Determining the absolute configuration of (+)-mefloquine HCl, the side-effect-reducing enantiomer of the antimalaria drug Lariam.

Even though the important antimalaria drug rac-erythro-mefloquine HCl has been on the market as Lariam for decades, the absolute configurations of its enantiomers have not been determined conclusively. This is needed, since the (−) enantiomer is believed to cause adverse side effects in malaria treatment resulting from binding to the adenosine receptor in the human brain. Since there are conflicting assignments based on enantioselective synthesis and anomalous X-ray diffraction, we determined the absolute configuration using a combination of NMR, optical rotatory dispersion (ORD), and circular dichroism (CD) spectroscopy together with density functional theory calculations. First, structural models of erythro-mefloquine HCl compatible with NMR-derived 3JHH scalar couplings, 15N chemical shifts, rotational Overhauser effects, and residual dipolar couplings were constructed. Second, we calculated ORD and CD spectra of the structural models and compared the calculated data with the experimental values. The experimental results for (−)-erythro-mefloquine HCl matched our calculated chiroptical data for the 11R,12S model. Accordingly, we conclude that the assignment of 11R,12S to (−)-erythro-mefloquine HCl is correct

Handwriting versus keyboarding: does writing modality affect quality of narratives written by beginning writers?

To date, there is no clear evidence to support choosing handwriting over keyboarding or vice versa as the modality children should use when they first learn to write. 102 Norwegian first-grade children from classrooms that used both electronic touchscreen keyboard on a digital tablet and pencil-and-paper for writing instruction wrote narratives in both modalities three months after starting school and were assessed on several literacy-related skills. The students’ texts were then analysed for a range of text features, and were rated holistically. Data were analysed using Bayesian methods. These permitted evaluation both of evidence in favour of a difference between modalities and of evidence in favour of there being no difference. We found moderate to strong evidence in favour of no difference between modalities. We also found moderate to strong evidence against modality effects being moderated by students’ literacy ability. Findings may be specific to students who are just starting to write, but suggest that for children at this stage of development writing performance is independent of modality

Birth weight influences cardiac structure, function and disease risk: evidence of a causal association

Background and Aims Low birth weight is a common pregnancy complication, which has been associated with higher risk of cardiometabolic disease in later life. Prior Mendelian randomization (MR) studies exploring this question do not distinguish the mechanistic contributions of variants that directly influence birth weight through the foetal genome (direct foetal effects), vs. variants influencing birth weight indirectly by causing an adverse intrauterine environment (indirect maternal effects). In this study, MR was used to assess whether birth weight, independent of intrauterine influences, is associated with cardiovascular disease risk and measures of adverse cardiac structure and function. Methods Uncorrelated (r2 < .001), genome-wide significant (P < 5 × 10−8) single nucleotide polymorphisms were extracted from genome-wide association studies summary statistics for birth weight overall, and after isolating direct foetal effects only. Inverse-variance weighted MR was utilized for analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 16 measures of cardiac structure and function. Multiple comparisons were accounted for by Benjamini–Hochberg correction. Results Lower genetically-predicted birth weight, isolating direct foetal effects only, was associated with an increased risk of coronary artery disease (odds ratio 1.21, 95% confidence interval 1.06–1.37; P = .031), smaller chamber volumes, and lower stroke volume, but higher contractility. Conclusions The results of this study support a causal role of low birth weight in cardiovascular disease, even after accounting for the influence of the intrauterine environment. This suggests that individuals with a low birth weight may benefit from early targeted cardiovascular disease prevention strategies, independent of whether this was linked to an adverse intrauterine environment during gestation

Body mass index and subfertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study.

Funder: Folkehelseinstituttet/Norwegian Institute of Public HealthFunder: Norwegian Ministry of Health and Care ServicesFunder: Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and ResearchFunder: Norwegian Ministry of Education and ResearchStudy questionWhat is the association between BMI and subfertility?Summary answerWe observed a J-shaped relationship between BMI and subfertility in both sexes, when using both a standard multivariable regression and Mendelian randomization (MR) analysis.What is known alreadyHigh BMI in both women and men is associated with subfertility in observational studies and this relationship is further substantiated by a few small randomized controlled trials of weight reduction and success of assisted reproduction. Women with low BMI also have lower conception rates with assisted reproduction technologies.Study design, size, durationCohort study (the Norwegian Mother, Father and Child Cohort Study), 28 341 women and 26 252 men, recruited from all over Norway between 1999 and 2008.Participants/materials, setting, methodsWomen (average age 30, average BMI 23.1 kg/m2) and men (average age 33, average BMI 25.5 kg/m2) had available genotype data and provided self-reported information on time-to-pregnancy and BMI. A total of 10% of couples were subfertile (time-to-pregnancy ≥12 months).Main results and the role of chanceOur findings support a J-shaped association between BMI and subfertility in both sexes using multivariable logistic regression models. Non-linear MR validated this relationship. A 1 kg/m2 greater genetically predicted BMI was linked to 18% greater odds of subfertility (95% CI 5% to 31%) in obese women (≥30.0 kg/m2) and 15% lower odds of subfertility (-24% to -2%) in women with BMI Limitations, reasons for cautionThe main limitations of our study were that we did not know whether the subfertility was driven by the women, men or both; the exclusive consideration of individuals of northern European ancestry; and the limited amount of participants with obesity or BMI values Wider implications of the findingsOur results support a causal effect of obesity on subfertility in women and men. Our findings also expand the current evidence by indicating that individuals with BMI values Study funding/competing interest(s)The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This project received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 947684). It was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. D.A.L. is a UK National Institute for Health Research Senior Investigator (NF-SI-0611-10196) and is supported by the US National Institutes of Health (R01 DK10324) and a European Research Council Advanced Grant (DevelopObese; 669545). The funders had no role in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. D.A.L. receives (or has received in the last 10 years) research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. The rest of the authors declare that no competing interests exist.Trial registration numberN/A

Body mass index and risk of dying from a bloodstream infection: A Mendelian randomization study.

BACKGROUND: In observational studies of the general population, higher body mass index (BMI) has been associated with increased incidence of and mortality from bloodstream infection (BSI) and sepsis. On the other hand, higher BMI has been observed to be apparently protective among patients with infection and sepsis. We aimed to evaluate the causal association of BMI with risk of and mortality from BSI. METHODS AND FINDINGS: We used a population-based cohort in Norway followed from 1995 to 2017 (the Trøndelag Health Study [HUNT]), and carried out linear and nonlinear Mendelian randomization analyses. Among 55,908 participants, the mean age at enrollment was 48.3 years, 26,324 (47.1%) were men, and mean BMI was 26.3 kg/m2. During a median 21 years of follow-up, 2,547 (4.6%) participants experienced a BSI, and 451 (0.8%) died from BSI. Compared with a genetically predicted BMI of 25 kg/m2, a genetically predicted BMI of 30 kg/m2 was associated with a hazard ratio for BSI incidence of 1.78 (95% CI: 1.40 to 2.27; p < 0.001) and for BSI mortality of 2.56 (95% CI: 1.31 to 4.99; p = 0.006) in the general population, and a hazard ratio for BSI mortality of 2.34 (95% CI: 1.11 to 4.94; p = 0.025) in an inverse-probability-weighted analysis of patients with BSI. Limitations of this study include a risk of pleiotropic effects that may affect causal inference, and that only participants of European ancestry were considered. CONCLUSIONS: Supportive of a causal relationship, genetically predicted BMI was positively associated with BSI incidence and mortality in this cohort. Our findings contradict the "obesity paradox," where previous traditional epidemiological studies have found increased BMI to be apparently protective in terms of mortality for patients with BSI or sepsis

Structure and Mode-of-Action of the Two-Peptide (Class-IIb) Bacteriocins

This review focuses on the structure and mode-of-action of the two-peptide (class-IIb) bacteriocins that consist of two different peptides whose genes are next to each other in the same operon. Optimal antibacterial activity requires the presence of both peptides in about equal amounts. The two peptides are synthesized as preforms that contain a 15–30 residue double-glycine-type N-terminal leader sequence that is cleaved off at the C-terminal side of two glycine residues by a dedicated ABC-transporter that concomitantly transfers the bacteriocin peptides across cell membranes. Two-peptide bacteriocins render the membrane of sensitive bacteria permeable to a selected group of ions, indicating that the bacteriocins form or induce the formation of pores that display specificity with respect to the transport of molecules. Based on structure–function studies, it has been proposed that the two peptides of two-peptide bacteriocins form a membrane-penetrating helix–helix structure involving helix–helix-interacting GxxxG-motifs that are present in all characterized two-peptide bacteriocins. It has also been suggested that the membrane-penetrating helix–helix structure interacts with an integrated membrane protein, thereby triggering a conformational alteration in the protein, which in turn causes membrane-leakage. This proposed mode-of-action is similar to the mode-of-action of the pediocin-like (class-IIa) bacteriocins and lactococcin A (a class-IId bacteriocin), which bind to a membrane-embedded part of the mannose phosphotransferase permease in a manner that causes membrane-leakage and cell death

Patterns of adiposity, vascular phenotypes and cognitive function in the 1946 British Birth Cohort.

BACKGROUND: The relationship between long-term exposure to whole body or central obesity and cognitive function, as well as its potential determinants, remain controversial. In this study, we assessed (1) the potential impact of 30 years exposure to different patterns of whole body and central adiposity on cognitive function at 60-64 years, (2) whether trajectories of central adiposity can provide additional information on later cognitive function compared to trajectories of whole body adiposity, and (3) the influence of vascular phenotypes on these associations. METHODS: The study included 1249 participants from the prospective cohort MRC National Survey of Health and Development. Body mass index (BMI), waist circumference (WC), and vascular (carotid intima-media thickness, carotid-femoral pulse wave velocity) and cognitive function (memory, processing speed, reaction time) data, at 60-64 years, were used to assess the associations between different patterns of adult WC or BMI (from 36 years of age) and late midlife cognitive performance, as well as the proportion of this association explained by cardiovascular phenotypes. RESULTS: Longer exposure to elevated WC was related to lower memory performance (p < 0.001 for both) and longer choice reaction time (p = 0.003). A faster gain of WC between 36 and 43 years of age was associated with the largest change in reaction time and memory test (P < 0.05 for all). Similar associations were observed when patterns of WC were substituted with patterns of BMI, but when WC and BMI were included in the same model, only patterns of WC remained significantly associated with cognitive function. Participants who dropped one BMI category and maintained a lower BMI had similar memory performance to those of normal weight during the whole follow-up. Conversely, those who dropped and subsequently regained one BMI category had a memory function similar to those with 30 years exposure to elevated BMI. Adjustment for vascular phenotypes, levels of cardiovascular risk factors, physical activity, education, childhood cognition and socioeconomic position did not affect these associations. CONCLUSIONS: Longer exposure to elevated WC or BMI and faster WC or BMI gains between 36 and 43 years are related to lower cognitive function at 60-64 years. Patterns of WC in adulthood could provide additional information in predicting late midlife cognitive function than patterns of BMI. The acquisition of an adverse cardiovascular phenotype associated with adiposity is unlikely to account for these relationships

Intra-operative MRI facilitates tumour resection during trans-sphenoidal surgery for pituitary adenomas

Background During trans-sphenoidal microsurgical resection of pituitary adenomas, the extent of resection may be difficult to assess, especially when extensive suprasellar and parasellar growth has occurred. In this prospective study, we investigated whether intra-operative magnetic resonance imaging (iMRI) can facilitate tumour resection. Methods Twenty patients with macroadenomas, (16 non-functioning, three growth-hormone secreting and one pharmaco-resistant prolactinoma) were selected for surgery in the iMRI. The mean tumour diameter was 27 mm (range 11–41). The mean parasellar grade, according to the Knosp classification, was 2.3. Pre-operative coronal and sagittal T1-weighted and T2-weighted images were obtained. The trans-sphenoidal tumour resection was performed at the edge of the tunnel of a Signa SP 0.5-Tesla MRI. The surgeon aimed at a radical tumour resection that was followed by a peri-operative MRI scan. When a residual tumour was visualised and deemed resectable, an extended resection was performed, followed by another MRI scan. This procedure was repeated until the imaging results were satisfactory. In all patients, we were able to obtain images to assess the extent of resection and to classify the resection as either total or subtotal. Results After primary resection, eight out of 20 cases were classified as total resections. A second resection was performed in 11 of 12 cases classified as subtotal resections, and in four of these, total resection was achieved. A third resection was performed in three of the remaining seven cases with subtotal resections, but we did not achieve total resection in any of these cases. Therefore, the use of iMRI increased the number of patients with total resection from 8/20 (40%) to 12/20 (60%). The only observed complication was a transient spinal fluid leakage. Conclusion Intra-operative MRI during trans-sphenoidal microsurgery is useful in selected patients for a safe and more complete resection. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited

Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses.

Observational studies exploring whether there is a nonlinear effect of blood pressure on cardiovascular disease (CVD) risk are hindered by confounding. This limitation can be overcome by leveraging randomly allocated genetic variants in nonlinear Mendelian randomization analyses. Based on their association with blood pressure traits in a genome-wide association study of 299 024 European ancestry individuals, we selected 253 genetic variants to proxy the effect of modifying systolic and diastolic blood pressure. Considering the outcomes of incident coronary artery disease, stroke and the combined outcome of CVD, linear and nonlinear Mendelian randomization analyses were performed on 255 714 European ancestry participants without a history of CVD or antihypertensive medication use. There was no evidence favoring nonlinear relationships of genetically proxied systolic and diastolic blood pressure with the cardiovascular outcomes over linear relationships. For every 10-mm Hg increase in genetically proxied systolic blood pressure, risk of incident CVD increased by 49% (hazard ratio, 1.49 [95% CI, 1.38-1.61]), with similar estimates obtained for coronary artery disease (hazard ratio, 1.50 [95% CI, 1.38-1.63]) and stroke (hazard ratio, 1.44 [95% CI, 1.22-1.70]). Genetically proxied blood pressure had a similar relationship with CVD in men and women. These findings provide evidence to support that even for individuals who do not have elevated blood pressure, public health interventions achieving persistent blood pressure reduction will be of considerable benefit in the primary prevention of CVD