| 1. |
- Bravo, L, et al.
(author)
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- 2021
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swepub:Mat__t
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| 2. |
- Tabiri, S, et al.
(author)
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- 2021
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swepub:Mat__t
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| 5. |
- Khatri, C, et al.
(author)
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Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study
- 2021
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In: BMJ open. - : BMJ. - 2044-6055. ; 11:11, s. e050830-
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Journal article (peer-reviewed)abstract
- Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.SettingProspective, international, multicentre, observational cohort study.ParticipantsPatients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.ResultsThis study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p<0.001), age >80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).ConclusionsPatients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration numberNCT04323644
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| 9. |
- Bonham, LW, et al.
(author)
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Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
- 2019
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10854-
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Journal article (peer-reviewed)abstract
- The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.
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| 10. |
- Bosco, C, et al.
(author)
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Exploring the high-resolution mapping of gender-disaggregated development indicators
- 2017
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In: Journal of the Royal Society, Interface. - : The Royal Society. - 1742-5662 .- 1742-5689. ; 14:129
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Journal article (peer-reviewed)abstract
- Improved understanding of geographical variation and inequity in health status, wealth and access to resources within countries is increasingly being recognized as central to meeting development goals. Development and health indicators assessed at national or subnational scale can often conceal important inequities, with the rural poor often least well represented. The ability to target limited resources is fundamental, especially in an international context where funding for health and development comes under pressure. This has recently prompted the exploration of the potential of spatial interpolation methods based on geolocated clusters from national household survey data for the high-resolution mapping of features such as population age structures, vaccination coverage and access to sanitation. It remains unclear, however, how predictable these different factors are across different settings, variables and between demographic groups. Here we test the accuracy of spatial interpolation methods in producing gender-disaggregated high-resolution maps of the rates of literacy, stunting and the use of modern contraceptive methods from a combination of geolocated demographic and health surveys cluster data and geospatial covariates. Bayesian geostatistical and machine learning modelling methods were tested across four low-income countries and varying gridded environmental and socio-economic covariate datasets to build 1×1 km spatial resolution maps with uncertainty estimates. Results show the potential of the approach in producing high-resolution maps of key gender-disaggregated socio-economic indicators, with explained variance through cross-validation being as high as 74–75% for female literacy in Nigeria and Kenya, and in the 50–70% range for many other variables. However, substantial variations by both country and variable were seen, with many variables showing poor mapping accuracies in the range of 2–30% explained variance using both geostatistical and machine learning approaches. The analyses offer a robust basis for the construction of timely maps with levels of detail that support geographically stratified decision-making and the monitoring of progress towards development goals. However, the great variability in results between countries and variables highlights the challenges in applying these interpolation methods universally across multiple countries, and the importance of validation and quantifying uncertainty if this is undertaken.
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| 13. |
- Figlioli, G, et al.
(author)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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In: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Journal article (peer-reviewed)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 14. |
- Gerkin, RC, et al.
(author)
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The best COVID-19 predictor is recent smell loss: a cross-sectional study
- 2020
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In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
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Journal article (other academic/artistic)abstract
- BackgroundCOVID-19 has heterogeneous manifestations, though one of the most common symptoms is a sudden loss of smell (anosmia or hyposmia). We investigated whether olfactory loss is a reliable predictor of COVID-19.MethodsThis preregistered, cross-sectional study used a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified singular and cumulative predictors of COVID-19 status and post-COVID-19 olfactory recovery.ResultsBoth C19+ and C19-groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both single and cumulative feature models (ROC AUC=0.72), with additional features providing negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms, such as fever or cough. Olfactory recovery within 40 days was reported for ∼50% of participants and was best predicted by time since illness onset.ConclusionsAs smell loss is the best predictor of COVID-19, we developed the ODoR-19 tool, a 0-10 scale to screen for recent olfactory loss. Numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4<OR<10), which can be deployed when viral lab tests are impractical or unavailable.
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| 15. |
- Horejs, CM, et al.
(author)
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Preventing tissue fibrosis by local biomaterials interfacing of specific cryptic extracellular matrix information
- 2017
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8, s. 15509-
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Journal article (peer-reviewed)abstract
- Matrix metalloproteinases (MMPs) contribute to the breakdown of tissue structures such as the basement membrane, promoting tissue fibrosis. Here we developed an electrospun membrane biofunctionalized with a fragment of the laminin β1-chain to modulate the expression of MMP2 in this context. We demonstrate that interfacing of the β1-fragment with the mesothelium of the peritoneal membrane via a biomaterial abrogates the release of active MMP2 in response to transforming growth factor β1 and rescues tissue integrity ex vivo and in vivo in a mouse model of peritoneal fibrosis. Importantly, our data demonstrate that the membrane inhibits MMP2 expression. Changes in the expression of epithelial-to-mesenchymal transition (EMT)-related molecules further point towards a contribution of the modulation of EMT. Biomaterial-based presentation of regulatory basement membrane signals directly addresses limitations of current therapeutic approaches by enabling a localized and specific method to counteract MMP2 release applicable to a broad range of therapeutic targets.
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