TBMaLT, a flexible toolkit for combining tight-binding and machine learning.

Tight-binding approaches, especially the Density Functional Tight-Binding (DFTB) and the extended tight-binding schemes, allow for efficient quantum mechanical simulations of large systems and long-time scales. They are derived from ab initio density functional theory using pragmatic approximations and some empirical terms, ensuring a fine balance between speed and accuracy. Their accuracy can be improved by tuning the empirical parameters using machine learning techniques, especially when information about the local environment of the atoms is incorporated. As the significant quantum mechanical contributions are still provided by the tight-binding models, and only short-ranged corrections are fitted, the learning procedure is typically shorter and more transferable as it were with predicting the quantum mechanical properties directly with machine learning without an underlying physically motivated model. As a further advantage, derived quantum mechanical quantities can be calculated based on the tight-binding model without the need for additional learning. We have developed the open-source framework-Tight-Binding Machine Learning Toolkit-which allows the easy implementation of such combined approaches. The toolkit currently contains layers for the DFTB method and an interface to the GFN1-xTB Hamiltonian, but due to its modular structure and its well-defined interfaces, additional atom-based schemes can be implemented easily. We are discussing the general structure of the framework, some essential implementation details, and several proof-of-concept applications demonstrating the perspectives of the combined methods and the functionality of the toolkit.

[Rank of outcome parameters in the treatment of depression : Results of a Delphi panel survey]. / Präferenz von Zielparametern bei der Behandlung der Depression : Ergebnisse einer Delphi-Panel-Erhebung.

BACKGROUND: In the context of new drug benefit assessments a list of outcome parameter are evaluated. Currently it is unclear, how different outcome parameters are weighed in the overall assessment. OBJECTIVES: The objective of the survey is to rank relevant outcome parameters in the treatment of depression, which may be considered in benefit the assessment of new antidepressants. MATERIALS AND METHODS: In 2015 a Delphi panel survey with 30 general practitioners and specialists in Germany was performed regarding the benefit assessment of antidepressants. On the basis of two fictive casuistics (patients with depressive disorders) the physicians weighed a range of relevant outcome parameters regarding efficacy, quality of life, safety and tolerability according to their relevance to clinical practice. RESULTS: Regarding efficacy, response, remission and recovery were rated as the most important outcomes. Regarding quality of life, handling of the daily household activities and mental performance were rated as most important. Suicidality was rated as the most important outcome regarding safety and tolerability. CONCLUSIONS: Individual outcome parameters were rated differently by the physicians regarding their relevance to clinical practice. The results indicate that outcome parameters should be weighed differently when assessing the overall benefit of new antidepressants.

Comparing Nalmefene and Naltrexone in Alcohol Dependence: Are there any Differences? Results from an Indirect Meta-Analysis.

BACKGROUND: The mu-opioid antagonist naltrexone is one of the few approved pharmacotherapies for the treatment of alcohol dependence. Recently, the mu-opioid antagonist and partial kappa agonist nalmefene was approved by the European Medicines Agency for the reduction of alcohol consumption in adult patients with alcohol dependence. To date, no head-to-head studies have compared the efficacy and safety of naltrexone and nalmefene in reducing alcohol consumption. METHODS: An indirect meta-analysis of randomized controlled studies on these 2 medications was conducted. A random effects model was used to measure effects and compare the 2 medications. 4 placebo-controlled studies with nalmefene and 13 with naltrexone were included. RESULTS: A statistically significant advantage of nalmefene towards naltrexone in the 2 patient-relevant outcome efficacy criteria, quantity and frequency of drinking, was found. Both drugs had a benign safety profile. CONCLUSIONS: This indirect meta-analysis indicates an advantage of nalmefene over naltrexone. Nalmefene is an effective and well-tolerated medication for the reduction of alcohol consumption. Additional data are necessary to demonstrate possible advantages of nalmefene over naltrexone in the treatment of alcohol dependence.

Treatment of comorbid anxiety and depression with escitalopram: results of a post-marketing surveillance study.

INTRODUCTION: In this 16-week post-marketing surveillance (PMS) study, antidepressant effects and tolerability of escitalopram was examined in 2 911 patients with comorbid depression and anxiety. METHODS: Antidepressant effects were assessed using a modified version of the Montgomery-Åsberg depression rating scale (svMADRS), the Hamilton anxiety scale (HAMA) and the hospital anxiety depression scale (HADS-D) and the clinical global impression scale (CGI-S, CGI-I). RESULTS: Treatment was completed by 2 718 patients, whose severity of depression decreased from a mean svMADRS total score of 33.0 to 8.9. At the end of the study, the remission rate (svMADRS≤12) was 72.9% and the response rate (≥50% decrease in svMADRS score) was 83.1% (LOCF). Similarly, the severity of anxiety symptoms decreased from a mean HAMA total score of 28.8-8.8; the remission rate (HAMA<10) was 63.9% and the response rate (decrease≥50%) was 80.2%. The most frequent adverse events were nausea (1.6%), agitation (1.1%) and fatigue (0.7%). DISCUSSION: Antidepressant effects and good tolerability of escitalopram were confirmed in everyday practice in patients with comorbid depression and anxiety. The high response and remission rates were within the range reported in previous RTC's of escitalopram vs. comparators or vs. placebo.

Intradermal delivery of vaccines: potential benefits and current challenges.

Delivery of vaccine antigens to the dermis and/or epidermis of human skin (i.e. intradermal delivery) might be more efficient than injection into the muscle or subcutaneous tissue, thereby reducing the volumes of antigen. This is known as dose-sparing and has been demonstrated in clinical trials with some, but not all, vaccines. Dose-sparing could be beneficial to immunization programmes by potentially reducing the costs of purchase, distribution and storage of vaccines; increasing vaccine availability and effectiveness. The data obtained with intradermal delivery of some vaccines are encouraging and warrant further study and development; however significant gaps in knowledge and operational challenges such as reformulation, optimizing vaccine presentation and development of novel devices to aid intradermal vaccine delivery need to be addressed. Modelling of the costs and potential savings resulting from intradermal delivery should be done to provide realistic expectations of the potential benefits and to support cases for investment. Implementation and uptake of intradermal vaccine delivery requires further research and development, which depends upon collaboration between multiple stakeholders in the field of vaccination.

Adjuvants for malaria vaccines.

There is a renewed enthusiasm about subunit vaccines for malaria coincident with the formation of new alliances and partnerships raising international public awareness, attracting increased resources and the re-focusing of research programs on adjuvant development for infectious disease vaccines. It is generally accepted that subunit vaccines for malaria will require adjuvants to induce protective immune responses, and availability of suitable adjuvants has in the past been a barrier to the development of malaria vaccines. Several novel adjuvants are now in licensed products or in late stage clinical development, while several others are in the earlier development pipeline. Successful vaccine development requires knowing which adjuvants to use and knowing how to formulate adjuvants and antigens to achieve stable, safe, and immunogenic vaccines. For the majority of vaccine researchers this information is not readily available, nor is access to well-characterized adjuvants. In this minireview, we outline the current state of adjuvant research and development as it pertains to effective malaria vaccines.

Malaria vaccine development: progress and challenges.

A safe and effective malaria vaccine would contribute greatly to the control and prevention of the disease. Although a review of global activity in malaria vaccine development does reflect significant activity, progress has remained slow. This article discusses the current vaccine candidates, with emphasis on those in the clinic, and explains the numerous challenges to making and evaluating malaria vaccines, which have resulted in only a few approaches being adopted and repeatedly evaluated. Against a parasite with more than 5200 genes, the lack of definitive knowledge regarding the nature of protective immunity and absence of reliable surrogates of protection are among the key challenges to a rational evaluation and prioritization of candidate vaccines. Pursuing the current R&D strategies may not result in the availability of a vaccine with characteristics suitable to impact significantly on disease morbidity in developing countries. Therefore, it is critical that the main challenges to malaria vaccine development be unambiguously identified and collectively addressed.

Ricin B-chain promotes the internalisation of liposomal contents into rat hepatoma cells.

Ricin B-chain covalently attached to liposomes has been shown to promote the binding of the liposomes to rat hepatoma cells through its galactosyl binding site. Internalisation of the bound liposomes is demonstrated by the cytotoxicity of methotrexate-containing liposomes, the transfection of cells with targeted liposomes containing pSV2-neo DNA and the intracellular activity of an enzyme encapsulated in liposomes targeted with the ricin B-chain.

Induction of immune response against a short synthetic peptide antigen coupled to small neutral liposomes containing monophosphoryl lipid A.

We have investigated the parameters affecting the immunogenicity of a short synthetic hexapeptide associated with liposomes. The model peptide used had the sequence IRGERA which corresponds to the C-terminal hexapeptide region of histone H3. Immunogenicity was measured by the ability of anti-peptide antibodies to cross-react with the parent protein. By itself, the peptide was not able to induce significant antibody production. However, liposomes were shown to be able to render the peptide immunogenic, nevertheless a number of parameters were important: to be immunogenic the peptide had to be surface bound, rather than entrapped within the liposomes, and an adjuvant, monophosphoryl lipid A (MPLA), had to be present in the same population of liposomes. Additionally, the intensity and duration of the immune response were found to be dependent both on the charge of the liposomes; neutral liposomes yielding a longer lasting response than negatively charged liposomes, and on the immunisation schedule where a long time period between immunisation and boosting yielded a better result than a short time period. To account for these phenomena we propose a model in which surface-bound antigen targets liposomal MPLA to B lymphocytes specific for the antigen. These results demonstrate that liposomes containing the non-toxic adjuvant MPLA can act as carriers to induce a long-lasting IgG response against peptides, eliminating the need of protein carriers and conventional adjuvants. Such an approach may be useful for designing synthetic vaccines.

Dedicated immunosensing of the mouse intestinal epithelium facilitated by a pair of genetically coupled lectin-like receptors.

The integrity of the intestinal epithelium is constantly surveyed by a peculiar subset of innate-like T lymphocytes embedded in the epithelial cell layer, hence called intestinal intraepithelial lymphocytes (IELs). IELs are thought to act as "first-line" sentinels sensing the state of adjacent epithelial cells via both T-cell receptors and auxiliary receptors. Auxiliary receptors modulating IEL activity include C-type lectin-like receptors encoded in the natural killer gene complex such as NKG2D. Here, we report that the CTLR Nkrp1g is expressed by a subpopulation of mouse CD103(+) IELs allowing immunosensing of the intestinal epithelium through ligation of the genetically coupled CTLR Clr-f that is almost exclusively expressed on differentiated intestinal epithelial cells (IECs). Most of these Nkrp1g-expressing IELs exhibit a γδTCR(bright)Nkg2a(-) phenotype and are intimately associated with the intestinal epithelium. As Clr-f expression strongly inhibits effector functions of Nkrp1g-expressing cells and is upregulated upon poly(I:C) challenge, Clr-f molecules may quench reactivity of these IELs towards the epithelial barrier that is constantly provoked by microbial and antigenic stimuli. Altogether, we here newly characterize a genetically linked C-type lectin-like receptor/ligand pair with a highly restricted tissue expression that apparently evolved to allow for a dedicated immunosurveillance of the mouse intestinal epithelium.

Incidence of cardiac arrests and unexpected deaths in surgical patients before and after implementation of a rapid response system.

BACKGROUND: Rapid response systems (RRSs) are considered an important tool for improving patient safety. We studied the effect of an RRS on the incidence of cardiac arrests and unexpected deaths. METHODS: Retrospective before- after study in a university medical centre. We included 1376 surgical patients before (period 1) and 2410 patients after introduction of the RRS (period 2). Outcome measures were corrected for the baseline covariates age, gender and ASA. RESULTS: The number of patients who experienced a cardiac arrest and/or who died unexpectedly decreased non significantly from 0.50% (7/1376) in period 1 to 0.25% (6/2410) in period 2 (odds ratio (OR) 0.43, CI 0.14-1.30). The individual number of cardiac arrests decreased non-significantly from 0.29% (4/1367) to 0.12% (3/2410) (OR 0.38, CI 0.09-1.73) and the number of unexpected deaths decreased non-significantly from 0.36% (5/1376) to 0.17% (4/2410) (OR 0.42, CI 0.11-1.59). In contrast, the number of unplanned ICU admissions increased from 2.47% (34/1376) in period 1 to 4.15% (100/2400) in period 2 (OR 1.66, CI 1.07-2.55). Median APACHE ll score at unplanned ICU admissions was 16 in period 1 versus 16 in period 2 (NS). Adherence to RRS procedures. Observed abnormal early warning scores ≤72 h preceding a cardiac arrest, unexpected death or an unplanned ICU admission increased from 65% (24/37 events) in period 1 to 91% (91/101 events) in period 2 (p < 0.001). Related ward physician interventions increased from 38% (9/24 events) to 89% (81/91 events) (p < 0.001). In period 2, ward physicians activated the medical emergency team in 65% of the events (59/91), although in 16% (15/91 events) activation was delayed for one or two days. The overall medical emergency team dose was 56/1000 admissions. CONCLUSIONS: Introduction of an RRS resulted in a 50% reduction in cardiac arrest rates and/or unexpected death. However, this decrease was not statistically significant partly due to the low base-line incidence. Moreover, delayed activation due to the two-tiered medical emergency team activation procedure and suboptimal adherence of the ward staff to the RRS procedures may have further abated the positive results.

Technology transfer hub for pandemic influenza vaccine.

Increase of influenza vaccine production capacity in developing countries has been identified as an important element of global pandemic preparedness. Nevertheless, technology transfer for influenza vaccine production to developing country vaccine manufacturers has proven difficult because of lack of interested technology providers. As an alternative to an individual provider-recipient relationship, a technology and training platform (a "hub") for a generic non-proprietary process was established at a public sector European manufacturer's site. The conditions for setting up such a platform and the potential applicability of this model to other biologicals are discussed.

Efficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention--a randomized, double-blind, multicentre, placebo-controlled study.

The efficacy and tolerability of a CO(2)-extract of feverfew (MIG-99, 6.25 mg t.i.d.) for migraine prevention were investigated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients (N = 170 intention-to-treat; MIG-99, N = 89; placebo, N = 81) suffering from migraine according to International Headache Society criteria were treated for 16 weeks after a 4-week baseline period. The primary endpoint was the average number of migraine attacks per 28 days during the treatment months 2 and 3 compared with baseline. Safety parameters included adverse events, laboratory parameters, vital signs and physical examination. The migraine frequency decreased from 4.76 by 1.9 attacks per month in the MIG-99 group and by 1.3 attacks in the placebo group (P = 0.0456). Logistic regression of responder rates showed an odds ratio of 3.4 in favour of MIG-99 (P = 0.0049). Adverse events possibly related to study medication were 9/107 (8.4%) with MIG-99 and 11/108 (10.2%) with placebo (P = 0.654). MIG-99 is effective and shows a favourable benefit-risk ratio.

Lyophilized liposomes as shelf items for the preparation of immunogenic liposome-peptide conjugates.

The conjugation of peptides to liposomes, while relatively simple, does represent a technical hurdle to some laboratories wishing to use such liposomes as vehicles to render peptides immunogenic. For such laboratories, having liposomes available as shelf items instead of having to prepare liposomes each time they are required may make liposomes more attractive. In this paper we report that small unilamellar liposomes bearing maleimide groups at their surface, and containing the adjuvant monophosphoryl lipid A, can be lyophilized and stored without loss of functionality or biological activity. On rehydration, peptides bearing cysteine residues are readily attached and the resulting conjugates exhibit the same immunogenicity as freshly prepared liposomes. These constructs avoid the use of protein carriers and also the use of Freund's adjuvant for raising antibodies against peptides.

Synthesis of arginine aldehydes for the preparation of pseudopeptides.

The synthesis of optically active aldehydes from N alpha-Boc-amino acids by reduction of the corresponding O,N-dimethyl-hydroxamates, while proceeding smoothly for most amino acids, has presented significant problems in the case of arginine. We demonstrate here that this difficulty can be overcome by the use of arginine derivatives in which the guanidino group is completely protected, such as in the case of N alpha-Boc-Arg(di-Z). In the case of nitro-, tosyl- or pmc-protected arginine, no satisfactory aldehyde formation can be obtained. It appears that in these cases the guanidino group is insufficiently protected and inhibits the formation of aldehydes. We also demonstrate that aldehydes can be readily obtained from N alpha-Fmoc protected amino acids.

Differential therapy of mild to moderate depressive episodes (ICD-10 F 32.0; F 32.1) with St. John's wort.

The purpose of this report was to evaluate specific depressive symptoms that are most suitable for a therapy with the Ze 117 St. John's wort extract. We examined the antidepressant efficacy and drug safety of Ze 117 and fluoxetine in a multicentric prospective randomized double-blind parallel group comparison according to generally accepted guidelines such as the Declaration of Helsinki and GCP. We treated outpatients (n = 240; Ze 117: 126; fluoxetine: 114) with mild to moderate depressive episodes (ICD-10: F 32.0, F 32.1; HAMD range: 16-24) with either two tablets St John's wort (Ze 117; 500 mg extract/day) or fluoxetine (20 mg/day) for 6 weeks. Antidepressant efficacy was evaluated with the validated HAMD psychometric method. A validated analysis of HAMD subscores was made to verify the efficacy for certain depressive symptoms. The main results were: * The HAMD responder rate was 60% in the Ze 117 group compared to 40% in the fluoxetine group (p = 0.005). * Particularly, there was a marked decrease of depressive agitation (pre-post comparison: 46%) and anxiety symptoms (44%) during the therapy with St. John's wort. Depressive obstruction (44%) and sleep disorders (43%) were reduced during the treatment, too. There were no statistically significant differences between the treatment groups. * Adverse events occurred in 28 patients (25%) in the fluoxetine group and in 18 (14%) of the St. John's wort group (p < 0.07). St. John's wort extract is a clinically effective equivalent to fluoxetine regarding overall depressive symptoms and main symptoms of depressive episodes. An especially interesting overall observation is that Ze 117 is particularly effective in depressive patients suffering from anxiety symptoms. St. John's wort revealed better safety and tolerability data than fluoxetine.

Isolation of nuclei from melittin-destabilized cells.

Melittin, the hydrophobic polypeptide from bee venom, sufficiently destabilizes the plasma membrane of cultured cells to allow cell disruption in the absence of detergents with minimal homogenization. Nuclei are thus isolated in high yield with intact nuclear membranes and high transcriptional activity.