| 1. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 2. |
- Almanza-Aguilera, Enrique, et al.
(författare)
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Impact in Plasma Metabolome as Effect of Lifestyle Intervention for Weight-Loss Reveals Metabolic Benefits in Metabolically Healthy Obese Women
- 2018
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3907 .- 1535-3893. ; 17:8, s. 2600-2610
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Tidskriftsartikel (refereegranskat)abstract
- Little is known regarding metabolic benefits of weight loss (WL) on the metabolically healthy obese (MHO) patients. We aimed to examine the impact of a lifestyle weight loss (LWL) treatment on the plasma metabolomic profile in MHO individuals. Plasma samples from 57 MHO women allocated to an intensive LWL treatment group (TG, hypocaloric Mediterranean diet and regular physical activity, n = 30) or to a control group (CG, general recommendations of a healthy diet and physical activity, n = 27) were analyzed using an untargeted1H NMR metabolomics approach at baseline, after 3 months (intervention), and 12 months (follow-up). The impact of the LWL intervention on plasma metabolome was statistically significant at 3 months but not at follow-up and included higher levels of formate and phosphocreatine and lower levels of LDL/VLDL (signals) and trimethylamine in the TG. These metabolites were also correlated with WL. Higher myo-inositol, methylguanidine, and 3-hydroxybutyrate, and lower proline, were also found in the TG; higher levels of hippurate and asparagine, and lower levels of 2-hydroxybutyrate and creatine, were associated with WL. The current findings suggest that an intensive LWL treatment, and the consequent WL, leads to an improved plasma metabolic profile in MHO women through its impact on energy, amino acid, lipoprotein, and microbial metabolism.
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| 3. |
- Almanza-Aguilera, Enrique, et al.
(författare)
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Intake of the total, classes, and subclasses of (poly)phenols and risk of prostate cancer : a prospective analysis of the EPIC study
- 2023
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:16
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Tidskriftsartikel (refereegranskat)abstract
- Existing epidemiological evidence regarding the potential role of (poly)phenol intake in prostate cancer (PCa) risk is scarce and, in the case of flavonoids, it has been suggested that their intake may increase PCa risk. We investigated the associations between the intake of the total and individual classes and subclasses of (poly)phenols and the risk of PCa, including clinically relevant subtypes. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort included 131,425 adult men from seven European countries. (Poly)phenol intake at baseline was assessed by combining validated center/country-specific dietary questionnaires and the Phenol-Explorer database. Multivariable-adjusted Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). In total, 6939 incident PCa cases (including 3501 low-grade and 710 high-grade, 2446 localized and 1268 advanced, and 914 fatal Pca cases) were identified during a mean follow-up of 14 years. No associations were observed between the total intake of (poly)phenols and the risk of PCa, either overall (HRlog2 = 0.99, 95% CI 0.94–1.04) or according to PCa subtype. Null associations were also found between all classes (phenolic acids, flavonoids, lignans, and stilbenes) and subclasses of (poly)phenol intake and the risk of PCa, overall and according to PCa subtype. The results of the current large prospective cohort study do not support any association between (poly)phenol intake and PCa incidence.
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| 4. |
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| 5. |
- Chesnut, Randall, et al.
(författare)
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A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring : the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC)
- 2020
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Ingår i: Intensive Care Medicine. - : Springer. - 0342-4642 .- 1432-1238. ; 46:5, s. 919-929
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Tidskriftsartikel (refereegranskat)abstract
- Background: Current guidelines for the treatment of adult severe traumatic brain injury (sTBI) consist of high-quality evidence reports, but they are no longer accompanied by management protocols, as these require expert opinion to bridge the gap between published evidence and patient care. We aimed to establish a modern sTBI protocol for adult patients with both intracranial pressure (ICP) and brain oxygen monitors in place.Methods: Our consensus working group consisted of 42 experienced and actively practicing sTBI opinion leaders from six continents. Having previously established a protocol for the treatment of patients with ICP monitoring alone, we addressed patients who have a brain oxygen monitor in addition to an ICP monitor. The management protocols were developed through a Delphi-method-based consensus approach and were finalized at an in-person meeting.Results: We established three distinct treatment protocols, each with three tiers whereby higher tiers involve therapies with higher risk. One protocol addresses the management of ICP elevation when brain oxygenation is normal. A second addresses management of brain hypoxia with normal ICP. The third protocol addresses the situation when both intracranial hypertension and brain hypoxia are present. The panel considered issues pertaining to blood transfusion and ventilator management when designing the different algorithms.Conclusions: These protocols are intended to assist clinicians in the management of patients with both ICP and brain oxygen monitors but they do not reflect either a standard-of-care or a substitute for thoughtful individualized management. These protocols should be used in conjunction with recommendations for basic care, management of critical neuroworsening and weaning treatment recently published in conjunction with the Seattle International Brain Injury Consensus Conference.
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| 6. |
- Chesnut, Randall M., et al.
(författare)
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Perceived Utility of Intracranial Pressure Monitoring in Traumatic Brain Injury : A Seattle International Brain Injury Consensus Conference Consensus-Based Analysis and Recommendations
- 2023
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Ingår i: Neurosurgery. - : Oxford University Press. - 0148-396X .- 1524-4040. ; 93:2, s. 399-408
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Intracranial pressure (ICP) monitoring is widely practiced, but the indications are incompletely developed, and guidelines are poorly followed. OBJECTIVE: To study the monitoring practices of an established expert panel (the clinical working group from the Seattle International Brain Injury Consensus Conference effort) to examine the match between monitoring guidelines and their clinical decision-making and offer guidance for clinicians considering monitor insertion.METHODS: We polled the 42 Seattle International Brain Injury Consensus Conference panel members' ICP monitoring decisions for virtual patients, using matrices of presenting signs (Glasgow Coma Scale [GCS] total or GCS motor, pupillary examination, and computed tomography diagnosis). Monitor insertion decisions were yes, no, or unsure (traffic light approach). We analyzed their responses for weighting of the presenting signs in decision-making using univariate regression.RESULTS: Heatmaps constructed from the choices of 41 panel members revealed wider ICP monitor use than predicted by guidelines. Clinical examination (GCS) was by far the most important characteristic and differed from guidelines in being nonlinear. The modified Marshall computed tomography classification was second and pupils third. We constructed a heatmap and listed the main clinical determinants representing 80% ICP monitor insertion consensus for our recommendations.CONCLUSION: Candidacy for ICP monitoring exceeds published indicators for monitor insertion, suggesting the clinical perception that the value of ICP data is greater than simply detecting and monitoring severe intracranial hypertension. Monitor insertion heatmaps are offered as potential guidance for ICP monitor insertion and to stimulate research into what actually drives monitor insertion in unconstrained, real-world conditions.
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| 7. |
- Domingo Prim, Judit, 1989-
(författare)
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The RNA exosome and the maintenance of genome integrity
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The RNA exosome is a ribonucleolytic complex that acts on different RNA substrates and plays important roles in RNA metabolism. In recent years, the synthesis and the processing of RNA have been directly linked to the integrity of the genome. RNAs can either be the responsible for genomic instability or, on the contrary, can participate in the DNA damage response. Damage-induced RNAs (diRNAs) are short non-coding RNAs that have been implicated in the repair of DNA double-strand breaks (DSBs) by homologous recombination. The implication of specialized RNAs in DNA damage and repair led us to investigate whether the exosome was involved in DNA repair.In Paper I, we have shown by fluorescence microscopy and chromatin immunoprecipitation that the exosome catalytic subunit RRP6/EXOSC10 is recruited to DSBs in Drosophila and human cells. Depletion of this subunit or overexpression of a catalytically inactive mutant makes the cells more sensitive to radiation and unable to recruit the homologous recombination factor RAD51 to DSBs, which is consistent with RRP6/EXOSC10 playing a role in homologous recombination, both in insect and mammalian cells. The results obtained with the RRP6 inactive mutant also suggest that the ribonucleolytic activity of RRP6 is required for DNA repair. However, the mechanisms by which RNAs and the exosome are implicated in DNA repair need to be further investigated.In Paper II, we describe how transcription of DSB-flanking sequences by RNA polymerase II gives rise to damage-induced long non-coding RNAs that are processed into diRNAs. The direct detection of diRNAs had been elusive and their existence had been questioned, but our results show that damage-induced transcription and diRNA production occur at DSBs in endogenous, repetitive genomic sequences in mammalian cells. However, our exhaustive next-generation sequencing failed to detect diRNAs derived from DSBs in unique sequences. The diRNAs produced at repetitive loci bind to Argonaute and belong to two different subpopulations. One of them is Dicer-dependent and has a length of 21-22 nucleotides. The other one is not yet well characterized and is probably composed of degradation products from other ribonucleases.Finally, in Paper III, we have demonstrated that EXOSC10 is one of the ribonucleases involved in RNA degradation at DSBs. By strand-specific quantitative PCR and RNA-seq, we show that the levels of diRNA precursors and diRNAs are increased in the absence of EXOSC10. Moreover, EXOSC10-depleted cells fail to recruit RPA to DSBs, and this defect is restored by RNase A digestion. Depletion of EXOSC10 also results in extended DNA resected tracks, as shown by both single-molecule analysis of resected tracks and quantitative amplification of single-stranded DNA. These results suggest that EXOSC10 is involved in RNA degradation at DSBs to allow RPA recruitment and regulated resection.The work presented in this thesis supports the conclusion that damage-induced RNAs are synthesized de novo by RNA polymerase II at DSBs in mammalian cells. In repetitive genomic loci, these RNAs are processed into diRNAs that bind Argonaute. Regardless of whether diRNAs are functional or not, their precursors have to be degraded. The main function of the exosome, and more specifically EXOSC10, in the maintenance of the integrity of the genome is to degrade these transcripts in order to allow faithful repair of DNA double-strand breaks by homologous recombination.
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| 8. |
- Hawryluk, Gregory W. J., et al.
(författare)
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A management algorithm for patients with intracranial pressure monitoring : the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC)
- 2019
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Ingår i: Intensive Care Medicine. - : Springer. - 0342-4642 .- 1432-1238. ; 45:12, s. 1783-1794
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Tidskriftsartikel (refereegranskat)abstract
- Background: Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation's sTBI Management Guidelines, as they were not evidence-based.Methods: We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists' decision tendencies were the focus of recommendations.Results: We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination.Conclusions: Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.
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| 9. |
- Jimeno, Sonia, et al.
(författare)
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ADAR-mediated RNA editing of DNA : RNA hybrids is required for DNA double strand break repair
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Different roles of specific RNA-related factors in DNA repair have now been reported. Here the authors reveal a role for RNA-editing by ADAR in DNA end resection following double strand break formation and a change in pattern of ADAR2-mediated A-to-I editing. The maintenance of genomic stability requires the coordination of multiple cellular tasks upon the appearance of DNA lesions. RNA editing, the post-transcriptional sequence alteration of RNA, has a profound effect on cell homeostasis, but its implication in the response to DNA damage was not previously explored. Here we show that, in response to DNA breaks, an overall change of the Adenosine-to-Inosine RNA editing is observed, a phenomenon we call the RNA Editing DAmage Response (REDAR). REDAR relies on the checkpoint kinase ATR and the recombination factor CtIP. Moreover, depletion of the RNA editing enzyme ADAR2 renders cells hypersensitive to genotoxic agents, increases genomic instability and hampers homologous recombination by impairing DNA resection. Such a role of ADAR2 in DNA repair goes beyond the recoding of specific transcripts, but depends on ADAR2 editing DNA:RNA hybrids to ease their dissolution.
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| 10. |
- Kapidzic, Zlatan, et al.
(författare)
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Bolt fatigue in CFRP joints
- 2022
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Ingår i: International Journal of Fatigue. - : ELSEVIER SCI LTD. - 0142-1123 .- 1879-3452. ; 164
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Tidskriftsartikel (refereegranskat)abstract
- Bending of titanium bolts in in-plane loaded composite joints is potentially fatigue critical. We propose an analytical model for calculation of bending stress in protruding and countersunk-head bolts in composite joints. The model allows for presence of liquid shim and considers the load transfer by friction. We perform experiments on six types of joints, including variants with and without liquid shim or frictionless tape between the plates, and with different levels of bolt pretension. Using the bending stress, we fit an S-N equation to the test results and compare predictions of variable-amplitude fatigue life to experimental results from the literature.
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| 11. |
- Lin, Qinyun, 1990, et al.
(författare)
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Social-spatial network structures among young urban and suburban persons who inject drugs in a large metropolitan area
- 2023
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Ingår i: INTERNATIONAL JOURNAL OF DRUG POLICY. - 0955-3959 .- 1873-4758. ; 122
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recent studies underscore the significance of adopting a syndemics approach to study opioid misuse, overdose, hepatitis C (HCV) and HIV infections, within the broader context of social and environmental contexts in already marginalized communities. Social interactions and spatial contexts are crucial structural factors that remain relatively underexplored. This study examines the intersections of social interactions and spatial contexts around injection drug use. More specifically, we investigate the experiences of different residential groups among young (aged 18-30) people who inject drugs (PWID) regarding their social interactions, travel behaviors, and locations connected to their risk behaviors. By doing so, we aim to achieve a more comprehensive understanding of the multidimensional risk environment, thereby facilitating the development of informed policies.Methods: We collected and examined data regarding young PWID's egocentric injection network and geographic activity spaces (i.e., where they reside, inject drugs, purchase drugs, and meet sex partners). Participants were stratified based on the location of all place(s) of residence in the past year i.e., urban, suburban, and transient (both urban and suburban) to i) elucidate geospatial concentration of risk activities within multidimensional risk environments based on kernel density estimates; and ii) examine spatialized social networks for each residential group.Results: Participants were mostly non-Hispanic white (59%); 42% were urban residents, 28% suburban, and 30% transient. We identified a spatial area with concentrated risky activities for each residential group on the West side of Chicago in Illinois where a large outdoor drug market area is located. The urban group (80%) reported a smaller concentrated area (14 census tracts) compared to the transient (93%) and suburban (91%) with 30 and 51 tracts, respectively. Compared to other areas in Chicago, the identified area had significantly higher neighborhood disadvantages. Significant differences were observed in social network structures and travel behaviors: suburban participants had the most homogenous network in terms of age and residence, transient participants had the largest network (degree) and more non-redundant connections, while the urban group had the shortest travel distance for all types of risk activities.Conclusion: Distinct residential groups exhibit varying patterns of network interaction, travel behaviors, and geographical contexts related to their risk behaviors. Nonetheless, these groups share common concentrated risk activity spaces in a large outdoor urban drug market area, underscoring the significance of accounting for risk spaces and social networks in addressing syndemics within PWID populations.
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| 12. |
- Sarigul, Buse, et al.
(författare)
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Prognostication and Goals of Care Decisions in Severe Traumatic Brain Injury : A Survey of The Seattle International Severe Traumatic Brain Injury Consensus Conference Working Group
- 2023
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 40:15-16, s. 1707-1717
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Tidskriftsartikel (refereegranskat)abstract
- Best practice guidelines have advanced severe traumatic brain injury (TBI) care; however, there is little that currently informs goals of care decisions and processes despite their importance and frequency. Panelists from the Seattle International severe traumatic Brain Injury Consensus Conference (SIBICC) participated in a survey consisting of 24 questions. Questions queried use of prognostic calculators, variability in and responsibility for goals of care decisions, and acceptability of neurological outcomes, as well as putative means of improving decisions that might limit care. A total of 97.6% of the 42 SIBICC panelists completed the survey. Responses to most questions were highly variable. Overall, panelists reported infrequent use of prognostic calculators, and observed variability in patient prognostication and goals of care decisions. They felt that it would be beneficial for physicians to improve consensus on what constitutes an acceptable neurological outcome as well as what chance of achieving that outcome is acceptable. Panelists felt that the public should help to define what constitutes a good outcome and expressed some support for a "nihilism guard." More than 50% of panelists felt that if it was certain to be permanent, a vegetative state or lower severe disability would justify a withdrawal of care decision, whereas 15% felt that upper severe disability justified such a decision. Whether conceptualizing an ideal or existing prognostic calculator to predict death or an unacceptable outcome, on average a 64-69% chance of a poor outcome was felt to justify treatment withdrawal. These results demonstrate important variability in goals of care decision making and a desire to reduce this variability. Our panel of recognized TBI experts opined on the neurological outcomes and chances of those outcomes that might prompt consideration of care withdrawal; however, imprecision of prognostication and existing prognostication tools is a significant impediment to standardizing the approach to care-limiting decisions.
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| 13. |
- Savolainen, Linda, 1974-
(författare)
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Transcription Associated Recombination in Mammalian Cells
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is increasing evidence that the movement of the transcription machinery through DNA has profound effects on the genomic stability. One such example is a phenomenon known as Transcription Associated Recombination (TAR). Transcription enhances recombination levels to a high degree in all organisms studied, from bacteria to mammals. The underlying causes of the high recombination levels observed are unknown, as are the rationale for the rather riskyhazardous recombination event in this context. Recombination is not a risk-free event; there is e.g. the chancerisk for of loss of heterozygozity, which may eventually lead to tumour formation. So, why is TAR so ubiquitous? This thesis deals with the factors inducing TAR, trying to elucidate the mechanisms catalyzing this event. The proteins involved in executing TAR are unknown in mammals, and one of the aims of this thesis havehas been to investigate the role of well-known DNA repair proteins in TAR. In order to do so, cell lines deficient in crucial DNA repair proteins were stably transfected with a novel recombination construct. Transcription can be controlled over this recombination construct, enabling the detection of transcription associated recombination. We found that TAR is dependent on replication and that inhibition of transcription elongation had no further effect on TAR levels in our system. Further, we found that TAR employs a recombination pathway mechanistically separate from the recombination pathway induced by DNA double strand breaks. This pathway is dependent on BRCA2, a protein required for homologous recombination, but independent of the RAD51 paralog XRCC2. In subsequent studies, we found that the XPD subunit of the combined transcription and repair factor TFIIH is required for TAR, but is dispensable for DNA DSB repair by HR. We went on to investigate the connection between HR repair of UV damages and transcription and found that repair of UV damages requires transcription, but not via the transcription-coupled repair pathway. In conclusion, we found that TAR operates by a recombination pathway separate from DNA double strand break induced recombination. We found a connection with stalled replication, and revealed several of the proteins required for TAR in mammals.
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| 14. |
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