Citations

AbstractBACKGROUNDClinical practice guidelines recommend estimation of glomerular filtration rate (eGFR) using validated equations based on serum creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys). However, when compared with the measured GFR (mGFR), only eGFRcr-cys meets recommended performance standards. Our goal was to develop a more accurate eGFR method using a panel of metabolites without creatinine, cystatin C, or demographic variables.METHODSAn ultra-performance liquid chromatography–tandem mass spectrometry assay for acetylthreonine, phenylacetylglutamine, pseudouridine, and tryptophan was developed, and a 20-day, multiinstrument analytical validation was conducted. The assay was tested in 2424 participants with mGFR data from 4 independent research studies. A new GFR equation (eGFRmet) was developed in a random subset (n = 1615) and evaluated in the remaining participants (n = 809). Performance was assessed as the frequency of large errors [estimates that differed from mGFR by at least 30% (1 − P30); goal <10%].RESULTSThe assay had a mean imprecision (≤10% intraassay, ≤6.9% interassay), linearity over the quantitative range (r2 > 0.98), and analyte recovery (98.5%–113%). There was no carryover, no interferences observed, and analyte stability was established. In addition, 1 − P30 in the validation set for eGFRmet (10.0%) was more accurate than eGFRcr (13.1%) and eGFRcys (12.0%) but not eGFRcr-cys (8.7%). Combining metabolites, creatinine, cystatin C, and demographics led to the most accurate equation (7.0%). Neither equation had substantial variation among population subgroups.CONCLUSIONSThe new eGFRmet equation could serve as a confirmatory test for GFR estimation.

Background: The efficacy of a neuromuscular training (NMT) program to ameliorate known hip biomechanical risk factors for athletes with anterior cruciate ligament reconstruction (ACLR) is currently unknown. Purpose/Hypothesis: The purpose was to quantify the effects of an NMT program on hip biomechanics among athletes with ACLR and to compare posttraining hip biomechanics with a control group. The hypotheses were that known hip biomechanical risk factors of anterior cruciate ligament (ACL) injury would be significantly reduced among athletes with ACLR after the NMT program and that posttraining hip biomechanics between the ACLR and control cohorts would not differ. Study Design: Controlled laboratory study. Methods: Twenty-eight athletes (n = 18, ACLR; n = 10, uninjured) completed a 12-session NMT program. Biomechanical evaluation of a jump-landing task was done before and after completion of the program. Repeated measures analysis of variance was performed to understand the effect of NMT within the ACLR cohort. Two-way analysis of variance was used to compare both groups. Post hoc testing was done for significant interactions. Hip biomechanical variables at initial contact are reported. Results: The athletes with ACLR who completed the NMT program had a significant session × limb interaction ( P = .01) for hip external rotation moment and a significant main effect of session for hip flexion angle ( P = .049) and moment ( P < .001). There was a significant change for the involved ( P = .04; 528% increase) and uninvolved ( P = .04; 57% decrease) limbs from pre- to posttraining for hip rotation moment. The ACLR cohort had an increase in hip flexion angle (14% change) and a decrease in hip flexion moment (65% change) from pre- to posttraining. Posttraining comparison for these same hip biomechanical variables of interest revealed no significant interactions ( P > .05) between the ACLR and control cohorts. There was a significant main effect of group ( P = .02) for hip flexion angle, as the ACLR cohort demonstrated greater hip flexion angle than that of the control group. Conclusion: For athletes with ACLR, hip biomechanical measures of ACL injury risk show significant improvements after completion of an NMT program. Clinical Relevance: Athletes with ACLR who are participating in an NMT program may ameliorate known hip biomechanical risk factors for an ACL injury.

Summary Objective To identify predictors of hypothalamic‐pituitary‐adrenal ( HPA ) axis recovery interval and severity of glucocorticoid withdrawal symptoms ( GWS ) in patients undergoing adrenalectomy for corticotropin‐independent cortisol excess. Design This is a retrospective study of patients with mild autonomous cortisol excess ( MACE ), moderate and severe Cushing syndrome ( CS ) who developed adrenal insufficiency after unilateral adrenalectomy between 1998 and 2017. Results Adrenalectomy was performed in 81 patients (79% women, median age 52 years [ IQR 42‐62]). HPA axis recovery occurred at a median of 4.3 months ( IQR 1.6‐11.4) after adrenalectomy (severe CS vs moderate CS vs MACE : median 11.4 vs 2.8 vs 2.1 months, P < 0.01). Main predictors of HPA axis recovery interval included: preoperative serum cortisol concentration after 1‐mg overnight dexamethasone suppression test >10 μg/ dL or >276 nmol/L (9.7 vs 1.3 months if cortisol ≤10 μg/ dL or ≤276 nmol/L, P < 0.01); body mass index (for every 3 kg/m 2 decrease, glucocorticoid taper increased by 1 month, P < 0.05); age <45 (11.4 vs 2.3 months if ≥45 years, P < 0.05); duration of symptoms prior to diagnosis >1 year (11.4 vs 2.8 months if ≤1 year); moon facies (11.4 vs 2.2 months if no rounding of the face); and myopathy (13.1 vs 2.7 months if no myopathy, P < 0.05). Patients with severe CS had a higher incidence of GWS compared to patients with MACE (66.7% vs 40.0%, P < 0.05) with a median of 1 and 0 events/patient, respectively. Conclusions The HPA axis recovery interval was the longest for patients with severe CS . Surprisingly, patients with moderate CS recovered their HPA axis as quickly as those with MACE . Glucocorticoid withdrawal symptoms were observed in all groups, with more events in patients with severe CS . This study emphasizes the need to counsel patients on expectations for HPA axis recovery and address intervention for GWS based on individual preoperative parameters.

Objectives: This study aims to determine the impact of controlling cochlear-source mechanism on the accuracy with which auditory status is identified using otoacoustic emissions (OAEs) in two groups of subjects with normal hearing (NH) and subjects with mild to moderate hearing loss. Design: Data were collected from 212 subjects with NH and with mild to moderate hearing loss who fell into two categories based on a distortion product OAE (DPOAE) screening protocol: the uncertain-identification group (where errors were likely) and the certain-identification group (where errors were unlikely). DPOAE fine-structure patterns were recorded at intervals surrounding f 2 = 1, 2 and 4 kHz (f 2/f 1 ratio = 1.22), with L 2 = 35, 45, and 55 dB SPL (L 1/L 2 ratio = 10 dB). The discrete cosine transform was used to smooth fine structure, limiting the source contribution to the distortion source only. Reflection-source OAEs were also recorded using amplitude-modulated stimulus frequency OAEs (AM-SFOAE). Area under the relative operating characteristic (A ROC) curve was used to quantify test accuracy when the source contribution was controlled versus the condition where both sources contribute. Additionally, failure rate, fixed at 5% for NH ears, as a function of behavioral-threshold category was evaluated. Results: When data for the entire subject group were examined, reducing the reflection-source contribution to the DPOAE did not result in better test performance than the best control condition at any frequency tested. When the subjects with NH were restricted to those with confirmed fine structure, A ROC analyses indicated that reducing the reflection-source contribution resulted in several small increases in the accuracy (2%–5%) with which auditory status was identified relative to the best control condition. This improvement was observed for the lowest stimulus levels (i.e., L 2 = 35 or 45 dB SPL). In this subset of subjects, distortion-source DPOAEs resulted in more accurate identification of mild hearing loss for a fixed false-positive rate of 5% in NH ears at lower L 2’s, conditions with poor accuracy in the larger group of subjects. The impact of controlling the source contribution on the identification of moderate losses was less clear in the reduced subject group, with some conditions where the distortion-source DPOAE was more accurate than the control condition and other conditions where there was no change. There was no evidence that reflection-source AM-SFOAEs more accurately identified ears with hearing loss when compared to any of the DPOAE conditions in either the large or reduced group of subjects. Conclusion: While improvements in test accuracy were observed for some subjects and some conditions (e.g., mild hearing losses and low stimulus levels in the reduced subset of subjects), these results suggest that restricting cochlear source contribution by “smoothing” DPOAE fine structure is not expected to improve DPOAE test accuracy in a general population of subjects. Likewise, recording reflection-source OAEs using the AM-SFOAE technique would not be expected to more accurately identify hearing status compared to mixed- or single-source DPOAEs.

Background OnabotulinumtoxinA has been demonstrated to be effective for the preventive treatment of headache in individuals with chronic migraine and has been approved and recommended for this patient population. While the therapeutic effect of onabotulinumtoxinA on migraine headache is well documented, there is limited information on the effect of onabotulinumtoxinA on migraine aura. Objective Given the prolonged and often debilitating nature of aura in patients with hemiplegic migraine, our group sought to examine the effect of onabotulinumtoxinA on aura frequency and severity in this specific subset of migraine patients. Methods All clinical notes from July 1, 1994 to December 1, 2017 at our institution were retrospectively reviewed to identify patients diagnosed with hemiplegic migraine who received at least one set of onabotulinumtoxinA injections. Thirty‐four patients were identified; and of those, 23 were excluded due to incomplete documentation regarding aura symptoms at follow‐up visits. The clinical notes of the remaining 11 patients (4 with familial hemiplegic migraine [FHM] and 7 with sporadic hemiplegic migraine [SHM]) were reviewed, and the frequency and description of their headaches and aura before and after receiving onabotulinumtoxinA were recorded. Results Nine of the 11 patients in our series noted a decrease in the frequency, severity, and/or duration of their aura after receiving onabotulinumtoxinA. Of the 2 non‐responders, one was FHM and one was SHM. Of the 9 that noticed improved aura symptoms, 6 described a “wearing off” effect of onabotulinumtoxinA around week 9 or 10 of the 12‐week cycle, with subsequent improvement after the next round. Conclusion For 9 of 11 patients with hemiplegic migraine, onabotulinumtoxinA was helpful not only in reducing the frequency and severity of headaches but also in reducing the frequency and severity of the aura. In this manuscript, we speculate on potential pathophysiologic mechanisms that could have contributed to this effect.

AbstractBackgroundCalciphylaxis is a devastating multifactorial disorder of the subcutaneous fat that is known to be associated with hypercoagulability. Recent literature has proposed subclassifying patients with calciphylaxis as having warfarin‐associated or warfarin‐unassociated disease.AimWe aimed to determine whether patients with warfarin‐associated calciphylaxis differ clinically from patients with warfarin‐unassociated calciphylaxis.Materials and methodsWe performed a subgroup analysis of patients with nonuremic calciphylaxis from a previously studied cohort and compared clinical and outcomes features of patients who were taking warfarin at the time of disease onset to those of patients who were not.ResultsNineteen patients with nonuremic calciphylaxis were identified, including 10 (53%) who had been on warfarin at the time of disease onset and 9 (47%) who had not. Of all clinical and outcomes parameters tested, no significant differences were detected between the two groups.Discussion and ConclusionsThough this study is limited by its retrospective nature and the relatively small number of patients studied, available data do not support subclassifying patients with nonuremic calciphylaxis as having warfarin‐associated or warfarin‐unassociated disease. Rather, the body of literature would suggest that identification and correction of underlying disorders of hypercoagulability should be prioritized.

The control of epithelial cell proliferation, differentiation, and apoptosis requires a balance between signaling and transcriptional regulation. Recent developments in pancreatic cell research have revealed that transforming growth factor-β (TGF-β) signaling is important for the regulation of each of these phenomena. More importantly, perturbations in this pathway are associated with pancreatic cancer. A chief example of these alterations is the mutation in the TGF-β-regulated transcription factor Smad4/DPC4 that is found in a large percentage of pancreatic tumors. Surprisingly, studies on transcription factors have remained an underrepresented area of pancreatic research. However, the discovery of Smad4/DPC4 as a transcription factor fueled further studies aimed at characterizing transcription factors involved in normal and neoplastic pancreatic cell growth. Our laboratory recently described the existence of a novel family of zinc finger transcription factors, TGF-β-inducible early-response gene (TIEG)1 and TIEG2, from the exocrine pancreas that, similarly to Smads, participate in the TGF-β response and inhibit epithelial cell proliferation. This review therefore focuses on describing the structure and function of these two families of transcription factor proteins that are becoming key players in the regulation of pancreatic cell growth.