Leveraging the Apple Ecosystem: Easy Viewing and Sharing of Three-dimensional Perforator Visualizations via iPad/iPhone-based Augmented Reality.

We introduce a novel technique using augmented reality (AR) on smartphones and tablets, making it possible for surgeons to review perforator anatomy in three dimensions on the go. Autologous breast reconstruction with abdominal flaps remains challenging due to the highly variable anatomy of the deep inferior epigastric artery. Computed tomography angiography has mitigated some but not all challenges. Previously, volume rendering and different headsets were used to enable better three-dimensional (3D) review for surgeons. However, surgeons have been dependent on others to provide 3D imaging data. Leveraging the ubiquity of Apple devices, our approach permits surgeons to review 3D models of deep inferior epigastric artery anatomy segmented from abdominal computed tomography angiography directly on their iPhone/iPad. Segmentation can be performed in common radiology software. The models are converted to the universal scene description zipped format, which allows immediate use on Apple devices without third-party software. They can be easily shared using secure, Health Insurance Portability and Accountability Act-compliant sharing services already provided by most hospitals. Surgeons can simply open the file on their mobile device to explore the images in 3D using "object mode" natively without additional applications or can switch to AR mode to pin the model in their real-world surroundings for intuitive exploration. We believe patient-specific 3D anatomy models are a powerful tool for intuitive understanding and communication of complex perforator anatomy and would be a valuable addition in routine clinical practice and education. Using this one-click solution on existing devices that is simple to implement, we hope to streamline the adoption of AR models by plastic surgeons.

Effects of Medicaid managed care on early detection of cancer: Evidence from mandatory Medicaid managed care program in Pennsylvania.

OBJECTIVE: To examine changes in late- versus early-stage diagnosis of cancer associated with the introduction of mandatory Medicaid managed care (MMC) in Pennsylvania. DATA SOURCES AND STUDY SETTING: We analyzed data from the Pennsylvania cancer registry (2010-2018) for adult Medicaid beneficiaries aged 21-64 newly diagnosed with a solid tumor. To ascertain Medicaid and managed care status around diagnosis, we linked the cancer registry to statewide hospital-based facility records collected by an independent state agency (Pennsylvania Health Care Cost Containment Council). STUDY DESIGN: We leveraged a natural experiment arising from county-level variation in mandatory MMC in Pennsylvania. Using a stacked difference-in-differences design, we compared changes in the probability of late-stage cancer diagnosis among those residing in counties that newly transitioned to mandatory managed care to contemporaneous changes among those in counties with mature MMC programs. DATA COLLECTION/EXTRACTION METHODS: N/A. PRINCIPAL FINDINGS: Mandatory MMC was associated with a reduced probability of late-stage cancer diagnosis (-3.9 percentage points; 95% CI: -7.2, -0.5; p = 0.02), particularly for screening-amenable cancers (-5.5 percentage points; 95% CI: -10.4, -0.6; p = 0.03). We found no significant changes in late-stage diagnosis among non-screening amenable cancers. CONCLUSIONS: In Pennsylvania, the implementation of mandatory MMC for adult Medicaid beneficiaries was associated with earlier stage of diagnosis among newly diagnosed cancer patients with Medicaid, especially those diagnosed with screening-amenable cancers. Considering that over half of the sample was diagnosed with late-stage cancer even after the transition to mandatory MMC, Medicaid programs and managed care organizations should continue to carefully monitor receipt of cancer screening and design strategies to reduce barriers to guideline-concordant screening or diagnostic procedures.

Bridging Neuroscience and AI: Environmental Enrichment as a Model for Forward Knowledge Transfer.

Continual learning (CL) refers to an agent's capability to learn from a continuous stream of data and transfer knowledge without forgetting old information. One crucial aspect of CL is forward transfer, i.e., improved and faster learning on a new task by leveraging information from prior knowledge. While this ability comes naturally to biological brains, it poses a significant challenge for artificial intelligence (AI). Here, we suggest that environmental enrichment (EE) can be used as a biological model for studying forward transfer, inspiring human-like AI development. EE refers to animal studies that enhance cognitive, social, motor, and sensory stimulation and is a model for what, in humans, is referred to as 'cognitive reserve'. Enriched animals show significant improvement in learning speed and performance on new tasks, typically exhibiting forward transfer. We explore anatomical, molecular, and neuronal changes post-EE and discuss how artificial neural networks (ANNs) can be used to predict neural computation changes after enriched experiences. Finally, we provide a synergistic way of combining neuroscience and AI research that paves the path toward developing AI capable of rapid and efficient new task learning.

Valence photoelectron imaging of molecular oxybenzone.

An oxybenzone molecule in the gas phase was characterized by mass spectrometry and angle-resolved photoelectron spectroscopy, using both single and multiphoton ionization schemes. A tabletop high harmonic generation source with a monochromator was used for single-photon ionization of oxybenzone with photon energies of up to 35.7 eV. From this, vertical ionization and appearance energies, as well as energy-dependent anisotropy parameters were retrieved and compared with the results from DFT calculations. For two-photon ionization using 4.7 eV light, we found a higher appearance energy than in the extreme ultraviolet (EUV) case, highlighting the possible influence of an intermediate state on the photoionization process. We found no differences in the mass spectra when ionizing oxybenzone by single-photons between 17.2 and 35.7 eV. However, for the multiphoton ionization, the fragmentation process was found to be sensitive to the photoionization order and laser intensity. The "softest" method was found to be two-photon ionization using 4.7 eV light, which led to no measurable fragmentation up to an intensity of 5 × 1012 W cm-2.

CSF Proteomics in Patients With Progressive Supranuclear Palsy.

BACKGROUND AND OBJECTIVES: Identification of fluid biomarkers for progressive supranuclear palsy (PSP) is critical to enhance therapeutic development. We implemented unbiased DNA aptamer (SOMAmer) proteomics to identify novel CSF PSP biomarkers. METHODS: This is a cross-sectional study in original (18 clinically diagnosed PSP-Richardson syndrome [PSP-RS], 28 cognitively healthy controls]), validation (23 PSP-RS, 26 healthy controls), and neuropathology-confirmed (21 PSP, 52 non-PSP frontotemporal lobar degeneration) cohorts. Participants were recruited through the University of California, San Francisco, and the 4-Repeat Neuroimaging Initiative. The original and neuropathology cohorts were analyzed with the SomaScan platform version 3.0 (5026-plex) and the validation cohort with version 4.1 (7595-plex). Clinical severity was measured with the PSP Rating Scale (PSPRS). CSF proteomic data were analyzed to identify differentially expressed targets, implicated biological pathways using enrichment and weighted consensus gene coexpression analyses, diagnostic value of top targets with receiver-operating characteristic curves, and associations with disease severity with linear regressions. RESULTS: A total of 136 participants were included (median age 70.6 ± 8 years, 68 [50%] women). One hundred fifty-five of 5,026 (3.1%), 959 of 7,595 (12.6%), and 321 of 5,026 (6.3%) SOMAmers were differentially expressed in PSP compared with controls in original, validation, and neuropathology-confirmed cohorts, with most of the SOMAmers showing reduced signal (83.1%, 95.1%, and 73.2%, respectively). Three coexpression modules were associated with PSP across cohorts: (1) synaptic function/JAK-STAT (ß = -0.044, corrected p = 0.002), (2) vesicle cytoskeletal trafficking (ß = 0.039, p = 0.007), and (3) cytokine-cytokine receptor interaction (ß = -0.032, p = 0.035) pathways. Axon guidance was the top dysregulated pathway in PSP in original (strength = 1.71, p < 0.001), validation (strength = 0.84, p < 0.001), and neuropathology-confirmed (strength = 0.78, p < 0.001) cohorts. A panel of axon guidance pathway proteins discriminated between PSP and controls in original (area under the curve [AUC] = 0.924), validation (AUC = 0.815), and neuropathology-confirmed (AUC = 0.932) cohorts. Two inflammatory proteins, galectin-10 and cytotoxic T lymphocyte-associated protein-4, correlated with PSPRS scores across cohorts. DISCUSSION: Axon guidance pathway proteins and several other molecular pathways are downregulated in PSP, compared with controls. Proteins in these pathways may be useful targets for biomarker or therapeutic development.

Suture Packaging as a Marker for Intraoperative Image Alignment in Augmented Reality on Mobile Devices.

Preoperative vascular imaging has become standard practice in the planning of microsurgical breast reconstruction. Currently, translating perforator locations from radiological findings to a patient's abdomen is often not easy or intuitive. Techniques using three-dimensional printing or patient-specific guides have been introduced to superimpose anatomy onto the abdomen for reference. Augmented and mixed reality is currently actively investigated for perforator mapping by superimposing virtual models directly onto the patient. Most techniques have found only limited adoption due to complexity and price. Additionally, a critical step is aligning virtual models to patients. We propose repurposing suture packaging as an image tracking marker. Tracking markers allow quick and easy alignment of virtual models to the individual patient's anatomy. Current techniques are often complicated or expensive and limit intraoperative use of augmented reality models. Suture packs are sterile, readily available, and can be used to align abdominal models on the patients. Using an iPad, the augmented reality models automatically align in the correct position by using a suture pack as a tracking marker. Given the ubiquity of iPads, the combination of these devices with readily available suture packs will predictably lower the barrier to entry and utilization of this technology. Here, our workflow is presented along with its intraoperative utilization. Additionally, we investigated the accuracy of this technology.

Head-to-Head Comparison of Tau and Amyloid Positron Emission Tomography Visual Reads for Differential Diagnosis of Neurodegenerative Disorders: An International, Multicenter Study.

OBJECTIVE: We compared the accuracy of amyloid and [18F]Flortaucipir (FTP) tau positron emission tomography (PET) visual reads for distinguishing patients with mild cognitive impairment (MCI) or dementia with fluid biomarker support of Alzheimer's disease (AD). METHODS: Participants with FTP-PET, amyloid-PET, and diagnosis of dementia-AD (n = 102), MCI-AD (n = 41), non-AD diseases (n = 76), and controls (n = 20) were included. AD status was determined independent of PET by cerebrospinal fluid or plasma biomarkers. The mean age was 66.9 years, and 44.8% were women. Three readers interpreted scans blindly and independently. Amyloid-PET was classified as positive/negative using tracer-specific criteria. FTP-PET was classified as positive with medial temporal lobe (MTL) binding as the minimum uptake indicating AD tau (tau-MTL+), positive with posterolateral temporal or extratemporal cortical binding in an AD-like pattern (tau-CTX+), or negative. The majority of scan interpretations were used to calculate diagnostic accuracy of visual reads in detecting MCI/dementia with fluid biomarker support for AD (MCI/dementia-AD). RESULTS: Sensitivity of amyloid-PET for MCI/dementia-AD was 95.8% (95% confidence interval 91.1-98.4%), which was comparable to tau-CTX+ 92.3% (86.7-96.1%, p = 0.67) and tau-MTL+ 97.2% (93.0-99.2%, p = 0.27). Specificity of amyloid-PET for biomarker-negative healthy and disease controls was 84.4% (75.5-91.0%), which was like tau-CTX+ 88.5% (80.4-94.1%, p = 0.34), and trended toward being higher than tau-MTL+ 75.0% (65.1-83.3%, p = 0.08). Tau-CTX+ had higher specificity than tau-MTL+ (p = 0.0002), but sensitivity was lower (p = 0.02), driven by decreased sensitivity for MCI-AD (80.5% [65.1-91.2] vs. 95.1% [83.5-99.4], p = 0.03). INTERPRETATION: Amyloid- and tau-PET visual reads have similar sensitivity/specificity for detecting AD in cognitively impaired patients. Visual tau-PET interpretations requiring cortical binding outside MTL increase specificity, but lower sensitivity for MCI-AD. ANN NEUROL 2024.

An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome.

INTRODUCTION: Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization. METHODS: We described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling. RESULTS: ANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways. DISCUSSION: This study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity. HIGHLIGHTS: ANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.

Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes.

Comparing Perceptions of Virtual and In-Person Interviews: Results From a National Survey of Internal Medicine Residents.

Background Since 2020, virtual interviews have become the typical way in which applicants assess residency programs. It is unknown whether the change from in-person to virtual interviews has been associated with changes in perceptions of the quality of information gathered by prospective applicants. Objective To ascertain perspectives on the satisfaction with, quality of, and accuracy of information gathered by internal medicine (IM) residency applicants from virtual and in-person interviews. Methods Twenty-nine thousand, seven hundred and seventy-six residents from US and Puerto Rico residency programs sitting for the 2022 American College of Physicians Internal Medicine In-Training Examination (IM-ITE) were surveyed. An optional, 5-question survey was administered at the end of the examination. Responses were analyzed based on interview format-virtual (postgraduate year [PGY]-1-2) or in-person (PGY-3)-and PGY. Results Of 29 776, 23 161 residents responded to the survey (77.8% response rate). Regardless of PGY, respondents reported a high degree of satisfaction with the quality of information gathered from their interview day, though there was a statistically significant difference between virtual and in-person [somewhat/very satisfied: In-person 5938 of 7410 (80.1%); 95% CI [79.2, 81.0] vs virtual 12 070 of 15 751 (76.6%); 95% CI [76.0, 77.3]:P<.001]. Residents in all PGYs reported sessions with residents and one-on-one interviews as the most important factors when creating their rank lists. Conclusions We found differences in satisfaction and perceptions of the quality of information gathered between IM residents who participated in virtual and in-person interviews. However, regardless of format, most respondents reported satisfaction with their interview experience.

Impact of planning horizon length on traits in an economic breeding goal and ranking of selection candidates in beef cattle.

In beef production herds, unique situations such as breeding system, economic parameters, and current phenotypic performance can affect the emphasis of traits in the breeding goal and consequently the weighting of traits within a selection index. An often overlooked component of breeding goals is the planning horizon, or the time span to consider the economic impact of a selection decision, that varies between enterprises. A platform for constructing economic selection indexes (iGENDEC) was used to determine the impact of planning horizon length, breeding system, and sale endpoint on the relative emphasis of traits in the breeding goal and the re-ranking of selection candidates. As part of this investigation, the adjustment of phenotypic means for hot carcass weight and planning horizons were used to determine the impact of the relative emphasis on hot carcass weight as its mean approached a predetermined discount threshold. General-purpose indexes were created for animals sold at weaning and slaughter for three breeding systems with six different planning horizons (2, 5, 10, 20, 30, and 50 yr). As planning horizon increased, the relative emphasis on weaning weight or hot carcass weight, which affected revenue, decreased while the relative emphasis on stayability and mature weight increased. As the phenotypic mean for hot carcass weight approached and surpassed a predetermined discount threshold, the relative emphasis decreased before increasing again, once the mean weight surpassed the threshold. Rank correlations between indexes with different sale endpoints was 0.71 ±â€…0.1. Within a slaughter endpoint, re-ranking occurred between short and long planning horizons (r = 0.78 ±â€…0.09) while that of a weaning endpoint was less substantial (r = 0.85 ±â€…0.10). Jacard index scores between indexes with different planning horizons ranged from 39.7% to 87.9% and from 47.9% to 78.7% for weaning and carcass endpoints, respectively, for the top 5% of selection candidates. These results illustrate that the determination of a planning horizon can impact the rank of selection candidates and increases in net profit.

SCOUT® Localization Using MRI Guidance: Initial Experience.

OBJECTIVE: The Food and Drug Administration approved the MRI-compatible wireless SCOUT localization system in April 2022. The purpose of this study was to evaluate feasibility of SCOUT localization under MRI guidance. We present our initial experience adopting MRI-guided SCOUT localization and compare it to MRI-guided wire localization. METHODS: Electronic medical records and imaging were retrospectively reviewed for all patients who underwent MRI-guided SCOUT or wire localization at our institution between October 2022 and July 2023. Statistical analysis was performed using 2-sample proportion and Wilcoxon rank-sum tests. RESULTS: There were 14 MRI-guided SCOUT and 23 MRI-guided wire localization cases during the study period. All SCOUTs were placed without complication and were considered to be in adequate proximity to the target. There was no significant difference in complication rate (P = .25) or days lapsed from MRI-detected abnormality to surgery (P = .82) between SCOUT and wire cases. SCOUT was placed at time of biopsy for 71% (10/14) of cases. 57% (8/14) of SCOUT cases were used for breast conservation surgery (BCS) compared to 100% (23/23) of wire cases (P <.01), with all 6 SCOUTs not used for BCS placed at time of biopsy. CONCLUSION: MRI-guided SCOUT localization is feasible and offers an alternative to MRI-guided wire localization, with no SCOUT complications reported. SCOUT placement at time of biopsy obviates the need for an additional procedure, but predicting appropriateness is challenging, with 60% (6/10) of SCOUTs placed at time of MRI-guided biopsy not used for subsequent localization surgery.

Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia.

Mutations in progranulin ( GRN ) cause frontotemporal dementia ( GRN -FTD) due to deficiency of the pleiotropic protein progranulin. GRN -FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN -FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn -/- mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn -/- RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

The Reconstructive Metaverse - Collaboration in Real-Time Shared Mixed Reality Environments for Microsurgical Reconstruction.

Plastic surgeons routinely use 3D-models in their clinical practice, from 3D-photography and surface imaging to 3D-segmentations from radiological scans. However, these models continue to be viewed on flattened 2D screens that do not enable an intuitive understanding of 3D-relationships and cause challenges regarding collaboration with colleagues. The Metaverse has been proposed as a new age of applications building on modern Mixed Reality headset technology that allows remote collaboration on virtual 3D-models in a shared physical-virtual space in real-time. We demonstrate the first use of the Metaverse in the context of reconstructive surgery, focusing on preoperative planning discussions and trainee education. Using a HoloLens headset with the Microsoft Mesh application, we performed planning sessions for 4 DIEP-flaps in our reconstructive metaverse on virtual patient-models segmented from routine CT angiography. In these sessions, surgeons discuss perforator anatomy and perforator selection strategies whilst comprehensively assessing the respective models. We demonstrate the workflow for a one-on-one interaction between an attending surgeon and a trainee in a video featuring both viewpoints as seen through the headset. We believe the Metaverse will provide novel opportunities to use the 3D-models that are already created in everyday plastic surgery practice in a more collaborative, immersive, accessible, and educational manner.

Body-size-dependent effects of landscape-level resource energetics on pollinator abundance in woodland remnants.

Land use change alters floral resource availability, thereby contributing to declines in important pollinators. However, the severity of land use impact varies by species, influenced by factors such as dispersal ability and resource specialization, both of which can correlate with body size. Here. we test whether floral resource availability in the surrounding landscape (the 'matrix') influences bee species' abundance in isolated remnant woodlands, and whether this effect varies with body size. We sampled quantitative flower-visitation networks within woodland remnants and quantified floral energy resources (nectar and pollen calories) available to each bee species both within the woodland and the matrix. Bee abundance in woodland increased with floral energy resources in the surrounding matrix, with strongest effects on larger-bodied species. Our findings suggest important but size-dependent effects of declining matrix floral resources on the persistence of bees in remnant woodlands, highlighting the need to incorporate landscape-level floral resources in conservation planning for pollinators in threatened natural habitats.

Psychosocial predictors of health behavior adherence in heart-failure patients with comorbid depression: a secondary analysis of the Hopeful Heart trial.

BACKGROUND: Depression affects 20-30% of individuals with heart failure (HF), and it is associated with worse health outcomes independent of disease severity. One potential explanation is the adverse impact of depression on HF patients' adherence to the health behaviors needed to self-manage their condition. The aim of this study is to identify characteristics associated with lower adherence in this population, which could help to recognize individuals at higher risk and eventually tailor health behavior interventions to their needs. METHODS: Using data from a randomized, controlled, collaborative care treatment trial in 629 patients with HF and comorbid depression, we performed mixed effects logistic regression analyses to examine the cross-sectional and prospective relationships between medical and psychosocial variables and health behavior adherence, including adherence to medications, a low-sodium diet, and physician appointments. RESULTS: In cross-sectional analyses, married marital status and higher physical health-related quality of life (HRQoL) were associated with greater overall adherence (compared to married, single Odds Ratio [OR] = 0.46, 95% Confidence Interval [CI] = 0.26-0.80; other OR = 0.60, CI = 0.38-0.94; p = .012. Physical HRQoL OR = 1.02, CI = 1.00-1.04, p = .047). Prospectively, greater levels of social support were associated with improved overall adherence one year later (OR = 1.04, 95% CI = 1.00-1.08, p = .037). Social support, HF symptom severity, race and ethnicity, and age were predictors of specific types of adherence. Neither depression nor optimism was significantly associated with adherence outcomes. CONCLUSIONS: These results provide important preliminary information about risk factors for poor adherence in patients with both HF and depression, which could, in turn, contribute to the development of interventions to promote adherence in this high-risk population. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02044211 ; registered 1/21/2014.

Expansion of highly interferon-responsive T cells in early-onset Alzheimer's disease.

INTRODUCTION: Altered immune signatures are emerging as a central theme in neurodegenerative disease, yet little is known about immune responses in early-onset Alzheimer's disease (EOAD). METHODS: We examined single-cell RNA-sequencing (scRNA-seq) data from peripheral blood mononuclear cells (PBMCs) and droplet digital polymerase chain reaction (ddPCR) data from CD4 T cells from participants with EOAD and clinically normal controls. RESULTS: We analyzed PBMCs from 16 individuals by scRNA-seq and discovered increased interferon signaling-associated gene (ISAG) expression and striking expansion of antiviral-like ISAGhi T cells in EOAD. Isolating CD4 T cells from 19 individuals, including four cases analyzed by scRNA-seq, we confirmed increased expression of ISAGhi marker genes. Publicly available cerebrospinal fluid leukocyte scRNA-seq data from late-onset mild cognitive impairment and AD also revealed increased expression of interferon-response genes. DISCUSSION: Antiviral-like ISAGhi T cells are expanded in EOAD. Additional research into these cells and the role of heightened peripheral IFN signaling in neurodegeneration is warranted. HIGHLIGHTS: Interferon-responsive T cells expanded in early-onset Alzheimer's disease (AD). Increased interferon-associated gene expression present in early- and late-onset AD. Peripheral immune changes in T and NK cells driven by females with early-onset AD.

Hierarchical gradients of encoded spatial and sensory information in the neocortex are attenuated by dorsal hippocampal lesions.

During navigation, the neocortex must actively integrate learned spatial context with current sensory experience to guide behaviours. However, the relative encoding of spatial and sensorimotor information among cortical cells, and whether hippocampal feedback continues to modify these properties in familiar environments, remains poorly understood. Thus, two-photon microscopy of male and female Thy1-GCaMP6s mice was used to longitudinally image neurons spanning superficial retrosplenial cortex and layers II-Va of primary and secondary motor cortices before and after bilateral dorsal hippocampal lesions. During behaviour on a familiar cued treadmill, the locations of two added obstacles were interchanged to decouple place-tuning from cue-tuning among the position correlated cells with fields at those locations. The subpopulations of place- and cue-tuned cells each formed interareal gradients such that higher-level cortical regions exhibited higher fractions of place cells, whereas lower-level regions exhibited higher fractions of cue cells. Position correlated cells in motor cortex also formed translaminar gradients; cells closer to the cortical surface were more likely to exhibit fields and were more sparsely and precisely tuned than deeper cells. After dorsal hippocampal lesions, a neural representation of the learned environment persisted but retrosplenial cortex exhibited significantly increased cue-tuning and, in motor cortices, both position correlated cell recruitment and population activity at the unstable obstacle locations became more homogeneously elevated across laminae. Altogether, these results support that the hippocampus continues to modulate cortical responses in familiar environments, and the relative impact of top-down feedback obeys hierarchical interareal and interlaminar gradients opposite to the flow of bottom-up sensory inputs.Significance statement During learning, the hippocampus imparts spatial context to memory representations throughout the superficial neocortex. However, the post-learning role of the hippocampus has not been well defined. The results of this study suggest that, during navigation of a familiar environment, the hippocampus continues to link unreliable sensory attributes to a stable contextual framework, effectively updating the learned model of the environment. The results are also consistent with top-down suppression of sensory-evoked activity during behaviour, which varied in strength according to hierarchical proximity to the hippocampus. This effect was abolished by bilateral lesions of the dorsal hippocampus, supporting that the hippocampus plays an ongoing role in propagating context-dependent predictions throughout the cortical hierarchy, a core hypothesis of the predictive coding theoretical framework.

Evaluating Cardiac Lead Safety Using Observational, Real-World Data: EP PASSION Proof-of-Concept Study.

BACKGROUND: Traditional post-approval study (PAS) designs have been accepted by regulatory authorities to fulfill post-marketing requirements for cardiac leads but they have several limitations. OBJECTIVES: The authors conducted a proof-of-concept study of alternative methods that utilize real-world data (RWD) to evaluate lead safety in large patient populations. METHODS: Abbott patient device databases were linked with Medicare Fee-For-Service (FFS) claims to identify lead complications among patients implanted with Abbott Optisure™ lead. A 1:1 comparison between the PAS method and RWD method of detecting mechanical lead-related complication events was conducted in 444 PAS subjects who were enrolled in Medicare FFS. Agreement between methods was evaluated using McNemar's test and Cohen's kappa. Survival free from complications at 3 years was compared between the PAS and RWD cohorts using an equivalence acceptance criterion of ±2.5%. RESULTS: There were 1,171 PAS patients and 5,804 Medicare FFS patients who received an Optisure™ lead between August 27, 2014 - June 14, 2016. Patients were followed through December 31, 2018. Complete agreement was found between PAS-reported and claims-detected complications (McNemar's p-value=1.00, Cohen's Kappa = 1.0). Survival free from complications at 3 years using the RWD method was 98.4% (95% CL: 98.0%-98.7%), which was within the acceptable range of the PAS 98.4% (95% CL: 97.6%-99.0%). CONCLUSION: These results show a close agreement between RWD-detected and PAS-reported lead complication rates, which highlight the potential benefits of RWD-based methods to enhance the generation of clinical evidence for lead safety.

High Initial Heart Rate Score is an Independent Predictor of New Atrial High-Rate Episodes in Pacemaker Patients with Sinus Node Dysfunction.

BACKGROUND: Heart Rate Score (HRSc), the percent of atrial depolarizations in the largest paced/sensed 10-bpm histogram bin recorded in cardiac devices, is associated with several adverse outcomes but it remains uncertain if HRSc independently predicts atrial high-rate episodes (AHREs) in patients with sinus node dysfunction (SND) undergoing pacemaker (PM) implantation. OBJECTIVE: To determine if initial HRSc post-PM implant predicts new-onset AHREs in patients with SND. METHODS: Patients had Boston Scientific PMs implanted for SND from 2012-2021 at Cleveland Clinic, University of Occupational and Environmental Health, Japan, Kyushu Rosai Hospital, and JCHO Kyushu Hospital. Patients were excluded if they had atrial fibrillation before PM implant or AHREs within 3-months post-implant. Subsequent AHREs post-implant were evaluated and correlated with HRSc. RESULTS: Over 48.9 (IQR 25.7-50.4) months, 130 consecutive PM patients (76±10 years, 40% male) had a median initial HRSc of 74(57-86)%. AHREs defined by >1%, >6h/day burden, and ATR events>24h developed in 27/130(21%), 15/130(12%), and 9/130(7%), respectively. For each definition, patients with HRSc≥80% had higher occurrence of AHREs than those with HRSc<80% (both p=0.008, log-rank test). After adjusting for age, race, comorbidities, left ventricular ejection fraction, left atrial diameter, and cumulative %RA/RV pacing, initial HRSc ≥80% (HR:3.33, 95% CI:1.35-8.18; P=0.009) and male sex (HR:2.59, 95% CI:1.06-6.33; P=0.04) independently predicted AHREs. CONCLUSION: HRSc≥80% is associated with new-onset, device-determined AHREs for patients undergoing PM implant for SND. HRSc may have prognostic and therapeutic implications.