| 1. |
- Pennells, Lisa, et al.
(författare)
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Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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| 2. |
- Dahal, Prabin, et al.
(författare)
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Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria : a WorldWide Antimalarial Resistance Network individual participant data meta-analysis
- 2019
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Ingår i: Malaria Journal. - : BMC. - 1475-2875. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.Conclusions: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.
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| 3. |
- Baker, Maggie, et al.
(författare)
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Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques
- 2017
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 114:44, s. 11769-11774
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Tidskriftsartikel (refereegranskat)abstract
- Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR, for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to deter mine whether a gain-of-function nonsynonymous OXTR SNP inter acted with early stress to influence relevant behavioral stress reactivity phenotypes (n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavior al differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders.
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| 4. |
- Rittweger, Joern, et al.
(författare)
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On the combined effects of normobaric hypoxia and bed rest upon bone and mineral metabolism : Results from the PlanHab study
- 2016
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Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 91, s. 130-138
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Tidskriftsartikel (refereegranskat)abstract
- Bone losses are common as a consequence of unloading and also in patients with chronic obstructive pulmonary disease (COPD). Although hypoxia has been implicated as an important factor to drive bone loss, its interaction with unloading remains unresolved. The objective therefore was to assess whether human bone loss caused by unloading could be aggravated by chronic hypoxia. In a cross-over designed study, 14 healthy young men underwent 21-day interventions of bed rest in normoxia (NBR), bed rest in hypoxia (HBR), and hypoxic ambulatory confinement (HAmb). Hypoxic conditions were equivalent to 4000 m altitude. Bone metabolism (NTX, P1NP, sclerostin, DKK1) and phospho-calcic homeostasis (calcium and phosphate serum levels and urinary excretion, PTH) were assessed from regular blood samples and 24-hour urine collections, and tibia and femur bone mineral content was assessed by peripheral quantitative computed tomography (pQCT). Urinary NTX excretion increased (P<0.001) to a similar extent in NBR and HBR (P = 0.69) and P1NP serum levels decreased (P = 0.0035) with likewise no difference between NBR and HBR (P = 0.88). Serum total calcium was increased during bed rest by 0.059 (day D05, SE 0.05 mM) to 0.091 mM (day D21, P < 0.001), with no additional effect by hypoxia during bed rest (P = 0.199). HAmb led, at least temporally, to increased total serum calcium, to reduced serum phosphate, and to reduced phosphate and calcium excretion. In conclusion, hypoxia did not aggravate bed rest-induced bone resorption, but led to changes in phospho-calcic homeostasis likely caused by hyperventilation. Whether hyperventilation could have mitigated the effects of hypoxia in this study remains to be established.
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| 5. |
- Simpson, Elizabeth A, et al.
(författare)
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Comments: Animal studies help clarify misunderstandings about neonatal imitation (vol. 40, articelID e400, 2017)
- 2017
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Ingår i: Behavioral and Brain Sciences. - : Cambridge University Press. - 0140-525X .- 1469-1825. ; 40
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Empirical studies are incompatible with the proposal that neonatal imitation is arousal driven or declining with age. Nonhuman primate studies reveal a functioning brain mirror system from birth, developmental continuity in imitation and later sociability, and the malleability of neonatal imitation, shaped by the early environment. A narrow focus on arousal effects and reflexes may grossly underestimate neonatal capacities.
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| 6. |
- Simpson, Elizabeth J., et al.
(författare)
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PlanHab : the combined and separate effects of 16 days of bed rest and normobaric hypoxic confinement on circulating lipids and indices of insulin sensitivity in healthy men
- 2016
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Ingår i: Journal of applied physiology. - : AMER PHYSIOLOGICAL SOC. - 8750-7587 .- 1522-1601. ; 120:8, s. 947-955
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Tidskriftsartikel (refereegranskat)abstract
- PlanHab is a planetary habitat simulation study. The atmosphere within future space habitats is anticipated to have reduced PO2, but information is scarce as to how physiological systems may respond to combined exposure to moderate hypoxia and reduced gravity. This study investigated, using a randomized-crossover design, how insulin sensitivity, glucose tolerance, and circulating lipids were affected by 16 days of horizontal bed rest in normobaric normoxia [NBR: FIO2 = 0.209; PIO2 = 133.1 (0.3) mmHg], horizontal bed rest in normobaric hypoxia [HBR: FIO2 = 0.141 (0.004); PIO2 = 90.0 (0.4) mmHg], and confinement in normobaric hypoxia combined with daily moderate intensity exercise (HAMB). A mixed-meal tolerance test, with arterialized-venous blood sampling, was performed in 11 healthy, nonobese men (25-45 yr) before (V1) and on the morning of day 17 of each intervention (V2). Postprandial glucose and c-peptide response were increased at V2 of both bed rest interventions (P < 0.05 in each case), with c-peptide: insulin ratio higher at V2 in HAMB and HBR, both in the fed and fasted state (P < 0.005 in each case). Fasting total cholesterol was reduced at V2 in HAMB [-0.47 (0.36) mmol/l; P < 0.005] and HBR [-0.55 (0.41) mmol/l; P < 0.005]. Fasting HDL was lower at V2 in all interventions, with the reduction observed in HBR [-0.30 (0.21) mmol/l] greater than that measured in HAMB [-0.13 (0.14) mmol/l; P < 0.005] and NBR [-0.17 (0.15) mmol/l; P < 0.05]. Hypoxia did not alter the adverse effects of bed rest on insulin sensitivity and glucose tolerance but appeared to increase insulin clearance. The negative effect of bed rest on HDL was compounded in hypoxia, which may have implications for long-term health of those living in future space habitats.
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