Belatacept with time-limited tacrolimus coimmunosuppression modifies the 3-year risk of eplet mismatch in kidney transplantation.

Solid organ transplant donor-recipient eplet mismatch has been correlated with donor-specific antibody (DSA) formation, antibody-mediated rejection, and overall rejection rates. However, studies have been predominantly in patients on tacrolimus-based immunosuppression regimens and have not fully explored differences in ethnically and racially diverse populations. Evidence indicates that patients on belatacept have lower rates of DSA formation, suggesting mediation of the immunogenicity of mismatched human leukocyte antigen polymorphisms. We performed a retrospective, single-center analysis of class II eplet disparity in a cohort of kidney transplant recipients treated using belatacept with tacrolimus induction (Bela/TacTL) or tacrolimus regimens between 2016 and 2019. Bela/TacTL (n = 294) and tacrolimus (n = 294) cohorts were propensity score-matched with standardized difference <0.15. Single-molecule eplet risk level was associated with immune event rates for both groups. In Cox regression analysis stratified by eplet risk level, Bela/TacTL immunosuppression was associated with a decreased rate of DSA (hazard ratio [HR] = 0.4), antibody-mediated rejection (HR = 0.2), and rejection (HR = 0.45). In the low-risk group, cumulative graft failure was lower for patients on Bela/TacTL (P < .02). Analysis of eplet mismatch burden may be a useful adjunct in identifying high-risk populations with increased immunosuppression requirements and should encourage the design of allocation rules to incentivize lower-risk pairings without negatively impacting equity in access.

Does Psychosocial Stress Impact Cognitive Reappraisal? Behavioral and Neural Evidence.

Cognitive reappraisal (CR) is regarded as an effective emotion regulation strategy. Acute stress, however, is believed to impair the functioning of prefrontal-based neural systems, which could result in lessened effectiveness of CR under stress. This study tested the behavioral and neurobiological impact of acute stress on CR. While undergoing fMRI, adult participants ( n = 54) passively viewed or used CR to regulate their response to negative and neutral pictures and provided ratings of their negative affect in response to each picture. Half of the participants experienced an fMRI-adapted acute psychosocial stress manipulation similar to the Trier Social Stress Test, and a control group received parallel manipulations without the stressful components. Relative to the control group, the stress group exhibited heightened stress as indexed by self-report, heart rate, and salivary cortisol throughout the scan. Contrary to our hypothesis, we found that reappraisal success was equivalent in the control and stress groups, as was electrodermal response to the pictures. Heart rate deceleration, a physiological response typically evoked by aversive pictures, was blunted in response to negative pictures and heightened in response to neutral pictures in the stress group. In the brain, we found weak evidence of stress-induced increases of reappraisal-related activity in parts of the PFC and left amygdala, but these relationships were statistically fragile. Together, these findings suggest that both the self-reported and neural effects of CR may be robust to at least moderate levels of stress, informing theoretical models of stress effects on cognition and emotion.

Content Recommendation Systems in Web-Based Mental Health Care: Real-world Application and Formative Evaluation.

BACKGROUND: Recommender systems have great potential in mental health care to personalize self-guided content for patients, allowing them to supplement their mental health treatment in a scalable way. OBJECTIVE: In this paper, we describe and evaluate 2 knowledge-based content recommendation systems as parts of Ginger, an on-demand mental health platform, to bolster engagement in self-guided mental health content. METHODS: We developed two algorithms to provide content recommendations in the Ginger mental health smartphone app: (1) one that uses users' responses to app onboarding questions to recommend content cards and (2) one that uses the semantic similarity between the transcript of a coaching conversation and the description of content cards to make recommendations after every session. As a measure of success for these recommendation algorithms, we examined the relevance of content cards to users' conversations with their coach and completion rates of selected content within the app measured over 14,018 users. RESULTS: In a real-world setting, content consumed in the recommendations section (or "Explore" in the app) had the highest completion rates (3353/7871, 42.6%) compared to other sections of the app, which had an average completion rate of 37.35% (21,982/58,614; P<.001). Within the app's recommendations section, conversation-based content recommendations had 11.4% (1108/2364) higher completion rates per card than onboarding response-based recommendations (1712/4067; P=.003) and 26.1% higher than random recommendations (534/1440; P=.005). Studied via subject matter experts' annotations, conversation-based recommendations had a 16.1% higher relevance rate for the top 5 recommended cards, averaged across sessions of varying lengths, compared to a random control (110 conversational sessions). Finally, it was observed that both age and gender variables were sensitive to different recommendation methods, with responsiveness to personalized recommendations being higher if the users were older than 35 years or identified as male. CONCLUSIONS: Recommender systems can help scale and supplement digital mental health care with personalized content and self-care recommendations. Onboarding-based recommendations are ideal for "cold starting" the process of recommending content for new users and users that tend to use the app just for content but not for therapy or coaching. The conversation-based recommendation algorithm allows for dynamic recommendations based on information gathered during coaching sessions, which is a critical capability, given the changing nature of mental health needs during treatment. The proposed algorithms are just one step toward the direction of outcome-driven personalization in mental health. Our future work will involve a robust causal evaluation of these algorithms using randomized controlled trials, along with consumer feedback-driven improvement of these algorithms, to drive better clinical outcomes.

Wave-spec: a preprocessing package for mass spectrometry data.

UNLABELLED: Wave-spec is a pre-processing package for mass spectrometry (MS) data. The package includes several novel algorithms that overcome conventional difficulties with the pre-processing of such data. In this application note, we demonstrate step-by-step use of this package on a real-world MALDI dataset. AVAILABILITY: The package can be downloaded at http://www.vicc.org/biostatistics/supp.php. A shared mailbox (wave-spec@vanderbilt.edu) also is available for questions regarding application of the package.

hlaR: A rapid and reproducible tool to identify eplet mismatches between transplant donors and recipients.

Eplet mismatch load, both overall and at the single molecule level, correlates with transplant recipient outcomes. However, precise eplet assessment requires high-resolution HLA typing of both the donor and recipient. Anything less than high-resolution typing requires imputation of HLA types. The currently available methods to identify eplet mismatch are both tedious and demanding. Therefore, we developed a software package and user-friendly web application (hlaR), that simplifies the workflow of eplet analysis, provides functions to impute high-resolution from low-resolution data and calculates both overall and single molecule eplet mismatch for single or multiple donor recipient pairs. Compared to manual assessments using currently available tools (namely, HLAMatchMaker), hlaR resulted in only minimal discrepancy in eplet mismatches (mean absolute difference of 0.56 for class I and 0.86 for class II for unique sum across loci). Additionally, output of the single molecule eplet function compared well to manual calculation, with an average single antigen count increase of 0.19. Importantly, the hlaR tool permits rapid and reproducible imputation and eplet mismatch including comparison between eplet reference tables (e.g. HLAMatchMaker version 2 or 3). Users can import data from a spreadsheet rather than relying on keystroke entry of individual donor and recipient data, thus reducing the risk of data entry errors. The resulting improved scalability of the hlaR tool is highlighted by plotting analysis time against the size of the input dataset. The new hlaR tool can provide eplet mismatch data with a streamlined workflow. With decreased effort from the end user, eplet matching and mismatch load data can be further incorporated into both research and clinical use.

Dramatic functional improvement following bariatric surgery in a patient with pulmonary arterial hypertension and morbid obesity.

Pulmonary arterial hypertension (PAH) and morbid obesity both dramatically impair functional capacity. New therapies have emerged for both conditions, including pharmaceutical agents for the former and bariatric surgery for the latter. The presence of both conditions simultaneously, however, may limit the applicability and effectiveness of these therapies. We report a case of a morbidly obese patient with severe PAH and functional impairment. A three-drug combination regimen consisting of oral bosentan and sildenafil, and inhaled iloprost produced sufficient hemodynamic improvement to allow for the performance of bariatric surgery. Over the subsequent 7 months, body weight, oxygen requirement, functional class, and 6-min walk distance all improved dramatically despite the persistence of PAH. While such surgery is typically denied to patients with PAH, we suggest that aggressive medical therapy for patients with PAH may allow for its safe performance, and that the clinical improvement resulting from the subsequent weight loss may be quite dramatic.

Identification of CXCR3 receptor agonists in combinatorial small-molecule libraries.

In a high-throughput screen of four million compounds from combinatorial libraries for small-molecule modulators of the chemokine receptor CXCR3, two classes of receptor agonists, based on tetrahydroisoquinoline and piperidinyl diazepanone templates, were identified. Several of these compounds stimulated calcium flux in HEK293 cells expressing the recombinant human CXCR3 receptor with efficacies and kinetics similar to those of native ligand CXCL11/I-TAC and stimulated chemotaxis of activated human T-cells. The agonist small molecules also inhibited binding of another CXCR3 ligand, CXCL10/IP-10, to the receptor. The response to small-molecule agonists was inhibited by a CXCR3-specific small-molecule antagonist previously identified within the same combinatorial compound collection but structurally unrelated to the agonists. Remarkably, while other, non-amino acid substituents were present in the majority of the library compounds screened, the agonists from both classes contained a positively charged amino acid component, with preference for Arg>Lys, as well as a hydrophobic component.

Identification and initial evaluation of 4-N-aryl-[1,4]diazepane ureas as potent CXCR3 antagonists.

The identification and evaluation of aryl-[1,4]diazepane ureas as functional antagonists of the chemokine receptor CXCR3 are described. Specific examples exhibit IC(50) values of approximately 60 nM in a calcium mobilization functional assay, and dose-dependently inhibit CXCR3 functional response to CXCL11 (interferon-inducible T-cell alpha chemoattractant/I-TAC) as measured by T-cell chemotaxis, with a potency of approximately 100 nM.

Sudden cardiac death: implantable cardioverter defibrillators and pharmacological treatments.

Sudden cardiac death (SCD) is the leading cause of death in advanced heart failure and cardiomyopathy patients, regardless of the underlying causes of cardiomyopathy. Ventricular tachycardia and ventricular fibrillation are the causes of SCD. This article examines pharmacological interventions and mostly, the role of implantable cardioverter defibrllators in preventing SCD in heart failure patients. The indications for various methods of treatment of SCD are discussed in this article.