Citations

Objective We sought to investigate whether long-term clinical outcomes differ following percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in patients with three-vessel disease (3VD) and lesions in the proximal left anterior descending artery (P-LAD). Methods This post-hoc analysis of the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) Extended Survival study included patients with 3VD who were classified according to the presence or absence of lesions located in the P-LAD. Ten-year all-cause death and 5-year major adverse cardiac or cerebrovascular events (MACCE) were assessed. Results Among 1088 patients with 3VD, 559 (51.4%) had involvement of P-LAD and their 10-year mortality was numerically higher following PCI versus CABG (28.9% vs 21.9%; HR: 1.39, 95% CI 0.99 to 1.95). Although patients without P-LAD lesions had significantly higher 10-year mortality following PCI compared with CABG, there was no evidence of a treatment-by-subgroup interaction (28.8% vs 20.2%; HR: 1.47, 95% CI 1.03 to 2.09, pinteraction=0.837). The incidence of MACCE at 5 years was significantly higher with PCI than CABG, irrespective of involvement of P-LAD (with P-LAD: HR: 1.86, 95% CI 1.36 to 2.55; without P-LAD: HR: 1.54, 95% CI 1.11 to 2.12; pinteraction=0.408). Individualised assessment using the SYNTAX Score II 2020 established that a quarter of patients with P-LAD lesions had significantly higher mortality with PCI than CABG, whereas in the remaining three-quarters CABG had similar mortality. Conclusions Among patients with 3VD, the presence or absence of a P-LAD lesion was not associated with any treatment effect on long-term outcomes following PCI or CABG. Trial registration number SYNTAXES: NCT03417050; SYNTAX: NCT00114972.

Abstract Background: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: Although the standard approach did not identify significant signals, the eQTL set–based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set–based genetic association approach. Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set–based genetic association approach as an alternative method for TWAS analysis.

AbstractIntroduction Second anterior cruciate ligament (SACL) injuries are a devastating complication following return to sport (RTS). Appropriate and safe RTS criteria that reduce the risk of SACL injuries are needed. The goal of this study was to investigate the relationship between functional and isokinetic testing at 6 months following primary ACL reconstruction (ACLR) as risk factors for SACL injuries.Methods Patients with primary ACLR from 1990 to 2010 were identified. Those with 6-month postoperative functional and isokinetic testing and a minimum of 2-year follow-up were included. Functional testing included vertical jump, single-leg hop, and single-leg triple hop. Isokinetic testing included concentric quadriceps and hamstrings (HSs) strength at 60 and 180 degree/s speeds. Statistical analysis evaluated the significance of the various tests between those with and without a secondary tear.Results In total, 344 patients with a mean age of 26.0 ± 9.8 years at an average time of 9.1 ± 3.5 years of follow-up were analyzed. Fifty-nine patients (17%) experienced SACL injuries at an average time of 4.8 years following ACLR with 34 (58%) ipsilateral graft ruptures and 25 (43%) contralateral tears. Several isokinetic measures were significantly different between the NO SACL and the SACL groups: quadriceps 60 degree/s limb symmetry index (LSI) (75 vs. 82% p = 0.01), HS 60 degree/s LSI (92 vs. 97%, p = 0.04), quadriceps 180 degree/s involved/body weight (BW) (41 vs. 47%, p = 0.04), and HS 180 degree/s involved/BW (30 vs. 34%, p = 0.04). Patients with involved limb peak quadriceps torque value greater than 65 or 50% of BW (60 and 180 degree/s) had a 2.2 and 3.1 times higher risk of an SACL injury.Conclusions Patients with certain elevated isokinetic scores in the injured limb at 6 months after ACLR experienced a higher rate of subsequent ACL injuries than those who had lower peak torque. Although a quantitative only analysis may not be sufficient to determine RTS criteria, clinicians should caution high-performing patients about the risk of subsequent ACL injury.Level of Evidence Cohort study; 3.

10022 Background: nab-Sirolimus (formerly know ABI-009 and nab-rapamycin) is a novel human albumin-bound preparation of sirolimus, a potent mTOR inhibitor. We report results of a Phase I study of ABI-009 alone and in combination with irinotecan and temozolomide in children with relapsed/refractory solid or CNS tumors. Methods: Patients (age 1-21 years) with relapsed/refractory solid or CNS tumors were eligible. Using a rolling 6 design, ABI-009 was administered intravenously as a single agent on Days 1 and 8 of cycle 1 (cycle = 21d), then subsequent cycles ABI-009 was administered in combination with temozolomide (125 mg/m2/dose, maximum 250 mg/dose) orally once daily x 5 on Days 1-5 and irinotecan 90 mg/m2/dose orally once daily x 5 on Days 1-5. Three dose levels (DL) of ABI-009 were investigated (DL1: 35mg/m2/dose, DL-1: 20mg/m2/dose, and DL-2: 15mg/m2/dose). The maximum tolerated dose (MTD) or Recommended Phase 2 Dose (RP2D) was established based on dose limiting toxicity (DLT) observed during Cycle 1 and 2. At the RP2D, additional patients were enrolled for pharmacokinetics (PK). Results: 33 patients were enrolled (32 eligible and 1 ineligible); 11 did not experience DLT but were not evaluable for toxicity due to progressive disease or physician decision to discontinue protocol therapy prior to completion of cycle 2; 17 [median age 13 (2-20) years] were evaluable for determination of MTD during dose escalation, 6 were enrolled on the PK cohort, of which 3 were evaluable to toxicity. At DL1, 2/5 patients experienced DLT (thrombocytopenia during cycle 1 (n = 1) and cycle 2 (n = 1)); at DL-1, 2/6 patients experienced DLT (thrombocytopenia in cycle 1); at DL-2, 1/6 patients experienced DLT (thrombocytopenia in cycle 1). PK expansion enrolled at DL-2 and 1/3 participants evaluable for toxicity had a DLT (mucositis). Overall, at DL-2, 2/9 patients (22%) had DLT. One patient with Ewing Sarcoma had a partial response and remained on study for 35 cycles; Patients (one each) with Ewing Sarcoma, Wilms Tumor, and Pineoblastoma had stable disease, ranging from 3-6 cycles. Conclusions: Thrombocytopenia was dose limiting for ABI-009 alone and in combination with temozolomide and irinotecan. The MTD for ABI-009 is 15mg/m2/dose days 1 and 8 in combination with 5 daily doses of temozolomide 125 mg/m2/dose and oral irinotecan 90 mg/m2/dose. One patient had a partial response, 3 patients had prolonged stable disease. Pharmacokinetics and pharmacodynamics are pending and will inform future trials. Clinical trial information: NCT02975882.

Abstract Introduction Risk of sudden death in multiple system atrophy (SuD-MSA) is greatest during sleep. Mechanisms underlying SuD-MSA may involve impaired brainstem arousal and cardiovascular responses to hypercapnia in MSA patients. We hypothesized that nocturnal arousal-related tachycardia events are reduced in MSA patients. We analyzed whether nocturnal pulse event frequency was altered in patients with MSA compared to patients with sleep disordered breathing without MSA utilizing portable overnight oximetry. Methods We retrospectively analyzed 46 probable MSA and 46 age-sex matched patients with sleep disordered breathing (SDB) without MSA, excluding patients receiving cardioactive medications. Nocturnal oxyhemoglobin desaturation indices (ODI) and pulse event indices (PEI) were automatically recorded for all patients using portable overnight oximetry. We calculated a PEI/ODI ratio to determine the relationship between probable breathing-related arousals and pulse rate change. Cardiovagal function was assessed by heart rate to deep breathing and Valsalva ratio in patients with MSA and Composite Autonomic Severity Score was assigned. Group comparisons were made with non-parametric tests. Multivariable regression explored relationships between oximetry variables and clinical characteristics. Results Average age at overnight oximetry was 62.9 ± 7.7 years. Total respiratory events between MSA patients compared with OSA controls were similar (95.0 ± 118.6 vs 73.5± 54.2, p=0.61). Total pulse events were lower in MSA than OSA controls without MSA (25.5±44.2 vs 111.6±120.2, p<0.001), as were pulse events per hour (3.1 ± 5.3 vs. 12.8 ± 10.8, p <0.001). The ratio of PEI/ODI was lower in MSA than OSA patients without MSA (p<0.001). Twelve (26%) MSA patients had zero pulse rate events, while all OSA patients without MSA had at least 1 pulse rate event (p<0.001). The number of pulse events was not associated with severity of cardiovagal dysfunction on daytime autonomic function testing. Conclusion Patients with MSA have fewer pulse rate events when compared with SDB patients without MSA, despite similar overall respiratory event frequency. The number of pulse events was not explained by severity of daytime autonomic dysfunction in those with MSA. Whether nocturnal pulse event response to sleep disordered breathing is a marker of disease severity or plays a role in SuD-MSA deserves further study. Support (If Any)

Abstract Introduction Accurate, early diagnosis of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is crucial given its injury potential and neurological prognosis. We aimed to analyze visual and automated REM sleep without atonia (RSWA) diagnostic thresholds in a current cohort of iRBD patients using submentalis (SM) and individual four limb electromyography (EMG) recordings, including bilateral flexor digitorum superificialis (FDS) and anterior tibialis (AT) during polysomnography. Methods We analyzed RSWA in 20 iRBD patients and 20 age-sex-AHI matched controls who underwent polysomnography between 2017-2021 for phasic burst durations, phasic, tonic, and "any" muscle activity, and automated REM atonia index (RAI). Group RSWA metrics were analyzed with non-parametric comparisons, logistic regression, and receiver operating characteristic (ROC) curves to determine optimal diagnostic cutoff thresholds for iRBD. Correlation explored associative relationships between RSWA metrics, and principal components analysis (PCA) defined determinants of RSWA metric variance. Results All mean RSWA metrics were higher in iRBD patients than controls (p<0.05), except for left and bilateral AT phasic density and duration. RSWA(phasic%, AUC; "any"%, AUC) cutoffs were: SM (6.5%, AUC=90.2; 6.5%, AUC=92.5); L FDS (7.3%, AUC=95.8; 7.3%, AUC=95.8%); R FDS (5.4%, AUC=93.5; 5.8%, AUC=93.2%); Bilateral FDS (10.7%, AUC=96; 15.3%, AUC=95.8); L AT (6.7%, AUC=74.5; 6.7%, AUC=74.8%); R AT (4.7%, AUC=76.8; 4.7%, AUC=76.8%); Bilateral AT (7.5%, AUC=77.5; 7.5%, AUC=77.5%), combined SM/FDS (15.0%, AUC=95.5; 15.1%; AUC=95.8), combined SM/AT (16.5%, AUC=85.8; 21.0%; AUC=88.8),tonic (0.5%; AUC=85.9), and RAI (0.90; AUC=91.4). Phasic burst duration cutoffs were: SM=0.7s (AUC=90.2), L FDS=0.5 s (AUC=83.2), R FDS=0.6 (AUC=85.2), L AT=0.3 s (AUC=65.0) and R AT=0.4 s (AUC=77.0). PCA demonstrated that FDS and combined SM/FDS and SM/AT RSWA metrics best explained RSWA variance and differentiated controls from RBD, while SM and AT alone were less explanatory. Conclusion This study provides evidence for quantitative RSWA diagnostic thresholds applicable in current iRBD populations, and confirms the key importance of FDS to assure accurate iRBD diagnosis. Interestingly, these RSWA diagnostic thresholds are lower than previously determined thresholds, suggesting secular trends toward earlier iRBD detection and heterogeneous disease duration relative to polysomnography acquisition, underscoring the necessity of future large scale prospective, multicenter polysomnographic analyses to determine definitive iRBD diagnostic RSWA thresholds. Support (If Any)

Abstract Introduction Discontinuation of opioid medications may be associated with emergence of restless legs syndrome (RLS), which may complicate opioid withdrawal. However, this has not been systematically studied. We aimed to prospectively determine the frequency of the occurrence and severity of RLS symptoms in patients undergoing physician supervised opioid tapering during a 3-week interdisciplinary pain rehabilitation program. Methods Adult patients undergoing prescription opioid taper were prospectively recruited during their participation in the Mayo Pain Rehabilitation Center from 2016 to 2021. Subjects completed the Cambridge-Hopkins RLS Questionnaire 13 and International Restless Legs Syndrome Study Group Rating Scale (IRLS) at baseline, midpoint, and dismissal from the program as well as 2 weeks, 1 and 3 months after dismissal from the program. Results 101 patients participated with 61% being female taking a mean morphine equivalent dose of 46.6 ± 49.0 mg. Baseline prevalence of RLS symptoms was 29% (29/101), increasing to 32% (32/101) at midpoint of treatment and further to 35% (34/97) at dismissal from the program. Frequency of RLS symptoms peaked 2 weeks after dismissal at 38% (30/78) and steadily declined to 35% (28/80) and 31% (21/68) at 1 month and 3 months after dismissal, respectively. Thirty-five percent of patients without baseline RLS symptoms reported de novo RLS symptoms at some point during their opioid taper. RLS severity score followed a similar trend as the presence of symptoms with a baseline of 16.6 ± 10.0. RLS severity score was maximum at 19.1 ± 7.3 one month following dismissal and decreased but remained elevated above baseline at 3 months following dismissal. Conclusion Symptoms of RLS occurred in over a third of patients on chronic opioids and increased during opioid withdrawal, appearing to peak in frequency and severity 2-4 weeks after discontinuation and gradually improved 3 months after discontinuation. Over one-third of patients in our cohort developed de novo symptoms of RLS at some point during their opioid withdrawal. Physicians supervising individuals undergoing opioid withdrawal should be aware of the potential development of RLS symptoms which may hinder successful opioid withdrawal. Support (If Any)

Abstract Introduction REM sleep without atonia (RSWA) is the neurophysiological substrate of REM sleep behavior disorder (RBD), a form of prodromal parkinsonism in most older adults. Isolated RSWA (without clinical RBD) elevation was demonstrated recently in older adults following SARS-CoV2 (COVID-19) infection, but comparison to controls was not reported. We aimed to comparatively analyze RSWA between patients with previous COVID-19 infection and COVID-19 negative controls. Methods 25 patients with previous COVID-19 infection were compared to 25 age-sex matched controls who tested negative for COVID-19 prior to polysomnography. Patients receiving medications known to increase RSWA were excluded. We reviewed medical records to determine clinical features and quantitatively analyzed RSWA in the submentalis (SM) and anterior tibialis (AT) muscles for phasic, tonic, and “any” muscle activity, phasic burst duration, and the automated REM atonia index. Non-parametric analyses compared clinical and polysomnographic features between groups, with combined SM and AT RSWA as the defined primary outcome. The comparative frequency of COVID-19 positive cases and COVID-19 negative controls who met or exceeded proposed isolated RSWA thresholds was also determined. Results COVID-19 patients had significantly greater RSWA than COVID-19 negative controls in the combined SM and AT muscles (p = 0.00076). Most other RSWA metrics were also higher in COVID-19 patients than controls (p<0.03), except tonic muscle activity, phasic burst durations, and RAI. Isolated RSWA occurred more frequently in COVID-19 (9 patients, 36%) than controls (3, 12%; p>0.05). No patients had a clinical history or polysomnographic evidence for parasomnia behavior or a primary neurological condition. Conclusion Quantitative RSWA amounts were comparatively greater in COVID-19 patients than in COVID-19 tested-negative controls, suggesting association of previous COVID-19 infection with central nervous system brainstem dysfunction in the region of the dorsal pons and/or ventromedial medulla. Further prospective studies are needed to determine whether RSWA is a predisposing influence to, or consequence of, COVID-19 infection in these patients, and whether COVID-19 survivors might harbor neurodegenerative risk or disease markers. Support (If Any)