Developing evaluation measures for health departments sharing and linking HIV and STI surveillance data.

Enhancing data sharing, quality, and use across siloed HIV and STI programs is critical for national and global initiatives to reduce new HIV infections and improve the health of people with HIV. As part of the Enhancing Linkage of STI and HIV Surveillance Data in the Ryan White HIV/AIDS Program initiative, four health departments (HDs) in the U.S. received technical assistance to better share and link their HIV and STI surveillance data. The process used to develop evaluation measures assessing implementation and outcomes of linking HIV and STI data systems involved six steps: 1) measure selection and development, 2) review and refinement, 3) testing, 4) implementation and data collection, 5) data quality review and feedback, and 6) dissemination. Findings from pilot testing warranted slight adaptations, including starting with a core set of measures and progressively scaling up. Early findings showed improvements in data quality over time. Lessons learned included identifying and engaging key stakeholders early; developing resources to assist HDs; and considering measure development as iterative processes requiring periodic review and reassessment to ensure continued utility. These findings can guide programs and evaluations, especially those linking data across multiple systems, in developing measures to track implementation and outcomes over time.

Assessing Multisensory Sensitivity Across Scales: Using the Resulting Core Factors to Create the Multisensory Amplification Scale.

Multisensory sensitivity (MSS), observed in some chronic pain patients, may reflect a generalized central nervous system sensitivity. While several surveys measure aspects of MSS, there remains no gold standard. We explored the underlying constructs of 4 MSS-related surveys (80 items in total) using factor analyses using REDCap surveys (N = 614, 58.7% with pain). Four core- and 6 associated-MSS factors were identified from the items assessed. None of these surveys addressed all major sensory systems and most included additional related constructs. A revised version of the Somatosensory Amplification Scale was developed, encompassing 5 core MSS systems: vision, hearing, smell, tactile, and internal bodily sensations: the 12-item Multisensory Amplification Scale (MSAS). The MSAS demonstrated good internal consistency (alpha = 0.82), test-retest reliability (ICC3,1 = 0.90), and construct validity in the original and in a new, separate cohort (R = 0.54-0.79, P < .0001). Further, the odds of having pain were 2-3.5 times higher in the highest sex-specific MSAS quartile relative to the lowest MSAS quartile, after adjusting for age, sex, BMI, and pain schema (P < .03). The MSAS provides a psychometrically comprehensive, brief, and promising tool for measuring the core-dimensions of MSS. PERSPECTIVE: Multiple multisensory sensitivity (MSS) tools are used, but without exploration of their underlying domains. We found several measures lacking core MSS domains, thus we modified an existing scale to encompass 5 core MSS domains: light, smell, sound, tactile, and internal bodily sensations using only 12 items, with good psychometric properties.

Cytotoxic T lymphocyte antigen-4 regulates development of xenogenic graft versus host disease in mice via modulation of host immune responses induced by changes in human T cell engraftment and gene expression.

Graft versus host disease (GvHD) is a major clinical problem with a significant unmet medical need. We examined the role of cytotoxic T lymphocyte antigen-4 (CTLA-4) in a xenogenic GvHD (xeno-GvHD) model induced by injection of human peripheral mononuclear cells (hPBMC) into irradiated non-obese diabetic (NOD) SCID gamma (NSG) mice. Targeting the CTLA-4 pathway by treatment with CTLA-4 immunoglobulin (Ig) prevented xeno-GvHD, while anti-CTLA-4 antibody treatment exacerbated the lethality and morbidity associated with GvHD. Xeno-GvHD is associated with infiltration of hPBMCs into the lungs, spleen, stomach, liver and colon and an increase in human proinflammatory cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-5. Infiltration of donor cells and increases in cytokines were attenuated by treatment with CTLA-4 Ig, but remained either unaffected or enhanced by anti-CTLA-4 antibody. Further, splenic human T cell phenotyping showed that CTLA-4 Ig treatment prevented the engraftment of human CD45+ cells, while anti-CTLA-4 antibody enhanced donor T cell expansion, particularly CD4+ (CD45RO+ ) subsets, including T box transcription factor TBX21 (Tbet)+ CXCR3+ and CD25+ forkhead box protein 3 (FoxP3) cells. Comprehensive analysis of transcriptional profiling of human cells isolated from mouse spleen identified a set of 417 differentially expressed genes (DEGs) by CTLA-4 Ig treatment and 13 DEGs by anti-CTLA-4 antibody treatment. The CTLA-4 Ig regulated DEGs mapped to down-regulated apoptosis, inflammasome, T helper type 17 (Th17) and regulatory T cell (Treg ) pathways and enhanced Toll-like receptor (TLR) receptor signaling, TNF family signaling, complement system and epigenetic and transcriptional regulation, whereas anti-CTLA-4 antibody produced minimal to no impact on these gene pathways. Our results show an important role of co-inhibitory CTLA-4 signaling in xeno-GvHD and suggest the therapeutic utility of other immune checkpoint co-inhibitory pathways in the treatment of immune-mediated diseases driven by hyperactive T cells.

Mitochondrial pyruvate carriers are required for myocardial stress adaptation.

In addition to fatty acids, glucose and lactate are important myocardial substrates under physiologic and stress conditions. They are metabolized to pyruvate, which enters mitochondria via the mitochondrial pyruvate carrier (MPC) for citric acid cycle metabolism. In the present study, we show that MPC-mediated mitochondrial pyruvate utilization is essential for the partitioning of glucose-derived cytosolic metabolic intermediates, which modulate myocardial stress adaptation. Mice with cardiomyocyte-restricted deletion of subunit 1 of MPC (cMPC1-/-) developed age-dependent pathologic cardiac hypertrophy, transitioning to a dilated cardiomyopathy and premature death. Hypertrophied hearts accumulated lactate, pyruvate and glycogen, and displayed increased protein O-linked N-acetylglucosamine, which was prevented by increasing availability of non-glucose substrates in vivo by a ketogenic diet (KD) or a high-fat diet, which reversed the structural, metabolic and functional remodelling of non-stressed cMPC1-/- hearts. Although concurrent short-term KDs did not rescue cMPC1-/- hearts from rapid decompensation and early mortality after pressure overload, 3 weeks of a KD before transverse aortic constriction was sufficient to rescue this phenotype. Together, our results highlight the centrality of pyruvate metabolism to myocardial metabolism and function.

A Cryo-pulverization Protocol for Processing Mouse Paws to Evaluate Molecular Pathways of Tissue Inflammation in a Collagen Induced Arthritis Model.

Profiling molecular changes in local tissues is crucial to understand the mechanism(s) of action of therapeutic candidates in vivo. In the field of arthritis research, many studies are focused on inflamed joints that are composed of a complex mixture of bone, cartilage, muscle, stromal cells and immune cells. Here, we established a reliable and robust mechanical method to disrupt inflamed mouse paws into homogeneous pulverized samples in a cryogenically controlled environment. Protein and RNA lysates were processed to enable proteomic and transcriptional endpoints and molecular characterization of relevant disease pathways in local tissue.

PD-L1- and calcitriol-dependent liposomal antigen-specific regulation of systemic inflammatory autoimmune disease.

Autoimmune diseases resulting from MHC class II-restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions. PD-L1 expression was upregulated in dLNs of immunized relative to naive mice. Subcutaneous administration of liposomes encapsulating OVA323-339 and calcitriol targeted dLN PD-L1hi DCs of immunized mice and reduced their MHC class II expression. OVA323-339/calcitriol liposomes suppressed expansion, differentiation, and function of Teffs and induced Foxp3+ and IL-10+ peripheral Tregs in an antigen-specific manner, which was dependent on PD-L1. Peptide/calcitriol liposomes modulated CD40 expression by human DCs and promoted Treg induction in vitro. Liposomes encapsulating calcitriol and disease-associated peptides suppressed the severity of rheumatoid arthritis and Goodpasture's vasculitis models with suppression of antigen-specific memory T cell differentiation and function. Accordingly, peptide/calcitriol liposomes leverage DC PD-L1 for antigen-specific T cell regulation and induce antigen-specific tolerance in inflammatory autoimmune diseases.

Evaluation of Project RISE, an HIV Prevention Intervention for Black Bisexual Men Using an Ecosystems Approach.

Black men who have sex with men and women (MSMW) are among the populations at highest risk for HIV infection. We describe the evaluation of Project RISE, a six-session individual-level intervention developed for black MSMW using an ecosystems approach. A randomized controlled trial was used to test the effect of the intervention on sexual risk outcomes. Eligibility criteria included having both male and female sex partners in the past 12 months. Complete data at 5-month follow-up were collected from 86.7% of the 165 participants. In analyses controlling for HIV status, age, and baseline risk, intervention participants were found to have significantly greater reductions in number of female partners (p < 0.05) and total male and female partners (p < 0.05) at follow-up, compared to the control group. Intervention participants also were significantly more likely to report a reduction in number of sex episodes without a condom with female partners (p < 0.05) and with all partners (p < 0.02) at follow-up, compared to the control group.

A mathematical model for timing the release from sequestration and the resultant Brownian migration of SeqA clusters in E. coli.

DNA replication in Escherichia coli is initiated by DnaA binding to oriC, the replication origin. During the process of assembly of the replication factory, the DnaA is released back into the cytoplasm, where it is competent to reinitiate replication. Premature reinitiation is prevented by binding SeqA to newly formed GATC sites near the replication origin. Resolution of the resulting SeqA cluster is one aspect of timing for reinitiation. A Markov model accounting for the competition between SeqA binding and methylation for one or several GATC sites relates the timing to reaction rates, and consequently to the concentrations of SeqA and methylase. A model is proposed for segregation, the motion of the two daughter DNAs into opposite poles of the cell before septation. This model assumes that the binding of SeqA and its subsequent clustering results in loops from both daughter nucleoids attached to the SeqA cluster at the GATC sites. As desequestration occurs, the cluster is divided in two, one associated with each daughter. As the loops of DNA uncoil, the two subclusters migrate apart due to the Brownian ratchet effect of the DNA loop.