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Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1‐SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04–1.12; P <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P =0.11) or in the reverse direction (β=−0.012; P =0.076). Additional bidirectional Mendelian randomization analyses revealed that low‐density lipoprotein cholesterol had a causal effect on mtDNA CN (β=−0.084; P <0.001), but the reverse direction was not significant ( P =0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low‐density lipoprotein cholesterol level ( P =0.52), whereas there was a strong direct causal effect of higher low‐density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=−0.092; P <0.001). Conclusions Our findings indicate that high low‐density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Abstract Disclosure: D.Z. Erickson: None. D. Donegan: None. J. Van Gompel: None. J. Atkinson: None. M. Link: None. F. Meyer: None. M. Peris-Celda: None. G. Spears: None. J. Bornhorst: None. M. Hoplin: None. Dysnatremias are common after neurosurgical procedures. Depending on the cohort assessed, transient arginine vasopressin deficiency (AVD) following neurological procedures is seen in up to 46% of patients which can delay discharge. Copeptin (COPEP), a stable surrogate marker of arginine vasopressin, has demonstrated utility in the prediction of postoperative AVD, however COPEP cutoff and sample timing has varied. Aim: To assess the optimal sampling time and cut point concentration of COPEP to predict the development of post-surgical AVD. Method: Adults who had transsphenoidal surgery (TSS) for a sellar or suprasellar mass between February 2020 and April 2022 without pre-existing AVD were prospectively enrolled if agreeable. Two COPEP samples (immunofluorescent assay on B.R.A.H.M.S Kryptor Compact PLUS) included “early” sample 1-6 hours following extubation, and another post-op day 1 (POD1, 10-30 hours of extubation). Patients were assessed for the development of AVD; defined as new onset hypotonic (&lt; 295 mmol/kg) polyuria (&gt;50 ml/kg/d) without other causes. Patient demographics and tumor characteristics were collected. Results: 192 patients (median age 54.5 (39.8-67.0) years with 54.2% female) were included. Surgical indications included non-functioning pituitary adenoma (N=101), functioning pituitary adenoma (N= 78), disorders or the craniopharyngeal duct (N=10) and other (N=3). Median COPEP levels were associated with age, but not sex. Median COPEP levels were significantly lower at both time points in patients who developed AVD (N=20, 10.4%) vs those who did not, (early: 4.9 vs 18.7 pmol/L, P= &lt;0.001; POD1: 3.35 vs 4.9 pmol/L, P=&lt;0.001). Change in median COPEP level between the 2 sample times was lower in those who developed AVD -1.8 pmol/L vs who did not -12.6 pmol/L (P&lt;0.001). ROC curve analysis of early COPEP indicated that a level &gt;20.3 pmol/L had a negative predictive value (NPV) of 97% whereas POD1 level &gt;6.7 pmolL had a NPV of 96%. In univariate logistic analysis, lower early COPEP was associated with higher risk of AVD (OR=0.34, CI 0.26 -0.62, p=0.008), with an optimal cut point of 8.5 pmol/L. A similar association was seen for POD1 COPEP (OR=0.19, CI 0.07- 0.53, p= 0.002), which had an optimal cut point of 4.3 pmol/L. In patients with disorders of the craniopharyngeal system vs those who had TSS for other reasons, AVD was more common (60% vs 9%, P&lt;0.001) and median COPEP levels were lower at both time points. Those without AVD who received stress dose steroids intraoperatively had lower median early COPEP (11.7 vs 19.1 pmol/L, P=0.27). Conclusion: In early samples taken following extubation, the optimal COPEP cut point for AVD diagnosis was 8.5 pmol/L and a level of &gt;20.3 pmol/L has predicative utility in excluding AVD. However, caution should be used in patients who are administered glucocorticoids intra-operatively as this was associated with a lower median COPEP level. Presentation: Thursday, June 15, 2023

Abstract: Objectives: Locally low-rank (LLR) denoising of functional magnetic resonance imaging (fMRI) time series image data is extended to multi-echo (ME) data. The proposed method extends the capabilities of non-physiologic noise suppression beyond single-echo applications with a dedicated ME algorithm. Materials and Methods: Following an institutional review board (IRB) approved protocol, resting-state fMRI data were acquired in 7 healthy subjects. A compact 3T scanner enabled whole-brain acquisition of multiband ME fMRI data at high spatial resolution (1.4 × 1.4 × 2.8 mm3) with a 1810 ms repetition time (TR). Image data were denoised with ME-LLR preceding functional processing. The results of connectivity maps generated from denoised data were compared with maps generated with equivalent processing of non-denoised images. To assess ME-LLR as a method to reduce scan time, comparisons were made between maps computed from image data with full and retrospectively truncated durations. Assessments were completed with seed-based connectivity analyses using echo-combined image data. In a feasibility assessment, nondenoised and denoised full-duration echo-combined data were equivalently processed with independent component analysis (ICA) and compared. Results: ME-LLR denoising yielded strengthened resting-state network connectivity maps after nuisance regression and seed-based connectivity analysis. In assessing ME-LLR as a scan reduction mechanism, maps generated from denoised data at half scan time showed comparable quality with maps generated from full-duration, non-denoised data, at both single subject and group levels. ME-LLR substantially increased temporal signal-to-noise ratio (tSNR) for image data respective to each individual echo and for image data after nuisance regression. Among echo-specific image volumes, increases in tSNR yielded by ME-LLR were most pronounced for image data with the longest echo time and thereby lowest SNR. ICA showed resting-state networks consistently identified between non-denoised and denoised data, with clearer demarcation of networks for ME-LLR. Conclusions: ME-LLR is demonstrated to suppress non-physiologic noise, enhance functional connectivity map quality, and could potentially facilitate scan time reduction in ME-fMRI.

Background: There are different types of grafts for rhinoplasty, each with certain advantages and disadvantages. Fresh frozen cadaveric costal allograft (CCA) provides an alternative to rhinoplasties. The aim of this study was to compare the outcomes of fresh frozen CCA and traditional autologous costal cartilage in cosmetic and reconstructive rhinoplasty procedures. Methods: This is a prospective, single-center, nonrandomized, open-label clinical trial. Objective assessment to evaluate warping, resorption, and displacement of the cartilage was achieved by measuring the differences of standardized values (deviation angle, nasofrontal angle, total facial convexity, nasofacial angle, and nasolabial angle) obtained at 6-months and 12-months postoperative follow-up on standard two-dimensional photographs (Δ = ∣measurement6 − measurement12∣). Subjective assessment was measured by the FACE-Q assessment. Results: Fifty eligible patients between March 2017 and October 2020 were included. The average age was 43.9 ± 16.6 years and the mean follow-up period was 14.8 months. In the control group, the changes (Δ) in the deviation angle and nasolabial angle were greater than in the CCA group (P < 0.05). In the CCA group, the mean score of satisfaction with nose improved at 6 months and 1 year postoperatively (P < 0.05). The mean score of satisfaction with nostrils and overall facial appearance also increased in the CCA group at 6 months postoperatively (P < 0.05). Six patients from the CCA group and 10 patients from the control group experienced postoperative complications. Conclusions: Fresh frozen CCA is a safe and reliable source of rhinoplasty grafts. It is aseptic, readily available, and free of donor site complications.

AbstractIntroductionThe humerus is a common site of metastases and primary tumors. For some patients with a segmental defect and/or diaphyseal cortical destruction a cemented intercalary device may provide a more reliable construct, however data on their use is limited.MethodsWe reviewed 43 (28 male and 15 female) patients treated with an intercalary humeral spacer at a single tertiary referral center between 1989 and 2022. Humeral lesions were most commonly secondary to metastatic disease (n = 29, 68%), with 25 (58%) patients presenting with a pathologic fracture. Mean age and body mass index were 66 years and 27.9 kg/m2. First generation taper joint device were used in 22 patients and second‐generation lap device in 21 patients.ResultsFollowing reconstruction the 2‐year overall survival was 30%. Mechanical complications occurred in 11 patients, most commonly aseptic loosening (n = 6, 14%). With death as a competing risk, the cumulative incidence of mechanical failure was 28% at 2‐years postoperative. Following the procedure, mean Musculoskeletal Tumor Society scores was 70% and mean shoulder elevation was 87°.ConclusionReconstruction of the humeral diaphysis with an intercalary endoprosthesis provides restoration of function of the upper extremity, however, is associated with one in four patients having mechanical failure.

ObjectiveTo develop evidence‐based consensus recommendations for the optimal timing of hip and knee arthroplasty to improve patient‐important outcomes including, but not limited to, pain, function, infection, hospitalization, and death at 1 year for patients with symptomatic and radiographic moderate‐to‐severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis of the hip or knee who have previously attempted nonoperative therapy, and for whom nonoperative therapy was ineffective, and who have chosen to undergo elective hip or knee arthroplasty (collectively referred to as TJA).MethodsWe developed 13 clinically relevant population, intervention, comparator, outcomes (PICO) questions. After a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence (high, moderate, low, or very low), and evidence tables were created. A Voting Panel, including 13 physicians and patients, discussed the PICO questions until consensus was achieved on the direction (for/against) and strength (strong/conditional) of the recommendations.ResultsThe panel conditionally recommended against delaying TJA to pursue additional nonoperative treatment including physical therapy, nonsteroidal antiinflammatory drugs, ambulatory aids, and intraarticular injections. It conditionally recommended delaying TJA for nicotine reduction or cessation. The panel conditionally recommended delay for better glycemic control for patients who have diabetes mellitus, although no specific measure or level was identified. There was consensus that obesity by itself was not a reason for delay, but that weight loss should be strongly encouraged, and the increase in operative risk should be discussed. The panel conditionally recommended against delay in patients who have severe deformity or bone loss, or in patients who have a neuropathic joint. Evidence for all recommendations was graded as low or very low quality.ConclusionThis guideline provides evidence‐based recommendations regarding the optimal timing of TJA in patients who have symptomatic and radiographic moderate‐to‐severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis for whom nonoperative therapy was ineffective to improve patient‐important outcomes, including pain, function, infection, hospitalization, and death at 1 year. We acknowledge that the evidence is of low quality primarily due to indirectness and hope future research will allow for further refinement of the recommendations.