Citations

Background: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. Methods: We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. Results: The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35–1.86; P =2.6×10 − 10 ). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14–2.57; P =0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17–2.24; P =0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18–4.75; P =0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. Conclusions: Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.

Abstract Purpose: The purpose of this study was to assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827). Experimental Design: BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS). Nominal P values with no multiplicity adjustment describe the strength of observed associations. Results: Per central review by RECIST v1.1, 583 of 655 patients had baseline measurable disease and were included in this post hoc analysis. Median BTS was 10.2 cm (range, 1–89.5). Larger median BTS was associated with Eastern Cooperative Oncology Group performance status 1, elevated lactate dehydrogenase (LDH), stage M1c disease, and liver metastases (with or without any other sites; all P ≤ 0.001). In univariate analyses, BTS below the median was associated with higher ORR (44% vs. 23%; P < 0.001) and improved OS (HR, 0.38; P < 0.001). In multivariate analyses, BTS below the median remained an independent prognostic marker of OS (P < 0.001) but not ORR. In 459 patients with available tumor programmed death ligand 1 (PD-L1) expression, BTS below the median and PD-L1–positive tumors were independently associated with higher ORR and longer OS. Conclusions: BTS is associated with many other baseline clinical factors but is also independently prognostic of survival in pembrolizumab-treated patients with advanced melanoma. Clin Cancer Res; 24(20); 4960–7. ©2018 AACR. See related commentary by Warner and Postow, p. 4915

OBJECTIVEThe long-term effects of surgical fusion on the growing subaxial cervical spine are largely unknown. Recent cross-sectional studies have demonstrated that there is continued growth of the cervical spine through the teenage years. The purpose of this multicenter study was to determine the effects of rigid instrumentation and fusion on the growing subaxial cervical spine by investigating vertical growth, cervical alignment, cervical curvature, and adjacent-segment instability over time.METHODSA total of 15 centers participated in this multi-institutional retrospective study. Cases involving children less than 16 years of age who underwent rigid instrumentation and fusion of the subaxial cervical spine (C-2 and T-1 inclusive) with at least 1 year of clinical and radiographic follow-up were investigated. Charts were reviewed for clinical data. Postoperative and most recent radiographs, CT, and MR images were used to measure vertical growth and assess alignment and stability.RESULTSEighty-one patients were included in the study, with a mean follow-up of 33 months. Ninety-five percent of patients had complete clinical resolution or significant improvement in symptoms. Postoperative cervical kyphosis was seen in only 4 patients (5%), and none developed a swan-neck deformity, unintended adjacent-level fusion, or instability. Of patients with at least 2 years of follow-up, 62% demonstrated growth across the fusion construct. On average, vertical growth was 79% (4-level constructs), 83% (3-level constructs), or 100% (2-level constructs) of expected growth. When comparing the group with continued vertical growth to the one without growth, there were no statistically significant differences in terms of age, sex, underlying etiology, surgical approach, or number of levels fused.CONCLUSIONSContinued vertical growth of the subaxial spine occurs in nearly two-thirds of children after rigid instrumentation and fusion of the subaxial spine. Failure of continued vertical growth is not associated with the patient’s age, sex, underlying etiology, number of levels fused, or surgical approach. Further studies are needed to understand this dichotomy and determine the long-term biomechanical effects of surgery on the growing pediatric cervical spine.

It is unknown whether the greater total work of breathing (WOB) with aging is due to greater elastic and/or resistive WOB. We hypothesized that older compared with younger adults would exhibit a greater total WOB at matched ventilations (V̇e) during graded exercise, secondary to greater inspiratory resistive and elastic as well as expiratory resistive WOB. Older (OA: 60 ± 8 yr; n = 9) and younger (YA: 38 ± 7 yr; n = 9) adults performed an incremental cycling test to volitional fatigue. Esophageal pressure, inspiratory (IRV) and expiratory reserve volumes (ERV), expiratory flow limitation (EFL), and ventilatory variables were measured at matched V̇e (i.e., 25, 50, and 75 l/min) during exercise. The inspiratory resistive and elastic as well as expiratory resistive WOB were quantified using the Otis method. At V̇e of 75 l/min, older adults had greater %EFL and larger tidal volumes to inspiratory capacity but smaller relative IRV ( P ≤ 0.03) than younger adults. Older compared with younger adults had greater total WOB at V̇Eof 50 and 75 l/min (OA: 90 ± 43 vs. YA: 49 ± 21 J/min; P < 0.04 for both). At V̇e of 75 l/min, older adults had greater inspiratory elastic and resistive WOB (OA: 44 ± 27 vs. YA: 24 ± 22 and OA: 23 ± 15 vs. YA: 11 ± 3 J/min, respectively, P < 0.03 for both) and expiratory resistive WOB (OA: 23 ± 19 vs. YA: 14 ± 9 J/min, P = 0.02) than younger adults. These data demonstrate that aging-induced pulmonary alterations result in greater inspiratory elastic and resistive as well as expiratory resistive WOB, which may have implications for the integrated response during exercise.NEW & NOTEWORTHY Aging-induced changes to the pulmonary system result in increased work of breathing (WOB) during exercise. However, it is not known whether this higher WOB with aging is due to differences in elastic and/or resistive WOB. Herein, we demonstrate that older adults exhibited greater inspiratory elastic and resistive as well as expiratory resistive WOB during exercise.

Background: Recent epidemiologic reports have demonstrated rising injury rates in Major League Baseball (MLB) and Minor League Baseball (MiLB). Although several studies have recently been published on specific injuries, the majority of injuries have not yet been formally studied. Purpose: The purpose of this study is to (1) generate a summative analysis of all injuries that occur in MLB and MiLB, (2) identify the 50 most common injuries, and (3) generate focused reports and fact sheets on the characteristics of each of those diagnoses. Study Design: Case series; Level of evidence, 4. Methods: The MLB Health and Injury Tracking System was used to identify injuries occurring in MLB and MiLB players from 2011 to 2016. Injuries were defined as those that occurred during normal baseball activity and resulted in at least 1 day out of play. A multitude of player and injury characteristics were analyzed, and detailed reports of the 50 most commonly occurring injuries were generated. Results: A total of 49,955 injuries occurred during the study period; 45,123 were non–season ending, and they resulted in 722,176 days out of play. The mean (median) days missed per injury was 16 (6) days. Overall, 39.1% of all injuries occurred in pitchers. The upper extremity was involved in 39% of injuries, while 35% occurred in the hip/groin/lower extremity. Surgery was required in 6.5% of cases, and 9.7% of injuries were season ending. Hamstring strains were the most common injury (n = 3337), followed by rotator cuff strain/tear (n = 1874), paralumbar muscle strain (n = 1313), biceps tendinitis (n = 1264), oblique strain (n = 1249), and elbow ulnar collateral ligament injury (n = 1191). The diagnoses that were most likely to end a player’s season were elbow ulnar collateral ligament injury (60% season ending) and superior labrum anterior and posterior tear (50.9% season ending). Conclusion: Contrary to prior reports relying on disabled list data, the annual number of injuries in professional baseball remained steady from 2011 to 2016. Similar trends were noted for the annual number of days missed and mean days missed per injury. Although the mean days missed per injury was high (16), the median was much lower at 6 days.

Background: Although vascularity plays a critical role in healing after ulnar collateral ligament (UCL) reconstruction, intraosseous blood flow to the medial epicondyle (ME) and sublime tubercle remains undefined. Purpose: To quantify vascular disruption caused by tunnel drilling with the modified Jobe and docking techniques for UCL reconstruction. Study Design: Controlled laboratory study. Methods: Eight matched pairs (16 specimens) of fresh-frozen cadaveric upper extremities were randomized to 1 of 2 study groups: docking technique or modified Jobe technique. One elbow in each pair underwent tunnel drilling by the assigned technique, while the contralateral elbow served as a control. Pregadolinium and postgadolinium magnetic resonance imaging were performed to quantify intraosseous vascularity within the ME, trochlea, and proximal ulna. Three-dimensional computed tomography (CT) and gross dissection were performed to assess terminal vessel integrity. Results: Ulnar tunnel drilling had minimal impact on vascularity of the proximal ulna, with maintenance of >95% blood flow for each technique. Perfusion in the ME was reduced 14% (to 86% of baseline) for the docking technique and 60% (to 40% of baseline) for the modified Jobe technique (mean difference, 46%; P = .029). Three-dimensional CT and gross dissection revealed increased disruption of small perforating vessels of the posterior aspect of the ME for the modified Jobe technique. Conclusion: Although tunnel drilling in the sublime tubercle appears to have a minimal effect on intraosseous vascularity of the proximal ulna, both the docking and modified Jobe techniques reduce flow in the ME. This reduction was 4 times greater for the modified Jobe technique, and these findings have important implications for UCL reconstruction surgery. Clinical Relevance: As the rate of revision UCL reconstructions continues to rise, investigation into causes for failure of primary surgery is needed. One potential cause is poor tendon-to-bone healing due to inadequate vascularity. This study quantifies the amount of vascular insult that is incurred in the ME during UCL reconstruction. While vascular insult is only one of many factors that affects the surgical success rate, surgeons performing this procedure should be mindful of this potential for vascular disruption.

AbstractAtopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high‐level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option. Several clinical trials with level 1 evidence have supported the use of topical treatments for mild to moderate atopic dermatitis in adults and children, but these trials have had little consistency in protocol design. Consensus recommendations will help standardize clinical development and trial design for children. The Food and Drug Administration issues guidance documents for industry as a source for “the Agency's current thinking on a particular subject.” Although they are nonbinding, industry considers these documents to be the standard for clinical development and trial design. Our consensus group is the first to specifically address clinical trial design in this population. We developed a draft guidance document for industry, Developing Drugs for Treatment of Atopic Dermatitis in Children (≥3 months to <18 years of age). This draft guidance has been submitted to the Food and Drug Administration based on a provision in the Federal Register (Good Guidance Practices).

Background: A more detailed assessment of the anatomy of the entire medial ulnar collateral ligament complex (MUCLC) is desired as the rate of medial elbow reconstruction surgery continues to rise. Purpose: To quantify the anatomy of the MUCLC, including the anterior bundle (AB), posterior bundle (PB), and transverse ligament (TL). Study Design: Descriptive laboratory study. Methods: Ten unpaired, fresh-frozen cadaveric elbows underwent 3-dimensional (3D) digitization and computed tomography with 3D reconstruction. Ligament footprint areas and geometries, distances to key bony landmarks, and isometry were determined. A surgeon digitized the visual center of each footprint, and this location was compared with the geometric centroid calculated from the outline of the digitized footprint. Results: The mean surface area of the AB was 324.2 mm 2 , with an origin footprint of 32.3 mm 2 and an elongated insertional footprint of 187.6 mm 2 (length, 29.7 mm). The mean area of the PB was 116.6 mm 2 (origin, 25.9 mm 2 ; insertion, 15.8 mm 2 ), and the mean surface area of the TL was 134.5 mm 2 (origin, 21.2 mm 2 ; insertion, 16.7 mm 2 ). The geometric centroids of all footprints could be predicted within 0.8 to 1.3 mm, with the exception of the AB insertion centroid, which was 7.6 mm distal to the perceived center at the apex of the sublime tubercle. While the PB remained relatively isometric from 0° to 90° of flexion ( P = .606), the AB lengthened by 2.2 mm ( P < .001). Conclusion: Contrary to several historical reports, the insertional footprint of the AB was larger, elongated, and tapered. The TL demonstrated a previously unrecognized expansive soft tissue insertion directly onto the AB, and additional analysis of the biomechanical contribution of this structure is needed. Clinical Relevance: These findings may serve as a foundation for future study of the MUCLC and help refine current surgical reconstruction techniques.