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Botvinik-Nezer, Rotem et al., Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses. The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset. Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed., European Union’s Horizon 2020 research and innovation programme (https://ec.europa.eu/programmes/horizon2020/en) under the Marie Skłodowska-Curie grant agreement no. 665501. A. Eed was supported by a predoctoral fellowship La Caixa-Severo Ochoa from Obra Social La Caixa. S.B.E. was supported by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 785907 (HBP SGA2).

In 2008, the US FDA issued an alert about an increased risk of psychiatric events associated with montelukast. Recent national pharmacovigilance analyses in Sweden, France and Spain detected a potential increase in reporting risk of the association. Our objective was to analyse spontaneous reports of psychiatric events in children and adolescents worldwide treated with montelukast. We conducted a retrospective analysis of Individual Case Safety Reports (ICSRs) recorded up to 1 January 2015 in the World Health Organization (WHO) database (VigiBase®), in which montelukast was associated with ‘psychiatric disorders’. We used the Bayesian Confidence Propagation Neural Network (BCPNN) approach for signal generation. A total of 14,670 ICSRs for montelukast were recorded, of which 2630 corresponded to psychiatric disorders in people aged

Despite the increase in the substitution of branded medicinal product with generic drugs, this is a controversial issue for some pharmacological groups (such as contraceptives).The aim of the present clinical trial was to assess the bioequivalence and tolerability of two oral formulations of desogestrel.Thirty-three healthy female volunteers participated in this randomized and two-way crossover study. During two separate experimental periods, with at least four weeks of washout period, women received a single oral dose of 75 μg of desogestrel from each of the formulations (test formulation and reference formulation). Desogestrel bioavailability was determined by the measurement of 3-ketodesogestrel plasma concentration.Pharmacokinetic parameters were comparable and the 90% CI for the ratio of C(max) (96.14-114.53%) and AUC(0-t) (105.73-123.83%) values for the test and reference formulations fell within the established regulatory interval (80-125%). Both formulations were also comparable in terms of tolerability.From the results of this study it can be concluded that test formulation (desogestrel 75 μg, Cyndea PHARMA S.L.) is bioequivalent to the reference formulation (Cerazet® 75 μg, Organon Española S.A.).

OBJECTIVE: To identify the consumption pathway and strategies of coping with antidepressants use from the patients perspective. DESIGN: Qualitative research. SETTING: Tenerife. SAMPLING: Theoretical sampling until saturation. METHOD: A total of 17 open interviews with patients who consumed antidepressants whether combined with tranquilisers or not. The age range was between 35-85 years, and there were 13 women. Ten lived in a more urban setting and the rest in rural areas. Interviews were audio-recorded, transcribed verbatim and analysed using a modified Grounded Theory supported by the software program ATLAS.ti. RESULTS: The process identified as coping with antidepressants, was called “struggling internally and externally.” It consisted of the individual assessment of the benefits and risks of medication use (internal struggle), addressing stigma and social pressure (external struggle). The outcome of the assessment made by patients may lead to different strategies for adjusting to drug treatment: “unconditional acceptance”, “resigned acceptance” or “forced acceptance”. CONCLUSIONS: Understanding the evaluation process that the patient needs to go through, given the internal and external struggle in which they are immersed, can be useful to develop interventions that improve medication use. In fact, physicians have an important role, although not always explicitly sought in resolving the dilemma posed by patients using antidepressant drugs and, therefore, reducing the length of patient suffering.

Although erectile dysfunction (ED) is known to hamper quality of life (QoL) of afflicted men and their partners, there are few validated instruments for assessing the couple's sexual QoL. The Sexual Life Quality of Life Questionnaire (SLQQ) was developed in the United States for this purpose, and so it has been used in clinical studies. Yet, the original description did not address some important psychometric properties included in the Food and Drug Administration 2006 guidance for patient-reported outcome instruments.The aims of this study were to validate a Spanish language version of the modified SLQQ (mSLQQ), and to evaluate on it those psychometric properties lacking in the seminal description, namely discriminant validity and test-retest stability.Psychometric validation of the translated SLQQ was conducted on 164 ED patients and their sexual partners, and 60 age-matched non-dysfunctional couples. At baseline, all subjects completed the mSLQQ QoL and the 12-item Short-Form Health Survey questionnaires, and the men the International Index of Erectile Function. Two weeks later, ED patients abstaining from any ED medication and their partners repeated the mSLQQ QoL (104 valid couples). Oral medication for ED was then prescribed. Four weeks thereafter, they completed the QoL and treatment satisfaction scales of the SLQQ.The mSLQQ QoL scores of men and women at different times for psychometric analyses. Results. Cronbach alpha coefficients indicated good internal consistency. Large differences between control and ED couples, and close association with ED severity demonstrated discriminant and convergent validity, respectively. High intra-class correlation coefficients and similar mean scores at first and second visits substantiated test-retest stability. Significant increases after treatment with robust effect size demonstrated sensitivity to change in both patients and partners.This adaptation of the SLQQ shows psychometric properties comparable to the original description. The additional properties demonstrated here fully validate the mSLQQ as a tool for evaluating sexual QoL in ED patients and their partners.

Background Budesonide has a long history as intranasal drug, with many marketed products. Efforts should be made to demonstrate the therapeutic equivalence and safety comparability between them. Given that systemic availability significantly varies from formulations, the clinical comparability of diverse products comes to be of clinical interest and a regulatory requirement. The aim of the present study was to compare the systemic availability, pharmacodynamic effect, and safety of two intranasal budesonide formulations for the treatment of rhinitis. Methods Eighteen healthy volunteers participated in this randomised, controlled, crossover, clinical trial. On two separated days, subjects received a single dose of 512 μg budesonide (4 puffs per nostril) from each of the assayed devices (Budesonida nasal 64®, Aldo-Union, Spain and Rhinocort 64®, AstraZeneca, Spain). Budesonide availability was determined by the measurement of budesonide plasma concentration. The pharmacodynamic effect on the hypothalamic-adrenal axis was evaluated as both plasma and urine cortisol levels. Adverse events were tabulated and described. Budesonide availability between formulations was compared by the calculation of 90%CI intervals of the ratios of the main pharmacokinetic parameters describing budesonide bioavailability. Plasma cortisol concentration-time curves were compared by means of a GLM for Repeated Measures. Urine cortisol excretion between formulations was compared through the Wilcoxon's test. Results All the enroled volunteers successfully completed the study. Pharmacokinetic parameters were comparable in terms of AUCt (2.6 ± 1.5 vs 2.2 ± 0.7), AUCi (2.9 ± 1.5 vs 2.4 ± 0.7), tmax (0.4 ± 0.1 vs 0.4 ± 0.2), Cmax/AUCi (0.3 ± 0.1 vs 0.3 ± 0.0), and MRT (5.0 ± 1.4 vs 4.5 ± 0.6), but not in the case of Cmax (0.9 ± 0.3 vs 0.7 ± 0.2) and t1/2 (3.7 ± 1.8 vs 2.9 ± 0.4). The pharmacodynamic effects, measured as the effect over plasma and urine cortisol, were also comparables between both formulations. No severe adverse events were reported and tolerance was comparable between formulations. Conclusion The systemic availability of intranasal budesonide was comparable for both formulations in terms of most pharmacokinetic parameters. The pharmacodynamic effect on hypothalamic-pituitary-adrenal axis was also similar. Side effects were scarce and equivalent between the two products. This methodology to compare different budesonide-containing devices is reliable and easy to perform, and should be recommended for similar products intented to be marketed or already on the market. Trial registration No Eudra CT: 2005-003727-39

Two particular polymorphisms, namely PON1-192 and PON2-311, in the genes encoding the antioxidant enzymes paraoxonase-1 (PON1) and paraoxonase-2 (PON2) have been associated with an increased risk of acute myocardial infarction (AMI). However, previous findings have been contradictory. The aim of this study was to investigate the association between the PON1-192 and PON2-311 polymorphisms and their interaction on AMI risk.This case-control study involved 746 consecutive AMI patients and 1796 control subjects without cardiovascular disease, who were randomly selected from the same population from which the patients came. All participants were recruited between 1999 and 2000 from four Spanish autonomous regions. All were assessed for the presence of PON1-192 and PON2-311 and for classical cardiovascular risk factors. Multivariate analysis was carried out using logistic regression modeling.The odds ratios (OR) of AMI for patients with the PON1-192 QQ and PON2-311 SS genotypes (who comprised 50% and 66% of the population, respectively) were 1.26 (95% confidence interval [CI], 1.02-1.55) and 1.25 (95% CI, 1.04-1.50), respectively, compared with R and C allele carriers. Moreover, in patients with both QQ and SS genotypes, the adjusted OR of AMI increased to 1.41 (95% CI, 1.13-1.76).Our results indicate that the PON1-192 and PON2-311 polymorphisms were independent risk factors of AMI in our population.

Available online 22 August 2021. White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process. This work was conducted in part using the resources of the Ad- vanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. KS, BL, CH were supported by the Na- tional Institutes of Health under award numbers R01EB017230, and T32EB001628, and in part by ViSE/VICTR VR3029 and the National Center for Research Resources, Grant UL1 RR024975-01. This work was also possible thanks to the support of the Institutional Research Chair in NeuroInformatics of Universitéde Sherbrooke, NSERC and Compute Canada (MD, FR). MP received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sk ł odowska-Curie grant agreement No 754462. The Wisconsin group acknowledges the support from a core grant to the Waisman Cen- ter from the National Institute of Child Health and Human Develop- ment (IDDRC U54 HD090256). NSF OAC-1916518, NSF IIS-1912270, NSF IIS-1636893, NSF BCS-1734853, NIH NIBIB 1R01EB029272-01, and a Microsoft Faculty Fellowship to F.P. LF acknowledges the sup- port of the Cluster of Excellence Matters of Activity. Image Space Mate- rial funded by the Deutsche Forschungsgemeinschaft (DFG, German Re- search Foundation) under Germany´s Excellence Strategy –EXC 2025. SW is supported by a Medical Research Council PhD Studentship UK [MR/N013913/1]. The Nottingham group’s processing was performed using the University of Nottingham’s Augusta HPC service and the Pre- cision Imaging Beacon Cluster. JPA, MA and SMS acknowledges the support of FCT - Fundação para a Ciência e a Tecnologia within CIN- TESIS, R&D Unit (reference UID/IC/4255/2013). MM was funded by the Wellcome Trust through a Sir Henry Wellcome Postdoctoral Fellow- ship [213722/Z/18/Z]. EJC-R is supported by the Swiss National Sci- ence Foundation (SNSF, Ambizione grant PZ00P2 185814/1). CMWT is supported by a Sir Henry Wellcome Fellowship (215944/Z/19/Z) and a Veni grant from the Dutch Research Council (NWO) (17331). FC acknowledges the support of the National Health and Medical Re- search Council of Australia (APP1091593 and APP1117724) and the Australian Research Council (DP170101815). NSF OAC-1916518, NSF IIS-1912270, NSF IIS-1636893, NSF BCS-1734853, Microsoft Faculty Fellowship to F.P. D.B. was partially supported by NIH NIMH T32- MH103213 to William Hetrick (Indiana University). CL is partly sup- ported by NIH grants P41 EB027061 and P30 NS076408 “Institutional Center Cores for Advanced Neuroimaging. JYMY received positional funding from the Royal Children’s Hospital Foundation (RCH 1000). JYMY, JC, and CEK acknowledge the support of the Royal Children’s Hospital Foundation, Murdoch Children’s Research Institute, The Uni- versity of Melbourne Department of Paediatrics, and the Victorian Gov- ernment’s Operational Infrastructure Support Program. C-HY is grateful to the Ministry of Science and Technology of Taiwan (MOST 109-2222- E-182-001-MY3) for the support. LC acknowledges support from CONA- CYT and UNAM. ARM acknowledges support from CONACYT. LJO, YR, and FZ were supported by NIH P41EB015902 and R01MH119222. AJG was supported by P41EB015898. NM was supported by R01MH119222, K24MH116366, and R01MH111917. This project has received funding from the European Union’s Horizon 2020 Research and Innovation Pro- gramme under Grant Agreement No. 785907 & 945539 (HBP SGA2 & SGA3), and from the ANR IFOPASUBA- 19-CE45-0022-01. PG, CR, NL and AV were partially supported by ANID-Basal FB0008 and ANID- FONDECYT 1190701 grants. We would like to acknowledge John C Gore, Hiromasa Takemura, Anastasia Yendiki, and Riccardo Galbusera for their helplful suggestions regarding the analysis, figures, and discussions.