Citations

AbstractAlpha-synucleinopathies can be identified in their prodromal phase, raising several ethical issues. In this review, we first provide definitions of prodromal α-synucleinopathies and discuss the importance of distinguishing between prodromes and risk factors. Next, we discuss the implications of a diagnosis of prodromal α-synucleinopathy and considerations regarding prognostic counseling in both clinical and research settings. We review available data on patient preferences regarding disclosure as well as providers' perspectives. We examine the pros and cons of disclosing a diagnosis of prodromal α-synucleinopathy, taking into consideration the differences between clinical and research settings. Asking about willingness to know in clinical and research settings and the shared decision-making process applied to prognostic counseling is discussed. Concerning research settings, ethical aspects regarding clinical trials are addressed. Availability of direct-to-consumer technologies will likely lead to novel contexts requiring prognostic counseling, and future neuroprotective or neuromodulating treatments may require further considerations on the timing, role, and importance of prognostic counseling. Recommendations on how to address ethical gaps should be a priority for patients, medical professional societies, and research workgroups. Ethical issues must be considered as an integral part of the overall clinical and research approach to prodromal synucleinopathies.

Abstract Objective The Financial Capacity Instrument-Short Form (FCI-SF) is a performance-based measure of everyday financial skills that takes 15 min to administer. Although the FCI-SF has demonstrated excellent psychometric properties, advanced psychometric methods such as item response theory (IRT) can provide important information on the performance of individual test items in measuring financial capacity and in distinguishing between healthy and cognitively impaired individuals. Method Participants were 272 older adults diagnosed with mild cognitive impairment (MCI) and 1,344 cognitively healthy controls recruited from the Mayo Clinic Study of Aging at the Mayo Clinic in Rochester, Minnesota and also from the Cognitive Observations in Seniors study at the University of Alabama at Birmingham. Participants in each study were administered the FCI-SF, which evaluates coin/currency calculation, financial conceptual knowledge, use of a checkbook/register, and use of a bank statement. Results A unidimensional two-parameter logistic model best fit the 37 FCI-SF Test items, and most FCI-SF items fit the unidimensional two-parameter model well. The results indicated that all FCI-SF items robustly distinguished cognitively healthy controls from persons with MCI. Conclusions The study results showed that the FCI-SF performed well under IRT analysis, further highlighted the psychometric properties of the FCI-SF as a valid and reliable measure of financial capacity, and demonstrated the clinical utility of the FCI-SF in distinguishing between cognitively normal and cognitively impaired individuals.

Abstract Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.

Abstract Primary sclerosing cholangitis (PSC) is a complex bile duct disorder. Its etiology is incompletely understood, but environmental chemicals likely contribute to risk. Patients with PSC have an altered bile metabolome, which may be influenced by environmental chemicals. This novel study utilized state-of-the-art high-resolution mass spectrometry (HRMS) with bile samples to provide the first characterization of environmental chemicals and metabolomics (collectively, the exposome) in PSC patients located in the United States of America (USA) (n = 24) and Norway (n = 30). First, environmental chemical- and metabolome-wide association studies were conducted to assess geographic-based similarities and differences in the bile of PSC patients. Nine environmental chemicals (false discovery rate, FDR < 0.20) and 3143 metabolic features (FDR < 0.05) differed by site. Next, pathway analysis was performed to identify metabolomic pathways that were similarly and differentially enriched by the site. Fifteen pathways were differentially enriched (P < .05) in the categories of amino acid, glycan, carbohydrate, energy, and vitamin/cofactor metabolism. Finally, chemicals and pathways were integrated to derive exposure–effect correlation networks by site. These networks demonstrate the shared and differential chemical–metabolome associations by site and highlight important pathways that are likely relevant to PSC. The USA patients demonstrated higher environmental chemical bile content and increased associations between chemicals and metabolic pathways than those in Norway. Polychlorinated biphenyl (PCB)-118 and PCB-101 were identified as chemicals of interest for additional investigation in PSC given broad associations with metabolomic pathways in both the USA and Norway patients. Associated pathways include glycan degradation pathways, which play a key role in microbiome regulation and thus may be implicated in PSC pathophysiology.

Abstract Background and study aims Concomitant hiatal hernia (HH) repair with transoral incisionless fundoplication (TIF) is a therapeutic option for patients with HH > 2 cm and gastroesophageal reflux disease (GERD). Data comparing this approach with laparoscopic Nissen fundoplication (LNF) are lacking. We performed an exploratory analysis to compare these two approaches' adverse events (AEs) and clinical outcomes. Patients and methods This was a multicenter retrospective cohort study of HH repair followed by LNF versus HH repair followed by TIF in patients with GERD and moderate HH (2–5 cm). AEs were assessed using the Clavien-Dindo classification. Symptoms (heartburn/regurgitation, bloating, and dysphagia) were compared at 6 and 12 months. Results A total of 125 patients with HH repair with TIF and 70 with HH repair with LNF were compared. There was no difference in rates of discontinuing or decreasing proton pump inhibitor use, dysphagia, esophagitis, disrupted wrap, and HH recurrence between the two groups (P > 0.05). The length of hospital stay (1 day vs. 2 days), 30-day readmission rate (0 vs. 4.3 %), early AE rate (0 vs. 18.6 %), and early serious AE rate (0 vs. 4.3 %) favored TIF (all P < 0.05). The rate of new or worse than baseline bloating was lower in the TIF group at 6 months (13.8 % vs. 30.0 %, P = 0.009). Conclusions Concomitant HH repair with TIF is feasible and associated with lower early and serious AEs compared to LNF. Further comparative efficacy studies are warranted.

Background: Epidemiological studies of lateral ankle sprains in NCAA sports are important in appraising the burden of this injury and informing prevention efforts. Purpose: To describe the epidemiology of lateral ankle sprains in NCAA sports during the 2014-15 through 2018-19 seasons. Study Design: Descriptive epidemiology study. Methods: Injury and exposure information collected within the NCAA Injury Surveillance Program (ISP) were examined. Counts, rates, and proportions of lateral ankle sprains were used to describe injury incidence by sport, event type (practices, competitions), season segment (preseason, regular season, postseason), injury mechanism (player contact, noncontact, and surface contact, injury history (new, recurrent), and time loss (time loss [≥1 day], non–time loss). Injury rate ratios (IRRs) were used to examine differential injury rates, and injury proportion ratios (IPRs) were used to examine differential distributions. Results: A total of 3910 lateral ankle sprains were reported (4.61 per 10,000 athlete exposures) during the study period, and the overall rate was highest in men’s basketball (11.82 per 10,000 athlete exposures). The competition-related injury rate was higher than the practice-related rate (IRR, 3.24; 95% CI, 3.04-3.45), and across season segments, the overall rate was highest in preseason (4.99 per 10,000 athlete exposures). Lateral ankle sprains were most often attributed to player-contact mechanisms in men’s (43.2%) and women’s sports (35.1%), although injuries were more prevalently attributed to player contact in men’s than in women’s sports (IPR, 1.23; 95% CI, 1.13-1.34). Overall, 49.7% of all lateral ankle sprains were time loss injuries. Conclusions: The findings of this study are consistent with previous epidemiological investigations of lateral ankle sprains among NCAA athletes. Results offer additional context on differential injury mechanisms between men’s and women’s sports and on injury risk across the competitive season. Future research may examine the effectiveness of deploying injury prevention programs before the start of a season.

Abstract CD8+ T cells represent a relatively under studied cell type in allergic lung inflammation, despite their presence in the mucosal tissues. This is because CD8+ T cells are normally associated with a Th1 response as opposed to Th2 or Th17 responses, as are the most cases with allergic inflammation. However, recent papers have shown the production of Th2 and Th17 cytokines in these cells, yet knowledge of their physiological role in allergic inflammation is incomplete. The presence of IL-17 in asthma patients contributes to a severe, steroid resistant phenotype. Therefore, determining contributors of IL-17 and their physiological role is paramount to understanding the disease. Our preliminary data which suggests memory Tc17 cells are generated in CD4-/- mice when sensitized intranasally to ovalbumin with IL-33. We believe Tc17 cells are responsible for the inflammation because the inflamed lung tissue contained elevated IL-17, and stimulated T cells from inflamed tissue produced elevated levels of IL-17 as well. Additionally, we were unable to induce inflammation in Rag-/- mice or TCRβ-/- mice, which pinpoints the cell responsible to CD8+ T cells in CD4-/- mice. Using these mice to study an exaggerated phenotype will allow us to more easily detect the contributions that happen to a lesser degree in wild type animals. This work create a more complete picture of the disease environment and lead to therapies which can account for the contribution of this cell type.

Abstract We used an established model of asthma that involves intranasal administration of the fungal extract of Alternaria. Upon lung exposure to Alternaria, IL-33 was released by epithelial cells within one hour, followed by increased production of IL-5 in the lungs. We also found elevated serum levels of IL-5 in response to Alternaria exposure, which reached a peak at 6 hours post Alternaria administration. After prolonged exposure to Alternaria over 6 days, a significant increase in mature eosinophils was observed in bone marrow. In addition, the serum from mice challenged with Alternaria was able to stimulate bone marrow cells to undergo eosinophil maturation in vitro. Intraperitoneal administration of IL-5-blocking antibody in vivo decreased eosinophil maturation in bone marrow in response to intranasal Alternaria below intranasal PBS baseline levels. We have shown the source of IL-5 is by type 2 innate lymphoid cells directly through IL-5 reporter mice, and indirectly through IL-5 serum levels in CD127 knockout mice. Taken together, this study illustrates that the type 2 innate immune responses in the lungs leads to enhanced production of eosinophils in the bone marrow through the increase in lung and blood levels of IL-5. Thus, distant organs communicate during allergic inflammation by using cytokines as mediators. This concept will aid in the identification of novel therapeutic strategies to alleviate symptoms of asthma and allergic diseases.