Letting Go: Conceptualizing intervention de-implementation in public health and social service settings

The discontinuation of interventions that should be stopped, or de-implementation, has emerged as a novel line of inquiry within dissemination and implementation science. As this area grows in human services research, like public health and social work, theory is needed to help guide scientific endeavors. Given the infancy of de-implementation, this conceptual narrative provides a definition and criteria for determining if an intervention should be de-implemented. We identify three criteria for identifying interventions appropriate for de-implementation: (a) interventions that are not effective or harmful, (b) interventions that are not the most effective or efficient to provide, and (c) interventions that are no longer necessary. Detailed, well-documented examples illustrate each of the criteria. We describe de-implementation frameworks, but also demonstrate how other existing implementation frameworks might be applied to de-implementation research as a supplement. Finally, we conclude with a discussion of de-implementation in the context of other stages of implementation, like sustainability and adoption; next steps for de-implementation research, especially identifying interventions appropriate for de-implementation in a systematic manner; and highlight special ethical considerations to advance the field of de-implementation research

Examining Evidence-based Intervention Sustainability and De-adoption in the Context of HIV Prevention

Evidence-based interventions (EBIs), which demonstrate efficacy in research settings, are rarely sustained when implemented in public health organizations. Rather, EBIs are often de-adopted - potentially undermining the positive benefits of the EBIs for the communities that access them. The lack of sustainability is particularly troubling among public health organizations that provide HIV-related services given that many vulnerable, at-risk individuals rely on these services for prevention and care. Characterizing the relationships among the many factors theorized to influence EBI sustainability and subsequent population outcomes may be a critical step to improving our understanding of how EBIs are sustained. Furthermore, the potential impact of EBI de-adoption is relatively unexplored. Given that new EBIs will continue to emerge, this dissertation research contributes to a growing body of knowledge dedicated to understanding the end phases of EBI implementation - sustainability and de-adoption - for HIV prevention in local settings. To achieve this goal, a multi-stage study was conducted, the results of which are presented in two manuscripts. First, a mixed-methods case study of a community-based organization dedicated entirely to HIV prevention that implemented and de-adopted RESPECT, an HIV prevention EBI was conducted. This case study and other existing data were used to inform the construction of an agent-based model, an innovative simulation approach. The agent-based model was then used to examine the impact of human resources on EBI sustainability and population risk over time. The results from these analyses, presented in the first manuscript included in this dissertation, suggest that human resources are integral to EBI sustainability, and adequate human resources must be invested to sustain EBIs and maximize benefit for communities over time. Data from the case study were also used to examine the impact of de-adopting RESPECT in this agency. The results from these analyses, presented in the second manuscript included in this dissertation, demonstrate how de-adopting an EBI has consequences, many of which are negative, for individual staff, the agency, and the community. This work can be used to inform conceptual frameworks and methods informing the study of EBI sustainability and de-adoption. This work can also be used to make recommendations for HIV prevention policy and the promotion of EBIs in practice. A continued focus on sustainability and de-adoption is a crucial opportunity to improve EBI success to maximize the benefit of EBIs for communities

Sustainability in pediatric hospitals: An exploration at the intersection of quality improvement and implementation science

BACKGROUND: Although new evidence-based practices are frequently implemented in clinical settings, many are not sustained, limiting the intended impact. Within implementation science, there is a gap in understanding sustainability. Pediatric healthcare settings have a robust history of quality improvement (QI), which includes a focus on continuation of change efforts. QI capability and sustainability capacity, therefore, serve as a useful concept for connecting the broader fields of QI and implementation science to provide insights on improving care. This study addresses these gaps in understanding of sustainability in pediatric settings and its relationship to QI. METHODS: This is a cross-sectional observational study conducted within pediatric academic medical centers in the United States. Clinicians surveyed worked with one of three evidence-based clinical programs: perioperative antimicrobial stewardship prescribing, early mobility in the intensive care unit, and massive blood transfusion administration. Participants completed two assessments: (1) the Clinical Sustainability Assessment Tool (CSAT) and (2) a 19-question assessment that included demographics and validation questions, specifically a subset of questions from the RESULTS: A total of 181 individuals from three different programs and 30 sites were included in the final analyses. QI capability scores were assessed as a single construct (5-point Likert scale), with an average response of 4.16 (higher scores indicate greater QI capability). The overall CSAT score (7-point Likert scale) was the highest for massive transfusion programs (5.51, SD = 0.91), followed by early mobility (5.25, SD = 0.92) and perioperative antibiotic prescribing (4.91, SD = 1.07). Mixed-effects modeling illustrated that after controlling for person and setting level variables, higher perceptions of QI capabilities were significantly related to overall clinical sustainability. CONCLUSION: Organizations and programs with higher QI capabilities had a higher sustainability capacity, even when controlling for differences at the individual and intervention levels. Organizational factors that enable evidence-based interventions should be further studied, especially as they relate to sustainability. Issues to be considered by practitioners when planning for sustainability include bedside provider perceptions, intervention achievability, frequency of delivery, and organizational influences

A scoping review of de-implementation frameworks and models

BACKGROUND: Reduction or elimination of inappropriate, ineffective, or potentially harmful healthcare services and public health programs can help to ensure limited resources are used effectively. Frameworks and models (FM) are valuable tools in conceptualizing and guiding the study of de-implementation. This scoping review sought to identify and characterize FM that can be used to study de-implementation as a phenomenon and identify gaps in the literature to inform future model development and application for research. METHODS: We searched nine databases and eleven journals from a broad array of disciplines (e.g., healthcare, public health, public policy) for de-implementation studies published between 1990 and June 2020. Two raters independently screened titles and abstracts, and then a pair of raters screened all full text records. We extracted information related to setting, discipline, study design, methodology, and FM characteristics from included studies. RESULTS: The final search yielded 1860 records, from which we screened 126 full text records. We extracted data from 27 articles containing 27 unique FM. Most FM (n = 21) were applicable to two or more levels of the Socio-Ecological Framework, and most commonly assessed constructs were at the organization level (n = 18). Most FM (n = 18) depicted a linear relationship between constructs, few depicted a more complex structure, such as a nested or cyclical relationship. Thirteen studies applied FM in empirical investigations of de-implementation, while 14 articles were commentary or review papers that included FM. CONCLUSION: De-implementation is a process studied in a broad array of disciplines, yet implementation science has thus far been limited in the integration of learnings from other fields. This review offers an overview of visual representations of FM that implementation researchers and practitioners can use to inform their work. Additional work is needed to test and refine existing FM and to determine the extent to which FM developed in one setting or for a particular topic can be applied to other contexts. Given the extensive availability of FM in implementation science, we suggest researchers build from existing FM rather than recreating novel FM. REGISTRATION: Not registered

Experiences from the Missouri Antimicrobial Stewardship Collaborative: A mixed methods study

We performed a mixed-methods study to evaluate antimicrobial stewardship program (ASP) uptake and to assess variability of program implementation in Missouri hospitals. Despite increasing uptake of ASPs in Missouri, there is wide variability in both the scope and sophistication of these programs

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Particulate matter exposure during pregnancy is associated with birth weight, but not gestational age, 1962-1992: a cohort study

<p>Abstract</p> <p>Background</p> <p>Exposure to air pollutants is suggested to adversely affect fetal growth, but the evidence remains inconsistent in relation to specific outcomes and exposure windows.</p> <p>Methods</p> <p>Using birth records from the two major maternity hospitals in Newcastle upon Tyne in northern England between 1961 and 1992, we constructed a database of all births to mothers resident within the city. Weekly black smoke exposure levels from routine data recorded at 20 air pollution monitoring stations were obtained and individual exposures were estimated via a two-stage modeling strategy, incorporating temporally and spatially varying covariates. Regression analyses, including 88,679 births, assessed potential associations between exposure to black smoke and birth weight, gestational age and birth weight standardized for gestational age and sex.</p> <p>Results</p> <p>Significant associations were seen between black smoke and both standardized and unstandardized birth weight, but not for gestational age when adjusted for potential confounders. Not all associations were linear. For an increase in whole pregnancy black smoke exposure, from the 1^st(7.4 μg/m³) to the 25^th(17.2 μg/m³), 50^th(33.8 μg/m³), 75^th(108.3 μg/m³), and 90^th(180.8 μg/m³) percentiles, the adjusted estimated decreases in birth weight were 33 g (SE 1.05), 62 g (1.63), 98 g (2.26) and 109 g (2.44) respectively. A significant interaction was observed between socio-economic deprivation and black smoke on both standardized and unstandardized birth weight with increasing effects of black smoke in reducing birth weight seen with increasing socio-economic disadvantage.</p> <p>Conclusions</p> <p>The findings of this study progress the hypothesis that the association between black smoke and birth weight may be mediated through intrauterine growth restriction. The associations between black smoke and birth weight were of the same order of magnitude as those reported for passive smoking. These findings add to the growing evidence of the harmful effects of air pollution on birth outcomes.</p

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year