| 62241. |
- Sparrelid, Ernesto, et al.
(författare)
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How should liver hypertrophy be stimulated? A comparison of upfront associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and portal vein embolization (PVE) with rescue possibility
- 2021
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Ingår i: Hepatobiliary surgery and nutrition. - : AME Publishing Company. - 2304-3881 .- 2304-389X. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The role of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in comparison to portal vein embolization (PVE) is debated. The aim of this study was to compare successful resection rates (RR) with upfront ALPPS vs. PVE with rescue ALPPS on demand and to compare the hypertrophy of the liver between ALPPS and PVE plus subsequent rescue ALPPS. Methods: A retrospective analysis of all patients treated with PVE for colorectal liver metastasis (CRLM) or ALPPS (any diagnosis, rescue ALPPS included) at five Scandinavian university hospitals during the years 2013-2016 was conducted. A Chi-square test and a Mann-Whitney U test were used to assess the difference between the groups. A successful RR was defined as liver resection without a 90-day mortality. Results: A total of 189 patients were included. Successful RR was in 84.5% of the patients with ALPPS upfront and in 73.3% of the patients with PVE and rescue ALPPS on demand (P=0.080). The hypertrophy of the future liver remnants (FLRs) with ALPPS upfront was 71% (48-97%) compared to 96% (82-113%) after PVE and rescue ALPPS (P=0.010). Conclusions: Upfront ALPPS offers a somewhat higher successful RR than PVE with rescue ALPPS on demand. The sequential combination of PVE and ALPPS leads to a higher overall degree of hypertrophy than upfront ALPPS.
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| 62242. |
- Sparring, Vibeke, et al.
(författare)
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One size fits none : a qualitative study investigating nine national quality registries' conditions for use in quality improvement, research and interaction with patients
- 2018
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Ingår i: BMC Health Services Research. - : BioMed Central. - 1472-6963. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Swedish National Quality Registries (NQRs) are observational clinical registries that have long been seen as an underused resource for research and quality improvement (QI) in health care. In recent years, NQRs have also been recognised as an area where patients can be involved, contributing with self-reported experiences and estimations of health effects. This study aimed to investigate what the registry management perceived as barriers and facilitators for the use of NQRs in QI, research, and interaction with patients, and main activities undertaken to enhance their use for these purposes. The aim was further to identify potential differences between various types of NQRs for their use in these areas.Methods: In this multiple case study, nine NQRs were purposively selected. Interviews (n = 18) were conducted and analysed iteratively using conventional and directed content analysis.Results: A recent national investment initiative enabled more intensive work with development areas previously identified by the NQR management teams. The recent focus on value-based health care and other contemporary national healthcare investments aiming at QI and public benchmarking were perceived as facilitating factors. Having to perform double registrations due to shortcomings in digital systems was perceived as a barrier, as was the lack of authority on behalf of the registry management to request participation in NQRs and QI activities based on registry outcomes. The registry management teams used three strategies to enhance the use of NQRs: ensuring registering of correct and complete data, ensuring updated and understandable information available for patients, clinicians, researchers and others stakeholders, and intensifying cooperation with them. Varied characteristics of the NQRs influenced their use, and the possibility to reach various end-users was connected to the focus area and context of the NQRs.Conclusions: The recent national investment initiative contributed to already ongoing work to strengthen the use of NQRs. To further increase the use, the demands of stakeholders and end-users must be in focus, but also an understanding of the NQRs' various characteristics and challenges. The end-users may have in common a need for training in the methodology of registry based research and benchmarking, and how to be more patient-centred.
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| 62243. |
- Sparve, Erik, et al.
(författare)
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Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839
- 2014
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 350:2, s. 469-478
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Tidskriftsartikel (refereegranskat)abstract
- Corrected QT interval (QTc) prolongation in humans is usually predictable based on results from preclinical findings. This study confirms the signal from preclinical cardiac repolarization models (human ether-a-go-go-related gene, guinea pig monophasic action potential, and dog telemetry) on the clinical effects on the QTc interval. A thorough QT/QTc study is generally required for bioavailable pharmaceutical compounds to determine whether or not a drug shows a QTc effect above a threshold of regulatory interest. However, as demonstrated in this AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate] single-ascending-dose (SAD) study, high-resolution digital electrocardiogram data, in combination with adequate efficacy biomarker and pharmacokinetic data and nonlinear mixed effects modeling, can provide the basis to safely explore the margins to allow for robust modeling of clinical effect versus the electrophysiological risk marker. We also conclude that a carefully conducted SAD study may provide reliable data for effective early strategic decision making ahead of the thorough QT/QTc study.
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| 62244. |
- Spaulding, Kirsty, et al.
(författare)
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Dynamics of Hippocampal Neurogenesis in Adult Humans
- 2013
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Ingår i: Cell. - Maryland Heights, MO, USA : Elsevier. - 0092-8674 .- 1097-4172. ; 153:6, s. 1219-1227
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Tidskriftsartikel (refereegranskat)abstract
- Adult-born hippocampal neurons are important for cognitive plasticity in rodents. There is evidence for hippocampal neurogenesis in adult humans, although whether its extent is sufficient to have func- tional significance has been questioned. We have assessed the generation of hippocampal cells in humans by measuring the concentration of nuclear- bomb-test-derived 14C in genomic DNA, and we present an integrated model of the cell turnover dy- namics. We found that a large subpopulation of hip- pocampal neurons constituting one-third of the neu- rons is subject to exchange. In adult humans, 700 new neurons are added in each hippocampus per day, corresponding to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging. We conclude that neu- rons are generated throughout adulthood and that the rates are comparable in middle-aged humans and mice, suggesting that adult hippocampal neuro- genesis may contribute to human brain function.
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| 62245. |
- Spectre, Galia, et al.
(författare)
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Meal intake increases circulating procoagulant microparticles in patients with type 1 and type 2 diabetes mellitus
- 2019
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Ingår i: Platelets. - : Informa UK Limited. - 0953-7104 .- 1369-1635. ; 30:3, s. 348-355
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes mellitus (DM) is associated with prothrombotic alterations, and postprandial hyperglycemia is an independent risk factor for cardiovascular complications. We therefore investigated whether a standardized mixed meal alters circulating microparticles (MPs) and their procoagulant activity in DM patients. Patients with DM type 1 (T1DM, n = 11) and type 2 (T2DM; n = 9) were studied before and 90 min after a standardized meal (without premeal insulin). MPs in plasma derived from platelets (PMPs), endothelial cells (EMPs), or monocytes (MMPs) were measured by flow cytometry. MP-induced thrombin generation in plasma was assessed by a calibrated automated thrombogram. In the fasting state, MPs did not differ significantly between T1DM and T2DM. Meal intake increased the following microparticles: PMPs expressing phosphatidylserine (by 55%, on average), P-selectin (by 86%), and tissue factor (TF; by 112%); EMPs expressing E-selectin (by 96%) and MMPs expressing TF (by 164%), with no significant group differences between T1DM and T2DM. There were no increments in EMPs expressing phosphatidylserine or TF. Meal intake increased MP-induced thrombin generation similarly in T1DM and T2DM with increased endogenous thrombin potential (p = 0.02) and peak thrombin (p = 0.03) and shortened time to peak (p = 0.02). Phosphatidylserine inhibition by lactadherin completely abolished MP-induced thrombin generation, while an anti-TF antibody had no effect. In conclusion, meal intake increased several types of circulating MPs in patients with diabetes mellitus. These MPs have a procoagulant potential, which is related to phosphatidylserine expression and negatively charged MP surfaces rather than to TF.
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| 62246. |
- Spelman, T., et al.
(författare)
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The association between disease activity and health-related quality of life in RRMS patients
- 2017
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Ingår i: Value in Health. - : ELSEVIER SCIENCE INC. - 1098-3015 .- 1524-4733. ; 20:9, s. A728-A728
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: Relapse-remitting multiple sclerosis (RRMS) is the most common disease course of multiple sclerosis (MS) patients. Disease activity (DA) has been shown to impact intermediate clinical outcomes including relapse rates and disease progression. However, it is unclear to what extent DA is related to ultimate health outcomes such as health-related quality of life (HRQoL). This study investigates the association between HRQoL and DA. Methods: Generic HRQoL was measured using the EQ-5D-3L utility instrument index value under the United Kingdom tariff. A cohort of 3496 adult RRMS patients enrolled in the Swedish population-based MS register during 1996-2015 (inclusive) was included from the date of first recorded EQ-5D-3L assessment (baseline). Patients were grouped according to DA within +/- 12 months of baseline. Active disease was the reference group, defined as 1+ relapse or T2 lesion. Two high disease activity groups were considered: HDA-R defined as 2+ relapses recorded within 1 year of each other, or Highly Active RRMS (HA-RRMS) defined as 9+ T2 lesions or 1+ gadolinium-enhanced T1 lesion. Patients not fulfilling any DA criteria were labelled unclassified. A general estimating equation was used to analyse the association between longitudinal EQ-5D-3L and disease activity group; adjusting for age, sex, proportion of time treated with disease modifying treatment (%DMT), and time since registry enrolment. Results: HA-RRMS was associated with a statistically significant decrease in EQ-5D-3L (coefficient -0.01, p=0.04). HDA-R and unclassified patients were not statistically significantly associated with EQ-5D-3L. Female sex and increasing age were significantly associated with decreasing EQ-5D-3L, while %DMT and time since registry enrolment were significantly associated with increasing EQ-5D-3L. Conclusions: HA-RRMS is associated with lower HRQoL over time, although it is unclear whether it is clinically significant. Additional data and modelling may be required to uncover the subtleties of the relationship between DA and HRQoL.
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| 62247. |
- Spence, J David, et al.
(författare)
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Stroke Prevention in Older Adults : Recent Advances.
- 2020
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 51:12, s. 3770-3777
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Tidskriftsartikel (refereegranskat)abstract
- The risks of stroke and dementia increase steeply with age, and both are preventable. At present, the best way to preserve cognitive function is to prevent stroke. Therapeutic nihilism based on age is common and unwarranted. We address recent advances in stroke prevention that could contribute greatly to prevention of stroke and dementia at a time when the aging of the population threatens to markedly increase the incidence of both. Issues discussed: (1) old patients benefit even more from lipid-lowering therapy than do younger patients; (2) patients with stiff arteries are at risk from a target systolic blood pressure <120 mm Hg; (3) the interaction of the intestinal microbiome, age, and renal function has important dietary implications for older adults; (4) anticoagulation with direct-acting oral anticoagulants should be prescribed more to old patients with atrial fibrillation; (5) B vitamins to lower homocysteine prevent stroke; and (6) most old patients in whom intervention is warranted for carotid stenosis would benefit more from endarterectomy than from stenting. An 80-year-old person has much to lose from a stroke and should not have effective therapy withheld on account of age. Lipid-lowering therapy, a more plant-based diet, appropriate anticoagulation or antiplatelet therapy, appropriate blood pressure control, B vitamins to lower homocysteine, and judicious intervention for carotid stenosis could do much to reduce the growing burden of stroke and dementia.
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| 62248. |
- Sperber, Jesper, et al.
(författare)
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Pre-exposure to mechanical ventilation and endotoxemia increases Pseudomonas aeruginosa growth in lung tissue during experimental porcine pneumonia
- 2020
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Immune system suppression during critical care contributes to the risk of acquired bacterial infections with Pseudomonas (P.) aeruginosa. Repeated exposure to endotoxin can attenuate systemic inflammatory cytokine responses. Mechanical ventilation affects the systemic inflammatory response to various stimuli.Aim: To study the effect of pre-exposure to mechanical ventilation with and without endotoxin-induced systemic inflammation on P. aeruginosa growth and wet-to-dry weight measurements on lung tissue and plasma and bronchoalveolar lavage levels of tumor necrosis factor alpha, interleukins 6 and 10.Methods: Two groups of pigs were exposed to mechanical ventilation for 24 hours before bacterial inoculation and six h of experimental pneumonia (total experimental time 30 h): A(30h+Etx) (n = 6, endotoxin 0.063 mu g x kg(-1) x h(-1)) and B-30h (n = 6, saline). A third group, C-6h (n = 8), started the experiment at the bacterial inoculation unexposed to endotoxin or mechanical ventilation (total experimental time 6 h). Bacterial inoculation was performed by tracheal instillation of 1x10(11) colony-forming units of P. aeruginosa. Bacterial cultures and wet-to-dry weight ratio analyses were done on lung tissue samples postmortem. Separate group comparisons were done between A(30h+Etx) vs.B-30h (Inflammation) and B-30h vs. C-6h (Ventilation Time) during the bacterial phase of 6 h.Results: P. aeruginosa growth was highest in A(30h+Etx), and lowest in C-6h (Inflammation and Ventilation Time both p<0.05). Lung wet-to-dry weight ratios were highest in A(30h+Etx) and lowest in B-30h (Inflammation p<0.01, Ventilation Time p<0.05). C-6h had the highest TNF-alpha levels in plasma (Ventilation Time p<0.01). No differences in bronchoalveolar lavage variables between the groups were observed.Conclusions: Mechanical ventilation and systemic inflammation before the onset of pneumonia increase the growth of P. aeruginosa in lung tissue. The attenuated growth of P. aeruginosa in the non-pre-exposed animals (C-6h) was associated with a higher systemic TNF-alpha production elicited from the bacterial challenge.
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| 62249. |
- Sperk, Maike, et al.
(författare)
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Plasma soluble factor following two decades prolonged suppressive antiretroviral therapy in HIV-1-positive males A cross-sectional study
- 2018
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Ingår i: Medicine. - : LIPPINCOTT WILLIAMS & WILKINS. - 0025-7974 .- 1536-5964. ; 97:5
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Tidskriftsartikel (refereegranskat)abstract
- Acute human immunodeficiency virus (HIV) infection is associated with a marked induction of several pathways that are linked to inflammation and CD4(+) T-cell depletion. Many of these processes do not fully resolve on short-term combination antiretroviral therapy (cART) (<5 years), despite complete and durable suppression of viremia. The effects of long-term (>15 years) successful antiretroviral therapy (ART) and the linkage between levels of biomarkers remain unclear. Therefore, the present study aims to assess the host plasma proteome in a well-defined clinical material from HIV-1-positive male patients on successful long-term ART (>15 years) and compared them with age-matched healthy controls and treatment-naive male patients with viremia in a cross-sectional manner. Plasma samples were obtained from 3 categories of age-matched HIV-1-positive male patients on long-term successfully (ART, n=10) with a median (Interquartile range, IQR) of 19 (17-20) years, treatment-naive patients with viremia (VP, n=14), and HIV-1-negative persons (HC, n=11). Plasma proteome was analyzed using the proximity extension assay targeting 92 factors. Statistical analyses were performed with GraphPad Prism v7, R-packages, and Qlucore Omics Explorer v3.2. Functional enrichment analysis was performed by Kyoto Encyclopedia of Genes and Genomes (KEGG), and interactions of specific molecules were identified using Path Designer integrated into Ingenuity Pathway Analysis (IPA). Group wise comparison identified 53 soluble factors, which differed between the groups (P < .05). Cluster analysis identified 13 discrete soluble factors (CD8A, CRTAM, CXCL13, EGF, CD5, CD40, CXCL9, Gal-1, IL12RB1, KLRD1, PD-1, CASP-8 and TNFRSF9) between the studied groups (adjusted P < .001). The long-term successfully ART-treated individuals clustered and networked with the HC while VPs clustered separately. All of the proinflammatory cytokines and chemokines were normalized back to levels of healthy controls in long-term successfully ART-treated individuals, but not the levels of KLRD1 and PGDFB. sKLRD1 that is involved in the regulation of natural killer cell (NK) mediated cytotoxicity, failed to be restored to the level of HIV-negative individuals despite successful long-term ART. Additional analysis of NK cells along with T-cell subsets can provide insights into the long-term effects of ART on the immune system.
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| 62250. |
- Spetz, Anna-Lena, et al.
(författare)
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Functional gene transfer of HIV DNA by an HIV receptor-independent mechanism
- 1999
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Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 163:2, s. 736-742
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Tidskriftsartikel (refereegranskat)abstract
- HIV-1 enters target cells mainly via binding to CD4 and its coreceptors. The presence of HIV-1 in CD4(-) cells suggests, however, that there exist other mechanisms for viral entry, Here it is reported that HIV-1 DNA may be transferred from one cell to another by uptake of apoptotic bodies in a CD4-independent way. This was investigated by coculturing CD4(-), chemokine receptor CCR5(-) and CXCR4(-) human fetal fibroblasts with apoptotic HIV-1-infected HuT78 cells or apoptotic PBMC isolated from HIV-1-infected patients. After 2 wk of coculture, fibroblasts contained HIV-1 DNA and expressed HIV-1 proteins p24 and gp120, Transfer of HIV-1 DNA was verified by coculturing fibroblasts with apoptotic bodies derived from cells infected with a defective HIV-1 virus. These cells contain one integrated copy of a reverse transcriptase (RT)-negative HIV-1 strain (8E5/LAV RT- cells) and consequently cannot produce free virus, Intracellular HIV-1 gag DNA was detected in both fibroblasts and dendritic cells after coculture with apoptotic 8E5/LAV RT- cells. Transfer of viral DNA after uptake of apoptotic bodies mag explain HIV-1 infection of CD4(-) cells in vivo and furthermore may be relevant for Ag presentation.
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