Citations

AbstractPhenylketonuria (PKU) is the most common inborn error of metabolism of the liver, and results from mutations of both alleles of the phenylalanine hydroxylase gene (PAH). As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno‐associated virus (AAV) vector. Here we use the synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon‐optimized human PAH gene, with or without an intron spacer, to the Pahenu2 mouse model of PKU. Dose‐dependent transduction of the liver and expression of PAH mRNA were present with both vectors, resulting in significant and durable reduction of circulating phenylalanine, reaching near control levels in males. Coat color of treated Pahenu2 mice reflected an increase in pigmentation from brown to the black color of control animals, further indicating functional restoration of phenylalanine metabolism and its byproduct melanin. There were no adverse effects associated with administration of AAV up to 5 × 1012 VG/kg, the highest dose tested. Only minor and/or transient variations in some liver enzymes were observed in some of the AAV‐dosed animals which were not associated with pathology findings in the liver. Finally, there was no impact on cell turnover or apoptosis as evaluated by Ki‐67 and TUNEL staining, further supporting the safety of this approach. This study demonstrates the therapeutic potential of AAV Anc80 to safely and durably cure PKU in a mouse model, supporting development for clinical consideration.

Abstract Background Persistent organ failure (POF) is the strongest determinant of mortality in acute pancreatitis (AP). There is a paucity of data regarding the impact of different POF attributes on mortality and the role of different characteristics of systemic inflammatory response syndrome (SIRS) in the risk of developing POF. Objective We aimed to assess the association of POF dynamic features with mortality and SIRS characteristics with POF. Methods We studied 1544 AP subjects prospectively enrolled at 22 international centers (APPRENTICE consortium). First, we estimated the association of onset, duration, and maximal score of SIRS with POF. Then, we evaluated the risk of mortality based on POF onset, duration, number, type, and sequence of organs affected. Analyses were adjusted for potential confounders. Results 58% had SIRS, 11% developed POF, and 2.5% died. Early SIRS, persistent SIRS, and maximal SIRS score ≥ 3 were independently associated with higher risk of POF ( p < 0.05). Mortality risk in POF was higher with two (33%, odds ratio [OR] = 10.8, 3.3–34.9) and three (48%, OR = 20.2, 5.9–68.6) organs failing, in comparison to single POF (4%). In subjects with multiple POF, mortality was higher when the cardiovascular and respiratory systems failed first or concurrently as compared to when the renal system failed first or concurrently with other organ ( p < 0.05). In multivariate regression model, the number and sequence of organs affected in POF were associated with mortality ( p < 0.05). Onset and duration of POF had no impact mortality. Conclusion In AP patients with POF, the risk of mortality is influenced by the number, type, and sequence of organs affected. These results are useful for future revisions of AP severity classification systems.

Abstract Background Observational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks. Methods Our primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse-variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided. Results The genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease; P = .03), 3% increased risk of colon cancer (P = .02), 4% increased risk of proximal colon cancer (P = .01), and 3% increased risk of colorectal cancer among females (P = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups. Conclusions Genetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.

Background: Measurement is a critical component for any field. Systematic reviews are a way to locate measures and uncover gaps in current measurement practices. The present study identified measures used in behavioral health settings that assessed all constructs within the Process domain and two constructs from the Inner setting domain as defined by the Consolidated Framework for Implementation Research (CFIR). While previous conceptual work has established the importance social networks and key stakeholders play throughout the implementation process, measurement studies have not focused on investigating the quality of how these activities are being carried out. Methods: The review occurred in three phases: Phase I, data collection included (1) search string generation, (2) title and abstract screening, (3) full text review, (4) mapping to CFIR-constructs, and (5) “cited-by” searches. Phase II, data extraction, consisted of coding information relevant to the nine psychometric properties included in the Psychometric And Pragmatic Rating Scale (PAPERS). In Phase III, data analysis was completed. Results: Measures were identified in only seven constructs: Structural characteristics ( n = 13), Networks and communication ( n = 29), Engaging ( n = 1), Opinion leaders ( n = 5), Champions ( n = 5), Planning ( n = 5), and Reflecting and evaluating ( n = 5). No quantitative assessment measures of Formally appointed implementation leaders, External change agents, or Executing were identified. Internal consistency and norms were reported on most often, whereas no studies reported on discriminant validity or responsiveness. Not one measure in the sample reported all nine psychometric properties evaluated by the PAPERS. Scores in the identified sample of measures ranged from “-2” to “10” out of a total of “36.” Conclusions: Overall measures demonstrated minimal to adequate evidence and available psychometric information was limited. The majority were study specific, limiting their generalizability. Future work should focus on more rigorous measure development and testing of currently existing measures, while moving away from creating new, single use measures. Plain Language Summary: How we measure the processes and players involved for implementing evidence-based interventions is crucial to understanding what factors are helping or hurting the intervention’s use in practice and how to take the intervention to scale. Unfortunately, measures of these factors—stakeholders, their networks and communication, and their implementation activities—have received little attention. This study sought to identify and evaluate the quality of these types of measures. Our review focused on collecting measures used for identifying influential staff members, known as opinion leaders and champions, and investigating how they plan, execute, engage, and evaluate the hard work of implementation. Upon identifying these measures, we collected all published information about their uses to evaluate the quality of their evidence with respect to their ability to produce consistent results across items within each use (i.e., reliable) and if they assess what they are intending to measure (i.e., valid). Our searches located over 40 measures deployed in behavioral health settings for evaluation. We observed a dearth of evidence for reliability and validity and when evidence existed the quality was low. These findings tell us that more measurement work is needed to better understand how to optimize players and processes for the purposes of successful implementation.