a significant improvement (p < 0.0001) in functional Harris hip scores. Conclusions: This study refutes previous evidence showing increased risk of complications following total hip arthroplasty in patients with cerebral palsy. Total hip arthroplasty is a durable treatment option and provides clinically important pain relief and functional improvement in patients with cerebral palsy. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Introduction: E-consultations are asynchronous text-based consultations between providers which can facilitate patient access to timely specialty care. In contrast to traditional face-to-face consults, conveying and completing recommendations of the specialist is the responsibility of the referring provider. This presents a new workflow for primary care providers who have multiple options (face-to-face, telephone, letter, secure message) to communicate the e-consultation recommendations. This study examines how primary care providers are managing this new workflow. Methods: We performed a retrospective random sampling of e-consultations with individual medical record review and classified e-consultations by type of recommendation, how recommendations were communicated to patients, and whether recommendations were carried out. Results: We randomly selected 220 e-consultations in 13 different specialties for review. In all, 85% of e-consultations contained recommendations for referring providers. Recommendations on medication(s) were most common (35%) followed by recommendations on ordering laboratory tests (29%). In all, 25% of the time e-consultants gave multiple possible courses of action for referring providers to choose from. Patient notification of recommendations was found for 192 (87%) of e-consultations with providers performing the notification 63% of the time and nursing staff performing the notification 37% of the time. The communication back to the patients included communication via nurse telephone calls (37%), provider telephone calls (23%), secure messages (24%), face-to-face visits (11%), and by written correspondence (5%). Discussion: Managing recommendations from e-consultations results in a new workflow for primary care providers. Healthcare institutions that utilize e-consults should be aware of this new workflow. Further study is needed to determine best practices for this task that is now increasing in primary care.

AbstractBased on cytoarchitecture, the posterior cingulate cortex (PCC) is thought to be comprised of two distinct functional subregions: the dorsal and ventral PCC (dPCC and vPCC). However, functional subregions do not completely match anatomical boundaries in the human brain. To understand the relationship between the functional organization of regions and anatomical features, it is necessary to apply parcellation algorithms based on functional properties. We therefore defined functionally informed subregions in the human PCC by parcellation of regions with similar patterns of functional connectivity in the resting brain. We used various patterns of functional connectivity, namely local, whole‐brain and diffuse functional connections of the PCC, and various clustering methods, namely hierarchical, spectral, andk‐means clustering to investigate the subregions of the PCC. Overall, the approximate anatomical boundaries and predicted functional regions were highly overlapped to each other. Using hierarchical clustering, the PCC could be clearly separated into two anatomical subregions, namely the dPCC and vPCC, and further divided into four subregions segregated by local functional connectivity patterns. We show that the PCC could be separated into two (dPCC and vPCC) or four subregions based on local functional connections and hierarchical clustering, and that subregions of PCC display differential global functional connectivity, particularly along the dorsal‐ventral axis. These results suggest that differences in functional connectivity between dPCC and vPCC may be due to differences in local connectivity between these functionally hierarchical subregions of the PCC.Hum Brain Mapp 38:2808–2818, 2017. ©2017 Wiley Periodicals, Inc.