Comparison of Standard 1.5 T vs. 3 T Optimized Protocols in Patients Treated with Glatiramer Acetate. A Serial MRI Pilot Study

This study explored the effect of glatiramer acetate (GA, 20 mg) on lesion activity using the 1.5 T standard MRI protocol (single dose gadolinium [Gd] and 5-min delay) or optimized 3 T protocol (triple dose of Gd, 20-min delay and application of an off-resonance saturated magnetization transfer pulse). A 15-month, phase IV, open-label, single-blinded, prospective, observational study included 12 patients with relapsing-remitting multiple sclerosis who underwent serial MRI scans (Days −45, −20, 0; the minus ign indicates the number of days before GA treatment; and on Days 30, 60, 90, 120, 150, 180, 270 and 360 during GA treatment) on 1.5 T and 3 T protocols. Cumulative number and volume of Gd enhancing (Gd-E) and T2 lesions were calculated. At Days −45 and 0, there were higher number (p < 0.01) and volume (p < 0.05) of Gd-E lesions on 3 T optimized compared to 1.5 T standard protocol. However, at 180 and 360 days of the study, no significant differences in total and cumulative number of new Gd-E and T 2 lesions were found between the two protocols. Compared to pre-treatment period, at Days 180 and 360 a significantly greater decrease in the cumulative number of Gd-E lesions (p = 0.03 and 0.021, respectively) was found using the 3 T vs. the 1.5 T protocol (p = NS for both time points). This MRI mechanistic study suggests that GA may exert a greater effect on decreasing lesion activity as measured on 3 T optimized compared to 1.5 T standard protocol

Mutational and Structural Analysis of KIR3DL1 Reveals a Lineage-Defining Allotypic Dimorphism That Impacts Both HLA and Peptide Sensitivity

Killer Ig-like receptors (KIRs) control the activation of human NK cells via interactions with peptide-laden HLAs. KIR3DL1 is a highly polymorphic inhibitory receptor that recognizes a diverse array of HLA molecules expressing the Bw4 epitope, a group with multiple polymorphisms incorporating variants within the Bw4 motif. Genetic studies suggest that KIR3DL1 variation has functional significance in several disease states, including HIV infection. However, owing to differences across KIR3DL1 allotypes, HLA-Bw4, and associated peptides, the mechanistic link with biological outcome remains unclear. In this study, we elucidated the impact of KIR3DL1 polymorphism on peptide-laden HLA recognition. Mutational analysis revealed that KIR residues involved in water-mediated contacts with the HLA-presented peptide influence peptide binding specificity. In particular, residue 282 (glutamate) in the D2 domain underpins the lack of tolerance of negatively charged C-terminal peptide residues. Allotypic KIR3DL1 variants, defined by neighboring residue 283, displayed differential sensitivities to HLA-bound peptide, including the variable HLA-B*57:01–restricted HIV-1 Gag-derived epitope TW10. Residue 283, which has undergone positive selection during the evolution of human KIRs, also played a central role in Bw4 subtype recognition by KIR3DL1. Collectively, our findings uncover a common molecular regulator that controls HLA and peptide discrimination without participating directly in peptide-laden HLA interactions. Furthermore, they provide insight into the mechanics of interaction and generate simple, easily assessed criteria for the definition of KIR3DL1 functional groupings that will be relevant in many clinical applications, including bone marrow transplantation

Pandemic intake questionnaire to improve quality, effectiveness, and efficiency of outpatient neurologic and developmental care at the Kennedy Krieger institute during the COVID-19 pandemic

BackgroundThe COVID-19 pandemic uniquely affects patients with neurologic and developmental disabilities at the Kennedy Krieger Institute. These patients are at increased risk of co-morbidities, increasing their risk of contracting COVID-19. Disruptions in their home and school routines, and restrictions accessing crucial healthcare services has had a significant impact.MethodsA Pandemic Intake questionnaire regarding COVID-19 related medical concerns of guardians of patients was distributed using Qualtrics. Data from May-December 2020 were merged with demographic information of patients from 10 clinics (Center for Autism and Related Disorders (CARD), Neurology, Epigenetics, Neurogenetics, Center for Development and Learning (CDL) Sickle Cell, Spinal Cord, Sturge-Weber syndrome (SWS), Tourette's, and Metabolism). A provider feedback survey was distributed to program directors to assess the effectiveness of this intervention.ResultsAnalysis included responses from 1643 guardians of pediatric patients (mean age 9.5 years, range 0–21.6 years). Guardians of patients in more medically complicated clinics reported perceived increased risk of COVID-19 (p &lt; 0.001) and inability to obtain therapies (p &lt; 0.001) and surgeries (p &lt; 0.001). Guardian responses from CARD had increased reports of worsening behavior (p = 0.01). Providers increased availability of in-person and virtual therapies and visits and made referrals for additional care to address this. In a survey of medical providers, five out of six program directors who received the responses to this survey found this questionnaire helpful in caring for their patients.ConclusionThis quality improvement project successfully implemented a pre-visit questionnaire to quickly assess areas of impact of COVID-19 on patients with neurodevelopmental disorders. During the pandemic, results identified several major areas of impact, including patient populations at increased risk for behavioral changes, sleep and/or disruptions of medical care. Most program directors reported improved patient care as a result

The role of metacognition in self-critical rumination: an investigation in individuals presenting with low self-esteem

Background: No research, to date, has directly investigated the role of metacognition in self-critical rumination and low self-esteem. Aim: To investigate the presence of metacognitive beliefs about self-critical rumination; the goal of self-critical rumination and its stop signal; and the degree of detachment from intrusive self-critical thoughts. Method: Ten individuals reporting both a self-acknowledged tendency to judge themselves critically and having low self-esteem were assessed using metacognitive profiling, a semi-structured interview. Results: All participants endorsed both positive and negative metacognitive beliefs about self-critical rumination. Positive metacognitive beliefs concerned the usefulness of self-critical rumination as a means of improving cognitive performance and enhancing motivation. Negative metacognitive beliefs concerned the uncontrollability of self-critical rumination and its negative impact on mood, motivation and perception of self-worth. The primary goal of engaging in self-critical rumination was to achieve a better or clearer understanding of a given trigger situation or to feel more motivated to resolve it. However, only four participants were able to identify when this goal had been achieved, which was if the trigger situation were not to occur again. Participants unanimously stated that they were either unable to detach from their self-critical thoughts or could do so some of the time with varying degrees of success. More often than not, though, self-critical thoughts were viewed as facts, would rarely be seen as distorted or biased, and could take hours or days to dissipate. Conclusions: These findings provide preliminary evidence that specific facets of metacognition play a role in the escalation and perseveration of self-critical rumination

Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition

Natural killer (NK) cells play a key role in immunity, but how HLA class I (HLA-I) and killer cell immunoglobulin-like receptor 3DL1 (KIR3DL1) polymorphism impacts disease outcome remains unclear. KIR3DL1 (*001/*005/*015) tetramers were screened for reactivity against a panel of HLA-I molecules. This revealed different and distinct hierarchies of specificity for each KIR3DL1 allotype, with KIR3DL1*005 recognizing the widest array of HLA-I ligands. These differences were further reflected in functional studies using NK clones expressing these specific KIR3DL1 allotypes. Unexpectedly, the Ile/Thr80 dimorphism in the Bw4-motif did not categorically define strong/weak KIR3DL1 recognition. Although the KIR3DL1*001, *005, and *015 polymorphisms are remote from the KIR3DL1-HLA-I interface, the structures of these three KIR3DL1-HLA-I complexes showed that the broader HLA-I specificity of KIR3DL1*005 correlated with an altered KIR3DL1*005 interdomain positioning and increased mobility within its ligand-binding site. Collectively, we provide a generic framework for understanding the impact of KIR3DL1 polymorphism on the recognition of HLA-I allomorphs

Efficacy of Chlorhexidine Varnish for the Prevention of Adult Caries: A Randomized Trial

The Prevention of Adult Caries Study, an NIDCR-funded multicenter, double-blind, randomized clinical trial, enrolled 983 adults (aged 18-80 yrs) at high risk for developing caries (20 or more intact teeth and 2 or more lesions at screening) to test the efficacy of a chlorhexidine diacetate 10% weight per volume (w/v) dental coating (CHX). We excluded participants for whom the study treatment was contraindicated or whose health might affect outcomes or ability to complete the study. Participants were randomly assigned to receive either the CHX coating (n = 490) or a placebo control (n = 493). Coatings were applied weekly for 4 weeks and a fifth time 6 months later. The primary outcome (total net D1-2FS increment) was the sum of weighted counts of changes in tooth surface status over 13 months. We observed no significant difference between the two treatment arms in either the intention-to-treat or per-protocol analyses. Analysis of 3 protocol-specified secondary outcomes produced similar findings. This trial failed to find that 10% (w/v) chlorhexidine diacetate coating was superior to placebo coating for the prevention of new caries (Clinicaltrials.gov registration number NCT00357877)

Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation

Among the 1 of 10 children who are born preterm annually in the United States, 6% are born before the third trimester. Among children who survive birth before the 28th week of gestation, the risks of autism spectrum disorder (ASD) and non-autistic social impairment are severalfold higher than in the general population. We examined the relationship between top quartile inflammation-related protein concentrations among children born extremely preterm and ASD or, separately, a high score on the Social Responsiveness Scale (SRS total score ≥65) among those who did not meet ASD criteria, using information only from the subset of children whose DAS-II verbal or non-verbal IQ was ≥70, who were assessed for ASD, and who had proteins measured in blood collected on ≥2 days (N = 763). ASD (N = 36) assessed at age 10 years is associated with recurrent top quartile concentrations of inflammation-related proteins during the first post-natal month (e.g., SAA odds ratio (OR); 95% confidence interval (CI): 2.5; 1.2–5.3) and IL-6 (OR; 95% CI: 2.6; 1.03–6.4)). Top quartile concentrations of neurotrophic proteins appear to moderate the increased risk of ASD associated with repeated top quartile concentrations of inflammation-related proteins. High (top quartile) concentrations of SAA are associated with elevated risk of ASD (2.8; 1.2–6.7) when Ang-1 concentrations are below the top quartile, but not when Ang-1 concentrations are high (1.3; 0.3–5.8). Similarly, high concentrations of TNF-α are associated with heightened risk of SRS-defined social impairment (N = 130) (2.0; 1.1–3.8) when ANG-1 concentrations are not high, but not when ANG-1 concentrations are elevated (0.5; 0.1–4.2)