Evolution of white matter hyperintensity segmentation methods and implementation over the past two decades; an incomplete shift towards deep learning.

This systematic review examines the prevalence, underlying mechanisms, cohort characteristics, evaluation criteria, and cohort types in white matter hyperintensity (WMH) pipeline and implementation literature spanning the last two decades. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we categorized WMH segmentation tools based on their methodologies from January 1, 2000, to November 18, 2022. Inclusion criteria involved articles using openly available techniques with detailed descriptions, focusing on WMH as a primary outcome. Our analysis identified 1007 visual rating scales, 118 pipeline development articles, and 509 implementation articles. These studies predominantly explored aging, dementia, psychiatric disorders, and small vessel disease, with aging and dementia being the most prevalent cohorts. Deep learning emerged as the most frequently developed segmentation technique, indicative of a heightened scrutiny in new technique development over the past two decades. We illustrate observed patterns and discrepancies between published and implemented WMH techniques. Despite increasingly sophisticated quantitative segmentation options, visual rating scales persist, with the SPM technique being the most utilized among quantitative methods and potentially serving as a reference standard for newer techniques. Our findings highlight the need for future standards in WMH segmentation, and we provide recommendations based on these observations.

Protein-protein conjugation enhances the immunogenicity of SARS-CoV-2 receptor-binding domain (RBD) vaccines.

Several effective SARS-CoV-2 vaccines have been developed using different technologies. Although these vaccines target the isolates collected early in the pandemic, many have protected against serious illness from newer variants. Nevertheless, efficacy has diminished against successive variants and the need for effective and affordable vaccines persists especially in the developing world. Here, we adapted our protein-protein conjugate vaccine technology to generate a vaccine based on receptor-binding domain (RBD) antigen. RBD was conjugated to a carrier protein, EcoCRM®, to generate two types of conjugates: crosslinked and radial conjugates. In the crosslinked conjugate, antigen and carrier are chemically crosslinked; in the radial conjugate, the antigen is conjugated to the carrier by site-specific conjugation. With AS01 adjuvant, both conjugates showed enhanced immunogenicity in mice compared to RBD, with a Th1 bias. In hACE2 binding inhibition and pseudovirus neutralization assays, sera from mice vaccinated with the radial conjugate demonstrated strong functional activity.

Characteristics of subjective cognitive decline associated with amyloid positivity.

INTRODUCTION: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. METHODS: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms with amyloid positivity. RESULTS: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE ε4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. DISCUSSION: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.

Malaria transmission-blocking conjugate vaccine in ALFQ adjuvant induces durable functional immune responses in rhesus macaques.

Malaria transmission-blocking vaccines candidates based on Pfs25 and Pfs230 have advanced to clinical studies. Exoprotein A (EPA) conjugate of Pfs25 in Alhydrogel® developed functional immunity in humans, with limited durability. Pfs230 conjugated to EPA (Pfs230D1-EPA) with liposomal adjuvant AS01 is currently in clinical trials in Mali. Studies with these conjugates revealed that non-human primates are better than mice to recapitulate the human immunogenicity and functional activity. Here, we evaluated the effect of ALFQ, a liposomal adjuvant consisting of TLR4 agonist and QS21, on the immunogenicity of Pfs25-EPA and Pfs230D1-EPA in Rhesus macaques. Both conjugates generated strong antibody responses and functional activity after two vaccinations though activity declined rapidly. A third vaccination of Pfs230D1-EPA induced functional activity lasting at least 9 months. Antibody avidity increased with each vaccination and correlated strongly with functional activity. IgG subclass analysis showed induction of Th1 and Th2 subclass antibody levels that correlated with activity.

Correlates of Alcohol-Using Network Size Among Men Who Have Sex with Men in San Francisco, CA.

Men who have sex with men (MSM) have a high prevalence of hazardous alcohol consumption. While network-level characteristics such as social network size have been indicated as upstream determinants of alcohol use in general population samples, no studies have examined factors associated with alcohol using network size (ANS), among MSM.This secondary analysis examined demographic, substance use, and sexual behavior correlates of ANS using data from a diverse sample of alcohol-using MSM in San Francisco (N = 252). Associations were calculated using multivariable negative binomial regression, adjusting for age, race, education, and employment.The median ANS was 10. Factors associated with larger ANS in multivariable analyses included identifying as Hispanic/Latino, having completed a college education or higher, having a higher Alcohol Use Disorders Identification Test (AUDIT) score, having a greater number of sexual partners, polysubstance use, and being unaware of one's own HIV status. Factors associated with smaller ANS included being between 18 and 24 years of age, reporting a low income, and having any lifetime history of injection drug use.For MSM, ANS was associated with increased likelihood of hazardous alcohol use, as well specific individual-level substance use and sexual risk behaviors. These results highlight the role of ANS in hazardous alcohol consumption and sexually transmitted infection transmission among MSM. These results also indicate ways that research and intervention programs aimed at reducing alcohol use among MSM might be improved through network-based recruitment or engagement. Finally, these results suggest the need for further research on HIV-unknown MSM.

Toward a Universal Readout for 18F-Labeled Amyloid Tracers: The CAPTAINs Study.

To date, 3 18F-labeled PET tracers have been approved for assessing cerebral amyloid plaque pathology in the diagnostic workup of suspected Alzheimer disease (AD). Although scanning protocols are relatively similar across tracers, U.S. Food and Drug Administration- and the European Medicines Agency-approved visual rating protocols differ among the 3 tracers. This proof-of-concept study assessed the comparability of the 3 approved visual rating protocols to classify a scan as amyloid-positive or -negative, when applied by groups of experts and nonexperts to all 3 amyloid tracers. Methods: In an international multicenter approach, both expert (n = 4) and nonexpert raters (n = 3) rated scans acquired with 18F-florbetaben, 18F-florbetapir and 18F-flutemetamol. Scans obtained with each tracer were presented for reading according to all 3 approved visual rating protocols. In a randomized order, every single scan was rated by each reader according to all 3 protocols. Raters were blinded for the amyloid tracer used and asked to rate each scan as positive or negative, giving a confidence judgment after each response. Percentage of visual reader agreement, interrater reliability, and agreement of each visual read with binary quantitative measures (fixed SUV ratio threshold for positive or negative scans) were computed. These metrics were analyzed separately for expert and nonexpert groups. Results: No significant differences in using the different approved visual rating protocols were observed across the different metrics of agreement in the group of experts. Nominal differences suggested that the 18F-florbetaben visual rating protocol achieved the highest interrater reliability and accuracy especially under low confidence conditions. For the group of nonexpert raters, significant differences between the different visual rating protocols were observed with overall moderate-to-fair accuracy and with the highest reliability for the 18F-florbetapir visual rating protocol. Conclusion: We observed high interrater agreement despite applying different visual rating protocols for all 18F-labeled amyloid tracers. This implies that the results of the visual interpretation of amyloid imaging can be well standardized and do not depend on the rating protocol in experts. Consequently, the creation of a universal visual assessment protocol for all amyloid imaging tracers appears feasible, which could benefit especially the less-experienced readers.

Decrease in p3-Alcß37 and p3-Alcß40, products of Alcadein ß generated by γ-secretase cleavages, in aged monkeys and patients with Alzheimer's disease.

INTRODUCTION: Neuronal p3-Alcß peptides are generated from the precursor protein Alcadein ß (Alcß) through cleavage by α- and γ-secretases of the amyloid ß (Aß) protein precursor (APP). To reveal whether p3-Alcß is involved in Alzheimer's disease (AD) contributes for the development of novel therapy and/or drug targets. METHODS: We developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcß in the cerebrospinal fluid (CSF). RESULTS: In monkeys, CSF p3-Alcß decreases with age, and the aging is also accompanied by decreased brain expression of Alcß. In humans, CSF p3-Alcß levels decrease to a greater extent in those with AD than in age-matched controls. Subjects carrying presenilin gene mutations show a significantly lower CSF p3-Alcß level. A cell study with an inverse modulator of γ-secretase remarkably reduces the generation of p3-Alcß37 while increasing the production of Aß42. DISCUSSION: Aging decreases the generation of p3-Alcß, and further significant decrease of p3-Alcß caused by aberrant γ-secretase activity may accelerate pathogenesis in AD.

Low-threshold extended-release naltrexone for high utilizers of public services with severe alcohol use disorder: A pilot study.

Extended-release naltrexone (XRNTX) is an effective treatment for alcohol use disorder (AUD). We sought to evaluate the feasibility, acceptability, and preliminary effectiveness and cost-effectiveness of XRNTX delivered as a stand-alone service to persons with severe AUD who are high utilizers of multiple urgent and emergency medical services (HUMS). Of 15 HUMS persons with severe AUD selected based on chart review, 11 agreed to participate. Participants received a mean of 4.5 injections (range 2-7). Modest benefits from XRNTX were observed in terms of patients' Urge-to-Drink Score and the costs of emergency medical services utilized. Though limited by a small sample size, costs including client utilization and study related expenses during the post-enrollment period were less than client utilization costs in the pre-enrollment period. We also observed non-significant improvements in the number of drinking days, but no change in quality of life as measured by the EQ-5D. Eighty-eight percent of participants perceived XRNTX as helping with their drinking. Findings need to be replicated in a larger study, however if replicated, the cost savings could be substantial.

Behavioral intervention to reduce opioid overdose among high-risk persons with opioid use disorder: A pilot randomized controlled trial.

OBJECTIVE: The United States is amidst an opioid epidemic, including synthetic opioids that may result in rapid death, leaving minimal opportunity for bystander rescue. We pilot tested a behavioral intervention to reduce the occurrence of opioid overdose among opioid dependent persons at high-risk for subsequent overdose. MATERIALS AND METHODS: We conducted a single-blinded randomized-controlled trial of a repeated dose motivational interviewing intervention (REBOOT) to reduce overdose versus treatment as usual, defined as information and referrals, over 16 months at the San Francisco Department of Public Health from 2014-2016. Participants were 18-65 years of age, had opioid use disorder by Structured Clinical Interview, active opioid use, opioid overdose within 5 years, and prior receipt of naloxone kits. The intervention was administered at months 0, 4, 8, and 12, preceded by the assessment which was also administered at month 16. Dual primary outcomes were any overdose event and number of events, collected by computer-assisted personal interview, as well as any fatal overdose events per vital records. RESULTS: A total of 78 persons were screened and 63 enrolled. Mean age was 43 years, 67% were born male, 65% White, 17% African-American, and 14% Latino. Ninety-two percent of visits and 93% of counseling sessions were completed. At baseline, 33.3% of participants had experienced an overdose in the past four months, with a similar mean number of overdoses in both arms (p = 0.95); 29% overdosed during follow-up. By intention-to-treat, participants assigned to REBOOT were less likely to experience any overdose (incidence rate ratio [IRR] 0.62 [95%CI 0.41-0.92, p = 0.019) and experienced fewer overdose events (IRR 0.46, 95%CI 0.24-0.90, p = 0.023), findings that were robust to sensitivity analyses. There were no differences between arms in days of opioid use, substance use treatment, or naloxone carriage. CONCLUSIONS: REBOOT reduced the occurrence of any opioid overdose and the number of overdoses. TRIAL REGISTRATION: clinicaltrials.gov NCT02093559.