Longitudinal assessment of glymphatic changes following mild traumatic brain injury: Insights from perivascular space burden and DTI-ALPS imaging.

Introduction: Traumatic brain injury (TBI) even in the mild form may result in long-lasting post-concussion symptoms. TBI is also a known risk to late-life neurodegeneration. Recent studies suggest that dysfunction in the glymphatic system, responsible for clearing protein waste from the brain, may play a pivotal role in the development of dementia following TBI. Given the diverse nature of TBI, longitudinal investigations are essential to comprehending the dynamic changes in the glymphatic system and its implications for recovery. Methods: In this prospective study, we evaluated two promising glymphatic imaging markers, namely the enlarged perivascular space (ePVS) burden and Diffusion Tensor Imaging-based ALPS index, in 44 patients with mTBI at two early post-injury time points: approximately 14 days (14Day) and 6-12 months (6-12Mon) post-injury, while also examining their associations with post-concussion symptoms. Additionally, 37 controls, comprising both orthopedic patients and healthy individuals, were included for comparative analysis. Results: Our key findings include: (1) White matter ePVS burden (WM-ePVS) and ALPS index exhibit significant correlations with age. (2) Elevated WM-ePVS burden in acute mTBI (14Day) is significantly linked to a higher number of post-concussion symptoms, particularly memory problems. (3) The increase in the ALPS index from acute (14Day) to the chronic (6-12Mon) phases in mTBI patients correlates with improvement in sleep measures. Furthermore, incorporating WM-ePVS burden and the ALPS index from acute phase enhances the prediction of chronic memory problems beyond socio-demographic and basic clinical information. Conclusion: ePVS burden and ALPS index offers distinct values in assessing glymphatic structure and activity. Early evaluation of glymphatic function could be crucial for understanding TBI recovery and developing targeted interventions to improve patient outcomes.

Influence of deep eutectic solvents on redox biocatalysis involving alcohol dehydrogenases.

Redox biocatalysis plays an increasingly important role in modern organic synthesis. The recent integration of novel media such as deep eutectic solvents (DESs) has significantly impacted this field of chemical biology. Alcohol dehydrogenases (ADHs) are important biocatalysts where their unique specificity is used for enantioselective synthesis. This review explores aspects of redox biocatalysis in the presence of DES both with whole cells and with isolated ADHs. In both cases, the presence of DES has a significant influence on the outcome of reactions albeit via different mechanisms. For whole cells, DES was shown to be a useful tool to direct product formation or configuration - a process of solvent engineering. Whole cells can tolerate DES as media components for the solubilization of hydrophobic substrates. In some cases, DES in the growth medium altered the enantioselectivity of whole cell transformations by solvent control. For isolated enzymes, on the other hand, the presence of DES promotes substrate solubility as well as enhancing enzyme stability and activity. DES can be employed as a smart solvent or smart cosubstrate particularly for cofactor regeneration purposes. From the literatures examined, it is suggested that DES based on choline chloride (ChCl) such as ChCl:Glycerol (Gly), ChCl:Glucose (Glu), and ChCl:1,4-butanediol (1,4-BD) are useful starting points for ADH-based redox biocatalysis. However, each specific reaction will require optimisation due to the influence of several factors on biocatalysis in DES. These include solvent composition, enzyme source, temperature, pH and ionic strength as well as the substrates and products under investigation.

Longitudinal Assessment of Glymphatic Changes Following Mild Traumatic Brain Injury: Insights from PVS burden and DTI-ALPS Imaging.

Traumatic brain injury (TBI) even in the mild form may result in long-lasting post-concussion symptoms. TBI is also a known risk to late-life neurodegeneration. Recent studies suggest that dysfunction in the glymphatic system, responsible for clearing protein waste from the brain, may play a pivotal role in the development of dementia following TBI. Given the diverse nature of TBI, longitudinal investigations are essential to comprehending the dynamic changes in the glymphatic system and its implications for recovery. In this prospective study, we evaluated two promising glymphatic imaging markers, namely the enlarged perivascular space (ePVS) burden and Diffusion Tensor Imaging-based ALPS index, in 44 patients with mTBI at two early post-injury time points: approximately 14 days (14Day) and 6-12 months (6-12Mon) post-injury, while also examining their associations with post-concussion symptoms. Additionally, 37 controls, comprising both orthopedic patients and healthy individuals, were included for comparative analysis. Our key findings include: 1) White matter ePVS burden (WM-ePVS) and ALPS index exhibit significant correlations with age. 2) Elevated WM-ePVS burden in acute mTBI (14Day) is significantly linked to a higher number of post-concussion symptoms, particularly memory problems. 3) The increase in the ALPS index from acute (14Day) to the chronic (6-12Mon) phases in mTBI patients correlates with improvement in sleep measures. Furthermore, incorporating WM-ePVS burden and the ALPS index from acute phase enhances the prediction of chronic memory problems beyond socio-demographic and basic clinical information, highlighting their distinct roles in assessing glymphatic structure and activity. Early evaluation of glymphatic function could be crucial for understanding TBI recovery and developing targeted interventions to improve patient outcomes.

Was the massive increase in use of teratogenic agrichemicals in western states (USA) associated with declines in wild ruminant populations between 1994 and 2013?

Population declines were documented in multiple ruminant species in Montana and surrounding states starting in 1995. While weather, food sources, and predation certainly contributed, the declines were often attributed, at least partly, to unexplained factors. Use of teratogenic agrichemicals, notably neonicotinoid insecticides, fungicides, and glyphosate-based herbicides, massively increased regionally in 1994-96. The question explored in this review is whether this vastly increased use of these teratogenic pesticides might have contributed to observed population declines. We provide references and data documenting that specific developmental malformations on vertebrates can be associated with exposure to one or more of these agrichemicals. These pesticides are known to disrupt thyroid and other hormonal functions, mitochondrial functions, and biomineralization, all of which are particularly harmful to developing fetuses. Exposures can manifest as impaired embryonic development of craniofacial features, internal and reproductive organs, and musculoskeletal/integumental systems, often resulting in reproductive failure or weakened neonates. This paper reviews: a) studies of ruminant populations in the region, especially elk and white-tailed deer, prior to and after 1994; b) published and new data on underdeveloped facial bones in regional ruminants; c) published and new data on reproductive abnormalities in live and necropsied animals before and after 1994; and d) studies documenting the effects of exposures to three of the most applied teratogenic chemicals. While answers to the question posed above are complex and insufficient evidence is available for definitive answers, this review provides ideas for further consideration.

Downregulation of Glis3 in INS1 cells exposed to chronically elevated glucose contributes to glucotoxicity-associated ß cell dysfunction.

Chronically elevated levels of glucose are deleterious to pancreatic ß cells and contribute to ß cell dysfunction, which is characterized by decreased insulin production and a loss of ß cell identity. The Krüppel-like transcription factor, Glis3 has previously been shown to positively regulate insulin transcription and mutations within the Glis3 locus have been associated with the development of several pathologies including type 2 diabetes mellitus. In this report, we show that Glis3 is significantly downregulated at the transcriptional level in INS1 832/13 cells within hours of being subjected to high glucose concentrations and that diminished expression of Glis3 is at least partly attributable to increased oxidative stress. CRISPR/Cas9-mediated knockdown of Glis3 indicated that the transcription factor was required to maintain normal levels of both insulin and MafA expression and reduced Glis3 expression was concomitant with an upregulation of ß cell disallowed genes. We provide evidence that Glis3 acts similarly to a pioneer factor at the insulin promoter where it permissively remodels the chromatin to allow access to a transcriptional regulatory complex including Pdx1 and MafA. Finally, evidence is presented that Glis3 can positively regulate MafA transcription through its pancreas-specific promoter and that MafA reciprocally regulates Glis3 expression. Collectively, these results suggest that decreased Glis3 expression in ß cells exposed to chronic hyperglycemia may contribute significantly to reduced insulin transcription and a loss of ß cell identity.

Endothelial LAT1 (SLC7A5) Mediates S-Nitrosothiol Import and Modulates Respiratory Sequelae of Red Blood Cell Transfusion In Vivo.

BACKGROUND: Increased adhesivity of red blood cells (RBCs) to endothelial cells (ECs) may contribute to organ dysfunction in malaria, sickle cell disease, and diabetes. RBCs normally export nitric oxide (NO)-derived vascular signals, facilitating blood flow. S-nitrosothiols (SNOs) are thiol adducts formed in RBCs from precursor NO upon the oxygenation-linked allosteric transition in hemoglobin. RBCs export these vasoregulatory SNOs on demand, thereby regulating regional blood flow and preventing RBC-EC adhesion, and the large (system L) neutral amino acid transporter 1 (LAT1; SLC7A5) appears to mediate SNO export by RBCs. METHODS: To determine the role of LAT1-mediated SNO import by ECs generally and of LAT1-mediated SNO import by ECs in RBC SNO-dependent modulation of RBC sequestration and blood oxygenation in vivo, we engineered LAT1fl/fl; Cdh5-Cre+ mice, in which the putative SNO transporter LAT1 can be inducibly depleted (knocked down, KD) specifically in ECs ("LAT1ECKD"). RESULTS: We show that LAT1 in mouse lung ECs mediates cellular SNO uptake. ECs from LAT1ECKD mice (tamoxifen-induced LAT1fl/fl; Cdh5-Cre+) import SNOs poorly ex vivo compared with ECs from wild-type (tamoxifen-treated LAT1fl/fl; Cdh5-Cre-) mice. In vivo, endothelial depletion of LAT1 increased RBC sequestration in the lung and decreased blood oxygenation after RBC transfusion. CONCLUSION: This is the first study showing a role for SNO transport by LAT1 in ECs in a genetic mouse model. We provide the first direct evidence for the coordination of RBC SNO export with EC SNO import via LAT1. SNO flux via LAT1 modulates RBC-EC sequestration in lungs after transfusion, and its disruption impairs blood oxygenation by the lung.

Long access heroin self-administration significantly alters gut microbiome composition and structure.

Introduction: It is well known that chronic opioid use disorder is associated with alterations in gastrointestinal (GI) function that include constipation, reduced motility, and increased bacterial translocation due to compromised gut barrier function. These signs of disrupted GI function can be associated with alterations in the gut microbiome. However, it is not known if long-access opioid self-administration has effects on the gut microbiome. Methods: We used 16S rRNA gene sequencing to investigate the gut microbiome in three independent cohorts (N=40 for each) of NIH heterogeneous stock rats before onset of long-access heroin self-administration (i.e., naïve status), at the end of a 15-day period of self-administration, and after post-extinction reinstatement. Measures of microbial α- and ß-diversity were evaluated for all phases. High-dimensional class comparisons were carried out with MaAsLin2. PICRUSt2 was used for predicting functional pathways impacted by heroin based on marker gene sequences. Results: Community α-diversity was not altered by heroin at any of the three phases by comparison to saline-yoked controls. Analyses of ß-diversity showed that the heroin and saline-yoked groups clustered significantly apart from each other using the Bray-Curtis (community structure) index. Heroin caused significant alterations at the ASV level at the self-administration and extinction phases. At the phylum level, the relative abundance of Firmicutes was increased at the self-administration phase. Deferribacteres was decreased in heroin whereas Patescibacteria was increased in heroin at the extinction phase. Potential biomarkers for heroin emerged from the MaAsLin2 analysis. Bacterial metabolomic pathways relating to degradation of carboxylic acids, nucleotides, nucleosides, carbohydrates, and glycogen were increased by heroin while pathways relating to biosynthesis of vitamins, propionic acid, fatty acids, and lipids were decreased. Discussion: These findings support the view that long access heroin self-administration significantly alters the structure of the gut microbiome by comparison to saline-yoked controls. Inferred metabolic pathway alterations suggest the development of a microbial imbalance favoring gut inflammation and energy expenditure. Potential microbial biomarkers and related functional pathways likely invoked by heroin self-administration could be targets for therapeutic intervention.

Spectral analysis of non-contrast fluoroscopy for evaluation of pulmonary perfusion: Feasibility and sensitivity testing with a phantom.

BACKGROUND: Oscillating x-ray attenuation in the lungs provides an opportunity to evaluate pulmonary perfusion without contrast. Recent intensity-based methods have been compared to pulmonary scintigraphy and CT angiography but lack rigorous phantom studies. PURPOSE: A new method to quantify the periodic signal amplitude was employed using spectral analysis. Performance was characterized using a water phantom capable of creating an oscillating x-ray attenuation at physiologic amplitudes. Feasibility in detecting abnormal perfusion was performed on a volunteer with pulmonary vascular disease and compared to pulmonary angiography, the clinical gold standard. METHODS: For each fluoroscopic acquisition, the normalized temporal signal from each pixel was decomposed into its frequency components using Fourier transformation, and the spectral amplitude, defined as the x-ray pulsatility index (XPI), was determined at the desired frequency using a band-pass filter. XPI was displayed as a pixel-wise parametric colormap. Based on XPI maps generated using two human volunteers, a water bath phantom was constructed with a fluctuating fluid height and a 1 cm diameter pulsatility defect. Contrast-to-noise (CNR) of the defect was measured using fluoroscopy images acquired at variable fluid height fluctuation (0.1-1.9 mm) and oscillation frequency (30-60 bpm). Various sampling frame rates (3-30 fps) and acquisition durations (1.8-8 s) using truncated datasets were reconstructed from full datasets. Fluoroscopic images were obtained in a patient just prior to pulmonary angiography in the same projection. RESULTS: XPI maps in human subjects showed high signal to background contrast with high central XPI measuring up to 0.5. Phantom experiments revealed CNR was linearly correlated to fluid height change (r2 = 0.998). CNR is proportional to increasing sampling frame rate and increasing acquisition duration as expected with Fourier analysis. XPI map displayed multifocal perfusion defects in good agreement with pulmonary angiography. CONCLUSION: Spectral analysis is an accurate and sensitive method to detect small changes in periodic x-ray attenuation using a short fluoroscopic acquisition. This method demonstrated good agreement to pulmonary angiography and shows promise for clinical imaging of pulmonary perfusion using standard fluoroscopic methods.

Poor Oral Health Is Associated With Inflammation, Aortic Valve Calcification, and Brain Volume Among Forager-Farmers.

Poor oral health is associated with cardiovascular disease and dementia. Potential pathways include sepsis from oral bacteria, systemic inflammation, and nutritional deficiencies. However, in post-industrialized populations, links between oral health and chronic disease may be confounded because the lower socioeconomic exposome (poor diet, pollution, and low physical activity) often entails insufficient dental care. We assessed tooth loss, caries, and damaged teeth, in relation to cardiovascular and brain aging among the Tsimane, a subsistence population living a relatively traditional forager-horticulturalist lifestyle with poor dental health, but minimal cardiovascular disease and dementia. Dental health was assessed by a physician in 739 participants aged 40-92 years with cardiac and brain health measured by chest computed tomography (CT; n = 728) and brain CT (n = 605). A subset of 356 individuals aged 60+ were also assessed for dementia and mild cognitive impairment (n = 33 impaired). Tooth loss was highly prevalent, with 2.2 teeth lost per decade and a 2-fold greater loss in women. The number of teeth with exposed pulp was associated with higher inflammation, as measured by cytokine levels and white blood cell counts, and lower body mass index. Coronary artery calcium and thoracic aortic calcium were not associated with tooth loss or damaged teeth. However, aortic valve calcification and brain tissue loss were higher in those who had more teeth with exposed pulp. Overall, these results suggest that dental health is associated with indicators of chronic diseases in the absence of typical confounds, even in a population with low cardiovascular and dementia risk factors.

Extremal Kerr Black Holes as Amplifiers of New Physics.

We show that extremal Kerr black holes are sensitive probes of new physics. Stringy or quantum corrections to general relativity are expected to generate higher-curvature terms in the gravitational action. We show that in the presence of these terms, asymptotically flat extremal rotating black holes have curvature singularities on their horizon. Furthermore, near-extremal black holes can have large yet finite tidal forces for infalling observers. In addition, we consider five-dimensional extremal charged black holes and show that higher-curvature terms can have a large effect on the horizon geometry.

Estimating state-specific population-based hospitalization rates from in-state hospital discharge data.

OBJECTIVE: To develop weights to estimate state population-based hospitalization rates for all residents of a state using only data from in-state hospitals which exclude residents treated in other states. DATA SOURCES AND STUDY SETTING: Agency for Healthcare Research and Quality, Healthcare Cost and Utilization Project (HCUP), State Inpatient Databases (SID), 2018-2019, 47 states+DC. STUDY DESIGN: We identified characteristics for patients hospitalized in each state differentiating movers (discharges for patients hospitalized outside state of residence) from stayers (discharges for patients hospitalized in state of residence) and created weights based on 2018 data informed by these characteristics. We calculated standard errors using a sampling framework and compared weight-based estimates against complete observed values for 2019. DATA COLLECTION/EXTRACTION METHODS: SID are based on administrative billing records collected by hospitals, shared with statewide data organizations, and provided to HCUP. PRINCIPAL FINDINGS: Of 34,186,766 discharged patients in 2018, 4.2% were movers. A higher share of movers (vs. stayers) lived in state border and rural counties; a lower share had discharges billed to Medicaid or were hospitalized for maternal/neonatal services. The difference between 2019 observed and estimated total discharges for all included states and DC was 9402 (mean absolute percentage error = 0.2%). We overestimated discharges with an expected payer of Medicaid, from the lowest income communities, and for maternal/neonatal care. We underestimated discharges with an expected payer of private insurance, from the highest income communities, and with injury diagnoses and surgical services. Estimates for most subsets were not within a 95% confidence interval, likely due to factors impossible to account for (e.g., hospital closures/openings, shifting consumer preferences). CONCLUSIONS: The weights offer a practical solution for researchers with access to only a single state's data to account for movers when calculating population-based hospitalization rates.

Pre-Younger Dryas megafaunal extirpation at Rancho La Brea linked to fire-driven state shift.

The cause, or causes, of the Pleistocene megafaunal extinctions have been difficult to establish, in part because poor spatiotemporal resolution in the fossil record hinders alignment of species disappearances with archeological and environmental data. We obtained 172 new radiocarbon dates on megafauna from Rancho La Brea in California spanning 15.6 to 10.0 thousand calendar years before present (ka). Seven species of extinct megafauna disappeared by 12.9 ka, before the onset of the Younger Dryas. Comparison with high-resolution regional datasets revealed that these disappearances coincided with an ecological state shift that followed aridification and vegetation changes during the Bølling-Allerød (14.69 to 12.89 ka). Time-series modeling implicates large-scale fires as the primary cause of the extirpations, and the catalyst of this state shift may have been mounting human impacts in a drying, warming, and increasingly fire-prone ecosystem.

Photothermal-Starvation Therapy Nanomodulator Capable of Inhibiting Colorectal Cancer Recurrence and Metastasis by Energy Metabolism Reduction.

The recurrence and metastasis of colorectal cancer (CRC) have been considered as a severe challenge in clinical treatment. Recent studies have demonstrated that matrix metalloproteinases (MMPs) and lactate can promote local tumor angiogenesis, recurrence, and metastasis. The expression of MMPs is highly dependent on energy metabolism, and lactate is considered an alternative energy source for tumor proliferation and metastasis. Therefore, using a rational approach, a photothermal-starvation therapy nanomodulator that can reduce energy metabolism to suppress CRC recurrence and metastasis is designed. To design a suitable nanomodulator, glucose oxidase (GOX), indocyanine green (IR820), and α-cyano-4-hydroxycinnamic acid (CHC) into nanoparticles by a coassembly method are combined. The photothermal properties of IR820 provide the appropriate temperature and oxygen supply for the enzymatic reaction of GOX to promote intracellular glucose consumption. CHC inhibits the expression of monocarboxylate transporter 1 (MCT1), the transporter of lactic acid into cells, and also reduces oxygen consumption and promotes the GOX reaction. Additionally, altering adenosine triphosphate synthesis to block heat shock proteins expression can be an effective means to prevent IR820-mediated photothermal therapy resistance. Thus, this dual photothermal-starvation therapy nanomodulator efficiently suppresses the recurrence and metastasis of CRC by depleting intracellular nutrients.

Approaches to Avoid Proteolysis During Protein Expression and Purification.

All cells contain proteases, which hydrolyze the peptide bonds between amino acids of a protein backbone. Typically, proteases are prevented from nonspecific proteolysis by regulation and by their physical separation into different subcellular compartments; however, this segregation is not retained during cell lysis, which is the initial step in any protein isolation procedure. Prevention of proteolysis during protein purification often takes the form of a two-pronged approach: first, inhibition of proteolysis in situ, followed by the early separation of the protease from the protein of interest via chromatographic purification. Protease inhibitors are routinely used to limit the effect of the proteases before they are physically separated from the protein of interest via column chromatography. In this chapter, commonly used approaches to reducing or avoiding proteolysis during protein expression and purification are reviewed.

Protein Extraction and Purification by Differential Solubilization.

The preparation of purified soluble proteins for biochemical studies is essential and the solubility of a protein of interest in various media is central to this process. Selectively altering the solubility of a protein is a rapid and economical step in protein purification and is based on exploiting the inherent physicochemical properties of a polypeptide. Precipitation of proteins, released from cells upon lysis, is often used to concentrate a protein of interest before further purification steps (e.g., ion exchange chromatography, size exclusion chromatography etc).Recombinant proteins may be expressed in host cells as insoluble inclusion bodies due to various influences during overexpression. Such inclusion bodies can often be solubilized to be reconstituted as functional, correctly folded proteins.In this chapter, we examine strategies for extraction/precipitation/solubilization of proteins for protein purification. We also present bioinformatic tools to aid in understanding a protein's propensity to aggregate/solubilize that will be a useful starting point for the development of protein extraction, precipitation, and selective re-solubilization procedures.

Aspects of molar form and dietary proclivities of African colobines.

This study investigates aspects of molar form in three African colobine species: Colobus polykomos, Colobus angolensis, and Piliocolobus badius. Our samples of C. polykomos and P. badius are from the Taï Forest, Ivory Coast; our sample of C. angolensis is from Diani, Kenya. To the extent that protective layers surrounding seeds are hard, we predicted that molar features related to hard-object feeding would be more pronounced in Colobus than they are Piliocolobus, as seed-eating generally occurs at higher frequencies in species of the former. We further predicted that among the colobines we studied, these features would be most pronounced in Taï Forest C. polykomos, which feeds on Pentaclethra macrophylla seeds encased within hard and tough seed pods. We compared overall enamel thickness, enamel thickness distribution, absolute crown strength, cusp tip geometry, and flare among molar samples. Sample sizes per species and molar type varied per comparison. We predicted differences in all variables except overall enamel thickness, which we expected would be invariant among colobines as a result of selection for thin enamel in these folivorous species. Of the variables we examined, only molar flare differed significantly between Colobus and Piliocolobus. Our findings suggest that molar flare, an ancient feature of cercopithecoid molars, was retained in Colobus but not in Piliocolobus, perhaps as a result of differences in the seed-eating proclivities of the two genera. Contrary to predictions, none of the aspects of molar form we investigated tracked current dietary differences in seed-eating between the two Colobus species. Finally, we explored the possibility that molar flare and absolute crown strength, when analyzed together, might afford greater differentiation among these colobine species. A multivariate t test of molar flare and absolute crown strength differentiated C. polykomos and P. badius, possibly reflecting known niche divergence between these two sympatric Taï Forest species.

Clinical and economic outcomes in patients with chronic obstructive pulmonary disease initiating maintenance therapy with tiotropium bromide/olodaterol or fluticasone furoate/umeclidinium/vilanterol.

BACKGROUND: Clinical practice guidelines recommend dual long-acting muscarinic antagonists (LAMAs)/long-acting ß2agonists (LABAs) as maintenance therapy in patients with chronic obstructive pulmonary disease (COPD) and dyspnea or exercise intolerance. Escalation to triple therapy (TT) (LAMA/LABA/inhaled corticosteroid) is conditionally recommended for patients with continued exacerbations on dual LAMA/LABA therapy. Despite this guidance, TT use is widespread across COPD severities, which could impact clinical and economic outcomes. OBJECTIVE: To compare COPD exacerbations, pneumonia events, and disease-related and all-cause health care resource utilization and costs (in 2020 US dollars) in patients initiating fixed-dose combinations of either LAMA/LABA (tiotropium/olodaterol [TIO + OLO]) or TT (fluticasone furoate/umeclidinium/vilanterol [FF + UMEC + VI]). METHODS: This retrospective observational study of administrative claims included patients with COPD aged 40 years or older initiating TIO + OLO or FF + UMEC + VI from June 2015 to November 2019. TIO + OLO and FF + UMEC + VI cohorts in the overall and maintenance-naive populations were 1:1 propensity score matched on baseline demographics, comorbidities, COPD medications, health care resource utilization, and costs. Multivariable regression compared clinical and economic outcomes up to 12 months in FF + UMEC + VI vs TIO + OLO postmatched cohorts. RESULTS: After matching, there were 5,658 and 3,025 pairs in the overall and maintenance-naive populations, respectively. In the overall population, the risk of any (moderate or severe) exacerbation was 7% lower in FF + UMEC + VI vs TIO + OLO initiators (adjusted hazard ratio [aHR] = 0.93; 95% CI = 0.86-1.0; P = 0.047). There was no difference in the adjusted risk of any exacerbation in the maintenance-naive population (aHR = 0.99; 95% CI = 0.88-1.10). Pneumonia risk was not statistically different between cohorts in the overall (aHR = 1.12; 95% CI = 0.98-1.27) and maintenance-naive (aHR = 1.13; 95% CI = 0.95-1.36) populations. COPD- and/or pneumonia-related adjusted total annualized costs (95% CI) were significantly greater for FF + UMEC + VI vs TIO + OLO in the overall ($17,633 [16,661-18,604] vs $14,558 [13,709-15,407]; P < 0.001; differences [% of relative increase] = $3,075 [21.1%]) and maintenancenaive ($19,032 [17,466-20,598] vs $15,004 [13,786-16,223]; P < 0.001; $4,028 [26.8%]) populations, with significantly higher pharmacy costs with FF + UMEC + VI (overall: $6,567 [6,503-6,632] vs $4,729 [4,676-4,783]; P < 0.001; $1,838 [38.9%]; maintenance-naive: $6,642 [6,560-6,724] vs $4,750 [4,676-4,825]; P < 0.001; $1,892 [39.8%]). CONCLUSIONS: A lower risk of exacerbation was observed with FF + UMEC + VI vs TIO + OLO in the overall population but not among the maintenance-naive population. Patients with COPD initiating TIO + OLO had lower annualized costs than FF + UMEC + VI initiators in the overall and maintenance-naive populations. Thus, in the maintenance-naive population, initiation with dual LAMA/LABA therapy per practice guidelines can improve real-world economic outcomes. Study registration number: ClinicalTrials.gov (identifier: NCT05127304). DISCLOSURES: The study was funded by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, BIPI grants all external authors access to relevant clinical study data. In adherence with the BIPI Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete and other criteria are met. Dr Sethi has received honoraria/fees for consulting/speaking from Astra-Zeneca, BIPI, and GlaxoSmithKline. He has received consulting fees for serving on data safety monitoring boards from Nuvaira and Pulmotect. He has received consulting fees from Apellis and Aerogen. His institution has received research funds for his participation in clinical trials from Regeneron and AstraZeneca. Ms Palli was an employee of BIPI at the time the study was conducted. Drs Clark and Shaikh are employees of BIPI. Ms Buysman and Mr Sargent are employees and Dr Bengtson was an employee of Optum, which was contracted by BIPI to conduct this study. Dr Ferguson reports grants and personal fees from Boehringer Ingelheim during the conduct of the study; grants from Novartis, Altavant, and Knopp; grants and personal fees from AstraZeneca, Verona, Theravance, Teva, and GlaxoSmithKline; and personal fees from Galderma, Orpheris, Dev.Pro, Syneos, and Ionis outside the submitted work. He was a paid consultant for BIPI for this study. The authors received no direct compensation related to the development of the manuscript. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Healthcare Resource Utilization, Cost and Clinical Outcomes in Patients Diagnosed with COPD Initiating Tiotropium Bromide/Olodaterol versus Fluticasone Furoate/Umeclidinium/Vilanterol Based on Exacerbation History.

Background: ATS and GOLD guidelines recommend treating low-exacerbation risk COPD patients with dual (LAMA/LABA) agents and reserving triple therapy (TT; LAMA/LABA and inhaled corticosteroids [ICS]) for severe cases with higher-exacerbation risk. However, TT often is prescribed across the COPD spectrum. This study compared COPD exacerbations, pneumonia diagnosis, healthcare resource utilization, and costs for patients initiating tiotropium bromide/olodaterol (TIO/OLO) and a TT, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), stratified by exacerbation history. Methods: COPD patients who initiated TIO/OLO or FF/UMEC/VI between 06/01/2015-11/30/2019 (index date=first pharmacy fill-date with ≥30 consecutive treatment days) were identified from the Optum Research Database. Patients were ≥40 years old and continuously enrolled for 12 months during the baseline period and ≥30 days during follow-up. Patients were stratified into GOLD A/B (0-1 baseline non-hospitalized exacerbation), No exacerbation (subset of GOLD A/B), and GOLD C/D (≥2 non-hospitalized and/or ≥1 hospitalized baseline exacerbation). Baseline characteristics were balanced with propensity score matching (1:1). Adjusted risks of exacerbation, pneumonia diagnosis, and COPD and/or pneumonia-related utilization and costs were evaluated. Results: Adjusted exacerbation risk was similar in GOLD A/B and No exacerbation subgroups, and lower in GOLD C/D for FF/UMEC/VI versus TIO/OLO initiators (hazard ratio: 0.87; 95% CI: 0.78, 0.98, p=0.020). Adjusted pneumonia risk was similar between cohorts across the GOLD subgroups. Adjusted COPD and/or pneumonia-related population annualized pharmacy costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators across subgroups, p<0.001. Adjusted COPD and/or pneumonia-related population annualized total healthcare costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators in the GOLD A/B and No exacerbation, subgroups, p<0.001 (cost ratio [95% CI]: 1.25 [1.13, 1.38] and 1.21 [1.09, 1.36], respectively), but similar in the GOLD C/D subgroup. Conclusion: These real-world results support ATS and GOLD recommendations for treating low-exacerbation risk COPD patients with dual bronchodilators and TT for more severe, higher-exacerbation risk COPD patients.

Alzheimer's Disease: A Brief History of Immunotherapies Targeting Amyloid ß.

Alzheimer's disease (AD) is the most common form of dementia and may contribute to 60-70% of cases. Worldwide, around 50 million people suffer from dementia and the prediction is that the number will more than triple by 2050, as the population ages. Extracellular protein aggregation and plaque deposition as well as accumulation of intracellular neurofibrillary tangles, all leading to neurodegeneration, are the hallmarks of brains with Alzheimer's disease. Therapeutic strategies including active and passive immunizations have been widely explored in the last two decades. Several compounds have shown promising results in many AD animal models. To date, only symptomatic treatments are available and because of the alarming epidemiological data, novel therapeutic strategies to prevent, mitigate, or delay the onset of AD are required. In this mini-review, we focus on our understanding of AD pathobiology and discuss current active and passive immunomodulating therapies targeting amyloid-ß protein.