A practical guide to adopting Bayesian analyses in clinical research.

Background: Bayesian statistical approaches are extensively used in new statistical methods but have not been adopted at the same rate in clinical and translational (C&T) research. The goal of this paper is to accelerate the transition of new methods into practice by improving the C&T researcher's ability to gain confidence in interpreting and implementing Bayesian analyses. Methods: We developed a Bayesian data analysis plan and implemented that plan for a two-arm clinical trial comparing the effectiveness of a new opioid in reducing time to discharge from the post-operative anesthesia unit and nerve block usage in surgery. Through this application, we offer a brief tutorial on Bayesian methods and exhibit how to apply four Bayesian statistical packages from STATA, SAS, and RStan to conduct linear and logistic regression analyses in clinical research. Results: The analysis results in our application were robust to statistical package and consistent across a wide range of prior distributions. STATA was the most approachable package for linear regression but was more limited in the models that could be fitted and easily summarized. SAS and R offered more straightforward documentation and data management for the posteriors. They also offered direct programming of the likelihood making them more easily extendable to complex problems. Conclusion: Bayesian analysis is now accessible to a broad range of data analysts and should be considered in more C&T research analyses. This will allow C&T research teams the ability to adopt and interpret Bayesian methodology in more complex problems where Bayesian approaches are often needed.

Sublingual Sufentanil vs. Intravenous Fentanyl for the Treatment of Acute Postoperative Pain in the Ambulatory Surgery Center: A Randomized Clinical Trial.

Objectives: Sublingual sufentanil is a novel opioid medication to treat moderate to severe pain postoperatively. This study's aim was to determine if a single dose of a sublingual sufentanil tablet (SST) is as efficacious as a single dose of intravenous (IV) fentanyl in readiness to discharge from ambulatory surgery. Methods: This was a two-arm, parallel group, randomized prospective outcomes study conducted at a single, free-standing ambulatory surgery center. Patients aged 18-80 undergoing general anesthesia who developed a postoperative pain score of ≥ 4 were enrolled and randomized to receive either 30 mcg SST or 50 mcg IV fentanyl. After their initial randomized dose, rescue IV fentanyl followed by oral oxycodone if needed. Recovery length of stay from arrival in the postanesthesia care unit until readiness to discharge criteria was met based on phase 2 discharge criteria. Results: 75 patients were analyzed. Readiness to discharge from the recovery room was not significantly different between either group (IV fentanyl median 65 minutes; IQR 56-89; SST 73 min, IQR 58-89; p=0.903). There was no significant difference in the amount of morphine equivalents (MME) of rescue opioids needed (IV fentanyl median rescue MME of 22.5, IQR 13.1-23.4; SST median rescue MME of 15.0, IQR 7.5-30.0; p=0.742). The change in pain from PACU initially, and on discharge was not significantly different (IV fentanyl initial pain minus pain on discharge median 3, IQR 2-4; SST initial pain minus pain on discharge median 4, IQR 2-5.5; p=0.079). There was no difference in the six-item screener and the Overall Benefit of Analgesic Survey Score. Discussion. In conclusion, patients who received a sublingual sufentanil 30 mcg tablet had no significant differences in PACU length of stay or rescue analgesic usage when compared to intravenous fentanyl 50 mcg.

Comparing liposomal bupivacaine plus bupivacaine to bupivacaine alone in interscalene blocks for rotator cuff repair surgery: a randomized clinical trial.

BACKGROUND: Single-injection interscalene brachial plexus blocks are used for analgesia for rotator cuff repair (RCR) but have limited duration. The value of adding liposomal bupivacaine (LB) to prolong single-injection interscalene blocks is unclear. The purpose of this trial is to evaluate the addition of LB to regular bupivacaine interscalene blocks for patients undergoing arthroscopic RCR. METHODS: In this prospective, randomized trial, 70 patients undergoing primary RCR with equal group allocation were randomized by random number generator to receive an interscalene block with 20 mL of 0.5% bupivacaine or 10 mL 0.5% bupivacaine plus 133 mg LB. The primary outcome was cumulative opioid consumption within 72 hours of the procedure. Secondary outcomes included maximum pain scores and quality of recovery 15 survey scores. RESULTS: 70 of the 80 randomized patients were included in final analysis following exclusion for protocol violations and loss to follow-up. Cumulative opioid consumption (oral morphine equivalents) within 72 hours in patients receiving LB was a median (IQR) of 31.9 mg (0, 73.1) compared with 45.0 mg (15.0, 108.8) among patients receiving bupivacaine alone (p=0.312). Patients receiving LB demonstrated mixed results regarding worst pain scores with improvements at 24 hours and 72 hours, but not 48 hours. CONCLUSIONS: LB added to bupivacaine interscalene blocks does not reduce opioid consumption within 72 hours following arthroscopic RCR. TRIAL REGISTRATION NUMBER: NCT03587584.

Evaluation of Diaphragmatic Function after Interscalene Block with Liposomal Bupivacaine: A Randomized Controlled Trial.

BACKGROUND: Interscalene blocks provide analgesia for shoulder surgery but also cause phrenic nerve paralysis. Liposomal bupivacaine is approved for use in interscalene blocks with the potential to provide longer pain control. However, the impact of liposomal bupivacaine on the phrenic nerve has not been evaluated. It was hypothesized that patients who received an interscalene block with both bupivacaine and liposomal bupivacaine would have a decreased diaphragmatic excursion when compared to bupivacaine alone at 24 h. METHODS: This was a double-blinded study of adult patients who were randomized to receive an interscalene block with either 20 ml 0.5% bupivacaine (bupivacaine group) or 10 ml 0.5% bupivacaine plus 10 ml liposomal bupivacaine (liposomal bupivacaine group). Twenty-six patients were randomized with 22 included in the analysis. Diaphragmatic excursion (via ultrasound) and spirometry were assessed before the block, in the postanesthesia care unit, and at 24 h postblock. The primary outcome was diaphragm excursion with sigh. No adverse events were observed. RESULTS: At 24 h, the liposomal bupivacaine group median [25th, 75th], had a greater percent change in diaphragmatic excursion during sigh breath compared to the bupivacaine group, -24% [-30, -9] versus 9% [-8, 26], difference in location, 32 (95% CI, 12 to 52), P = 0.007. Five patients in the liposomal bupivacaine group had a greater than 25% reduction in diaphragmatic excursion at 24 h versus zero in the bupivacaine group. They also had a significantly greater percent reduction in forced expiratory volume in 1 s and forced vital capacity compared with the bupivacaine group at 24 h (median decrease of 22% vs. 2%, P = 0.006, and median decrease of 19% vs. 1%, P = 0.049, respectively). CONCLUSIONS: The addition of liposomal bupivacaine to bupivacaine in an interscalene block results in statistically significant reductions in diaphragm excursion and pulmonary function testing 24 h after block placement when compared to bupivacaine alone. This reduction, however, falls within the range of normal diaphragmatic function.

Ultrasound-guided subcostal transversus abdominis plane block with liposomal bupivacaine compared to bupivacaine infiltration for patients undergoing robotic-assisted and laparoscopic hysterectomy: a prospective randomized study.

PURPOSE: To determine if a transversus abdominis plane (TAP) block with liposomal bupivacaine reduces total postoperative opioid use in the first 72 hrs following laparoscopic or robotic hysterectomy compared to port-site infiltration with 0.25% bupivacaine. METHODS: Patients received either a true TAP block procedure with 266 mg liposomal bupivacaine and 50 mg of 0.25% bupivacaine and sham port infiltration or sham TAP block procedure with true port-site infiltration with 100-125 mg of 0.25% bupivacaine. All patients had a standardized, scheduled, non-opioid pain management plan. The primary outcome was total IV morphine equivalents used in the first 72 hrs following surgery. Secondary outcomes included assessment of postoperative pain over the study period and quality of recovery measures. RESULTS: Patients undergoing TAP blockade required fewer total opioid equivalents during the observation period than patients allocated to infiltration (median 21 versus 25 mg IV Morphine equivalents, P=0.03). Opioid use was highest in the first 24 hrs after surgery, with less difference between the groups during days 2 and 3 postoperatively. There were 5 in the TAP group and 0 in the infiltration group were opioid free at 72 hrs. Those in the TAP group had improved quality of recovery (QoR15) with no change in overall benefit of analgesia score. CONCLUSION: TAP blockade reduced the requirement for opioid pain medication in the first 72 hrs after surgery, had more patients opioid free at 72 hrs, and improved patients' quality of their recovery.

The addition of intrathecal morphine to a transversus abdominis plane block with liposome bupivacaine provides more effective analgesia than transversus abdominis plane block with liposome bupivacaine alone: a retrospective study.

OBJECTIVE: The purpose of this study was to determine if the standardization of using liposomal bupivacaine in transversus abdominis plane (LB TAP) blocks eliminated the benefit of intrathecal morphine (ITM) in patients after undergoing a cesarean section. METHODS: This was a retrospective review of 358 patients who underwent cesarean section over an 11-month period. Patients were divided into two groups: those who received only an LB TAP (67 patients) vs those who received an LB TAP and ITM (291 patients). All blocks were placed bilaterally under ultrasound guidance after closure of the surgical incision, and morphine was added to the spinal used for the case. RESULTS: The group that received ITM in addition to the LB TAP received less opioids in the first 24 hours (median 5 range 0-150 mg morphine equivalents [ME] vs 15 range 0-76 mg ME; P<0.001) and less opioids overall (35 mg range 0-450 mg ME vs 47.5 mg range 0-189 mg ME; P=0.041) when compared to the LB TAP block only group. There was no difference between the two groups in opioid use from 24 to 48 hours or 48 to 72 hours. CONCLUSION: Patients who received ITM in addition to an LB TAP block received less opioids in the first 24 hours and overall when compared to those who received an LB TAP alone. This suggests that ITM still plays a role in providing analgesia to patients who have also received an LB TAP block as a part of their multimodal pain regimen for cesarean sections.

Sporadic Meningioangiomatosis: Bystander or Curious Culprit.

In this report, we describe two cases of sporadic meningioangiomatosis (MA) - a rare condition of the central nervous system known to cause headaches, seizures and other focal neurologic deficits. Both patients presented with headache and vision change, somewhat suggestive of migraine. The combination of magnetic resonance imaging (MRI) and computerized tomography (CT) can establish the diagnosis of MA.

Factor XIII Subunit A Immunohistochemical Expression is Associated With Inferior Outcomes in Acute Promyelocytic Leukemia.

Coagulation factor XIII subunit A (FXIIIa) intracellular expression has been described in platelets, megakaryocytes, monocytic cells, and leukemic blasts. Flow cytometric-based studies have suggested prognostic implications of FXIIIa expression, especially within the acute promyelocytic leukemia (APL) subgroup of acute myeloid leukemia (AML); however, its prognostic correlate by immunohistochemistry (IHC) is unknown. The aims of this study were to (1) define the clinicopathologic features of FXIIIa IHC-positive AML and (2) compare APL with other AML subtypes. Eighty-seven bone marrow biopsies or clot/particle preparations from our institution were evaluated with FXIIIa IHC. The study cohort consisted of bone marrow evaluations of 36 consecutive pretherapy APL, 42 selected pretherapy non-APL AML, and 9 negative staging cases. FXIIIa IHC expression was correlated with clinical and pathologic features and overall survival (OS). Leukemic blast FXIIIa cytoplasmic positivity was noted in 56% (20/36) APL and 74% (31/42) non-APL AML (P=0.10). FXIIIa IHC expression was associated with inferior OS within the APL cohort (P=0.04). No OS differences were noted in comparing FXIIIa IHC expression in all AML (P=0.17), or FXIIIa IHC expression within favorable, intermediate or adverse cytogenetic groups (P=0.14, 0.22 and 0.87, respectively). FXIIIa IHC expression is observed among a broad spectrum of AML subtypes and is not characterized by specific pathologic features. However, within the APL subgroup, FXIIIa IHC expression is associated with an inferior outcome and may be useful for additional prognostic risk stratification.

Disseminated Blastomycosis Mimicking Malignancy.

Blastomycosis is an endemic fungal infection commonly found within the Mississippi and Ohio River basins and Great Lakes region. While patients typically present with acute pneumonia, Blastomyces dermatitidis has the potential to spread hematogenously, resulting in disseminated infection of multiple organs. In this report, we describe a 57-year-old male with disseminated blastomycosis acquired in South Dakota. The diagnostic evaluation was confounded by concern for malignancy given the involvement of multiple locations, including brain, lungs, adrenal glands, and testes. Despite aggressive therapy with amphotericin B, the patient succumbed to this infection.

The influence of the noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) resection diagnosis on the false-positive thyroid cytology rate relates to quality assurance thresholds and the application of NIFTP criteria.

BACKGROUND: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a newly defined entity and recent studies have suggested a decrease of a few percentage points in the rate of malignancy (ROM) for the positive-for-malignancy (PFM) cytology category as a result of NIFTP implementation. However, the distinction between a diagnosis of PFM and one of suspicious for malignancy (SFM) may depend on a variety of factors. In the current study, the authors investigated the ROM for the PFM and SFM diagnoses before and after histologic NIFTP reclassification. METHODS: Cytology cases with PFM and SFM diagnoses and subsequent surgical resection specimens were searched in the files of the study institution from September 2008 to September 2016. The surgical pathology cases of noninvasive encapsulated follicular variant of papillary thyroid carcinoma were reexamined to determine whether they qualified for NIFTP. The distinct ROMs for the PFM and SFM cases were calculated accordingly. RESULTS: The authors' search identified 338 cases of PFM and 139 cases of SFM with a resection outcome. Before NIFTP reclassification, the PFM cases had a ROM of 99.4%; after NIFTP reclassification, the ROM was 99.1% (P = .6861). The ROM of the SFM cases decreased from 75.5% to 66.9% with NIFTP reclassification (P = .1402). One case in the PFM group and 6 cases in the SFM group could not be verified due to insufficient sampling. CONCLUSIONS: In the current large series, NIFTP reclassification did not appear to significantly alter the high ROM for the PFM diagnosis. The authors attribute this finding to a strict quality assurance policy, an emphasis on key cytologic criteria, and systematic application of the NIFTP criteria to follicular-patterned lesions. Cancer Cytopathol 2017;125:692-700. © 2017 American Cancer Society.

Sensitive Detection of Mono- and Polyclonal ESR1 Mutations in Primary Tumors, Metastatic Lesions, and Cell-Free DNA of Breast Cancer Patients.

PURPOSE: Given the clinical relevance of ESR1 mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of ESR1 mutations in primary and metastatic breast cancer, and in cell-free DNA (cfDNA). EXPERIMENTAL DESIGN: Six ESR1 mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05% to 0.16%, in primary tumors (n = 43), bone (n = 12) and brain metastases (n = 38), and cfDNA (n = 29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed. RESULTS: ESR1 mutations were detected for D538G (n = 13), Y537S (n = 3), and Y537C (n = 1), and not for K303R, S463P, or Y537N. Mutation rates were 7.0% (3/43 primary tumors), 9.1% (1/11 bone metastases), 12.5% (3/24 brain metastases), and 24.1% (7/29 cfDNA). Two patients showed polyclonal disease with more than one ESR1 mutation. Mutation allele frequencies were 0.07% to 0.2% in primary tumors, 1.4% in bone metastases, 34.3% to 44.9% in brain metastases, and 0.2% to 13.7% in cfDNA. In cases with both cfDNA and metastatic samples (n = 5), mutations were detected in both (n = 3) or in cfDNA only (n = 2). Treatment was associated with changes in ESR1 mutation detection and allele frequency. CONCLUSIONS: ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases, suggesting that in some tumors rare ESR1-mutant clones are enriched by endocrine therapy. Further studies should address whether sensitive detection of ESR1 mutations in primary breast cancer and in serial blood draws may be predictive for development of resistant disease. See related commentary by Gu and Fuqua, p. 1034.

The Many Faces of Granulomatosis With Polyangiitis: A Review of the Head and Neck Imaging Manifestations.

OBJECTIVE: Wegener granulomatosis has recently been renamed as granulomatosis with polyangiitis (GPA). In this review, we examine the clinical criteria and pathologic and pathophysiologic mechanisms of GPA, with an emphasis on findings encountered in the realm of head and neck imaging. Particular attention is paid to generating an appropriate differential diagnosis, because many of the imaging features of GPA overlap with those of other diseases, most notably lymphoma and sarcoidosis. Recent therapeutic advancements have underscored the importance of the radiologist in suggesting the diagnosis early, resulting in earlier treatment and decreased patient morbidity. This is particularly true for the head and neck manifestations of GPA; although they are less common, they often herald a refractory disease course that requires aggressive immunosuppressive therapy. Knowledge of common and uncommon imaging findings enables the radiologist to diagnose GPA early enough to start treatment promptly and reduce patient morbidity. CONCLUSION: Although there are no reliable pathognomonic imaging features for GPA, the present article attempts to identify patterns of disease that are suggestive of the disease. The diagnosis ultimately relies on a constellation of radiographic findings, laboratory values, and accurate clinical history.

Evaluating breast lymphoplasmacytic infiltrates: a multiparameter immunohistochemical study, including assessment of IgG4.

Lymphoplasmacytic infiltrates in the breast, a modified skin appendage, include lymphocytic lobulitis, other nonspecific benign proliferations, and mucosa-associated lymphoid tissue (MALT)-type lymphoma. Distinguishing these entities, all of which may be B-cell rich and may have associated sclerosis, can be difficult. In addition, the proportion that represents IgG4-related disease is unknown, and the similarity of MALT lymphomas to primary cutaneous marginal zone lymphoma is uncertain. To address these questions, the clinical, histologic, and immunohistochemical features of 50 benign and malignant breast lymphoplasmacytic infiltrates (10 lymphocytic lobulitis, 1 granulomatous, 19 not otherwise specified, 20 MALT lymphomas) were evaluated. Compared with the MALT lymphomas, benign cases had a less dense infiltrate (P < .001), fewer but more histologically apparent germinal centers (P < .001), and more marked fibrosis (P < .0001). Greater than 60% B cells were present in 23% (7/30) benign cases versus 75% (15/20) MALT lymphomas (P = .0003). Plasma cells were predominantly IgG+ in 83% (24/29) benign cases and predominantly IgM+ in 73% (14/19) MALT lymphomas (P < .0001). None of the benign cases had greater than 50 IgG4+ plasma cells/high-power field, and only 1 lymphocytic lobulitis case had an IgG4/IgG ratio exceeding 40% and no clinical evidence for extramammary IgG4-related disease. Although there may be some overlapping features, routine histopathology together with limited immunohistochemical stains can distinguish benign from neoplastic lymphoplasmacytic infiltrates in the breast. Despite frequent sclerosis, the breast is not a common site of unrecognized IgG4-related sclerosing disease. Although there are similarities, breast MALT lymphomas can be separated from cutaneous marginal zone lymphoma.

Overuse of testing in preoperative evaluation and syncope: a survey of hospitalists.

BACKGROUND: Health care reform efforts and initiatives seek to improve quality and reduce costs by eliminating unnecessary care. However, little is known about overuse and its drivers, especially in hospitals. OBJECTIVE: To assess the extent of and factors associated with overuse of testing in U.S. hospitals. DESIGN: National survey of practice patterns for 2 common clinical vignettes: preoperative evaluation and syncope. Respondents were randomly selected and randomly provided 1 of 4 versions of each vignette. Each version contained identical clinical information but varied in factors that could change physician behavior. Respondents were asked to identify what they believed most hospitalists at their institution would recommend in each vignette. SETTING: Mailed survey conducted from June through October 2011. PARTICIPANTS: Physicians practicing adult hospital medicine in the United States. MEASUREMENTS: Responses indicating overuse (more testing than recommended by American College of Cardiology/American Heart Association guidelines). RESULTS: 68% (1020 of 1500) of hospitalists responded. They reported overuse in 52% to 65% of the preoperative evaluation vignettes and 82% to 85% of the syncope vignettes. Overuse more frequently resulted from a physician's desire to reassure patients or themselves than an incorrect belief that it was clinically indicated (preoperative evaluation, 63% vs. 37%; syncope, 69% vs. 31%; P < 0.001 for each). LIMITATION: Survey responses may not represent actual clinical choices. CONCLUSION: Physicians reported substantial overuse in 2 common clinical situations in the hospital. Improving provider knowledge of guidelines may help reduce overuse, but despite awareness of the guidelines, physicians often deviate from them to reassure patients or themselves. PRIMARY FUNDING SOURCE: Blue Cross Blue Shield of Michigan Foundation, Department of Veterans Affairs Center for Clinical Management Research, University of Michigan Specialist-Hospitalist Allied Research Program, and Ann Arbor Veterans Affairs/University of Michigan Patient Safety Enhancement Program.