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.

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).

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/ .

[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.

[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.

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.

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.

Fibroblast growth factor-mediated crosstalk in cancer etiology and treatment.

It is becoming increasingly evident that multiple cell types within the tumor work together to drive tumour progression and impact on both the response to therapy and the dissemination of tumour cells throughout the body. Fibroblast growth factor signalling (FGF) is perturbed in a number of tumors, serving to drive tumor cell proliferation and migration, but also has a central role in orchestrating the plethora of cells that comprise the tumor microenvironment. This review focuses on how this family of signalling molecules can influence the interactions between tumor cells and their surrounding environment. Unraveling the complexities of FGF signalling between the distinct cell types of a tumor may identify additional opportunities for FGF-targeted compounds in therapy and could help combat drug resistance. Developmental Dynamics 246:493-501, 2017. © 2017 Wiley Periodicals, Inc.

Outcomes of patients with atypical haemolytic uraemic syndrome with native and transplanted kidneys treated with eculizumab: a pooled post hoc analysis.

Atypical haemolytic uraemic syndrome (aHUS) often leads to end-stage renal disease (ESRD) and kidney transplantation; graft loss rates are high due to disease recurrence. A post hoc analysis of four prospective clinical trials in aHUS was performed to evaluate eculizumab, a terminal complement inhibitor, in patients with native or transplanted kidneys. The trials included 26-week treatment and extension periods. Dialysis, transplant and graft loss were evaluated. Study endpoints included complete thrombotic microangiopathy (TMA) response, TMA event-free status, haematologic and renal parameters and adverse events. Of 100 patients, 74 had native kidneys and 26 in the transplant subgroup had a collective history of 38 grafts. No patients lost grafts and only one with pre-existing ESRD received a transplant on treatment. Efficacy endpoints were achieved similarly in both subgroups. After 26 weeks, mean absolute estimated glomerular filtration rate increased from baseline to 61 and 37 ml/min/1.73 m2 in native (n = 71; P < 0.0001) and transplanted kidney (n = 25; P = 0.0092) subgroups. Two patients (one/subgroup) developed meningococcal infections; both recovered, one continued therapy. Eculizumab was well tolerated. Eculizumab improved haematologic and renal outcomes in both subgroups. In patients with histories of multiple graft losses, eculizumab protected kidney function.

High-frequency ultrasound quantification of acute radiation dermatitis: pilot study of patients undergoing radiotherapy for breast cancer.

BACKGROUND: Acute radiation dermatitis (ARD) is a frequent complication after breast cancer radiotherapy and is usually assessed by semi-quantitative clinical scores, which may be subject to inter-observer variability. High-frequency ultrasound imaging of the skin can reliably quantify thickness and edema in diseased skin. We aimed to compare the relative increase in dermal thickness of the irradiated zone in breast-cancer patients undergoing radiotherapy, with clinical severity. METHODS: A consecutive series of patients undergoing treatment for breast cancer by lumpectomy and radiotherapy in a 6-month period also underwent clinical and ultrasound evaluation of ARD. RESULTS: We included 34 female patients 17 had grade 1 (group 1), 17 had grade 2 or grade 3 ARD (group 2). The mean relative increase in dermal thickness in irradiated skin (RIDTIS) was greater for group 2 than 1: 0.53 vs 0.29 mm (P=.023). On univariate analysis, ARD was associated with skin phototype, breast volume and RIDTIS, and on multivariable analysis, breast volume and age remained predictive of the disease. CONCLUSION: Patients with more severe dermatitis showed significantly increased dermal thickness. Dermal thickness is a quantitative variable that could help quantify the efficacy of drugs and improve the treatment of this disease in patients undergoing radiotherapy.

Terminal Complement Inhibitor Eculizumab in Adult Patients With Atypical Hemolytic Uremic Syndrome: A Single-Arm, Open-Label Trial.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe end-organ damage. Eculizumab, a terminal complement inhibitor approved for aHUS treatment, was reported to improve hematologic and renal parameters in 2 prior prospective phase 2 studies. This is the largest prospective study of eculizumab in aHUS to date, conducted in an adult population. STUDY DESIGN: Open-label single-arm phase 2 trial. SETTING & PARTICIPANTS: Patients 18 years or older with aHUS (platelet count <150 × 10(3)/µL, hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥1.5 × upper limit of normal [ULN], and serum creatinine ≥ ULN) were included in this multicenter multinational study. INTERVENTION: Intravenous eculizumab (900mg/wk for 4 weeks, 1,200mg at week 5 and then every 2 weeks) for 26 weeks. OUTCOMES & MEASUREMENTS: Primary end point was complete TMA response within 26 weeks, defined as hematologic normalization (platelet count ≥150 × 10(3)/µL, LDH ≤ ULN), and preservation of kidney function (<25% serum creatinine increase from baseline), confirmed by 2 or more consecutive measurements obtained 4 or more weeks apart. RESULTS: 41 patients were treated; 38 (93%) completed 26 weeks of treatment. 30 (73%) were included during their first TMA manifestation. 30 (73%) had complete TMA response. Platelet counts and estimated glomerular filtration rates increased from baseline (P<0.001). All 35 patients on baseline plasma exchange/plasma infusion discontinued by week 26. Of 24 patients requiring baseline dialysis, 5 recovered kidney function before eculizumab initiation and 15 of the remaining 19 (79%) discontinued dialysis during eculizumab treatment. No patients lost existing transplants. Quality-of-life measures were significantly improved. Two patients developed meningococcal infections; both recovered, and 1 remained on eculizumab treatment. LIMITATIONS: Single-arm open-label design. CONCLUSIONS: Results highlight the benefits of eculizumab in adult patients with aHUS: improvement in hematologic, renal, and quality-of-life parameters; dialysis discontinuation; and transplant protection.

Slowing of information processing speed without motor slowing in multiple sclerosis observed during two crossing-off tasks.

INTRODUCTION: Slowing of information processing speed (IPS) is often considered one of the primary deficits seen in multiple sclerosis (MS). IPS is usually measured by tasks that involve many cognitive functions. The aim of this study was to determine whether similar IPS slowing can also be observed during two simple, timed, psychomotor crossing-off tasks. METHOD: The Crossing-Off Test (COT), a simple psychomotor task, was performed under two conditions (COT1 corresponded to writing habits, COT2 used horizontal sweeping) in 25 relapsing-remitting MS patients (EDSS 0-1) and 25 healthy controls. RESULTS: The MS group compared with the control group was impaired on COT1 (P=0.0043) and not on COT2 (P=0.4), and the COT1 performance of MS patients with EDSS 1 was more impaired than those of patients with EDSS 0 (P=0.008). DISCUSSION/CONCLUSION: These results indicate that only some of the IPS cognitive subcomponents linked with COT1 tasks are initially involved in the slowing of IPS during MS, suggesting that different mechanisms are involved in each tested version of the COT.

Pregnancy-related listeriosis in France, 1984 to 2011, with a focus on 606 cases from 1999 to 2011.

This study describes trends in the incidence of pregnancy-related listeriosis in France between 1984 and 2011, and presents the major characteristics of 606 cases reported between 1999 and 2011 to the French Institute for Public Health Surveillance through the mandatory notification system. The incidence of pregnancy-related listeriosis decreased by a factor of 12 from 1984 to 2011. This reduction was a result of progressive implementation of specific Listeria monocytogenes control measures in food production. A lower incidence of pregnancy-related listeriosis was observed in regions with a lower prevalence of toxoplasmosis. Given that dietary recommendations in pregnancy target both toxoplasmosis and listeriosis prevention, we suppose that recommendations may have been delivered and followed more frequently in these regions. Cases reported between 1999 and 2011 (n=606) were classified as maternal infections with ongoing pregnancy (n=89, 15%), fetal loss (n=166, 27%), or live-born neonatal listeriosis (n=351, 58%). The majority of live-born neonatal listeriosis cases (n=216, 64%) were preterm births (22­36 weeks of gestation), of whom 14% (n=30) were extremely preterm births (22­27 weeks of gestation). Eighty per cent of mothers reported having eaten high risk food during pregnancy. A better awareness of dietary recommendations in pregnant women is therefore necessary.

First Report of Umbel Browning and Stem Necrosis Caused by Diaporthe angelicae on Carrot in France.

In 2011, carrot (Daucus carota L.) seed production occurred on 2,900 ha, which accounts for approximately 25% of the area devoted to the production of vegetable fine seeds. Since 2007, symptoms of umbel browning have been regularly observed in carrot production areas located in the central region. Initially, triangular necrotic lesions appeared on carrot umbels that later spread to the entire umbels and often progressed to the stems. Diseased umbels became dried prematurely, compromising seed development. The loss in seed production was estimated at approximately 8% of the harvested carrot umbels during the cropping seasons of spring and summer 2007 and 2008 in France. In collaboration with seed companies, diseased carrot stems were collected from seven fields of seed production (eight plants per field) and a fungus was isolated from the tissue. The cultures were grown on malt (2%) agar (1.5%) medium and incubated for 2 weeks at 22°C in darkness. Young fungal colonies were white and a brownish green pigmentation developed when the colonies became older. The same color was observed from the top and on the reverse of the colonies. To induce sporulation, isolates were grown on water agar (1.5%) medium in the presence of carrot stem fragments for 1 week at 22°C in darkness, followed by 1 week at 22°C in white light under a 16-h photoperiod. Pycnidia were produced on stem fragments and contained alpha and beta conidia typical of the genus Diaporthe (2). Alternatively, pycnidia were also obtained on malt agar medium after 2 weeks of culture at 25°C in white light under a 12-h photoperiod. The size of alpha and beta conidia was 6.3 ± 0.5 × 2.3 ± 0.4 µm and 23.3 ± 1.8 × 0.9 ± 0.2 µm, respectively (n = 170). In order to confirm the identification at the genus level and determine the species, DNA was extracted from the mycelium of three representative isolates and the ITS regions of the ribosomal DNA were amplified using universal primers (1). The sequences of the amplified products (GenBank Accession Nos. KF240772 to KF240774) were 100% identical with the ITS sequence of a Diaporthe angelicae isolate deposited in the NCBI database (CBS 111592 isolate, KC343027). To confirm pathogenicity, the three isolates of D. angelicae were inoculated on carrot umbels in the greenhouse. A total of nine plants were inoculated (three plants per isolate). Using a micropipette, 10 µl of a conidial suspension containing alpha and beta conidia (105 conidia mL-1) were deposited at the base of the primary umbel and two secondary umbels, which were wounded before inoculation using a scalpel blade. Seven inoculated plants developed triangular, necrotic lesions that were typical umbel browning. D. angelicae was re-isolated on malt agar medium from the inoculated diseased carrot umbels. To our knowledge, this is the first report of D. angelicae in carrot cultivated for seed production in France. The disease resembles the lesions described in the Netherlands in 1951 on carrot inflorescence caused by Phomopsis dauci (3). In future experiments, it would be crucial to precisely determine if D. angelicae could be transmitted to the seeds. References: (1) M. A. Innis et al. PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, CA, 1990. (2) J. M. Santos and A. J. L. Philips. Fungal Divers. 34:111, 2009. (3) J. A. von Arx. Eur. J. Plant Pathol. 57:44, 1951.

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.

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.

Pertussis incidence among adolescents and adults surveyed in general practices in the Paris area, France, May 2008 to March 2009.

Since the introduction in 1998 of an adolescent pertussis vaccine booster (for persons aged 11-13 years) in France, the incidence of pertussis in adolescents and adults has been unknown. We therefore undertook a study to estimate the incidence of pertussis in these population groups and to evaluate the feasibility of a real-time electronic surveillance system for pertussis in general practices in France. The general practitioners selected for the study were located in Paris and the surrounding area. Polymerase chain reaction (PCR) or measurement of anti-pertussis toxin IgG levels by enzyme-linked immunosorbent assay (ELISA) was used to confirm the infection. Among the 204 patients enrolled in the study, 46 (23%) were diagnosed as having pertussis: 21 were confirmed cases, 24 were clinical cases and one was an epidemiological case. The median age of the 204 patients was 44 years and 134 (66%) were female. The median duration of the patients' cough at enrolment was 24 days. No clinical difference was observed between those with and without a pertussis diagnosis. The incidence of pertussis was estimated to be 145 (95% confidence interval: 121-168) per 100,000 population based on the results from the 10-month study period (calculated for 12 months). Problems in sample collection were identified: pertussis sentinel surveillance cannot be developed without training the staff of medical laboratories who take the biological samples. French health authorities were alerted and training procedures were developed.

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 .