The Intra-aortic Balloon Pump: A Focused Review of Physiology, Transport Logistics, Mechanics, and Complications.

Critical care transport medicine (CCTM) teams are playing an increasing role in the care of patients in cardiogenic shock requiring mechanical circulatory support devices. Hence, it is important that CCTM providers are familiar with the pathophysiology of cardiogenic shock, the role of mechanical circulatory support, and the management of these devices in the transport environment. The intra-aortic balloon pump is a widely used and accessible cardiac support device capable of increasing cardiac output and reducing work on the left ventricle through diastolic augmentation and counterpulsation. This article reviews essential CCTM-based considerations for patients supported by intra-aortic balloon pump, including indications for placement, mechanics and physiology, potential issues during transport, and associated complications.

Advancing Health Policy and Outcomes for People With Intellectual or Developmental Disabilities: A Community-Led Agenda.

Importance: At least 10 million people in the United States have an intellectual and/or developmental disability (IDD). People with IDD experience considerably higher rates of poor overall health, chronic conditions including diabetes, mental health challenges, maternal mortality, and preventable deaths. This Special Communication proposes national goals based on a community-led consensus model that advances priority health outcomes for people with IDD and their caregivers/partners and identifies critical policy opportunities and challenges in achieving these goals. A community-led consensus agenda offers a foundation for focusing research, improving data collection and quality measurement, enhancing coverage and payment for services, and investing in a prepared clinical workforce and infrastructure in ways that align with lived experiences and perspectives of community members. Observations: People with IDD prioritize holistic health outcomes and tailored supports and services, driven by personalized health goals, which shift over their life course. Caregivers/partners need support for their own well-being, and easy access to resources to optimize how they support loved ones with IDD. Development of an adequately prepared clinical workforce to serve people with IDD requires national and regional policy changes that incentivize and structure training and continuing education. Ensuring effective and high-value coverage, payment, and clinical decisions requires investments in new data repositories and data-sharing infrastructure, shared learning across public and private payers, and development of new technologies and tools to empower people with IDD to actively participate in their own health care. Conclusions and Relevance: Consensus health priorities identified in this project and centered on IDD community members' perspectives are generalizable to many other patient populations. Public and private payers and regulators setting standards for health information technology have an opportunity to promote clinical data collection that focuses on individuals' needs, quality measurement that emphasizes person-centered goals rather than primarily clinical guidelines, and direct involvement of community members in the design of payment policies. Clinical education leaders, accrediting bodies, and investors/entrepreneurs have an opportunity to innovate a better prepared health care workforce and shared data infrastructure to support value-based care programs.

Post-COVID-19 recovery and geriatric rehabilitation care: a European inter-country comparative study.

PURPOSE: There is variation in organization of geriatric rehabilitation across Europe. The purpose of this study was to describe the selection criteria for referral to geriatric rehabilitation, care provided, and recovery trajectories of post-COVID-19 patients referred to geriatric rehabilitation in Europe. METHODS: This observational cohort study included 723 patients in 59 care facilities for geriatric rehabilitation across 10 countries. Patient data were collected from medical records on admission to geriatric rehabilitation (between September 2020 and October 2021), discharge, 6 weeks and 6 months follow-up. The primary and secondary outcomes were recovery in daily functioning (Barthel Index) and Quality of Life (EQ-5D-5L) from admission to discharge. These were examined using linear mixed models with two levels (measurements nested in patients) and country as an independent variable. Random intercept and random linear slope parameters were added when they improved model fit. A survey about organization of geriatric rehabilitation for post-COVID-19 patients was filled out by country coordinators and data were analyzed using descriptive statistics and inductive coding of answers to open questions. RESULTS: Patients had a mean age of 75.7 years old and 52.4% were male. Many countries used various combinations of the selection criteria, such as functional status, age, frailty, Comprehensive Geriatric Assessment, comorbidities, and cognitive impairments. Most patients received physiotherapy (88.8%) and occupational therapy (69.7%), but there was substantial variance between countries in the percentages of patients that received protein or calorie enriched diets, oxygen therapy, and other treatment components. In all countries, patients showed recovery in daily functioning and quality of life, although there was variation in between countries in rate of recovery. Daily functioning seemed to increase most rapidly in the Czech Republic, Germany, and Russia. The steepest increases in quality of life were seen in the Czech Republic, Germany, and Spain. CONCLUSION: Post-COVID-19 patients showed recovery during geriatric rehabilitation, albeit at variable rates. The observed variation may be explained by the heterogeneity in selection criteria and care provided. This study highlights the need for harmonization of measurements in geriatric rehabilitation order to perform explanatory research and optimize geriatric rehabilitation throughout Europe to ensure optimal patient recovery.

Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.

The outer mitochondrial membrane (OMM) creates a boundary that imports most of the mitochondrial proteome while removing extraneous or damaged proteins. How the OMM senses aberrant proteins and remodels to maintain OMM integrity remains unresolved. Previously, we identified a mitochondrial remodeling mechanism called the mitochondrial-derived compartment (MDC) that removes a subset of the mitochondrial proteome. Here, we show that MDCs specifically sequester proteins localized only at the OMM, providing an explanation for how select mitochondrial proteins are incorporated into MDCs. Remarkably, selective sorting into MDCs also occurs within the OMM, as subunits of the translocase of the outer membrane (TOM) complex are excluded from MDCs unless assembly of the TOM complex is impaired. Considering that overloading the OMM with mitochondrial membrane proteins or mistargeted tail-anchored membrane proteins induces MDCs to form and sequester these proteins, we propose that one functional role of MDCs is to create an OMM-enriched trap that segregates and sequesters excess proteins from the mitochondrial surface.

Opportunities to Improve Antibiotic Prescribing for Adults With Acute Sinusitis, United States, 2016-2020.

Background: Better understanding differences associated with antibiotic prescribing for acute sinusitis can help inform antibiotic stewardship strategies. We characterized antibiotic prescribing patterns for acute sinusitis among commercially insured adults and explored differences by patient- and prescriber-level factors. Methods: Outpatient encounters among adults aged 18 to 64 years diagnosed with sinusitis between 2016 and 2020 were identified by national administrative claims data. We classified antibiotic agents-first-line (amoxicillin-clavulanate or amoxicillin) and second-line (doxycycline, levofloxacin, or moxifloxacin)-and ≤7-day durations as guideline concordant based on clinical practice guidelines. Modified Poisson regression was used to examine the association between patient- and prescriber-level factors and guideline-concordant antibiotic prescribing. Results: Among 4 689 850 sinusitis encounters, 53% resulted in a guideline-concordant agent, 30% in a guideline-discordant agent, and 17% in no antibiotic prescription. About 75% of first-line agents and 63% of second-line agents were prescribed for >7 days, exceeding the length of therapy recommended by clinical guidelines. Adults with sinusitis living in a rural area were less likely to receive a prescription with guideline-concordant antibiotic selection (adjusted risk ratio [aRR], 0.92; 95% CI, .92-.92) and duration (aRR, 0.77; 95% CI, .76-.77). When compared with encounters in an office setting, urgent care encounters were less likely to result in a prescription with a guideline-concordant duration (aRR, 0.76; 95% CI, .75-.76). Conclusions: Opportunities still exist to optimize antibiotic agent selection and treatment duration for adults with acute sinusitis, especially in rural areas and urgent care settings. Recognizing specific patient- and prescriber-level factors associated with antibiotic prescribing can help inform antibiotic stewardship interventions.

Basal parasympathetic deficits in C9orf72 hexanucleotide repeat expansion carriers relate to smaller frontoinsula and thalamus volume and lower empathy.

Diminished basal parasympathetic nervous system activity is a feature of frontotemporal dementia that relates to left frontoinsula dysfunction and empathy impairment. Individuals with a pathogenic expansion of the hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, provide a unique opportunity to examine whether parasympathetic activity is disrupted in genetic forms of frontotemporal dementia and to investigate when parasympathetic deficits manifest in the pathophysiological cascade. We measured baseline respiratory sinus arrhythmia, a parasympathetic measure of heart rate variability, over two minutes in a sample of 102 participants that included 19 asymptomatic expansion carriers (C9+ asymp), 14 expansion carriers with mild cognitive impairment (C9+ MCI), 16 symptomatic expansion carriers with frontotemporal dementia (C9+ FTD), and 53 expansion-negative healthy controls (C9- HC) who also underwent structural magnetic resonance imaging. In follow-up analyses, we compared baseline respiratory sinus arrhythmia in the C9+ FTD group with an independent age-, sex-, and clinical severity-matched group of 26 people with sporadic behavioral variant frontotemporal dementia. The Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating-Sum of Boxes score was used to quantify behavioral symptom severity, and informant ratings on the Interpersonal Reactivity Index provided measures of participants' current emotional (empathic concern) and cognitive (perspective-taking) empathy. Results indicated that the C9+ FTD group had lower baseline respiratory sinus arrhythmia than the C9+ MCI, C9+ asymp, and C9- HC groups, a deficit that was comparable to that of sporadic behavioral variant frontotemporal dementia. Linear regression analyses indicated that lower baseline respiratory sinus arrhythmia was associated with worse behavioral symptom severity and lower empathic concern and perspective-taking across the C9orf72 expansion carrier clinical spectrum. Whole-brain voxel-based morphometry analyses in participants with C9orf72 pathogenic expansions found that lower baseline respiratory sinus arrhythmia correlated with smaller gray matter volume in the left frontoinsula and bilateral thalamus, key structures that support parasympathetic function, and in the bilateral parietal lobes, occipital lobes, and cerebellum, regions that are also vulnerable in individuals with C9orf72 expansions. This study provides novel evidence that basal parasympathetic functioning is diminished in FTD due to C9orf72 expansions and suggests that baseline respiratory sinus arrhythmia may be a potential non-invasive biomarker that is sensitive to behavioral symptoms in the early stages of disease.

The PACT Act-Expanding Coverage and Access for Veterans.

This Viewpoint examines the implementation of the Sergeant First Class Heath Robinson Honoring Our Promise to Address Comprehensive Toxics Act, known as the PACT Act, which expanded health care for millions of veterans from any era exposed to toxic hazards.

The neonatal Fc receptor (FcRn) is a pan-arterivirus receptor.

Arteriviruses infect a variety of mammalian hosts, but the receptors used by these viruses to enter cells are poorly understood. We identified the neonatal Fc receptor (FcRn) as an important pro-viral host factor via comparative genome-wide CRISPR-knockout screens with multiple arteriviruses. Using a panel of cell lines and divergent arteriviruses, we demonstrate that FcRn is required for the entry step of arterivirus infection and serves as a molecular barrier to arterivirus cross-species infection. We also show that FcRn synergizes with another known arterivirus entry factor, CD163, to mediate arterivirus entry. Overexpression of FcRn and CD163 sensitizes non-permissive cells to infection and enables the culture of fastidious arteriviruses. Treatment of multiple cell lines with a pre-clinical anti-FcRn monoclonal antibody blocked infection and rescued cells from arterivirus-induced death. Altogether, this study identifies FcRn as a novel pan-arterivirus receptor, with implications for arterivirus emergence, cross-species infection, and host-directed pan-arterivirus countermeasure development.

Association of bradykinin receptor 2 (BDKRB2) variants with physical performance and muscle mass: Findings from the LACE sarcopenia trial.

INTRODUCTION: Understanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722-9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia. METHODS: We performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants' blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures. RESULTS: Data from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9-1, p<0.001), suggesting an improvement. In men, the -9-9 genotype was associated with lower arm fat (-9-9 2.39kg vs -9+9 2.72kg vs +9+9 2.76kg, p = 0.019). CONCLUSION: In men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass.

Predictors of intraocular pressure response and survival after phacoemulsification for glaucomatous eyes in the IRIS registry (Intelligent Research in Sight).

This retrospective cohort study describes the real-world incidence and maintenance of clinically meaningful intraocular pressure (IOP) reduction ("response") following stand-alone phacoemulsification for 667,987 eyes with suspected or confirmed glaucoma in the IRIS Registry (Intelligent Research in Sight) from 1/1/2013-9/30/2019. Intraocular pressure responders had ≥ 20% IOP reduction in daily mean IOP from baseline on two consecutive postoperative visits. We declared failure if a responder no longer maintained ≥ 20% IOP reduction. The estimated IOP responder rate was 41.3% by Kaplan-Meier analysis. Multivariate analysis demonstrated relationships between IOP response and baseline IOP (hazard ratio (HR) (95% confidence interval)) 1.48 (1.48-1.49), per 3 mmHg, P < 0.0001), age (HR 1.14 (1.13-1.14), per 10 years, P < 0.0001), male sex (HR 1.13 (1.12-1.15), P < 0.0001), prostaglandin analogue (HR 0.88 (0.87-0.90), P < 0.0001), and Rho-kinase inhibitor use (HR 1.50 (1.32-1.70), P = 0.01). Fifty percent of IOP responders failed at a median time of 14.3 months. Multivariate analysis demonstrated relationships between failure and baseline IOP (HR 0.75 (0.75-0.76), per 3 mmHg, P < 0.0001), nitric oxide donating prostaglandin (HR 1.78 (1.46-2.18), P < 0.0001) and Rho-kinase inhibitor use (HR 1.73 (1.43-2.09), P < 0.0001). Clinicians may counsel glaucoma patients with risk factors on whether to anticipate an IOP response and its expected duration after stand-alone phacoemulsification.

Mitochondrial-derived compartments are multilamellar domains that encase membrane cargo and cytosol.

Preserving the health of the mitochondrial network is critical to cell viability and longevity. To do so, mitochondria employ several membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and compartments (MDCs) to selectively remove portions of the organelle. In contrast to well-characterized MDVs, the distinguishing features of MDC formation and composition remain unclear. Here, we used electron tomography to observe that MDCs form as large, multilamellar domains that generate concentric spherical compartments emerging from mitochondrial tubules at ER-mitochondria contact sites. Time-lapse fluorescence microscopy of MDC biogenesis revealed that mitochondrial membrane extensions repeatedly elongate, coalesce, and invaginate to form these compartments that encase multiple layers of membrane. As such, MDCs strongly sequester portions of the outer mitochondrial membrane, securing membrane cargo into a protected domain, while also enclosing cytosolic material within the MDC lumen. Collectively, our results provide a model for MDC formation and describe key features that distinguish MDCs from other previously identified mitochondrial structures and cargo-sorting domains.

Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). METHOD: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. RESULTS: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP. CONCLUSIONS: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

The effect of pre-operative exercise training on post-operative cognitive function: a systematic review.

BACKGROUND: With population aging and advances in surgical and anesthetic procedures, the incidence of surgery in patients over the age of 65 years is increasing. One post-operative complication often encountered by older surgical patients is post-operative cognitive dysfunction (POCD). Preoperative exercise training can improve the overall physiological resilience of older surgical patients, yet its impact on post-operative cognition is less well-established. METHODS: Six databases (Medline (OVID); EMBASE (OVID); EMCARE (OVID); CINAHL (EBSCOHost), the Cochrane Library, and PubMed) were searched for studies reporting the effect of pre-operative physical training on post-operative cognition. The quality of evidence was assessed using the Mixed Methods Assessment Tool. RESULTS: A total of 3983 studies were initially identified, three of which met the inclusion criteria for this review. Two studies were pilot randomized trials, and one was a prospective randomized trial. Two of the studies were high-quality. Each study used a different type of physical exercise and cognition assessment tool. Across the studies, post-operative cognition (p = 0.005) and attention (p = 0.04) were found to be better in the intervention groups compared to control, with one study reporting no difference between the groups. CONCLUSION: Preoperative physical training may improve post-operative cognitive function, although more research with a consistent endpoint is required. Future studies should focus on patients at high risk of POCD, such as older adults, and explore the impact of different exercise regimes, including frequency, intensity, time, and type.

Large-Area Intercalated Two-Dimensional Pb/Graphene Heterostructure as a Platform for Generating Spin-Orbit Torque.

A scalable platform to synthesize ultrathin heavy metals may enable high-efficiency charge-to-spin conversion for next-generation spintronics. Here, we report the synthesis of air-stable, epitaxially registered monolayer Pb underneath graphene on SiC (0001) by confinement heteroepitaxy (CHet). Diffraction, spectroscopy, and microscopy reveal that CHet-based Pb intercalation predominantly exhibits a mottled hexagonal superstructure due to an ordered network of Frenkel-Kontorova-like domain walls. The system's air stability enables ex situ spin torque ferromagnetic resonance (ST-FMR) measurements that demonstrate charge-to-spin conversion in graphene/Pb/ferromagnet heterostructures with a 1.5× increase in the effective field ratio compared to control samples.

Amino acids trigger MDC-dependent mitochondrial remodeling by altering mitochondrial function.

Cells utilize numerous pathways to maintain mitochondrial homeostasis, including a recently identified mechanism that adjusts the content of the outer mitochondrial membrane (OMM) through formation of OMM-derived multilamellar domains called mitochondrial-derived compartments, or MDCs. MDCs are triggered by perturbations in mitochondrial lipid and protein content, as well as increases in intracellular amino acids. Here, we sought to understand how amino acids trigger MDCs. We show that amino acid-activation of MDCs is dependent on the functional state of mitochondria. While amino acid excess triggers MDC formation when cells are grown on fermentable carbon sources, stimulating mitochondrial biogenesis blocks MDC formation. Moreover, amino acid elevation depletes TCA cycle metabolites in yeast, and preventing consumption of TCA cycle intermediates for amino acid catabolism suppresses MDC formation. Finally, we show that directly impairing the TCA cycle is sufficient to trigger MDC formation in the absence of amino acid stress. These results demonstrate that amino acids stimulate MDC formation by perturbing mitochondrial metabolism.

Esophageal epithelial Ikkß deletion promotes eosinophilic esophagitis in experimental allergy mouse model.

Background: Eosinophilic esophagitis (EoE) is a chronic T helper type 2 (Th2)-associated inflammatory disorder triggered by food allergens, resulting in esophageal dysfunction through edema, fibrosis, and tissue remodeling. The role of epithelial remodeling in EoE pathogenesis is critical but not fully understood. Objective: To investigate the role of epithelial IKKß/NFκB signaling in EoE pathogenesis using a mouse model with conditional Ikk ß knockout in esophageal epithelial cells ( Ikk ß EEC-KO ). Methods: EoE was induced in Ikkß EEC-KO mice through skin sensitization with MC903/Ovalbumin (OVA) followed by intraesophageal OVA challenge. Histological and transcriptional analyses were performed to assess EoE features. Single-cell RNA sequencing (scRNA-seq) was used to profile esophageal mucosal cell populations and gene expression changes. Results: Ikkß EEC-KO /EoE mice exhibited hallmark EoE features, including eosinophil infiltration, intraepithelial eosinophils, microabscesses, basal cell hyperplasia, and lamina propria remodeling. RNA-seq revealed significant alterations in IKKß/NFκB signaling pathways, with decreased expression of RELA and increased expression of IKKß negative regulators. scRNA- seq analyses identified disrupted epithelial differentiation and barrier integrity, alongside increased type 2 immune responses and peptidase activity. Conclusion: Our study demonstrates that loss of epithelial IKKß signaling exacerbates EoE pathogenesis, highlighting the critical role of this pathway in maintaining epithelial homeostasis and preventing allergic inflammation. The Ikkß EEC-KO /EoE mouse model closely mirrors human EoE, providing a valuable tool for investigating disease mechanisms and therapeutic targets. This model can facilitate the development of strategies to prevent chronic inflammation and tissue remodeling in EoE. Key Messages: Critical Role of Epithelial IKKß/NFκB Signaling: Loss of this signaling exacerbates EoE, causing eosinophil infiltration, basal cell hyperplasia, and tissue remodeling, highlighting its importance in esophageal health.Molecular Insights and Therapeutic Targets: scRNA-seq identified disrupted epithelial differentiation, barrier integrity, and enhanced type 2 immune responses, suggesting potential therapeutic targets for EoE. Relevance of the Ikkß EEC-KO /EoE Mouse Model: This model replicates human EoE features, making it a valuable tool for studying EoE mechanisms and testing treatments, which can drive the development of effective therapies. Capsule Summary: This study reveals the crucial role of epithelial IKKß/NFκB signaling in EoE, providing insights into disease mechanisms and potential therapeutic targets, highly relevant for advancing clinical management of EoE.

Comorbid neuropathology and atypical presentation of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) neuropathological changes present with amnestic and nonamnestic (atypical) syndromes. The contribution of comorbid neuropathology as a substratum of atypical expression of AD remains under investigated. METHODS: We examined whether atypical AD exhibited increased comorbid neuropathology compared to typical AD and if such neuropathologies contributed to the accelerated clinical decline in atypical AD. RESULTS: We examined 60 atypical and 101 typical AD clinicopathological cases. The number of comorbid pathologies was similar between the groups (p = 0.09). Argyrophilic grain disease was associated with atypical presentation (p = 0.008) after accounting for sex, age of onset, and disease duration. Vascular brain injury was more common in typical AD (p = 0.022). Atypical cases had a steeper Mini-Mental Status Examination (MMSE) decline over time (p = 0.033). DISCUSSION: Comorbid neuropathological changes are unlikely to contribute to atypical AD presentation and the steeper cognitive decline seen in this cohort. Highlights: Autopsy cohort of 60 atypical and 101 typical AD; does comorbid pathology explain atypical presentation?Atypical versus Typical AD: No significant differences in comorbid neuropathologies were found (p = 0.09).Argyrophilic Grain Disease Association: significantly correlates with atypical AD presentations, suggesting a unique neuropathological pattern (p = 0.008).Vascular Brain Injury Prevalence: Vascular brain injury is more common in typical AD than in atypical AD (p = 0.022).Cognitive Decline in Atypical AD: Atypical AD patients experience a steeper cognitive decline measured by MMSE than those with typical AD despite lacking more comorbid neuropathology, highlighting the severity of atypical AD pathogenesis (p = 0.033).

Analytical and behavioral characterization of 1-hexanoyl-LSD (1H-LSD).

The development of lysergic acid diethylamide (LSD) derivatives and analogs continues to inform the design of novel receptor probes and potentially new medicines. On the other hand, a number of newly developed LSD derivatives have also emerged as recreational drugs, leading to reports of their detection in some countries. One position in the ergoline scaffold of LSD that is frequently targeted is the N1-position; numerous N1-alkylcarbonyl LSD derivatives have been reported where the acyl chain is attached to the indole nitrogen, for example, in the form of linear n-alkane substituents, which represent higher homologs of the prototypical 1-acetyl-N,N-diethyllysergamide (1A-LSD, ALD-52). In this study, 1-hexanoyl-LSD (1H-LSD, SYN-L-027), a novel N1-acyl LSD derivative, was characterized analytically using standard techniques, followed by evaluation of its in vivo behavioral effects using the mouse head-twitch response (HTR) assay in C57BL/6J mice. 1H-LSD induced the HTR, with a median effective dose (ED50) of 192.4 µg/kg (equivalent to 387 nmol/kg), making it roughly equipotent to ALD-52 when tested previously under similar conditions. Similar to other N1-acylated analogs, 1H-LSD is anticipated to by hydrolyzed to LSD in vivo and acts as a prodrug. It is currently unknown whether 1H-LSD has appeared as on the research chemical market or is being used recreationally.