Multi-and many-objective optimization: present and future in de novo drug design.

de novo Drug Design (dnDD) aims to create new molecules that satisfy multiple conflicting objectives. Since several desired properties can be considered in the optimization process, dnDD is naturally categorized as a many-objective optimization problem (ManyOOP), where more than three objectives must be simultaneously optimized. However, a large number of objectives typically pose several challenges that affect the choice and the design of optimization methodologies. Herein, we cover the application of multi- and many-objective optimization methods, particularly those based on Evolutionary Computation and Machine Learning techniques, to enlighten their potential application in dnDD. Additionally, we comprehensively analyze how molecular properties used in the optimization process are applied as either objectives or constraints to the problem. Finally, we discuss future research in many-objective optimization for dnDD, highlighting two important possible impacts: i) its integration with the development of multi-target approaches to accelerate the discovery of innovative and more efficacious drug therapies and ii) its role as a catalyst for new developments in more fundamental and general methodological frameworks in the field.

Synthesis and biological evaluation of 4-hydroxy-methylpiperidinyl-N-benzyl-acylarylhydrazone hybrids designed as novel multifunctional drug candidates for Alzheimer's disease.

The search for new drug candidates against Alzheimer's disease (AD) remains a complex challenge for medicinal chemists due to its multifactorial pathogenesis and incompletely understood physiopathology. In this context, we have explored the molecular hybridization of pharmacophore structural fragments from known bioactive molecules, aiming to obtain a novel molecular architecture in new chemical entities capable of concomitantly interacting with multiple targets in a so-called multi-target directed ligands (MTDLs) approach. This work describes the synthesis of 4-hydroxymethyl)piperidine-N-benzyl-acyl-hydrazone derivatives 5a-l, designed as novel MTDLs, showing improved multifunctional properties compared to the previously reported parent series of N-benzyl-(3-hydroxy)piperidine-acyl-hydrazone derivatives 4. The new improved derivatives were studied in silico, regarding their mode of interaction with AChE enzyme, and in vitro, for evaluation of their effects on the selective inhibition of cholinesterases, cellular antioxidant, and neuroprotective activities as their cytotoxicity in human neuroblastoma (SH-SY5Y) cells. Overall, compound PQM-181 (5 k) showed the best balanced selective and non-competitive inhibition of AChE (IC50 = 5.9 µM, SI > 5.1), with an additional antioxidant activity (IC50 = 7.45 µM) against neuronal t-BOOH-induced oxidative stress and neuroprotective ability against neurotoxicity elicited by both t-BOOH and OAß1-42, and a moderate ability to interfere in Aß1-42 aggregates, with low cytotoxicity and good predictive druggability properties, suggesting a multifunctional pharmacological profile suitable for further drug development against AD.

Coral-ID: A forensically validated genetic test to identify precious coral material and its application to objects seized from illegal traffic.

The production and trade of objects manufactured from the skeletal axis of coralid precious corals is a historically, culturally and economically important global industry. Coralids are members of the diverse Coralliidae family, which contains several species complexes and morphospecies. For most precious coral found in the jewelry trade, the color remains the sole clue and link to the taxonomic identity of the individual. Different coralid species have however similar or overlapping colors resulting in difficulty to taxonomically identify jewelry objects, including four species listed by the Convention on the International Trade of Endangered Species (CITES) whose international transport and trade requires species-specific and country of origin documentation. We aimed at developing a reliable method to taxonomically identify coralid material with the objective of distinguishing CITES protected species from their non-protected counterparts. We present Coral-ID, a genetic assay to taxonomically classify coralid objects using quasi non-destructive sampling. The assay classifies the analyzed sample in one of six taxonomic categories and performs at least presumptive separation of CITES-listed and non-listed species in all cases. Developmental validation experiments prove that Coral-ID is a specific, accurate and very sensitive method. As the first attempt to randomly sample corals in the trade to identify them, we applied Coral-ID on 20 precious coral objects seized by custom authorities upon import to in Switzerland. Thirteen (65%) of these samples could be analyzed; three of these were found to be presumptively CITES-listed, and 10 of them have proven to originate from non-CITES-listed species.

Drug design and repurposing with DockThor-VS web server focusing on SARS-CoV-2 therapeutic targets and their non-synonym variants.

The COVID-19 caused by the SARS-CoV-2 virus was declared a pandemic disease in March 2020 by the World Health Organization (WHO). Structure-Based Drug Design strategies based on docking methodologies have been widely used for both new drug development and drug repurposing to find effective treatments against this disease. In this work, we present the developments implemented in the DockThor-VS web server to provide a virtual screening (VS) platform with curated structures of potential therapeutic targets from SARS-CoV-2 incorporating genetic information regarding relevant non-synonymous variations. The web server facilitates repurposing VS experiments providing curated libraries of currently available drugs on the market. At present, DockThor-VS provides ready-for-docking 3D structures for wild type and selected mutations for Nsp3 (papain-like, PLpro domain), Nsp5 (Mpro, 3CLpro), Nsp12 (RdRp), Nsp15 (NendoU), N protein, and Spike. We performed VS experiments of FDA-approved drugs considering the therapeutic targets available at the web server to assess the impact of considering different structures and mutations to identify possible new treatments of SARS-CoV-2 infections. The DockThor-VS is freely available at www.dockthor.lncc.br .

New machine learning and physics-based scoring functions for drug discovery.

Scoring functions are essential for modern in silico drug discovery. However, the accurate prediction of binding affinity by scoring functions remains a challenging task. The performance of scoring functions is very heterogeneous across different target classes. Scoring functions based on precise physics-based descriptors better representing protein-ligand recognition process are strongly needed. We developed a set of new empirical scoring functions, named DockTScore, by explicitly accounting for physics-based terms combined with machine learning. Target-specific scoring functions were developed for two important drug targets, proteases and protein-protein interactions, representing an original class of molecules for drug discovery. Multiple linear regression (MLR), support vector machine and random forest algorithms were employed to derive general and target-specific scoring functions involving optimized MMFF94S force-field terms, solvation and lipophilic interactions terms, and an improved term accounting for ligand torsional entropy contribution to ligand binding. DockTScore scoring functions demonstrated to be competitive with the current best-evaluated scoring functions in terms of binding energy prediction and ranking on four DUD-E datasets and will be useful for in silico drug design for diverse proteins as well as for specific targets such as proteases and protein-protein interactions. Currently, the MLR DockTScore is available at www.dockthor.lncc.br .

5-Year outcomes of the prospective and randomized CISTCERT study comparing steroid withdrawal to replacement of cyclosporine with everolimus in de novo kidney transplant patients.

Withdrawal of either steroids or calcineurin inhibitors are two strategies to reduce treatment-related side effects and improve long-term outcomes of kidney transplantation. The CISTCERT study compared the efficacy and safety of these two strategies. In this multicenter, randomized controlled trial, 151 incident kidney transplant recipients received cyclosporine (CsA), mycophenolic acid (MPA), and steroids during three months, followed by either steroid withdrawal (CsA/MPA) or replacement of cyclosporine with everolimus (EVL) (EVL/MPA/steroids). 5-year patient survival (89% vs. 86%; P = NS) and death-censored graft survival (95% vs. 96%; P = NS) were comparable in the CsA/MPA and EVL/MPA/steroids arm, respectively. 51 CrEDTA clearance was comparable in the intention-to-treat analysis, but in the on-treatment population, the EVL/MPA/steroids arm exhibited a superior 51 CrEDTA clearance at 1 and 5 years after transplantation (61.6 vs. 52.4, P = 0.05 and 59.1 vs. 46.2ml/min/1.73 m2 , P = 0.042). Numerically more and more severe rejections were observed in the EVL/MPA/steroids arm, which also experienced a higher incidence of posttransplant diabetes (26% vs. 6%, P = 0.0016) and infections. No significant differences were observed in cardiovascular outcomes and malignancy. Both regimens provide an excellent long-term patient survival and graft survival. Regarding graft function, EVL/MPA/steroids is an attractive strategy for patients with good tolerability who remain free of rejection. (ClinicalTrials.gov number: NCT00903188; EudraCT Number 2007-005844-26).

Isobenzofuran-1(3H)-ones as new tyrosinase inhibitors: Biological activity and interaction studies by molecular docking and NMR.

Tyrosinase is a multifunctional, glycosylated and copper-containing oxidase enzyme that can be found in animals, plants, and fungi. It is involved in several biological processes such as melanin biosynthesis. In this work, a series of isobenzofuran-1(3H)-ones was evaluated as tyrosinase inhibitors. It was found that compounds phthalaldehydic acid (1), 3-(2,6-dihydroxy-4-isopropylphenyl)isobenzofuran-1(3H)-one (7), and 2-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-1,3-phenylene diacetate (9) were the most potent compounds inhibiting tyrosinase activity in a concentration dependent manner. Ligand-enzyme NMR studies and docking investigations allowed to map the atoms of the ligands involved in the interaction with the copper atoms present in the active site of the tyrosinase. This behaviour is similar to kojic acid, a well know tyrosinase inhibitor and used as positive control in the biological assays. The findings herein described pave the way for future rational design of new tyrosinase inhibitors.

[Cesarean sections in the Centre-Val de Loire region: Practices and indications-the Robson Classification]. / Césarienne en Centre-Val de Loire ­ Pratiques et Indications ­ Classification de Robson.

BACKGROUND: To study the cesarean section (c-section) practices in the French Centre-Val de Loire region: incidence of planned c-section and rate variations between maternities, incidence of potentially avoidable cesarean sections. METHODS: The data were extracted from the 2016 regional birth register, which permitted classification of each planned c-section according to the pre-existing risk of c-section (high or low) as defined by the Robson classification. To enhance the data, especially the indications for c-section, which are not included in the register, a survey was conducted from September 2016 to February 2017 in all of the 20 maternities in the region. RESULTS: In 2016, nearly 26,000 women gave birth in the CVL region, of whom 19.2% by c-section (7.0% planned c-sections). The planned c-section rate was higher for breech presentation and scarred uterus, and decreased according to level of the maternity (I 41% - II 35% - III 32%). Concerning the c-section indications, 1,979 c-sections were studied during the period (18.6% of births), including 762 planned c-sections (7.1% of births). Among them, 246 (32%) were potentially avoidable, mainly isolated indications of scarred uterus with only one previous c-section or breech presentation, and 17 due to unfavorable radiologic pelvimetry in nulliparous women. CONCLUSION: Specific actions were identified: targeted use of radiologic pelvimetry, targeted c-section on scarred uterus with only one previous cesarean section or breech presentation, as recommended by the national guidelines. The Robson classification should be widely used to evaluate and enhance practices, in particularly through painstakingly interpreted inter-maternity comparisons.

DNA fingerprinting: an effective tool for taxonomic identification of precious corals in jewelry.

Precious coral species have been used to produce jewelry and ornaments since antiquity. Due to the high value and demand for corals, some coral beds have been heavily fished over past centuries. Fishing and international trade regulations were put in place to regulate fishing practices in recent decades. To this date, the control of precious coral exploitation and enforcement of trade rules have been somewhat impaired by the fact that different species of worked coral samples can be extremely difficult to distinguish, even for trained experts. Here, we developed methods to use DNA recovered from precious coral samples worked for jewelry to identify their species. We evaluated purity and quantity of DNA extracted using five different techniques. Then, a minimally invasive sampling protocol was tested, which allowed genetic analysis without compromising the value of the worked coral objects.The best performing DNA extraction technique applies decalcification of the skeletal material with EDTA in the presence of laurylsarcosyl and proteinase, and purification of the DNA with a commercial silica membrane. This method yielded pure DNA in all cases using 100 mg coral material and in over half of the cases when using "quasi non-destructive" sampling with sampled material amounts as low as 2.3 mg. Sequence data of the recovered DNA gave an indication that the range of precious coral species present in the trade is broader than previously anticipated.

[Involuntary detention and seclusion measures in psychiatry: Where are we now? A regional Centre-Val de Loire 2012-2017 study]. / Soins sans consentement et mesures d'isolement en psychiatrie adulte : où en est-on ? L'exemple de la région Centre-Val de Loire via le Programme de médicalisation des systèmes d'information 2012­2017.

BACKGROUND: The French legal framework in psychiatry for involuntary detention (ID) and seclusion measures was modified in 2011 and 2016, respectively. This study aimed to describe the evolution of ID and seclusion measures in the Centre-Val de Loire region (CVL France) between 2012 and 2017, using the psychiatric hospital discharge database. METHODS: A cross-sectional study was conducted, including adult patients (≥ 18 years old) from CVL hospitalized in psychiatry or included in a care program (outpatient care) between 2012 and 2017. Hospital stays for each patient were identified by an anonymized number. RESULTS: In 2017 in CVL, 13,942 patients were hospitalised for psychiatric reasons, with 2378 in ID (17%), a proportion that has remained stable since 2012. Among them, 3% were in care due to imminent danger (+ 54% since 2013, stabilisation since 2016), and 11% were hospitalized following a third party request (-13%). However, regarding location results varied from one department to the next. Seclusion measures involved 10% of full-time patients (stable), 27% of ID patients and 3% of those under voluntary care (stable). One quarter of the secluded patients were in voluntary care. Mean seclusion duration was 12 days, consecutive or not, and somewhat less for patients in voluntary care alone (10 days). CONCLUSION: The region wide ID rate and average duration of seclusion were lower than the nationwide rate (24% in full-time ID in 2015; 15 days of seclusion/patient), whereas the number of imminent danger procedures increased, as did the persistence of seclusion measures for patients in voluntary care (recommended only as a last resort and/or for ID patients). These results should lead to renewed assessment of care center practices. The French psychiatric hospital discharge database has several limitations, including lack of financial incentive and highly complex structuration. However, since 2018 new data regarding seclusion and restraint measures have been added to the existing registry, and they should facilitate more accurate analyses, particularly as concerns restraint.

Highly Flexible Ligand Docking: Benchmarking of the DockThor Program on the LEADS-PEP Protein-Peptide Data Set.

Protein-peptide interactions play a crucial role in many cellular and biological functions, which justify the increasing interest in the development of peptide-based drugs. However, predicting experimental binding modes and affinities in protein-peptide docking remains a great challenge for most docking programs due to some particularities of this class of ligands, such as the high degree of flexibility. In this paper, we present the performance of the DockThor program on the LEADS-PEP data set, a benchmarking set composed of 53 diverse protein-peptide complexes with peptides ranging from 3 to 12 residues and with up to 51 rotatable bonds. The DockThor performance for pose prediction on redocking studies was compared with some state-of-the-art docking programs that were also evaluated on the LEADS-PEP data set, AutoDock, AutoDock Vina, Surflex, GOLD, Glide, rDock, and DINC, as well as with the task-specific docking protocol HPepDock. Our results indicate that DockThor could dock 40% of the cases with an overall backbone RMSD below 2.5 Å when the top-scored docking pose was considered, exhibiting similar results to Glide and outperforming other protein-ligand docking programs, whereas rDock and HPepDock achieved superior results. Assessing the docking poses closest to the crystal structure (i.e., best-RMSD pose), DockThor achieved a success rate of 60% in pose prediction. Due to the great overall performance of handling peptidic compounds, the DockThor program can be considered as suitable for docking highly flexible and challenging ligands, with up to 40 rotatable bonds. DockThor is freely available as a virtual screening Web server at https://www.dockthor.lncc.br/ .

Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study.

BACKGROUND: Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). METHODS: In five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated. RESULTS: Of 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P = 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P = 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment. CONCLUSIONS: As expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment.

Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study.

BACKGROUND: There are limited long-term outcome data in eculizumab-treated patients with atypical hemolytic uremic syndrome (aHUS). We report final results from the largest prospective, observational, multicenter study of patients with aHUS treated with eculizumab. METHODS: Patients with aHUS who participated in any of five parent eculizumab trials and received at least one eculizumab infusion were eligible for enrollment in a long-term follow-up study. Rates of thrombotic microangiopathy (TMA) manifestations off versus on eculizumab were evaluated. Additional endpoints included change from baseline estimated glomerular filtration rate (eGFR), long-term renal outcomes, and serious targeted treatment-emergent adverse events. RESULTS: Among 93 patients (0-80 years of age), 51 (55%) remained on eculizumab and 42 (45%) discontinued; for those who discontinued, 21 (50%) reinitiated therapy. Patients who reinitiated eculizumab had similar baseline clinical characteristics to patients who remained on eculizumab, with higher likelihood of genetic/autoimmune complement abnormalities, more prior TMAs, and longer disease course versus those who did not reinitiate. Mean eGFR improved rapidly and remained stable for up to 6 years on eculizumab. In patients who discontinued, there was a trend toward decreasing renal function over time from discontinuation. Additionally, off-treatment TMA manifestation rates were higher in those aged < 18 years at diagnosis, with identified genetic/autoimmune complement abnormalities, or history of multiple TMAs prior to eculizumab initiation. The safety profile was consistent with previous studies. Three definite and one possible meningococcal infections related to eculizumab were reported and resolved with treatment. Three deaths unrelated to eculizumab were reported. CONCLUSIONS: The current study confirms the efficacy and safety of eculizumab in aHUS, particularly with regard to long-term renal function and TMA events. Pediatric age at disease onset and presence of genetic or autoimmune complement abnormalities are risk factors for TMA events off treatment. Overall, patients who discontinue eculizumab may be at risk for additional TMA manifestations and renal function decreases. Discontinuation of eculizumab, with careful monitoring, is an option in select patients with consideration of patient preference, organ function normalization, and risk factors for relapse, including mutational analysis, age of onset, and history of multiple TMA episodes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01522170 , January 31, 2012.

Multidisciplinary team meeting for complex bone and joint infections diagnosis: The PHICTOS study.

BACKGROUND: In France, the most severe bone and joint infections (BJI), called "complex" (CBJI), are assessed in a multidisciplinary team meeting (MTM) in a reference center. However, the definition of CBJI, drawn up by the Health Ministry, is not consensual between physicians. The objective was to estimate the agreement for CBJI classification. METHODS: Initially, five experts from one MTM classified twice, one-month apart, 24 cases as non-BJI, simple BJI or CBJI, using the complete medical record. Secondly, six MTMs classified the same cases using standardized information. Agreements were estimated using Fleiss and Cohen kappa (κ) coefficients. RESULTS: Inter-expert agreement during one MTM was moderate (κ=0.49), and fair (κ=0.23) when the four non-BJIs were excluded. Intra-expert agreement was moderate (κ=0.50, range 0.27-0.90), not improved with experience. The overall inter-MTM agreement was moderate (κ=0.58), it was better between MTMs with professor (κ=0.65) than without (κ=0.51) and with longer median time per case (κ=0.60) than shorter (κ=0.47). When the four non-BJIs were excluded, the overall agreement decreased (κ=0.40). CONCLUSION: The first step confirmed the heterogeneity of CBJI classification between experts. The seemingly better inter-MTM than inter-expert agreement could be an argument in favour of MTMs, which are moreover a privileged place to enhance expertise. Further studies are needed to assess these results as well as the quality of care and medico-economic outcomes after a MTM.

Empirical Scoring Functions for Structure-Based Virtual Screening: Applications, Critical Aspects, and Challenges.

Structure-based virtual screening (VS) is a widely used approach that employs the knowledge of the three-dimensional structure of the target of interest in the design of new lead compounds from large-scale molecular docking experiments. Through the prediction of the binding mode and affinity of a small molecule within the binding site of the target of interest, it is possible to understand important properties related to the binding process. Empirical scoring functions are widely used for pose and affinity prediction. Although pose prediction is performed with satisfactory accuracy, the correct prediction of binding affinity is still a challenging task and crucial for the success of structure-based VS experiments. There are several efforts in distinct fronts to develop even more sophisticated and accurate models for filtering and ranking large libraries of compounds. This paper will cover some recent successful applications and methodological advances, including strategies to explore the ligand entropy and solvent effects, training with sophisticated machine-learning techniques, and the use of quantum mechanics. Particular emphasis will be given to the discussion of critical aspects and further directions for the development of more accurate empirical scoring functions.

Key features of bone and joint infections following the implementation of reference centers in France.

OBJECTIVES: French reference centers for bone and joint infections (BJI) were implemented from 2009 onwards to improve the management of complex BJIs. This study compared BJI burden before and after the implementation of these reference centers. PATIENTS AND METHODS: BJI hospital stays were selected from the 2008 and 2013 national hospital discharge database using a validated algorithm, adding the new complex BJI code created in 2011. Epidemiology and economic burden were assessed. RESULTS: BJI prevalence increased in 2013 (70 vs. 54/100,000 in 2008). Characteristics of BJI remained similar between 2008 and 2013: septic arthritis (50%), increasing prevalence with age and sex, case fatality 5%, mean length of stay 17.5 days, rehospitalization 20%. However, device-associated BJIs increased (34 vs. 26%) as well as costs (€421 million vs. €259 in 2008). Similar device-associated BJI characteristics between 2008 and 2013 were: septic arthritis (70%), case fatality (3%), but with more hospitalizations in reference centers (34 vs. 30%) and a higher cost per stay. Among the 7% of coded complex BJIs, the mean length of stay was 22.2 days and mean cost was €11,960. CONCLUSIONS: BJI prevalence highly increased in France. Complex BJI prevalence assessment is complicated by the absence of clinical consensus and probable undercoding. A validation of clinical case definition of complex BJI is required.

Design, synthesis and pharmacological evaluation of N-benzyl-piperidinyl-aryl-acylhydrazone derivatives as donepezil hybrids: Discovery of novel multi-target anti-alzheimer prototype drug candidates.

A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AßO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AßO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment.

Discovery of naphthyl-N-acylhydrazone p38α MAPK inhibitors with in vivo anti-inflammatory and anti-TNF-α activity.

Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen-activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti-inflammatory profile of new naphthyl-N-acylhydrazone derivatives using animal models. Although all tested compounds (3a-d) have been characterized as p38α MAPK inhibitors and have showed in vivo anti-inflammatory action, LASSBio-1824 (3b) presented the best performance as p38α MAPK inhibitor, with IC50  = 4.45 µm, and also demonstrated to be the most promising anti-inflammatory prototype, with good in vivo anti-TNF-α profile after oral administration.

National epidemiological study reveals longer paediatric bone and joint infection stays for infants and in general hospitals.

AIM: Published studies have suggested that two to five days of intravenous treatment could effectively treat paediatric bone and joint infections (PBJI), allowing a faster discharge. This study analysed the factors associated with PBJI hospital stays lasting longer than five days using the French National Hospital Discharge Database. METHODS: We selected children under 15 years hospitalised in 2013 with haematogenous PBJIs using a validated French algorithm based on specific diagnosis and surgical procedure codes. Risk factors for stays of more than five days were analysed using logistic regression. RESULTS: In 2013, 2717 children were hospitalised for PBJI, with 49% staying more than five days. The overall incidence of 22 per 100 000, was highest in males and toddlers. The main causes were septic arthritis (50%) and osteomyelitis (46%) and 50% of the pathogens were Staphylococci. The odd ratios for stays of five days or more were infancy, coded bacteria and sickle cell disease (7.0), having spondylodiscitis rather than septic arthritis (2.2) and being hospitalised in a general hospital rather than a teaching hospital (1.6). CONCLUSION: Half of the hospital stays exceeded five days, despite scientific evidence supporting a shorter intravenous antibiotherapy regimen. Greater knowledge and widespread use of short treatment regimens are needed.