Development and Use of Human Recombinant 64Cu-rHCF as a Kidney Glomerulus-Targeted Contrast Agent for Positron Emission Tomography.

In this work, we develop recombinant human cationic ferritin (rHCF) as a contrast agent to detect glomeruli in the kidney using positron emission tomography (PET). We first expressed recombinant human ferritin (rHF) in E. coli and then functionalized and radiolabeled it with Copper-64 (64Cu) to form 64Cu-rHCF. Intravenously injected 64Cu-rHCF bound to kidney glomeruli and was detected by PET. A subchronic toxicity study after an intravenous injection of rHCF revealed no significant toxicity. The development of rHCF is an important step toward the potential clinical translation of CF to detect the nephron number in humans.

Psychosis Risk: Time to Look Empirically at a First-step Economical-pragmatic Way to Examine Anomalous Self-experience. Exploring the SQuEASE-11.

BACKGROUND: Since the late 1990s, there has been a worldwide surge of scientific interest in the pre-psychotic phase, resulting in the introduction of several clinical tools for early detection. The predictive accuracy of these tools has been limited, motivating the need for methodological and perspectival improvements. The EASE manual supports systematic assessment of anomalous self-experience, and proposes an overall model of understanding how most psychotic experiences may be initially generated on the basis of a unifying, fundamental, pre-reflective distortion of subjectivity. STUDY DESIGN: The EASE is time-consuming, so in order to spread the use of this essential perspective of psychosis risk we selected prototypical and frequent phenomena from the EASE, combining them into SQuEASE-11. To investigate this instrument for clinical relevance, basic psychometric properties, factor structure, and relationships with gold standard instruments and the full EASE, it was administered as an interview in the STEP intervention trial (Melbourne, Australia), with 328 clinical high-risk for psychosis (CHR-P) patients. STUDY RESULTS: The SQuEASE-11 had moderate internal consistency and revealed two correlated factors. Significant relationships were observed between the SQuEASE-11 and the widely used and validated instruments CAARMS, BPRS, SANS, MADRS, DACOBS, and SOFAS. The correlation with the full EASE was very strong. CONCLUSIONS: These 11 items do not necessarily relate specifically to ipseity disturbance, but the SQuEASE-11 seems to be a clinically relevant and brief supplementary first-line interview in CHR-P subjects. It may give a qualified indication of the need for a complete EASE interview, and it may also, importantly, inform treatment planning.

Implications of the shift to DSM-5 for alcohol use disorder prevalence estimates in the National Survey on Drug Use and Health.

BACKGROUND AND AIMS: The Substance Abuse and Mental Health Services Administration's annual National Survey on Drug Use and Health (NSDUH) is a commonly used source for estimating trends in alcohol use disorders (AUD) in the United States. From 2015 to 2019 the annual prevalence of people diagnosed with either Diagnostic and Statistical Manual 4th edition (DSM-IV) alcohol abuse or dependence ranged from 5.3 to 5.9%. More recent estimates, using the DSM 5th edition (DSM-5) AUD diagnostic formulation, have been higher, with AUD base rates ranging from 10.1 to 10.7% from 2020 to 2022. This study aimed to compare the past 12-month base rates of AUD in the United States general population when using the DSM-5 versus DSM-IV AUD (i.e. abuse or dependence) and assess the AUD severity of individuals captured with each diagnostic formulation using DSM-5 AUD symptom counts. METHODS: We examined descriptive trends in the rate of past-year NSDUH AUD diagnoses from 2015 to 2022. We contrasted them with trends in drinking behavior: the percentage of individuals who had ever reported drinking and the number of drinking days and binge drinking days for those who drink. We also analyzed the concordance between DSM-IV and DSM-5 AUD diagnoses in the 2020 NSDUH, which concurrently assessed AUD with both diagnostic formulations. RESULTS: The transition to DSM-5 AUD formulation coincided with a drastic increase in AUD prevalence rates that occurred without increases in drinking behavior. In 2020 NSDUH data, the estimated past-year DSM-5 AUD prevalence rate was 10.1% compared with a 5.4% rate of past-year DSM-IV abuse or dependence. The DSM-5 AUD formulation captured more mild-severity individuals than the DSM-IV formulation. CONCLUSIONS: Higher recent base rates of alcohol use disorders (AUD) in the National Survey on Drug Use and Health are likely, at least partially, explained by measurement changes in AUD; specifically, the shift from DSM-IV abuse or dependence to DSM-5 AUD. The DSM-5 formulation appears substantially more inclusive than the DSM-IV formulation, leading to a larger number of mild severity individuals being captured.

Before, during, and after: An Argument for Safety and Improved Outcome of Thrombolysis in Acute Ischemic Stroke with Direct Oral Anticoagulant Treatment.

Direct oral anticoagulants are the primary stroke prevention option in patients with atrial fibrillation. Anticoagulant use before stroke, however, might inhibit clinician comfort with thrombolysis if a stroke does occur. Resuming anticoagulants after ischemic stroke is also problematic for fear of hemorrhage. We describe extensive literature showing that thrombolysis is safe after stroke with direct anticoagulant use. Early reinstitution of direct anticoagulant treatment is associated with lower risk of embolic recurrence and lower hemorrhage risk. The use of direct anticoagulants before, during, and after thrombolysis appears to be safe and is likely to promote improved outcomes after ischemic stroke. ANN NEUROL 2024.

Resting-state EEG data before and after cognitive activity across the adult lifespan and a 5-year follow-up.

This dataset consists of 64-channels resting-state EEG recordings of 608 participants aged between 20 and 70 years, 61.8% female, as well as follow-up measurements after approximately 5 years of 208 participants, starting 2021. The EEG was measured for three minutes with eyes open and eyes closed before and after a 2-hour block of cognitive experimental tasks. The data set is part of the Dortmund Vital Study, a prospective study on the determinants of healthy cognitive aging. The dataset can be used for (1) analyzing cross-sectional resting-state EEG of healthy individuals across the adult life span; (2) generating normalization data sets for comparison of resting-state EEG data of patients with clinically relevant disorders; (3) studying effects of performing cognitive tasks on resting-state EEG and age; (4) exploring intra-individual changes in resting-state EEG and effects of task performance over a time period of about 5 years. The data are provided in Brain Imaging Data Structure (BIDS) format and are available on OpenNeuro.

Antibiotics at End of Life: Where Are We Now and Where Are We Going? A Narrative Review.

BACKGROUND: Antibiotics are frequently prescribed at the end of life, though the benefits and harms are not well understood. METHODS: We abstracted relevant findings from articles published in English in the past 25 years to answer questions generated by discussion among the authors and with stakeholders in Palliative Care and Infectious Diseases. FINDINGS: Prescribing practices vary based on individual situation and geographic location. Patients with cancer and those hospitalized receive more antibiotics than those enrolled in outpatient hospice. Urinary tract infections and pulmonary infections are the most common conditions treated with antibiotics at the end of life -most often with penicillin derivatives and vancomycin in the hospital, fluoroquinolones in outpatient, and cephalosporins in both settings. When asked, patients most often prefer limiting antibiotics to symptom management at the end of life. Physicians' over-estimation of patient preference for antibiotics and the increased probability of misdiagnosis increases antibiotic prescription rates. Antibiotics can improve symptoms when used for specific diseases at the cost of drug reactions, resistant organisms, and delayed discharge. Antibiotic use has variable results on survival duration. Antimicrobial stewardship exists in hospital and long-term care facilities, but not outpatient hospice groups. Stewardship interventions could increase proper use of antibiotics, but more information is needed to apply these interventions to hospice groups. CONCLUSIONS: Antibiotics at the end of life are impactful and efforts to educate patients and providers will be invaluable in optimizing care.

Immunoglobulin A vasculitis with periorbital edema and severe renal involvement: A case report.

Immunoglobulin A (IgA) vasculitis, or Henoch-Schonlein purpura, is the most common systemic vasculitis in children, clinically presenting as palpable purpura in combination with arthritis, gastrointestinal involvement, or kidney injury. Subcutaneous edema is reported in patients with IgA vasculitis, and it commonly affects the lower extremities, especially around joints. Here, we report a case of IgA vasculitis with a rare presentation of edema isolated to the periorbital area in a 7-year-old boy, who subsequently developed crescentic glomerulonephritis with nephrotic range proteinuria. Isolated periorbital edema is an uncommon cutaneous feature of IgA vasculitis.

Incorporating a weight-of-evidence approach into a tiered assessment for chemicals management, with emphasis on program development and applications in developing countries and emerging economies.

A flexible approach is described for incorporating a weight-of-evidence (WoE) methodology into a tiered ecological risk assessment (ERA)/management framework for chemicals. The approach is oriented toward informing decisions about chemicals. Communication is regarded as a critical component of the risk assessment process. The paper resulted from insights gained from seven ERA workshops held by SETAC (Society of Environmental Toxicology and Chemistry, www.setac.org) in the Asia-Pacific, African, and Latin American regions. Formal ERA methods are not fully developed or applied in many of these countries and assessments often begin with tables of risk values and test methods from countries where ERA is already implemented. While appropriate and sometimes necessary, workshop participants had questions about the reliability and relevance of using this information for regionally specific ecosystems with different receptors, fate processes, and exposure characteristics. The idea that an assessment of reliability and relevance of available information and the need for additional information was necessary at an early stage of the assessment process was considered. The judgment of reliability and relevance is central to WoE approaches along with the identification of information needs and the integration of such information. The need to engage in WoE considerations early and throughout the assessment process indicates that a tiered approach is appropriate for unifying the evaluation process in a consistent way from early screening-level steps to later more involved evaluations. The approach outlined in this article is complementary to WoE guidance developed by the Organization for Economic Co-operation and Development and many national guidance documents. To link assessments of risk to management decisions, emphasis is given to communications at each tier between the risk assessor (technical side) and the decision-makers (policy and regulatory side). Tools and information sources are suggested for each tier and suggestions are meant to be illustrative and not prescriptive. Integr Environ Assess Manag 2024;00:1-15. © 2024 SETAC.

Development of a Simple Analytical Model to Facilitate Preoperative Surgical Planning in Valve-Sparing Aortic Root Replacement.

PURPOSE: Valve-sparing root replacement (VSRR) is attractive for aortic root dilation as it preserves the native aortic valve (AoV). Low effective height (eH) after reconstruction is a risk factor for repair failure and reoperation. We developed and validated a quantitative AoV repair strategy to reliably restore normal valve proportions to promote long-term function. METHODS: Normal AoV proportions were used to derive geometric relationships for sinotubular junction diameter (DSTJ), free edge length (FEL), free edge angle, and commissure height. These relationships informed two models for predicting eH following VSRR: (1) assuming valve symmetry and (2) accounting for valve asymmetry. Porcine heart (n = 6) ex vivo validation was performed under 4 VSRR scenarios: "Ideal" (tube graft size targeting FEL/DSTJ = 1.28), "Oversized" (one graft size larger than Ideal), "Undersized" (two sizes smaller), and "Undersized + Plicated" (FEL/DSTJ = 1.28 restored with leaflet plication). RESULTS: Our analytical models predicted eH using preoperative measurements and estimated reconstructed dimensions. The Oversized graft exhibited similar eH to Ideal but higher regurgitation in the ex vivo model, whereas the Undersized graft demonstrated lower eH and regurgitation. Plication in the Undersized graft restored valve function (regurgitation & eH) similar to Ideal in the ex vivo model and above Ideal in the analytical models. Both analytical models predicted ex vivo eH well except in the Oversized and Undersized + Plicated conditions. CONCLUSION: Utilizing measurements from preoperative imaging and simple mathematical models, patient-specific operative plans for VSRR can be created by estimating valve dimensions necessary to achieve favorable valve features post-repair. Clinical application of this approach promises to improve consistency in achieving optimal long-term dimensions and durability.

Correlating Stroke Risk with Non-Invasive Tracing of Brain Blood Dynamic via a Portable Speckle Contrast Optical Spectroscopy Laser Device.

Stroke poses a significant global health threat, with millions affected annually, leading to substantial morbidity and mortality. Current stroke risk assessment for the general population relies on markers such as demographics, blood tests, and comorbidities. A minimally invasive, clinically scalable, and cost-effective way to directly measure cerebral blood flow presents an opportunity. This opportunity has potential to positively impact effective stroke risk assessment prevention and intervention. Physiological changes in the cerebral vascular system, particularly in response to carbon dioxide level changes and oxygen deprivation, such as during breath-holding, can offer insights into stroke risk assessment. However, existing methods for measuring cerebral perfusion reserve, such as blood flow and blood volume changes, are limited by either invasiveness or impracticality. Here, we propose a transcranial approach using speckle contrast optical spectroscopy (SCOS) to non-invasively monitor regional changes in brain blood flow and volume during breath-holding. Our study, conducted on 50 individuals classified into two groups (low-risk and higher-risk for stroke), shows significant differences in blood dynamic changes during breath-holding between the two groups, providing physiological insights for stroke risk assessment using a non-invasive quantification paradigm. Given its cost-effectiveness, scalability, portability, and simplicity, this laser-centric tool has significant potential in enhancing the pre-screening of stroke and mitigating strokes in the general population through early diagnosis and intervention.

Biomarker screening for pulmonary hypertension in VLBW infants at risk for bronchopulmonary dysplasia.

BACKGROUND: Very low birth weight (VLBW) infants demonstrate altered alveolar and pulmonary vascular development and carry an increased risk of developing bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Risk stratification for BPD-associated PH (BPD-PH) in at-risk infants may help tailor management, improve outcomes, and optimize resource utilization. METHODS: VLBW infants were screened for PH with blood gas measurements, serum NT-proBNP and bicarbonate (HCO3) levels, and echocardiograms if they remained on respiratory support at 34 weeks corrected gestational age. We then tested 11 models using different cutoffs for NT-proBNP and HCO3 to predict infants at low risk of BPD-PH. RESULTS: We identified PH in 34 of 192 (17.6%) VLBW infants. The median NT-proBNP in VLBWs with PH was 2769 pg/mL versus 917 pg/mL in those without PH (p < 0.0001). A model with NT-proBNP < 950 pg/mL and HCO3 < 32 mmol/L had a sensitivity of 100%, specificity of 34.2%, and negative predictive value of 100%. Using this model, 54 of 192 (28%) of the patients in this study would have been categorized as low risk for PH and could have avoided a screening echocardiogram. CONCLUSION: NT-proBNP and HCO3 together may serve as sensitive and cost-effective screening tools for BPD-PH in VLBW infants. IMPACT: NT-proBNP and HCO3 concentrations obtained together may help identify very low birth weight infants at risk for bronchopulmonary dysplasia who should undergo screening for pulmonary hypertension with echocardiography. This large dataset demonstrates that NT-proBNP and HCO3 levels together are more sensitive than NT-proBNP alone in identifying VLBW infants to undergo echocardiography. The combination of NT-proBNP and HCO3 levels may identify VLBW infants at low risk for pulmonary hypertension and thus those who may be able to avoid screening echocardiography.

Utilization of an artificial intelligence-enhanced, web-based application to review bile duct brushing cytologic specimens: A pilot study.

BACKGROUND: The authors previously developed an artificial intelligence (AI) to assist cytologists in the evaluation of digital whole-slide images (WSIs) generated from bile duct brushing specimens. The aim of this trial was to assess the efficiency and accuracy of cytologists using a novel application with this AI tool. METHODS: Consecutive bile duct brushing WSIs from indeterminate strictures were obtained. A multidisciplinary panel reviewed all relevant information and provided a central interpretation for each WSI as being "positive," "negative," or "indeterminate." The WSIs were then uploaded to the AI application. The AI scored each WSI as positive or negative for malignancy (i.e., computer-aided diagnosis [CADx]). For each WSI, the AI prioritized cytologic tiles by the likelihood that malignant material was present in the tile. Via the AI, blinded cytologists reviewed all WSIs and provided interpretations (i.e., computer-aided detection [CADe]). The diagnostic accuracies of the WSI evaluation via CADx, CADe, and the original clinical cytologic interpretation (official cytologic interpretation [OCI]) were compared. RESULTS: Of the 84 WSIs, 15 were positive, 42 were negative, and 27 were indeterminate after central review. The WSIs generated on average 141,950 tiles each. Cytologists using the AI evaluated 10.5 tiles per WSI before making an interpretation. Additionally, cytologists required an average of 84.1 s of total WSI evaluation. WSI interpretation accuracies for CADx (0.754; 95% CI, 0.622-0.859), CADe (0.807; 95% CI, 0.750-0.856), and OCI (0.807; 95% CI, 0.671-0.900) were similar. CONCLUSIONS: This trial demonstrates that an AI application allows cytologists to perform a triaged review of WSIs while maintaining accuracy.

Effect of post thrombolytic intracerebral hemorrhage volume on 90-day outcomes in acute ischemic stroke patients.

BACKGROUND AND PURPOSE: Post thrombolytic intracerebral hemorrhage (ICH) is associated with higher rate of death or disability in acute ischemic stroke patients. We investigated the relationship between post thrombolytic ICH volume and change in volume and death or disability at 90 days in acute ischemic stroke patients. METHODS: We analyzed 110 patents recruited in the Safety Evaluation of 3K3A-APC in Ischemic Stroke (RHAPSODY) trial who received intravenous tissue plasminogen activator (tPA) followed by mechanical thrombectomy (if indicated) and 3K3A-APC or placebo. ICH volume was measured at Day 2 and Day 7 using susceptibility weighted sequence (SWI) on magnetic resonance imaging (MRI). We also calculated the post thrombolytic ICH volume change between Day 2 and Day 7. Outcomes were determined by using utility weighted modified Rankin scale (UW-mRs) at 90-days, Outcomes were determined by using utility weighted modified Rankin scale (UW-mRS) at 90 days. To minimize interpretation bias, outcome assessors were blinded to the treatment allocation and clinical data.We adjusted for age, gender, National Institutes of Health Stroke Scale (NIHSS) score (<10,10-19 and ≥20), location of hemorrhage (single basal ganglia hemorrhage, single lobar, single cerebellum, and multiple sites) in multivariate regression analysis. RESULTS: A total of 88 (80%) of 110 patients had post thrombolytic ICH (mean volume 28.3 ml ± SD 62 ml). The strata of ICH volume were not associated with UW-mRs at 90 days: <20 cc (regression coefficient (RC)-0.05, p= 0.58), 20-39 cc (RC-0.22, p=0.17), or ≥40 cc (RC-0.34, p= 0.083) compared with no ICH after adjusting for potential confounders. Change in ICH mean volume 26.78 ml ±59.68, 52 had increase in volume) between Day 2 and day 7 was not associated with UW-mRS at 90 days (RC -67.71, p= 0.06). CONCLUSIONS: We did not observe any independent effect of post thrombolytic ICH volume on death or disability in acute ischemic stroke patients. Although further studies must be done, our data suggest that strategies to prevent ICH expansion such as antifibrinolytic medications and reduction in ICH volume such as surgical evacuation may not reduce death or disability in acute ischemic stroke patients with post thrombolytic ICH.

Context specific effects of substrate composition on the taxonomic and functional diversity of macroinvertebrate communities in temperate lowland streams.

Substrate composition has been widely recognised as a primary variable shaping lotic macroinvertebrate communities at the habitat unit level. However, fundamental understanding of how communities inhabiting mineralogical habitats (i.e., gravel, sand and silt) are structured across differing rivers is lacking. Moreover, research largely focusses on gravel beds and fine sediment in general (<2 mm) and as a result detailed field observations specifically of the sand and silt fractions are lacking. Using data from five UK streams collated from published studies, we assess taxonomic and functional biodiversity (alpha and beta diversity) at the habitat unit level (as defined by substrate composition of sand, silt and gravel). We found that the composition of taxonomic communities were clearly different in all habitat units for each individual stream (and at the landscape scale), with comparable, but less strong, distinctions between substrates for functional macroinvertebrate community composition. However, alpha diversity metrics and Local Contribution to Beta Diversity (LCBD) recorded among the different habitat units varied significantly across individual rivers, and the amount of variation explained by the habitat unit for taxonomic and functional composition demonstrated considerable differences suggesting strong context dependence. The depositional fine sediment habitats of sand and silt were found to support a discrete community composition and differing levels of alpha and beta diversity within and between rivers. We advocate that care should be taken when seeking to generalise biodiversity patterns at a landscape scale as our study highlights the high degree of context dependency when considering the role of the habitat template. Moreover, our results provide evidence that discriminating between the size fractions of fine sediment habitats (sand or silt) is important to fully elucidate the wider ecological importance of these habitats and the distinct taxonomic and functional biodiversity they support.

Objective Measures of Cardiometabolic Risk and Advanced Fibrosis Risk Progression in Primary Care Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND: We examined the association of objective measures of cardiometabolic risk with progression to a high-risk for advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) at initially low- and indeterminate-risk for advanced fibrosis. METHODS: We performed a retrospective cohort study of primary care patients with MASLD between 2012 and 2021. We evaluated patients with MASLD and low- or indeterminate-risk Fibrosis-4 Index (FIB-4) scores and followed them until the outcome of a high-risk FIB-4 (≥2.67), or the end of the study period. Exposures of interest were body mass index, systolic blood pressure, hemoglobin A1c, cholesterol, estimated glomerular filtration rate, and smoking status. Variables were categorized by the threshold for primary care therapy intensification. Unadjusted and adjusted Cox regression models were developed for the outcome of time to a high-risk FIB-4 value. RESULTS: The cohort included 1347 patients with a mean follow-up of 3.6 years (SD 2.7). Of the cohort, 258 (19%) had a subsequent FIB-4 > 2.67. In the fully adjusted Cox regression models, mean systolic blood pressure ≥ 150 mm Hg (1.57; 95% confidence interval (CI) 1.02-2.41) and glomerular filtration rate ≤ 59 ml/min (hazard ratio 2.78; 95%CI 2.17-3.58) were associated with an increased hazard of a high-risk FIB-4, while receiving a statin prescription (hazard ratio 0.51; 95%CI 0.39-0.66) was associated with a lower risk. CONCLUSIONS: Nearly 1 in 5 primary care patients with MASLD transitioned to a high-risk FIB-4 score during 3.6 years of follow-up, and uncontrolled blood pressure and reduced kidney function were associated with an increased hazard of a FIB-4 at high-risk for advanced fibrosis.

Development and Characterization of Syngeneic Orthotopic Transplant Models of Obesity-Responsive Triple-Negative Breast Cancer in C57BL/6J Mice.

Obesity is an established risk and progression factor for triple-negative breast cancer (TNBC), but preclinical studies to delineate the mechanisms underlying the obesity-TNBC link as well as strategies to break that link are constrained by the lack of tumor models syngeneic to obesity-prone mouse strains. C3(1)/SV40 T-antigen (C3-TAg) transgenic mice on an FVB genetic background develop tumors with molecular and pathologic features that closely resemble human TNBC, but FVB mice are resistant to diet-induced obesity (DIO). Herein, we sought to develop transplantable C3-TAg cell lines syngeneic to C57BL/6 mice, an inbred mouse strain that is sensitive to DIO. We backcrossed FVB-Tg(C3-1-TAg)cJeg/JegJ to C57BL/6 mice for ten generations, and spontaneous tumors from those mice were excised and used to generate four clonal cell lines (B6TAg1.02, B6TAg2.03, B6TAg2.10, and B6TAg2.51). We characterized the growth of the four cell lines in both lean and DIO C57BL/6J female mice and performed transcriptomic profiling. Each cell line was readily tumorigenic and had transcriptional profiles that clustered as claudin-low, yet markedly differed from each other in their rate of tumor progression and transcriptomic signatures for key metabolic, immune, and oncogenic signaling pathways. DIO accelerated tumor growth of orthotopically transplanted B6TAg1.02, B6TAg2.03, and B6TAg2.51 cells. Thus, the B6TAg cell lines described herein offer promising and diverse new models to augment the study of DIO-associated TNBC.

Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease.

INTRODUCTION: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology. METHODS: The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome). RESULTS: PEGASUS enrolled 95 participants (intent-to-treat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO (n = 51) versus placebo (n = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukin-15 increased from baseline to Week 24 within the placebo group (n = 34). In the PB and TURSO group (n = 33), reductions were observed in core AD biomarkers phosphorylated tau-181 (p-tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein-3 (FABP3); and gliosis biomarker chitinase 3-like protein 1 (YKL-40), while the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) increased. Between-group differences were observed for the Aß42/40 ratio, p-tau181, total tau, neurogranin, FABP3, YKL-40, interleukin-15, and 8-OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups. DISCUSSION: While between-group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD. Highlights: Proteostasis and mitochondrial stress play key roles in Alzheimer's disease (AD).Sodium phenylbutyrate and taurursodiol (PB and TURSO) targets these mechanisms.The PEGASUS trial was designed to assess PB and TURSO effects on biologic AD targets.PB and TURSO reduced exploratory biomarkers of AD and neurodegeneration.Supports further clinical development of PB and TURSO in neurodegenerative diseases.

Incident Benzodiazepine and Z-Drug Use and Subsequent Risk of Serious Infections.

BACKGROUND AND OBJECTIVES: Animal studies have suggested a link between benzodiazepine and related Z-drug (BZDR) use and immune dysfunction. Corresponding evidence in humans is limited and focuses mainly on pneumonia. This study aimed to assess the association of incident BZDR use with subsequent development of serious infections. METHODS: This Swedish register-based study included a population-based demographically matched cohort, a co-twin control cohort, and an active comparator cohort. Out of 7,362,979 individuals aged below 65 years who were BZDR naïve by 2007, 713,896 BZDR recipients with incident dispensation of any BZDRs between 2007 and 2019 were 1:1 matched to 713,896 nonrecipients from the general population; 9197 BZDR recipients were compared with their 9298 unexposed co-twins/co-multiples; and 434,900 BZDR recipients were compared with 428,074 incident selective serotonin reuptake inhibitor (SSRI) recipients. The outcomes were identified by the first inpatient or specialist outpatient diagnosis of serious infections in the National Patient Register, or death from any infections recorded as the underlying cause in the Cause of Death Register. Cox proportional hazards regression models were fitted and controlled for multiple confounders, including familial confounding and confounding by indication. To study a possible dose-response association, the cumulative dosage of BZDRs dispensed during the follow-up was estimated for each BZDR recipient and modeled as a time-varying exposure with dose categories in tertiles [≤ 20 defined daily doses (DDDs), > 20 DDDs ≤ 65, and > 65 DDDs). The risk of infections was assessed in BZDR recipients within each category of the cumulative BZDR dosage compared to their demographically matched nonrecipients. RESULTS: In the demographically matched cohort (average age at incident BZDR use 42.8 years, 56.9% female), the crude incidence rate of any serious infections in BZDR recipients and matched nonrecipients during 1-year follow-up was 4.18 [95% confidence intervals (CI) 4.13-4.23] and 1.86 (95% CI 1.83-1.89) per 100 person-years, respectively. After controlling for demographic, socioeconomic, clinical, and pharmacological confounders, BZDR use was associated with 83% relative increase in risk of any infections [hazard ratio (HR) 1.83, 95% CI 1.79-1.89]. The risk remained increased, although attenuated, in the co-twin cohort (HR 1.55, 95% CI 1.23-1.97) and active comparator cohort (HR 1.33, 95% CI 1.30-1.35). The observed risks were similar across different types of initial BZDRs and across individual BZDRs, and the risks increased with age at BZDR initiation. We also observed a dose-response association between cumulative BZDR dosage and risk of serious infections. CONCLUSIONS: BZDR initiation was associated with increased risks of serious infections, even when considering unmeasured familial confounding and confounding by indication. The exact pathways through which BZDRs may affect immune function, however, remain unclear. Further studies are needed to explore the neurobiological mechanisms underlying the association between BZDR use and serious infections, as it can lead to safer therapeutic strategies for patients requiring BZDR.