Predicting the distribution of the Chinese mystery snail, Cipangopaludina chinensis, a potentially invasive, non-indigenous species, in Atlantic Canada

v, 146 leaves : illustrations (some colour), colour maps ; 29 cmIncludes abstract and appendices.Includes bibliographical references.The Chinese mystery snail, Cipangopaludina chinensis, a freshwater mollusc indigenous to Eastern Asia, introduced to North America and Europe. Currently, little is known about C. chinensis in North America. My thesis objectives were to: (1) synthesize relevant literature and confirm whether C. chinensis should be considered invasive in North America, (2) determine the known species occurrence in continental North America highlighting reporting gaps, and (3) create a species distribution model for C. chinensis in the Maritimes. The literature review indicated that C. chinensis should be considered invasive in North America. The largest number of reported occurrences were in southern Ontario and northern US along the Great Lakes with the lowest in the Maritimes, the Prairies, Quebec, and near Lake Superior. Finally, a random forest model was developed to predict C. chinensis distribution in Nova Scotia, with highest probable occurrence in the Halifax-area, the New Brunswick-Nova Scotia border, and Cape Breton

The role of the NLRP3 inflammasome in gout

Gout is an inflammatory arthritis characterized by abrupt self-limiting attacks of inflammation caused by precipitation of monosodium urate crystals (MSU) in the joint. Recent studies suggest that orchestration of the MSU-induced inflammatory response is dependent on the proinflammatory cytokine IL-1β, underlined by promising results in early IL-1 inhibitor trials in gout patients. This IL-1-dependent innate inflammatory phenotype, which is observed in a number of diseases in addition to gout, is now understood to rely on the formation of the macromolecular NLRP3 inflammasome complex in response to the MSU ‘danger signal’. This review focuses on our current understanding of the NLRP3 inflammasome and its critical role in MSU-crystal induced inflammatory gout attacks. It also discusses the management of treatment-resistant acute and chronic tophaceous gout with IL-1 inhibitors; early clinical studies of rilonacept (IL-1 Trap), canakinumab (monoclonal anti-IL-1β antibody), and anakinra have all demonstrated treatment efficacy in such patients

Knee Pain Predicts Subsequent Shoulder Pain and the Association Is Mediated by Leg Weakness: Longitudinal Observational Data from the Osteoarthritis Initiative

Objective: To assess whether the ‘spread’ of joint pain is related to pain-associated muscle loss in one joint leading to increased loading and subsequent pain in other joints. Methods: Associations between persistent knee pain (pain in one or two knees over years 0-3 versus no persistent pain) and incident shoulder pain at year 4 were examined in participants from the longitudinal NIH Osteoarthritis Initiative (OAI). Associations were assessed using log multinomial modelling, adjusted for age, sex, BMI, depression score, other lower limb pain and baseline leg weakness (difficulty standing from a sitting position). Results: In older adults with clinically significant knee OA or at risk of knee OA (n=3486), the number of painful joints increased yearly, from 2.1 joints (95% CI 2.0, 2.2) at baseline increasing by 5.2% (95% CI 2.2%, 8.3%) at year 4. Shoulders were the next most commonly affected joint after knees (28.5%). Persistent pain in 1 or 2 knees increased risk of bilateral shoulder pain at year 4 (1 knee RR 1.59 (95% CI 0.97, 2.61); 2 knees RR 2.02 (1.17, 3.49)) after adjustment for confounders. Further adjustment for leg weakness attenuated effect sizes (1 knee RR 1.13 (95% CI 0.60, 2.11); 2 knees RR 1.44 (0.75, 2.77)), indicating mediation by functional leg weakness. Conclusions: Spread of joint pain is not random. Persistently painful knees predict new bilateral shoulder pain, which is likely mediated by leg weakness; suggesting that biomechanical factors influence the spread of pain

Assessing the probable distribution of the potentially invasive Chinese mystery snail, Cipangopaludina chinensis, in Nova Scotia using a random forest model approach

Published versionNon-native species that become invasive threaten natural biodiversity and can lead to socioeconomic impacts. Prediction of invasive species distributions is important to prevent further spread and protect vulnerable habitats and species at risk (SAR) from future invasions. The Chinese mystery snail, Cipangopaludina chinensis, native to Eastern Asia, is a non-native, potentially invasive, freshwater snail now widely established across North America, Belgium, and The Netherlands. This species was first reported in Nova Scotia, eastern Canada in 1955, but was not found to be established until the 1990s and now exists at high densities in several urban lakes. Nonetheless, the presence and potential distribution of this species in Nova Scotia remains unknown. Limited resources make it difficult to do a broad survey of freshwater lakes in Nova Scotia, however a species distribution probability model has the potential to direct focus to priority areas. We apply a random forest model in tandem with a combination of water quality, fish community, anthropogenic water use, and geomorphological data to predict C. chinensis habitat in Nova Scotia (NS), Canada. All predicted probabilities of suitable C. chinensisi habitats in Nova Scotia were > 50% and include Cape Breton Island, the Nova Scotia-New Brunswick border, and the Halifax Regional Municipality. Suitable habitats predicted for C. chinensis overlap with many SAR habitats, most notably brook floater mussel, Alasmidonta varicosa, and yellow lampmussel, Lampsila cariosa. Our results indicate that C. chinensis could become widespread throughout NS, appearing first in the aforementioned areas of highest probability. Further research is required to test C. chinensis ecological thresholds in order to improve the accuracy of future species distribution and habitat models, and to determine C. chinensis impacts on native freshwater mussel populations of conservation concern

UK poSt Arthroplasty Follow-up rEcommendations (UK SAFE): what does analysis of linked, routinely collected national datasets tell us about mid-late term revision risk after knee replacement?

OBJECTIVE: To identify patients at risk of mid-late term revision of knee replacement (KR) to inform targeted follow-up. DESIGN: Analysis of linked national datasets from primary and secondary care (Clinical Practice Research Datalink (CPRD GOLD), National Joint Registry (NJR), English Hospital Episode Statistics (HES) and Patient Reported Outcome Measures (PROMs)). PARTICIPANTS: Primary elective KRs aged ≥18 years. EVENT OF INTEREST: Revision surgery ≥5 years (mid-late term) postprimary KR. STATISTICAL METHODS: Cox regression modelling to ascertain risk factors of mid-late term revision. HRs and 95% CIs assessed association of sociodemographic factors, comorbidities, medication, surgical variables and PROMs with mid-late term revision. RESULTS: NJR-HES-PROMs data were available from 2008 to 2011 on 188 509 KR. CPRD GOLD-HES data covered 1995-2011 on 17 378 KR. Patients had minimum 5 years postprimary surgery to end 2016. Age and gender distribution were similar across datasets; mean age 70 years, 57% female. In NJR, there were 8607 (4.6%) revisions, median time-to-revision postprimary surgery 1.8 years (range 0-8.8), with 1055 (0.6%) mid-late term revisions; in CPRD GOLD, 877 (5.1%) revisions, median time-to-revision 4.2 years (range 0.02-18.3), with 352 (2.0%) mid-late term revisions.Reduced risk of revision after 5 years was associated with older age (HR: 0.95; 95% CI 0.95 to 0.96), obesity (0.70; 0.56 to 0.88), living in deprived areas (0.71; 0.58 to 0.87), non-white ethnicity (0.58; 0.43 to 0.78), better preoperative pain and functional limitation (0.42; 0.33 to 0.53), better 6-month postoperative pain and function (0.33; 0.26 to 0.41) or moderate anxiety/depression (0.73; 0.63 to 0.83) at primary surgery.Increased risk was associated with male gender (1.32; 1.04 to 1.67); when anticonvulsants (gabapentin and pregabalin) (1.58; 1.01 to 2.47) or opioids (1.36; 1.08 to 1.71) were required prior to primary surgery.No implant factors were identified. CONCLUSION: The risk of mid-late term KR revision is very low. Increased risk of revision is associated with patient case-mix factors, and there is evidence of sociodemographic inequality

Association between outpatient follow-up and incidence of revision after knee and hip replacements: a population-based cohort study

Background: Follow-up visits 5 or 7 years after surgery were recommended for people having primary hip or knee replacement. The benefits of this practice to patients and the healthcare system, however, have not yet been specifically examined. The aim of this study was to investigate the association between long-term follow-up outpatient hospital visits and revision rates for patients who undergo primary knee or hip replacement surgery. Methods: Cohorts were identified for patients undergoing knee or hip replacement surgery using medical records from primary care practices within the UK Clinical Practice Research Datalink (CPRD) GOLD dataset linked to hospital records from the English Hospital Episodes Statistics (HES) data. Two groups of patients were compared in terms of revision and mortality rates: those with at least one long-term (between five and 10 years since primary surgery) follow-up visit at the orthopaedic department (‘Follow-up’ group), and those without (‘No follow-up’ group). Results: A total of 9856 (4349 in the Follow-up group) patients with knee replacement and 10,837 (4870 in the Follow-up group) with hip replacement were included in the analysis. For knee replacement, the incidence of revision was 3.6% for those followed-up and 0.6% for those not followed-up. An adjusted regression model confirmed the difference in the hazard ratio (HR) for revision was statistically significant (HR: 5.65 [95% CI 3.62 to 8.81]). Mortality at 4 years was lower for the Follow-up (17%) compared to the No follow-up group (21%), but this difference was not statistically significant (HR: 0.95 [0.84 to 1.07]). For hip replacement, the incidence of revision rates were 3.2 and 1.4% for the follow-up and not follow-up groups, respectively, the difference being statistically significant (HR: 2.34 [1.71 to 3.20]). Mortality was lower for the Follow-up (15%) compared to the No follow-up group (21%), but the difference was not statistically significant (HR: 0.91 [0.81 to 1.02]). Conclusion: Patients attending follow-up orthopaedic consultations show a higher risk of revision surgery compared to those who are not followed-up. A cause for this difference could not be identified in this study but a likely explanation is that surgeons play an effective role as ultimate arbitrators when identifying patients to be included in long-term follow-up lists

Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer.

Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution.We thank the Human Research Tissue Bank at Addenbrooke’s Hospital which is supported by the NIHR Cambridge Biomedical Research Centre. We acknowledge the support of Cancer Research UK, the University of Cambridge, National Institute for Health Research Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre. Dr. Dawson was supported by an Australian National Breast Cancer Foundation and Victorian Cancer Agency Early Career Fellowship. Dr. Murtaza was supported by Science Foundation Arizona’s Bisgrove Scholars Early Tenure Track award.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms976

A Copine family member, Cpne8, is a candidate quantitative trait gene for prion disease incubation time in mouse

Prion disease incubation time in mice is determined by many factors including genetic background. The prion gene itself plays a major role in incubation time; however, other genes are also known to be important. Whilst quantitative trait loci (QTL) studies have identified multiple loci across the genome, these regions are often large, and with the exception of Hectd2 on Mmu19, no quantitative trait genes or nucleotides for prion disease incubation time have been demonstrated. In this study, we use the Northport heterogeneous stock of mice to reduce the size of a previously identified QTL on Mmu15 from approximately 25 to 1.2 cM. We further characterised the genes in this region and identify Cpne8, a member of the copine family, as the most promising candidate gene. We also show that Cpne8 mRNA is upregulated at the terminal stage of disease, supporting a role in prion disease. Applying these techniques to other loci will facilitate the identification of key pathways in prion disease pathogenesis

Proliferation of Aneuploid Human Cells is Limited by a p53-Dependent Mechanism

Most solid tumors are aneuploid, and it has been proposed that aneuploidy is the consequence of an elevated rate of chromosome missegregation in a process called chromosomal instability (CIN). However, the relationship of aneuploidy and CIN is unclear because the proliferation of cultured diploid cells is compromised by chromosome missegregation. The mechanism for this intolerance of nondiploid genomes is unknown. In this study, we show that in otherwise diploid human cells, chromosome missegregation causes a cell cycle delay with nuclear accumulation of the tumor suppressor p53 and the cyclin kinase inhibitor p21. Deletion of the p53 gene permits the accumulation of nondiploid cells such that CIN generates cells with aneuploid genomes that resemble many human tumors. Thus, the p53 pathway plays an important role in limiting the propagation of aneuploid human cells in culture to preserve the diploid karyotype of the population. These data fit with the concordance of aneuploidy and disruption of the p53 pathway in many tumors, but the presence of aneuploid cells in some normal human and mouse tissues indicates that there are known exceptions to the involvement of p53 in aneuploid cells and that tissue context may be important in how cells respond to aneuploidy

Base resolution maps reveal the importance of 5-hydroxymethylcytosine in a human glioblastoma

Aberrant genetic and epigenetic variations drive malignant transformation and are hallmarks of cancer. Using PCR-free sample preparation we achieved the first in-depth whole genome (hydroxyl)-methylcytosine, single-base-resolution maps from a glioblastoma tumour/margin sample of a patient. Our data provide new insights into how genetic and epigenetic variations are interrelated. In the tumour, global hypermethylation with a depletion of 5-hydroxymethylcytosine was observed. The majority of single nucleotide variations were identified as cytosine-to-thymine deamination products within CpG context, where cytosine was preferentially methylated in the margin. Notably, we observe that cells neighbouring tumour cells display epigenetic alterations characteristic of the tumour itself although genetically they appear “normal”. This shows the potential transfer of epigenetic information between cells that contributes to the intratumour heterogeneity of glioblastoma. Together, our reference (epi)-genome provides a human model system for future studies that aim to explore the link between genetic and epigenetic variations in cancer progression.Cancer Research UK 236 (Grant ID: C14303/A17197), Wellcome Trust (Grant ID: 099232/z/12/z