| 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. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Awad-Allah, Eman F. A., et al.
(författare)
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Phosphorus protects against cadmium-induced phytotoxicity by stimulating plasma membrane H+-ATPase activity
- 2023
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Ingår i: Journal of plant nutrition. - 0190-4167 .- 1532-4087. ; 46:16, s. 3918-3932
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Tidskriftsartikel (refereegranskat)abstract
- Proper plant nutrition can be an effective strategy to alleviate the phytotoxicity and damaging effects of Cd stress on plants and to avoid its entry into the food chain. This study aimed to investigate effects of phosphorus concentrations, and pH levels in the nutrient solution on Cd uptake, growth, photosynthetic characters, total phytochelatins (PCs), and plasma membrane ATPase activity of sugar beet (Beta vulgaris L.) plants grown in sand culture. Two successive experimental studies were carried out under controlled conditions. In the first study, 10-day-old sugar beet seedlings were irrigated with a half-strength Hoagland and Arnon nutrient solution, adjusted to different pH (3.5, 5.0, 6.0, 7.0, or 8.0), and containing 0, 0.15, or 0.30 mg Cd L−1 as CdCl2. In the second study, 10-day-old sugar beet seedlings were irrigated with the same nutrient solution (pH 6), but combined with different phosphorus concentrations (0, 10, 25 and 50 µg P ml−1 as KH2PO4) and Cd levels (0, 0.15, and 0.30 mg Cd L−1 as CdCl2). The first study revealed that pH had a strong influence on Cd uptake by sugar beet roots. Cd stress significantly decreased sugar beet growth and Mg2+-ATPase activity, whereas it increased total phytochelatins (PCs). Second study indicated an antagonistic effect between P and Cd. Furthermore, phosphorus had the potential to stimulate Mg2+-ATPase activity and synthesis of photosynthetic pigments and to promote growth of sugar beet seedlings. Cadmium induced phytotoxicity in sugar beet seedlings can be alleviated by a proper pH and phosphorus nutrition.
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| 4. |
- Bentham, James, et al.
(författare)
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A century of trends in adult human height
- 2016
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Ingår i: eLIFE. - 2050-084X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 5. |
- Bentham, James, et al.
(författare)
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A century of trends in adult human height
- 2016
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 6. |
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| 7. |
- Ibrahim, Eman, et al.
(författare)
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Assessment of ibrutinib scheduling on leukocyte, lymph node size and blood pressure dynamics in chronic lymphocytic leukemia through pharmacokinetic-pharmacodynamic models
- 2023
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Ingår i: CPT. - : WILEY. - 2163-8306. ; 12:9, s. 1305-1318
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Tidskriftsartikel (refereegranskat)abstract
- Ibrutinib is a Bruton tyrosine kinase (Btk) inhibitor for treating chronic lymphocytic leukemia (CLL). It has also been associated with hypertension. The optimal dosing schedule for mitigating this adverse effect is currently under discussion. A quantification of relationships between systemic ibrutinib exposure and efficacy (i.e., leukocyte count and sum of the product of perpendicular diameters [SPD] of lymph nodes) and hypertension toxicity (i.e., blood pressure), and their association with overall survival is needed. Here, we present a semi-mechanistic pharmacokinetic-pharmacodynamic modeling framework to characterize such relationships and facilitate dose optimization. Data from a phase Ib/II study were used, including ibrutinib plasma concentrations to derive daily 0-24-h area under the concentration-time curve, leukocyte count, SPD, survival, and blood pressure measurements. A nonlinear mixed effects modeling approach was applied, considering ibrutinib's pharmacological action and CLL cell dynamics. The final framework included (i) an integrated model for SPD and leukocytes consisting of four CLL cell subpopulations with ibrutinib inhibiting phosphorylated Btk production, ( ii) a turnover model in which ibrutinib stimulates an increase in blood pressure, and (iii) a competing risk model for dropout and death. Simulations predicted that the approved dosing schedule had a slightly higher efficacy (24-month, progression- free survival [PFS] 98%) than de-escalation schedules (24-month, average PFS approximate to 97%); the latter had, on average, approximate to 20% lower proportions of patients with hypertension. The developed modeling framework offers an improved understanding of the relationships among ibrutinib exposure, efficacy and toxicity biomarkers. This framework can serve as a platform to assess dosing schedules in a biologically plausible manner.
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| 8. |
- Ibrahim, Eman I. K., et al.
(författare)
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Bridging responses to a human telomerase reverse transcriptase-based peptide cancer vaccine candidate in a mechanism-based model
- 2024
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Ingår i: International Immunopharmacology. - : Elsevier. - 1567-5769 .- 1878-1705. ; 126
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic cancer vaccines are novel immuno-therapeutics, aiming to improve clinical outcomes with other immunotherapies. However, obstacles to their successful clinical development remain, which model-informed drug development approaches may address. UV1 is a telomerase based therapeutic cancer vaccine candidate being investigated in phase I clinical trials for multiple indications. We developed a mechanism-based model structure, using a nonlinear mixed‐effects modeling techniques, based on longitudinal tumor sizes (sum of the longest diameters, SLD), UV1-specific immunological assessment (stimulation index, SI) and overall survival (OS) data obtained from a UV1 phase I trial including non-small cell lung cancer (NSCLC) patients and a phase I/IIa trial including malignant melanoma (MM) patients. The final structure comprised a mechanistic tumor growth dynamics (TGD) model, a model describing the probability of observing a UV1-specific immune response (SI ≥ 3) and a time-to-event model for OS. The mechanistic TGD model accounted for the interplay between the vaccine peptides, immune system and tumor. The model-predicted UV1-specific effector CD4+ T cells induced tumor shrinkage with half-lives of 103 and 154 days in NSCLC and MM patients, respectively. The probability of observing a UV1-specific immune response was mainly driven by the model-predicted UV1-specific effector and memory CD4+ T cells. A high baseline SLD and a high relative increase from nadir were identified as main predictors for a reduced OS in NSCLC and MM patients, respectively. Our model predictions highlighted that additional maintenance doses, i.e. UV1 administration for longer periods, may result in more sustained tumor size shrinkage.
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| 9. |
- Ibrahim, Mahmoud A. A., et al.
(författare)
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In Silico Mining of Terpenes from Red-Sea Invertebrates for SARS-CoV-2 Main Protease (M-pro) Inhibitors
- 2021
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Ingår i: Molecules. - : MDPI AG. - 1431-5157 .- 1420-3049. ; 26:7
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Tidskriftsartikel (refereegranskat)abstract
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic, which generated more than 1.82 million deaths in 2020 alone, in addition to 83.8 million infections. Currently, there is no antiviral medication to treat COVID-19. In the search for drug leads, marine-derived metabolites are reported here as prospective SARS-CoV-2 inhibitors. Two hundred and twenty-seven terpene natural products isolated from the biodiverse Red-Sea ecosystem were screened for inhibitor activity against the SARS-CoV-2 main protease (M-pro) using molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area binding energy calculations. On the basis of in silico analyses, six terpenes demonstrated high potency as M-pro inhibitors with Delta G(binding) <= -40.0 kcal/mol. The stability and binding affinity of the most potent metabolite, erylosides B, were compared to the human immunodeficiency virus protease inhibitor, lopinavir. Erylosides B showed greater binding affinity towards SARS-CoV-2 M-pro than lopinavir over 100 ns with Delta G(binding) values of -51.9 vs. -33.6 kcal/mol, respectively. Protein-protein interactions indicate that erylosides B biochemical signaling shares gene components that mediate severe acute respiratory syndrome diseases, including the cytokine- and immune-signaling components BCL2L1, IL2, and PRKC. Pathway enrichment analysis and Boolean network modeling were performed towards a deep dissection and mining of the erylosides B target-function interactions. The current study identifies erylosides B as a promising anti-COVID-19 drug lead that warrants further in vitro and in vivo testing.
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| 10. |
- Knochel, Jane, et al.
(författare)
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A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts
- 2023
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Ingår i: CPT. - : WILEY. - 2163-8306. ; 12:12, s. 2038-2049
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Tidskriftsartikel (refereegranskat)abstract
- Disease progression in nonalcoholic steatohepatitis (NASH) is highly heterogenous and remains poorly understood. Fibrosis stage is currently the best predictor for development of end-stage liver disease and mortality. Better understanding and quantifying the impact of factors affecting NASH and fibrosis is essential to inform a clinical study design. We developed a population Markov model to describe the transition probability between fibrosis stages and mortality using a unique clinical nonalcoholic fatty liver disease cohort with serial biopsies over 3 decades. We evaluated covariate effects on all model parameters and performed clinical trial simulations to predict the fibrosis progression rate for external clinical cohorts. All parameters were estimated with good precision. Age and diagnosis of type 2 diabetes (T2D) were found to be significant predictors in the model. Increase in hepatic steatosis between visits was the most important predictor for progression of fibrosis. Fibrosis progression rate (FPR) was twofold higher for fibrosis stages 0 and 1 (F0-1) compared to fibrosis stage 2 and 3 (F2-3). A twofold increase in FPR was observed for T2D. A two-point steatosis worsening increased the FPR 11-fold. Predicted fibrosis progression was in good agreement with data from external clinical cohorts. Our fibrosis progression model shows that patient selection, particularly initial fibrosis stage distribution, can significantly impact fibrosis progression and as such the window for assessing drug efficacy in clinical trials. Our work highlights the increase in hepatic steatosis as the most important factor in increasing FPR, emphasizing the importance of well-defined lifestyle advise for reducing variability in NASH progression during clinical trials.
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