Citations

Abstract Background Thyroid carcinoma, which is rare in pediatric patients (age 0–18 years) but more common in adolescent and young adult (AYA) patients (age 15–39 years), carries the potential for morbidity and mortality. Methods Hybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements. This PAYA data series includes 41 patients with papillary thyroid carcinoma (PTC), 3 with anaplastic thyroid carcinoma (ATC), and 14 with medullary thyroid carcinoma (MTC). Results GAs were detected in 93% (54/58) of PAYA cases, with a mean of 1.4 GAs per case. In addition to BRAF V600E mutations, detected in 46% (19/41) of PAYA PTC cases and in 1 of 3 AYA ATC cases, oncogenic fusions involving RET, NTRK1, NTRK3, and ALK were detected in 37% (15/41) of PAYA PTC and 33% (1/3) of AYA ATC cases. Ninety-three percent (13/14) of MTC patients harbored RET alterations, including 3 novel insertions/deletions in exons 6 and 11. Two of these MTC patients with novel alterations in RET experienced clinical benefit from vandetanib treatment. Conclusion CGP identified diverse clinically relevant GAs in PAYA patients with thyroid carcinoma, including 83% (34/41) of PTC cases harboring activating kinase mutations or activating kinase rearrangements. These genomic observations and index cases exhibiting clinical benefit from targeted therapy suggest that young patients with advanced thyroid carcinoma can benefit from CGP and rationally matched targeted therapy.

Background: Therapy programs to treat thumb carpometacarpal (CMC) arthritis may engage selective activation and reeducation of thenar muscles, particularly the first dorsal interosseous (FDI) and opponens pollicis (OP) to reduce subluxation of the joint. We describe the effect of simulated selective activation of the FDI and OP muscles upon radiographic subluxation of the thumb CMC joint. Methods: In a cadaver model of CMC subluxation, loads were applied to the FDI, the OP, and then concomitantly at 0%, 25%, 50%, 75%, and 100% maximal loads and radial subluxation of the joint and reduction in subluxation was measured. Results: Selective activation of the OP, alone, improved the subluxation ratio (SR) in a dose-dependent manner. Selective activation of FDI, alone, demonstrated minimal effects on SR. Concomitant activation of OP and FDI improved the SR across all loading states, and activation of 75% and greater, when compared with FDI activation alone, resulted in a statistically significant improvement in SR to within 10% of the presubluxed joint. Conclusions: Concomitant activation of the FDI and OP acts to reduce subluxation of the thumb CMC joint in a dose-dependent fashion. The OP is likely the predominant reducing force. Hand therapy programs that focus on selective strengthening programs likely function in part to encourage patients to activate the easily palpable and easily understood FDI. Concomitant coactivation of the OP may be the major reducing force to elicit clinical and radiographic reduction of subluxation, improved thumb positioning, and reduction of pain and arthritic symptoms.

Despite the widespread inclusion of diversity-related curricula in U.S. medical training, racial disparities in the quality of care and physician bias in medical treatment persist. The present study examined the effects of both formal and informal experiences on non-African American medical students’ ( N = 2,922) attitudes toward African Americans in a longitudinal study of 49 randomly selected U.S. medical schools. We assessed the effects of experiences related to medical training, accounting for prior experiences and attitudes. Contact with African Americans predicted positive attitudes toward African Americans relative to white people, even beyond the effects of prior attitudes. Furthermore, students who reported having witnessed instructors make negative racial comments or jokes were significantly more willing to express racial bias themselves, even after accounting for the effects of contact. Examining the effects of informal experiences on racial attitudes may help develop a more effective medical training environment and reduce racial disparities in healthcare.

Background Lower extremity peripheral arterial disease (PAD) is a common medical condition causing substantial morbidity. Limited data exist on whether discrepancies in PAD prevalence exist between the lower extremities using resting ankle-brachial indices (ABIs) and postexercise pressures. Objective We predicted the prevalence of PAD between the lower extremities. Methods and Results Consecutive patients who had undergone a noninvasive arterial lower extremity study at Mayo Clinic, Rochester, MN, between January 1996 and December 2012 with suspected PAD were retrospectively reviewed. We identified 12,312 consecutive patients who underwent an arterial lower extremity and an exercise treadmill study. Prevalence of PAD was assessed at rest and after exercise using two criteria: a resting ABI ≤ 0.90 and a postexercise pressure decrease of > 30 mm Hg. Mean age was 67 ± 12 years and there were 4,780 (39%) women studied. At rest, we found a higher prevalence of PAD on the left extremity (27.4%) compared with the right (24.6%) (p < 0.0001). After exercise, we found a higher prevalence of PAD on the right extremity (25.1%) compared with the left (19.0%) (p < 0.0001). These discrepancies between the prevalence of PAD at rest and after exercise were present in women and men. Conclusion Using validated criteria of a resting ABI of ≤ 0.90 and postexercise ankle pressure decrease > 30 mm Hg, our results suggest that there is a significantly higher prevalence of PAD in the left lower extremity at rest, in contrast to a greater prevalence of abnormal postexercise testing in the right lower extremity. The reason(s) of these discrepancies remain to be studied.

Liver X receptors (LXRs) are transcription factors essential for cholesterol homeostasis and lipogenesis. LXRα has been implicated in regulating hepatic triglyceride (TG) accumulation upon both influx of adipose-derived fatty acids (FAs) during fasting and stimulation of de novo FA synthesis by chemical agonism of LXR. However, whether or not a convergent mechanism is employed to drive deposition of FAs from these 2 different sources in TGs is undetermined. Here, we report that the G0/G1 Switch Gene 2 (G0S2), a selective inhibitor of intracellular TG hydrolysis/lipolysis, is a direct target gene of LXRα. Transcriptional activation is conferred by LXRα binding to a direct repeat 4 (DR4) motif in the G0S2 promoter. While LXRα –/– mice exhibited decreased hepatic G0S2 expression, adenoviral expression of G0S2 was sufficient to restore fasting-induced TG storage and glycogen depletion in the liver of these mice. In response to LXR agonist T0901317, G0S2 ablation prevented hepatic steatosis and hypertriglyceridemia without affecting the beneficial effects on HDL. Thus, the LXRα-G0S2 axis plays a distinct role in regulating hepatic TG during both fasting and pharmacological activation of LXR.