Citations

AbstractThe current standard technique for cardiopulmonary resuscitation (CPR), initially described in the early 1960s, has quickly become the expected response for all persons found without a pulse or respiration. Despite the potentially lifesaving properties of external cardiac massage, the mainstay of resuscitation, it consists of repeated blunt force trauma to the chest, which can lead to extensive traumatic skeletal and nonskeletal injuries. Numerous autopsy‐based studies have documented the incidence and patterns of rib and sternal fractures associated with attempted CPR, but there is relatively little data on the incidence and severity of nonskeletal CPR‐related injuries. We reviewed reports from 1878 autopsies performed between September 2017 and December 2019 (inclusive), for documentation of CPR‐related injuries. Among these cases, there were 93 cases with resuscitation‐related nonskeletal injuries. The most common type of injury identified were visceral contusions, documented in 57.0% of cases. These contusions predominantly involved the heart, lungs, neck soft tissue, and surrounding structures. Resuscitation‐related lacerations were seen in 17.2% of the cases, most predominantly involving the pericardium, heart, and liver. Statistical analysis of the data demonstrated that lacerations were more likely to be seen in females and with associated sternal fractures. Additionally, hemothoraces were present in 34.4% of cases and hemopericardium was seen in 8.6% of cases. This study provides additional documentation of the range, severity, and incidence of various types of resuscitation‐related visceral injuries to better assist autopsy pathologists in distinguishing these injuries from other antecedent traumatic injuries.

Introduction: Phenome-wide association studies (PheWAS) using electronic medical record (EMR)-linked biobanks have been used not only to identify and replicate known associations of genetic variants with disease phenotypes but have also resulted in the discovery of potentially novel genotype-phenotype relationships. The natriuretic peptide (NP) system plays an important role in a broad range of disease processes including cardiovascular and inflammatory diseases. We hypothesized that performing a PheWAS using previously known functional genetic variants of the NP system may result in novel disease associations that could provide mechanistic insights in an unbiased manner. Methods: We scanned for associations between 9 single-nucleotide polymorphisms (SNPs) in the NP system and 27 EMR-derived chronic disease phenotypes in 3,025 individuals participating in a case-control study of peripheral arterial disease. The EMR phenotypes were identified using two or more ICD-9-CM diagnosis codes based on the AHRQ Clinical Classifications Software (CCS). The relationship of SNPs and phenotypes were modeled using logistic regression adjusting for gender. Results: We identified rs5065, a SNP located in the stop codon of exon 3 of the NPPA gene, to be the strongest associated SNP with rheumatoid arthritis (RA) (OR=0.78, p=0.0008, q-value=0.11). The SNP leads to the extension of atrial natriuretic peptide (ANP) by 2 additional arginines at the C terminus. Cardiovascular disease is known to be the leading cause of death in patients with RA and ANP plays an important immunomodulatory role by inhibiting inducible nitric oxide synthase, reducing TNF-α production and attenuating prostaglandin E2 production in macrophages. Circulating NPs have been used to screen for occult cardiac disease and are associated with mortality in RA. This study demonstrates for the first time the importance of the relationship between genetic variation in the NP system and RA. Conclusions: PheWAS was successfully used as a tool to identify a novel association of functional genetic variation in the NPPA gene with RA. The observation is hypothesis generating and further replication studies are required to determine the role of rs5065 in cardiovascular outcomes of RA.

Introduction: Compared to Whites, African-Americans (AAs) have 82% lower odds of meeting ideal levels for five or more cardiovascular (CV) health components that comprise the American Heart Association’s Life’s Simple 7, an evidenced-based metric of seven health promoting behaviors and biological factors that improve CV outcomes. Given expanding mobile technology use among AAs, mobile health (mHealth) interventions are promising avenues to promote CV health within this population. Hypothesis: An evidence-based, theory-informed, culturally relevant, community-based mHealth lifestyle intervention would improve CV health among AAs adults. Methods: Five predominately AA churches collaborated in a community-based participatory research approach to develop a 10-week CV health and wellness digital application-based program ( FAITH! App ). We enrolled AA adults [N=50, mean age 49.6 (SD 12.7), 70% women (35/50)] into a single group, 10-week intervention centered on the FAITH! App with adjunct in-person sessions. The FAITH! App included ten core video education modules from health professionals on CV health, interactive diet/physical activity self-monitoring and a sharing board. The primary outcome was change in individual CV health behaviors (body mass index, physical activity, diet, cigarette smoking) and biological factors (blood pressure (BP), total cholesterol, fasting glucose) from baseline to post-intervention at 28 weeks. Results: Participants were overall high CV risk at baseline (hypertensive [40% (20/50)] with poor/intermediate physical activity [79% (37/47)] and diet [72% (36/50)]). At 28 weeks, there were substantial improvements in CV health factors (systolic and diastolic BPs), CV health behaviors (diet, physical activity) and psychological/psychosocial variables to promote behavior change ( Table 1 ). Conclusions: This study supports the benefits of a culturally relevant, community-based mHealth lifestyle intervention to promote CV health among AAs with high cardiometabolic risk.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

The SB transposon system has been used as an insertional mutagen to study tumor development. This novel system involves the mobilization of a transposon (e.g. T2/onc) by a tranposase source (e.g. Rosa26‐SB11) in transgenic mice. We serially sectioned FFPE brains from 154 mice and identified 15 infiltrating gliomas that morphologically resembled small cell astrocytomas, as well as one PNET. The gliomas involved cerebral hemispheres (n=8) or posterior fossa (n=7). The tumors demonstrated remarkable infiltration of underlying brain parenchyma with secondary structuring (i.e. subpial, perivascular and perineuronal aggregation); round to oval cells with irregular nuclear contours, scant cell processes and variable mitotic activity (median 4/10 hpf, range 2–9); and pseudopalisading necrosis (n=5). Endothelial proliferation and calcification were absent. Immunohistochemical stains for GFAP and S100 strongly labeled reactive astrocytes, but minimal immunoreactivity was also seen in occasional small tumor cells. In 14 of 15 mice the genotype was T2/onc/SB11 positive; three mice were p19 Arf +/− , one mouse was p19 Arf −/− and one was Blm −/− . The PNET filling the third ventricle was identified in a control mouse homozygous mutant for p19 Arf , but transgenic only for the T2/Onc concatomer. This tumor, in contrast to the gliomas, demonstrated uniform synaptophysin staining and did not label with GFAP or S100.These results demonstrate that the SB transposon system is a valid model to study gliomagenesis in mice.

Thiopurine drugs such as 6‐mercaptopurine (6‐MP) and 6‐thioguanine (6‐TG) are effective immunosuppressants and antineoplastic agents. We used a genome‐wide approach to identify genes that might contribute to individual variation in thiopurine response. Basal gene expression profiles, genome‐wide SNP data, and 6‐MP and 6‐TG Cell growth inhibition (GI50) values were generated for 200 Coriell Institute “Human Variation Panel” lymphoblastoid cell lines. Gene expression and genome‐wide SNPs were correlated with GI50 values to identify candidate genes that might contribute to thiopurine response. We identified 104 expression probes and 161 SNPs, as well as 315 gene probes and 579 SNPs that correlated significantly with GI50 values for 6‐MP and 6‐TG, respectively (P<10 −5 and 10 −6 , respectively). Three genes, CD83 , TXNDC13 and SNAP23 , contained SNPs that contributed significantly to both 6‐MP and 6‐TG cytotoxicity and were also significantly associated with expression levels (P<10 −4 ), suggesting a “three‐way model” involving genotype, gene expression and cytotoxicity. GBP5 , a gene with an expression level that correlated negatively with 6‐MP and 6‐TG GI50 values, sensitized leukemia cells when overexpressed. Functional studies of the remainder of the candidate genes are being performed. These results may enhance our ability to predict thiopurine response phenotypes. NIH GM28157.

Objectives Betaine‐homocysteine methyltransferase (BHMT) catalyzes the remethylation of homocysteine. BHMT in the human liver is responsible for up to 25% of homocysteine metabolism. Knowledge of the relationship between genetic polymorphisms and BHMT phenotypes could enhance our understanding of the role of this reaction in drug metabolism. Methods Levels of BHMT enzyme activity and immunoreactive protein were measured in 268 human liver biopsies. Twelve tag BHMT SNPs from our own gene resequencing and HapMap data were used to genotype DNA from these samples. Genotype‐phenotype association analysis was then performed. BHMT enzyme activity averaged 0.077 ± 0.028 units/μg, with a 12 fold variation. Results BHMT protein levels averaged 6.9 ± 3.3 units/μg, with a 50‐fold variation. Three SNPs (rs41272270, rs16876512, and rs6875201), located 28kb upstream, in the 5′‐UTR and in intron 1 of BHMT , respectively, were significantly correlated with both phenotypes (p<10 −8 for enzyme activity and p<10 −5 for protein level). rs41272270 was associated with altered protein binding during electrophoresis mobility shift assay. Conclusions Three tag SNPs were significantly associated with human hepatic BHMT enzyme activity and immunoreactive protein. These observations may help us understand the regulation of BHMT in the human liver and its role in drug metabolism. Supported by NIH U01 GM61388, R01 GM28157, R01 CA132780.

Abstract Background Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. Methods A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study–specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. Results Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (Ptrend &lt; .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; Pdifference = 2.1 x 10-6). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (Pdifference &lt; .001). Conclusion Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.

AimsThe diagnosis of focal nodular hyperplasia (FNH) and the interpretation of glutamine synthetase (GS) staining can be challenging on biopsies. We aimed to evaluate the reproducibility of needle biopsy diagnosis of FNH, the effect of GS immunohistochemistry on FNH diagnosis, and which histological features are most useful for the diagnosis of FNH.Methods and resultsThe study included virtual needle biopsies generated from 75 resection specimens (30 FNHs, 15 hepatocellular adenomas, 15 hepatocellular carcinomas, and 15 non‐lesional liver specimens). Pathologists were reasonably accurate (83.1%) in the diagnosis of FNH with haematoxylin and eosin alone. Ductular reaction and nodularity had the highest sensitivity for a diagnosis of FNH (88.1% and 82.2%, respectively), whereas central scar was the most specific feature (90.6%). The presence of two or more of the classic histological features had 89.6% sensitivity and 86.2% specificity for a diagnosis of FNH. Diagnostic accuracy was significantly higher with the addition of a GS stain. A map‐like GS staining pattern was highly specific (99.3%) for FNH. However, GS staining was interpreted as non‐map‐like in 14.4% of reviews of true FNH cases, and overall interobserver agreement for interpretation of the GS staining pattern was only moderate (kappa = 0.42).ConclusionsPathologists are reasonably accurate in the diagnosis of FNH on virtual biopsies, and GS staining improves accuracy. However, a subset of FNH cases remain challenging. Steatosis and a pseudo‐map‐like GS staining pattern were associated with increased difficulty. Therefore, although a map‐like GS staining pattern is useful for confirmation of a diagnosis, the lack of a map‐like GS staining pattern on needle biopsy does not necessarily exclude a diagnosis of FNH.