Pharmacological and Combined Interventions for the Acute Depressive Episode: Focus on Efficacy and Tolerability

Background: Use of antidepressants is the gold standard therapy for major depression. However, despite the large number of commercially available antidepressant drugs there are several differences among them in efficacy, tolerability, and cost-effectiveness. In addition the optimal augmentation strategy is still not clear when dealing with treatment-resistant depression, a condition that affects 15% to 40% of depressed patients. Methods: We therefore reviewed the main characteristics of these drugs regarding their efficacy, tolerability, side effects and cost-effectiveness, by accessing all meta-analyses and systematic reviews published from 2004 to 2009. In addition, we reviewed the augmentation strategy of associated antidepressants with neurostimulation therapies (such as transcranial magnetic stimulation [TMS] and transcranial direct current stimulation [tDCS]). A search was undertaken in MEDLINE, Web of Science, Cochrane, and Scielo databases. We included: 21 meta-analyses of antidepressant trials, 15 neurostimulation clinical trials and 8 studies of pharmacoeconomics. We then performed a comprehensive review on these articles. Results and Conclusion: Although recent meta-analyses suggest sertraline and escitalopram might have increased efficacy/tolerability, other studies and large pragmatic trials have not found these to be superior to other antidepressant drugs. Also, we did not identify any superior drug in terms of cost-effectiveness due to the different designs observed among pharmacoecomics studies. Side effects such as sexual dysfunction, gastrointestinal problems and weight gain were common causes of discontinuation. Tolerability was an important issue for novel neurostimulation interventions, such as TMS and tDCS. These therapies might be interesting augmentation strategies, considering their benign profile of side effects, if proper safety parameters are adopted

Pharmacological and combined interventions for the acute depressive episode: focus on efficacy and tolerability

Andre R Brunoni1, Renerio Fraguas Jr1, Felipe Fregni21Department and Institute of Psychiatry, University of Sao Paulo, Brazil; 2Laboratory of Neuromodulation, Spaulding Rehabilitation Center, Harvard Medical School and Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USABackground: Use of antidepressants is the gold standard therapy for major depression. However, despite the large number of commercially available antidepressant drugs there are several differences among them in efficacy, tolerability, and cost-effectiveness. In addition the optimal augmentation strategy is still not clear when dealing with treatment-resistant depression, a condition that affects 15% to 40% of depressed patients.Methods: We therefore reviewed the main characteristics of these drugs regarding their efficacy, tolerability, side effects and cost-effectiveness, by accessing all meta-analyses and systematic reviews published from 2004 to 2009. In addition, we reviewed the augmentation strategy of associated antidepressants with neurostimulation therapies (such as transcranial magnetic stimulation [TMS] and transcranial direct current stimulation [tDCS]). A search was undertaken in MEDLINE, Web of Science, Cochrane, and Scielo databases. We included: 21 meta-analyses of antidepressant trials, 15 neurostimulation clinical trials and 8 studies of pharmacoeconomics. We then performed a comprehensive review on these articles.Results and Conclusion: Although recent meta-analyses suggest sertraline and escitalopram might have increased efficacy/tolerability, other studies and large pragmatic trials have not found these to be superior to other antidepressant drugs. Also, we did not identify any superior drug in terms of cost-effectiveness due to the different designs observed among pharmacoecomics studies. Side effects such as sexual dysfunction, gastrointestinal problems and weight gain were common causes of discontinuation. Tolerability was an important issue for novel neurostimulation interventions, such as TMS and tDCS. These therapies might be interesting augmentation strategies, considering their benign profile of side effects, if proper safety parameters are adopted.Keywords: acute depressive episode, pharmacological interventions, combined intervention

Liberal Typing for Functional Logic Programs

We propose a new type system for functional logic programming which is more liberal than the classical Damas-Milner usually adopted, but it is also restrictive enough to ensure type soundness. Starting from Damas-Milner typing of expressions we propose a new notion of well-typed program that adds support for type-indexed functions, existential types, opaque higher-order patterns and generic functions-as shown by an extensive collection of examples that illustrate the possibilities of our proposal. In the negative side, the types of functions must be declared, and therefore types are checked but not inferred. Another consequence is that parametricity is lost, although the impact of this flaw is limited as "free theorems" were already compromised in functional logic programming because of non-determinism

Synthesis and ex vivo biodistribution of two 68Ga-labeled tetrazine tracers : comparison of pharmacokinetics

Peer reviewe

Women as Industry 4.0. entrepreneurs : unlocking the potential of entrepreneurship in higher education in STEM-related fields

Industry 4.0 is the realization of digital transformation including enhanced productivity and flexibility due to real-time decision making which is possible due to the high-speed internet, the internet of things, and smart machines capable of autonomously exchanging information, triggering actions, and controlling each other independently. A high level of education and skills is increasingly more important in the job market over the next years necessitating finding a balance among behavioural, technological, analytical, and entrepreneurial skills. EU and governments worldwide should invest in closing the gender gap in science, technology, engineering, and mathematics (STEM) education as this will directly impact the economic growth. Even though there is some progress in the hiring percentage of women in large technological companies, a clear glass ceiling in leadership roles still remains. Here, we have undertaken a pilot study at University Complutense of Madrid (UCM, Spain) aimed at empowering women in academia to transition from the “publish or perish” paradigm towards creating and protecting their intellectual property to close the gender gap in STEM fields and leadership roles and training to fuel the development of innovative start-ups addressing societal challenges. A total of 20 participants inclusive of UCM staff and postrgraduate and postdoctoral researchers were enrolled after successfully obtaining at least a score of 5 out of 10 in custom-made Entrepreneurial competency test provided by Business and Professional Women Association (BPW, Spain) and theGrowBox Innovation Ltd. The study, approved by the UCM ethical committee, was conducted after participants engaged and completed a training program on “Enterpreneurship in STEM-related fields in Higher Education” aimed to introduce the participants to the entrepreneurial world. Programme involved a structured training programme covering the (i) business canvas design, (ii) development of minimum viable product (MVP), (iii) market evaluation, (iv) finance analysis using the Growbox platform, (v) introduction to venture capital, and (vi) human resources management followed by individual mentoring sessions prior completion of their business plans that were pitched to a panel of mentors and BPW representatives. Finally, all participants completed an anonymous survey of 12 open questions to evaluate the impact of the training in awakening the entrepreneurial spirit in academic researchers in Higher Education in STEM-related fields. Three quarters of participants were novices in terms of Enterpreneurship, but all after the programme presented a complete business plan. The three points that women identified as prohibitive factors were lack of self-confidence, ambition, and knowledge in the fields of patent filing, finance and marketing. Participants were likely to initiate their own start-up in the next five years but had mixed fillings regarding the complexity of the process. Nine months after the course ended, four out of 20 participants have been successful in attracting initial funding to support the initiation of a start-up involving protected intellectual property and managed to secure an award to provide them with office space to build their company. The long-term impact of this training programme will need to be followed. Entrepreneurial training is crucial to be embedded in curricula for postgraduate and if possible undergraduate students to pursue a major transformation targeting the STEM-related fields in Higher Education to enable women in becoming key participants and leaders in the Industry 4.0 era

Observation of confined current ribbon in JET plasmas

we report the identification of a localised current structure inside the JET plasma. It is a field aligned closed helical ribbon, carrying current in the same direction as the background current profile (co-current), rotating toroidally with the ion velocity (co-rotating). It appears to be located at a flat spot in the plasma pressure profile, at the top of the pedestal. The structure appears spontaneously in low density, high rotation plasmas, and can last up to 1.4 s, a time comparable to a local resistive time. It considerably delays the appearance of the first ELM.Comment: 10 pages, 6 figure

Mental disorders of known aetiology and precision medicine in psychiatry: a promising but neglected alliance [Editorial]

Personalized or precision medicine is predicated on the assumption that the average response to treatment is not necessarily representative of the response of each individual. A commitment to personalized medicine demands an effort to bring evidence-based medicine and personalized medicine closer together. The use of relatively homogeneous groups, defined using a priori criteria, may constitute a promising initial step for developing more accurate risk-prediction models with which to advance the development of personalized evidence-based medicine approaches to heterogeneous syndromes such as schizophrenia. However, this can lead to a paradoxical situation in the field of psychiatry. Since there has been a tendency to loosely define psychiatric disorders as ones without a known aetiology, the discovery of an aetiology for psychiatric syndromes (e.g. 22q11.2 deletion syndrome in some cases of schizophrenia), while offering a path toward more precise treatments, may also lead to their reclassification away from psychiatry. We contend that psychiatric disorders with a known aetiology should not be removed from the field of psychiatry. This knowledge should be used instead to guide treatment, inasmuch as psychotherapies, pharmacotherapies and other treatments can all be valid approaches to mental disorders. The translation of the personalized clinical approach inherent to psychiatry into evidence-based precision medicine can lead to the development of novel treatment options for mental disorders and improve outcomes

Inorganic and organic geochemical fingerprinting of sediment sources and ocean circulation on a complex continental margin (São Paulo Bight, Brazil)

In this study, we use inorganic (metal) and organic (bulk and molecular) markers in sediment samples of the south-eastern Brazilian margin to investigate the response of geochemical fingerprints to the complex hydrodynamic processes present in the area. Results indicate the potential of export of terrigenous siliciclastic and organic constituents to the upper slope, even in an area with limited fluvial supply. Metal contents and especially the ln(Ti = Al) and ln(Fe = K) ratios make it possible to recognise the extension of shelf sediments toward the upper slope. Potassium, here expressedas ln(K = Sc) and ln(K = Al) ratios used as proxies of illite–kaolinite variations, proved to be an important parameter, especially because it allowed us to decipher the imprint of the northward flow of the Intermediate Western Boundary Current (IWBC) in comparison to the southward flows of the Brazil Current (BC) and Deep Western Boundary Current (DWBC). Using organic matter analyses, we were able to evaluate the extent of terrestrial contributions to the outer shelf and slope, even without the presence of significant fluvial input. In addition, molecular markers signify a slight increase in the input of C4-derived plants to the slope sediments, transported from distant areas by the main alongshore boundary currents, indicating that the terrestrial fraction of the organic matter deposited on the slope has a distinct origin when compared to shelf sediments

Synthesis and ex vivo biodistribution of two 68Ga-labeled tetrazine tracers: Comparison of pharmacokinetics

Pretargeted PET imaging allows the use of radiotracers labeled with short-living PET radionuclides for tracing drugs with slow pharmacokinetics. Recently, especially methods based on bioorthogonal chemistry have been under intensive investigation for pretargeted PET imaging. The pharmacokinetics of the radiotracer is one of the factors that determine the success of the pretargeted strategy. Here, we report synthesis and biological evaluation of two 68Ga-labeled tetrazine (Tz)-based radiotracers, [68Ga]Ga-HBED-CC-PEG4-Tz ([68Ga]4) and [68Ga]Ga-DOTA-PEG4-Tz ([68Ga]6), aiming for development of new tracer candidates for pretargeted PET imaging based on the inverse electron demand Diels-Alder (IEDDA) ligation between a tetrazine and a strained alkene, such as trans-cyclooctene (TCO). Excellent radiochemical yield (RCY) was obtained for [68Ga]4 (RCY > 96%) and slightly lower for [68Ga]6 (RCY > 88%). Radiolabeling of HBED-CC-Tz proved to be faster and more efficient under milder conditions compared to the DOTA analogue. The two tracers exhibited excellent radiolabel stability both in vitro and in vivo. Moreover, [68Ga]4 was successfully used for radiolabeling two different TCO-functionalized nanoparticles in vitro: Hepatitis E virus nanoparticles (HEVNPs) and porous silicon nanoparticles (PSiNPs)