Neuro R2 score: Predicting high-risk neurologic readmissions within 30 days.

OBJECTIVE: To evaluate clinical and demographic factors of patients with neurologic disorders to determine which patient characteristics are significant for predicting 30-day hospital readmissions to develop a readmission risk predictor specific to patients with neurologic disorders. METHODS: We performed a retrospective single-center chart review for all patients admitted to the Department of Neurology or neurologic intensive care unit from January 1, 2013, to December 31, 2017. Clinical and demographic factors were analyzed to determine the association with readmission. Multivariable logistic regression analysis was performed and validated to develop a simple tool (Neuro R2 score) for predicting patients with neurologic disorders at high risk for hospital readmission. RESULTS: After removal of planned readmissions and patients who died in the hospital, the records of 4,876 patients with 314 (6.4%) readmission events were analyzed. The strongest predictors for readmission were Charlson disease count (odds ratio [OR] 1.20, 95% confidence interval [CI] 1.06-1.35, p = 0.005), urgent or emergent admission (OR 1.50, 95% CI 1.04-2.17, p = 0.031), discharge to rehabilitation (OR 1.66, 95% CI 1.16-2.35, p = 0.005), cancer (OR 1.70, 95% CI 1.15-2.50, p = 0.007), brain tumor (OR 1.82, 95% CI 1.08-3.09, p < 0.03), cerebrovascular disease (OR 2.18, 95% CI 1.53-3.11, p < 0.001), and discharge to skilled nursing facility (OR 2.43, 95% CI 1.65-3.57, p < 0.001). CONCLUSIONS: The Neuro R2 score was developed to predict readmission risk, specifically in patients with neurologic disorders. Future research could include further validation of this readmission risk tool and strategies to reduce readmission in patients with the highest risk.

Community-based prehabilitation before elective major surgery: the PREP-WELL quality improvement project.

Optimising health and well-being before elective major surgery via prehabilitation initiatives is important for good postoperative outcomes. In a busy tertiary centre in North East England, the lack of a formal prehabilitation service meant that opportunities were being missed to optimise patients for surgery. This quality improvement project aimed to implement and evaluate a community-based prehabilitation service for people awaiting elective major surgery: PREP-WELL. A multidisciplinary, cross-sector team introduced PREP-WELL in January 2018. PREP-WELL provided comprehensive assessment and management of perioperative risk factors in the weeks before surgery. During a 12-month pilot, patients were referred from five surgical specialties at James Cook University Hospital. Data were collected on participant characteristics, behavioural and health outcomes, intervention acceptability and costs, and process-related factors. By December 2018, 159 referrals had been received, with 75 patients (47%) agreeing to participate. Most participants opted for a supervised programme (72%) and were awaiting vascular (43%) or orthopaedic (35%) surgery. Median programme duration was 8 weeks. The service was delivered as intended with participants providing positive feedback. Health-related quality of life (HRQoL; EuroQol 5D (EQ-5D) utility) and functional capacity (6 min walk distance) increased on average from service entry to exit, with mean (95% CI) changes of 0.108 (-0.023 to 0.240) and 35 m (-5 to 76 m), respectively. Further increases in EQ5D utility were observed at 3 months post surgery. Substantially more participants were achieving recommended physical activity levels at exit and 3 months post surgery compared with at entry. The mean cost of the intervention was £405 per patient; £52 per week. The service was successfully implemented within existing preoperative pathways. Most participants were very satisfied and improved their risk profile preoperatively. Funding has been obtained to support service development and expansion for at least 2 more years. During this period, alternative pathways will be developed to facilitate wider access and greater uptake.

Distinct Polymorphisms in HLA Class I Molecules Govern Their Susceptibility to Peptide Editing by TAPBPR.

Understanding how peptide selection is controlled on different major histocompatibility complex class I (MHC I) molecules is pivotal for determining how variations in these proteins influence our predisposition to infectious diseases, cancer, and autoinflammatory conditions. Although the intracellular chaperone TAPBPR edits MHC I peptides, it is unclear which allotypes are subjected to TAPBPR-mediated peptide editing. Here, we examine the ability of 97 different human leukocyte antigen (HLA) class I allotypes to interact with TAPBPR. We reveal a striking preference of TAPBPR for HLA-A, particularly for supertypes A2 and A24, over HLA-B and -C molecules. We demonstrate that the increased propensity of these HLA-A molecules to undergo TAPBPR-mediated peptide editing is determined by molecular features of the HLA-A F pocket, specifically residues H114 and Y116. This work reveals that specific polymorphisms in MHC I strongly influence their susceptibility to chaperone-mediated peptide editing, which may play a significant role in disease predisposition.

Evaluation of Hospital-wide Readmission Risk Calculator to Predict 30-Day Readmission in Neurocritical Care Patients.

BACKGROUND AND PURPOSE: Thirty-day hospital readmissions have been shown to be a measure of quality and result in higher mortality and increased costs. Readmissions are a target for hospitals and payers; thus, several centers have developed predictive readmission scores to identify high-risk patients. The purpose of this study was to evaluate the current hospital-wide readmission risk calculator and the ability of this tool to predict 30-day readmissions in the neurocritical care population. METHODS: A retrospective chart review was performed that included 340 consecutive patients admitted to our neuroscience critical care unit. Data including readmission scores, reason for admission, length of stay, and whether they were readmitted were recorded. RESULTS: After removing patients without readmission scores or who died at the end of the original admission, the records of N = 279 patients were analyzed. Patients were more likely to be readmitted if they were initially emergently hospitalized or if there was a history of malignancy. Readmitted patients had a longer original hospital length of stay. Furthermore, 65.8% of the patients who were given a "low risk" for readmission were readmitted within 30 days. CONCLUSIONS: This small set of data in a specific patient population found that the current risk prediction score was inaccurate in predicting readmission in the neuroscience intensive care unit population. Further evaluation is needed of a larger patient population to generalize these results for all neuroscience intensive care unit patients. To design an accurate readmission risk tool, centers should create unique readmission scores based on less heterogeneous patient populations.

Telomere length in the colon is related to colorectal adenoma prevalence.

Telomere length has been associated with risk of several cancers. However, studies of the relationship between telomere length and colorectal cancer risk have been inconsistent. This study examined the relationship between telomere length in normal colon tissue and the prevalence of colorectal adenoma, a precursor to colorectal cancer. This nested case-control study consisted of 85 patients aged 40 to 65 undergoing a screening colonoscopy: 40 cases with adenoma(s) detected at colonoscopy and 45 controls with normal colonoscopy. During the colonoscopy, two pinch biopsies of healthy, normal appearing mucosa were obtained from the descending colon. Relative telomere length (rTL) was quantified in DNA extracted from colon mucosa using quantitative real-time PCR. Logistic regression was used to assess the relationship between telomere length and adenoma prevalence and estimate odds ratios and 95% confidence intervals. rTL was significantly longer in colon tissue of individuals with adenomas compared to healthy individuals (p = 0.008). When rTL was categorized into quartiles according to the distribution of rTL among controls, individuals with the longest telomeres had increased odds of adenoma when compared to individuals with shortest telomeres (OR = 4.58, 95% CI: 1.19, 17.7). This study suggests that long telomeres in normal colon tissue are associated with increased colorectal cancer risk.

Bulky DNA adduct levels in normal-appearing colon mucosa, and the prevalence of colorectal adenomas.

PURPOSE: Examine the association between bulky DNA adduct levels in colon mucosa and colorectal adenoma prevalence, and explore the correlation between adduct levels in leukocytes and colon tissue. METHODS: Bulky DNA adduct levels were measured using 32P-postlabelling in biopsies of normal-appearing colon tissue and blood donated by 202 patients. Multivariable logistic regression was used to examine associations between DNA adducts, and interactions of DNA adduct-DNA repair polymorphisms, with the prevalence of colorectal adenomas. Correlation between blood and tissue levels of DNA adducts was evaluated using Spearman's correlation coefficient. RESULTS: An interaction between bulky DNA adduct levels and XPA rs1800975 on prevalence of colorectal adenoma was observed. Among individuals with lower DNA repair activity, increased DNA adduct levels were associated with increased colorectal adenoma prevalence (OR = 1.41 per SD increase, 95%CI: 0.92-2.18). Conversely, among individuals with normal DNA activity, an inverse association was observed (OR = 0.60 per SD increase, 95%CI: 0.34-1.07). Blood and colon DNA adduct levels were inversely correlated (ρ = -0.20). CONCLUSIONS: Among genetically susceptible individuals, higher bulky DNA adducts in the colon was associated with the prevalence of colorectal adenomas. The inverse correlation between blood and colon tissue measures demonstrates the importance of quantifying biomarkers in target tissues.

Exposure to meat-derived carcinogens and bulky DNA adduct levels in normal-appearing colon mucosa.

INTRODUCTION: Meat consumption is a risk factor for colorectal cancer. This research investigated the relationship between meat-derived carcinogen exposure and bulky DNA adduct levels, a biomarker of DNA damage, in colon mucosa. METHODS: Least squares regression was used to examine the relationship between meat-derived carcinogen exposure (PhIP and meat mutagenicity) and bulky DNA adduct levels in normal-appearing colon tissue measured using 32P-postlabelling among 202 patients undergoing a screening colonoscopy. Gene-diet interactions between carcinogen exposure and genetic factors relevant to biotransformation and DNA repair were also examined. Genotyping was conducting using the MassARRAY® iPLEX® Gold SNP Genotyping assay. RESULTS: PhIP and higher meat mutagenicity exposures were not associated with levels of bulky DNA adducts in colon mucosa. The XPC polymorphism (rs2228001) was found to associate with bulky DNA adduct levels, whereby genotypes conferring lower DNA repair activity were associated with higher DNA adduct levels than the normal activity genotype. Among individuals with genotypes associated with lower DNA repair (XPD, rs13181 and rs1799179) or detoxification activity (GSTP1, rs1695), higher PhIP or meat mutagenicity exposures were associated with higher DNA adduct levels. Significant interactions between the XPC polymorphism (rs2228000) and both dietary PhIP and meat mutagenicity on DNA adduct levels was observed, but associations were inconsistent with the a priori hypothesized direction of effect. CONCLUSION: Exposure to meat-derived carcinogens may be associated with increased DNA damage occurring directly in the colon among genetically susceptible individuals.

The Influence of Alcohol Consumption, Cigarette Smoking, and Physical Activity on Leukocyte Telomere Length.

BACKGROUND: Telomeres protect from DNA degradation and maintain chromosomal stability. Short telomeres have been associated with an increased risk of cancer at several sites. However, there is limited knowledge about the lifestyle determinants of telomere length. We aimed to determine the effect of three factors, known to be important in cancer etiology, on relative leukocyte telomere length (rLTL): alcohol consumption, smoking, and physical activity. METHODS: This cross-sectional study included 477 healthy volunteers ages 20 to 50 years who completed a questionnaire and provided a fasting blood sample. Multiplex quantitative real-time PCR (qPCR) was used to measure rLTL. Regression coefficients were calculated using multiple linear regression while controlling for important covariates. RESULTS: There was no association between alcohol consumption and rLTL. Daily smokers and those in the middle and lower tertile of pack-years smoking had shorter rLTL than never daily smokers (P = 0.02). Data were suggestive of a linear trend with total physical activity (P = 0.06). Compared with the lowest quartile, the highest quartile of vigorous physical activity was associated with longer rLTL. A significant linear trend of increasing rLTL with increasing vigorous physical activity was observed (P = 0.02). CONCLUSIONS: Cigarette smoking and vigorous physical activity have an impact on telomere length. Smoking was related to shorter telomere length while vigorous physical activity was related to longer telomeres. IMPACT: The findings from this study suggest that lifestyle may play an important role in telomere dynamics and also suggest that engaging in healthy behaviors may mitigate the effect of harmful behaviors on telomere length.

Gene-diet interactions in exposure to heterocyclic aromatic amines and bulky DNA adduct levels in blood leukocytes.

Heterocyclic aromatic amines (HAAs), carcinogens produced in meat when cooked at high temperatures, are an emerging biologic explanation for the meat-colorectal cancer relationship. HAAs form DNA adducts; left unrepaired, adducts can induce mutations, which may initiate/promote carcinogenesis. The purpose of this research was to investigate the relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct levels. Least squares regression was used to examine the relationship between dietary HAA exposure and bulky DNA adduct levels in blood measured using (32)P-postlabeling among 99 healthy volunteers. Gene-diet interactions between dietary HAAs and genetic factors relevant to the biotransformation of HAAs and DNA repair were also examined. No main effects of dietary HAAs on bulky DNA adduct levels was found. However, those with the putative NAT1 rapid acetylator phenotype had lower adduct levels than those with the slow acetylator phenotype (P = 0.02). Furthermore, having five or more 'at-risk' genotypes was associated with higher bulky DNA adduct levels (P = 0.03). Gene-diet interactions were observed between NAT1 polymorphisms and dietary HAAs (P < 0.05); among the slow acetylator phenotype, higher intakes of HAAs were associated with an increase in DNA adduct levels compared to lower intakes. This study provides evidence of a biologic relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct formation. However, the lack of a strong main effect of HAAs suggests that dietary HAAs are not a large contributor to bulky DNA adducts in this population; future studies should consider relevant gene-diet interactions to clarify the role of HAAs in carcinogenesis.

Meat-derived carcinogens, genetic susceptibility and colorectal adenoma risk.

Exposure to heterocyclic aromatic amines (HAAs), carcinogens produced when meat is cooked at high temperatures, is an emerging risk factor for colorectal cancer (CRC). In a cross-sectional study of 342 patients undergoing a screening colonoscopy, the role of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), the three most abundant HAAs found in cooked meats, and total mutagenic activity in cooked meats were examined in relation to colorectal adenoma risk. Given that genetic differences in the ability to biotransform HAAs and repair DNA are postulated to modify the HAA-CRC relationship, gene-diet interactions were also examined. Among the total study population, no relationships were observed between dietary HAAs or meat mutagenicity, and colorectal adenoma risk; however, in males, positive associations between dietary HAAs/meat mutagenicity exposures and adenoma risk were suggestive of a relationship. In a separate analysis, polymorphisms in CYP1B1 were found to be associated with colorectal adenoma risk. Additionally, gene-diet interactions were observed for dietary PhIP and polymorphisms in CYP1B1 and XPD, dietary DiMeIQx and XPD polymorphisms, and meat mutagenicity exposure and CYP1B1 polymorphisms. Overall, increased colorectal adenoma risk was observed with higher HAA/meat mutagenicity exposures among those with polymorphisms which confer greater activity to biotransform HAAs and/or lower ability to repair DNA. This research supports the link between dietary HAAs and genetic susceptibility in colorectal adenoma etiology. The vast majority of CRCs arise from colorectal adenomas; thus, the results of this study suggest that changes in meat preparation practices limiting the production of HAAs may be beneficial for CRC prevention.

Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types.

The likelihood for immunological rejection of Human Leukocyte Antigens (HLA)-mismatched induced pluripotent stem cells (iPSCs) limits their therapeutic potential. Here we show how a tissue bank from 150 selected homozygous HLA-typed volunteers could match 93% of the UK population with a minimal requirement for immunosuppression. Our model provides a practical approach for using existing HLA-typed samples to generate an iPSC stem cell bank that circumvents prospective typing of a large number of individuals.