| 1. |
- Bosch Campos, Ana, et al.
(författare)
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PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer
- 2015
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 7:283, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase a (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.
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| 2. |
- Chuquimia, Olga D., et al.
(författare)
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Molecular analyses of fecal bacteria and hydrodynamic modeling for microbial risk assessment of a drinking water source
- 2020
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Ingår i: Water (Switzerland). - : MDPI AG. - 2073-4441 .- 2073-4441. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Safe water is a global concern, and methods to accurately monitor quality of water are vital. To assess the risks related to bacterial pathogen load in Lake Vomb that provides drinking water to the southern part of Sweden, this study combined molecular analyses of enterobacteria and bacterial pathogens in water using quantitiative real-time PCR with hydrodynamic modeling and quantitative microbial risk assessment (QMRA). A real-time PCR assay to detect enterobacteria was set up by primers targeting ssrA. Between February 2015 and May 2016, presence of ssrA gene copies as well as Campylobacter spp., Salmonella spp., and EHEC O157 DNA was analyzed by real-time PCR at several locations in the catchment of Lake Vomb and its tributaries Bjorkaan, Borstbacken, and Torpsbacken. Bjorkaan had the highest detected concentrations of the ssrA gene and, according to the results of hydrodynamic modeling, contributed most to the contamination of the water intake in the lake. None of the water samples were positive for genes encoding EHEC O157 and Campylobacter spp., while invA (Salmonella spp.) was present in 11 samples. The QMRA showed that the suggested acceptable risk level (daily probability of infection <2.7 x 10-7) is achieved with a 95% probability, if the Salmonella concentrations in the water intake are below 101 bacteria/100 mL. If a UV-disinfection step is installed, the Salmonella concentration at the water intake should not exceed 106 bacteria/100 mL.
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| 3. |
- Guzman Otazo, Carol Jessica
(författare)
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Bacterial communities and antibiotic resistance in human-impacted water environments
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- From a One-Health concept the health of humans, animals and the environment is interconnected and what happens to one of the domains will affect the other two simultaneously. This concept can be applied not only to the transmission of bacterial infectious diseases but also to the transmission of antibiotic resistance. While bacterial infectious diseases caused by water-borne pathogens are still a leading cause of morbidity and mortality worldwide, the development and spread of antibiotic resistant bacteria is threatening human health like never before. If we are not able to control the generation and spread of antibiotic resistant bacteria, in the near future thousands of people will die of infections that were treatable before. The relationship between human and animal health has been widely studied before but the environment is usually set aside minimizing the impact and effect of contaminated environments on human and animal health. Contaminated water environments represent a suitable place for the accumulation, spread and transmission of pathogenic and antibiotic resistant bacteria. In that sense, water environments are good interfaces where the transfer of antibiotic resistance determinants between bacteria might occur. Hence water environments might represent a good place for the surveillance of pathogenic bacteria and antibiotic resistance. In this thesis we aimed to characterize pathogenic and non-pathogenic bacterial communities as well as antibiotic resistant bacteria and antibiotic resistance genes in highly contaminated rivers in La Paz and Oruro in Bolivia as well as in a waster water pump at a suburban community in Oslo. We also aimed to evaluate the potential of bacterial communities from contaminated water environments to transfer antibiotic resistance determinants to E. coli and test the effect of heavy metals in the occurrence and transfer of antibiotic resistance. We found high prevalence of enterobacteria, pathogenic E. coli and other diarrheal bacteria in water, agricultural soil and vegetables from an urban-impacted basin in La Paz, Bolivia (Paper I). Moreover, we repeatedly found the globally distributed and multi-drug resistant E. coli sequence types ST131 in Norway and ST648 both in Bolivia and Norway showing the important role of the environment for the dispersion of pathogenic and antibiotic resistant bacteria (Paper I and II). Additionally, we proved a high capability of bacterial communities from contaminated water environments to transfer antibiotic resistance determinants to E. coli. We showed that presence of metals such as ZnSO4 and CuSO4 in conjugation experiments might favor the transfer/acquisition of more diverse phenotypic multi-drug resistance profiles and mobile genetic elements carrying higher diversity of genes including extended spectrum beta-lactamases and other relevant genes conferring important advantages to the bacterial host (Paper III). Bacterial donors from contaminated irrigation water transferred a high diversity of antibiotic resistance determinants at considerable levels showing the potential risk of transmission of antibiotic resistance to human populations by contaminated irrigation water and vegetables (Paper III). We did not find significant associations between metal composition, bacterial communities and the abundance of selected antibiotic resistance determinants in acid mine drainage contaminated watersheds in Oruro, Bolivia (Paper IV).
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| 4. |
- Guzman-Parra, Jose, et al.
(författare)
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Attitudes and use of information and communication technologies in older adults with mild cognitive impairment or early stages of dementia and their caregivers : cross-sectional study
- 2020
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Ingår i: Journal of Medical Internet Research. - : JMIR Publications. - 1438-8871. ; 22:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Information and communication technologies are promising tools to increase the quality of life of people with dementia or mild cognitive impairment and that of their caregivers. However, there are barriers to their use associated with sociodemographic factors and negative attitudes, as well as inadequate knowledge about technologies. OBJECTIVE: The aim of this study was to analyze technophilia (attitudes toward new technologies) and the use of smartphones and tablets along with associated factors in people with dementia/mild cognitive impairment and their caregivers. METHODS: Data from the first visit of the Support Monitoring and Reminder for Mild Dementia (SMART4MD) randomized multicenter clinical trial were used for this analysis. Data were obtained from two European countries, Spain and Sweden, and from three centers: Consorci Sanitari de Terrassa (Catalonia, Spain), Servicio Andaluz de Salud (Andalusia, Spain), and the Blekinge Institute of Technology (Sweden). Participants with a score between 20 and 28 in the Mini Mental State Examination, with memory problems (for more than 6 months), and who were over the age of 55 years were included in the study, along with their caregivers. The bivariate Chi square and Mann-Whitney tests, and multivariate linear and logistic regression models were used for statistical analysis. RESULTS: A total of 1086 dyads were included (N=2172). Overall, 299 (27.53%) of people with dementia/mild cognitive impairment had a diagnosis of dementia. In addition, 588 (54.14%) of people with dementia/mild cognitive impairment reported using a smartphone almost every day, and 106 (9.76%) used specific apps or software to support their memory. Among the caregivers, 839 (77.26%) used smartphones and tablets almost every day, and 181 (16.67%) used specific apps or software to support their memory. The people with dementia/mild cognitive impairment showed a lower level of technophilia in comparison to that of their caregivers after adjusting for confounders (B=0.074, P=.02) with differences in technology enthusiasm (B=0.360, P<.001), but not in technology anxiety (B=-0.042, P=.37). Technophilia was associated with lower age (B=-0.009, P=.004), male gender (B=-0.160, P<.001), higher education level (P=.01), living arrangement (living with children vs single; B=-2.538, P=.01), country of residence (Sweden vs Spain; B=0.256, P<.001), lower depression (B=-0.046, P<.001), and better health status (B=0.004, P<.001) in people with dementia/mild cognitive impairment. Among caregivers, technophilia was associated with comparable sociodemographic factors (except for living arrangement), along with a lower caregiver burden (B=-0.005, P=.04) and better quality of life (B=0.348, P<.001). CONCLUSIONS: Technophilia was associated with a better quality of life and sociodemographic variables in people with dementia/mild cognitive impairment and caregivers, suggesting potential barriers for technological interventions. People with dementia/mild cognitive impairment frequently use smartphones and tablets, but the use of specific apps or software to support memory is limited. Interventions using these technologies are needed to overcome barriers in this population related to sociodemographic characteristics and the lack of enthusiasm for new technologies. TRIAL REGISTRATION: ClinicalTrials.gov NCT03325699; https://clinicaltrials.gov/ct2/show/NCT03325699. ©Jose Guzman-Parra, Pilar Barnestein-Fonseca, Gloria Guerrero-Pertiñez, Peter Anderberg, Luis Jimenez-Fernandez, Esperanza Valero-Moreno, Jessica Marian Goodman-Casanova, Antonio Cuesta-Vargas, Maite Garolera, Maria Quintana, Rebeca I García-Betances, Evi Lemmens, Johan Sanmartin Berglund, Fermin Mayoral-Cleries.
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| 5. |
- Jung, Christian, et al.
(författare)
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A comparison of very old patients admitted to intensive care unit after acute versus elective surgery or intervention
- 2019
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Ingår i: Journal of critical care. - : W B SAUNDERS CO-ELSEVIER INC. - 0883-9441 .- 1557-8615. ; 52, s. 141-148
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to evaluate differences in outcome between patients admitted to intensive care unit (ICU) after elective versus acute surgery in a multinational cohort of very old patients (80 years; VIP). Predictors of mortality, with special emphasis on frailty, were assessed.Methods: In total, 5063 VIPs were induded in this analysis, 922 were admitted after elective surgery or intervention, 4141 acutely, with 402 after acute surgery. Differences were calculated using Mann-Whitney-U test and Wilcoxon test. Univariate and multivariable logistic regression were used to assess associations with mortality.Results: Compared patients admitted after acute surgery, patients admitted after elective surgery suffered less often from frailty as defined as CFS (28% vs 46%; p < 0.001), evidenced lower SOFA scores (4 +/- 5 vs 7 +/- 7; p < 0.001). Presence of frailty (CFS >4) was associated with significantly increased mortality both in elective surgery patients (7% vs 12%; p = 0.01), in acute surgery (7% vs 12%; p = 0.02).Conclusions: VIPs admitted to ICU after elective surgery evidenced favorable outcome over patients after acute surgery even after correction for relevant confounders. Frailty might be used to guide clinicians in risk stratification in both patients admitted after elective and acute surgery.
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| 6. |
- Lozano, Rafael, et al.
(författare)
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Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017
- 2018
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Ingår i: The Lancet. - : Elsevier. - 1474-547X .- 0140-6736. ; 392:10159, s. 2091-2138
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Tidskriftsartikel (refereegranskat)abstract
- Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59·4 (IQR 35·4–67·3), ranging from a low of 11·6 (95% uncertainty interval 9·6–14·0) to a high of 84·9 (83·1–86·7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030.
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| 7. |
- Manzano-Nunez, Ramiro, et al.
(författare)
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Outcomes and management approaches of resuscitative endovascular balloon occlusion of the aorta based on the income of countries
- 2020
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Ingår i: World Journal of Emergency Surgery. - : Springer Science and Business Media LLC. - 1749-7922. ; 15:57
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Tidskriftsartikel (refereegranskat)abstract
- © 2020 The Author(s). Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) could provide a survival benefit to severely injured patients as it may improve their initial ability to survive the hemorrhagic shock. Although the evidence supporting the use of REBOA is not conclusive, its use has expanded worldwide. We aim to compare the management approaches and clinical outcomes of trauma patients treated with REBOA according to the countries' income based on the World Bank Country and Lending Groups. Methods: We used data from the AORTA (USA) and the ABOTrauma (multinational) registries. Patients were stratified into two groups: (1) high-income countries (HICs) and (2) low-to-middle income countries (LMICs). Propensity score matching extracted 1:1 matched pairs of subjects who were from an LMIC or a HIC based on age, gender, the presence of pupillary response on admission, impeding hypotension (SBP ≤ 80), trauma mechanism, ISS, the necessity of CPR on arrival, the location of REBOA insertion (emergency room or operating room) and the amount of PRBCs transfused in the first 24 h. Logistic regression (LR) was used to examine the association of LMICs and mortality. Results: A total of 817 trauma patients from 14 countries were included. Blind percutaneous approach and surgical cutdown were the preferred means of femoral cannulation in HICs and LIMCs, respectively. Patients from LMICs had a significantly higher occurrence of MODS and respiratory failure. LR showed no differences in mortality for LMICs when compared to HICs; neither in the non-matched cohort (OR = 0.63; 95% CI: 0.36-1.09; p = 0.1) nor in the matched cohort (OR = 1.45; 95% CI: 0.63-3,33; p = 0.3). Conclusion: There is considerable variation in the management practices of REBOA and the outcomes associated with this intervention between HICs and LMICs. Although we found significant differences in multiorgan and respiratory failure rates, there were no differences in the risk-adjusted odds of mortality between the groups analyzed. Trauma surgeons practicing REBOA around the world should joint efforts to standardize the practice of this endovascular technology worldwide.
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| 8. |
- Wilkinson, John L., et al.
(författare)
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Pharmaceutical pollution of the world's rivers
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:8
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Tidskriftsartikel (refereegranskat)abstract
- Environmental exposure to active pharmaceutical ingredients (APIs) can have negative effects on the health of ecosystems and humans. While numerous studies have monitored APIs in rivers, these employ different analytical methods, measure different APIs, and have ignored many of the countries of the world. This makes it difficult to quantify the scale of the problem from a global perspective. Furthermore, comparison of the existing data, generated for different studies/regions/continents, is challenging due to the vast differences between the analytical methodologies employed. Here, we present a global-scale study of API pollution in 258 of the world's rivers, representing the environmental influence of 471.4 million people across 137 geographic regions. Samples were obtained from 1,052 locations in 104 countries (representing all continents and 36 countries not previously studied for API contamination) and analyzed for 61 APIs. Highest cumulative API concentrations were observed in sub-Saharan Africa, south Asia, and South America. The most contaminated sites were in low- to middle-income countries and were associated with areas with poor wastewater and waste management infrastructure and pharmaceutical manufacturing. The most frequently detected APIs were carbamazepine, metformin, and caffeine (a compound also arising from lifestyle use), which were detected at over half of the sites monitored. Concentrations of at least one API at 25.7% of the sampling sites were greater than concentrations considered safe for aquatic organisms, or which are of concern in terms of selection for antimicrobial resistance. Therefore, pharmaceutical pollution poses a global threat to environmental and human health, as well as to delivery of the United Nations Sustainable Development Goals.
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