Risk of cancer following primary total hip replacement or primary resurfacing arthroplasty of the hip : A retrospective cohort study in Scotland

Acknowledgements: We are grateful to Lee Barnsdale, Doug Clark, and Richard Dobbie for advice and assistance with data preparation before analysis, and to the three anonymous referees for their helpful comments and suggestions.Peer reviewedPublisher PD

Factors associated with zidovudine substitution in HIV/AIDS patients attending Badung Hospital, Bali, Indonesia between 2006-2014

Background: Zidovudine (AZT) is the most commonly used drug in first line antiretroviral therapy (ART) in Indonesia; however, substitution due to its side effect is common. The majority of HIV positive patients in Badung Hospital Bali are treated with AZT yet no longitudinal studies in Bali have investigated the number of substitutions or the factors associated with it.Methods: A retrospective cohort study of HIV positive persons aged >15 years, receiving AZT between 1st January 2006 – 31st August 2014 was conducted. Persons were included from their date of starting AZT. Cox proportional hazard models were applied to estimate the risk and time to substitution. Substitution was defined as single drug change due to side effects and initiating another drug of the same class.Results: During our study 260 patients started AZT, of which 77 (29.6%) experienced substitution. The risk of substitution was 19 per 100 person years. Of those 77, the median time to AZT substitution was 69 days (IQR 25-178). Factors significantly associated with an increased risk of AZT substitution included women (HR 1.79; 95% CI 1.09-2.94), having low hemoglobin levels <10g% (HR 2.72; 95% CI 1.02-7.21), clinical stage III and IV (HR 3.53; 95% CI 1.26-6.19) at the time of starting AZT, and starting ART after 2012 (HR 3.83; 95% CI 2.19-6.70).Conclusions: Present study identified individuals that may be at a high risk of AZT substitution who should be monitored more closely or consideration given to initiating them on another treatment regimen

Comparative evaluation of three TSPO PET radiotracers in a LPS-induced model of mild neuroinflammation in rats.

PURPOSE: Over the past 20 years, neuroinflammation (NI) has increasingly been recognised as having an important role in  many neurodegenerative diseases, including Alzheimer's disease. As such, being able to image NI non-invasively in patients is critical to monitor pathological processes and potential therapies targeting neuroinflammation. The translocator protein (TSPO) has proven a reliable NI biomarker for positron emission tomography (PET) imaging. However, if TSPO imaging in acute conditions such as stroke provides strong and reliable signals, TSPO imaging in neurodegenerative diseases has proven more challenging. Here, we report results comparing the recently developed TSPO tracers [(18)F]GE-180 and [(18)F]DPA-714 with (R)-[(11)C]PK11195 in a rodent model of subtle focal inflammation. PROCEDURES: Adult male Wistar rats were stereotactically injected with 1 μg lipopolysaccharide in the right striatum. Three days later, animals underwent a 60-min PET scan with (R)-[(11)C]PK11195 and [(18)F]GE-180 (n = 6) or [(18)F]DPA-714 (n = 6). Ten animals were scanned with either [(18)F]GE-180 (n = 5) or [(18)F]DPA-714 (n = 5) only. Kinetic analysis of PET data was performed using the simplified reference tissue model (SRTM) with a contralateral reference region or a novel data-driven input to estimate binding potential BPND. Autoradiography and immunohistochemistry were performed to confirm in vivo results. RESULTS: At 40-60 min post-injection, [(18)F]GE-180 dual-scanned animals showed a significantly increased core/contralateral uptake ratio vs. the same animals scanned with (R)-[(11)C]PK11195 (3.41 ± 1.09 vs. 2.43 ± 0.39, p = 0.03); [(18)]DPA-714 did not (2.80 ± 0.69 vs. 2.26 ± 0.41). Kinetic modelling with a contralateral reference region identified significantly higher binding potential (BPND) in the core of the LPS injection site with [(18)F]GE-180 but not with [(18)F]DPA-714 vs. (R)-[(11)C]PK11195. A cerebellar reference region and novel data-driven input to the SRTM were unable to distinguish differences in tracer BPND. CONCLUSIONS: Second-generation TSPO-PET tracers are able to accurately detect mild-level NI. In this model, [(18)F]GE-180 shows a higher core/contralateral ratio and BPND when compared to (R)-[(11)C]PK11195, while [(18)F]DPA-714 did not

Targeting the MAPK7/MMP9 axis for metastasis in primary bone cancer

Metastasis is the leading cause of cancer-related death. This multistage process involves contribution from both tumour cells and the tumour stroma to release metastatic cells into the circulation. Circulating tumour cells (CTCs) survive circulatory cytotoxicity, extravasate and colonise secondary sites effecting metastatic outcome. Reprogramming the transcriptomic landscape is a metastatic hallmark, but detecting underlying master regulators that drive pathological gene expression is a key challenge, especially in childhood cancer. Here we used whole tumour plus single-cell RNA-sequencing in primary bone cancer and CTCs to perform weighted gene co-expression network analysis to systematically detect coordinated changes in metastatic transcript expression. This approach with comparisons applied to data collected from cell line models, clinical samples and xenograft mouse models revealed mitogen-activated protein kinase 7/matrix metallopeptidase 9 (MAPK7/MMP9) signalling as a driver for primary bone cancer metastasis. RNA interference knockdown of MAPK7 reduces proliferation, colony formation, migration, tumour growth, macrophage residency/polarisation and lung metastasis. Parallel to these observations were reduction of activated interleukins IL1B, IL6, IL8 plus mesenchymal markers VIM and VEGF in response to MAPK7 loss. Our results implicate a newly discovered, multidimensional MAPK7/MMP9 signalling hub in primary bone cancer metastasis that is clinically actionable

Prevalence and Outcomes for Heavily Treatment-Experienced (HTE) Individuals Living with Human Immunodeficiency Virus in a European Cohort

BACKGROUND: Although antiretroviral treatments have improved survival of persons living with HIV, their long-term use may limit available drug options. We estimated the prevalence of heavily treatment-experienced (HTE) status and the potential clinical consequences of becoming HTE. SETTING: EuroSIDA, a European multicentre prospective cohort study. METHODS: A composite definition for HTE was developed, based on estimates of antiretroviral resistance and prior exposure to specific antiretroviral regimens. Risks of progressing to clinical outcomes were assessed by Poisson regression, comparing every HTE individual with three randomly-selected controls who never became HTE. RESULTS: Of 15,570 individuals under follow-up in 2010-2016, 1617 (10.4%, 95% CI 9.9-10.9%) were classified as HTE. 1093 individuals became HTE during prospective follow-up (HTE incidence rate 1.76, CI 1.66-1.87 per 100 person-years of follow-up). The number of HTE individuals was highest in West/Central Europe (636/4019 persons, 15.7%) and lowest in East Europe (26/2279 persons, 1.1%). Although most HTE individuals maintained controlled viral loads (<400 copies/ml), many had low CD4 counts (≤350 cells/µl). After controlling for age, immunological parameters and pre-existing comorbidities, HTE status was not associated with the risk of new AIDS (adjusted incidence rate ratio, aIRR 1.44, CI 0.86-2.40, p = 0.16) or non-AIDS clinical events (aIRR 0.96, CI 0.74-1.25, p = 0.77). CONCLUSIONS: HTE prevalence increased with time. After adjusting for key confounding factors, there was no evidence for an increased risk of new AIDS or non-AIDS clinical events in HTE. Additional therapeutic options and effective management of comorbidities remain important to reduce clinical complications in HTE individuals

Development and Validation of a Risk Score for Febrile Neutropenia After Chemotherapy in Patients With Cancer: The FENCE Score

Background: Febrile neutropenia (FN) after chemotherapy causes a high burden of morbidity and mortality. We aimed to develop and validate a risk score to predict FN in the first cycle of chemotherapy. Methods: We included patients with solid cancers and diffuse large B-cell lymphomas at Rigshospitalet, University of Copenhagen, 2010-2016. Predictors of FN were analyzed using Poisson regression and random split-sampling. Results: Among 6294 patients in the derivation cohort, 360 developed FN. Female sex, older age, cancer type, disease stage, low albumin, elevated bilirubin, low creatinine clearance, infection before chemotherapy, and number of and type of chemotherapy drugs predicted FN. Compared with those at low risk (n = 2520, 40.0%), the incidence rate ratio of developing FN was 4.8 (95% confidence interval [CI] = 2.9 to 8.1), 8.7 (95% CI = 5.3 to 14.1) and 24.0 (95% CI = 15.2 to 38.0) in the intermediate (n = 1294, 20.6%), high (n = 1249, 19.8%) and very high (n = 1231, 19.6%) risk groups, respectively, corresponding to a number needed to treat with granulocyte colony-stimulating factors to avoid one FN event in the first cycle of 284, 60, 34 and 14. The discriminatory ability (Harrell's C-statistic = 0.80, 95% CI = 0.78 to 0.82) was similar in the validation cohort (n = 3163) (0.79, 95% CI = 0.75 to 0.82). Conclusion: We developed and internally validated a risk score for FN in the first cycle of chemotherapy. The FENCE score is available online and provides good differentiation of risk groups

CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE.

BACKGROUND: Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. METHODS AND FINDINGS: Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements 500 copies/µl, the first of two consecutive measurements between 50-500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30-0.40) for counts <200 cells/µl, 0.81 (0.71-0.92) for counts 200 to <350 cells/µl, 0.74 (0.66-0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92-0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl. CONCLUSIONS: Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl

From Mantle to Motzfeldt : a genetic model for syenite-hosted Ta,Nb-mineralisation

This research summarises many years of field and lab studies on the area, but the most recent work (2016) has received funding from the European Union’s Horizon 2020 research and innovation programme (grant agreement No 689909).A genetic model for the Motzfeldt Tantalum-Niobium-rich syenite in south-west Greenland, considered to be one of the world’s largest Ta prospects, is presented. The Motzfeldt primary magma formed early in regional Gardar (1273 ± 6 Ma) rifting. Isotope signatures indicate that the Hf had multiple sources involving juvenile Gardar Hf mixed with older (Palaeoproterozoic or Archaean) Hf. We infer that other High Field Strength Elements (HFSE) similarly had multiple sources. The magma differentiated in the crust and ascended before emplacement at the regional unconformity between Ketilidian basement and Eriksfjord supracrustals. The HFSE-rich magmas crystallised Ta-rich pyrochlore which formed pyrochlore-rich crystal mushes, and it is these pyrochlore-rich horizons, rich in Ta and Nb, that are the focus of exploration. The roof zone chilled and repeated sheeting at the roof provided a complex suite of cross-cutting syenite variants, including pyrochlore microsyenite, in a ‘Hot Sheeted Roof’ model. The area was subject to hydrothermal alteration which recrystallized alkali feldspar to coarse perthite and modified the mafic minerals to hematite, creating the friable and striking pink-nature of the Motzfeldt Sø Centre. Carbon and oxygen isotope investigation of carbonate constrains fluid evolution and shows that carbonate is primarily mantle-derived but late-stage hydrothermal alteration moved the oxygen isotopes towards more positive values (up to 21‰). The hydrothermal fluid was exceptionally fluorine-rich and mobilised many elements including U and Pb but did not transport HFSE such as Ta, Hf and Nb. Although the U and Pb content of the pyrochlore was enhanced by the fluid, the HFSE contents remained unchanged and therefore Hf isotopes were unaffected by fluid interaction. While the effect on hydrothermal alteration on the visual appearance of the rock is striking, magmatic processes concentrated HFSE including Ta and the hydrothermal phase has not altered the grade. Exploration for HFSE mineralisation commonly relies on airborne radiometric surveying which is particularly sensitive to the presence of U, Th. A crucial lesson from Motzfeldt is that the best target is unaltered pyrochlore which was identified less easily by radiometric survey. Careful petrological/mineral studies are necessary before airborne survey data can be fully interpreted.PreprintPostprintPeer reviewe

Simultaneous interrogation of interferometric and Bragg grating sensors

We propose a new method for the simultaneous interrogation of conventional two-beam interferometers and Bragg grating sensors. The technique employs an unbalanced Mach-Zehnder interferometer illuminated by a single low coherence source, which acts as a wavelength-tunable source for the grating and as a path-matched filter for the Fizeau interferometer, thus providing a high phase resolution output for each sensor. The grating sensor demonstrates a dynamic strain resolution of ~0.05 µ.epsilon/√Hz at 20 Hz, while the interferometric phase resolution is better than 1 mrad/√Hz at 20 Hz, corresponding to an rms mirror displacement of 0.08 nm