Indiana University-Purdue University Indianapolis (IUPUI) / Voltage-gated sodium channels (Navs) undergo remarkably complex modes of modulation to fine tune membrane excitability and neuronal firing properties. In neurons, the isoform Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Thus, Nav1.6 modulation and dysfunction may profoundly impact the input-output properties of neurons in normal and pathological conditions. Phosphorylation is a powerful and reversible mechanism that exquisitely modulates ion channels. To this end, the multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) can transduce neuronal activity through phosphorylation of diverse substrates to serve as a master regulator of neuronal function. Because Nav1.6 and CaMKII are independently linked to excitability disorders, I sought to investigate modulation of Nav1.6 function by CaMKII signaling to reveal an important mechanism underlying neuronal excitability. Multiple biochemical approaches show Nav1.6 is a novel substrate for CaMKII and reveal multi-site phosphorylation within the L1 domain; a hotspot for post-translational regulation in other Nav isoforms. Consistent with these findings, pharmacological inhibition of CaMKII reduces transient and persistent sodium currents in Purkinje neurons. Because Nav1.6 is the predominant sodium current observed in Purkinje neurons, these data suggest that Nav1.6 may be modulated through CaMKII signaling. In support of this, my studies demonstrate that CaMKII inhibition significantly attenuates Nav1.6 transient and persistent sodium currents and shifts the voltage-dependence of activation to more depolarizing potentials in heterologous cells. Interestingly, I show that these functional effects are likely mediated by CaMKII phosphorylation of Nav1.6 at S561 and T642, and that each phosphorylation site regulates distinct biophysical characteristics of the channel. These findings are further extended to investigate CaMKII modulation of disease-linked mutant Nav1.6 channels. I show that different Nav1.6 mutants display distinct responses to CaMKII modulation and reveal that acute CaMKII inhibition attenuates gain-of-function effects produced by mutant channels. Importantly, computational simulations modeling the effects of CaMKII inhibition on WT and mutant Nav1.6 channels demonstrate dramatic reductions in neuronal excitability in Purkinje and cortical pyramidal cell models. Together, these findings suggest that CaMKII modulation of Nav1.6 may be a powerful mechanism to regulate physiological and pathological neuronal excitability. / 2022-02-02

Entrepreneurs in integrated care face some of the same challenges in empirically demonstrating impact, regardless of the model of care they espouse. In this editorial, 2 leading model developers reflect on the state of the science in primary care integration, including research gaps and promising research underway. We asked these leaders to discuss conceptual areas of shared concern, and we present those with reference to the metaphor of the translational research bridge. Their insights resonate with one another and suggest a role for collaboration to advance empirical support for the implementation of integrated care.

Indiana University-Purdue University Indianapolis (IUPUI) / Translational research has proven to be a powerful process that bridges the gap between basic science and medical practice. The complexity of translational research is two-fold: integration of vast amount of information in disparate silos, and dissemination of discoveries to stakeholders with different interests. We designed and implemented a hybrid knowledge discovery framework. We developed strategies to leverage both traditional biomedical databases and Health Social Network Communities content in the discovery process. Heuristic and quantitative evaluations were carried out in Colorectal Cancer and Amyotrophic Lateral Sclerosis disease areas. The results demonstrate the potential of our approach to bridge silos and to identify hidden links among clinical observations, drugs, genes and diseases, which may eventually lead to the discovery of novel disease targets, biomarkers and therapies.

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As we discussed in our first editorial in the December 2018 issue (Polaha & Sunderji, 2018), an emerging science of knowledge translation (also known as implementation and dissemination science) aims to bridge the disconnect between evidence and practice. Researchers are increasingly engaging with knowledge users and other stakeholders as a key strategy to promote uptake. This may include policymakers, payers, and—the focus of this editorial—patients. Patient-oriented research is featured in national research agendas around the world including in Canada (Canadian Institutes of Health Research, 2018) and the United States (Patient-Centered Outcomes Research Institute, see https://www.pcori.org/), in part as it may contribute one solution to the “bench to bedside” gap (Greenhalgh, Jackson, Shaw, & Janamian, 2016; Jull, Giles, & Graham, 2017; McGavin, 2017). In this editorial, we provide a general introduction to research, its potential, and its realized value. We also suggest strategies for conducting patient-oriented research effectively, including a description of common barriers and how they can be dealt with. We hope this background will inspire you to get started with patient-oriented research and to learn more, as well as to share your patient-oriented research through Families, Systems, & Health.

No description available.

With medical evidence constantly advancing, the health care system faces pressure to generate, apply and integrate innovations to improve the quality of patient care. This dissertation examines how organizational characteristics influence these processes. The first study, a systematic review, investigates how organizational features influence the translation of basic research findings to clinical applications. Results showed a dearth of peer-reviewed literature on this topic, despite a proliferation of efforts to accelerate translational research by manipulating organizational structures and processes. Few studies effectively linked structures, processes and outcomes and no organizational feature was associated conclusively with translation of research into clinical practice. The second study draws on in-depth qualitative interviews (82 participants at 10 hospitals) to understand how hospitals that reduced readmission rates had applied innovations in clinical practice and organizational context. High performing and low performing hospitals had both implemented similar clinical practice changes in their efforts to reduce readmissions; however, high performing hospitals reported greater investment in creating an organizational context to facilitate readmissions. This included more extensive efforts to improve collaboration within the hospital, greater coordination between the hospital and outside providers, deeper engagement in learning and problem solving related to readmissions, and greater senior leadership support. The third study draws on an expanded set of interviews from the same data collection (90 participants at 10 hospitals) to investigate mechanisms through which innovations become integrated into hospital routines. Despite a well-developed literature on the initial implementation of new practices, we have limited knowledge about the mechanisms by which integration occurs. Results showed that when an innovation was integrated successfully, a small number of key staff held the innovation in place for as long as a year while more permanent integrating mechanisms began to work. Innovations that proved intrinsically rewarding to staff integrated through shifts in attitudes and norms over time. Innovations that did not provide direct benefits to staff were integrated through changed incentives or automation. Together, these studies illuminate opportunities for hospitals to improve patient care by managing the organizational context in which innovations are deployed. Understanding how organizational context affects translation requires further research. / 2017-10-02T00:00:00Z

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Comorbid substance use disorders (SUDs) are highly prevalent in bipolar disorder (BD), with up to 60% of individuals with BD developing an SUD at some point in their lifetime. In addition, research suggests that individuals with this comorbid presentation (BD+SUD) typically have worse outcomes -- including increased mortality, morbidity, and functional impairment -- than individuals with BD alone. Given the increased illness burden associated with BD+SUD, I conducted a systematic review evaluating existing psychosocial treatments for individuals with these comorbidities. Results from this review indicated that no existing psychosocial treatments for these comorbid conditions effectively target both the substance use and mood domain of symptoms. An alternative path to treatment development is to identify mechanisms that underlie BD+SUD that can subsequently be targeted in treatment. Accordingly, I evaluated impairments in risk avoidance (a tendency to engage in a persistent pattern of problematic behaviors despite negative outcomes resulting from such behaviors) as a potential mechanism underlying negative illness outcomes in BD+SUD. Participants with BD (n = 45) or BD+SUD (n = 31) in a relatively euthymic mood state completed clinical risk behavior assessments, laboratory-based risk avoidance assessments, and neurocognitive assessments in a single study session. I hypothesized that the BD+SUD group would exhibit increased clinical risk behaviors, increased impairments on laboratory-based measures of risk avoidance, and increased deficits on neurocognitive assessments relative to the bipolar disorder alone group. Contrary to my hypotheses, results indicated a lack of notable between-group differences in clinical risk behaviors, laboratory-based risk avoidance assessments, and neurocognitive assessments, with the exception of self-reported executive dysfunction which was elevated among individuals with BD+SUD. Collapsing across group, I found that increased discounting of delayed rewards, older age, and an earlier age of (hypo)mania onset predicted increased clinical risk behaviors. These findings underscore the potential importance of delay discounting as a mechanistic target for reducing clinical risk behaviors among individuals with BD both with and without comorbid SUDs. I also discuss the neurocognitive correlates of delay discounting and interventions for addressing delay discounting as potential new directions for treating the disability associated with BD.

Background: Heparin-induced thrombocytopenia (HIT) is an iatrogenic immune-mediated prothrombotic disorder that is a direct consequence of heparin therapy. In HIT, antibodies are generated against complexes of platelet factor-4 (PF4) and heparin. Immunoglobulin G (IgG) antibodies bind to PF4/heparin complexes and cause Fc-receptor-mediated activation of platelets and monocytes. PF4 binds endogenous heparin-like polyanions to reveal cross-reactive epitopes that can also bind anti-PF4/heparin antibodies. Based on this observation, researchers have suggested that exposure to PF4/polyanion complexes can sensitize immune cells to become activated to produce HIT antibodies following iatrogenic heparin exposure. Research objective: The objective of this study is to determine whether the preoperative PF4-dependent immune response is associated with postoperative anti-PF4/heparin antibody production in a cohort of patients undergoing cardiopulmonary bypass surgery. Materials and methods: To assess the preoperative immune response to PF4, we utilized two assays: (1) a 3H-thymidine uptake assay to measure peripheral blood mononuclear cell (PBMC) proliferation in response to in vitro stimulation with PF4 and (2) a PBMC ELISPOT assay to measure the preoperative frequency of PF4-specific antibody-secreting cells. Proliferation was quantified as a stimulation index (SI). We then utilized a PF4/heparin-dependent enzyme immunoassay to measure the in vivo levels of anti-PF4/heparin antibodies produced by these patients in the postoperative period. Results: Our findings suggest that preoperative PF4-dependent proliferation is not associated with postoperative polyspecific anti-PF4/heparin antibody production [Spearman’s ρ (95% CI) = –0.02 (–0.32, 0.28), P = 0.91]. PF4-dependent proliferation had a weak negative association with postoperative anti-PF4/heparin IgG antibody production [Spearman’s ρ (95% CI) = –0.31 (–0.56, –0.02), P = 0.04], but was not associated with postoperative IgM or IgA anti-PF4/heparin antibody production [IgM: Spearman’s ρ (95% CI) = –0.04 (–0.33, 0.26), P = 0.78; IgA: Spearman’s ρ (95% CI) = –0.05 (–0.34, 0.25), P = 0.73]. Qualitative analysis demonstrated that two patients who had the strongest preoperative PF4-dependent proliferation responses produced the highest postoperative levels of anti-PF4/heparin IgM antibodies, but this relationship was not observed with postoperative anti-PF4/heparin IgG antibodies. Moreover, the preoperative frequency of PF4-specific antibody-secreting cells (ASCs) was also not associated with postoperative levels of anti-PF4/heparin IgM or IgG antibodies [IgM: Spearman’s ρ (95% CI) = 0.30 (–0.79, 0.93), P = 0.683; IgG: Spearman’s ρ (95% CI) = –0.21 (–0.92, 0.83), P = 0.600]; however, this was only completed on five patients and so the sample size should be increased before any meaningful conclusions can be drawn. We also demonstrated that PF4-dependent proliferation increases 5–6 days following cardiopulmonary bypass surgery [geometric mean (GM) postoperative PF4 alone proliferation (in SI) vs. GM preoperative PF4 alone proliferation (in SI) ± SEM: 23.7 ± 1.3 vs. 6.9 ± 1.5, P = 0.009]. Conclusions: Based on our findings, we conclude that preoperative PF4-dependent proliferation is unable to predict postoperative anti-PF4/heparin antibody production in this cohort of cardiopulmonary bypass patients. Due to the small sample size, we are unable to make conclusive statements regarding the relationship between preoperative PF4-specific ASC frequency and postoperative anti-PF4/heparin antibody production, but our findings would suggest that an association does not exist between these two variables in this patient cohort. Cardiopulmonary bypass surgery, however, may mobilize the postoperative immune cell repertoire to become activated against the self-protein PF4 and may therefore contribute to the postoperative HIT immune response. / Thesis / Master of Science (MSc) / Background: Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder that is a direct consequence of heparin therapy. In HIT, antibodies are generated against complexes of platelet factor-4 (PF4) and heparin. Antibodies bind to PF4/heparin complexes and cause activation of platelets and monocytes. Researchers have suggested that exposure to PF4/polyanion complexes can sensitize immune cells to become activated to produce HIT antibodies following iatrogenic heparin exposure. Research objective: The objective of this study is to determine whether the preoperative PF4-dependent immune response is associated with postoperative anti-PF4/heparin antibody production in a cohort of patients undergoing cardiopulmonary bypass surgery. Materials and methods: To assess the preoperative immune response to PF4, we measured cellular proliferation in response to PF4 stimulation and the preoperative frequency of PF4-specific antibody-secreting cells. We also measured the level of anti-PF4/heparin antibodies following surgery. Results: Our findings suggest that preoperative PF4-dependent proliferation is not associated with postoperative anti-PF4/heparin antibody production. Moreover, the preoperative frequency of PF4-specific antibody-secreting cells (ASCs) was also not associated with postoperative levels of anti-PF4/heparin antibodies; however, this was only completed on five patients and so the sample size should be increased before any meaningful conclusions can be drawn. We also demonstrated that proliferation increases 5–6 days following cardiopulmonary bypass surgery. Conclusions: Based on our findings, we conclude that preoperative proliferation is unable to predict postoperative anti-PF4/heparin antibody production in this cohort of patients. Due to the small sample size, we are unable to make conclusive statements regarding the relationship between preoperative ASC frequency and postoperative anti-PF4/heparin antibody production. Cardiopulmonary bypass surgery, however, may mobilize the postoperative immune cell repertoire to become activated against the self-protein PF4 and may therefore contribute to the HIT immune response.