Publications by authors named "Mark Jenkins"

475 Publications

Metagenomic Analysis of 16S Amplicons Corroborates Counts on Select Agar and PCR Analyses of Bacteria in Broiler Farm Litter.

Avian Dis 2021 Dec;65(4):554-558

Animal Biosciences and Biotechnology Laboratory, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD 20705.

The purpose of this study was twofold-first, to determine whether analysis of bacterial 16S ribosomal RNA (rRNA) in poultry litter corroborated standard counts and PCR assay, and second, to find whether a correlation between 16S rRNA analysis and or toxin PCR intensity with chick mortality existed. At three time points of growout (0, 2, and 4 wk) litter samples were collected from 23 broiler houses representing eight farms during a coccidiosis vaccine control program. DNA extracted from these samples was used for microbiota determination by sequencing the hypervariable V3-V4 region of bacterial 16s rRNA. Obtained sequences were analyzed by QIIME 2 and the Greengenes database for taxonomic composition and relative abundance of in the litter bacterial population. counts on select agar and semiquantitative PCR for were compared with 16S analysis for equivalence testing. Relative abundance of estimated by 16S analysis and semiquantitative PCR for and toxin DNA were analyzed by Pearson linear correlation and statistical equivalence analyses with cumulative chick mortality at 4 and 9 wk growout. When data from all time points were combined, abundance estimates by 16S were statistically equivalent (α = 0.10) to both PCR and counts. Yet, no correlations were observed between any estimate of abundance and cumulative percent chick mortality at 4 or 9 wk growout. However, correlation analyses revealed a significant linear relationship between signal at 0 wk ( = 0.55) and 4 wk ( = 0.46) and cumulative mortality at 9 wk growout ( < 0.05). Similarly, abundance of at 0 and 2 wk showed a linear relationship with cumulative percent mortality at both 4 and 9 wk growout (0.44 ≤ ≤ 0.54, < 0.05). No correlations were observed between any other genera or species determined by 16S and cumulative percent chick mortality.
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http://dx.doi.org/10.1637/aviandiseases-D-21-00054DOI Listing
December 2021

The safety and efficacy of using moxibustion and or acupuncture for cancer-related insomnia: a systematic review and meta-analysis of randomised controlled trials.

Palliat Care Soc Pract 2022 10;16:26323524211070569. Epub 2022 Jan 10.

Discipline of Nursing, Murdoch University, Perth, WA, Australia.

Introduction: This study aimed to synthesise the best available evidence on the safety and efficacy of using moxibustion and/or acupuncture to manage cancer-related insomnia (CRI).

Methods: The PRISMA framework guided the review. Nine databases were searched from its inception to July 2020, published in English or Chinese. Randomised clinical trials (RCTs) of moxibustion and or acupuncture for the treatment of CRI were selected for inclusion. Methodological quality was assessed using the method suggested by the Cochrane collaboration. The Cochrane Review Manager was used to conduct a meta-analysis.

Results: Fourteen RCTs met the eligibility criteria. Twelve RCTs used the Pittsburgh Sleep Quality Index (PSQI) score as continuous data and a meta-analysis showed positive effects of moxibustion and or acupuncture ( = 997, mean difference (MD) = -1.84, 95% confidence interval (CI) = -2.75 to -0.94,  < 0.01). Five RCTs using continuous data and a meta-analysis in these studies also showed significant difference between two groups ( = 358, risk ratio (RR) = 0.45, 95% CI = 0.26-0.80,  = 39%).

Conclusion: The meta-analyses demonstrated that moxibustion and or acupuncture showed a positive effect in managing CRI. Such modalities could be considered an add-on option in the current CRI management regimen.
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http://dx.doi.org/10.1177/26323524211070569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755931PMC
January 2022

Risk Stratification for Early-Onset Colorectal Cancer Using a Combination of Genetic and Environmental Risk Scores: An International Multi-Center Study.

J Natl Cancer Inst 2022 Jan 13. Epub 2022 Jan 13.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.

Background: Incidence of colorectal cancer (CRC) among individuals aged less than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS), of 141 variants.

Methods: Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3,486 cases and 3,890 controls aged less than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve.

Results: Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per standard deviation of ERS = 1.14, 95% confidence interval [CI] = 1.08, 1.20; odds ratio per standard deviation of PRS = 1.59, 95% CI = 1.51, 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615, 0.647). Based on absolute risks, we can expect 26 excess cases per 10,000 men and 21 per 10,000 women, among those scoring at the 90th percentile for both risk scores.

Conclusions: Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.
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http://dx.doi.org/10.1093/jnci/djac003DOI Listing
January 2022

The SMARTscreen Trial: a randomised controlled trial investigating the efficacy of a GP-endorsed narrative SMS to increase participation in the Australian National Bowel Cancer Screening Program.

Trials 2022 Jan 12;23(1):31. Epub 2022 Jan 12.

Centre for Cancer Research, University of Melbourne, Melbourne, Australia.

Background: Increasing participation in the Australian National Bowel Cancer Screening Program (NBCSP) is the most efficient and cost-effective way of reducing mortality associated with colorectal cancer by detecting and treating early-stage disease. Currently, only 44% of Australians aged 50-74 years complete the NBCSP. This efficacy trial aims to test whether this SMS intervention is an effective method for increasing participation in the NBCSP. Furthermore, a process evaluation will explore the barriers and facilitators to sending the SMS from general practice.

Methods: We will recruit 20 general practices in the western region of Victoria, Australia to participate in a cluster randomised controlled trial. General practices will be randomly allocated with a 1:1 ratio to either a control or intervention group. Established general practice software will be used to identify patients aged 50 to 60 years old who are due to receive a NBCSP kit in the next month. The SMS intervention includes GP endorsement and links to narrative messages about the benefits of and instructions on how to complete the NBCSP kit. It will be sent from intervention general practices to eligible patients prior to receiving the NBCSP kit. We require 1400 eligible patients to provide 80% power with a two-sided 5% significance level to detect a 10% increase in CRC screening participation in the intervention group compared to the control group. Our primary outcome is the difference in the proportion of eligible patients who completed a faecal occult blood test (FOBT) between the intervention and control group for up to 12 months after the SMS was sent, as recorded in their electronic medical record (EMR). A process evaluation using interview data collected from general practice staff (GP, practice managers, nurses) and patients will explore the feasibility and acceptability of sending and receiving a SMS to prompt completing a NBCSP kit.

Discussion: This efficacy trial will provide initial trial evidence of the utility of an SMS narrative intervention to increase participation in the NBCSP. The results will inform decisions about the need for and design of a larger, multi-state trial of this SMS intervention to determine its cost-effectiveness and future implementation.

Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12620001020976 . Registered on 17 October 2020.
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http://dx.doi.org/10.1186/s13063-021-05877-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8753594PMC
January 2022

Genome-wide association study identifies tumor anatomical site-specific risk variants for colorectal cancer survival.

Sci Rep 2022 Jan 7;12(1):127. Epub 2022 Jan 7.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30-1.69, p = 8.47 × 10) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65-2.77, p = 9.19 × 10 and rs144717887, HR = 2.01, 95% CI 1.57-2.58, p = 3.14 × 10), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings.
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http://dx.doi.org/10.1038/s41598-021-03945-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741984PMC
January 2022

Genetic variants associated with circulating C-reactive protein levels and colorectal cancer survival: Sex-specific and lifestyle factors specific associations.

Int J Cancer 2021 Dec 9. Epub 2021 Dec 9.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Elevated blood levels of C-reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC-specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI-EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC-specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow-up, 3547 (64.8%) were due to CRC. No variants were associated with CRC-specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC-specific mortality (corrected P  = .0004); women had higher CRC-specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04-1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82-0.94). There was no evidence of interactions between CRP-associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP-associated variant in relation to CRC-specific mortality. Future replication of this association and functional annotation of the variant are needed.
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http://dx.doi.org/10.1002/ijc.33897DOI Listing
December 2021

Primary care placements in the post-COVID era: A qualitative evaluation of a final year undergraduate clerkship.

Med Teach 2021 Dec 3:1-9. Epub 2021 Dec 3.

Primary Care Unit, University of Cambridge, Cambridge, UK.

Introduction: In March 2020, UK primary care changed dramatically due to the COVID-19 pandemic. It now has a much greater reliance on triaging, e-consultations, remote consultations, online meetings and less home visits. Re-evaluating the nature and value of learning medicine in primary care has therefore become a priority.

Method: 70 final-year medical students placed in 38 GP practices (primary care centres) across the East of England undertook a 5-week clerkship during November 2020. A sample of 10 students and 11 supervising general practitioners from 16 different GP practices were interviewed following the placement. Qualitative analysis was conducted to determine their perceptions regarding the nature and value of learning medicine in primary care now compared with prior to the pandemic.

Results: A variety of models of implementing supervised student consultations were identified. Although contact with patients was felt to be less than pre-pandemic placements, triaging systems appeared to have increased the educational value of each individual student-patient contact. Remote consultations were essential to achieving adequate case-mix and they conferred specific educational benefits. However, depending on how they were supervised, they could have the potential to decrease students' level of responsibility for patient care.

Conclusions: Undergraduate primary care placements in the post-COVID era can still possess the educationally valuable attributes documented in the pre-pandemic literature. However, this is dependent on specific factors regarding their delivery.
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http://dx.doi.org/10.1080/0142159X.2021.1990239DOI Listing
December 2021

Rare germline variants in the AXIN2 gene in families with colonic polyposis and colorectal cancer.

Fam Cancer 2021 Nov 24. Epub 2021 Nov 24.

Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, Australia.

Germline loss-of-function variants in AXIN2 are associated with oligodontia and ectodermal dysplasia. The association between colorectal cancer (CRC) and colonic polyposis is less clear despite this gene now being included in multi-gene panels for CRC. Study participants were people with genetically unexplained colonic polyposis recruited to the Genetics of Colonic Polyposis Study who had a rare germline AXIN2 gene variant identified from either clinical multi-gene panel testing (n=2) or from whole genome/exome sequencing (n=2). Variant segregation in relatives and characterisation of tumour tissue were performed where possible. Four different germline pathogenic variants in AXIN2 were identified in four families. Five of the seven carriers of the c.1049delC, p.Pro350Leufs*13 variant, two of the six carriers of the c.1994dupG, p.Asn666Glnfs*41 variant, all three carriers of c.1972delA, p.Ser658Alafs*31 variant and the single proband carrier of the c.2405G>C, p.Arg802Thr variant, which creates an alternate splice form resulting in a frameshift mutation (p.Glu763Ilefs*42), were affected by CRC and/or polyposis. Carriers had a mean age at diagnosis of CRC/polyposis of 52.5 ± 9.2 years. Colonic polyps were typically pan colonic with counts ranging from 5 to >100 (median 12.5) comprising predominantly adenomatous polyps but also serrated polyps. Two CRCs from carriers displayed evidence of a second hit via loss of heterozygosity. Oligodontia was observed in carriers from two families. Germline AXIN2 pathogenic variants from four families were associated with CRC and/or polyposis in multiple family members. These findings support the inclusion of AXIN2 in CRC and polyposis multigene panels for clinical testing.
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http://dx.doi.org/10.1007/s10689-021-00283-9DOI Listing
November 2021

Using Surveillance With Near-Real-Time Alerts During a Cluster of Overdoses From Fentanyl-Contaminated Crack Cocaine, Connecticut, June 2019.

Public Health Rep 2021 Nov-Dec;136(1_suppl):18S-23S

Greater Hartford Harm Reduction Coalition, Inc, Hartford, CT, USA.

In 2019, Connecticut launched an opioid overdose-monitoring program to provide rapid intervention and limit opioid overdose-related harms. The Connecticut Statewide Opioid Response Directive (SWORD)-a collaboration among the Connecticut State Department of Public Health, Connecticut Poison Control Center (CPCC), emergency medical services (EMS), New England High Intensity Drug Trafficking Area (HIDTA), and local harm reduction groups-required EMS providers to call in all suspected opioid overdoses to the CPCC. A centralized data collection system and the HIDTA overdose mapping tool were used to identify outbreaks and direct interventions. We describe the successful identification of a cluster of fentanyl-contaminated crack cocaine overdoses leading to a rapid public health response. On June 1, 2019, paramedics called in to the CPCC 2 people with suspected opioid overdose who reported exclusive use of crack cocaine after being resuscitated with naloxone. When CPCC specialists in poison information followed up on the patients' status with the emergency department, they learned of 2 similar cases, raising suspicion that a batch of crack cocaine was mixed with an opioid, possibly fentanyl. The overdose mapping tool pinpointed the overdose nexus to a neighborhood in Hartford, Connecticut; the CPCC supervisor alerted the Connecticut State Department of Public Health, which in turn notified local health departments, public safety officials, and harm reduction groups. Harm reduction groups distributed fentanyl test strips and naloxone to crack cocaine users and warned them of the dangers of using alone. The outbreak lasted 5 days and tallied at least 22 overdoses, including 6 deaths. SWORD's near-real-time EMS reporting combined with the overdose mapping tool enabled rapid recognition of this overdose cluster, and the public health response likely prevented additional overdoses and loss of life.
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http://dx.doi.org/10.1177/00333549211015662DOI Listing
December 2021

Dynamically expressed genes provide candidate viability biomarkers in a model coccidian.

PLoS One 2021 1;16(10):e0258157. Epub 2021 Oct 1.

United States Department of Agriculture, Agricultural Research Service, Beltsville Agricultural Research Center, Beltsville, MD, United States of America.

Eimeria parasites cause enteric disease in livestock and the closely related Cyclospora cayetanensis causes human disease. Oocysts of these coccidian parasites undergo maturation (sporulation) before becoming infectious. Here, we assessed transcription in maturing oocysts of Eimeria acervulina, a widespread chicken parasite, predicted gene functions, and determined which of these genes also occur in C. cayetanensis. RNA-Sequencing yielded ~2 billion paired-end reads, 92% of which mapped to the E. acervulina genome. The ~6,900 annotated genes underwent temporally-coordinated patterns of gene expression. Fifty-three genes each contributed >1,000 transcripts per million (TPM) throughout the study interval, including cation-transporting ATPases, an oocyst wall protein, a palmitoyltransferase, membrane proteins, and hypothetical proteins. These genes were enriched for 285 gene ontology (GO) terms and 13 genes were ascribed to 17 KEGG pathways, defining housekeeping processes and functions important throughout sporulation. Expression differed in mature and immature oocysts for 40% (2,928) of all genes; of these, nearly two-thirds (1,843) increased their expression over time. Eight genes expressed most in immature oocysts, encoding proteins promoting oocyst maturation and development, were assigned to 37 GO terms and 5 KEGG pathways. Fifty-six genes underwent significant upregulation in mature oocysts, each contributing at least 1,000 TPM. Of these, 40 were annotated by 215 GO assignments and 9 were associated with 18 KEGG pathways, encoding products involved in respiration, carbon fixation, energy utilization, invasion, motility, and stress and detoxification responses. Sporulation orchestrates coordinated changes in the expression of many genes, most especially those governing metabolic activity. Establishing the long-term fate of these transcripts in sporulated oocysts and in senescent and deceased oocysts will further elucidate the biology of coccidian development, and may provide tools to assay infectiousness of parasite cohorts. Moreover, because many of these genes have homologues in C. cayetanensis, they may prove useful as biomarkers for risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258157PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486141PMC
November 2021

Informed choice and attitudes regarding a genomic test to predict risk of colorectal cancer in general practice.

Patient Educ Couns 2021 Aug 8. Epub 2021 Aug 8.

Centre for Cancer Research, University of Melbourne, Melbourne, Australia; Department of General Practice, University of Melbourne, Melbourne, Australia; The Primary Care Unit, University of Cambridge, Cambridge, UK. Electronic address:

Objective: A genomic test to predict personal risk of colorectal cancer (CRC) that targets screening and could be feasibly implemented in primary care. We explored informed decision-making and attitudes towards genomic testing in this setting.

Methods: A CRC genomic test was offered to 150 general practice patients with brief discussion of its implications. We measured informed choice about the test, consisting knowledge, attitudes and test uptake. Sixteen purposively-sampled participants were interviewed.

Results: Of 150, 142 (95%) completed the informed choice measure and of 27 invited, 16 (59%) completed an interview. 73% made an informed choice about the test. Interviews revealed that participants with inadequate knowledge on the informed choice scale still understood the gist of the test. While positive attitudes were most prevalent, some had concerns, and many were indifferent to the test. Positive attitudes included: that risk information could facilitate risk reduction; negative attitudes included: that risk results could cause worry and be used for insurance discrimination; indifferent attitudes included: that the test seemed benign and it was easy to do.

Conclusions: Our study adds to the evidence that genomic tests for CRC risk do not pose significant concern to patients in community settings.

Practice Implications: As genomic tests become more prevalent, this study's findings can be used to facilitate informed decision-making and ensure equitable access.
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http://dx.doi.org/10.1016/j.pec.2021.08.008DOI Listing
August 2021

Association Between Smoking and Molecular Subtypes of Colorectal Cancer.

JNCI Cancer Spectr 2021 Aug 14;5(4):pkab056. Epub 2021 Jun 14.

Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

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 mutation, 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 ( < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and . 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; = 2.1 x 10). The association was also stronger in tumors that were positive, MSI high, or wild type when combined ( < .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.
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http://dx.doi.org/10.1093/jncics/pkab056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346704PMC
August 2021

Quantifying the Effect of Location Matching on Accuracy of Multiparametric Magnetic Resonance Imaging Prior to Prostate Biopsy-A Multicentre Study.

Eur Urol Open Sci 2020 Jul 12;20:28-36. Epub 2020 Aug 12.

Department of Urology, St Vincent's Hospital Melbourne, Victoria, Australia.

Background: Multiparametric magnetic resonance imaging (mpMRI) has shown promise to improve detection of prostate cancer over conventional methods. However, most studies do not describe whether the location of mpMRI lesions match that of cancer found at biopsy, which may lead to an overestimation of accuracy.

Objective: To quantitate the effect of mapping locations of mpMRI lesions to locations of positive biopsy cores on the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of mpMRI.

Design Setting And Participant: We retrospectively identified patients having mpMRI of the prostate preceding prostate biopsy at three centres from 2013 to 2016. Men with targetable lesions on imaging underwent directed biopsy in addition to systematic biopsy. We correlated locations of positive mpMRI lesions with those of positive biopsy cores, defining a match when both were in the same sector of the prostate. We defined positive mpMRI as Prostate Imaging Reporting and Data System (PI-RADS) score ≥4 and significant cancer at biopsy as grade group ≥2.

Outcome Measurements And Statistical Analysis: Sensitivity, specificity, PPV, and NPV were calculated with and without location matching.

Results And Limitations: Of 446 patients, 247 (55.4%) had positive mpMRI and 232 (52.0%) had significant cancer at biopsy. Sensitivity and NPV for detecting significant cancer with location matching (both 63.4%) were decreased compared with those without location matching (77.6% and 73.9%, respectively). Of the 85 significant cancers not detected by mpMRI, most were of grade group 2 (64.7%, 55/85).

Conclusions: We report a 10-15% decrease in sensitivity and NPV when location matching was used to detect significant prostate cancer by mpMRI. False negative mpMRI remains an issue, highlighting the continued need for biopsy and for improving the standards around imaging quality and reporting.

Patient Summary: The true accuracy of multiparametric magnetic resonance imaging (mpMRI) must be determined to interpret results and better counsel patients. We mapped the location of positive mpMRI lesions to where cancer was found at biopsy and found, when compared with matching to cancer anywhere in the prostate, that the accuracy of mpMRI decreased by 10-15%.
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http://dx.doi.org/10.1016/j.euros.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317842PMC
July 2020

Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer.

Cancers (Basel) 2021 Jul 14;13(14). Epub 2021 Jul 14.

Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.

gene or protein deficiency or loss-of-function in colorectal cancer can cause a DNA mismatch repair defect known as "elevated microsatellite alterations at selected tetranucleotide repeats" (EMAST). A high percentage of MSI-H tumors exhibit EMAST, while MSI-L is also linked with EMAST. However, the distribution of CpG island methylator phenotype (CIMP) within the EMAST spectrum is not known. Five tetranucleotide repeat and five MSI markers were used to classify 100 sporadic colorectal tumours for EMAST, MSI-H and MSI-L according to the number of unstable markers detected. Promoter methylation was determined using methylation-specific PCR for , , (p16) and five CIMP marker genes. EMAST was found in 55% of sporadic colorectal carcinomas. Carcinomas with only one positive marker (EMAST-1/5, 26%) were associated with advanced tumour stage, increased lymph node metastasis, MSI-L and lack of CIMP-H. EMAST-2/5 (16%) carcinomas displayed some methylation but MSI was rare. Carcinomas with 3 positive EMAST markers (13%) were more likely to have a proximal colon location and be MSI-H and CIMP-H. Our study suggests that EMAST/MSI-L is a valuable prognostic and predictive marker for colorectal carcinomas that do not display the high methylation phenotype CIMP-H.
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http://dx.doi.org/10.3390/cancers13143529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308094PMC
July 2021

An RCT of a decision aid to support informed choices about taking aspirin to prevent colorectal cancer and other chronic diseases: a study protocol for the SITA (Should I Take Aspirin?) trial.

Trials 2021 Jul 15;22(1):452. Epub 2021 Jul 15.

Centre for Cancer Research, University of Melbourne, Melbourne, Australia.

Background: Australian guidelines recommend that all people aged 50-70 years old actively consider taking daily low-dose aspirin (100-300 mg per day) for 2.5 to 5 years to reduce their risk of colorectal cancer (CRC). Despite the change of national CRC prevention guidelines, there has been no active implementation of the guidelines into clinical practice. We aim to test the efficacy of a health consultation and decision aid, using a novel expected frequency tree (EFT) to present the benefits and harms of low dose aspirin prior to a general practice consultation with patients aged 50-70 years, on informed decision-making and uptake of aspirin.

Methods: Approximately five to seven general practices in Victoria, Australia, will be recruited to participate. Patients 50-70 years old, attending an appointment with their general practitioner (GP) for any reason, will be invited to participate in the trial. Two hundred fifty-eight eligible participants will be randomly allocated 1:1 to intervention or active control arms using a computer-generated allocation sequence stratified by general practice, sex, and mode of trial delivery (face-to-face or teletrial). There are two co-primary outcomes: informed decision-making at 1-month post randomisation, measured by the Multi-dimensional Measure of Informed Choice (MMIC), and self-reported daily use of aspirin at 6 months. Secondary outcomes include decisional conflict at 1-month and other behavioural changes to reduce CRC risk at both time points.

Discussion: This trial will test the efficacy of novel methods for implementing national guidelines to support informed decision-making about taking aspirin in 50-70-year-olds to reduce the risk of CRC and other chronic diseases.

Trial Registration: The Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620001003965 . Registered on 10 October 2020.
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http://dx.doi.org/10.1186/s13063-021-05365-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280579PMC
July 2021

Language abilities in children born to mothers diagnosed with diabetes: A systematic review and meta-analysis.

Early Hum Dev 2021 Aug 4;159:105420. Epub 2021 Jul 4.

Queen's Medical Centre, School of Health Sciences, The University of Nottingham, Nottingham NG7 2HA, UK. Electronic address:

Background: This meta-analysis reviewed and synthesized the available evidence on the association between intrauterine exposure to maternal diabetes and language abilities in children.

Method: MEDLINE/PubMed, EMBASE, PsycINFO, Proquest Dissertations and Theses Global, and Google Scholar databases were searched through December 2020. Studies were systematically searched, and effect sizes were calculated using random effects models.

Results: Twelve studies were identified for inclusion in this review, however, only 10 were included in the meta-analysis. Sample size ranged from 9 to 115 participants in the diabetes group and 28 to 8192 in the control and aged around 3 years. The pooled results of the meta-analysis showed a trend of decreased language abilities in receptive (z = -3.49, df = 10, I = 34, p = 0.001), expressive language development (z = -2.29, df = 11, I = 94%, p = 0.022) and general communication (z = -4.12, df = 4, I = 2, p = 0.001) However, results showed a limited effect of maternal diabetes on children's language abilities after excluding high-risk categories such as children born to mothers with other gestational comorbidities, obesity and low socio-economic status.

Conclusion: Our meta-analysis recognises that exposure to maternal diabetes during pregnancy intersects with other factors within the intrauterine environment to create the conditions for reduced language abilities in the child. Multiple factors may contribute to the observed differences between groups in the meta-analysis. A focus on interventions to maintain optimal blood glucose levels during pregnancy and to screen for early developmental delay after birth is recommended.
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http://dx.doi.org/10.1016/j.earlhumdev.2021.105420DOI Listing
August 2021

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in and : A Prospective Lynch Syndrome Database Study.

J Clin Med 2021 Jun 28;10(13). Epub 2021 Jun 28.

Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, 4031 Basel, Switzerland.

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 and genes.

Methods: Carriers of pathogenic variants of () and () 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 and .
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http://dx.doi.org/10.3390/jcm10132856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269121PMC
June 2021

The development of the Western Australian Haemodialysis Vascular Access Complexity instrument.

J Ren Care 2021 Jun 28. Epub 2021 Jun 28.

Alliance for Vascular Access Teaching and Research, Menzies Health Institute Queensland, Southport, Queensland, Australia.

Background: The Western Australian Haemodialysis Vascular Access Classification instrument was developed to classify the cannulation complexity of the arteriovenous fistula or arteriovenous graft as simple, challenging, or complex. Although the instrument was developed by experts in haemodialysis nursing, the instrument had not undergone formal validity or reliability testing.

Objectives: Evaluate the Western Australian Haemodialysis Vascular Access Classification instrument for content validity, interrater and test-retest reliability.

Design: Prospective cohort study.

Participants: Content validity was assessed by haemodialysis nursing experts (n = 8). The reliability testing occurred in one in-centre and one satellite haemodialysis unit in Western Australia from September to November 2019. Reliability testing was performed by 38 haemodialysis nurses in 67 patients receiving haemodialysis and 247 episodes of cannulation.

Measurements: Interrater and test-retest reliability assessment was conducted using κ, adjusted κ, Bland-Altman plots, intraclass correlation coefficient and Pearson's correlation coefficient.

Results: The final version of the instrument (n = 20 items) had individual item-level content validity indices ranging from 0.625 to 1.00 with a scale-level content validity index of 0.89. For both interrater (n = 172 pairs) and test-retest (n = 101 pairs), most individual variables had excellent adjusted κ (n = 33 variables), some fair to good agreement (n = 6 variables) and one variable with poor agreement. The classification of simple, challenging and complex demonstrated adjusted κ of fair to good, to excellent agreement for interrater reliability with lower levels of agreement for test-retest reliability.

Conclusions: This instrument may be used to match a competency-assessed nurse to perform the cannulation thereby minimising the risk of missed cannulation and trauma.
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http://dx.doi.org/10.1111/jorc.12390DOI Listing
June 2021

Vaccination with Neospora caninum-cyclophilin and -profilin confers partial protection against experimental neosporosis-induced abortion in sheep.

Vaccine 2021 07 24;39(32):4534-4544. Epub 2021 Jun 24.

Animal Parasitic Diseases Laboratory, Beltsville Agricultural Research Center, Agricultural Research Service, USDA, Beltsville, MD 20705, United States. Electronic address:

The purpose of this study was to evaluate the protective efficacy of a vaccine consisting of recombinant Neospora caninum-cyclophilin (NcCyP) and -profilin (NcPro) in sheep. At 42 d and 21 d prior to mating, adult Dorset ewes were immunized with the rNcCyP-rNcPro vaccine (Group 1) or co-purifying non-recombinant (NR) control vaccine (Group 2). At 90 days post-mating, all immunized ewes and were challenged by intravenous injection with 10Nesopora caninum Illinois tachyzoites (NcTZ). Significant protection (P < 0.05) was observed in Group 1 with 9 out of 13 ewes giving birth to live-born lambs (69.2%), whereas all Group 2 ewes aborted (6/6). Neospora caninum was detected by PCR in both fetal and placental tissues from all Group 2 aborting ewes and in the placental tissues of Group 1 aborting ewes. In contrast, tissues and placentas of Group 1 live-born lambs were Neospora DNA-negative. Immunoreactive Neospora antigens were demonstrated in placentas associated with abortions, but not in tissues of aborted fetuses or those of the live-born lambs and their associated placentas. Anti-NcCyP and anti-NcPro titers were high in sera from Group 1 ewes and were further boosted by challenge infection, resulting in long-lasting (≥14.5 mos.) elevated titers. Lambs born to Group 1 ewes also had high NcCyP and NcPro titers in pre-colostrum sera. Immunofluorescence staining (IFA) of NcTZ with Group 1 post-immunization sera revealed both surface and internal TZ staining, a pattern consistent with that observed with rabbit sera to rNcCyP or rNcPro. Infection of NR-vaccinated ewes produced high but transient anti-NcCyP and anti-NcPro Ab titers. The results indicate that the NcCyP-NcPro vaccine elicited strong anti-N. caninum responses and conferred significant protection against abortion and transplacental transmission of N. caninum TZ in sheep.
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http://dx.doi.org/10.1016/j.vaccine.2021.06.032DOI Listing
July 2021

DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer.

Cancers (Basel) 2021 May 25;13(11). Epub 2021 May 25.

Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia.

We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50-70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group; 13 of these DMRs/genes were replicated in EOCRC compared with LOCRCs from TCGA. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift, and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups ( = 3.7 × 10) and young people without CRC ( = 5.8 × 10). EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. Accelerated ageing in normal mucosa from people with EOCRC potentially underlies the earlier age of diagnosis in CRC carcinogenesis.
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http://dx.doi.org/10.3390/cancers13112589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199056PMC
May 2021

A Meta-Analysis of Obesity and Risk of Colorectal Cancer in Patients with Lynch Syndrome: The Impact of Sex and Genetics.

Nutrients 2021 May 20;13(5). Epub 2021 May 20.

Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, 20141 Milan, Italy.

There appears to be a sex-specific association between obesity and colorectal neoplasia in patients with Lynch Syndrome (LS). We meta-analyzed studies reporting on obesity and colorectal cancer (CRC) risk in LS patients to test whether obese subjects were at increased risk of cancer compared to those of normal weight. We explored also a possible sex-specific relationship between adiposity and CRC risk among patients with LS. The summary relative risk (SRR) and 95% confidence intervals (CI) were calculated through random effect models. We investigated the causes of between-study heterogeneity and assessed the presence of publication bias. We were able to retrieve suitable data from four independent studies. We found a twofold risk of CRC in obese men compared to nonobese men (SRR = 2.09; 95%CI: 1.23-3.55, I = 33%), and no indication of publication bias ( = 0.13). No significantly increased risk due to obesity was found for women. A 49% increased CRC risk for obesity was found for subjects with an mutation (SRR = 1.49; 95%CI: 1.11-1.99, I = 0%). These results confirm the different effects of sex on obesity and CRC risk and also support the public measures to reduce overweight in people with LS, particularly for men.
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http://dx.doi.org/10.3390/nu13051736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160758PMC
May 2021

Nongenetic Determinants of Risk for Early-Onset Colorectal Cancer.

JNCI Cancer Spectr 2021 Jun 20;5(3):pkab029. Epub 2021 May 20.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite.

Methods: Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite.

Results: Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27;  = .04).

Conclusion: In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease.
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http://dx.doi.org/10.1093/jncics/pkab029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134523PMC
June 2021

Genetically Predicted Circulating C-Reactive Protein Concentration and Colorectal Cancer Survival: A Mendelian Randomization Consortium Study.

Cancer Epidemiol Biomarkers Prev 2021 07 10;30(7):1349-1358. Epub 2021 May 10.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer-specific survival.

Methods: We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer-specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components.

Results: Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer-specific survival (HD, -1.15; 95% CI, -2.76 to 0.47 per 100,000 person-years; = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location.

Conclusions: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer-specific survival.

Impact: Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254760PMC
July 2021

Assessment of a Polygenic Risk Score for Colorectal Cancer to Predict Risk of Lynch Syndrome Colorectal Cancer.

JNCI Cancer Spectr 2021 Apr 8;5(2):pkab022. Epub 2021 Mar 8.

Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Victoria, Australia.

It was not known whether the polygenic risk scores (PRSs) that predict colorectal cancer could predict colorectal cancer for people with inherited pathogenic variants in DNA mismatch repair genes-people with Lynch syndrome. We tested a PRS comprising 107 established single-nucleotide polymorphisms associated with colorectal cancer in European populations for 826 European-descent carriers of pathogenic variants in DNA mismatch repair genes (293 , 314 , 126 , 71 , and 22 ) from the Colon Cancer Family Registry, of whom 504 had colorectal cancer. There was no evidence of an association between the PRS and colorectal cancer risk, irrespective of which DNA mismatch repair gene was mutated, or sex (all 2-sided >.05). The hazard ratio per standard deviation of the PRS for colorectal cancer was 0.97 (95% confidence interval = 0.88 to 1.06; 2-sided =.51). Whereas PRSs are predictive of colorectal cancer in the general population, they do not predict Lynch syndrome colorectal cancer.
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http://dx.doi.org/10.1093/jncics/pkab022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062848PMC
April 2021

The impact of blood sampling technique, including the use of peripheral intravenous cannula, on haemolysis rates: A cohort study.

J Clin Nurs 2021 Jul 7;30(13-14):1916-1926. Epub 2021 Apr 7.

School of Nursing and Midwifery, Edith Cowan University, Joondalup, WA, Australia.

Aims: To explore the relationship between blood sampling techniques and haemolysis.

Background: Haemolysis rates of blood samples have been thought to be influenced by the method of collection. There is a lack of research evidence available to clearly show the comparative risk of haemolysis across different blood sampling methods, including venepuncture and use of peripheral intravenous cannulas.

Design: A prospective cohort study. Reporting followed the STROBE checklist.

Methods: A trained observer was used to record blood sampling techniques over a 10-week period between April and June 2019. These records were then linked to pathology haemolysis results. Multivariable logistic regression was used to model patient and blood draw characteristics affecting haemolysis.

Results: Most of the blood samples were not haemolysed (n = 324, 87.1%). Multivariable analysis showed haemolysis was associated with increased tourniquet duration and if the level of tube was less than half full. Univariable analysis showed haemolysis was associated with increased age of the patient, the difficulty of cannulation/ venepuncture and increased number of attempts. No difference was found in the haemolysis rate related to the qualification of the blood collector.

Conclusion: There was no significant difference in haemolysis rates associated with sampling blood from a PIVC compared with venepuncture. Research should be undertaken to determine whether education on the factors influencing haemolysis is useful in decreasing haemolysis rates.

Relevance To Clinical Practice: There was no association with increased haemolysis rates when drawing blood via venepuncture compared with a peripheral intravenous cannula. Haemolysis of blood samples was associated with increased tourniquet duration, if level of the tube was less than half-filled, increased age of the patient and difficulty of blood draw. Awareness of the risk of haemolysis associated with specific blood sampling methods may assist clinicians to improve care.
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http://dx.doi.org/10.1111/jocn.15744DOI Listing
July 2021

Effect of Intrawound Vancomycin Powder in Operatively Treated High-risk Tibia Fractures: A Randomized Clinical Trial.

JAMA Surg 2021 05 12;156(5):e207259. Epub 2021 May 12.

Department of Orthopaedic Surgery, Indiana University Methodist Hospital, Indianapolis.

Importance: Despite the widespread use of systemic antibiotics to prevent infections in surgically treated patients with fracture, high rates of surgical site infection persist.

Objective: To examine the effect of intrawound vancomycin powder in reducing deep surgical site infections.

Design, Setting, And Participants: This open-label randomized clinical trial enrolled adult patients with an operatively treated tibial plateau or pilon fracture who met the criteria for a high risk of infection from January 1, 2015, through June 30, 2017, with 12 months of follow-up (final follow-up assessments completed in April 2018) at 36 US trauma centers.

Interventions: A standard infection prevention protocol with (n = 481) or without (n = 499) 1000 mg of intrawound vancomycin powder.

Main Outcomes And Measures: The primary outcome was a deep surgical site infection within 182 days of definitive fracture fixation. A post hoc comparison assessed the treatment effect on gram-positive and gram-negative-only infections. Other secondary outcomes included superficial surgical site infection, nonunion, and wound dehiscence.

Results: The analysis included 980 patients (mean [SD] age, 45.7 [13.7] years; 617 [63.0%] male) with 91% of the expected person-time of follow-up for the primary outcome. Within 182 days, deep surgical site infection was observed in 29 of 481 patients in the treatment group and 46 of 499 patients in the control group. The time-to-event estimated probability of deep infection by 182 days was 6.4% in the treatment group and 9.8% in the control group (risk difference, -3.4%; 95% CI, -6.9% to 0.1%; P = .06). A post hoc analysis of the effect of treatment on gram-positive (risk difference, -3.7%; 95% CI, -6.7% to -0.8%; P = .02) and gram-negative-only (risk difference, 0.3%; 95% CI, -1.6% to 2.1%; P = .78) infections found that the effect of vancomycin powder was a result of its reduction in gram-positive infections.

Conclusions And Relevance: Among patients with operatively treated tibial articular fractures at a high risk of infection, intrawound vancomycin powder at the time of definitive fracture fixation reduced the risk of a gram-positive deep surgical site infection, consistent with the activity of vancomycin.

Trial Registration: ClinicalTrials.gov Identifier: NCT02227446.
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http://dx.doi.org/10.1001/jamasurg.2020.7259DOI Listing
May 2021

Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Eur J Cancer 2021 05 17;148:124-133. Epub 2021 Mar 17.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany; MGZ- Medical Genetics Center, Munich, Germany; The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark's Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK; European Hereditary Tumour Group (EHTG), C/o Lindsays, Caledonian Exchange, 19A Canning Street, Edinburgh, EH3 8HE, United Kingdom.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.

Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.

Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.
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http://dx.doi.org/10.1016/j.ejca.2021.02.022DOI Listing
May 2021

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.

Am J Clin Nutr 2021 06;113(6):1490-1502

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.

Objectives: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).

Methods: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.

Results: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.

Conclusions: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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http://dx.doi.org/10.1093/ajcn/nqab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168352PMC
June 2021

The effects of tributyrin supplementation on weight gain and intestinal gene expression in broiler chickens during Eimeria maxima-induced coccidiosis.

Poult Sci 2021 Apr 18;100(4):100984. Epub 2021 Jan 18.

Animal Biosciences and Biotechnology Laboratory, Henry A. Wallace Beltsville Agricultural Research Center, Beltsville, MD 20705, USA. Electronic address:

Butyrate is a feed additive that has been shown to have antibacterial properties and improve gut health in broilers. Here, we examined the performance and gene expression changes in the ileum of tributyrin-supplemented broilers infected with coccidia. Ninety-six, Ross 708 broilers were fed either a control corn-soybean-based diet (-BE) or a diet supplemented with 0.25% (w/w) tributyrin (+BE). Birds were further divided into groups that were inoculated with Eimeria maxima oocysts (EM) or sham-inoculated (C) on day 21 posthatch. At 7 d postinfection (7 d PI), the peak of pathology in E. maxima infection, tributyrin-supplemented birds had significantly improved feed conversion ratios (FCR, P < 0.05) and body weight gain (BWG, P < 0.05) compared with -BE-infected birds, despite both groups having similar feed intake (FI, P > 0.05). However, at 10 d post-infection (10 d PI) no significant effects of feed type or infection were observed. Gene expression in the ileum was examined for insights into possible effects of infection and tributyrin supplementation on genes encoding proteins related to immunity, digestion, and gut barrier integrity. Among immune-related genes examined, IL-1B and LEAP2 were only significantly affected at 7 d PI. Transcription of genes related to digestion (APN, MCT1, FABP2, and MUC2) were primarily influenced by infection at 7 d PI and tributyrin supplementation (FABP2 and MUC2) at 10 d PI. With exception of ZO1, tight junction genes were affected by either infection or feed type at 7 d PI. At 10 d PI, only CLDN1 was not affected by either infection or feed type. Overall tributyrin shows promise as a supplement to improve performance during coccidiosis in broiler chickens; however, its effect on gene expression and mode of action requires further research.
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http://dx.doi.org/10.1016/j.psj.2021.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921011PMC
April 2021
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