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Abstract Background Analytical and post-analytical errors are a persistent problem, which can be benchmarked using sigma metrics. Manual processes are associated with error rates of 3–4 sigma. Secondary review of manual reporting is meant to reduce/eliminate errors and is widely used, yet the true efficacy of manual secondary review is difficult to assess. Kidney stone analysis is a manually intensive process, requiring personnel to identify stone composition from spectra and to transcribe stone percent composition into an LIS system. Recently, we developed an AI program that allows for quantitative determination of kidney stone composition from spectra. This allows for a unique opportunity to estimate error rates associated with manual reporting and those following secondary review by means of subsequent AI quality assurance analysis. Methods Experienced technologists assessed stone composition and estimated the percent of each component (± 10%), based on Fourier transform infrared (FTIR) spectroscopy. These manual spectral composition assessments are secondarily reviewed by other experienced technologists for identity and percentage composition accuracy. The recently described Kidney stone AI spectral analysis (RokkStar) was implemented to assess reported stone composition identity and percent composition for agreement following secondary review in 159 334 stone reports. AI flagged discrepant reports were reviewed by personnel and reports were revised when appropriate. Secondary reviewer error detection rate was obtained by monitoring detection in a subset of 7440 kidney stones, and was that rate was extrapolated to establish secondary review error detection rate over the entire data set. The sum (total error) of estimated secondary reviewer error detection, and well as AI-mediated error detection, and all client reported errors were used to determine error rates in sigma following manual reporting, secondary review, and AI quality assurance. Results Manual entry led to an estimated 2060 errors in 159 334 stone reports, yielding an initial sigma value of 3.73. Secondary manual review resulted in an estimated 1909 (error detection rate of 92.5%) of these errors being detected over the entire report set, improving the sigma value to 4.61. Post-verification AI caught an additional 138 errors, leading to an improved post-AI sigma value of 5.27. Post-AI quality assurance, there were 13 remaining errors, 9 of which were manual reporting process deviations subsequently caught by laboratory staff, and 4 were reporting errors observed by client physicians. All 13 of these errors involved usual stone constituents or typographical errors that were not assessed by the current AI quality assurance version. Conclusion This study represents a unique large-scale estimate of efficacy of secondary result review by means of AI quality assurance review. While the presence of undetected errors cannot be completely ruled out, in this case the relative paucity of client reported errors, as well the alignment of the estimated rate of manual errors with previous reports may indicate that most errors were detected in this system. Importantly, manual secondary review improved errors rates by ∼0.9 sigma, and the use of AI further improved estimated overall sigma metric by ∼0.7, leading to a “world class” 5+ sigma level for this complex reporting process.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors reduce risk of hospitalization for heart failure in patients who have heart failure with preserved ejection fraction (HFpEF), but the hemodynamic mechanisms underlying these benefits remain unclear. This study sought to determine whether treatment with dapagliflozin affects pulmonary capillary wedge pressure (PCWP) at rest and during exercise in patients with HFpEF. METHODS: This was a single-center, double-blinded, randomized, placebo-controlled trial testing the effects of 10 mg of dapagliflozin once daily in patients with HFpEF. Patients with New York Heart Association class II or III heart failure, ejection fraction ≥50%, and elevated PCWP during exercise were recruited. Cardiac hemodynamics were measured at rest and during exercise using high-fidelity micromanometers at baseline and after 24 weeks of treatment. The primary end point was a change from baseline in rest and peak exercise PCWPs that incorporated both measurements, and was compared using a mixed-model likelihood ratio test. Key secondary end points included body weight and directly measured blood and plasma volumes. Expired gas analysis was performed evaluate oxygen transport in tandem with arterial lactate sampling. RESULTS: Among 38 patients completing baseline assessments (median age 68 years; 66% women; 71% obese), 37 completed the trial. Treatment with dapagliflozin resulted in reduction in the primary end point of change in PCWP at rest and during exercise at 24 weeks relative to treatment with placebo (likelihood ratio test for overall changes in PCWP; P <0.001), with lower PCWP at rest (estimated treatment difference [ETD], −3.5 mm Hg [95% CI, −6.6 to −0.4]; P =0.029) and maximal exercise (ETD, −5.7 mm Hg [95% CI, −10.8 to −0.7]; P =0.027). Body weight was reduced with dapagliflozin (ETD, −3.5 kg [95% CI, −5.9 to −1.1]; P =0.006), as was plasma volume (ETD, −285 mL [95% CI, −510 to −60]; P =0.014), but there was no significant effect on red blood cell volume. There were no differences in oxygen consumption at 20-W or peak exercise, but dapagliflozin decreased arterial lactate at 20 W (−0.70 ± 0.77 versus 0.37 ± 1.29 mM; P =0.006). CONCLUSIONS: In patients with HFpEF, treatment with dapagliflozin reduces resting and exercise PCWP, along with the favorable effects on plasma volume and body weight. These findings provide new insight into the hemodynamic mechanisms of benefit with sodium-glucose cotransporter-2 inhibitors in HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04730947.

OBJECTIVE Neuromuscular choristoma (NMC) is a rare developmental malformation of peripheral nerve that is frequently associated with the development of a desmoid-type fibromatosis (DTF). Both NMC and NMC-DTF typically contain pathogenic CTNNB1 mutations and NMC-DTF develop only within the NMC-affected nerve territory. The authors aimed to determine if there is a nerve-driven mechanism involved in the formation of NMC-DTF from the underlying NMC-affected nerve. METHODS Retrospective review was performed for patients evaluated in the authors’ institution with a diagnosis of NMC-DTF in the sciatic nerve (or lumbosacral plexus). MRI and FDG PET/CT studies were reviewed to determine the specific relationship and configuration of NMC and DTF lesions along the sciatic nerve. RESULTS Ten patients were identified with sciatic nerve NMC and NMC-DTF involving the lumbosacral plexus, sciatic nerve, or sciatic nerve branches. All primary NMC-DTF lesions were located in the sciatic nerve territory. Eight cases of NMC-DTF demonstrated circumferential encasement of the sciatic nerve, and one abutted the sciatic nerve. One patient had a primary DTF remote from the sciatic nerve, but subsequently developed multifocal DTF within the NMC nerve territory, including 2 satellite DTFs that circumferentially encased the parent nerve. Five patients had a total of 8 satellite DTFs, 4 of which abutted the parent nerve and 3 that circumferentially involved the parent nerve. CONCLUSIONS Based on clinical and radiological data, a novel mechanism of NMC-DTF development from soft tissues innervated by NMC-affected nerve segments is proposed, reflecting their shared molecular genetic alteration. The authors believe the DTF develops outward from the NMC in a radial fashion or it arises in the NMC and wraps around it as it grows. In either scenario, NMC-DTF develops directly from the nerve, likely arising from (myo)fibroblasts within the stromal microenvironment of the NMC and grows outward into the surrounding soft tissues. Clinical implications for patient diagnosis and treatment are presented based on the proposed pathogenetic mechanism.

Background: Tibial spine fractures (TSFs) are uncommon injuries that may result in substantial morbidity in children. A variety of open and arthroscopic techniques are used to treat these fractures, but no single standardized operative method has been identified. Purpose: To systematically review the literature on pediatric TSFs to determine the current treatment approaches, outcomes, and complications. Study Design: Meta-analysis; Level of evidence, 4. Methods: A systematic review of the literature was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines using PubMed, Embase, and Cochrane databases. Studies evaluating treatment and outcomes of patients <18 years old were included. Patient demographic characteristics, fracture characteristics, treatments, and outcomes were abstracted. Descriptive statistics were used to summarize categorical and quantitative variables, and a meta-analytic technique was used to compare observational studies with sufficient data. Results: A total of 47 studies were included, totaling 1922 TSFs in patients (66.4% male) with a mean age of 12 years (range, 3-18 years). The operative approach was open reduction and internal fixation in 291 cases and arthroscopic reduction and internal fixation in 1236 cases; screw fixation was used in 411 cases and suture fixation, in 586 cases. A total of 13 nonunions were reported, occurring most frequently in Meyers and McKeever type III fractures (n = 6) and in fractures that were treated nonoperatively (n = 10). Arthrofibrosis rates were reported in 33 studies (n = 1700), and arthrofibrosis was present in 190 patients (11.2%). Range of motion loss occurred significantly more frequently in patients with type III and IV fractures ( P < .001), and secondary anterior cruciate ligament (ACL) injury occurred most frequently in patients with type I and II fractures ( P = .008). No statistically significant differences were found with regard to rates of nonunion, arthrofibrosis, range of motion loss, laxity, or secondary ACL injury between fixation methods (screw vs suture). Conclusion: Despite variation in TSF treatment, good overall outcomes have been reported with low complication rates in both open and arthroscopic treatment and with both screw and suture fixation. Arthrofibrosis remains a concern after surgical treatment for TSF, but no significant difference in incidence was found between the analysis groups. Larger studies are necessary to compare outcomes and form a consensus on how to treat and manage patients with TSFs.

Background: We developed a deep learning algorithm to predict elevated coronary artery calcium (CAC) score from 12-lead electrocardiograms (CAC- ECG). We tested the hypothesis that this CAC-ECG algorithm will independently predict long-term survival. Methods: We leveraged a historical cohort of 43,210 consecutive patients who from the years 1997-2020 underwent clinically indicated ECG-gated unenhanced chest computed tomography (CT) to identify and quantify CAC and had an ECG within 1 year of the CT. Data on cardiovascular risk (CV) factors, and to calculate the Pooled Cohort Equation (PCE) for ASCVD was collected as part of preventive cardiology or general medical evaluations. We used the oldest CAC in record and excluded those taking statins at the time of the CAC. The algorithm was trained in 60% of the cohort, and the association between CAC-ECG and survival was evaluated with multivariate cox proportional hazard models in 40% of the remaining observations. Results: Of the 17,284 evaluated patients, mean ± SD age 55.9 ± 9.9, 33% female, 3,714 (21%) had elevated CAC ≥ 300. During an average of 15±5.9 years follow-up, 848 (5%) patients died. The algorithm’s area under the receiving operating characteristics curve (ROC), sensitivity, specificity, and accuracy to detect a CAC ≥ 300 were 0.83, 0.90%, 0.56%, 0.60%. Those with elevated CAC had a nearly two-fold risk of death, a value similar to those deemed positive by the ECG-CAC algorithm ( Figure A ). Risk of death increased with CAC-ECG probability quartiles ( Figure A ). The CAC-ECG algorithm enhanced predicted capabilities of the PCE across all ASCVD risk subgroups ( Figure B ), as well as in those with no CAC and elevated CAC ( Figure C ), all p for trend <0.001. Conclusions: A deep learning-enabled CAC-ECG algorithm was independently associated with long-term survival and enhanced current risk prediction paradigms. The CAC-ECG algorithm could help identify individuals at risk in primary prevention of CV disease.

581 Background: Several studies have established the crucial role of preexisting immune response measured by tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC). Emerging studies showed that not only the number of TILs but also the location of TILs is as critical. There are 3 distinct immune landscapes described based on the locations of TILs, namely immune enriched (IN), immune excluded (IE), and immune desert (ID), which are associated with outcomes in TNBC treated with immune-checkpoint inhibitors. Here we evaluated characteristics associated with each immune landscape. Methods: NanoString IO360, Digital Spatial Profiling (DSP), and CosMx, a spatial multi-omics single-cell imaging platform, were used. DSP was used to quantify 39 immune-related proteins in stromal and tumor-enriched segments from 44 TNBC samples from the FinXX trial (NCT00114816) and 276 samples from the Mayo Clinic (MC) TNBC cohort (Leon-Ferre BCRT 2018). CosMx was performed in 75 samples from the MC TNBC cohort. First, tumors with TIL quantified by H&E ≤ 30% were classified as ID. The rest of the tumors were categorized according to the intratumoral CD8 protein expression by DSP, with IE having intratumoral CD8 in the lower median and IN having intratumoral CD8 in the upper median. Differential expression listed as log fold change (FC) was estimated from the linear mixed model with significance defined as two-sided p < 0.05. Results: Using DSP in the FinXX trial, intratumoral and stromal higher HLA-DR (FC 1.68, p = 0.001), B2M (FC 0.8, p = 0.005), CD4 (FC 0.74, p = 0.01), and CD40 (FC 1.56, p = 0.001) were associated with IN compared to ID. When comparing IE and IN, higher intratumoral CD11c (FC 0.97, p = 0.01) and stromal CD4 (FC 0.89, p = 0.047), CD20 (FC 0.85, p = 0.016), CD40 (FC 0.95, p = 0.045), and CD27 (FC 0.84, p = 0.024) were associated with IN. Similar findings were observed in the MC cohort. Moreover, intratumoral NY-ESO-1 expression (FC 0.55, p = 0.03) was associated with IN. Using GSEA with IO360 in the FinXX trial, PI3K-Akt signaling was associated with ID compared to IN (p = 0.01). We further evaluated the differential gene expression in a spatially resolved manner using CosMx with single-cell sequencing in the MC cohort. Expressions of MHC class I and class II in tumor cells, including HLA-A, HLA-B, HLA-C, HLA-DRA, HLA-DRB1, HLA-DPA1, and HLA-E, were associated with IN compared to ID and IE. Conclusions: Using an in-depth analysis with spatially defined context, we identified characteristics associated with distinct immune landscapes in TNBC. Our study highlights the potential future implications of intratumoral MHC expression, CD40, and PI3K-AKT as biomarkers and therapeutic targets. Clinical trial information: NCT00114816 .

Increased cognitive hyperarousal is a proposed mechanism associated with clinical poor sleep including insomnia. An objective marker of nocturnal hyperarousal is high frequency electroencephalography during sleep, including increased beta frequency during stage two (N2) sleep. Acute and chronic poor sleep quality are associated with autonomic dysfunction, but little is known regarding the relationship between nocturnal beta frequency intrusion and nocturnal autonomic function. The purpose of this study was to explore the association between beta spectral power during stage two (N2) sleep and nocturnal heart rate variability (HRV) in healthy female and male adults. We hypothesized that heightened beta spectral power during N2 sleep would be associated with reduced nocturnal HRV. Twenty-four participants (12 males, 12 females; age, 25 ± 1 years; BMI 27 ± 1 kg/m2) underwent an 8-hour overnight sleep opportunity with continuous polysomnography and 5-lead electrocardiogram monitoring. Periods of 5 – 10 minutes of stable N2 sleep absent of cortical arousals, respiratory events, and limb movement-associated arousals were identified (one per cycle) for analysis. Periods from the first two cycles of N2 sleep from the full night were selected for analysis. Beta spectral power from the central and frontal regions and nocturnal HRV data were analyzed and averaged across each hemisphere. Time-domain HRV was quantified as the root mean squared of successive differences (RMSSD) and proportion of R-R intervals (RRI) varying by greater than 50 ms (pNN50). An inverse correlation was observed between central beta power and RRI (R= -0.473, p=0.019), pNN50 (R= -0.450, p=0.028), and RMSSD (R= -0.406, p=0.049). This was paralleled by a similar relationship between frontal beta and RRI (R= -0.487, p=0.016) and pNN50 (R= -0.423, p=0.039). Our results indicate a negative association between N2 beta power and nocturnal HRV measures. These findings suggest that nocturnal hyperarousal may be associated with poor cardiac autonomic function and has implications for individuals with insomnia in whom cognitive hyperarousal is frequently reported. Support is provided by the National Institutes of Health (AA-024892, U54GM115371; P20GM103474, 2TL1 TR002318). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Heightened anxiety is associated with an increased risk for cardiovascular diseases such as coronary heart disease and hypertension. While hyperactivity of the sympathetic nervous system has been suggested to mediate this relationship, direct measures of muscle sympathetic nerve activity (MSNA) in people with elevated anxiety have indicated little, if any, alterations in baseline sympathetic function. However, studies examining anxiety and MSNA have been limited by small sample sizes and lack of detail on anxiety severity, limiting the ability to investigate subtle interactions. The present study assessed associations between trait anxiety, mean arterial pressure (MAP), and MSNA using a large, representative sample of healthy young men and women, with an exploratory assessment of sex-specific interactions. We hypothesized that heightened trait anxiety would be associated with elevated resting MAP and MSNA. Trait anxiety was assessed using the Spielberger Trait Anxiety Inventory (STAI) in 97 healthy adults (52 male, 45 female; 25±1 years; 26±1 kg/m2). In each participant, the average of three seated brachial blood pressures was recorded and used in subsequent analysis. All participants underwent an autonomic function test that simultaneously assessed heart rate (HR), beat-to-beat blood pressure, MSNA burst frequency (BF) and incidence (BI) during 5-10 minutes of supine rest. MSNA recordings were captured in 91 participants. Multiple regression was used to test the relationship between STAI, MAP, MSNA, and HR while accounting for age and sex. Sex-specific interactions were explored with correlations controlling for age. The regression model significantly predicted MAP (R2=.196, P<0.001), BF (R2=.136, P=0.005), and BI (R2=.150, P=0.003), but not HR (R2=.055, P=0.155). STAI scores were independently associated with MAP (β=.207, P=0.029), BF (β=.245, P=0.016), and BI (β=.224, P=0.027). In males, STAI was correlated with MAP (R=.277, P=0.049), BF (R=.363, P=0.009), and BI (R=.346, P=0.013), but not HR (R=.140, P=0.326). In contrast, STAI was not associated with MAP (R=.174, P=0.260), BF (R=.094, P=0.574), BI (R=.069, P=0.681), or HR (R=.226, P=0.141) in females. In a large sample of healthy adults, our results highlight the relationship between the severity of trait anxiety, resting blood pressure, and sympathetic outflow, with a more pronounced relationship in males. Support: NIH (AA-024892, 1R15HL140596-01, AG064038-01A1, U54GM115371; P20GM103474, 2TL1 TR002318). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.