Citations

Abstract Aims The increasing adoption of transcatheter tricuspid valve replacement (TTVR) offers a promising therapeutic option for patients with severe tricuspid regurgitation. However, many of these patients have pre-existing cardiac implantable electronic devices (CIEDs), raising concerns about potential lead-related complications. Despite these concerns, limited data exist on the impact of TTVR on CIED integrity and function. This study aimed to evaluate the impact of TTVR on CIED lead function, including pacing thresholds, sensing, and impedance, in patients undergoing TTVR with the EVOQUE valve system. Methods and results A retrospective observational study was conducted at Mayo Clinic Rochester, including 32 consecutive patients who underwent TTVR with pre-existing CIEDs. A total of 32 patients were included, with a mean age of 79.2 ± 8.4 years; 59% were female. A total of 62.5% had a permanent pacemaker, 12.5% had an implantable cardioverter-defibrillator, 15.6% had a cardiac resynchronization therapy pacemaker, and 9.4% had a cardiac resynchronization therapy defibrillator. Following TTVR, 10 (31%) of patients developed lead function changes during a median device follow-up of 210 days (IQR: 43–307 days). The right ventricular lead was primarily affected, with only one case involving an atrial lead. Neither the Ottawa score nor the anatomical lead position reliably predicted lead abnormality (P = 0.86 and P = 0.53, respectively). R-wave sensing changes were the most common lead change observed, affecting 55% of cases. In 67% of these cases, R-wave sensing alterations occurred as an isolated finding, with no significant change in impedance or thresholds, and were managed conservatively without any need for device reprogramming. Four patients (13%) had findings concerning for a lead insulation breach, in which one (3%) required a lead revision. Among five patients with follow-up exceeding 600 days, two patients exhibited a statistically significant gradual decline in impedance without other lead dysfunction, suggesting potential subclinical lead degradation. Conclusion Transcatheter tricuspid valve replacement with the EVOQUE system in the setting of cardiac device leads is associated with lead function changes in 31%. The majority of lead-related changes were managed conservatively, but 13% of patients had findings concerning for an insulation breach. Future studies should focus on refining implantation techniques and defining optimal strategies for managing device-lead interactions in this population.

Abstract INTRODUCTION Increased white matter hyperintensity (WMH) volume is a common but non‐specific finding in AD. This study investigates the effect of baseline WMH volume and APO E ε4 on magnetic resonance imaging (MRI)‐visible hemorrhagic lesion emergence. METHODS We included A4 participants with 0/1 hemorrhagic lesion at baseline and >1 post‐baseline MRI. We examined age, sex, amyloid, WMH, APOE ε4, and cardiovascular risk as predictors of whether people would accrue ≥2 hemorrhagic lesions by their last MRI. RESULTS Among 1097 individuals with 0/1 baseline lesion, 120 had at least two hemorrhagic lesions on their last MRI. Elevated baseline WMH (odds ratio [OR] = 2.3, p = 0.002) and APOE ɛ4/ɛ4 (OR = 4.8, p < 0.001) independently predicted membership to this group. Both hetero‐ and homozygous APOE ɛ4 carriers with low WMH volume had a low risk of accumulating hemorrhagic lesions. DISCUSSION These results support the independent consideration of WMH and APOE ɛ4 in the natural history of hemorrhagic lesion accumulation and suggest that individuals with low WMH volume have a low short‐term risk, irrespective of APOE genotype. Trial Registration : NCT02008357 Highlights Elevated baseline white matter lesion volume is related to the risk of ARIA‐H emergence. The effects of white matter lesion volume and APOE ɛ4 on ARIA‐H are independent. APOE ɛ4 carriers with low white matter lesion volume had a low risk of ARIA‐H emergence.

Abstract Our understanding of Alzheimer's disease (AD) and related dementias (ADRD) has grown exponentially, thanks to significant investments by the National Institute on Aging (NIA). This article celebrates the 40th anniversary of the NIA's Alzheimer's Disease Research Centers, highlighting the pivotal role of neuropathology as the bedrock for neurodegeneration research. Neuropathology has championed the key principles of proteinopathy, selective vulnerability, and stereotypic spread. Furthermore, neuropathologic studies advanced our understanding of ADRD prevalence, heterogeneity, clinical–pathological correlations, and genetic underpinnings, spurring biomarker development for target engagement and disease monitoring. Disease‐modifying therapies for AD were inspired and informed by neuropathology. The neuropathology community is poised to refine diagnostics, leveraging digital pathology and integrating genetics and pathomics to enhance subtyping for novel precision medicine approaches. Despite some common misconceptions and logistical challenges, neuropathology continues to be a critical component of the ADRD research infrastructure, serving as a key bridge between allied basic and clinical sciences. Highlights We celebrate 40 years of NIA‐funded ADRCs and their contributions through neuropathology studies that have significantly advanced our understanding and treatment of ADRD. Neuropathology uncovers principles of neurodegenerative disease: proteinopathy, selective vulnerability, and stereotypic spread, informing diagnostics and therapies. Development of AD biomarkers with reference to neuropathology enhances accuracy in diagnosis and monitoring, paving the way for targeted disease‐modifying therapies. Integration of digital pathology, genetics, and novel tools in neurodegeneration research promises advanced precision medicine approaches and refined diagnostics. Misconceptions and logistical challenges to neuropathological research are addressed to improve understanding and collaboration.

ABSTRACT Background Atrial fibrillation (AF) is a prevalent arrhythmia that frequently coexists with cardiomyopathy, leading to deteriorated cardiovascular outcomes. Analyzing the trends associated with these conditions is essential for improving prevention strategies and management practices. Methods CDC WONDER (1999–2023) data were analyzed to assess AF with cardiomyopathy‐related mortality in patients aged ≥ 25. Using Joinpoint regression analysis, we calculated age‐adjusted mortality rates (AAMRs) per 100,000 patients and average annual percentage changes (AAPCs) to analyze mortality trends. Results AF with cardiomyopathy is responsible for 126,377 deaths among adults aged 25 and older. Alarmingly, AAMRs have surged from 1.8 per 100,000 in 1999 to 3.0 in 2023 (AAPC: 2.11, p < 0.001). The upward trend remains pronounced, particularly between 2016 and 2021, with an annual percentage change of 6.17 ( p = 0.02). Disparities in mortality rates are striking. Men face a higher AAMR than women (3.1 vs. 1.5), and Black individuals bear the heaviest burden at 2.4, closely followed by Whites at 2.3. Regionally, Vermont stands out with the highest AAMR at 3.6, while New York reports the lowest at 1.3. Both rural and urban areas maintain equal AAMRs of 2.1, yet the increase in rural regions is particularly concerning, reflecting an AAPC of 2.44 compared to 1.78 in urban settings. Conclusion The rising mortality rates from AF with cardiomyopathy in patients, particularly among men, Black individuals, and rural residents, demand urgent action. These concerning trends underscore a public health crisis that must be addressed.

Abstract Background Cyclin-dependent kinase 12 (CDK12) regulates general gene transcription elongation and plays multiple roles in RNA splicing, DNA damage-response, cell cycle, and genomic stability. However, transcriptional partners that guide CDK12-specific gene programs have not been identified. Genomic alterations in CDK12 have been observed in multiple cancers, exhibiting both pro-tumorigenic and tumor-suppressive functions, suggesting a context-dependent mechanism of action. Methods CDK12 copy number alterations and gene expression levels were analyzed in matched primary and brain metastatic patient tumors. Clinical significance was assessed by immunohistochemistry in a large cohort of primary breast cancer patient tumors. RNA sequencing, ChIP sequencing, and molecular studies were conducted to explore CDK12’s mechanism of action, and pharmacological studies were performed both in vitro and in vivo using models of advanced (endocrine-resistant and metastatic) estrogen receptor positive (ER+) disease. Results CDK12 amplifications and gene overexpression were observed in brain metastatic tumors. In ER+ primary patient tumors, high CDK12 protein expression was significantly associated with poor overall survival, particularly within the ER+/HER2-negative group. In ER+ endocrine resistant models, CDK12 regulated estrogen signaling pathways, with ER/MED1 identified as the master transcriptional complex directing CDK12-specific pro-tumorigenic gene programs. Pharmacological inhibition of CDK12 significantly reduced viability in endocrine resistant and metastatic cell and organoid models in vitro, and decreased metastatic spread in vivo. Conclusion This work describes a novel mechanism for CDK12, suggesting a potential vulnerability in ER+ breast cancer. These findings provide a basis for further investigation into the role of CDK12 inhibition as a therapeutic approach, particularly in advanced disease settings.

OBJECTIVE: To review currently available devices on pressure injury (PI) early detection, summarize challenges and opportunities to clinical implementation, and propose evaluation standards for device categories. DATA SOURCES: PubMed and US Food and Drug Administration (FDA) databases. STUDY SELECTION: Published in English from peer-reviewed journals with full text available. Excluded if opinion statements, lack of empirical data, or unrelated to project’s objective. DATA EXTRACTION: For both clinical device and research equipment: measurement mechanisms, measurement types, outcome/output, FDA classification, and indications for use. Addition data were extracted for clinical devices: instruction for use, end user, order requirement, and billable code. DATA SYNTHESIS: The 4 clinical devices are ultrasound, long-wave infrared thermography, subepidermal moisture assessment, and nearinfrared spectroscopy. The 3 research devices are laser Doppler flowmetry, laser speckle contrast imaging, and colorimetry. CONCLUSIONS: The measurement mechanisms of all devices are unique and different from each other. One commonality is that they could measure the nonvisual signs of PI (eg, inflammation, edema, ischemia, and hypoxia) except colorimeter. Some clinical devices are promising to assist with early identification of PIs, especially in individuals with dark skin tones. Currently, there is no reimbursement available for early detection of PI. Current evidence did not support replacing the standard skin assessment of visual inspection and palpation with the devices reviewed, rather using validated devices to augment the current practice standard. This is especially recommended for individuals identified as high risk for a PI on admission to a facility.

Abstract Objective To evaluate the effect of erenumab treatment beyond monthly migraine days in patients with high‐frequency episodic migraine who did not respond to at least one previous migraine preventive treatment. Background Reduction in monthly migraine days has been the efficacy standard for migraine preventive treatments; however, it does not fully capture the holistic benefit of the therapy. Erenumab, a monoclonal antibody targeting the calcitonin gene–related peptide pathway, has demonstrated reduction in monthly migraine days and improvement in function in patients with episodic and chronic migraine. Methods In this phase 4, interventional, double‐blind, randomized, placebo‐controlled, multicenter, global study, treatment with erenumab was assessed over 4 months in adults with high‐frequency episodic migraine. The study was conducted at 61 sites located across North America and Europe between September 2020 and October 2023. Patients with ≥1 qualifying oral triptan‐treated migraine attack at baseline were randomized to receive erenumab 140 mg or placebo subcutaneously once monthly. The primary endpoint was change from baseline in mean monthly hours of at least moderate headache pain intensity over months 1, 2, and 3; secondary endpoints included change from baseline in mean monthly function, mean monthly duration of at least moderate pain intensity in migraine attacks, and mean monthly peak migraine pain intensity. Safety outcomes were also assessed. Results Of 512 randomized patients, 510 received erenumab 140 mg ( n = 254) or placebo ( n = 256) once monthly. Demographics and baseline characteristics were balanced between the two treatment arms. Erenumab 140 mg was superior to placebo in reducing duration of moderate or severe headache pain intensity over months 1, 2, and 3 (least squares mean [95% confidence interval {CI}] difference, −7.95 [−11.45, −4.46]; p < 0.001). Compared with placebo, erenumab significantly reduced migraine functional impact as assessed by the four domains of the Migraine Functional Impact Questionnaire, with a least squares mean (95% CI) difference of −7.36 (−10.80, −3.92) for physical functioning, −7.10 (−10.34, −3.87) for usual activities, −6.82 (−10.37, −3.27) for social functioning, and − 7.05 (−10.76, −3.34) for emotional functioning ( p < 0.001 for all domains). Significant reductions with erenumab compared with placebo were also observed in duration of at least moderate pain intensity in residual or break‐through migraine attacks (least squares mean [95% CI] difference, −1.07 [−1.92, −0.22]; p = 0.013) and peak migraine pain intensity (−0.48 [−0.85, −0.11]; p = 0.011). Incidence of grade 3 adverse events was 1.6% with erenumab and 1.2% with placebo; no grade 4 or fatal adverse events were reported in either treatment arm. Conclusion Findings from the EMBRACE study demonstrated that treatment with erenumab in patients with high‐frequency episodic migraine can provide positive therapeutic effects on ictal burden and pain, with residual migraine attacks tending to be shorter and less painful, with less overall impact.

Objective: In order to streamline patient care and optimize outcomes, we have undertaken a protocol for patients with cranial/intracranial tumors whereby coordinated resection and reconstruction are performed in a single stage procedure using a virtually planned craniotomy, guides, and implants. This represents an advanced interdisciplinary approach offering operative efficiency while avoiding many clinical and technical challenges. We present our experience and a 9-patient series using this method. Methods: Patients with cranial/intracranial tumors which would create a defect from extirpation or with inadequate bone following repeated craniotomies were evaluated by neurosurgery and craniofacial surgery teams. A virtual surgical planning (VSP) webinar was attended by both services, where extirpation and reconstruction were simultaneously planned. For resection cases, cranial CT images were superimposed with MRI to register precise tumor location in relation to bone anatomy. The virtually planned craniotomy position was transferred to the operating room with a custom cutting guide registered to the patient’s cranial contours. Finally, immediate reconstruction was performed using a custom 3D polyether ether ketone (PEEK) implant designed to extend precisely to the edges of the guided craniotomy. Results: Nine patients age 29 to 79 years old (mean = 55) underwent coordinated tumor extirpation and cranial reconstruction via our workflow. They were followed for 28 to 65 months (mean = 42.2). There were no intraoperative complications. One patient developed transient blurry vision which resolved. One patient with history of repeated meningioma removal developed recurrence. All patients have healed without long-term complications, and there have been no explants from these procedures. Conclusion: Our single-stage protocol for cranial tumor extirpation and cranial reconstruction, which includes collaborative preoperative consultation and VSP, is versatile and effective. The use of computer-generated cutting guides and custom implants obviates intraoperative improvisation and minimizes reoperation. Ultimately, this interdisciplinary approach improves the esthetic and functional results for patients, representing an advancement in cranial defect reconstruction.

Background: The external environment continuously shapes human perception, often without conscious awareness. This influence can be objectively studied using non-invasive recordings of brain activity in controlled virtual reality (VR) settings. We hypothesized that brief presentations of natural features would elicit distinct neural oscillatory patterns detectable through changes in the spectral power of resting-state electroencephalogram (EEG) activity in specific brain regions. Methods: To test this, participants passively viewed three minimalist VR environments—with and without biophilic elements—while their EEG was recorded. Results: Our results revealed consistent changes in spectral power, particularly suppression in the alpha band and an increase in the theta band in the occipital cortex. Conclusions: These findings support the use of resting-state EEGs in immersive VR as a promising and objective method for evaluating how specific design elements influence neural activity, offering valuable insights into the field of neuro-architecture.