Numerous models, frameworks, and theories exist for specific aspects of implementation research, including for determinants, strategies, and outcomes. However, implementation research projects often ...fail to provide a coherent rationale or justification for how these aspects are selected and tested in relation to one another. Despite this need to better specify the conceptual linkages between the core elements involved in projects, few tools or methods have been developed to aid in this task. The Implementation Research Logic Model (IRLM) was created for this purpose and to enhance the rigor and transparency of describing the often-complex processes of improving the adoption of evidence-based interventions in healthcare delivery systems.
The IRLM structure and guiding principles were developed through a series of preliminary activities with multiple investigators representing diverse implementation research projects in terms of contexts, research designs, and implementation strategies being evaluated. The utility of the IRLM was evaluated in the course of a 2-day training to over 130 implementation researchers and healthcare delivery system partners.
Preliminary work with the IRLM produced a core structure and multiple variations for common implementation research designs and situations, as well as guiding principles and suggestions for use. Results of the survey indicated a high utility of the IRLM for multiple purposes, such as improving rigor and reproducibility of projects; serving as a "roadmap" for how the project is to be carried out; clearly reporting and specifying how the project is to be conducted; and understanding the connections between determinants, strategies, mechanisms, and outcomes for their project.
The IRLM is a semi-structured, principle-guided tool designed to improve the specification, rigor, reproducibility, and testable causal pathways involved in implementation research projects. The IRLM can also aid implementation researchers and implementation partners in the planning and execution of practice change initiatives. Adaptation and refinement of the IRLM are ongoing, as is the development of resources for use and applications to diverse projects, to address the challenges of this complex scientific field.
The HIV-1 fusion peptide, comprising 15 to 20 hydrophobic residues at the N terminus of the Env-gp41 subunit, is a critical component of the virus-cell entry machinery. Here, we report the ...identification of a neutralizing antibody, N123-VRC34.01, which targets the fusion peptide and blocks viral entry by inhibiting conformational changes in gp120 and gp41 subunits of Env required for entry. Crystal structures of N123-VRC34.01 liganded to the fusion peptide, and to the full Env trimer, revealed an epitope consisting of the N-terminal eight residues of the gp41 fusion peptide and glycan N88 of gp120, and molecular dynamics showed that the N-terminal portion of the fusion peptide can be solvent-exposed. These results reveal the fusion peptide to be a neutralizing antibody epitope and thus a target for vaccine design.
The rapid emergence and subsequent spread of the novel 2009 Influenza A/H1N1 virus (2009 H1N1) has prompted the World Health Organization to declare the first pandemic of the 21st century, ...highlighting the threat of influenza to public health and healthcare systems. Widespread resistance to both classes of influenza antivirals (adamantanes and neuraminidase inhibitors) occurs in both pandemic and seasonal viruses, rendering these drugs to be of marginal utility in the treatment modality. Worldwide, virtually all 2009 H1N1 and seasonal H3N2 strains are resistant to the adamantanes (rimantadine and amantadine), and the majority of seasonal H1N1 strains are resistant to oseltamivir, the most widely prescribed neuraminidase inhibitor (NAI). To address the need for more effective therapy, we evaluated the in vitro activity of a triple combination antiviral drug (TCAD) regimen composed of drugs with different mechanisms of action against drug-resistant seasonal and 2009 H1N1 influenza viruses. Amantadine, ribavirin, and oseltamivir, alone and in combination, were tested against amantadine- and oseltamivir-resistant influenza A viruses using an in vitro infection model in MDCK cells. Our data show that the triple combination was highly synergistic against drug-resistant viruses, and the synergy of the triple combination was significantly greater than the synergy of any double combination tested (P<0.05), including the combination of two NAIs. Surprisingly, amantadine and oseltamivir contributed to the antiviral activity of the TCAD regimen against amantadine- and oseltamivir-resistant viruses, respectively, at concentrations where they had no activity as single agents, and at concentrations that were clinically achievable. Our data demonstrate that the TCAD regimen composed of amantadine, ribavirin, and oseltamivir is highly synergistic against resistant viruses, including 2009 H1N1. The TCAD regimen overcomes baseline drug resistance to both classes of approved influenza antivirals, and thus may represent a highly active antiviral therapy for seasonal and pandemic influenza.
Genetic and clinical association studies have identified disrupted in schizophrenia 1 (DISC1) as a candidate risk gene for major mental illness. DISC1 is interrupted by a balanced chr(1;11) ...translocation in a Scottish family in which the translocation predisposes to psychiatric disorders. We investigate the consequences of DISC1 interruption in human neural cells using TALENs or CRISPR-Cas9 to target the DISC1 locus. We show that disruption of DISC1 near the site of the translocation results in decreased DISC1 protein levels because of nonsense-mediated decay of long splice variants. This results in an increased level of canonical Wnt signaling in neural progenitor cells and altered expression of fate markers such as Foxg1 and Tbr2. These gene expression changes are rescued by antagonizing Wnt signaling in a critical developmental window, supporting the hypothesis that DISC1-dependent suppression of basal Wnt signaling influences the distribution of cell types generated during cortical development.
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•We generate isogenic human iPSCs with an engineered disruption of the DISC1 gene•DISC1 disruption results in decreased expression of long DISC1 isoforms•DISC1 disruption affects the expression of NPC fate markers, including FoxG1 and Tbr2•DISC1 mutant NPCs show elevated baseline Wnt signaling and proliferation
Srikanth et al. report the generation of isogenic hiPSC lines with engineered mutations in two locations within the DISC1 gene. This disease-relevant disruption shows a loss of long isoforms, which, in turn, affects neural progenitor cell proliferation, baseline WNT signaling, and the expression of NPC fate markers such as FoxG1 and Tbr2.
We conducted a scoping review of contextual factors impeding uptake and adherence to pre-exposure prophylaxis in transgender communities as an in-depth analysis of the transgender population within a ...previously published systematic review. Using a machine learning screening process, title and abstract screening, and full-text review, the initial systematic review identified 353 articles for analysis. These articles were peer-reviewed, implementation-related studies of PrEP in the U.S. published after 2000. Twenty-two articles were identified in this search as transgender related. An additional eleven articles were identified through citations of these twenty-two articles, resulting in thirty-three articles in the current analysis. These thirty-three articles were qualitatively coded in NVivo using adapted constructs from the Consolidated Framework for Implementation Research as individual codes. Codes were thematically assessed. We point to barriers of implementing PrEP, including lack of intentional dissemination efforts and patience assistance, structural factors, including sex work, racism, and access to gender affirming health care, and lack of provider training. Finally, over 60% of articles lumped cisgender men who have sex with men with trans women. Such articles included sub-samples of transgender individuals that were not representative. We point to areas of growth for the field in this regard.
Implementation science groups change methods into two categories: (1) clinical, behavioral, or biomedical intervention targeting recipient's health outcomes and (2) implementation strategies ...targeting the delivery system. Differentiating interventions from strategies based on their intended functions is critical to accurately attributing their effects to health or implementation outcomes. However, in coordinating 200+ HIV implementation research projects and conducting systematic reviews, we identified change methods that had characteristics of both interventions and strategies that were inconsistently categorized. To alleviate confusion and improve change method specification, we propose that implementation science should adopt an extant but rarely used term-adjunctive interventions-to classify change methods that are distinct from the common intervention/strategy taxonomy.
Adjunctive interventions as change methods that target recipients (e.g., patients, participants) of a health intervention but are designed to increase recipients' motivation, self-efficacy, or capacity for initiating, adhering to, complying with, or engaging with the health intervention over time. In two of our published reviews on implementation of HIV interventions, 25 out of 45 coded change methods fell into this gray area between strategy and intervention. We also noted instances in which the same change method was labelled as the intervention ("the thing"), as an adjunctive intervention, or an implementation strategy in different studies-further muddying the waters. Adjunctive interventions are distinguished from other change methods by their intended targets, desired outcomes, and theory of action and causal processes. Whereas health interventions target recipients and have a direct, causal effect on the health outcome, adjunctive interventions enhance recipients' attitudes and behaviors to engage with the intervention and have an indirect causal link to the health outcome via increasing the probability of recipients' utilization and adherence to the intervention. Adjunctive interventions are incapable of directly producing the health outcome and will themselves require implementation strategies to effectively impact sustained uptake, utilization, and adherence. Case examples, logic modeling, and considerations (e.g., relationship to consumer engagement strategies) for adjunctive intervention research are provided.
Conceptualizing adjunctive interventions as a separate type of change method will advance implementation research by improving tests of effectiveness, and the specification of mechanisms and outcomes.
XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated ...with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.
Delivery and use of HIV pre-exposure prophylaxis (PrEP) are suboptimal in the United States. Previous reviews of barriers and facilitators have not used an implementation science lens, limiting ...comprehensiveness and the link to implementation strategies. To summarize the state of the science, we systematically reviewed determinants of PrEP implementation using the updated Consolidated Framework for Implementation Research (CFIR 2.0).
PrEP-eligible communities and delivery settings in the United States.
In January 2021, we searched Ovid MEDLINE, PsycINFO, and Web of Science for peer-reviewed articles related to HIV/AIDS, interventions, implementation, and determinants or strategies. We identified 286 primary research articles published after 1999 about US-based PrEP implementation. Team members extracted discrete "mentioned" and "measured" determinants, coding each by setting, population, valence, measurement, and CFIR 2.0 construct.
We identified 1776 mentioned and 1952 measured determinants from 254 to 239 articles, respectively. Two-thirds of measured determinants were of PrEP use by patients as opposed to delivery by providers. Articles contained few determinants in the inner setting or process domains (ie, related to the delivery context), even among studies of specific settings. Determinants across priority populations also focused on individual patients and providers rather than structural or logistical factors.
Our findings suggest substantial knowledge in the literature about general patient-level barriers to PrEP use and thus limited need for additional universal studies. Instead, future research should prioritize identifying determinants, especially facilitators, unique to understudied populations and focus on structural and logistical features within current and promising settings (eg, pharmacies) that support integration of PrEP into clinical practice.
The Ending the HIV Epidemic (EHE) initiative sets a goal to virtually eliminate new HIV infections in the United States by 2030. The plan is predicated on the fact that tools exist for diagnosis, ...prevention, and treatment, and the current scientific challenge is how to implement them effectively and with equity. Implementation research (IR) can help identify strategies that support effective implementation of HIV services.
NIH funded the Implementation Science Coordination Initiative (ISCI) to support rigorous and actionable IR by providing technical assistance to NIH-funded projects and supporting local implementation knowledge becoming generalizable knowledge.
We describe the formation of ISCI, the services it provided to the HIV field, and data it collected from 147 NIH-funded studies. We also provide an overview of this supplement issue as a dissemination strategy for HIV IR.
Our ability to reach EHE 2030 goals is strengthened by the knowledge compiled in this supplement, the services of ISCI and connected hubs, and a myriad of investigators and implementation partners collaborating to better understand what is needed to effectively implement the many evidence-based HIV interventions at our disposal.
Men who have sex with men (MSM) are disproportionately affected by HIV, accounting for two-thirds of HIV cases in the United States despite representing ∼5% of the adult population. Delivery and use ...of existing and highly effective HIV prevention and treatment strategies remain suboptimal among MSM. To summarize the state of the science, we systematically review implementation determinants and strategies of HIV-related health interventions using implementation science frameworks. Research on implementation barriers has focused predominantly on characteristics of individual recipients (e.g., ethnicity, age, drug use) and less so on deliverers (e.g., nurses, physicians), with little focus on system-level factors. Similarly, most strategies target recipients to influence their uptake and adherence, rather than improving and supporting implementation systems. HIV implementation research is burgeoning; future research is needed to broaden the examination of barriers at the provider and system levels, as well as expand knowledge on how to match strategies to barriers-particularly to address stigma. Collaboration and coordination among federal, state, and local public health agencies; community-based organizations; health care providers; and scientists are important for successful implementation of HIV-related health innovations.
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