Legal epidemiology of paediatric dog bite injuries.

BACKGROUND: Dog bite injuries cause over 100 000 paediatric emergency department visits annually. Our objective was to analyse associations between regional dog ownership laws and incidence of paediatric dog bites. METHODS: This observational study used an online search to locate local dog-related policies within Ohio cities. Data collected by Ohio Partners For Kids from 2011 through 2020 regarding claims for paediatric dog bite injuries were used to compare areas with and without located policies and the incidence of injury. RESULTS: Our cohort consisted of 6175 paediatric patients with dog bite injury encounters. A majority were white (79.1%), male (55.0%), 0-5 years old (39.2%) and did not require hospital admission (98.1%). Seventy-nine of 303 cities (26.1%) had city-specific policies related to dogs. Overall, the presence of dog-related policies was associated with lower incidence of dog bite injury claims (p=0.01). Specifically, metropolitan areas and the Central Ohio region had a significantly lower incidence when dog-related policies were present (324.85 per 100 000 children per year when present vs 398.56 when absent; p<0.05; 304.87 per 100 000 children per year when present vs 411.43 when absent; p<0.05). CONCLUSIONS: The presence of city-specific dog-related policies is associated with lower incidence of paediatric dog bite injury claims, suggesting that local policy impacts this important public health issue. There are limited dog-related policies addressing dog bite prevention, with inconsistencies in breadth and depth. Creating consistent, practical requirements among policies with vigorous enforcement could ameliorate public health concerns from paediatric dog bite injuries.

Pediatric dog bite injuries in the USA: a systematic review.

Introduction: Dog bites are one of the leading causes of non-fatal emergency room visits in children. These injuries not only cause physical harm but can lead to long-term psychological stress. This study evaluated the current literature related to pediatric dog bite injuries to identify research gaps which should be prioritized to improve a major public health concern. Methods: We performed a keyword search of PubMed, Scopus, and OVID Medline databases (January 1980- March 2020) for all published studies focused on dog bite injuries in the pediatric population (≤18 years of age) using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Results: Out of 1859 abstracts screened, 43 studies involving 86 880 patients were included. Twenty-nine studies were retrospective chart reviews characterizing the epidemiology of dog bites and their associated treatment outcomes; six were prospective cohort studies; two were cross-sectional studies; and six were experimental studies. Synthesized results demonstrate that children <9 years of age suffer the greatest burden of injuries, with children <6 years of age at higher risk of more severe injuries involving the head, neck, and face. Conclusion: Studies analyzing the prevention or psychosocial consequences of dog bites injuries are needed.

Implementation of a Level 1 Neuro Trauma Activation at a Tertiary Pediatric Trauma Center.

INTRODUCTION: Timely management improves outcomes in patients with traumatic brain injury (TBI), especially those requiring operative intervention. We implemented a "Level 1 Neuro" (L1N) trauma activation for severe TBI, aiming to decrease times to intervention. METHODS: We evaluated whether an L1N activation was associated with shorter times to operating room (OR) incision and pediatric intensive care unit (PICU) admission using multivariable regression models. Trauma patients with severe TBI undergoing operative intervention or PICU admission from January 2008-October 2020 met inclusion. The L1N cohort included patients meeting our institution's L1N criteria. The L1 and L2 cohorts included head injury patients with hAIS ≥3 and an L1 or L2 activation, respectively. RESULTS: Median hAIS, GCS, Rotterdam CT score, and ISS were 4.5 (4-5), 8 (3-15), 2 (1-3), and 17 (11-26), respectively. We demonstrate clinically shorter times to OR incision among L1N traumas (93.3 min) compared to L1 (106.7 min; P = 0.73) and L2 cohorts (133.5 min; P = 0.03). We also demonstrate clinically shorter times to anesthesia among L1N traumas (51.9 min) compared to L1 (70.1 min; P = 0.13) and L2 cohorts (101.3 min; P < 0.01). Median GCS, ISS and hAIS in the PICU patients were 10 (IQR:3-15), 17 (11-26), and 4 (3-4), respectively. We demonstrate clinically shorter times to PICU among L1N traumas (82.1 min) and the L2 cohort (154.7 min; P < 0.01). CONCLUSIONS: An L1N activation is associated with shorter times to anesthesia and OR management. Enhancing communication with standardized neurotrauma activation has the potential to improve timeliness of care in severe pediatric TBI.

Length of Stay per Total Body Surface Area Burn Relative to Mechanism: A Pediatric Injury Quality Improvement Collaborative Study.

Studies on length of stay (LOS) per total body surface area (TBSA) burn in pediatric patients are often limited to single institutions and are grouped in ranges of TBSA burn which lacks specific detail to counsel patients and families. A LOS to TBSA burn ratio of 1 has been widely accepted but not validated with multi-institution data. The objective of this study is to describe the current relationship of LOS per TBSA burn and LOS per TBSA burn relative to burn mechanism with the use of multi-institutional data. Data from the Pediatric Injury Quality Improvement Collaborative (PIQIC) were obtained for patients across five pediatric burn centers from July 2018 to September 2020. LOS per TBSA burn ratios were calculated. Descriptive statistics and generalized linear regression which modeled characteristics associated with LOS per TBSA ratio are described. Among the 1267 pediatric burn patients, the most common mechanism was scald (64%), followed by contact (17%) and flame (13%). The average LOS/TBSA burn ratio across all cases was 1.2 (SD = 2.1). In adjusted models, scald burns and chemical burns had similar LOS/TBSA burn ratios of 0.8 and 0.9, respectively, whereas all other burns had a significantly higher LOS/TBSA burn ratio (p<0.0001). LOS/TBSA burn ratios were similar across races, although Hispanics had a slightly higher ratio at 1.4 days. These data establish a multi-institution LOS per TBSA ratio across PIQIC centers and demonstrate a significant variation in the LOS per TBSA burn relative to the burn mechanism sustained.

Evaluating the analytical validity of circulating tumor DNA sequencing assays for precision oncology.

Circulating tumor DNA (ctDNA) sequencing is being rapidly adopted in precision oncology, but the accuracy, sensitivity and reproducibility of ctDNA assays is poorly understood. Here we report the findings of a multi-site, cross-platform evaluation of the analytical performance of five industry-leading ctDNA assays. We evaluated each stage of the ctDNA sequencing workflow with simulations, synthetic DNA spike-in experiments and proficiency testing on standardized, cell-line-derived reference samples. Above 0.5% variant allele frequency, ctDNA mutations were detected with high sensitivity, precision and reproducibility by all five assays, whereas, below this limit, detection became unreliable and varied widely between assays, especially when input material was limited. Missed mutations (false negatives) were more common than erroneous candidates (false positives), indicating that the reliable sampling of rare ctDNA fragments is the key challenge for ctDNA assays. This comprehensive evaluation of the analytical performance of ctDNA assays serves to inform best practice guidelines and provides a resource for precision oncology.

Fun ride or risky transport: Golf cart-related injuries treated in U.S. emergency departments from 2007 through 2017.

INTRODUCTION: Golf cart-related injuries constitute a substantial source of morbidity, most notably in pediatric populations. Despite the high rate of injuries, there have been no meaningful changes in golf cart design or legislation to reduce the overall burden of these injuries. This study sought to characterize the epidemiology of golf cart-related injuries treated in United States hospital emergency departments. METHOD: A retrospective analysis was conducted by using data from the National Electronic Injury Surveillance System for patients of all ages who were treated in emergency departments (EDs) (2007-2017) for a golf cart-related injury. RESULTS: From 2007 through 2017, an estimated 156,040 (95% CI = 102,402-209,679) patients were treated in U.S. EDs for golf cart-related injuries. The average rate of traumatic brain injuries (TBIs) in children (1.62 per 100,000 children) was more than three times that of TBIs in adults (0.52 per 100,000 adults; rate ratio = 2.38; 95% CI = 2.36-2.41) and nearly twice that of TBIs in seniors (1.11 per 100,000 seniors; rate ratio = 1.21; 95% CI = 1.19-1.22). The rate of injuries in seniors increased significantly by 67.6% from 4.81 per 100,000 seniors in 2007 to 8.06 per 100,000 seniors in 2017 (slope = 0.096; p = 0.041). CONCLUSIONS: Golf cart use remains an important source of injury for people of all ages, especially in children. As use continues to increase, it is unlikely that golf cart-related injuries will decrease without substantial changes to product design, regulation, and/or legislation. Practical Applications: Use of golf carts pose a considerable risk of injury and morbidity; safety recommendations should be followed.

Analytical performance evaluation of a commercial next generation sequencing liquid biopsy platform using plasma ctDNA, reference standards, and synthetic serial dilution samples derived from normal plasma.

BACKGROUND: Circulating tumor (ct) DNA assays performed in clinical laboratories provide tumor biomarker testing support for biopharmaceutical clinical trials. Yet it is neither practical nor economically feasible for many of these clinical laboratories to internally develop their own liquid biopsy assay. Commercially available ctDNA kits are a potential solution for laboratories seeking to incorporate liquid biopsy into their test menus. However, the scarcity of characterized patient samples and cost of purchasing validation reference standards creates a barrier to entry. In the current study, we evaluated the analytical performance of the AVENIO ctDNA liquid biopsy platform (Roche Sequencing Solutions) for use in our clinical laboratory. METHOD: Intra-laboratory performance evaluation of AVENIO ctDNA Targeted, Expanded, and Surveillance kits (Research Use Only) was performed according to College of American Pathologists (CAP) guidelines for the validation of targeted next generation sequencing assays using purchased reference standards, de-identified human plasma cell-free (cf) DNA samples, and contrived samples derived from commercially purchased normal and cancer human plasma. All samples were sequenced at read depths relevant to clinical settings using the NextSeq High Output kit (Illumina). RESULTS: At the clinically relevant read depth, Avenio ctDNA kits demonstrated 100% sensitivity in detecting single nucleotide variants (SNVs) at ≥0.5% allele frequency (AF) and 50% sensitivity in detecting SNVs at 0.1% AF using 20-40 ng sample input amount. The assay integrated seamlessly into our laboratory's NGS workflow with input DNA mass, target allele frequency (TAF), multiplexing, and number of reads optimized to support a high-throughput assay appropriate for biopharmaceutical trials. CONCLUSIONS: Our study demonstrates that AVENIO ctDNA liquid biopsy platform provides a viable alternative for efficient incorporation of liquid biopsy assays into the clinical laboratory for detecting somatic alterations as low as 0.5%. Accurate detection of variants lower than 0.5% could potentially be achieved by deeper sequencing when clinically indicated and economically feasible.

Inhibition of Pro-inflammatory and Anti-apoptotic Biomarkers during Experimental Oral Cancer Chemoprevention by Dietary Black Raspberries.

Oral cancer continues to be a significant public health problem worldwide. Recently conducted clinical trials demonstrate the ability of black raspberries (BRBs) to modulate biomarkers of molecular efficacy that supports a chemopreventive strategy against oral cancer. However, it is essential that a preclinical animal model of black raspberry (BRB) chemoprevention which recapitulates human oral carcinogenesis be developed, so that we can validate biomarkers and evaluate potential mechanisms of action. We therefore established the ability of BRBs to inhibit oral lesion formation in a carcinogen-induced rat oral cancer model and examined potential mechanisms. F344 rats were administered 4-nitroquinoline 1-oxide (4NQO) (20 µg/ml) in drinking water for 14 weeks followed by regular drinking water for 6 weeks. At week 14, rats were fed a diet containing either 5 or 10% BRB, or 0.4% ellagic acid (EA), a BRB phytochemical. Dietary administration of 5 and 10% BRB reduced oral lesion incidence and multiplicity by 39.3 and 28.6%, respectively. Histopathological analyses demonstrate the ability of BRBs and, to a lesser extent EA, to inhibit the progression of oral cancer. Oral lesion inhibition by BRBs was associated with a reduction in the mRNA expression of pro-inflammatory biomarkers Cxcl1, Mif, and Nfe2l2 as well as the anti-apoptotic and cell cycle associated markers Birc5, Aurka, Ccna1, and Ccna2. Cellular proliferation (Ki-67 staining) in tongue lesions was inhibited by BRBs and EA. Our study demonstrates that, in the rat 4NQO oral cancer model, dietary administration of BRBs inhibits oral carcinogenesis via inhibition of pro-inflammatory and anti-apoptotic pathways.

Interdomain Communication of the Chd1 Chromatin Remodeler across the DNA Gyres of the Nucleosome.

Chromatin remodelers use a helicase-like ATPase motor to reposition and reorganize nucleosomes along genomic DNA. Yet, how the ATPase motor communicates with other remodeler domains in the context of the nucleosome has so far been elusive. Here, we report for the Chd1 remodeler a unique organization of domains on the nucleosome that reveals direct domain-domain communication. Site-specific cross-linking shows that the chromodomains and ATPase motor bind to adjacent SHL1 and SHL2 sites, respectively, on nucleosomal DNA and pack against the DNA-binding domain on DNA exiting the nucleosome. This domain arrangement spans the two DNA gyres of the nucleosome and bridges both ends of a wrapped, ∼90-bp nucleosomal loop of DNA, suggesting a means for nucleosome assembly. This architecture illustrates how Chd1 senses DNA outside the nucleosome core and provides a basis for nucleosome spacing and directional sliding away from transcription factor barriers.

The Chd1 chromatin remodeler can sense both entry and exit sides of the nucleosome.

Chromatin remodelers are essential for establishing and maintaining the placement of nucleosomes along genomic DNA. Yet how chromatin remodelers recognize and respond to distinct chromatin environments surrounding nucleosomes is poorly understood. Here, we use Lac repressor as a tool to probe how a DNA-bound factor influences action of the Chd1 remodeler. We show that Chd1 preferentially shifts nucleosomes away from Lac repressor, demonstrating that a DNA-bound factor defines a barrier for nucleosome positioning. Rather than an absolute block in sliding, the barrier effect was achieved by altered rates of nucleosome sliding that biased redistribution of nucleosomes away from the bound Lac repressor site. Remarkably, in addition to slower sliding toward the LacO site, the presence of Lac repressor also stimulated sliding in the opposite direction. These experiments therefore demonstrate that Chd1 responds to the presence of a bound protein on both entry and exit sides of the nucleosome. This sensitivity to both sides of the nucleosome allows for a faster and sharper response than would be possible by responding to only the entry side, and we speculate that dual entry/exit sensitivity is also important for regularly spaced nucleosome arrays generated by Chd1 and the related ISWI remodelers.