Greater use of computerized decision support (DS) systems could address continuing safety and quality problems in healthcare, but the healthcare field has struggled to implement DS technology. This ...study surveys DS experience across multiple non-healthcare disciplines for new insights that are generalizable to healthcare provider decisions. In particular, it sought design principles and lessons learned from the other disciplines that could inform efforts to accelerate the adoption of clinical decision support (CDS).
Our systematic review drew broadly from non-healthcare databases in the basic sciences, social sciences, humanities, engineering, business, and defense: PsychINFO, BusinessSource Premier, Social Sciences Abstracts, Web of Science, and Defense Technical Information Center. Because our interest was in DS that could apply to clinical decisions, we selected articles that (1) provided a review, overview, discussion of lessons learned, or an evaluation of design or implementation aspects of DS within a non-healthcare discipline and (2) involved an element of human judgment at the individual level, as opposed to decisions that can be fully automated or that are made at the organizational level.
Clinical decisions share some similarities with decisions made by military commanders, business managers, and other leaders: they involve assessing new situations and choosing courses of action with major consequences, under time pressure, and with incomplete information. We identified seven high-level DS system design features from the non-healthcare literature that could be applied to CDS: providing broad, system-level perspectives; customizing interfaces to specific users and roles; making the DS reasoning transparent; presenting data effectively; generating multiple scenarios covering disparate outcomes (e.g., effective; effective with side effects; ineffective); allowing for contingent adaptations; and facilitating collaboration. The article provides examples of each feature. The DS literature also emphasizes the importance of organizational culture and training in implementation success. The literature contrasts "rational-analytic" vs. "naturalistic-intuitive" decision-making styles, but the best approach is often a balanced approach that combines both styles. It is also important for DS systems to enable exploration of multiple assumptions, and incorporation of new information in response to changing circumstances.
Complex, high-level decision-making has common features across disciplines as seemingly disparate as defense, business, and healthcare. National efforts to advance the health information technology agenda through broader CDS adoption could benefit by applying the DS principles identified in this review.
Abstract Objective Apply and compare two methods that identify signals for the need to update systematic reviews, using three Evidence-based Practice Center reports on omega-3 fatty acids as test ...cases. Study Design and Setting We applied the RAND method, which uses domain (subject matter) expert guidance, and a modified Ottawa method, which uses quantitative and qualitative signals. For both methods, we conducted focused electronic literature searches of recent studies using the key terms from the original reports. We assessed the agreement between the methods and qualitatively assessed the merits of each system. Results Agreement between the two methods was “substantial” or better (kappa > 0.62) in three of the four systematic reviews. Overall agreement between the methods was “substantial” (kappa = 0.64, 95% confidence interval CI 0.45–0.83). Conclusion The RAND and modified Ottawa methods appear to provide similar signals for the possible need to update systematic reviews in this pilot study. Future evaluation with a broader range of clinical topics and eventual comparisons between signals to update reports and the results of full evidence review updates will be needed. We propose a hybrid approach combining the best features of both methods, which should allow efficient review and assessment of the need to update.
VISTA (PD-1H) is an immune regulatory molecule considered part of the next wave of immuno-oncology targets. VISTA is an immunoglobulin (Ig) superfamily cell surface molecule mainly expressed on ...myeloid cells, and to some extent on NK cells and T cells. In previous preclinical studies, some VISTA-targeting antibodies provided immune inhibitory signals, while other antibodies triggered immune stimulatory signals. Importantly, for therapeutic antibodies, the isotype backbone can have a strong impact on antibody function. To elucidate the mode of action of immune stimulatory anti-VISTA antibodies, we studied three different anti-human VISTA antibody clones, each on three different IgG isotypes currently used for therapeutic antibodies: unaltered IgG1 (IgG1-WT), IgG1-KO (IgG1-LL234,235AA-variant with reduced Fc-effector function), and IgG4-Pro (IgG4- S228P-variant with stabilized hinge region). Antibody functionality was analysed in mixed leukocyte reaction (MLR) of human peripheral blood mononuclear cells (PBMCs), as a model system for ongoing immune reactions, on unstimulated human PBMCs, as a model system for a resting immune system, and also on acute myeloid leukemia (AML) patient samples to evaluate anti-VISTA antibody effects on primary tumor material. The functions of three anti-human VISTA antibodies were determined by their IgG isotype backbones. An MLR of healthy donor PBMCs was effectively augmented by anti-VISTA-IgG4-Pro and anti-VISTA-IgG1-WT antibodies, as indicated by increased levels of cytokines, T cell activation markers and T cell proliferation. However, in a culture of unstimulated PBMCs of single healthy donors, only anti-VISTA-IgG1-WT antibodies increased the activation marker HLA-DR on resting myeloid cells, and chemokine levels. Interestingly, interactions with different Fc-receptors were required for these effects, namely CD64 for augmentation of MLR, and CD16 for activation of resting myeloid cells. Furthermore, anti-VISTA-IgG1-KO antibodies had nearly no impact in any model system. Similarly, in AML patient samples, anti-VISTA-antibody on IgG4-Pro backbone, but not on IgG1-KO backbone, increased interactions, as a novel readout of activity, between immune cells and CD34+ AML cancer cells. In conclusion, the immune stimulatory effects of antagonistic anti-VISTA antibodies are defined by the antibody isotype and interaction with different Fc-gamma-receptors, highlighting the importance of understanding these interactions when designing immune stimulatory antibody therapeutics for immuno-oncology applications.
In recent years, microRNAs (miRNA), a class of non-coding RNA known to regulate protein expression post-transcriptionally, have been recognized as novel biomarkers of diseases.
In this systematic ...review, we identify miRNAs that are differentially expressed in Alzheimer's disease (AD) and/or mild cognitive impairment (MCI) and evaluate their accuracy as potential blood biomarkers.
Eligible studies of miRNAs in peripheral blood distinguishing patients with AD or MCI from cognitively normal controls were identified through standardized search strategies in Medline, PubMed, and Embase. MiRNAs that were differentially expressed were identified and where available their sensitivity and specificity for AD or MCI extracted from the retrieved studies.
Eighteen studies investigated the diagnostic value of miRNAs as peripheral biomarkers of AD/MCI. Twenty miRNAs were significantly upregulated and 32 miRNAs downregulated in AD compared to controls in ten AD studies. Nine miRNAs were consistently dysregulated in more than one study. Of the 8 MCI studies, only one miRNA, miR-132, was consistently upregulated in three independent studies. Of the studies that reported diagnostic accuracy data, the majority of miRNA panels and individual miRNAs had a sensitivity and specificity greater than 0.75.
Individual studies suggest that miRNAs can differentiate patients with AD/MCI from cognitively normal controls with modest accuracy. However, the literature is constrained by methodological differences between studies, with few studies assessing the same miRNAs. To become potential biomarkers for AD, further studies with standardized study designs for replication and validation are required. Results from this review may help researchers select candidate miRNAs for further investigation.
The CCR5-specific antibody Leronlimab is being investigated as a novel immunotherapy that can suppress HIV replication with minimal side effects. Here we studied the virological and immunological ...consequences of Leronlimab in chronically CCR5-tropic HIV-1 infected humans (n = 5) on suppressive antiretroviral therapy (ART) and in ART-naïve acutely CCR5-tropic SHIV infected rhesus macaques (n = 4). All five human participants transitioned from daily combination ART to self-administered weekly subcutaneous (SC) injections of 350 mg or 700 mg Leronlimab and to date all participants have sustained virologic suppression for over seven years. In all participants, Leronlimab fully occupied CCR5 receptors on peripheral blood CD4+ T cells and monocytes. In ART-naïve rhesus macaques acutely infected with CCR5-tropic SHIV, weekly SC injections of 50 mg/kg Leronlimab fully suppressed plasma viremia in half of the macaques. CCR5 receptor occupancy by Leronlimab occurred concomitant with rebound of CD4+ CCR5+ T-cells in peripheral blood, and full CCR5 receptor occupancy was found in multiple anatomical compartments. Our results demonstrate that weekly, self-administered Leronlimab was safe, well-tolerated, and efficacious for long-term virologic suppression and should be included in the arsenal of safe, easily administered, longer-acting antiretroviral treatments for people living with HIV-1. Trial Registration: ClinicalTrials.gov Identifiers: NCT02175680 and NCT02355184.
Macaques are physiologically relevant animal models of human immunology and infectious disease that have provided key insights and advanced clinical treatment in transplantation, vaccinology, and ...HIV/AIDS. However, the small size of macaques is a stumbling block for studies requiring large numbers of cells, such as hematopoietic stem cells (HSCs) for transplantation, antigen‐specific lymphocytes for in‐depth immunological analysis, and latently‐infected CD4+ T‐cells for HIV cure studies. Here, we provide a detailed protocol for collection of large numbers of HSCs and T‐cells from cynomolgus macaques as small as 3 kg using the Terumo Spectra Optia apheresis system, yielding an average of 5.0 × 109 total nucleated cells from mobilized animals and 1.2 × 109 total nucleated cells from nonmobilized animals per procedure. This report provides sufficient detail to adapt this apheresis technique at other institutions, which will facilitate more efficient and detailed analysis of HSCs and their progeny blood cells.
Allogeneic hematopoietic stem cell transplantation (HSCT) and xenotransplantation are accompanied by viral reactivations and virus‐associated complications resulting from immune deficiency. Here, in ...a Mauritian cynomolgus macaque model of fully MHC‐matched allogeneic HSCT, we report reactivations of cynomolgus polyomavirus, lymphocryptovirus, and cytomegalovirus, macaque viruses analogous to HSCT‐associated human counterparts BK virus, Epstein‐Barr virus, and human cytomegalovirus. Viral replication in recipient macaques resulted in characteristic disease manifestations observed in HSCT patients, such as polyomavirus‐associated hemorrhagic cystitis and tubulointerstitial nephritis or lymphocryptovirus‐associated post‐transplant lymphoproliferative disorder. However, in most cases, the reconstituted immune system, alone or in combination with short‐term pharmacological intervention, exerted control over viral replication, suggesting engraftment of functional donor‐derived immunity. Indeed, the donor‐derived reconstituted immune systems of two long‐term engrafted HSCT recipient macaques responded to live attenuated yellow fever 17D vaccine (YFV 17D) indistinguishably from untransplanted controls, mounting 17D‐targeted neutralizing antibody responses and clearing YFV 17D within 14 days. Together, these data demonstrate that this macaque model of allogeneic HSCT recapitulates clinical situations of opportunistic viral infections in transplant patients and provides a pre‐clinical model to test novel prophylactic and therapeutic modalities.
OP 2.1 CCR5 in HIV Prevention and Cure Wu, Helen L.; Webb, Gabriela M.; Sacha, Jonah B.
Journal of Virus Eradication,
December 2022, 2022-12-00, 2022-12-01, Volume:
8
Journal Article
Childhood trauma has been reported as a possible cause of future substance abuse in some countries. This study reports the prevalence of childhood trauma and examines its association with ...psychological distress among injecting drug users from mainland China.
The study was conducted in three government-operated drug rehabilitation facilities in Shanghai, China in 2007. The Early Trauma Inventory Self Report-Short Form (ETISR-SF) was used to evaluate 4 types (general, emotional, physical and sexual) and severity of childhood trauma, and the Symptom Checklist-90-Revised (SCL-90-R) to evaluate psychological distress.
Among 341 injecting drug users who completed the study, about 80% reported one or more types of childhood trauma, specifically 53% general trauma, 56% physical abuse, 36% emotional abuse and 26% sexual abuse. Compared to female injecting drug users, males reported significantly higher scores of general trauma and physical abuse, but lower sexual abuse scores. Hierarchical linear regression analyses showed that greater physical and emotional abuse in childhood predict greater current psychopathological distress among these injecting drug users in China.
The results reveal a high prevalence of childhood trauma among injecting drug users in China, and it is comparable to other similar studies in Western countries. It is important to consider the role of childhood trauma in the prevention and treatment of substance abuse.
PDF
