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ImportanceFinding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies.ObjectiveTo evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF.Design, Setting, and ParticipantsThis blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis.ExposureSkin biopsy for detection of phosphorylated α-synuclein.Main OutcomesRates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy.ResultsOf 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected.Conclusions and RelevanceIn this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Abstract Fracture risk increases with lower areal bone mineral density (aBMD); however, aBMD-related estimate of risk may decrease with age. This may depend on technical limitations of 2-dimensional (2D) dual energy X-ray absorptiometry (DXA) which are reduced with 3D high-resolution peripheral quantitative computed tomography (HR-pQCT). Our aim was to examine whether the predictive utility of HR-pQCT measures with fracture varies with age. We analyzed associations of HR-pQCT measures at the distal radius and distal tibia with two outcomes: incident fractures and major osteoporotic fractures. We censored follow-up time at first fracture, death, last contact or 8 years after baseline. We estimated hazard ratios (HR) and 95%CI for the association between bone traits and fracture incidence across age quintiles. Among 6835 men and women (ages 40–96) with at least one valid baseline HR-pQCT scan who were followed prospectively for a median of 48.3 months, 681 sustained fractures. After adjustment for confounders, bone parameters at both the radius and tibia were associated with higher fracture risk. The estimated HRs for fracture did not vary significantly across age quintiles for any HR-pQCT parameter measured at either the radius or tibia. In this large cohort, the homogeneity of the associations between the HR-pQCT measures and fracture risk across age groups persisted for all fractures and for major osteoporotic fractures. The patterns were similar regardless of the HR-pQCT measure, the type of fracture, or the statistical models. The stability of the associations between HR-pQCT measures and fracture over a broad age range shows that bone deficits or low volumetric density remain major determinants of fracture risk regardless of age group. The lower risk for fractures across measures of aBMD in older adults in other studies may be related to factors which interfere with DXA but not with HR-pQCT measures.

Background Context Several studies have shown that factors such as insurance type and patient income are associated with different readmission rates following certain orthopaedic procedures. The literature, however, remains sparse with regard to these demographic characteristics and their associations to perioperative lumbar spine fusion outcomes. Purpose The purpose of this study was to assess the associations between hospital type, insurance type, and patient median income to both 30-day complication and readmission rates following lumbar spine fusion. Patient Sample Patients who underwent primary lumbar spine fusion (n = 596,568) from 2010-2016 were queried from the National Readmissions Database (NRD). Outcome Measures Incidence of 30-day complication and readmission rates Methods All relevant diagnoses and procedures were identified using International Classification of Disease, 9th and 10th Edition (ICD-9, 10) codes. Hospital types were categorized as metropolitan non-teaching (n = 212,131), metropolitan teaching (n = 364,752), and rural (n = 19,685). Insurance types included: Medicare (n = 213,534), Medicaid (n = 78,520), private insurance (n = 196,648), and out-of-pocket (n = 45,025). Patient income was divided into the following quartiles: Q1 (n = 112,083), Q2 (n = 145,755), Q3 (n = 156,276), and Q4 (n = 147,289), wherein quartile 1 corresponded to lower income ranges and quartile 4 to higher ranges. Statistical analysis was conducted in R. Kruskal-Wallis tests with Dunn’s pairwise comparisons were performed to analyze differences in 30-day readmission and complication rates in patients who underwent lumbar spine fusion. Complications analyzed included infection, wound injury, hematoma, neurological injury, thromboembolic event, and hardware failure. Results 30-day readmission was significantly higher in metropolitan teaching hospitals compared to metropolitan non-teaching hospitals and rural hospitals ( P < .05). Patients from metropolitan teaching hospitals had significantly higher rates of infection ( P < .001), wound injury ( P < .001), hematoma ( P = .018), and hardware failure ( P < .002) compared to those treated at metropolitan non-teaching hospitals. Privately insured patients were significantly less likely to be readmitted at 30 days than those paying with Medicare or Medicaid ( P < .01). Patients with private insurance also experienced significantly lower rates of hematoma formation than Medicare beneficiaries and out-of-pocket payers ( P < .01), postoperative wound injury compared to Medicaid patients and out-of-pocket payers ( P < .005), and infection compared to all other groups ( P < .001). Patients in Quartile 4 experienced significantly greater rates of hematoma formation compared to those in Quartiles 1 and 2 and were more likely to experience a thromboembolic event compared to all other groups. Conclusion Patients undergoing lumbar spine fusion at metropolitan non-teaching hospitals and paying with private insurance had significantly lower 30-day readmission rates than their counterparts. Complications within 30 days following lumbar spine fusion were significantly higher in patients treated at metropolitan teaching hospitals and in Medicare and Medicaid beneficiaries. Aside from a few exceptions, however, patient income was generally not associated with differential complication rates.

ImportancePostoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence.ObjectiveTo evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins.Design, Setting, and ParticipantsThe American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (&amp;gt;1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023.Main Outcomes and MeasuresMain outcomes were risk factors for local recurrence.ResultsA total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group.Conclusions and RelevanceIn this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.

Post‐mortem analyses have identified carotid body hypertrophy in conditions of chronic hypoxemia, including sleep apnea; however, post‐mortem assessment limits the clinical relevance of such findings. We tested the hypotheses that: 1) carotid body size can be detected in living individuals by computed tomographic angiography (CTA), and 2) patients with sleep disordered breathing [Apnea Hypopnea Index (AHI) ≥ 30 events/hour] exhibit larger carotid bodies than those without sleep disordered breathing (AHI < 5 events/hour). A chart review was conducted from patients seen at the Mayo Clinic between January 2000 and February 2015 who had undergone neck CTA and polysomnography. From an initial pool of 583, 109 patients met our strict inclusion criteria. Widest axial measurements of the right and left carotid bodies were performed independently by two radiologists blinded to condition and average carotid body size was calculated for each patient of interest. Carotid body identification was possible in 81% of patients. Intra‐class correlation coefficients ranged from 0.93 to 0.95 (right carotid body: 0.93; left: 0.94; average: 0.95). From subjects with identifiable carotid bodies, widest axial measurements were greater in patients with high AHI (n=32; right: 2.9±0.2mm, left: 3.1±0.2mm, average: 3.0±0.1mm) compared to patients with low AHI (n=46; right: 2.5±0.1mm, left: 2.7±0.1mm, average: 2.6±0.1mm; p=0.04, p=0.04, p=0.02, respectively). Because participants in the high AHI group were significantly older than those in the low AHI group (65±2 years vs. 50±2 years; p<0.01), an analysis of covariance was performed to control for the influence of age on carotid body size. After adjusting for age, no differences in carotid body size were observed between the patient groups (p=0.45, p=0.59, p=0.54 for right, left, and average carotid body, respectively). Main findings are two‐fold: 1) carotid body size can be identified by CTA in approximately 80% of patients with good inter‐observer agreement, and 2) adults that exhibit sleep disordered breathing do not have larger carotid bodies when compared to controls, after adjusting for age. Support or Funding Information This work was supported by the National Institutes of Health [grant numbers T32 GM008685 (ARE), R01 DK090541 (MJJ)].

The purpose of this study was to explore dose dependent vasodilation responses of the individual compounds of Shakuyakukanzoto (SKT), a 1:1 combination of extracts from Paeony and Licorice roots: glycyrrhetic acid (GA), paeoniflorin (PF), and isoliquiritigenin (ISO). 20 young, healthy participants (13M/7W) had four intradermal microdialysis fibers placed in the forearm skin for local delivery of: 1) control (diluent), 2) GA, 3) PF, or 4) ISO at doses of 1, 10, 50, or 100 μm. Cutaneous red cell flux, an index of skin blood flow, was measured by laser‐Doppler flowmetry. Blood pressure (BP) was monitored continuously during fixed measurement periods via finger photo‐plethsmography (Finapres). Cutaneous vascular conductance (CVC) was derived as red cell flux divided by BP and was normalized as a percentage of baseline (%CVCbl, saline at 4 μl/min) and the maximum CVC (%CVCmax, 28mM sodium nitroprusside at 4 μl/min, local temperature 43°C). Mean CVC did not statistically differ between baseline and individual compound plateau (average of last 5 minutes of infusion) at any dose. The peak flux was significantly higher from baseline at doses 50 and 100 μm for control (56.17±13.32 vs. 96.73±20.32 and 44.64±5.68 vs. 80.21±9.54), PF (62.70±10.09 vs. 115.72±16.16 and 62.37±16.2 vs. 150.21±34.26), GA (48.37±4.41 vs. 71.76±7.16 and 58.36±13.68 vs. 91.51±3.41), and ISO (96.50±23.20 vs. 128.57±27.90 and 44.95±8.78 vs. 91.18±20.37) (p<0.05). However, peak CVC was significantly higher only for GA at dose 50 μm, as well as for control and PF at dose 100 μm compared to their respected baselines (GA: 0.60±0.06 vs. 1.01±0.11, control: 0.61±0.09 vs.1.55±0.61, PF: 0.81±0.20 vs. 1.30±0.30, p<0.05). There were no other significant differences between the control and the compounds for change in CVC from baseline to peak (ΔCVC), %CVCbl, or %CVCmax. There were no significant differences between doses 1, 10, or 50 as compared to 100 μm for other variables. These results suggest that the doses may be lower or below the threshold to cause a vasodilatory effect. Future studies that investigate higher doses of these compounds may be needed. Support or Funding Information The University of Oxford Systems Biology Project sponsored by Tsumura.

OBJECTIVE Men and women differ in cardiac output. We hypothesize a sex by genotype interaction may exist during a low‐dose adrenaline infusion affecting the β2 adrenergic receptor. METHODS Subjects: Ten males (mean ± SD: age=27.8±6.6, height=178.5±8.0cm, weight=83.9 ±12.4kg, BMI=26.3±2.9kg/m^2, BSA=2.0±0.2) and fourteen females (mean ± SD: age=26.3±5.9, height=164.3±7.0cm, weight=60.8±6.2kg, BMI=22.5±2.1kg/m^2, BSA=1.7±0.1) were studied. Three males were homozygous for Arginine (Arg/Arg) and 7 males were homozygous for Glycine (Gly/Gly) at position 16. In the female cohort, eight females were Arg/Arg and six females were Gly/Gly, at position 16. Procedure: A 1‐hour epinephrine infusion dosed at 5ng/kg/min was administered. BP was measured via an arterial catheter and HR via EKG. Stroke volume and Cardiac output were estimated via Modelflow and TPR was calculated. Plasma samples were collected at time: 0, 30, 45, 60, and 70 minutes and catecholamines measured using HPLC with electrochemical detection. Population Pharmacokinetic‐Pharmacodynamic Analysis: Plasma epinephrine concentrations and cardiac output responses were analyzed using the Nonlinear Mixed Effects (NLME) Stochastic Approximation Expectation‐Maximization (SAEM) algorithm in MATLAB® Simbiology TM (version 2015a, Mathworks, Natick, MA). The Visual Predictive Check was conducted using the R statistical software (version 3.2.2, The R Foundation for Statistical Computing, Vienna, Austria). RESULTS Epinephrine pharmacokinetics were well‐described using a one‐compartment model with an ‘effect compartment’ and elimination from the central compartment. The population mean estimates for the volume of distribution and elimination rate were 22.81 L (CV=27.52%) and 8.77 L/hour (13.00%), respectively. Cardiac Output was modeled using the Hill Stimulation Equation and resulted in mean population estimates of E0=4.94 L/min (13.56%) for baseline, Emax=34.86 L/min (38.61%), and EC50=2486.23 ng/L (CV=5.54%). Bodyweight (mean=70kg) and Sex:Genotypes were the main covariates for the model. A visual predictive check revealed adequate central tendency for the linked PK/PD model. Dosing (300ng/kg/hour for a 70kg individual) simulations resulted in a PK/PD profile stratified for the population mean and Sex:Genotype covariates. Plasma Concentration‐Response curves produced subpopulation (Male Arg/Arg, Male Gly/Gly, Female Arg/Arg, and Female Gly/Gly) differences. CONCLUSION Based on the plasma concentration‐response curves, the interaction of sex and genotype influences the ability to increase cardiac output during an infusion of low‐dose epinephrine. Support or Funding Information NIH T32 Clinical Pharmacology Fellowship Grant GM008685‐17.

Background/Objective Few studies have investigated associations between rheumatologic serology patterns and different interstitial lung disease (ILD) patterns. Methods We present novel findings of a historic cohort study (n = 454) with data collected from 2011 to 2021 within our hospital system. In this institutional review board–approved study, data regarding rheumatologic serologies and ILD patterns were noted based on chart review in patients with scleroderma. The Kruskal-Wallis rank sum and χ 2 tests were used for statistical analysis. Results Results showed a statistically significant association between anti-U1 snRNP with lymphoid interstitial pneumonia, which has not been previously described. Conclusions We demonstrated novel serologic associations with ILD patterns, which have important clinical implications. More robust and high-powered studies are needed to elucidate the role of serologic testing and their association with ILD phenotypes.