Standardizing effect size from linear regression models with log-transformed variables for meta-analysis

Background: Meta-analysis is very useful to summarize the effect of a treatment or a risk factor for a given disease. Often studies report results based on log-transformed variables in order to achieve the principal assumptions of a linear regression model. If this is the case for some, but not all studies, the effects need to be homogenized. Methods: We derived a set of formulae to transform absolute changes into relative ones, and vice versa, to allow including all results in a meta-analysis. We applied our procedure to all possible combinations of log-transformed independent or dependent variables. We also evaluated it in a simulation based on two variables either normally or asymmetrically distributed. Results: In all the scenarios, and based on different change criteria, the effect size estimated by the derived set of formulae was equivalent to the real effect size. To avoid biased estimates of the effect, this procedure should be used with caution in the case of independent variables with asymmetric distributions that significantly differ from the normal distribution. We illustrate an application of this procedure by an application to a meta-analysis on the potential effects on neurodevelopment in children exposed to arsenic and manganese. Conclusions: The procedure proposed has been shown to be valid and capable of expressing the effect size of a linear regression model based on different change criteria in the variables. Homogenizing the results from different studies beforehand allows them to be combined in a meta-analysis, independently of whether the transformations had been performed on the dependent and/or independent variables

Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial

Introduction: We assessed whether modest systemic cooling started within 6 hours of symptom onset improves functional outcome at three months in awake patients with acute ischaemic stroke. Patients and methods: In this European randomised open-label clinical trial with blinded outcome assessment, adult patients with acute ischaemic stroke were randomised to cooling to a target body temperature of 34.0–35.0°C, started within 6 h after stroke onset and maintained for 12 or 24 h , versus standard treatment. The primary outcome was the score on the modified Rankin Scale at 91 days, as analysed with ordinal logistic regression. Results: The trial was stopped after inclusion of 98 of the originally intended 1500 patients because of slow recruitment and cessation of funding. Forty-nine patients were randomised to hypothermia versus 49 to standard treatment. Four patients were lost to follow-up. Of patients randomised to hypothermia, 15 (31%) achieved the predefined cooling targets. The primary outcome did not differ between the groups (odds ratio for good outcome, 1.01; 95% confidence interval, 0.48–2.13; p = 0.97). The number of patients with one or more serious adverse events did not differ between groups (relative risk, 1.22; 95% confidence interval, 0.65–1.94; p = 0.52). Discussion: In this trial, cooling to a target of 34.0–35.0°C and maintaining this for 12 or 24 h was not feasible in the majority of patients. The final sample was underpowered to detect clinically relevant differences in outcomes. Conclusion: Before new trials are launched, the feasibility of cooling needs to be improved

A complete set of nascent transcription rates for yeast genes

The amount of mRNA in a cell is the result of two opposite reactions: transcription and mRNA degradation. These reactions are governed by kinetics laws, and the most regulated step for many genes is the transcription rate. The transcription rate, which is assumed to be exercised mainly at the RNA polymerase recruitment level, can be calculated using the RNA polymerase densities determined either by run-on or immunoprecipitation using specific antibodies. The yeast Saccharomyces cerevisiae is the ideal model organism to generate a complete set of nascent transcription rates that will prove useful for many gene regulation studies. By combining genomic data from both the GRO (Genomic Run-on) and the RNA pol ChIP-on-chip methods we generated a new, more accurate nascent transcription rate dataset. By comparing this dataset with the indirect ones obtained from the mRNA stabilities and mRNA amount datasets, we are able to obtain biological information about posttranscriptional regulation processes and a genomic snapshot of the location of the active transcriptional machinery. We have obtained nascent transcription rates for 4,670 yeast genes. The median RNA polymerase II density in the genes is 0.078 molecules/kb, which corresponds to an average of 0.096 molecules/gene. Most genes have transcription rates of between 2 and 30 mRNAs/hour and less than 1% of yeast genes have >1 RNA polymerase molecule/gene. Histone and ribosomal protein genes are the highest transcribed groups of genes and other than these exceptions the transcription of genes is an infrequent phenomenon in a yeast cell

Development of Trypanosoma cruzi in vitro assays to identify compounds suitable for progression in Chagas’ disease drug discovery

Chagas' disease is responsible for significant mortality and morbidity in Latin America. Current treatments display variable efficacy and have adverse side effects, hence more effective, better tolerated drugs are needed. However, recent efforts have proved unsuccessful with failure of the ergosterol biosynthesis inhibitor posaconazole in phase II clinical trials despite promising in vitro and in vivo studies. The lack of translation between laboratory experiments and clinical outcome is a major issue for further drug discovery efforts. Our goal was to identify cell-based assays that could differentiate current nitro-aromatic drugs nifurtimox and benznidazole from posaconazole. Using a panel of T. cruzi strains including the six major lineages (TcI-VI), we found that strain PAH179 (TcV) was markedly less susceptible to posaconazole in vitro. Determination of parasite doubling and cycling times as well as EdU labelling experiments all indicate that this lack of sensitivity is due to the slow doubling and cycling time of strain PAH179. This is in accordance with ergosterol biosynthesis inhibition by posaconazole leading to critically low ergosterol levels only after multiple rounds of division, and is further supported by the lack of effect of posaconazole on the non-replicative trypomastigote form. A washout experiment with prolonged posaconazole treatment showed that, even for more rapidly replicating strains, this compound cannot clear all parasites, indicative of a heterogeneous parasite population in vitro and potentially the presence of quiescent parasites. Benznidazole in contrast was able to kill all parasites. The work presented here shows clear differentiation between the nitro-aromatic drugs and posaconazole in several assays, and suggests that in vitro there may be clinically relevant heterogeneity in the parasite population that can be revealed in long-term washout experiments. Based on these findings we have adjusted our in vitro screening cascade so that only the most promising compounds are progressed to in vivo experiments

Whether weather matters: Evidence of association between in utero meteorological exposures and foetal growth among Indigenous and non-Indigenous mothers in rural Uganda

Pregnancy and birth outcomes have been found to be sensitive to meteorological variation, yet few studies explore this relationship in sub-Saharan Africa where infant mortality rates are the highest in the world. We address this research gap by examining the association between meteorological factors and birth weight in a rural population in southwestern Uganda. Our study included hospital birth records (n = 3197) from 2012 to 2015, for which we extracted meteorological exposure data for the three trimesters preceding each birth. We used linear regression, controlling for key covariates, to estimate the timing, strength, and direction of meteorological effects on birth weight. Our results indicated that precipitation during the third trimester had a positive association with birth weight, with more frequent days of precipitation associated with higher birth weight: we observed a 3.1g (95% CI: 1.0–5.3g) increase in birth weight per additional day of exposure to rainfall over 5mm. Increases in average daily temperature during the third trimester were also associated with birth weight, with an increase of 41.8g (95% CI: 0.6–82.9g) per additional degree Celsius. When the sample was stratified by season of birth, only infants born between June and November experienced a significant associated between meteorological exposures and birth weight. The association of meteorological variation with foetal growth seemed to differ by ethnicity; effect sizes of meteorological were greater among an Indigenous subset of the population, in particular for variation in temperature. Effects in all populations in this study are higher than estimates of the African continental average, highlighting the heterogeneity in the vulnerability of infant health to meteorological variation in different contexts. Our results indicate that while there is an association between meteorological variation and birth weight, the magnitude of these associations may vary across ethnic groups with differential socioeconomic resources, with implications for interventions to reduce these gradients and offset the health impacts predicted under climate change

Low urine pH and acid excretion do not predict bone fractures or the loss of bone mineral density: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>The acid-ash hypothesis, the alkaline diet, and related products are marketed to the general public. Websites, lay literature, and direct mail marketing encourage people to measure their urine pH to assess their health status and their risk of osteoporosis.</p> <p>The objectives of this study were to determine whether 1) low urine pH, or 2) acid excretion in urine [sulfate + chloride + 1.8x phosphate + organic acids] minus [sodium + potassium + 2x calcium + 2x magnesium mEq] in fasting morning urine predict: a) fragility fractures; and b) five-year change of bone mineral density (BMD) in adults.</p> <p>Methods</p> <p>Design: Cohort study: the prospective population-based Canadian Multicentre Osteoporosis Study. Multiple logistic regression was used to examine associations between acid excretion (urine pH and urine acid excretion) in fasting morning with the incidence of fractures (6804 person years). Multiple linear regression was used to examine associations between acid excretion with changes in BMD over 5-years at three sites: lumbar spine, femoral neck, and total hip (n = 651). Potential confounders controlled included: age, gender, family history of osteoporosis, physical activity, smoking, calcium intake, vitamin D status, estrogen status, medications, renal function, urine creatinine, body mass index, and change of body mass index.</p> <p>Results</p> <p>There were no associations between either urine pH or acid excretion and either the incidence of fractures or change of BMD after adjustment for confounders.</p> <p>Conclusion</p> <p>Urine pH and urine acid excretion do not predict osteoporosis risk.</p

The effects of mutant Ras proteins on the cell signalome

The genetic alterations in cancer cells are tightly linked to signaling pathway dysregulation. Ras is a key molecule that controls several tumorigenesis-related processes, and mutations in RAS genes often lead to unbiased intensification of signaling networks that fuel cancer progression. In this article, we review recent studies that describe mutant Ras-regulated signaling routes and their cross-talk. In addition to the two main Ras-driven signaling pathways, i.e., the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, we have also collected emerging data showing the importance of Ras in other signaling pathways, including the RAC/PAK, RalGDS/Ral, and PKC/PLC signaling pathways. Moreover, microRNA-regulated Ras-associated signaling pathways are also discussed to highlight the importance of Ras regulation in cancer. Finally, emerging data show that the signal alterations in specific cell types, such as cancer stem cells, could promote cancer development. Therefore, we also cover the up-to-date findings related to Ras-regulated signal transduction in cancer stem cells. © 2020, The Author(s)

Cross-cutting principles for planetary health education

Since the 2015 launch of the Rockefeller Foundation Lancet Commission on planetary health,1 an enormous groundswell of interest in planetary health education has emerged across many disciplines, institutions, and geographical regions. Advancing these global efforts in planetary health education will equip the next generation of scholars to address crucial questions in this emerging field and support the development of a community of practice. To provide a foundation for the growing interest and efforts in this field, the Planetary Health Alliance has facilitated the first attempt to create a set of principles for planetary health education that intersect education at all levels, across all scales, and in all regions of the world—ie, a set of cross-cutting principles