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C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72–related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming.

International audience; Background Although the triple positivity of antiphospholipid antibodies (aPL) is important for classifying high-risk patients, interpretation of aPL positivity, namely the lupus anticoagulant (LA), anti-cardiolipin (aCL), and anti-beta2-glycoprotein I autoantibodies (aB2GPI) remains challenging for thrombotic risk stratification. Objective To compare biological and clinical data between triple aPL- and single aCL-positive patients. Methods Of the 6500 patients assayed for aPL in daily practice within 3 years, we retrospectively analyzed data from 161 patients that were either triple aPL-positive or single aCL-positive with 5 years' follow-up for 121 of them. Results Whatever triple or single aPL positivity, we found a high prevalence of "carrier" patients (43%), which led us to question the clinical relevance of the triple aPL positivity. This result also justified the need to identify high-risk profiles. In asymptomatic patients, high risk of thrombotic events is associated with (1) two positive tests for LA or a Rosner Index >27 combined with both aCL-IgG and aB2GPI-IgG positivity, (2) persistent single aCL positivity without an associated autoimmune disease. In symptomatic patients, we demonstrated differences in the phenotype of patients and their therapeutic anticoagulation according to the number of positive aPL but we did not find differences in the number of clinical events, recurrence, or relapse, even in the absence of treatment. Conclusion This study shows that the thrombotic risk does not necessarily increase with the number of positive tests and raises the question of the therapeutic management of single aCL-positive patients.

Background Pituitary pars intermedia dysfunction (PPID) is a common endocrinopathy of horses diagnosed with a thyrotropin-releasing hormone (TRH) stimulation test. Hypothesis/objectives Describe the repeatability of TRH stimulation in horses with and without PPID in winter and autumn. Animals Twenty adult horses; 6 controls and 6 with PPID tested in autumn, 8 controls and 6 with PPID tested in winter with 3 controls and 3 with PPID tested in both seasons. Methods Thyrotropin-releasing hormone stimulation was performed on 2 consecutive occasions, 1 week before and 1 week after the winter solstice and the autumn equinox. Blood was collected before and 30 minutes after IV injection of 1 mg of TRH. ACTH concentration was determined by a chemiluminescent assay. Repeatability and test-retest reliability were assessed by repeated measures analysis of variance, intraclass correlation coefficient and within-horse coefficients of variation (CV). Bland-Altman plots were generated to visualize agreement between repetitions. Results In winter, no week effect was detected on the results of the TRH simulation and the test had an excellent test-retest reliability. In autumn, after-TRH ACTH concentrations were significantly lower on week 2 (P = .02) and the test only had a good test-retest reliability. There were significantly larger within-horse CV during autumn (P = .04) and after TRH stimulation (P = .04). There were 2 misclassifications in winter and 4 in autumn. Conclusions and clinical importance The TRH stimulation test was repeatable when performed 2 weeks apart in winter; however, in autumn, more variability in after-TRH ACTH concentrations resulted in decreased repeatability.

Background Formalin-fixed paraffin-embedded (FFPE) tissue has been the gold standard for routine pathology for general and cancer postoperative diagnostics. Despite robust histopathology, immunohistochemistry, and molecular methods, accurate diagnosis remains difficult for certain cases. Overall, the entire process can be time consuming, labor intensive, and does not reach over 90% diagnostic sensitivity and specificity. There is a growing need in onco-pathology for adjunct novel rapid, accurate, reliable, diagnostically sensitive, and specific methods for high-throughput biomolecular identification. Lipids have long been considered only as building blocks of cell membranes or signaling molecules, but have recently been introduced as central players in cancer. Due to sample processing, which limits their detection, lipid analysis directly from unprocessed FFPE tissues has never been reported. Methods We present a proof-of-concept with direct analysis of tissue-lipidomic signatures from FFPE tissues without dewaxing and minimal sample preparation using water-assisted laser desorption ionization mass spectrometry and deep-learning. Results On a cohort of difficult canine and human sarcoma cases, classification for canine sarcoma subtyping was possible with 99.1% accuracy using “5-fold” and 98.5% using “leave-one-patient out,” and 91.2% accuracy for human sarcoma using 5-fold and 73.8% using leave-one-patient out. The developed classification model enabled stratification of blind samples in 95% probability for discriminating 2 human sarcoma blind samples. Conclusion It is possible to create a rapid diagnostic platform to screen clinical FFPE tissues with minimal sample preparation for molecular pathology.

Background: Pyrazinamide (PZA) represents a milestone as a first-line antituberculosis drug due to its sterilizing activity against Mycobacterium tuberculosis. Materials & Methods: The protein changes induced by subinhibitory PZA exposure of M. tuberculosis in acidic pH were evaluated by a proteomic approach. Results: Among the 1059 M. tuberculosis proteins identified, the specific acidification in the culture medium induced the over-representation of MurF (Rv2157c), and its under-representation was induced by 12 h of PZA exposure. PanB (Rv2225) was over-represented at 24 h of PZA exposure. Conclusion: The authors highlight the over-representation of PanB in M. tuberculosis correlates of PZA action in acidic pH, reinforcing the role of the pantothenate pathway as a bacillus drug target to be explored.

Tuberculosis is a disease caused by Mycobacterium tuberculosis, with high mortality rates and an extended treatment that causes severe adverse effects, besides the emergence of resistant bacteria. ...

International audience; No abstract available

The post-operative pediatric cerebellar mutism syndrome (CMS) affects about one-third of children and adolescents following surgical removal of a posterior fossa tumor (PFT). According to the Posterior Fossa Society consensus working definition, CMS is characterized by delayed-onset mutism/reduced speech and emotional lability after cerebellar or 4th ventricle tumor surgery in children, and is frequently accompanied by additional features such as hypotonia and oropharyngeal dysfunction/dysphagia. The main objective of this work was to develop a diagnostic scale to grade CMS duration and severity. Thirty consecutively referred subjects, aged 1–17 years (median 8 years, IQR 3–10), were evaluated with the proposed Post-Operative Pediatric CMS Survey after surgical resection of a PFT and, in case of CMS, for 30 days after the onset (T0) or until symptom remission. At day 30 (T1), CMS was classified into mild, moderate, or severe according to the proposed scale. CMS occurred in 13 patients (43%, 95% C.I.: 25.5–62.6%), with mild severity in 4 cases (31%), moderate in 4 (31%), and severe in 5 (38%). At T1, longer symptom persistence was associated with greater severity (p = 0.01). Greater severity at T0 predicted greater severity at T1 (p = 0.0001). Children with a midline tumor location and those aged under 5 years at diagnosis were at higher risk of CMS (p = 0.025 and p = 0.008, respectively). In conclusion, the proposed scale is a simple and applicable tool for estimating the severity of CMS at its onset, monitoring its course over time, and providing an early prognostic stratification to guide treatment decisions. What is Known:• Post-operative pediatric Cerebellar Mutism Syndrome (CMS) is a complex phenomenon with a wide spectrum of symptoms that may manifest in children undergoing the resection of a posterior fossa tumor (PFT) and that can result into long-term impairment. What is New:• This study developed and pilot-tested an easily applicable diagnostic and severity scale to grade the duration and the severity of symptoms of the CMS.• The proposed scale was found to be a sensitive instrument to identify even mild CMS presentations.• By scoring not only the duration but also the severity of symptoms the scale allows a more accurate prognostic stratification for an optimal planning of clinical and rehabilitative interventions.

As neoplasias ósseas primárias são incomuns em gatos, sendo o osteossarcoma entre elas a mais frequente observada, geralmente em animais de meia idade e idosos. Esta neoplasia acomete o esqueleto apendicular, porém o esqueleto axial também pode ser afetado, sendo os ossos da cabeça e da pélvis os locais mais frequentes de lesões. O presente relato descreve um gato de onze anos com aumento de volume em membro pélvico direito, algia e claudicação. O diagnóstico presuntivo é realizado através do exame clínico, radiográfico e confirmação do histopatológico.

International audience

Objective: The purpose of this study was to determine the effects of the ethanolic extract of avocado seed flour on the estrous cycle characteristics, the concentrations of reproductive hormones [luteinizing hormone (LH) and estradiol], and the activities of some tissues (ovarian and uterine) that are markers of oxidative stress in female guinea pigs (Cavia porcellus). Materials and Methods: Twenty-four female cavies with normal estrous cycles and equivalent body weights (464.25 and 71.88 gm) were randomly assigned to four groups, each with six females. The control group received 1 ml of distilled water orally, whereas the EE100, EE200, and EE400 groups received 100, 200, and 400 mg/kg bw of ethanolic extract of Persea americana seed, respectively. Following that, three consecutive estrous cycles were observed using vaginal smears. After the trial, the females were slaughtered, and blood and organs were gathered for study. Results: The mean duration of the estrus phase is considerably (p < 0.05) longer in group EE100 animals than in control animals. LH concentrations were substantially (p < 0.05) higher in females in group EE200 than in controls. Total cholesterol levels typically dropped in females in the extract groups, but only significantly (p < 0.05) in those in group EE100 compared to the control group. Serum estradiol levels increased considerably (p < 0.05) in treated females compared to controls. Catalase activity rose considerably (p < 0.05) in the ovaries of group EE400 when compared to the control. Superoxide dismutase activity rose considerably (p < 0.05) in the uterus of female cavies given the extract compared to the control. Conclusion: Avocado seed ethanolic extract prolongs the estrus phase, increases estradiol and LH levels, and protects the uterus from oxidative stress in female cavies. [J Adv Vet Anim Res 2021; 8(3.000): 501-510]

The sap of Croton lechleri Müll. Arg. (Euphorbiaceae) is well-known in South American traditional medicine. This research investigated its activity against glycation and oxidative stress (glycoxidation) to estimate its usefulness in ROS-related diseases. The activity of the sap on albumin glycation, LDL oxidation and ROS formation was detected. C. lechleri sap inhibited BSA glycation and exhibited a protective effect against LDL oxidation; at the concentration of 0.8 µg/mL, it extended the Lag phase of almost 60%. Furthermore, the sap was studied on cell viability and ROS production in HUVEC showing valuable free-radical scavenging activity. In detail, the sap (1.0 and 10.0 μg/mL) significantly decreased the baseline level and H2O2-induced ROS production in HUVEC. This research showed for the first time the ability of C. lechleri sap to decrease the albumin glycation, LDL oxidation and ROS formation in HUVEC, supporting its potential in vascular diseases.

Enhancement of fibrinolysis constitutes a promising approach to treat thrombotic diseases. Venous thrombosis and thromboembolism risks are associated with increased plasma levels of TAFI (Thrombin Activatable Fibrinolysis Inhibitor) as well as its active form TAFIa. A new TAFIa inhibitor, namely S62798 has been identified. Its ability to enhance fibrinolysis was investigated both in vitro and in vivo in a mouse model of pulmonary thromboembolism, as well as its effect on bleeding. S62798 is a highly selective human, mouse and rat TAFIa inhibitor (IC50 = 11; 270; 178 nmol/L, respectively). It accelerates lysis of a human clot in vitro, evaluated by thromboelastometry (EC50 = 27 nmol/L). In a rat tail bleeding model, no effect of S62798 treatment was observed up to 20 mg/kg. Enhancement of endogenous fibrinolysis by S62798 was investigated in a mouse model of Tissue Factor-induced pulmonary thromboembolism. Intravenous administration of S62798 decreased pulmonary fibrin clots with a minimal effective dose of 0.03 mg/kg. Finally, effect of S62798 in combination with heparin was evaluated. When treatment of heparin was done in a curative setting, no effect was observed whereas a significantly decreased pulmonary fibrin deposition was observed in response to S62798 alone or in combination with heparin. This study demonstrates that S62798 is a potent TAFIa inhibitor with minimal risk of bleeding. In vivo, curative S62798 intravenous treatment, alone or associated with heparin, accelerated clot lysis by potentiating endogenous fibrinolysis and thus decreased pulmonary fibrin clots. S62798 is expected to be a therapeutic option for pulmonary embolism patients on top of anticoagulants.

Background Insecticide resistance has become a widespread problem causing a decline in the effectiveness of vector control tools in sub-Saharan Africa. In this situation, ongoing monitoring of vector susceptibility to insecticides is encouraged by the WHO to guide national malaria control programmes. Our study was conducted from April to November 2018 in Tchonka (Sud-Kivu, Democratic Republic of the Congo) and reported primary data on the resistance status of Anopheles funestus and Anopheles gambiae. Methods Insecticide susceptibility bioassays were performed on wild populations of A. funestus and A. gambiae using WHO insecticide-impregnated papers at discriminating concentration. In addition, PCR was performed to identify mosquito species and to detect kdr and ace-1R mutations involved in insecticide resistance. Results Bioassay results show resistance to all tested insecticides except pirimiphos-methyl, propoxur, fenitrothion and malathion with a mortality rate ranging from 95.48 to 99.86%. The addition of piperonyl butoxide (PBO) increased the susceptibility of vectors to deltamethrin and alpha-cypermethrin by exhibiting a mortality ranging from 91.50 to 95.86%. The kdr mutation was detected at high frequencies (approximately 0.98) within A. gambiae while ace-1R was not detected. Conclusions This study provides useful data on the insecticide resistance profiles of malaria vector populations to better manage vector control. Our results highlight that, despite the high level of resistance, organophosphorus compounds and pyrethroids + PBO remain effective against the vectors.

International audience; The coronavirus disease 2019 (COVID-19) outbreak has had a major impact on medical and surgical activities. A decline in facial trauma incidence was noticed during the lockdown period. The aim of this study was to evaluate the decline in maxillofacial trauma in France during this particular period. A retrospective multicentre comparative study was initiated in 13 major French public hospital centres. The incidence of facial trauma requiring surgery during the first month of lockdown was compared to that during equivalent periods in 2018 and 2019. Differences in the types of trauma were also analysed. Thirteen maxillofacial departments participated in the study. A significant decline in maxillofacial trauma volumes was observed when compared to equivalent periods in 2018 and 2019 (106 patients compared to 318 and 296 patients, respectively), with an average reduction of 65.5% (P = 0.00087). The proportion of trauma due to sports and leisure was reduced when compared to reports in the literature. As a consequence, in the context of a pandemic, the material and human resources related to this activity could be reallocated to the management of other pathologies that cannot be postponed.

Aim: To evaluate the modulatory effect of piperine (PIP) on streptomycin (SM) activity in Mycobacterium tuberculosis ( Mtb). Materials & methods: SM and PIP minimum inhibitory concentration (MIC) and combinatory activity were determined in Mtb H37Rv and in susceptible and resistant clinical isolates. Ethidium bromide accumulation assay and relative quantification of efflux pumps genes ( rv1258c, rv1218c and rv2942), after SM and SM+PIP combination exposure, were also performed. Results: PIP concentration of 25 μg/ml (1/4× MIC) was able to inhibit efflux pumps activity, to modulate SM activity in Mtb, and conducted changes in the relative quantification of efflux pumps genes. Conclusion: SM+PIP combination was able to rescue the SM-susceptible MIC values in SM-resistant Mtb.

(1) Background: The study aims to identify which imaging parameters are necessary for a new correct surgical approach in the study of choanal atresia, and which anatomical findings are essential for correct planning of endoscopic treatment in choanal atresia. (2) Methods: In this retrospective study, 19 patients with choanal atresia had high-resolution multiplanar imaging (14 cases aged ≤1 year and 5 cases aged 1 to 3 years) and 35 patients in the control group similarly distributed by age. Fourteen variables, the most relevant from a surgical point of view, were selected and measured. A comparison was made between the averages of the study group and the different control groups, either directly observed or selected from the literature, using Pearson’s correlation. (3) Results: In 14 out of 26 cases, the differences were statistically significant. There was a correlation between the structures assessed, such as choanal height, rostrum height, and age. (4) Conclusions: Thanks to volumetric reformatting, this work identified and provided the clinician with useful information that helped choose the correct surgical approach. Furthermore, it focused on which imaging parameters are necessary to improve the planning of the surgical correction of choanal atresia.

The present study was carried out in order to evaluate the effects of feed supplementation with spiruline powder on the oxidative stress markers, biochemical characteristics, and hematological parameters in rabbit doe. Twenty-one nulliparous and sexually mature does (7–8 months old) were distributed into three groups of seven does each, comparable in terms of body weight. After a week of feeding with experimental feed, does of each group were mated. During the trial, does of group 1 (control group) were fed ad libitum with a feed free from spiruline (control feed), while those of groups 2 and 3 received the control feed supplemented with spiruline powder at 0.6 and 1.2%, respectively. Immediately after parturition, blood was collected for analyses of hematological, biochemical, and oxidative stress parameters. Studied parameters included serum concentrations of total proteins, cholesterol, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), creatinine, and urea; malondialdehyde, reduced glutathione, catalase, and superoxide dismutase; and hematological parameters. The total protein concentration, number of white and red blood cells, platelets, hemoglobin, hematocrit, and mean corpuscular volume were significantly (P0.05) among treatments. Hence, these results show that feed supplementation with spirulina powder can improve rabbit doe health, notably at 1.2%, since optimal results were obtained at this percentage.

BACKGROUND AND AIMS Cannabis use (CU) is an etiologically complex behavior with several social, temperamental, neurocognitive, and behavioral precursors. Biometrical and molecular studies suggest an interplay of environmental and pleiotropic influences. However, it remains unclear whether identified genetic effects related to behavioral and temperamental characteristics have developmentally direct or indirect mechanisms on CU behavior. The Transmissible Liability Index (TLI) is a measure of continuous liability based on developmental precursors of substance use disorders. This study aimed to examine if the TLI plays a role in understanding genetic risk for CU behaviors. DESIGN Genome-wide association studies (n > 10 000; European Ancestry [EA]) of CU, risk tolerance, neuroticism, anxiety, and depression were used to construct polygenic scores (PGSs). Analyses assessed whether PGSs indirectly impacted risk for repeated use via TLI. SETTING United States of America. PARTICIPANTS From Add Health study, 4077 individuals of EA age 11 to 21 during baseline interview collection. MEASUREMENTS Outcomes were initiation and repeated cannabis use (>5× in lifetime). The TLI was parameterized using a latent factor from 21 questions assessing for precursors of disordered use. FINDINGS The marker-based heritability of TLI, initiation, and repeated use were significant, but modest (14%, P = 0.033; 15%, P = 0.025; and 17%, P = 0.008, respectively). TLI and repeated use were genetically correlated (rg = 0.76, P = 0.033). The PGS for CU was associated with increased risk for repeated use and PGS for risk tolerance and depression were associated with TLI. Mediation analyses indicated significant, but very weak, indirect effects of PGS for risk tolerance and depression on repeated CU via the TLI. CONCLUSIONS Adolescent behavioral and temperamental characteristics (i.e. the Transmissible Liability Index) appear to be early indicators of repeated cannabis use in adulthood. Although polygenic scores for cannabis use directly increased risk for repeated cannabis use, weak evidence was found for the role of polygenic scores of other internalizing/externalizing traits acting through adolescent derived Transmissible Liability Index on cannabis use behavior.

Purpose of Review Five years have passed since the World Health Organization released its Global Technical Strategy for Malaria (GTS). In that time, progress against malaria has plateaued. This review focuses on the implications of antimalarial drug resistance for the GTS and how interim progress in parasite genomics and antimalarial pharmacology offer a bulwark against it. Recent Findings For the first time, drug resistance–conferring genes have been identified and validated before their global expansion in malaria parasite populations. More efficient methods for their detection and elaboration have been developed, although low-density infections and polyclonality remain a nuisance to be solved. Clinical trials of alternative regimens for multidrug-resistant malaria have delivered promising results. New agents continue down the development pipeline, while a nascent infrastructure in sub-Saharan Africa for conducting phase I trials and trials of transmission-blocking agents has come to fruition after years of preparation. Summary These and other developments can help inform the GTS as the world looks ahead to the next two decades of its implementation. To remain ahead of the threat that drug resistance poses, wider application of genomic-based surveillance and optimization of existing and forthcoming antimalarial drugs are essential.

Background Endocrinopathic laminitis develops in association with insulin dysregulation, but the role of insulin in the pathogenesis remains unclear. Hyperinsulinemia can cause hypoaminoacidemia, which is associated with integumentary lesions in other species and therefore warrants investigation as a potential mechanism in laminitis. Objective Evaluate plasma amino acid concentrations in the euglycemic‐hyperinsulinemic clamp (EHC) and prolonged glucose infusion (PGI) laminitis models. Animals Sixteen Standardbred horses. Methods Prospective experimental study. Plasma amino acid concentrations were measured in samples collected every 6 hours from horses that underwent a 48‐hour EHC (n = 8) or 66‐hour PGI (n = 8) after a 24‐ or 6‐hour baseline period in EHC and PGI groups, respectively. Results Fifteen of the 20 measured amino acid concentrations decreased over time in both EHC and PGI horses (P

Background Breast cancer (BC) remains a leading cause of cancer-related death among women worldwide. The complexity of this disease, especially its heterogeneity, have prevented its eradication and driven resistance to treatments. To reach precision oncology to eradicate BC, therapy needs to be specific to each tumor clone. Yielding enough molecular information from tumor clones to identify new drug targets represents a technical challenge due to sample size limitation or loss of spatial resolution. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry combined with microproteomics enables a spatially-resolved unlabeled tumor imaging of its protein distribution, thus revealing proteomic clones. Our aims were to analyze the clonal proteome of luminal breast cancers, and explore its potential to expand new drug target discovery and drug repurposing. Methods A retrospective study at the Comprehensive Cancer Centre Oscar Lambret (Lille, France) was conducted to analyze 76 FFPE luminal HER2 negative tumors: 52 primary tumors from patients with early BC and 24 BC metastases. Patients gave their informed consent and the study was approved by the local institutional review board. MALDI mass spectrometry imaging and spatially-resolved on-tissue shotgun microproteomics were performed on FFPE slides of tumor tissue to determine the proteomic profile of selected clones using nanoLC-MS & MS/MS. Protein identification was performed using MaxQuant software against the Uniprot database. Functional annotation and characterization of the identified proteins were performed using Panther software. Candidate druggable targets were searched using DrugCentral druggable genome database, and their druggability level was assessed using the classification by the Illuminating the Druggable Genome Knowledge Management Center. The clonal proteome dataset was compared to publically available TCGA, BC360, and CDx datasets. Results The clonal proteome analysis identified a total of 2868 different proteins; 780 proteins were found in more than 50% of the patients. Panther analysis showed that 22% of the proteins were classified as enzymes, 15% were related to DNA processes, 6% were structural proteins, and less than 2% were related to immunity. Panther identified 139 pathways in the clonal proteome dataset. The clonal proteome analysis yielded the highest number of pathways compared to TCGA, BC360, and CDx datasets. 41 pathways (mainly metabolic pathways) were exclusive to the clonal proteome dataset. 1495 proteins of this dataset had an entry and were druggable in DrugCentral database, with 52% of them with known mechanisms of action and drug interaction. The main target classes were enzymes (60%), kinases (23%) and transporters (7%), whereas kinases were dominant in TCGA, BC360, and CDx datasets (46% to 77%). To explore the clonal proteome potential for repurposing anticancer drugs in luminal breast cancers, protein targets matching approved antineoplastic agents were searched using DrugCentral database. 97 approved anticancer drugs were identified, mostly chemotherapy (33%) or protein kinase inhibitors (28%), of whom only 17 were approved for breast cancer treatment. Compared to publically available TCGA, BC360, and CDx datasets, the clonal proteome analysis yielded the highest number of drug target candidate. Conclusion Mass spectrometry-based analysis of BC proteomic clones provides the technological means to access large functional molecular information at a clonal level to develop clone specific strategies for drug target discovery and drug repurposing in BC. Citation Format: Nawale Hajjaji, Soulaimane Aboulouard, Delphine Bertin, Yves Marie Robin, Isabelle Fournier, Michel Salzet. Proteomic profiling of specific tumor clones using spatially resolved mass spectrometry technologies for precision oncology [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-36.

The global malaria burden has decreased substantially, but gains have been uneven both within and between countries. In Zambia, the malaria burden remains high in northern and eastern regions of the country. To effectively reduce malaria transmission in these areas, evidence-based intervention strategies are needed. Zambia’s National Malaria Control Centre conducted targeted indoor residual spraying (IRS) in 40 high-burden districts from 2014 to 2016 using the novel organophosphate insecticide pirimiphos-methyl. The Southern and Central Africa International Centers of Excellence for Malaria Research conducted an evaluation of the impact of the IRS campaign on household vector abundance in Nchelenge District, Luapula Province. From April 2012 to July 2017, field teams conducted indoor overnight vector collections from 25 to 30 households per month using Centers for Disease Control light traps. Changes in indoor anopheline counts before versus after IRS were assessed by species using negative binomial regression models with robust standard errors, controlling for geographic and climatological covariates. Counts of Anopheles funestus declined by approximately 50% in the study area and within areas targeted for IRS, and counts of Anopheles gambiae declined by approximately 40%. Within targeted areas, An. funestus counts declined more in sprayed households than in unsprayed households; however, this relationship was not observed for An. gambiae. The moderate decrease in indoor vector abundance indicates that IRS with pirimiphos-methyl is an effective vector control measure, but a more comprehensive package of interventions is needed with sufficient coverage to effectively reduce the malaria burden in this setting.

International audience; No abstract available

International audience; Alzheimer's disease (AD) neuropathology is extremely heterogeneous, and the evolution from preclinical to mild cognitive impairment until dementia is driven by interacting genetic/biological mechanisms not fully captured by current clinical/research criteria. We characterized the heterogeneous "construct" of AD through a cerebrospinal fluid biomarker-guided stratification approach. We analyzed 5 validated pathophysiological cerebrospinal fluid biomarkers (Aβ1-42, t-tau, p-tau181, NFL, YKL-40) in 113 participants (healthy controls [N = 20], subjective memory complainers [N = 36], mild cognitive impairment [N = 20], and AD dementia [N = 37], age: 66.7 ± 10.4, 70.4 ± 7.7, 71.7 ± 8.4, 76.2 ± 3.5 years [mean ± SD], respectively) using Density-Based Spatial Clustering of Applications with Noise, which does not require a priori determination of the number of clusters. We found 5 distinct clusters (sizes: N = 38, 16, 24, 14, and 21) whose composition was independent of phenotypical groups. Two clusters showed biomarker profiles linked to neurodegenerative processes not associated with classical AD-related pathophysiology. One cluster was characterized by the neuroinflammation biomarker YKL-40. Combining nonlinear data aggregation with informative biomarkers can generate novel patient strata which are representative of cellular/molecular pathophysiology and may aid in predicting disease evolution and mechanistic drug response.

Background: Elastic stable intramedullary nailing has become the treatment of choice for femur shaft fractures in school-age children in developed world. However, in the sub-Saharan Africa, this management is still challenging because of the lack of fluoroscopy in more hospitals. We performed either primary open reduction and intramedullary K-wire fixation (PORIKF) or conservative treatment. The aim of this study was to compare the clinical and functional outcomes of these two procedures employed. Patients and Methods: This retrospective study included 62 children with 64 fractures (10 years on an average; range: 6–15 years) treating for femoral shaft fractures either by PORIKF (n = 21; 23 fractures) or skin traction followed by spica cast (n = 41) between 2008 and 2017. Outcomes were assessed using Flynn criteria. Comparisons were made by Fisher and Student's t-test with a significant P < 5%. Results: Outcomes were satisfactory in 21 cases (91%) in the PORIKF group compared with 32 (78%) in the conservative group (P = 0.3012). The average hospital stay was 18.6 days in the PORIKF group, whereas it was 20 in the conservative group (P = 0.0601). The mean time for bone union was 13.9 weeks in the PORIKF group and 13.2 weeks in the conservative group, (P = 0.4346). There was a statistically significant difference between the two groups in terms of major complications (P = 0.0177). One patient had osteomyelitis in the PORIKF group. Unacceptable shortening >2 cm was observed only in the conservative group. The average time to return to daily activities was 30 days shorter in the PORIKF group when compared to conservative group (P < 0.05). Conclusion: PORIKF provides better results than conservative treatment. Open reduction did not increase the rate of infectious complication.

Introduction: Human papillomavirus (HPV) infection remains the most common cause of cervical intraepithelial neoplasia. The objective of this study is to evaluate the sensitivity and predictive value of the HPV test associated with the cervico-uterine smear in the screening of cervical intraepithelial neoplasia in our environment. Methodology: This is a descriptive cross-sectional study of 625 women who consulted in the department of gynecology for cervical cancer screening, of whom 300 received an HPV test; during the period from January the 1st to December 31st, 2018 at Panzi general reference hospital (South-Kivu, DRC). Data analysis was done using Epi Info version 7 software. Results: For all respondents (n = 625), the cervico-uterine smear was normal in 82.88%, inflammatory in 2.4% of cases and with cellular atypia in 14.72%. The HPV test was positive in 87 respondents against 213 negatives cases, i.e. a prevalence of HPV of 29% [95% CI: 23.9% - 34.5%]. Among women with precancerous lesions, 27.6% had HPV infection; among those with normal smears, 29.3% of them had HPV infection; however, this difference was not statistically significant. Patients with dysplastic lesions, 31.3% had genotypes with very high carcinogenic potential; and for those with a normal Pap smear, 45.1% had genotypes with very high carcinogenic potential; however, this difference was also not statistically significant. Conclusion: The human papillomavirus test remains a very important indication cation in the detection of cervical intraepithelial neoplasia, its sensitivity remaining clearly superior to that of cytology, especially for high grade lesions.

Background: Happy hypoxia is a new feature found in COVID-19 patients. It consists of the presence of severe hypoxemia but normal breathing rate. Failure to identify this hypoxia may have negative consequences on the survival of the patient. The objective of the present study was to measure the frequency of patients with happy hypoxia and to evaluate their survival at the Kinshasa University Hospital (KUH). Methods: This was a historical cohort of 141 hospitalized patients with COVID-19 at KUH from March 23 to June 15, 2020. Happy hypoxia was defined as oxygen saturation below 90% without dyspnea. Socio-demographic data, co-morbidities, follow up time of hospitalization and outcomes were studied. Survival was assessed using the Kaplan Meier curve. Results: Out of 141 hospitalized patients with COVID-19, 79 (56%) patients were at the severe or critical stage and 9 (6.4%) had a happy hypoxia on admission. Patients who had happy hypoxia on admission were generally older than 60 years of age (55.6%) (p = 0.023). Comparison of survival curves, based on the presence or absence of happy hypoxia, shows a statistically significant difference (p = 0.001). The presence of happy hypoxia reduces survival. Conclusion: The frequency of happy hypoxia among COVID-19 patients was low. Survival was reduced in patients with happy hypoxia. Prehospital pulse oximetry could serve as an early warning signal for the detection of happy hypoxemia in COVID-19 patients.

Background Family history has traditionally been an essential part of clinical care to assess health risks. However, declining sequencing costs have precipitated a shift towards genomics-first approaches in population screening programs rendering the value of family history unknown. We evaluated the utility of incorporating family history information for genomic sequencing selection. Methods To ascertain the relationship between family histories on such population-level initiatives, we analysed whole genome sequences of 1750 research participants with no known pre-existing conditions, of which half received comprehensive family history assessment of up to four generations, focusing on 95 cancer genes. Results Amongst the 1750 participants, 866 (49.5%) had high-quality standardised family history available. Within this group, 73 (8.4%) participants had an increased family history risk of cancer (increased FH risk cohort) and 1 in 7 participants (n = 10/73) carried a clinically actionable variant inferring a sixfold increase compared with 1 in 47 participants (n = 17/793) assessed at average family history cancer risk (average FH risk cohort) (p = 0.00001) and a sevenfold increase compared to 1 in 52 participants (n = 17/884) where family history was not available (FH not available cohort) (p = 0.00001). The enrichment was further pronounced (up to 18-fold) when assessing only the 25 cancer genes in the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes. Furthermore, 63 (7.3%) participants had an increased family history cancer risk in the absence of an apparent clinically actionable variant. Conclusions These findings demonstrate that the collection and analysis of comprehensive family history and genomic data are complementary and in combination can prioritise individuals for genomic analysis. Thus, family history remains a critical component of health risk assessment, providing important actionable data when implementing genomics screening programs. Trial registration ClinicalTrials.gov NCT02791152. Retrospectively registered on May 31, 2016.

Background Diagnosis of pituitary pars intermedia dysfunction (PPID) is problematic because of large variations in ACTH concentrations. Hypothesis/Objectives Compare the test characteristics of baseline and post–thyrotropin‐releasing hormone (TRH) stimulation plasma ACTH concentrations in horses using diagnostic cutoff values (DCOVs) and reference intervals (RIs) and determine the clinical consequences of using each method. Animals One hundred six mature horses: 72 control cases and 34 PPID cases. Methods Prospective case‐controlled study. Horses underwent monthly TRH stimulation tests. Diagnostic cutoff values were determined monthly by receiver operating characteristic curves using the Youden index. Reference intervals were determined monthly by a robust method. For each case age, sex and body condition score (BCS) were recorded. Results Baseline ACTH concentrations varied by month (P

Background A prospective 2002–2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients’ molecular features. Methods Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68. Results Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66–126 mo), surviving after relapse no longer than those relapsing earlier (0–5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007). Conclusions Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up.

Aim: To evaluate the activity of (-)-camphene-based thiosemicarbazide (TSC) and 4-hydroxy-thiosemicarbazone (4-OH-TSZ), alone and in combination against Gram-positive. Material & methods: MIC were determined for Staphylococcus aureus, Enterococcus spp. reference strains and clinical isolates. Drug combination, time–kill and cytotoxicity assays were also performed. Results: TSC and 4-OH-TSZ demonstrated potent inhibitory activity against S. aureus and Enterococcus spp., including multidrug-resistant isolates (MIC ranging from 1.9 to 31.2 μg/ml), and were bactericidal for the reference strains of both Gram-positive tested. The derivatives proved to be selective for the bacteria and synergistic with oxacillin and vancomycin. Conclusion: (-)-Camphene-based derivatives can represent promising drug candidates against critical pathogens, such as S. aureus and Enterococcus spp., including MRSA and vancomycin resistance Enterococcus spp. isolates.

Receptor Interacting Protein 2 (RIP2) kinase inhibitors have been reported for therapeutic opportunities in inflammatory bowel diseases such as Ulcerative Colitis and Crohn's disease. During lead optimization, team identified 4-aminoquinoline series and several compounds from this series were investigated in rat and dog pharmacokinetic studies. While compounds such as GSKA and GSKB demonstrated acceptable pharmacokinetics in rat and dog, further progression of these compounds was halted due to adverse findings in advanced safety studies. Structurally similar analogues incorporating polarity at C-7 position of 4-aminoquinoline resulted in identification of GSKC - GSKF. Interestingly, following oral administration to rat at similar low dose, GSKC - GSKF demonstrated significantly low systemic drug exposure compared to GSKA and GSKB (3-17-fold difference). However, in dog, dose normalized oral systemic exposure for GSKC - GSKF was comparable to GSKA and GSKB (within 2-fold). A series of studies were conducted to understand the disconnect which highlighted that an intrinsic reduction in permeability and high P-glycoprotein (P-gp) efflux ratio for C-7 substituted analogues were driving pharmacokinetic disconnect between rat and dog. Oral absorption was minimally impacted in dog by P-gp mediated efflux compared to rat because the leakier gastrointestinal tract in dog likely overcomes this effect.

Purpose This study aims to estimate the acceptability of a future vaccine against COVID-19 and associated factors if offered in Congolese health-care workers (HCWs), since they have the highest direct exposure to the disease. Patients and methods We conducted an analytical cross-sectional study among 23 Congolese referral hospitals, including three university hospitals, located in three towns from March through 30 April 2020. The main outcome variable was healthcare workers' acceptance of a future vaccine against COVID-19. The associated factors of vaccination willingness were identified through a logistic regression analysis. Results A sample of 613 HCWs participated in the study and completed the study questionnaire, including 312 (50.9%) men and 301 (49.1%) women. Only 27.7% of HCWs said that they would accept a COVID-19 vaccine if it was available. From the logistic regression analysis, male healthcare workers (ORa=1.17, 95% CI: 1.15-2.60), primarily doctors (ORa=1.59; 95% CI:1.03-2.44) and having a positive attitude towards a COVID-19 vaccine (ORa=11.49; 95% CI: 5.88-22.46) were significantly associated with reporting willingness to be vaccinated. Conclusion For acceptability of vaccination against COVID-19 among others education among HCWs is crucial because health professionals' attitudes about vaccines are an important determinant of their own vaccine uptake and their likelihood of recommending the vaccine to their patients.

Summary Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1-and inducible co-stimulator-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor immunity.

International audience; Complications with bilateral sagittal split osteotomy (BSSO) can sometimes result from surgical inexperience. Our aim was to present a 3-dimensional printed mandibular model for BSSO training in a maxillofacial surgical education programme. A polymethacrylate mandibular model obtained from mandibular cone-beam computed tomographic (CT) images was designed and printed for use in training. Twenty-four residents were each asked to do a BSSO according to the Epker/Dal-Pont technique. The session was conducted as a simulation course with a final debriefing. A questionnaire before and after the test was filled in using a 10-point Likert scale to assess the participants' knowledge. The mandibular model provided a realistic way of handling the trabecular bone after cortical osteotomy, as well as in the splitting phase. Significant increases in knowledge and surgical skills were noted for all steps of the BSSO, particularly regarding the use of the piezoelectric device for osteotomy, and for management of wisdom teeth in the splitting zone (3.00 ±2.16 to 6.95 ±2.06 and 2.73 ±1.91 to 5.75 ±2.63, respectively; p1=0.0002 and p2=0.0003). We think that this is a valuable printed mandibular model for the development of surgical skills for BSSO in maxillofacial surgical residents.

Glanders is a contagious zoonotic disease caused by Burkholderia mallei. Following the detection of glanders positive horses using the OIE complement fixation test, the tissues of two horses were analysed by PCR. While PCR systems targeting the Burkholderia pseudomallei complex gave positive signals, the species-specific PCR systems targeting B. mallei (fliP-IS407A) and B. pseudomallei (orf11)-the OIE recommended targets-resulted in negative signals. However, the presence of B. mallei in these tissues was confirmed with a recently described B. mallei-specific real-time PCR system and genotyping with MLST- and SNP-based methods, performed on the most positive tissue, identified a genotype closely related to B. mallei strains recently isolated in the Middle East. This study leads to recommendations regarding the use of PCR systems for the molecular diagnosis of glanders, especially in regions where the circulating B. mallei strains have not yet been fully genetically characterized.

Introduction: The teeth are incline differently according to the vertical skeletal typology and the corresponding alveolar bones do not always have the same thickness. However, the conflicting results in the literature, mainly related to the classification of patients according to vertical characteristics, creates a challenge for the clinician in determining the characteristic inclinations of teeth in a specific patient. The objective of this study was to find out dental inclination and thickness of the alveolar bone around incisors and molars in different facial type. Materials & Method: The sample included 51 CBCT radiographs (28 females and 23 males) and subdivided into three subgroups according to vertical facial skeletal pattern (22 normodivergent subjects, 06 hypodivergent subjects and 23 hyperdivergent subjects). Reformatted CBCT images were used to measure the thickness of the vestibular and lingual alveolar bone around the incisors and first molars at two levels of root length (apical and middle) and their inclination. The Kruskal-Wallis test for the comparison of more than 2 means was applied for statistical analysis. Result: Alveolar bone thickness in the apical region of the lingual side in hyperdivergent subjects was thicker than in the other two groups. The bone wall is thicker in the lingual than in the vestibular, regardless of the vertical skeletal typology. These varied inclinations were more pronounced anterior sector. Conclusion: Dental inclinations have close relationships with the alveolar bone thicknesses associated with them. The apex of the root of the lower incisor is closer to the lingual alveolar crest when it was inclined in the lingual direction. There is a significant association between bone thickness around the teeth and facial skeletal divergence.

Background Pain remains a prevalent symptom for rheumatoid arthritis (RA) patients despite a wide therapeutic choice. The objective of this study was to provide a multidimensional evaluation of pain. Methods A total of 295 RA patients from 7 French rheumatology centres were enrolled in a cross‐sectional study. Patients completed a chronic pain assessment questionnaire approved by the French National Authority for Health, the health assessment questionnaire (HAQ) as well as depression and anxiety scales (HAD, Beck Depression Inventory, STAI). Disease activity (DAS28) and ESR were recorded. A multivariate descriptive analysis was undertaken using principal component analysis (PCA). Results 38.4% of patients had a pain score > 40 mm/100, although 83% were on biological treatment and 38.7% were in remission based on the RA activity score. The PCA analysis found four axes representing 70% of total variance. The axes, per cent of variance and variables represented were as follows: (a) axis 1, 41% variance, anxiety and depression scores, sensory and affective qualifier score, HAQ and pain impact on daily life; (b) axis 2, 13% variance, disease activity score (DAS28) and pain relief with current treatment; (c) axis 3, 9% of variance, RA duration and radiographic score and (d) axis 4, 6% of variance, DAS28 and ESR. Moderate to severe pain was significantly associated with axes 1 and 2. Conclusions Despite a high proportion of patients on biological treatments, 38.4% of patients continue to experience moderate to severe pain. Pain is associated with the RA activity score, but also with the depression and anxiety scores. Significance Substantial proportion of rheumatoid arthritis (RA) patients still experiences relevant pain, although more than 80% on biological treatment. Pain is primarily associated with anxiety and depression scores and with disease activity score. These findings highlight the need to assess patients’ mental well‐being alongside. Clinical measures of disease activity to better manage pain and guide treatment decisions.

In comparison with lymphomas and leukemias, chemotherapy of solid neoplasms, i.e., cancer, has much more limited success in curing the patient. This lack of efficacy of chemotherapy has been attributed to increased interstitial fluid pressure within cancers, which obstructs convection and only permits diffusion of oxygen and nutrients about 100 μm from blood vessels. As diffusion is limited to this distance, hypoxic and necrotic fractions within the tumor are observed beyond this region. The comparably small number of cancer cells that can be targeted with drugs inevitably leads to an ineffective treatment response. This study presents an analysis of the influence of interstitial fluid pressure on the chemotherapeutic effect in an HT29 human colon cancer xenograft mouse tumor model. To investigate the limited distribution of drugs into primary tumor and metastases, we developed a mathematical model describing tumor growth dynamics of oxygenated, hypoxic, and necrotic fractions, combined with a pharmacokinetic-pharmacodynamic model describing the behavior and effectivity of the chemotherapeutic agent. According to the numerical simulations, the age of the tumor at treatment was the decisive factor in the reduction in size of the primary tumor. This effect is mediated by the rapid decrease in the percentage of oxygenated cells within the tumor, which reduces the fraction of cells that can be affected by the drug. As in the primary tumor, interstitial fluid pressure builds up in metastases when they reach a specific size, leading to the formation of tumor fractions. This behavior is absent if the metastasis enters a dormant phase before the threshold for the development of interstitial fluid pressure has been reached. The small size of these metastases maximizes therapeutic success since they consist only of oxygenated cells, and the drug therefore affects all the cells.

To assess the efficacy of an herbal spray combining various essential oils, with a claim of mast cell stabilisation, antipruritic, anti-inflammatory, and insect repellent effects on the clinical presentation of insect bite hypersensitivity (IBH) in horses.Double-blinded, placebo-controlled, randomised, cross-over clinical trial.Twenty adult horses with clinical IBH were treated with a daily application of herbal spray or placebo for 28 days in a randomised, cross-over fashion, separated by a28-day washout period. Horses were examined and scored prior to and after the completion of each treatment. Histopathology was performed on four horses. Owners kept daily diaries of observations.The herbal spray significantly reduced the severity of all assessed parameters (pruritus, excoriations, lichenification and alopecia; P0.05) compared with baseline values (pretreatment) and with placebo. Owners reported improvement of pruritus in 19/20 horses (95%) with complete resolution in 17 horses (85%) following treatment. Skin biopsies showed resolution of orthokeratosis in 4/4 horses, reduced thickness of the stratum spinosum in 2/4 horses and complete resolution of histopathological abnormalities in 1/4 horses after treatment, compared with either no change or deterioration of histopathologic lesions after placebo. No side effects were observed.The tested herbal spray may be an effective treatment for the management of equine IBH.

Few studies all based on classical surveys have provided prevalence estimates of chronic pain (CP) in opioid-maintained patients (OMPs) but often had a limited patient sample size and a great variability in the prevalence estimates. This study sought to assess the prevalence of CP in the exhaustive population of OMPs using the capture-recapture method applied to the French nationwide health care database. Capture-recapture methods are increasingly used to estimate the prevalence of chronic conditions but have never been used in the specific context of CP in OMPs. Three large medical-administrative sources were used: the prescription drug database (A-list), the national hospital discharge database (M-list), and the pain center database (C-list). Between 2015 and 2016, 160,429 OMPs aged 15 years and older were identified and age- and sex-matched with 160,429 non-OMPs. All patients treated with analgesic drugs for ≥6 months (A-list) or diagnosed with CP (M- and C-list) were included. Capture-recapture analyses were performed to yield CP estimates with their 95% confidence intervals using log-linear models. In 2015 to 2016, 12,765 OMPs and 2938 non-OMPs with CP were captured. Most patients were male (67%) in OMPs and non-OMPs; median ages for OMPs and non-OMPs were 46 (interquartile range: 38-51) and 48 (41-53) years, respectively. The CP prevalence estimated in OMPs and non-OMPs ranged from 23.6% (14.9-46.2) to 32.1% (28.6-36.3) and from 7.28% (3.98-18.4) to 9.32% (7.42-12.1), respectively. This first study on CP in the exhaustive population of OMPs using the capture-recapture method demonstrated a high prevalence of CP in OMPs, 3- to 4-fold than in the general population.

Introduction: The ultrasound is widely used clinical practice focused on tissue repair, because it is a secure resource, minimally-invasive and low investment. However, despite the effects of ultrasound have been well described, the ideal relationship between dose and effect, still needs to be better elucidated and bounded. Objective: In this way, the objective of this study was to evaluate the influence of irradiation pulsed ultrasound and continuous in the viability of fibroblastic cells L929 in vitro. Method: The cells were distributed in TPP plates 12 wells in the concentration of 5x105 cells/µL and subdivided into the following groups: G1: control (not received radiation), G2: irradiated to 0.5 W/cm2 - 30% and G3: irradiated to 0.5 W/cm2 - 100%. Then received ultrasonic irradiation with intervals of 24, 48 and 72 hours, and after 24 hours of each irradiation was performed MTT cytotoxicity cell. Results: Among the three groups analyzed, only the G2 group showed a significant difference between the time 48 and 72 hours (p=0.05). In other times, despite variation in the percentage of viable cells, were not significant. When compared to peers at post-test, it was possible to observe a difference of 29% of viable cells between the groups G1 and G2 (p=0.05). However, the biggest difference was observed between the groups G2 and G3 (p=0.05). Conclusion: In this way, it can be concluded that irradiation pulsed ultrasound showed higher proliferation of fibroblasts L929 in time 48 hours, whereas in group irradiated in continuous mode, there was no statistically significant difference between the times.

Background: Physical inactivity (PI) is one of the most important risk factors that contribute to the development of chronic diseases, including cardiovascular diseases. Objective: To analyze the prevalence and associated factors with PI in adults from a Basic Health Unit in the city of Uraí, state of Paraná. Methods: An observational, descriptive, cross-sectional study was performed at Basic Health Unit of Uraí, and 100 subjects of both genders were evaluated, the average age of 47.55 ± 17.13 years. The data collection was carried through an interview where information of sociodemographic characteristics, consumption of alcoholic beverages, tobacco use, level of physical activity (PA) (IPAQ-8, short version), information of anthropometric measures, waist circumference, and rest blood pressure were collected. The Chi-square and Odds Ratio test was used, considering 95% of confidence interval, using the statistical package SPSS, version 20.0, with a significance level of p

The aim of this study was to investigate whether the use of handrail support during maximal exercise treadmill testing (ETT) would interfere in cardiac autonomic modulation kinetics when compared to not using handrail support. The hypothesis of overestimation in cardiac autonomic dynamics when the ETT is performed using handrail was tested. Thirty-five undergraduates (21.08 ± 2.98 years old) of both sexes, volunteered to undertake two ETT under the Ellestad protocol, in non-consecutive days. The first test (T1) was performed with handrail support and, after 7 days, the second test was performed (T2) without the support. Autonomic function was measured by heart rate variability (HRV) during both tests and resting. Estimated value of peak oxygen uptake (VO2) was 22.4% (p 2 persisted longer in T1 stages than in T2 and was verified in early stages (S2 and S3) of both ETTs. Our findings suggest that parasympathetic influences on HR were slightly prolonged during ETT when subjects hold onto the treadmill.

Minimum bactericidal concentration (MBC) assay is an accepted parameter for evaluating new antimicrobial agents, and it is frequently used as a research tool to provide a prediction of bacterial eradication. To the best of our knowledge, there is no standardization among researchers regarding the technique used to detect a drug's MBC in Mycobacterium tuberculosis. Thus, the aim of this systematic review is to discuss the available literature in determining a drug's MBC in M. tuberculosis, to find the most commonly used technique and standardize the process. A broad and rigorous literature search of three electronic databases (PubMed, Web of Knowledge, and LILACS) was performed according to the PRISMA statement. We considered studies that were published from January 1, 1990 to February 19, 2019. Google Scholar was also searched to increase the number of publications. We searched for articles using the MeSH terms "microbiological techniques," "Mycobacterium," "antibacterial agents." In addition, free terms were used in the search. The search yielded 6,674 publications. After filter application, 5,348 publications remained. Of these, we evaluated the full text of 187 publications. By applying the inclusion criteria, 69 studies were included in the present systematic review. In the literature analyzed, a great variety in the techniques used to determine a drug's MBC in M. tuberculosis was observed. The most common variability is related to the culture media used, culture incubation time, and the percentage of bacterial death for the drug to be considered as bactericidal. The most commonly used technique for drug's MBC determination was carried out using the drug's minimum inhibitory concentration (MIC) assay. Aliquots from prior MIC values were subcultured in Middlebrook agar and incubated for 4 weeks at 35°C for determining the colony forming unit (CFU) with relevance to detect 99.9% bacilli killed or reduction in 3 log10 viable bacilli.

A goal in precision medicine is to use patient-derived material to predict disease course and intervention outcomes. Here, we use mechanistic observations in a preclinical animal model to design an ex vivo platform that recreates genetic susceptibility to T-cell–mediated damage. Intestinal graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis. We further show that cocultured allogeneic T cells kill Atg16L1-mutant intestinal organoids from mice, which was associated with an aberrant epithelial interferon signature. Using this information, we demonstrate that pharmacologically inhibiting necroptosis or interferon signaling protects human organoids derived from individuals harboring a common ATG16L1 variant from allogeneic T-cell attack. Our study provides a roadmap for applying findings in animal models to individualized therapy that targets affected tissues.

Chromosomal rearrangement involving 14q32 region that results in TNF receptor associated factor 3 (TRAF3) dysfunctional mutation is the most frequent NF-κB pathway mutation in multiple myeloma (MM). Subsequent NF-κB inducing Kinase (NIK) stabilization plays a critical role in alternative NF-κB activation. However, disease progression resulting from TRAF3 dysregulation has not been well understood. In this study, we identified lymphocyte cellular protein 1 (LCP1) as a novel NIK-driven alternative NF-κB target in TRAF3 dysfunctional mutation using RNA-seq, ChIP-seq (RelA/p65 and p52 NF-κB) and other validation methods. LCP1 is exclusively activated in MM cells with TRAF3 loss-of-function mutation. In MM patients, higher LCP1 expression was significantly pronounced in poor prognosis groups such as 4p16 and MAF. CD138 negative MM patient cells showed elevated LCP1 expression and inhibition of LCP1 can sensitize proteasome inhibitor bortezomib in TRAF3 mutant MM cells in vitro. We report that LCP1 is a NIK-driven biomarker in TRAF3 dysfunctional MM and targeting LCP1 can provide a valuable therapeutic intervention in TRAF3 mutated MM.

Rationale: Respiratory syncytial virus (RSV) bronchiolitis causes significant infant mortality. Bronchiolitis is characterized by airway epithelial cell (AEC) death; however, the mode of death remains unknown. Objectives: To determine whether necroptosis contributes to RSV b r onchiolitis pathogenesis via HMGB1 (high mobility group box 1) release. Methods: Nasopharyngeal samples were collected from children presenting to the hospital with acute respiratory infection. Primary human AECs and neonatal mice were inoculated with RSV and murine Pneumovirus, respectively. Necroptosis was determined via viability assays and immunohistochemistry for RIPK1 (receptor-interacting protein kinase-1), MLKL (mixed lineage kinase domain-like pseudokinase) protein, and caspase-3. Necroptosis was blocked using pharmacological inhibitors and RIPK1 kinase-dead knockin mice. Measurements and Main Results: HMGB1 levels were elevated in nasopharyngeal samples of children with acute RSV infection. RSV-induced epithelial cell death was associated with increased phosphorylated RIPK1 and phosphorylated MLKL but not active caspase-3 expression. Inhibition of RIPK1 or MLKL attenuated RSV-induced HMGBI translocation and release, and lowered viral load. MLKL inhibition increased active caspase-3 expression in a caspase-8/9-dependent manner. In susceptible mice, Pneumovirus infection upregulated RIPK1 and MLKL expression in the airway epithelium at 8 to 10 days after infection, coinciding with AEC sloughing, HMGB1 release, and neutrophilic inflammation. Genetic or pharmacological inhibition of RIPK1 or MLKL attenuated these pathologies, lowered viral load, and prevented type 2 inflammation and airway remodeling. Necroptosis inhibition in early life ameliorated asthma progression induced by viral or allergen challenge in later life. Conclusions: Pneumovirus infection induces AEC necroptosis. Inhibition of necroptosis may be a viable strategy to limit the severity of viral bronchiolitis and break its nexus with asthma.