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High-speed waveforms (up to 20 GHz) in InGaAs/InAlAs modulation-doped field-effect transistors (FETs) are measured using 10–20 ps optical probe pulses via the quenching of the absorption in the quantum well gate channel due to Pauli exclusion. The technique is a noncontact probe of the charge density in the gate, and hence, of the logic state of the FET. This charge-sensitive probing technique is combined with voltage-sensitive electro-optic sampling to study internal dynamics of the FET. A gate channel charging time of 11 ps and a gate to drain propagation delay of 15 ps are measured. [ABSTRACT FROM AUTHOR]

Abstract Background The lung would be the first organ targeted in case of the use of Variola virus (the causative agent of smallpox) as a bioweapon. Pulmonary surfactant composed of lipids (90%) and proteins (10%) is considered the major physiological barrier against airborne pathogens. The principle phospholipid components of lung surfactant were examined in an in vitro model to characterize their interactions with VACV, a surrogate for variola virus. One of them, Dipalmitoyl phosphatidylglycerol (DPPG), was recently shown to inhibit VACV cell infection. Results The interactions of poxvirus particles from the Western Reserve strain (VACV-WR) and the Lister strain (VACV-List) with model membranes for pulmonary surfactant phospholipids, in particular DPPG, were studied by Electron Spin Resonance (ESR) and proton Nuclear Magnetic Resonance (1H-NMR). ESR experiments showed that DPPG exhibits specific interactions with both viruses, while NMR experiments allowed us to deduce its stoichiometry and to propose a model for the mechanism of interaction at the molecular level. Conclusions These results confirm the ability of DPPG to strongly bind to VACV and suggest that similar interactions occur with variola virus. Similar studies of the interactions between lipids and other airborne pathogens are warranted.

Objectives: An increased risk of mortality and postoperative side effects led to aprotinin (Trasylol®) withdrawal from the market in 2008, but since 2018 aprotinin has again been used in France. The French retrospective multicentre APACHE study (AProtinin versus tranexamic Acid in Cardiac surgery patients with High-risk for Excessive bleeding) compared the efficacy of tranexamic acid versus half-dose aprotinin. The aim of this study, ancillary to the APACHE study, is to carry out a medico-economic analysis of the use of these two antifibrinolytics on an APACHE subpopulation., Methods: Economic data on reimbursement by the French health insurance system were extracted from the program for the data processing of medical information, and quantitative data on the cost of healthcare products were obtained from the hospital pharmacy software., Results: The main analysis of costs for the population shows that the global valuation was not significantly different between the two treatment groups (P=0.60), but the costs of blood products included in the related hospital stay group (Groupe Homogène de séjour [GHS]) (whole blood, platelets and plasma) were higher for the tranexamic acid group (P=0.007). In a sub-analysis of patients alive at discharge, the costs of blood products in addition to GHS (blood-derived medicines) and the costs of blood products in the GHS were higher for the tranexamic acid group (P=0.04 and 0.001, respectively)., Conclusions: The additional cost of aprotinin at the time of purchase is offset by the additional costs of blood products in the tranexamic acid group., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

France has several monitoring systems that form the foundation of its health safety surveillance. This system is designed for the early detection of signals and their swift into an action system that enables timely, appropriate, and effective interventions to protect public health. These signals are considered alerts when sufficiently validated after an initial risk assessment and if they represent a potential threat to public health, necessitating an appropriate response. The French Addictovigilance Network (FAN) was established specifically to address complications associated with the use of psychoactive substances (PAS), both medicinal and non-medicinal, excluding alcohol and tobacco. This system, unique in Europe, provides information on one of the most complex vigilance systems due to its scope, and the risks associated with it are becoming an increasingly significant public health issue. FAN is at the forefront of identifying potential signals. It has been working closely with regional partners since 1990, particularly through a multi-source approach that combines data from various sources, in collaboration with local professionals. After outlining the missions of the addictovigilance centres and the general principles of signal detection in addictovigilance, this article will present recent examples involving similar products but different identifications or modes of consumption: synthetic cannabinoids, nitazene, pregabalin, methylphenidate. These examples demonstrate that while there are regional disparities, the risk of occurrence in other French regions should not be overlooked, and information should be rapidly communicated at the national level for preventive action., (Copyright © 2024 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: A highly effective therapy involving elexacaftor, tezacaftor, and ivacaftor (ETI) for cystic fibrosis (CF) patients has recently raised safety concerns regarding potential psychiatric disorders. The manuscript reports cases of suicide attempts in patients receiving ETI and investigates putative causality using the WHO spontaneous reporting database., Methods: First, four cases of suicide attempts/self-injury are described. Second, a disproportionality analysis was conducted using spontaneous reports collected in Vigibase through the standardised MedDRA Query (narrow version) "Suicide/Self-injury" and ETI exposure. Reporting Odds Ratio (ROR) was calculated for the main and subgroup (i/suicide attempt, ii/suicidal ideation) analyses. Sensitivity analyses were performed with variations in exposure, to ivacaftor/lumacaftor to assess the intrinsic psychiatric risk of CF patients, and paracetamol as a positive control for suicide attempt and a negative one for suicidal ideation. Exposure to reduced-dose ETI was studied to evaluate the dose-gradient effect., Results: Four cases of suicide attempt/self-injury occurred 3 to 13 months after ETI initiation in CF patients and were reported to the Bordeaux Pharmacovigilance centre. Aside, in Vigibase, ETI is associated with an increased likelihood of reporting suicidal behaviour (ROR 2.5, 95 % CI[2.1; 2.8]). A signal of disproportionate reporting was found for the subgroup of suicide attempts (1.4, 95 % CI[1.2; 1.8]), unlike ivacaftor/lumacaftor, which was associated only with the risk of reporting suicidal ideation. Significant ROR values were also found for reduced-dose ETI for all psychiatric effects studied except suicide attempt., Conclusions: ETI exposure is related with increased reporting of suicidal behaviour. A potential dose-dependent effect merits further investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Julie Macey declares participation on a Data Safety Monitoring Board and Advisory Board for Vertex Pharmaceuticals. The other authors have nothing to declare., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Incidence of hospitalisations related to psychoactive substance (H-PS) intoxication has been strongly decreased during the coronavirus disease 2019 (COVID-19) pandemic especially in young adult and French region of Nouvelle-Aquitaine was mostly concerned. This study aimed to describe (i) the incidence of H-PS in Bordeaux teaching hospital during and after the first 2020 lockdown in adults aged 18-29 years or 30+ then (ii) their characteristics specifically associated with the pandemic period by comparing 2020 with 2017-2019 baseline period., Material and Methods: This historical cohort study was conducted in adults admitted to the Bordeaux teaching hospital with main or associated diagnosis codes of intoxication with benzodiazepine, methadone, buprenorphine, codeine, morphine, heroin, cocaine, ecstasy and alcohol. Data were collected locally through the discharge database. Incidence and characteristics of H-PS were described according to patients' age, in 2020 before (01/01-16/03), during (17/03-10/05), and after the first lockdown (11/05-31/07)., Results: Among the 5,824 stays included over the study period, PS most involved were alcohol and benzodiazepines. Compared to baseline, the decrease in H-PS's incidence was more important in young adults (-40%; n baseline =450) in comparison to those aged 30+ (-18%; n baseline =1,101) during the pandemic period, especially during the lockdown compared to 2017 (-59%; n 2017 =145 vs. -35%; n 2017 =166) with far decrease in alcohol and ecstasy intoxications. Seriousness of hospitalisation indications was increased regardless of age during the pandemic. Particularly in young adults, the proportion of suicides attempts increased during lockdown compared to the baseline period (almost 50% vs. 29%) and the period after lockdown was associated with 1.7 more-time road accident increased and 3 more-time fights compared with pre-lockdown period., Discussion/conclusion: The period following lockdown should be considered at risk H-PS due to accident. Recreational use of alcohol and ecstasy could be a target for minimize serious consequences associated to PS use in young adult., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Little is known about psychoactive substance use in students, apart from tobacco, alcohol, and cannabis. This study investigated the prevalence of substance use and overlap between various psychoactive substances in students. This cross-sectional study was conducted in 10 066 students included in the i-Share cohort between January 1, 2015, and December 31, 2017. The baseline questionnaire was the key source of information. Psychoactive substances of interest (PSI) were cannabis, cocaine, amphetamines, nitrous oxide, poppers, and MDMA. Their patterns of use were categorized as lifetime, past year, and current use. The use of other psychoactive substances including alcohol and tobacco was described in PSI users and non-users. Most participants were female (75%), and their average age was 21 years. Lifetime use of at least one PSI was reported by 65.5% of participants. Cannabis was the most frequently used substance both over lifetime (57% of students) and past year (35%), followed by poppers and nitrous oxide (28% and 26% of students over lifetime, respectively). Among polydrug users (n = 1242), 65% used only nitrous oxide and poppers, showing a strong link between these two substances. Regular alcohol use, binge drinking, and current tobacco use were higher in PSI users than in non-users. Substance use was higher than previously found in both French and European studies in young people. Nitrous oxide use was particularly high. Regular alcohol use, binge drinking, and tobacco use could be used as markers to identify students at risk of PSI use to be targeted by prevention programs., (© 2022 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Purpose: To date, how medication reconciliation (MR) could be prioritized in younger patients remains poorly evaluated. This study aimed at assessing whether a MR prioritization strategy based on the identification of high-risk medication at patients' admission treatment could be of interest in non-elderly patients., Method: This prospective study was conducted between July and September 2017 in an internal medicine unit at Bordeaux teaching hospital. All patients aged 16 to 74 years and receiving at least two long-term treatments at admission were considered eligible. High-risk medications were defined on the basis of a pharmacovigilance study, which identified the drugs most involved in serious adverse effects reported in the Nouvelle-Aquitaine region in non-elderly adults. They included antithrombotics, analgesics, antipsychotics and cardiac therapies. MR-induced treatment changes were compared according to the existence of high-risk medications at admission in study participants., Results: Among the 92 study participants, 46 presented with high-risk medications at admission (median age 66 years, IQR 58-70) and 46 without such (median age 54 years, IQR 47-64). High risk-medications (HRM) existing at admission were antithrombotics (52.2%) and antipsychotics (22.4%). MR resulted in treatment changes in 37% of patients admitted with at-risk medications vs. 8.7% of those admitted without such (P=0.001). Overall, the mean number of treatment changes performed after MR was of 1 (95%CI 0.4-1.6) in patients with high-risk medication at admission and of 0.2 (95%CI 0-0.4) in patients without such. MR-induced treatment changes assessed as clinically major at least once by pharmacists or clinicians was greater in HRM group (43.5%) than in non-HRM group (31.6%). However, the consistency was low between clinicians and pharmacists, especially to distinguish the clinical importance of significant and minor interventions., Conclusion: Targeting high-risk medications at admission appeared efficient for the prioritization of MR in non-elderly patients hospitalised in internal medicine., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Unrecognized congenital hypothyroidism (CH) is the most common cause of preventable cognitive delay in children. Infants with CH appear normal and are usually asymptomatic at birth. Early detection is critical for prevention of intellectual disability. Standardized newborn screening can have a positive impact on cognitive development in infants with CH., (© Copyright 2021 Springer Publishing Company, LLC.)

Background: Postnatal growth failure is common in very preterm infants and is associated with worse neurodevelopmental outcome., Objective: To evaluate the cumulative impact of multiple evidence based strategies on the postnatal growth of extremely-low-birth-weight (ELBW) infants., Methods: We conducted a prospective observational study. Based on current literature, changes were implemented to provide optimal parenteral and enteral nutrition. Daily intakes of calories, protein, lipids and carbohydrates were calculated. The average growth velocity (GV) was calculated using 2-point exponential model and is reported as grams/kg/day. The length and head circumference gains are reported as centimeters/week., Results: The mean gestational age and birth weight for 38 ELBW survivors were 27.0 ± 2.1 weeks and 752 ± 147 g respectively. The GV was 13.2 ± 2.2 g/kg/day (range 8.8-17.4) and gains in length and head circumference were 0.88 ± 0.9 (range 0.15-1.42) and 0.71 ± 0.5 (range 0.22-0.96) centimeters/week respectively. Twenty nine (76.3%) infants were small-for-gestational-age (SGA) at discharge and 23 of these (60.5% of all infants) had weight below 3rd percentile. All 11 infants who were SGA at birth were SGA at discharge as well. Of 25 appropriate-for-gestational-age (AGA) infants at birth, 16 (64%) were SGA at discharge. The number of infants with length and head circumference below 10th percentile at birth and discharge were 11 (28.9%) and 29 (76.3%) for length and 20 (52.6%) and 27 (71.1%) for head circumference. Infants with multiple morbidities and more hospital days with no enteral feeds had lower GV., Conclusion: All infants born SGA at birth and majority of ELBW survivors born AGA at birth had weight, length and head circumference below 10th percentile at discharge despite aggressive nutrition supplementation., Competing Interests: Conflicts of interest We have no conflict of interest to report., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

This paper aims to present the main information presented at the 9th Meeting about addictovigilance in 2016 by four healthcare professionals and addiction experts on the issue of new psychoactive substance use. A new psychoactive substance (NPS) is defined as a narcotic or psychotropic drug, in pure form or in preparation, that is not controlled by the United Nations drug conventions, but which may pose a public health threat comparable to that posed by substances listed in these conventions. The emergence of NPS consumption is a worldwide concern. Although NPS are less consumed than established drugs, there has been a sharp increase in their use over the last few years, notably of synthetic cathinones, synthetic cannabinoids and, more recently, synthetic opioids. The latter in particular are involved in deaths in Europe. However, "established" drugs (MDMA [methylenedioxymethamphetamine], amphetamines, LSD, methamphetamine) are far from being dethroned by the more recent substances: they are considered "a safe bet" already "tried and tested" by many consumers over the years. MDMA, in particular, also known as ecstasy, which has been used as a recreational drug since the 1990s, saw its consumption decrease until 2010, and then increase again, especially in higher amounts; inexpensive and easily accessible, it is increasingly associated with emergency admissions or deaths in France. The perpetual appearance of new substances on the drug market is obligating to improve knowledge on these products, particularly by focusing on their analytical identification, and also by monitoring their use and harms., (Copyright © 2020 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

The Neonatal Critical Care Unit Book Club began with a common passion for reading and a need for socialization. There was also the hope that the club would foster a positive work culture and increase staff morale and resilience. In addition, the book club provided a mechanism for obtaining continuing education.The purpose of this article is to describe how a group of nurses participating in a book club were able to find support and encouragement during a pandemic., (© Copyright 2021 Springer Publishing Company, LLC.)

Plasma neurofilament light chain (pNfL) concentration is a biomarker for neuroaxonal injury and degeneration and can be used to monitor response to treatment. Spontaneous canine neurodegenerative diseases are a valuable comparative resource for understanding similar human conditions and as large animal treatment models. The features of pNfL concentration in healthy dogs is not well established. We present data reporting basic pNfL concentration trends in the Labrador Retriever breed. Fifty-five Labrador Retrievers were enrolled. pNfL concentration was measured and correlated to age, sex, neuter status, height, weight, body mass index, and coat color. We found increased pNfL with age (P < 0.0001), shorter stature (P = 0.009) and decreased body weight (P < 0.001). These are similar to findings reported in humans. pNfL concentration did not correlate with sex, BMI or coat color. This data further supports findings that pNfL increase with age in a canine population but highlights a need to consider weight and height when determining normal pNfL concentration in canine populations., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

In the United States, pregnant women are screened for hepatitis B antigen because of the significant risk of perinatal vertical transmission of hepatitis to the fetus. It is important that the maternal hepatitis B antigen screen is documented in the medical record to ensure appropriate prophylaxis for the neonate. The purpose of this column is to discuss the pathophysiology of hepatitis B, as well as the screening process and prophylaxis for the neonate., (© Copyright 2020 Springer Publishing Company, LLC.)

Abnormal activation of the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathway has been shown to drive the proliferation of a significant portion of hepatocellular carcinoma (HCC). Resistance and toxicity are serious drawbacks that have been observed upon use of the current first- and second-line treatment options for HCC, therefore warranting the investigation of alternative therapeutic approaches. We report the development and biological characterization of a covalent inhibitor that is highly potent and exquisitely specific to FGFR4. The crystal structure of this inhibitor in complex with FGFR4 was solved, confirming its covalent binding and revealing its binding mode. We also describe the first clickable probe for FGFR4 that can be used to directly measure target engagement in cells. Our compound exhibited great antitumor activity in HCC cell lines and tumor xenograft models. These results provide evidence of a promising therapeutic lead for the treatment of a subset of HCC patients.

Context: Ticagrelor was related to bradycardia in DISPERSE-II trial. This risk has been integrated into the European risk-management plan, and its use is warned in at-risk patients. Nevertheless, this risk was not systematically assessed nor measured., Objectives: To estimate the risk of bradyarrhythmia associated with ticagrelor., Study Design: Systematic review and meta-analysis., Data-Source: MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, ISI web of Science, clinicaltrial.gov, clinicaltrialsregister.eu., Study Selection: Randomized controlled trials (RCTs) and observational studies in patients treated with ticagrelor or comparator(s)., Meta-Analysis: Risk of bias in each RCT was assessed using Cochrane tool. Relative Risks (RR) with 95 % confidence intervals (95 %CI) were calculated for each RCT, and pooled using fixed-effect or random-effects models, when appropriate. Subgroup and sensitivity analyses were performed. A potential publication bias was searched., Results: Among 82 eligible studies, event data were missing for 56 studies, due to detected reporting bias (i.e. inability to confirm zero events). Fifteen RCTs were selected and the combined RR of bradyarrhythmia was 1.15 (95 %CI 1.05-1.26), and 1.29 (1.02-1.65) for severe bradyarrhythmia. The risk appeared to be dose dependent. Restricting the analysis only to RCTs performed in patients without previous bradyarrhythmia resulted in a non-increased risk., Conclusion: This meta-analysis confirmed the risk of bradyarrhythmia or severe bradyarrhythmia related to ticagrelor, and its use in patients without previous bradycardia was effective in preventing it. The evidence coming from this meta-analysis was low to moderate due to missing outcome in 2/3 of eligible studies. Waiting for access to these data, the use of ticagrelor in patients with risk factors of bradycardias should be avoided., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims: Azacitidine (AZA), a pyrimidine analogue, is validated for high-risk myelodysplastic syndrome or low-blast acute myeloid leukaemia in unfit patients for more intensive treatment. This study assessed the putative link between cardiac failure (CF) and AZA exposure., Methods: Cases of CF in patients treated with AZA were retrospectively collected and described from several centres of the Groupe Francophone des Myélodysplasies. A description analysis and a disproportionality analysis using Vigibase, the WHO Global Individual Case Safety Reports (ICSRs) database, were conducted on ICSRs by the Standardized MedDRA Queries (SMQ broad) cardiac failure and by preferred terms cardiac failure and cardiac failure acute. The reported odds ratio (ROR) and its 95% 2-sided confidence interval was computed by comparing the proportion of CF reports with the suspected drug (AZA) and the proportion of reports of the same adverse drug reaction with all other suspected drugs in the database during the same period., Results: In the 4 case reports, all patients presented a cardiovascular history. In 1 patient, CF recurred after AZA re-challenge. The pharmacovigilance analysis in Vigibase retrieved 307 ICSRs of CF (SMQ) with AZA. Significant disproportionality signals associated with AZA were identified by using the SMQ cardiac failure (ROR 1.3) and the preferred terms cardiac failure (ROR 5.1) and cardiac failure acute (ROR 23.2)., Conclusion: This study points to the potential role of AZA in the occurrence of CF. Cardiac evaluation before AZA initiation and regular monitoring of cardiac function during AZA treatment should be performed in patients with a history of cardiovascular disease., (© 2020 The British Pharmacological Society.)

Despite its power in identifying highly potent ligands for select protein targets, conventional medicinal chemistry is limited by its low throughput and lack of proteomic selectivity information. We seek to develop a chemoproteomic approach for discovering covalent ligands for protein targets in an unbiased, high-throughput manner. Tripartite probe compounds composed of a heterocyclic core, an electrophilic "warhead", and an alkyne tag have been designed and synthesized for covalently labeling and identifying targets in cells. We have developed a novel condensation reaction to prepare 2-chloromethylquinoline (2-CMQ), an electrophilic heterocycle. These chloromethylquinolines potently and covalently bind to a number of cellular protein targets, including prostaglandin E synthase 2 (PTGES2), a critical regulator of cell proliferation, apoptosis, angiogenesis, inflammation, and immune surveillance. The 2-CMQs that we have developed here are novel PTGES2 binders that have the potential to serve as therapies for the treatment of human diseases such as inflammation.

Ixodes scapularis ticks harbor a variety of microorganisms, including eukaryotes, bacteria and viruses. Some of these can be transmitted to and cause disease in humans and other vertebrates. Others are not pathogenic, but may impact the ability of the tick to harbor and transmit pathogens. A growing number of studies have examined the influence of bacteria on tick vector competence but the influence of the tick virome remains less clear, despite a surge in the discovery of tick-associated viruses. In this study, we performed shotgun RNA sequencing on 112 individual adult I. scapularis collected in Wisconsin, USA. We characterized the abundance, prevalence and co-infection rates of viruses, bacteria and eukaryotic microorganisms. We identified pairs of tick-infecting microorganisms whose observed co-infection rates were higher or lower than would be expected, or whose RNA levels were positively correlated in co-infected ticks. Many of these co-occurrence and correlation relationships involved two bunyaviruses, South Bay virus and blacklegged tick phlebovirus-1. These viruses were also the most prevalent microorganisms in the ticks we sampled, and had the highest average RNA levels. Evidence of associations between microbes included a positive correlation between RNA levels of South Bay virus and Borrelia burgdorferi , the Lyme disease agent. These findings contribute to the rationale for experimental studies on the impact of viruses on tick biology and vector competence.

Endocarditis is a serious and common disease that requires prolonged antimicrobial therapy. The recent shortage of oxacillin has led to the use of other antimicrobial agents such as cefazolin to treat endocarditis due to methicillin-sensitive Staphylococcus aureus. We describe four cases of life-threatening haemorrhagic complications (fatal in two cases) in patients treated with high-dose cefazolin. All of these patients with major bleeding presented with hypoprothrombinemia secondary to hypovitaminosis K. This adverse event may be due to inhibition of vitamin K epoxide reductase and/or gamma-glutamyl-carboxylase by the 2-methyl-1,2,3-thiadiazol-5-thiol group of cefazolin. This inhibition may result in hypoprothrombinemia by altering the synthesis of vitamin K-dependent coagulation factors. The increasing use of cefazolin, especially at a high dose and for a prolonged period of time, should be accompanied by regular monitoring of coagulation, including prothrombin index, and vitamin K supplementation., (Copyright © 2017 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.)

Purpose: To evaluate the efficacy and safety of XG-102 (brimapitide) compared to dexamethasone eye drops in the treatment of postoperative ocular inflammation., Design: Multicenter, randomized, parallel group, double-masked, noninferiority clinical trial., Methods: Patients who underwent anterior and posterior segments combined surgery or glaucoma surgery or complex posterior segment surgery were eligible to participate. Patients were administered a single subconjunctival injection of 250 μL XG-102 90 μg (n = 47) or 900 μg (n = 48) or placebo (n = 50) at the end of ocular surgery. Subconjunctival injection for each group (XG-102 90 μg, XG-102 900 μg, or placebo) was followed by eye drops instilled 4 times per day for 21 days with placebo, placebo, or dexamethasone solution, respectively. The primary outcome measure was anterior chamber cell grades at day 28 comparing XG-102 900 μg with dexamethasone., Results: The anterior cell grades for both XG-102 groups were noninferior to dexamethasone (-0.054 anterior cell grade [95% confidence interval -0.350-0.242]; P < .001 for noninferiority) for XG-102 900 μg and -0.086 anterior cell grade (95% confidence interval -0.214-0.385; P = .003 for noninferiority) for XG-102 90 μg. Rescue medication was introduced for 10 (21%), 7 (15%), and 2 (4%) patients allocated to the XG-102 90 μg, XG-102 900 μg, and dexamethasone groups, respectively. The difference between XG-102 90 μg and dexamethasone was statistically significant (P = .013). The number of patients for whom adverse events were reported and the nature of the events reported was similar between the 3 treatment groups., Conclusions: A single subconjunctival injection of XG-102 at the end of ocular surgery is noninferior to dexamethasone eye drops in the treatment of postoperative ocular inflammation., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: We aimed to investigate the safety, tolerability, and systemic diffusion of a single escalating dose of XG-102 (a 31-D-amino-acid peptide inhibiting JNK pathway activation), administered subconjunctivally in the treatment of post-surgery or post-trauma intraocular inflammation., Methods: This is a dose-escalating, tolerance Phase Ib study. Twenty patients with post-surgery or post-traumatic intraocular inflammation were assigned to 1 of the 4 dose escalating (45, 90, 450, or 900 μg XG-102) groups of 5 patients each. Patients were evaluated at 24, 48 h, 8, and 28 days following the administration of XG-102, including laboratory tests, standard eye examinations, vital signs, and occurrence of adverse events. A single plasma quantification of XG-102 was performed 30 min after administration, according to previous pharmacokinetics studies performed on volunteers., Results: A total of 17 non-serious adverse events, considered unrelated to the study treatment, were reported for 10 patients. The adverse event incidence was not related to the drug dose. All patients experienced a decrease in intraocular inflammation as of 24 h post-administration and this decrease was sustained up to 28 days thereafter. No patient required local injection or systemic administration of corticoids following the administration of XG-102. XG-102 was undetectable in the first 3 dose groups. In the fourth-dose group (900 μg) the XG-102 plasma levels were above the limit of detection for 3 patients and above the limit of quantification for 1 patient., Conclusions: In this first clinical trial using XG-102, administered as a single subconjunctival injection as adjunct therapy, in patients with recent post-surgery or post-trauma intraocular inflammation is safe and well tolerated. Further studies are required to evaluate its efficacy.

The aim of the study is to evaluate the safety, tolerability and pharmacokinetics (PK) of the JNK inhibitor XG-102 in a randomized, double blind, placebo controlled, sequential ascending dose parallel group Phase 1 Study. Three groups of male subjects received as randomly assigned ascending single XG-102 doses (10, 40, and 80 μg/kg; 6 subjects per dose) or placebo (2 subjects per dose) as an intravenous (IV) infusion over 60 min. Safety and tolerability were assessed by physical examination, vital signs, electrocardiography, eye examination, clinical laboratory tests and adverse events (AEs). PK was analyzed using noncompartmental methods. All reported AEs were mild to moderate and neither their number nor their distribution by System Organ Class suggest a dose relationship. Only headache and fatigue were considered probably or possibly study drug related. Headache frequency was similar for active and placebo, consequently this was not considered to be drug related but probably to study conditions. The other examinations did not show clinically relevant deviations or trends suggesting a XG-102 relationship. Geometric mean half-life was similar among doses, ranging from 0.36 to 0.65 h. Geometric mean XG-102 AUC0-last increased more than linearly with dose, 90% confidence intervals (CIs) did not overlap for the two highest doses. Geometric mean dose normalized C max values suggest a more than linear increase with dose but 90% CIs overlap. It may be concluded that XG-102 single IV doses of 10-80 μg/kg administered over 1 h to healthy male subjects were safe and well tolerated.

Vaccinia virus (VACV) was used as a surrogate of variola virus (VARV) (genus Orthopoxvirus), the causative agent of smallpox, to study Orthopoxvirus infection. VARV is principally transmitted between humans by aerosol droplets. Once inhaled, VARV first infects the respiratory tract where it could encounter surfactant components, such as soluble pattern recognition receptors. Surfactant protein D (SP-D), constitutively present in the lining fluids of the respiratory tract, plays important roles in innate host defense against virus infection. We investigated the role of SP-D in VACV infection and studied the A27 viral protein involvement in the interaction with SP-D. Interaction between SP-D and VACV caused viral inhibition in a lung cell model. Interaction of SP-D with VACV was mediated by the A27 viral protein. Binding required Ca2+ and interactions were blocked in the presence of excess of SP-D saccharide ligands. A27, which lacks glycosylation, directly interacted with SP-D. The interaction between SP-D and the viral particle was also observed using electron microscopy. Infection of mice lacking SP-D (SP-D-/-) resulted in increased mortality compared to SP-D+/+ mice. Altogether, our data show that SP-D participates in host defense against the vaccinia virus infection and that the interaction occurs with the viral surface protein A27.

Background Information: Vaccinia virus (VACV) was used as a surrogate of variola virus (genus Orthopoxvirus), the causative agent of smallpox, to study orthopoxvirus infection. VACV infects cells via attachment and fusion of the viral membrane with the host cell membrane. Glycosphingolipids, expressed in multiple organs, are major components of lipid rafts and have been associated with the infectious route of several pathogens., Results: We demonstrate that the VACV-WR (VACV Western-Reserve strain) displays no binding to Cer (ceramide) or to Gal-Cer (galactosylceramide), but binds to a natural sulfated derivative of these molecules: the Sulf (sulfatide) 3' sulfogalactosylceramide. The interaction between Sulf and VACV-WR resulted in a time-dependent inhibition of virus infection. Virus cell attachment was the crucial step inhibited by Sulf. Electron microscopy showed that SUVs (small unilamellar vesicles) enriched in Sulf bound to VACV particles. Both the A27 and L5 viral membrane proteins were shown to interact with Sulf, indicating that they could be the major viral ligands for Sulf. Soluble Sulf was successful in preventing mortality, but not morbidity, in a lethal mouse model infection with VACV-WR., Conclusions: Together the results suggest that Sulf could play a role as an alternate receptor for VACV-WR and probably other Orthopoxviruses.

Vaccinia virus (VACV) was used as a surrogate of Variola virus (genus Orthopoxvirus), the causative agent of smallpox, to study orthopoxvirus infection via the respiratory airway. Lung surfactant, a physiological barrier to infection encountered by the virus, is predominantly composed of phospholipids whose role during orthopoxvirus infection has not been investigated. An attenuated Lister strain, derived from the traditional smallpox vaccine and the Western Reserve (WR) strain, lethal for mice infected by the respiratory route, were examined for their ability to bind various surfactant phospholipids. Dipalmitoyl phosphatidylglycerol (DPPG) was found to interact with both VACV strains. DPPG incorporated in small unilamellar vesicle (SUV-DPPG) inhibited VACV cell infection, unlike other phospholipids tested. Both pre-incubation of virus with SUV-DPPG and pretreatment of the cell with SUV-DPPG inhibited cell infection. This specific DPPG effect was shown to be concentration and time dependent and to prevent the first step of the viral cycle, i.e. virus cell attachment. Cryo-electron microscopy highlighted the interaction between the virus and SUV-DPPG. In the presence of the phospholipid, virus particles displayed a hedgehog-like appearance due to the attachment of lipid vesicles. Mice infected intranasally with VACV-WR pre-incubated with SUV-DPPG survived a lethal infection. These data suggest that DPPG in lung surfactant could reduce the amount of orthopoxvirus particles able to infect pneumocytes at the beginning of a respiratory poxvirus infection. The knowledge acquired during this study of virus-DPPG interactions may be used to develop novel chemotherapeutic strategies for smallpox., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: The lung would be the first organ targeted in case of the use of Variola virus (the causative agent of smallpox) as a bioweapon. Pulmonary surfactant composed of lipids (90%) and proteins (10%) is considered the major physiological barrier against airborne pathogens. The principle phospholipid components of lung surfactant were examined in an in vitro model to characterize their interactions with VACV, a surrogate for variola virus. One of them, Dipalmitoyl phosphatidylglycerol (DPPG), was recently shown to inhibit VACV cell infection., Results: The interactions of poxvirus particles from the Western Reserve strain (VACV-WR) and the Lister strain (VACV-List) with model membranes for pulmonary surfactant phospholipids, in particular DPPG, were studied by Electron Spin Resonance (ESR) and proton Nuclear Magnetic Resonance (1H-NMR). ESR experiments showed that DPPG exhibits specific interactions with both viruses, while NMR experiments allowed us to deduce its stoichiometry and to propose a model for the mechanism of interaction at the molecular level., Conclusions: These results confirm the ability of DPPG to strongly bind to VACV and suggest that similar interactions occur with variola virus. Similar studies of the interactions between lipids and other airborne pathogens are warranted.