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Device infection is associated with increased mortality in cardiovascular implantable electronic device (CIED) recipients. However, published data regarding clinical predictors of mortality in patients with CIED infection are limited. In current investigation, we sought to identify patient and device-related factors associated with mortality in CIED infection cases. We performed a retrospective review of all cases of CIED infection admitted to Mayo Clinic Rochester from 1991 to 2008. Survival data were obtained from hospital medical records and United Sates Social Security Index. Key data regarding patient demographics, device features, comorbid conditions, clinical presentation, echocardiographic findings and management strategies were abstracted. Potential risk factors for short (30-day) and long-term mortality were analyzed using univariate and multivariable logistic and Cox proportional hazards regression models, respectively. 415 cases of CIED infection were identified from the institutional database. The mean duration of follow-up for the 243 patients who were alive at last follow-up was 6.9 years. In multivariable model, congestive heart failure (CHF, Odds ratio 9.31, 95% CI 2.08-41.67), chronic corticosteroid use (OR 4.04, 1.40-11.60) and presentation with CIED-related infective endocarditis (CIED-IE), (OR 5.6, 2.25-13.92) were associated with increased odds of short-term mortality. Independent predictors of long-term mortality on multivariable model included patients' age (hazard ratio for 10-year increase 1.2, 95% CI 1.06-1.36), CHF (HR 2.01, 1.42-2.86), metastatic malignancy (HR 5.99, 1.67-21.53), corticosteroid use (HR 1.97, 1.22-3.18), renal failure (HR 1.94, 1.37-2.74) and CIED-IE (HR 1.68, 1.17-2.41). Our investigation provides some novel insights into predictors of short- and long-term mortality in CIED infection cases. While comorbid conditions and immunocompromised host status were primary determinants of both short- and long-term mortality, complicated device infection (CIED-IE) is the only predictor that presents an opportunity for intervention where mortality may be reduced by early diagnosis and expedited device removal.

Abstract Introduction n this cross-validation study, the distributions of sleep biomarker-based neurodegenerative disorder (NDD) risk were evaluated across a spectrum of NDD patients and presumed controls which were independent of the model development dataset. Methods Variables that included age, time-REM, non-REM hypertonia, autonomic-activation index, spindle-duration, atypical-N3, time-supine, sleep-efficiency, relative-theta, and theta/alpha obtained with Sleep Profiler were used to train a 4-class machine learning algorithm that generated probabilities of NDD risk for the groups: Alzheimer’s dementia (AD), Lewy body disorder (LBD), prodromal synucleinopathy (pSYN based on REM sleep behavior disorder patients), and controls (CG). Records with CG output probabilities >70% were labeled Probably-normal, and from 45-70% Likely-normal with indications of a NDD added when the LBD, AD or pSYN risks exceeded approximately 25%. Similar thresholds were used to assign Likely- or Probable- LBD, AD, pSYN or Mixed based on the group probabilities. This cross-validation study was designed to use datasets that were independent of those used to train the classification algorithm. Thus, NDD risk distributions were evaluated in patients with mild cognitive impairment (MCI=71), Parkinson’s disease (PD=16), progressive supranuclear palsy (PSP=21) and control subjects (NC=41) with Mini-Mental State Exam scores>28 and/or normal for MCI by Petersen criteria. Results In the MCI group, NDD risk assignments were Probable-AD=26%, -Mixed=10%, -LBD=1%, Likely-AD= 7%, -Mixed=6%, -LBD=3%, -pSYN=1%, Likely-Normal indications-AD=9%, -pSYN=7%, -Mixed=4%, and Probably-Normal=26% In the PSP group, Probable-LBD=43%, -Mixed=29% and -pSYN=4%, Likely-Mixed=10%, Likely-Normal indications AD=10%, and Probably-Normal=4%. In the PD group, Probable-LBD=13%, -pSYN=13%, -AD=6%, Likely-Mixed=19%, -pSYN=6%, Likely-Normal Indications-pSYN=19%, -AD=12%, Likely-Normal=6% and Probably-Normal=6% In the NC group, 83% were assigned minimal NDD risk with Probably-Normal=70%, Likely-Normal plus indications=13%, but with Likely NDD=13% and Probable NDD=4%. Conclusion NDD risks were disbursed in a manner consistent with the range of severities expected In MCI and PD groups, with 25% exhibiting relatively normal sleep patterns. Over 70% of the PSP patients exhibited probable NDD risk, with patterns similar to those with LBD. The NC NDD risk distributions were consistent with those assigned to the CG used for model development. Support (if any) NIH grants R44AG050326, R44AG054256, RO1AG060477, R33AG064271, ULRR024150, R34AG056639.

Abstract Introduction In this pilot study, the diagnostic agreement for sleep biomarker-based neurodegenerative disorder (NDD) risk probabilities was evaluated in patients with Alzheimer’s disease dementia (AD), Lewy Body disease (LBD), and isolated REM sleep behavior disorder (iRBD) and controls with a Mini-Mental State Exam scores>28. Methods Sleep biomarkers recorded with the Sleep Profiler (Advanced Brain Monitoring, Inc) were used as inputs to a 4-class machine learning algorithm trained to assign NDD risk probabilities to AD=27, LBD=19, iRBD=15 and controls (CG=58). Input variables included age, time-REM, non-REM hypertonia, autonomic-activation index, spindle-duration, atypical-N3, time-supine, sleep-efficiency, relative-theta, and theta/alpha. Records with CG output probabilities >70% were labeled Probably-normal, and from 45-70% Likely-normal with indications of a NDD added when the LBD, AD or prodromal synucleinopathy (pSYN) risks exceeded approximately 25%. Similar thresholds were used to assign Likely- or Probable- LBD, AD, or pSYN based each of the group probabilities. Classification accuracies were evaluated in AD=37, LBD=19, iRBD=19 and CG=61 records. Longitudinal test-retest reliabilities were assessed for CG (n=45, range 8-56 months), and after six-months for LBD (n=10) and AD (n=9). Results In the AD group, NDD risk assignments were consistent with diagnoses=85%, with Probable-NDD=59%, Likely-NDD=11%, Normal plus AD/Mixed indications=15%, but with 5%=Probably-normal. In the LBD group, assigned risks were consistent with the diagnosis=79%, with Probable-NDD=74%, Normal with pSYN indications=5%, but with 11%=Probably-normal. In the iRBD group, Probable-NDD=42%, Normal plus pSYN indications=26% and Probably-normal=32%. In the CG group, 89% were assigned minimal NDD risks with Probably-normal=67%, Normal plus indications=22%, but with Likely NDD=8% and Probable NDD=3%. The AD test-retest reliability showed the same NDD classifications=78%, with slightly increasing=11% and decreased=11%. In the LBD group, the same NDD classifications were achieved=80%, with trending equivalence=10%, and decreasing severity=20%. The CG test-retest reliability showed the same NDD classifications=76%, with trending equivalence=22%, and increased severity=2%. Conclusion Consistencies between the diagnoses and assigned NDD risks and test-retest classification agreements were approximately 80% in the AD, LBD, and CG groups. In the iRBD group, the NDD risks were disbursed consistent with the range of expected severities. These results needed to be cross-validated in independent NDD datasets. Support (if any) NIH grants R44AG050326, R44AG054256, RO1AG060477, R33AG064271, ULRR024150, R34AG056639.

Abstract Introduction Insomnia is a common sleep disorder in pediatric patients with neurodevelopmental disabilities. There are no FDA approved medications for insomnia in the pediatric population, and treatment can be challenging. We present a case of successful treatment of sleep maintenance insomnia in a 15-year-old male with doxepin with supportive actigraphy data. Report of case(s) A 15-year-old male with a past history pertinent for a genetic neurodevelopmental disorder, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) was evaluated in Pediatric Sleep Medicine Clinic for long standing difficulties with sleep maintenance. He experienced frequent, prolonged nocturnal awakenings and early morning awakenings. Previous polysomnogram was negative for sleep disordered breathing. He previously trialed clonidine, guanfacine, trazodone, melatonin, and mirtazapine without significant benefit. Baseline actigraphy demonstrated frequent and prolonged nocturnal awakenings and early morning awakenings. He was initiated on doxepin 3 mg at bedtime, and it was subsequently increased to 6 mg at bedtime. Parental report and repeat actigraphy 4 months later (on doxepin 6 mg) demonstrated improvement in nocturnal awakenings and early morning awakenings. Conclusion Up to now, there are no FDA approved medications for the treatment of insomnia in the pediatric population. A prior study of patients with ASD and ADHD demonstrated the use of doxepin provided clinical improvement in sleep onset and maintenance insomnia based on subjective evidence with parental report. In this case, doxepin improved subjective report of insomnia and correlated with objective findings on actigraphy. Support (if any) NA

Abstract Introduction High sodium intake can increase blood pressure (BP) and future cardiovascular risk. Individuals with narcolepsy have an elevated cardiovascular comorbidity burden before considering medication-specific risks. Low-sodium oxybate (LXB; Xywav®) is approved by the US Food and Drug Administration (FDA) to treat excessive daytime sleepiness or cataplexy in patients ≥7 years of age with narcolepsy and idiopathic hypersomnia in adults. LXB has the same active moiety as high-sodium oxybates (sodium oxybate [SXB, Xyrem®] and fixed-dose SXB [Lumryz™]) but contains 92% less sodium. The objective of XYLO is to measure ambulatory and in-clinic systolic BP (SBP) changes after switching to LXB from a high-sodium oxybate in participants with narcolepsy (NCT05869773). Methods This 6-week, open-label, multicenter, switch study is enrolling participants 18–70 years of age with narcolepsy (type 1 or 2) taking 6–9 g/night of high-sodium oxybate for ≥6 weeks. Hybrid enrollment supports both on-site and decentralized (monitored at the participant’s home by mobile health professionals) participation, and may broaden the pool of eligible participants. After ≥2 weeks on stable high-sodium oxybate dose/regimens (screening period), participants switch to the same dose/regimen of LXB for 6 weeks (intervention period). The primary endpoint is the change in 24-hour SBP from baseline (the most recent screening measurement prior to switching) to the end-of-treatment visit (approximately 6 weeks after switching) measured via 24-hour ambulatory BP monitoring (ABPM). Secondary endpoints evaluate change from baseline to end-of-treatment visit in-clinic SBP, as well as daytime average SBP and nighttime average SBP measured via 24-hour ABPM. Results Recruitment began in June 2023. This study uses a group sequential design with an adaptive sample size target of 57–77 participants completing the 6-week intervention period. This design provides 90% power to detect a mean difference of 3.5 mmHg (a clinically relevant change) in 24-hour SBP (assuming a standard deviation of the differences in 24-hour SBP of 8 mmHg). Conclusion XYLO will enable the assessment of 24-hour BP changes following transition from a high-sodium oxybate to LXB. Planned hybrid enrollment with a decentralized option may increase study access leading to a more diverse clinical trial population. Support (if any) Jazz Pharmaceuticals

Abstract Introduction In this pilot study, sleep biomarker-based neurodegenerative disorder (NDD) risk was assessed in a clinical cohort of patients diagnosed with varying severity of obstructive sleep apnea (OSA). Methods Consecutive in-home multi-night Sleep Profiler records from a community sleep clinic were screened for age >54 years old. Cases with comorbid restless leg syndrome, hypersomnia, missing apnea-hypopnea indexes (AHI), AHI< 5 or single-night recordings were excluded. The 67 remaining records were 40% female, ages 63 + 7.4 years and up to 84 years old. NDD risk was assigned using a machine-learning algorithm combining age and nine sleep biomarkers to assign group probabilities: for Alzheimer’s disease, Lewy Body disease, prodromal synucleinopathy and controls (CG). Sleep biomarkers included: time-REM, non-REM hypertonia, autonomic-activation index, spindle-duration, atypical-N3, time-supine, sleep-efficiency, relative-theta, and theta/alpha. Those with CG probability score >70% were classified as “Probably-normal”. Those with CG probability between 45 - 70% were classified as “Likely-normal”. Insomnia severity >14 and a PHQ 9 > 5 were used as cutoffs for clinical insomnia and depression. Mann-Whitney U-tests were used to evaluate group differences. Results This cohort had 37% mild, 34% moderate, and 29% severe OSA. Self-reported comorbid insomnia and depression were present in 43%. Seventy-three percent of patients were classified as “Probably-normal”, 16% “Likely-normal”, 11% “Likely-NDD” or “Probable-NDD”. The “Probably-normal” group was younger than the rest of the cohort (62 + 6.2 years vs. 68 + 8.6 years, p< 0.01). Of those classified as “Probably-normal” (n=49), OSA was mild in 16, moderate in 17 and severe in 16. Mean AHI trended higher in the “Probably-normal” group than in those with elevated NDD risk (29 + 23.9 vs. 19 + 13.6 events/h, p=0.085). Conclusion Approximately 89% of the clinical cohort was classified as “Probably-normal” or “Likely-normal”. NDD risk was age-dependent. Interactions between OSA severity and NDD risk were not apparent in these findings, possibly related to group-wide effects. NDD risk, as measured by this model, did not appear to be adversely biased by untreated OSA. These results suggest a need for longitudinal studies to compare NDD risk in untreated OSA versus controls without sleep disordered breathing. Support (if any) NIH grants R44AG050326, R44AG054256, RO1AG060477, R33AG064271, ULRR024150, and R34AG056639.

Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (T PHEX ), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ + T PHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ + T PHEX . We also observed IFN-γ + T PHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19 + leukemia cells. An IFN-γ + T PHEX gene signature was recapitulated in T EX cells from human cancers, including myeloma and lymphoma. Here, we characterize a T EX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional T EX found in chronic viral infections. Thus, IFN-γ + T PHEX represent a potential target for immunotherapy of blood cancers.

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator–activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

AbstractBackgroundHigh dose rate brachytherapy is commonly used in the treatment of prostate cancer. Treatment planning is often performed under transrectal ultrasound (US) guidance, but brachytherapy needles can be challenging to digitize due to the presence of poor US conspicuity and imaging artifacts. The plan accuracy and quality, however, are dependent on the proper visualization of the needles with millimeter accuracy.PurposeThis work describes a technique for generating a color overlay of needle locations atop the grayscale US image. Prototype devices were developed to produce vibrations in the brachytherapy needles that generate a high contrast color Doppler (CD) signal that highlights the needle locations with superior contrast and reduced artifacts. Denoted by the acronym color VISION (Vibrationally Induced Shimmering for Identifying an Object's Nature), the technology has the potential to improve applicator conspicuity and facilitate automated applicator digitization.MethodsThree prototype vibrational devices with frequencies between 200–450 Hz were designed in‐house and evaluated with needle implants in a phantom and cadaveric male pelvis using: (1) an actuator attached to the front of a prostate needle template; (2) an actuator attached to the top of the needle template; and (3) a hand‐held actuator with a stylet, inserted directly into a needle's inner lumen. Acquired images were postprocessed in MATLAB to evaluate the potential for automated digitization.ResultsAll prototype devices produced localized shimmering in implanted brachytherapy needles in both the axial and sagittal planes. The template mounted actuators provided better vibrational coupling and ease of operation than the stylet prototype. The Michelson contrast, or visibility, of the shimmering CD signal was 100% compared with ≤40% for B‐mode imaging of a single needle. Proof‐of‐principle for automated applicator digitization using only the CD signal was demonstrated.ConclusionsThe color VISION prototype devices successfully coupled mechanical vibrations into brachytherapy needles to generate US CD shimmering and accurately highlight brachytherapy needle locations. The high contrast and natively registered signal are promising for future work to automate the needle digitization and provide a real‐time visual overlay of the applicator on the B‐mode US image.