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Recent advances on the development of bumped kinase inhibitors for treatment of cryptosporidiosis have focused on the 5-aminopyrazole-4-carboxamide scaffold, due to analogs that have less hERG inhibition, superior efficacy, and strong in vitro safety profiles. Three compounds, BKI-1770, -1841, and -1708, showed strong efficacy in C. parvum infected mice.

International audience; Rodents (Rodentia) are the most abundant and diverse order of mammals, present in all habitats, including urban areas. The traffic linked to globalisation has favoured their involvement in biological invasions that have an impact on local biodiversity, the economy and human health. In Franceville, Gabon, little is known about the rodent community. We therefore studied the composition and distribution of rodents along a gradient highlighting the heterogeneity of the city's landscape. The three habitat types studied showed no difference in small mammal abundance, while the diversity index was higher in the vegetated habitat (SDI = 0.73) compared to the outdoor (SDI = 0.71) and indoor (SDI = 0.45) habitats. Our work shows the importance of vegetal remnants in the city for the maintenance of native species. It also highlights the impact of introduced species on small mammal assemblages and the need for management to reduce the factors of their proliferation.

Although the emergence of Covid-19 in China has not been clearly elucidated, the hypothesis of an animal origin remains the most likely. It is supported by the presence of the horseshoe bat suspected to be the progenitor of SARS-CoV-2 and by the scarcity of pork, due to African swine fever, diverting consumers to exotic animals of breeding sold in the markets. During this pandemic, several animal species were affected by SARS-CoV-2. Sporadic cases were first reported in pets (dogs and cats) infected by their owners, then in large feline species and apes infected in zoos by their nurses. The most significant human-to-animal transmission has occurred in mink farms, especially in the Netherlands and Denmark, requiring the euthanasia of several million animals, with mink in turn having contaminated men and stray or nomadic cats. The study of natural or experimental transmissions of SARS-CoV-2 has made it possible to identify the most receptive animal species: American minks and raccoon dogs, and to a lesser extent stray or nomadic cats, which could become an animal reservoir due to their sensitivity to this virus and their extending prolificacy. The European Commission decided on May 17, 2021 to strengthen the surveillance of SARS-CoV-2 infections in minks and other mustelids, as well as in raccoon dogs, highlighting stressing that the epidemiological assessment of the risk presented by the he appearance of SARS-CoV-2 in these susceptible species was a public health priority.

The use of robotics is a growing area within the field of surgery, especially in orthopaedics. To date, there is no literature examining orthopaedic trainee perception of or comfort with robotics in orthopaedics. An assessment of the next generation's attitudes regarding this technology is necessary. An anonymous, national, web-based questionnaire containing 16 multiple-choice questions and 25 5-point Likert's scale questions was sent to 66 Accreditation Council for Graduate Medical Education (ACGME)-approved orthopaedic residency training programs. The survey was designed to discern the attitude of orthopaedic trainees toward robotics. Demographics, extent of exposure and training, and trainee perception regarding robotics were collected. A bivariate analysis using Pearson's Chi-square test or Fisher's was used to determine factors associated with trainee's future plans to use robotics. A total of 280 trainees completed the survey (response rate of 18%). Also, 67.9% have been exposed to and 42.9% trained to use robotics in surgical training. Of those trained, 44.4% were given increasing autonomy to use the technology. Further, 67.1% of trainees do not feel comfortable using robotic technology; however, 71.4% believe robotics has the potential to facilitate their education. Over 90% believe that robotic technology is here to stay. While residents have legitimate concerns about robotic implementation in orthopaedics, the majority of residents and fellows believe robotics will be a part of the future. However, few feel they receive adequate training or experience with the technology.

Background: The superior approach for total hip arthroplasty (THA) is a minimally invasive, tissue-sparing technique that may have clinical and economic benefits. The purpose of this study was to compare early outcomes between the posterior approach and the superior approach in primary THA. Our hypothesis was that the superior approach would have a noninferior length of stay (LOS), discharge destination, and blood loss compared with the posterior approach. Methods: All primary THAs performed by a single surgeon at one institution were retrospectively reviewed over a 2-year period (2015-2017). There were 676 patients, 40.4% of whom underwent a posterior approach and 59.6% underwent a superior approach. LOS, discharge destination, blood loss, and operating room time were analyzed. Gender, body mass index, and American Society of Anesthesiologists status were recorded and controlled. Results: The posterior approach was independently associated with an almost threefold higher risk of prolonged LOS (>2 days, P < .001) (odds ratio: 2.90, 95% confidence interval: 1.87-4.49; P < .001). The mean LOS for the superior approach was 1.71 days vs 2.17 days for the posterior group (P < .001). Fewer patients in the superior approach cohort were discharged to a rehabilitation facility (8.9% vs 17.9%, P < .001). The mean operative time was shorter in the superior group (91.8 vs 95.8, P = .001). There was no statistically significant difference in acute postoperative blood loss. There were no dislocations or reoperations in either group. Conclusions: The superior approach to THA was associated with a significantly shorter length of hospital stay and lower rate of discharge to rehab than the posterior approach. This approach can be used as a safe, minimally invasive, and tissue-sparing variation of a standard posterior approach for THA and has promising early outcomes.

Study Design Retrospective review. Objectives Cannabis is an antinociceptive which has been evaluated as a possible adjunct or substitute for opioid use in the treatment of acute pain. The aim of this study was to evaluate the association between preoperative cannabis usage and consumption of opioids for postoperative analgesia. Methods Patients who underwent one- or two-level posterior lumbar fusion surgery were categorized as cannabis users or non-cannabis users based on preoperative diagnoses of cannabis use. Total morphine equivalent dose was calculated for both in-house opioid consumption and postoperative prescription opioid usage. Age, ASA, BMI, depression, tobacco use, estimated blood loss, OR time, LOS, disposition to rehab, 30-day readmission, in-house opioid consumption and postoperative prescription opioid usage were compared between groups using t-tests. Results Of the 220 opioid naïve patients, 29 (13%) patients were identified as cannabis users while 191 (87%) were non-cannabis users. There were no significant associations between opioid naïve cannabis usage and ASA, BMI, tobacco use, EBL, OR time, LOS, disposition to rehab, or readmission. Opioid naïve cannabis users had greater association with depression (31.3% vs 13.7%, P=.017) and younger age (56.37 years vs 65.37 years, PConclusions Cannabis usage is associated with increased usage of opioids postoperatively, both while in-patient and post-discharge, after posterior lumbar spinal fusion surgery.

Glomerular filtration rate is the gold-standard method for assessment of renal function but is rarely performed in routine toxicity studies. Standard serum biomarkers of renal function are insensitive and become elevated only with significant loss of organ function. Symmetric dimethylarginine (SDMA) is a ubiquitous analyte that is freely filtered by the glomerulus and can be detected in serum. It has shown utility for the detection of renal injury in dogs and cats in clinical veterinary practice, but the potential utility of SDMA to detect renal injury in preclinical species or toxicity studies has not been thoroughly investigated. We utilized a well-characterized glomerular toxicant, puromycin aminonucleoside, to induce podocyte injury and subsequent proteinuria in young male Sprague-Dawley rats. At the end of 1 or 2 weeks, blood, urine, and kidney tissue were collected for analysis. One week following a single 50 mg/kg dose, urea nitrogen, creatinine, and albumin mean values were within historical control ranges, while SDMA was increased. Glomerular changes in these animals included periodic acid–Schiff positive globules within podocytes, podocyte hypertrophy by light microscopy, and podocyte degeneration with effacement of foot processes by electron microscopy (EM). Taken together, our data indicate that SDMA may be a useful biomarker for early detection of glomerular toxicities in rats.

Although lithium is widely used in current practice to treat bipolar disorder (BD) and treatment-resistant major depressive disorder (MDD) among older adults, little is known about its efficacy and tolerability in this population, which is generally excluded from randomized clinical trials. The objective of this study was to evaluate the efficacy and tolerability of long-term use of lithium among older adults with BD and MDD.Data from the Cohort of individuals with Schizophrenia and mood disorders Aged 55 years or more (CSA) were used. Two groups of patients with BD and MDD were compared: those who were currently receiving lithium versus those who were not. The effects of lithium on psychiatric (i.e., depressive symptoms severity, perceived clinical severity, rates of psychiatric admissions in the past-year), geriatric (overall and cognitive functioning) and physical outcomes (i.e., rates of non-psychiatric medical comorbidities and general hospital admissions in the past-year) were evaluated. All analyses were adjusted for age, sex, duration of disorder, diagnosis, smoking status, alcohol use, and use of antipsychotics, antiepileptics or antidepressants.Among the 281 older participants with BD or MDD, 15.7% were taking lithium for a mean duration of 12.5(SD = 11.6) years. Lithium use was associated with lower intensity of depressive symptoms, reduced perceived clinical global severity and lower benzodiazepine use (all p 0.05), without being linked to greater rates of medical comorbidities, except for hypothyroidism.Data were cross-sectional and data on lifetime history of psychotropic medications was not assessed.Our results suggest that long-term lithium use may be efficient and relatively well-tolerated in older adults with BD or treatment-resistant MDD.

This volume represents the proceedings of the homonymous international conference on all aspects of impact cratering and planetary science, which was held in October 2019 in Brasília, Brazil. The volume contains a sizable suite of contributions dealing with regional impact records (Australia, Sweden), impact craters and impactites, early Archean impacts and geophysical characteristics of impact structures, shock metamorphic investigations, post-impact hydrothermalism, and structural geology and morphometry of impact structures—on Earth and Mars. Many contributions report results from state-of-the-art investigations, for example, several that are based on electron backscatter diffraction studies, and deal with new potential chronometers and shock barometers (e.g., apatite). Established impact cratering workers and newcomers to the field will appreciate this multifaceted, multidisciplinary collection of impact cratering studies.

Bien que l’émergence de la Covid-19 en Chine n’ait pas été clairement élucidée, l’hypothèse d’une origine animale reste la plus probable. Elle est étayée par la présence de la chauve-souris fer à cheval suspectée d’être le progéniteur du SARS-CoV-2 et par la raréfaction de la viande de porc, due à la peste porcine africaine, détournant les consommateurs vers des animaux exotiques d’élevage vendus sur les marchés. Au cours de cette pandémie, plusieurs espèces animales ont été atteintes par le SARS-CoV-2. Des cas sporadiques ont d’abord été rapportés chez des animaux de compagnie (chiens et chats) contaminés par leurs propriétaires, puis des grands félins et des gorilles contaminés dans des zoos par leurs soigneurs. La transmission la plus importante de l’Homme à l’animal a eu lieu dans les élevages de visons, surtout aux Pays-Bas et au Danemark, nécessitant l’euthanasie de plusieurs millions d’animaux, les visons ayant, à leur tour, contaminé des hommes et des chats errants. L’étude des transmissions naturelles ou expérimentales du SARS-CoV-2 a permis d’identifier les espèces animales les plus réceptives : les visons d’Amérique et les chiens viverrins, et dans une moindre mesure les chats errants, qui pourraient devenir un réservoir animal en raison de leur sensibilité à ce virus et de leur prolificité. La Commission européenne a décidé le 17 mai 2021 de renforcer la surveillance des infections par le SARS-CoV-2 chez les visons et d’autres mustélidés, ainsi que chez des chiens viverrins, en soulignant que l’évaluation épidémiologique du risque que présente l’apparition du SARS-CoV-2 chez ces espèces sensibles était une priorité de santé publique.

Background: in the United States from 1999 to 2000 through 2017–2018, the prevalence of obesity increased from 30.5 to 42.4%, while the prevalence of severe obesity nearly doubled. In lumbar spine surgery, obesity is associated with increased complications, worse perioperative outcomes, and higher costs. The purpose of this study was to examine the association between body mass index (BMI) and opioid consumption in patients undergoing lumbar spine fusion surgery. We hypothesized that obese patients would require more opioids postoperatively. Methods: retrospective review of 306 patients who underwent one- or two-level posterior lumbar interbody fusion surgery between 2016 and 2020. Patients were stratified by BMI as follows: normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), obese I (30.0–34.9 kg/m2), and obese II–III (≥ 35.0 kg/m2). Patient demographics and preoperative characteristics were compared across BMI cohorts using one-way ANOVA and chi-square analysis. Patients with prior history of opioid use were excluded. Primary outcome measure was postoperative opioid consumption. Secondary outcomes included operative time, length of stay (LOS), discharge destination, and 30-day re-encounter rates. Outcomes were analyzed using multivariable linear regression adjusted for potential confounders. Results: of 306 total patients, 17.3% were normal weight, 39.9% were overweight, 25.5% were obese I, and 17.3% were obese II–III. Obesity was associated with longer operative times and length of stay (p

At the Eugene Marquis Center, high dose rate brachytherapy is part of the care offering. The risk analysis and the national experience feedback linked to the use of high activity sources show that blocking the source outside its storage position, during treatment, would be the main risk of exposure of ionizing radiation. In a process of radiation protection of patients and workers, and to limit the consequences of such an accident, the Eugene Marquis Center has set up periodic training with practical experience for all brachytherapy professionals. This article describes the experience feedback from this training by brachytherapy technicians.

Resume Au Centre Eugene Marquis la curietherapie de haut debit de dose fait partie de l’offre de soins. L’analyse des risques et le retour d’experience national lie a l’utilisation de source scellee de haute activite, montre que le blocage de la source en dehors de sa position de stockage, pendant un traitement, serait le principal risque d’exposition aux rayonnements ionisants. Dans une demarche de radioprotection des patients et des professionnels et pour limiter les consequences d’un tel accident, le Centre Eugene Marquis a mis en place une formation periodique avec mise en situation pratique a destination de tous les professionnels de la curietherapie. Cet article decrit le retour d’experience de cette formation par les manipulateurs de curietherapie.

Case We describe 2 cases of gross trunnion failure (GTF) in males with Centers for Disease Control and Prevention Class 3 obesity 10 years after metal-on-polyethylene total hip arthroplasty (THA) with a titanium-alloy femoral stem and Type 1 taper. One patient received a large diameter cobalt-chromium femoral head, whereas the other received a smaller diameter head, both with high-offset femoral stems. Conclusion This is the first report of GTF involving the Echo Bi-Metric femoral stem after metal-on-polyethylene THA, and surgeons should consider the potential complication of GTF when using this specific femoral stem with metal heads in obese male patients.

OBJECTIVES To review perinatal and neurodevelopmental outcome (NDO) following selective fetoscopic laser coagulation (SFLC), cord coagulation (CC) or expectant management of monochorionic diamniotic twin pregnancies complicated with selective intrauterine growth restriction (sIUGR) and absent or reverse end-diastolic flow (AREDF) in the umbilical arteries (UA). DESIGN AND SETTING Single-centre retrospective observational study. POPULATION 108 cases of sIUGR diagnosed before 26+6 weeks' gestation with AREDF in the UA. METHODS Survival rate and potential risk factors were analysed. NDO was assessed using parental questionnaires. MAIN OUTCOMES MEASURES Survival, gestational age at delivery and NDO. RESULTS SFLC, CC and EM were performed in 13, 50 and 45 cases, respectively, with an overall survival of 23.1, 40 and 77.8% and intrauterine demise of the co-twin of 30.8, 10 and 6.7% respectively. Intrauterine demise of the sIUGR twin occurred in 76.9 and 17.8% following SFLC and EM, respectively. The discordance in EFW at diagnosis was higher and absent/negative a-wave in the ductus venosus (DV) was more prevalent in the surgical groups. NDO in survivors at follow up was abnormal in 0 and 18% in the smaller twin following SFLC and EM, respectively, and in 25, 24 and 21% in the larger twin following SFLC, CC and EM, respectively. CONCLUSION SFLC yielded a poor result. EM seems a valid option when EFW discordance is

Resume Le developpement de la radiotherapie stereotaxique ces dix dernieres annees oblige les services de radiotherapie a redoubler d’effort dans le domaine de la qualite et de la gestion des risques. Des controles de plus en plus complexes et rigoureux des machines de traitement, mais aussi une formation solide des equipes doivent ainsi etre mis en place. L’hypofractionnement extreme necessite a la fois une vigilance accrue au pupitre et des procedures bien definies connues de tous. Les organisations mises en place contribuent a la maitrise de ces risques eleves. La presence medicale au debut des traitements est precisee de facon reglementaire depuis janvier 2017. Celle-ci permet non seulement d’assurer une securite, mais egalement une transmission d’informations vers les manipulateurs en electroradiologie. Au centre Eugene-Marquis, il a ete decide de definir des competences specifiques pour les manipulateurs en electroradiologie concernant les radiotherapies stereotaxiques sur les machines dediees a cette technique (Cyberknife® et Versa HD® type Novalis®). Une habilitation, formalisee apres un temps de formation, est reevaluee annuellement. La communication entre et dans les metiers de la radiotherapie joue aussi un role important pour maintenir un haut niveau d’echanges et un partage d’informations. Les moyens mis en œuvre au centre Eugene-Marquis permettent ainsi de mieux maitriser le risque de la radiotherapie stereotaxique, en accordant une part importante a la gestion des competences au poste de traitement.

A common concern for patients undergoing joint replacement is that the implant will increase their body weight. In an effort to determine if in fact the joint implant is heavier than the bone removed during surgery, the authors conducted a 3-year review from 11/2014 to 11/2017 of 339 patients who underwent total hip arthroplasty (THA) procedures performed by a single surgeon. In the 339 patients, the bone and tissue removed from the patient was weighed. Using the known weights of each component (cup, head, and stem), the authors calculated the total mass of the hip prosthetic implant. Using deidentified patient data, they reviewed only the weight of bone and tissue removed and the calculated weight of the implant placed in each THA performed by the single surgeon. They subtracted the mass of the bone and tissue removed during surgery from the total mass of the hip implant to determine the net weight differential in the patient following surgery and calculated an average net weight gain of 124.84 g in the 339 patients who underwent THA. This weight gain of 124.84 g is equivalent to 0.275 lbs. Previous studies have only looked at weight gain or loss following total joint replacement with respect to natural weight loss/gain that may be associated with improved mobility following surgery. This is the first study to measure the actual quantifiable net weight differential due to the joint replacement itself. The authors concluded that no appreciable weight gain following THA can be attributed to the weight of the implant.

BACKGROUND CONTEXT Back pain and spine surgery have been major drivers of opioid consumption and spine surgery has been linked to the opioid epidemic. With increased awareness of the opioid crisis, the focus postoperatively has shifted to managing surgical site pain while minimizing narcotic use. Numerous studies have compared clinical outcomes and fusion status of different lumbar interbody fusion techniques; however, there is limited literature evaluating narcotic consumption postoperatively between techniques. The aim of this study was to assess and compare in-house and postoperative opioid consumption among three surgical techniques. PURPOSE To examine posterior lumbar fusion surgical techniques and compare opioid consumption across the techniques. STUDY DESIGN/SETTING Retrospective review. PATIENT SAMPLE Three hundred and three patients who underwent one- or two-level posterior lumbar interbody fusion surgery. OUTCOME MEASURES Primary outcome measure was opioid consumption across surgical techniques both while in-patient and after discharge as determined by total morphine equivalent dose (MED). Secondary outcomes included operative time, length of stay, and discharge destination. Methods This is a retrospective review of patients who underwent one- or two-level posterior lumbar interbody fusion surgery at a single institution between 2016 and 2020. Patients were stratified by surgical technique: posterior lumbar interbody fusion (PLIF), minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF), and cortical screw (CS) instrumentation with interbody fusion. Age, ASA, BMI, depression, preoperative opioid use, EBL and OR time were recorded and compared across surgical groups using one-way ANOVA and chi-square analysis. Total morphine equivalent dose (MED) was tabulated for both in-house consumption and postoperative prescriptions and was compared across surgical techniques using ANOVA analysis. Results A total of 303 patients underwent one- or two-level posterior lumbar interbody fusion between 2016 and 2020. 123 patients underwent cortical screw instrumentation, 96 underwent PLIF and 84 underwent MIS-TLIF. There was a significantly higher percentage of patients who had a history of depression and were on preoperative opioids in the CS group (p=0.001, p=0.002). Patients with CS instrumentation required significantly less narcotics per day while in-house compared to PLIF and MIS-TLIF (MED 80.65 vs 97.85 vs 83.72, p = 0.030). Patients who underwent CS instrumentation received half the number of narcotics compared to PLIF patients after discharge (MED 956.15 vs 2260.89, p = 0.003). Conclusions Patients who underwent CS instrumentation required less narcotics postoperatively both while admitted and after discharge. CS instrumentation may be associated with less postoperative pain due to the less invasive approach, however, patient education and prescriber practice also play a role in postoperative narcotic consumption. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

BACKGROUND CONTEXT The prevalence of obesity continues to rise in the United States. The CDC published that from 1999-2000 through 2017-2018 the prevalence of obesity increased from 30.5% to 42.4% and the prevalence of severe obesity nearly doubled. In lumbar spine surgery, obesity is associated with increased complications, worse perioperative outcomes, and higher costs. Obesity is also linked to depression and anxiety, which have both been shown to increase the use of opioids. We hypothesize that patients who are obese require more opioids postoperatively. PURPOSE To examine the association between body mass index (BMI) and opioid consumption in patients undergoing lumbar spine fusion surgery. STUDY DESIGN/SETTING Retrospective review. PATIENT SAMPLE Three hundred and six patients who underwent one- or two-level posterior lumbar interbody fusion surgery. OUTCOME MEASURES Primary outcome measure was opioid consumption across obesity classes both while in-patient and after discharge as determined by total morphine equivalent dose (MED). Secondary outcomes included operative time, length of stay, and discharge destination. METHODS This is a retrospective review of patients who underwent one- or two-level posterior lumbar interbody fusion surgery between 2016 and 2020. Patients were stratified by BMI as follows: normal weight (18.5-24.9 kg/m2), overweight (25.0–29.9 kg/m2), obese I (30.0–34.9 kg/m2), and obese II–III (≥ 35.0 kg/m2). Patient demographics and preoperative characteristics were compared across the BMI cohorts using one-way ANOVA and chi-square analysis. RESULTS Three hundred and six patients were included in the analysis, of whom 19.3% (N=59) were normal weight, 38.9% (N=119) were overweight, 24.5% (N=75) were obese I, and 17.3% (N=53) were obese II-III. Obesity is associated with significantly longer operative times and length of stay (p CONCLUSIONS This study illustrates that obesity is associated with longer operative times, longer length of stay, and increased use of postoperative opioids. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Study Design Retrospective review. Objectives With increased awareness of the opioid crisis in spine surgery, the focus postoperatively has shifted to managing surgical site pain while minimizing opioid use. Numerous studies have compared outcomes and fusion status of different interbody fusion techniques; however, there is limited literature evaluating opioid consumption postoperatively between techniques. The aim of this study was to assess in-house and postoperative opioid consumption across 3 surgical techniques. Methods Patients were stratified by technique: posterior lumbar interbody fusion (PLIF), minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF), and cortical screw (CS) instrumentation with interbody fusion. Age, ASA, BMI, depression, preoperative opioid use, EBL, and OR time were recorded and compared across surgical groups using Welch’s ANOVA and chi-square analysis. Total morphine equivalent dose (MED) was tabulated for both in-house consumption and postoperative prescriptions and was compared across surgical techniques using Welch’s ANOVA analysis, Mann Whitney U tests, and linear regression. Results Two hundred and thirty nine patients underwent one- or two-level posterior lumbar interbody fusion between 2016 and 2020. One hundred and twenty one patients underwent CS instrumentation, 95 underwent PLIF, and 83 underwent MIS-TLIF. There was a significantly higher percentage of patients who had a history of depression and preoperative opioid consumption in the CS group ( P = .001, P = .009). CS instrumentation required significantly less total post-op opioids per kilogram bodyweight compared to MIS-TLIF and PLIF surgeries ( P = .029). Conclusions Patients who underwent CS instrumentation required less opioids postoperatively. CS instrumentation may be associated with less postoperative pain due to the less invasive approach, however, patient education and prescriber practice also play a role in postoperative opioid consumption.

Introduction This manuscript presents a successful integration of multi-timepoint biomarker blood sampling (e.g., cytokines) in a conscious dog cardiovascular study using automated blood sampling via vascular access ports in telemetry instrumented dogs. In addition to determining plasma exposure of the test compound, the assessment of biomarkers of interest allows for more comprehensive preclinical evaluation on a traditional conscious dog cardiovascular (CV) telemetry study especially for immunology and immune-oncology molecules. This model system provides a rapid and efficient means to quickly gain understanding of potential effects on key cardiovascular parameters in large species that are commonly used for preclinical safety evaluations while collecting multiple blood samples for drug and cytokine analysis. Methods Male beagle dogs were chronically implanted with telemetry devices (PhysioTel™ model D70-PCTP) and vascular access ports (SPMID-GRIDAC-5NC). BASi Culex-L automated blood sampling (ABS) (Bioanalytical Systems, Inc) system was used to collect blood samples at multiple time points for cytokine analysis. Four beagles received low-dose lipopolysaccharide solution (LPS) (0.1 and 0.5 μg/mL). The following cytokines were measured by Milliplex® map Canine Cytokine Magnetic Bead Panel: Interleukin (IL) 2, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, TNF-α, MCP-1, KC-like, GM-CSF, IFN gamma, and IP10. Results Low dose LPS administration induced a pronounced dose-dependent, transient release of key inflammatory cytokines (IL-2, IL-6, IL-10, TNF-α, MCP-1, and KC-like). Cytokine responses were similar to other canine and human endotoxin models. LPS administration led to an increase in body temperature, heart rate, and mean arterial pressure, as well as a decrease in QTcV interval. Conclusion Successful incorporation of cytokine analysis in telemetry instrumented dogs with vascular access ports allows for translational PK/PD modeling of both efficacy and safety of compounds in the immunology as well as the immune-oncology therapeutic areas designed to modulate the immune system. Remote collection of blood samples simultaneously with CV endpoints is a significant enhancement for assessment of biomarkers that are sensitive to animal handling and excitement associated with room disturbances which are obligatory with manual blood collection. Furthermore, implementing this approach has also refined our animal welfare procedure by reducing the handling during a study and thereby reducing stress (positive refinement 3R impact).

Introduction Unanticipated effects on the central nervous system are a concern during new drug development. A larval zebrafish locomotor assay can reveal seizure liability of experimental molecules before testing in mammals. Relative absorption of compounds by larvae is lacking in prior reports of such assays; having those data may be valuable for interpreting seizure liability assay performance. Methods Twenty-eight reference drugs were tested at multiple dose levels in fish water and analyzed by a blinded investigator. Responses of larval zebrafish were quantified during a 30 min dosing period. Predictive metrics were calculated by comparing fish activity to mammalian seizure liability for each drug. Drug level analysis was performed to calculate concentrations in dose solutions and larvae. Fifteen drug candidates with neuronal targets, some having preclinical convulsion findings in mammals, were tested similarly. Results The assay has good predictive value of established mammalian responses for reference drugs. Analysis of drug absorption by larval fish revealed a positive correlation between hyperactive behavior and pro-convulsive drug absorption. False negative results were associated with significantly lower compound absorption compared to true negative, or true positive results. The predictive value for preclinical toxicology findings was inferior to that suggested by reference drugs. Discussion Disproportionately low exposures in larvae giving false negative results demonstrate that drug exposure analysis can help interpret results. Due to the rigorous testing commonly performed in preclinical toxicology, predicting convulsions in those studies may be more difficult than predicting effects from marketed drugs.

The in vivo rodent Pig-a mutation assay is a sensitive test to identify exposure to mutagenic substances, and has been proposed as an assay for the identification of impurities for pharmaceuticals. Red blood cells (RBCs) and reticulocytes (RETs) are analyzed by flow cytometry after exposure to potentially mutagenic chemicals for cells deficient in the cell surface anchored protein CD59, representing mutation in the X-linked Pig-a gene. The full potential of the assay as well as its limitations are currently being explored. The current study investigated the effects of regenerative erythropoietic bone marrow responses on the frequency of Pig-a mutated reticulocytes (RETCD59- ) and erythrocytes (RBCCD59- ). We hypothesized that a robust regenerative erythropoietic response would not increase the basal frequency of RETCD59- or RBCCD59- cells. Two groups of six male Sprague-Dawley rats either had 2 mL of blood sampled each day via an indwelling catheter over a period of 5 days or were minimally sampled for hematology and used as controls. Blood was also then collected and evaluated 5, 18, and 49 days after the initial bleed period for the number of Pig-a mutant cells in either the RET or RBC population. Despite the expected decrease in hematocrit and the correlative increase in reticulocytes after bleeding, no increase in the number of Pig-a mutant cells was observed in male Sprague-Dawley rats that were bled for five consecutive days. These results indicate that changes in erythropoiesis and hematology parameters in rats appear to have no effect on the background levels of Pig-a mutated RETs and RBCs. Environ. Mol. Mutagen. 59:91-95, 2018. © 2017 Wiley Periodicals, Inc.

Bumped Kinase Inhibitors (BKIs), targeting Calcium-dependent Protein Kinase 1 (CDPK1) in apicomplexan parasites with a glycine gatekeeper, are promising new therapeutics for apicomplexan diseases. Here we will review advances, as well as challenges and lessons learned regarding efficacy, safety, and pharmacology, that have shaped our selection of pre-clinical candidates.

This paper presents results from an experiment designed to improve the understanding of the relationship between extreme breaking waves and their mechanical loading on heritage offshore lighthouses. The experiment, conducted at La Jument, an iconic French offshore lighthouse, featured several records of wave, current and structure accelerations acquired during severe storm conditions, with individual waves as high as 24 m. Data analysis focuses on a storm event marked by a strong peak in the horizontal accelerations measured inside La Jument. Thanks to stereo-video wave measurements synchronized to the acceleration record we were able to identify and describe the breaking wave responsible for this intense loading. Our observations suggest that this giant wave (19 m high) had a crest elevation high enough to directly hit the lighthouse tower, above the substructure. This paper reveals the potential for conducting ambitious field experiments from offshore lighthouses in order to collect valuable storm waves and wave loading observations. This offers a possible second service life for these heritage structures as in situ laboratories dedicated to the study of the coastal hydrodynamics and its interaction with marine structures. This article is part of the theme issue ‘Environmental loading of heritage structures’.

Little is known about the respective effects of depression and cognitive impairment on quality of life among older adults with schizophrenia spectrum disorder.We used data from the Cohort of individuals with Schizophrenia Aged 55-years or more (CSA) study, a large multicenter sample of older adults with schizophrenia or schizoaffective disorder (N = 353). Quality of life (QoL), depression and cognitive impairment were assessed using the Quality of Life Scale (QLS), the Center of Epidemiologic Studies Depression scale and the Mini-Mental State Examination, respectively. We used structural equation modeling to examine the shared and specific effects of depression and cognitive impairment on QoL, while adjusting for sociodemographic characteristics, general medical conditions, psychotropic medications and the duration of the disorder.Depression and cognitive impairment were positively associated (r = 0.24, p 0.01) and both independently and negatively impacted on QoL (standardized β = -0.41 and β = -0.32, both p 0.01) and on each QLS quality-of-life domains, except for depression on instrumental role and cognitive impairment on interpersonal relations in the sensitivity analyses excluding respondents with any missing data. Effects of depression and cognitive impairment on QoL were not due to specific depressive symptoms or specific cognitive domains, but rather mediated through two broad dimensions representing the shared effects across all depressive symptoms and all cognitive deficits, respectively.Because of the cross-sectional design of this study, measures of association do not imply causal associations.Mechanisms underlying these two broad dimensions should be considered as important potential targets to improve quality of life of this vulnerable population.

BACKGROUND CONTEXT Marijuana is an antinociceptive which has been evaluated as a possible adjunct or substitute for opioid use in the treatment of acute pain. The aim of this study was to evaluate the association between preoperative marijuana usage and consumption of opioids for postoperative analgesia. We hypothesized that marijuana usage may be associated with decreased usage of opioid analgesics in postoperative pain relief in patients undergoing spine surgery. PURPOSE To examine the association between marijuana use and opioid consumption in patients undergoing lumbar spine fusion surgery. STUDY DESIGN/SETTING Retrospective review. PATIENT SAMPLE Two hundred and twenty-one patients who underwent one- or two-level posterior lumbar interbody fusion surgery. OUTCOME MEASURES Primary outcome measures were opioid consumption in marijuana users and non- marijuana users both while in-patient and after discharge as determined by total morphine equivalent dose (MED). Secondary outcome measures included operative time, length of stay, discharge destination, and readmission rates. METHODS Retrospective review of 221 patients who underwent one- or two-level posterior lumbar fusion surgery between 2016 and 2020 at a single institution. Patients were categorized as marijuana users or non-marjiuana users based on preoperative diagnoses of marijuana use. Total morphine equivalent dose (MED) was calculated for both in-house opioid consumption and postoperative prescription opioid usage. Patients who were on opioids preoperatively were excluded. Patient demographics and preoperative characteristics were compared across the BMI cohorts using one-way ANOVA and chi-square analysis. RESULTS Of 221 total patients, 29 patients were identified as marijuana users while 192 were non- marijuana users. There were no significant associations between marijuana usage and age, ASA, BMI, tobacco use, EBL, OR time, LOS, or disposition to rehab. Marijuana users had greater association with depression (31% vs 12.5%, p=0.032) and 30-day readmission (17.2% vs 11.5% (p CONCLUSIONS Marijuana usage is associated with increased usage of opioids postoperatively, both while in patient and post-discharge, after posterior lumbar spine fusion surgery. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Resume Introduction Pour atteindre les recommandations nutritionnelles d’apports en proteines, energie, vitamines et oligo-elements chez le premature de moins de 2500 g, le lait de femme doit etre enrichi. Cet enrichissement entraine un risque d’hyperosmolalite au-dela de 500 mosm/kg et probablement au-dela en cas d’ajout de medicaments ou de vitamines. Objectif Nous avons etudie l’impact de l’apport quotidien d’Uvesterol ADEC® sur l’osmolarite du lait de femme fortifie. Materiel et methode Nous avons mesure l’osmolalite de 36 echantillons de lait de femme pasteurise non fortifie et fortifie (4 % Suppletine® avec 0,5 % Nutriprem® et 4 % Suppletine® avec 1 % Nutriprem®) additionne de 0,3 mL d’Uvesterol ADEC®. Le volume minimum de lait necessaire a la dilution de l’Uvesterol ADEC® pour maintenir l’osmolalite en dessous de 500 mosm/kg a ete determine. Resultats L’osmolalite de 2 mL de lait de femme fortifie additionne de 0,3 mL d’Uvesterol ADEC® est passee de 430 a 760 mosm/kg. L’osmolalite a decru proportionnellement a l’augmentation du volume de dilution ; lorsque l’Uvesterol ADEC® etait ajoute a une ration de 20 mL de lait de femme enrichi l’osmolalite retombait a son niveau initial. Conclusion Nous pouvons recommander de ne prescrire l’Uvesterol ADEC® chez le premature que lorsque sa ration de lait de femme depasse 20 mL par prise. En dessous, l’apport en vitamine D doit etre assure par la voie parenterale ou etre fractionne en 2 prises pour des rations de lait de femme depassant 10 mL. Il faut rester vigilant au risque d’hyperosmolalite du lait de femme fortifie.

The development of stereotaxic body radiotherapy in the last decade has forced the radiotherapy departments to redouble their efforts in the fields of quality and risk management. For this purpose, increasingly complex and rigorous controls of high performance machines as well as a solid team training must be put in place. Extreme hypofractionation requires both increased vigilance at the treatment desk and well-defined and known procedures. The in place organizations contribute to the control of the risks related to the stereotaxic body radiotherapy machines. The medical presence at the beginning of the treatment fractions has been specified as mandatory in a regulatory way since January 2017. This not only ensures security, but also transmits information to the radiation therapy technicians. At the Eugène-Marquis center, the skills of the technicians for stereotaxic body radiotherapy on two dedicated machines (Cyberknife